July 30, 2010

We have been monitoring ALL scientific research on marijuana/cannabis since about 1994 (and before that we purchased reference material from NIDA of all previous scientific studies). My husband is a nephrologist and clinical pharmacologist and my son is a rheumatologist. Both of these medical specialties require a depth of knowledge of pharmaceutical drugs that far surpasses that of most other subspecialties. One of the most important aspects of prescribing drugs of any sort is knowing the potential side effects and knowing how the drug will interact with other drugs or foods the individual may be taking. Every person is unique and drugs that are benign to one individual may be deadly for another. Penicillin is an excellent example because though it has saved millions of lives, it is also deadly for some. To date there are more than 20,000 published studies on marijuana and none of them offer proof of its safety or efficacy. That being said, I am attaching a file of documents relating to marijuana being a leading cause of drug-related emergency room episodes.

Fifteen years ago I attended a medical conference in Auckland, NZ with my husband. The doctor sitting next to me at dinner asked what I do. I told him that I was the unpaid head of a non-profit drug prevention organization. He said he didn’t think NZ had a drug problem. The doctor sitting across from us interjected that not only did NZ have a drug problem but that it was impacting the medical system. He said that he was head of the psychiatric unit at Auckland’s main hospital and that he would venture that at least 50% of those admitted for emergency psychiatric problems were there because of marijuana. I had heard that marijuana could cause psychiatric problems because two individuals I knew had kids who would go “round the twist” as they say in Auckland, whenever they smoked pot, and would end up in psychiatric care, but I had no idea is was that severe.

Then, about ten years ago, just after my husband became director of transplant for Legacy Hospital Systems, we went to dinner with one of the administrators and his wife. The wife asked what I do and I told her. She then volunteered that she was head of a triage unit in a psychiatric ward at another hospital and that it was her opinion that at least 65% of those admitted for emergency psychiatric problems were there because of marijuana.

re ingesting cannabis. One does not always know the potency of the cannabis being used or how much is in the product. Below is an exchange between a doctor who ingested “space cakes” and the editor of High Times Magazine. You will see that Ed Rosenthal (then the editor) acknowledges that marijuana can cause problems for even experienced users.

Marijuana is such an insidious drug that it may be years before we see the full extent of its potential to do harm. But a couple of things I think are VERY important and that is that marijuana has become a major factor in infertility (see Science Magazine for starters), and it destroys brain cells.

I am also attaching a document put together in 1999 (when there were only about 10,000 studies on marijuana) by a drug prevention specialist out of Canada. This document is called The Marijuana Connection and it categorizes the studies by side effect.

Source: Marijuana Research Review July 2010

Constituents of Cannabis Sativa L. (Marijuana)

In a document entitled “Constituents of Cannabis Sativa L. (Marijuana)” published by the University of Mississippi, Research Institute of

Pharmaceutical Sciences, Department of Pharmaceutics” (Ross SA, Elsohly MA. Constituents of Cannabis Sativa L. XXVIII A review of the natural

constituents: 1980-1994. J. Pharm Science. 1995;4:1-10, it states that marijuana contains 483 substances, 66 of which are cannabinoids. No

other plant contains cannabinoids.

Up to January, 2001, over 15,000 scientific papers have been published on cannabis and its constituents and many reviews have been written on

cannabis constituents and cannabinoid chemistry. A total of 483 natural constituents have been isolated and/or identified in Cannabis sativa

L., and they have been delineated as follows:

Cannabinoids 66
Nitrogenous Compounds 27
Amino acids 18
Proteins, Glycoproteins, Enzymes 11
Sugars & related compounds 34
Hydrocarbons 50
Simple Alcohols 7
Simple Aldehydes 12
Simple Keytones 13
Simple Acids 21
Fatty Acids 22
Simple Esters & Lactones 13
Steroids 11
Terpenes 120
Non-Cannabinoids Phenols 25
Flavonoids 21
Vitamins 1
Pigments 2
Elements 9

During the last quarter of the 20th century recreational use of
cannabis increased greatly across the world.1 Cannabis consumption
came to be seen as a normal leisure activity, and was regarded
as safe even by the medical establishment.2 However, in recent
years there has been considerable controversy over the use of
cannabis, with, for example, the UK government repeatedly
reviewing its safety.3 This concern has arisen from large prospective
epidemiological studies which have reported that use of
cannabis increases the risk of schizophrenia-like psychosis.4,5
However, these studies have not collected detailed data on the
patterns of use or potency of the cannabis used, which may be
important factors moderating the associated risk.6
The principal constituents of cannabis are D9-tetrahydrocannabinol
(D9-THC) and cannabidiol. The former is the main
psychoactive ingredient and in experimental studies it produces
transient psychotic symptoms and impaired memory in a dose dependent
manner.6,7 In contrast, cannabidiol does not induce
hallucinations or delusions, and it seems to antagonise the cognitive
impairment and psychotogenic effects caused by D9-THC.6
Until the early 2000s the most freely available type of cannabis
in the UK was cannabis resin (‘hash’), which had approximately
70% of the ‘street’ market, followed by traditional imported herbal
cannabis and then sinsemilla (‘skunk’). Cannabis resin contains
2–4% D9-THC and a similar proportion of cannabidiol, whereas
herbal cannabis contains a similar percentage of D9-THC but no
cannabidiol.8,9 However, sinsemilla (skunk) has increasingly taken
over the UK market and its THC concentration, and to a lesser
extent that of imported herbal cannabis, has been consistently
rising. For example, seizures of cannabis on the streets of England
in 2008 by the police showed that sinsemilla had a market share
of more than 70%, and had reached a D9-THC concentration of
12–18% with virtually no cannabidiol.8,9

Smith has suggested that such high-potency cannabis might be
especially harmful to mental health.10 We therefore compared
patterns and types of cannabis use in people experiencing their
first episode of psychosis and in a healthy control sample.
Specifically, we sought to test the hypothesis that daily use of
high-potency cannabis is associated with a particularly high risk
of psychosis.

Method
Sample
We approached all patients aged 18–65 years who presented with a
first episode of psychosis to the Lambeth, Southwark and Croydon
adult in-patient units of the South London & Maudsley Mental
Health National Health Service (NHS) Foundation Trust between
December 2005 and October 2008. We validated clinical diagnosis
by administering the Schedules for Clinical Assessment in
Neuropsychiatry (SCAN).11 Patients who met ICD–10 criteria
for a diagnosis of psychosis (codes F20–F29 and F30–F33)12 were
invited to participate in the study; cases with a diagnosis of
organic psychosis were excluded. During the same period we
recruited a healthy control group (n = 174) from the local
population living in the area served by the Trust, by means of
internet and newspaper advertisements, and distribution of
leaflets at train stations, shops and job centres. Cannabis was
not mentioned in these advertisements. Particular attention was
directed to attempting to obtain a control sample similar to the
patient sample in age, gender, ethnicity, educational qualifications
and employment status. Those who agreed to participate were
administered the Psychosis Screening Questionnaire,13 and
excluded if they met criteria for a psychotic disorder or reported
a previous diagnosis of psychotic illness.
Ethical permission was obtained from the Trust and the
Institute of Psychiatry research ethics committee. All study
participants signed a consent form allowing publication of data
originating from the study.

Background
People who use cannabis have an increased risk of
psychosis, an effect attributed to the active ingredient D9-
tetrahydrocannabinol (D9-THC). There has recently been
concern over an increase in the concentration of D9-THC in
the cannabis available in many countries.

Aims
To investigate whether people with a first episode of
psychosis were particularly likely to use high-potency
cannabis.

Method
We collected information on cannabis use from 280 cases
presenting with a first episode of psychosis to the South
London & Maudsley National Health Service (NHS) Foundation
Trust, and from 174 healthy controls recruited from the local
population.

Results
There was no significant difference between cases and
controls in whether they had ever taken cannabis, or age at
first use. However, those in the cases group were more
likely to be current daily users (OR = 6.4) and to have smoked
cannabis for more than 5 years (OR = 2.1). Among those who
used cannabis, 78% of the cases group used high-potency
cannabis (sinsemilla, ‘skunk’) compared with 37% of the
control group (OR 6.8).

Conclusions
The finding that people with a first episode of psychosis had
smoked higher-potency cannabis, for longer and with greater
frequency, than a healthy control group is consistent with
the hypothesis that D9-THC is the active ingredient
increasing risk of psychosis. This has important public health
implications, given the increased availability and use of highpotency
cannabis.

Source: The British Journal of Psychiatry (2009)
195, 488–491. doi: 10.1192/bjp.bp.109.064220

Historian looks at resistance to the “NIDA paradigm.”

The history of addiction as a brain disease “looks a lot like the history of atoms or germs, insofar as these were older and controversial ideas for which scientific confirmation later became available,” writes historian David Courtwright, author of Forces of Habit: Drugs and the Making of the Modern World.

In a recent issue of the social science journal BioSocieties, Courtwright surveys the history of the disease paradigm of drug addiction, and, in doing so, brings into focus several key dilemmas related to what former National Institute on Drug Abuse (NIDA) director Alan Leshner once characterized as the “quintessential biobehavioral disorder.”

The scientific evidence available to us at present largely supports a statement like Leshner’s. Researchers have documented long-term changes in brain structure and function due to drug abuse, and neuroimaging technologies have resulted in maps of the abnormal neuronal activity addicts exhibit. Courtwright cites the discovery of the endogenous opioid system, the mapping of receptor pathways, and the growing understanding of the mesolimbic dopamine reward pathway as evidence of clinical confirmation of theories about addictive disease that has been floating around in one form or another for many years.

Why then, Courtwright asks, does the medical profession largely stay clear of issues having to do with our law enforcement-driven drug war? Why are clinical professionals not on the front lines of revolt over this issue? “If addiction was beyond the individual’s control, then criminal punishment was as inappropriate as jailing a schizophrenic who wandered into an emergency room,” the author writes.

The most obvious reason for this conundrum, says Courtwright, is that “the brain disease model has so far failed to yield much practical therapeutic value.” The disease paradigm has not greatly increased the amount of “actionable etiology” available to medical and public health practitioners. “Clinicians have acquired some drugs, such as Wellbutrin and Chantix for smokers, Campral for alcoholics or buprenorphine for heroin addicts, but no magic bullets.” Physicians and health workers are “stuck in therapeutic limbo,” Courtwright believes. “The drug-abuse field is characterized by, at best, incomplete and contested medicalization.”

Moreover, unlike the current situation in the case of, say, diabetes or schizophrenia, “at least four important groups continue to wrestle for control of the addiction field.” (Medical personnel, police, social scientists, and political officials.) Social scientists, in particular, are frequently skeptical about the NIDA disease paradigm “as part of a broader post-World War II pattern of resistance against biological explanations of behavior, genetic research and the neo-Darwinian renaissance.”

Social scientists and neuroscientists “still live in their own gated academic communities,” Courtwright alleges. “There is a lot more at stake in the brain disease debate than our understanding of addiction.”

However, these problems do not mean that valuable findings in one area–addictive disease theory–cannot produce innovations in other research fields as well. In fact, such spinoffs happen all the time. Courtwright points to advancements in our understanding of evolution: “Michael Kuhar has argued that, because the brain co-evolved with neurotransmitters, it can usually manage its internal chemistry quite well. But it did not co-evolve with drugs, understood as recently introduced and wholly exogenous super-neurotransmitters that can override the brain’s control mechanisms.”

The author also cites spinoffs in economic studies: “The permanent alteration of neurons and the development of addiction in some, but not all, users also helped explain the commercial and tax appeal of drugs, insofar as they were nondurable goods with relatively inflexible demand curves. Even non-addicted users tended to consume more over time, because of tolerance.”

In the end, it is just possible to contemplate some sort of fusion, or meeting of the minds, over the disease model. As Courtwright speculates, “it may turn out that the tension between the personality and brain disease models is more apparent than real.” He cites as evidence such connections as the fit between impulsive, thrill-seeking behavior and an associated paucity of dopamine D2 and D3 receptors in the midbrain region. The result? Such people “have less inhibition of dopamine, and experience more reward when stimulated by risky behavior.” A nice fit. And the number of nice fits between social science and brain science continues to accumulate.

“If the brain disease model ever yields a pharmacotherapy that curbs craving, or a vaccine that blocks drug euphoria, as some researchers hope,” Courtwright says, “we should expect the rapid medicalization of the field. Under those dramatically cost-effective circumstances, politicians and police would be more willing to surrender authority to physicians.”

Graphics Credit: http://alcoholanddrugabuse.org

SOURCE:HTTP://ADDICTION-DIRKH.BLOGSPOT.COM/2010/06/ WEDNESDAY, JUNE 23, 2010

There has been a considerable scientific effort over the past three decades in to identifying and understanding the core features of alcohol and drug dependence. This work really began in 1976 when the British psychiatrist Griffith Edwards and his American colleague Milton M. Gross collaborated to produce a formulation of what had previously been understood as ‘alcoholism’ – the alcohol dependence syndrome.
The alcohol dependence syndrome was seen as a cluster of seven elements that concur. It was argued that not all elements may be present in every case, but the picture is sufficiently regular and coherent to permit clinical recognition.   The syndrome was also considered to exist in degrees of severity rather than as a categorical absolute. Thus, the proper question is not ‘whether a person is dependent on alcohol’, but ‘how far along the path of dependence has a person progressed’.   The following elements are the template for which the degree of dependence is judged:

Narrowing of the drinking repertoire

A normal drinker’s consumption and choice of drink varies from day to day and week to week, with the drinking being patterned by varying internal cues and external circumstances.   The dependent person may drink to the same extent whether it is workday, weekend or holiday, irrespective of whether he is alone or in company, and whatever his mood. With advanced dependency, the drinking may become timetabled to maintain high alcohol levels.
Increased salience of the need for alcohol over competing needs and responsibilities
As dependence advances, the person gives priority to maintaining their intake. Their partner’s distressed complaints are ignored, income is used to support their drinking rather than provide for the family, and the need for drink may become more important for the person with liver damage than consideration of survival. A person who used to have moral standards now begs, borrows and steals to pay for drinking.

An acquired tolerance of alcohol

A given amount of alcohol will have a smaller effect on the dependent person than on a naïve drinker due to changes in brain function arising from repeated consumption of alcohol. Tolerance is also shown by the dependent person being able to sustain an alcohol intake and go about their business at blood alcohol levels that would incapacitate the non-tolerant individual.   However, in later stages of dependence this tolerance declines and the drinker is incapacitated by quantities of alcohol that he would previously hold easily.

Withdrawal symptoms

These vary from a mild shaking of the hands in the morning through to convulsions and the life-threatening illness of delirium tremens (confusion, hallucinations, tremor). As dependence increases, so does the frequency and severity of the symptoms. Symptoms of withdrawal may occur during the day as blood alcohol levels drop.    The four key symptoms are tremor, nausea, sweating and mood disturbance. A person may wake in the morning with soaking sweats, or they may vomit in the morning. In the early stages, a person may feel a ‘bit edgy’, but as dependence develops, they may experience terrible agitation and depression, or may show phobic reactions. Other symptoms include muscle cramps, sleep disturbance, hallucinations and grand mal seizures.

Relief or avoidance of withdrawal symptoms by further drinking

In the earlier stages of dependence, the person may feel at lunchtime that the first drink of the day ‘will help me straighten up a bit’.   At the other extreme, a person may require a drink every morning before they can get out of bed. They may try to maintain steady alcohol levels which they may have learnt to recognise as being comfortable above the danger level for withdrawal.

Subjective awareness of compulsion to drink

The person may become aware of their ability to lose control: ‘If I have one or two, I won’t stop’. They may start to experience and express their craving for alcohol. Cues for craving include the feeling of intoxication, incipient withdrawal, mood or situational cues (e.g. seeing a drinking friend). They may constantly think about alcohol when experiencing withdrawal.

Reinstatement after abstinence

If a severely dependent drinker is abstinent for a year and then attempts to return to social drinking, it is likely that within a few days they will be back to an intensity of withdrawal experience which had previously taken many years of drinking to develop. Dependence has memory.
There is no signpost to a person becoming dependent. Whilst a severely dependent person is easy to recognise, it can be difficult to detect a problem in the early stages.    Clearly, it is essential to be able to diagnose early problems, before drinking gets out of hand and there is a precipitous decline in the quality of life that accompanies increasing dependence.
In the latter stages of dependence, there may be rapidly mounting intensity of morning distress, appalling shakes and suicidal thoughts and delirium tremens. Gross and incapacitating intoxication becomes common.
The person is intoxicated after a couple of drinks, there is a gross and repeated amnesia (they may disappear for several days but not remember where), and there are desperate attempts to avoid withdrawal by topping up.   Drinking makes the person very ill – this is partly due to mounting intensity of morning distress, but also due to various alcohol-induced physical problems (e.g. liver disease). Psychiatric disorders may become common at this stage

Source: www.wiredin.org.uk 2009

Two NIDA-funded studies identify health risks that  underscore the importance of curbing marijuana abuse.

BY PATRICK ZICKLER, NIDA Notes Contributing Writer                             

A large new epidemiological study suggests that marijuana smoke can cause the same types of respiratory damage as tobacco smoke. Significant associations between marijuana smoking and a variety of respiratory diseases also have been confirmed by an extensive review of clinical literature.

MONITORING THE EFFECTS OF TOBACCO AND MARIJUANA

Dr. Brent Moore and colleagues at Yale University, the National Cancer Institute, and the University of Vermont evaluated data from a nationally representative sample of 6,728 adults. Their analysis indicated that a history of more than 100 lifetime episodes of smoking marijuana, with at least one episode in the past month, increased an individual’s risk of chronic bronchitis, coughing on most days, wheezing, chest sounds without a cold, and increased phlegm.

“The most significant difference between tobacco smoke and marijuana smoke is their principal active ingredients—nicotine in tobacco and delta-9-tetrahydrocannabinol (THC) in marijuana. Beyond that, marijuana contains at least as much tar and half again as many carcinogens as smoke from conventional tobacco,” says Dr. Moore. “Quitting marijuana smoking may benefit respiratory health as much as quitting cigarettes, in addition to the clear and considerable health, psychological, and social benefits of no longer abusing an illicit drug.”

The information Dr. Moore and his colleagues analyzed was gathered through the third National Health and Nutrition Examination Survey (NHANES III), conducted between 1988 and 1994. Participants included 4,789 nonsmokers of either tobacco or marijuana; 1,525 smokers of tobacco but not marijuana; 320 smokers of both marijuana and tobacco; and 94 who smoked marijuana only. On average, marijuana abusers had smoked the drug on 10 of the preceding 30 days, with 16 percent reporting daily or almost daily smoking. Tobacco smokers consumed roughly the same number of cigarettes—averaging 19.2 per day—whether or not they also smoked marijuana. Survey participants answered questions about their experiences of a range of respiratory symptoms and were examined for signs of respiratory abnormalities.

The researchers concluded that tobacco smokers who also smoked marijuana had a higher prevalence of most respiratory symptoms than tobacco-only smokers. Compared with tobacco-only smokers, however, those who also smoked marijuana were less likely to have had pneumonia during the previous year or to show spirometric evidence of obstructive pulmonary disorder. Commenting on this finding, Dr. Moore says that it is important to note that the marijuana smokers in the sample were significantly younger (average age 31.2 years) than the tobacco smokers (average age 41.5 years). “The marijuana-related respiratory effects correspond to a relatively young population, and NHANES III did not ask participants older than age 59 about drug use,” he adds. “It is likely that respiratory effects will be higher in older marijuana smokers, and, because of the high prevalence of tobacco use among marijuana smokers, there appears to be an increased risk for illness due to cumulative effects of smoking both drugs.”

MARIJUANA’S LONG-TERM PULMONARY EFFECTS

Further evidence of marijuana’s respiratory toxicity emerged from a study conducted by Dr. Donald Tashkin at the University of California, Los Angeles. Dr. Tashkin conducted an extensive review of clinical and epidemiological research to determine the extent to which chronic marijuana smoking might lead to long-term pulmonary effects and diseases similar to those caused by tobacco. Unlike the NHANES III data examined by Dr. Moore, the studies evaluated by Dr. Tashkin made it possible to assess a possible association between marijuana smoking and respiratory cancers.

The results of animal and cell culture studies are mixed with respect to the carcinogenic effects of THC, some studies showing that THC promotes lung cancer growth and others showing an anti-tumoral effect on a variety of malignancies. Although the results of epidemiological studies are also mixed, a large, recently completed case-control study has failed to find a direct link between marijuana use (including heavy use) and lung, throat, or other head and neck cancers. “Nevertheless, there is evidence that suggests precarcinogenic effects in respiratory tissue,” Dr. Tashkin says. “Biopsies of bronchial tissue provide evidence that regular marijuana smoking injures airway epithelial cells, leading to dysregulation of bronchial epithelial cell growth and eventually to possible malignant changes.” Moreover, he adds, because marijuana smokers typically hold their breath four times as long as tobacco smokers after inhaling, marijuana smoking deposits significantly more tar and known carcinogens within the tar, such as polycyclic aromatic hydrocarbons, in the airways. In addition to precancerous changes, Dr. Tashkin found that marijuana smoking is associated with a range of damaging pulmonary effects, including inhibition of the tumor-killing and bactericidal activity of alveolar macrophages, the primary immune cells within the lung.

Taken together, Dr. Tashkin’s survey of clinical and epidemiological studies and Dr. Moore’s assessment of self-reported and clinically observed effects provide an extensive catalog of respiratory and pulmonary damage associated with marijuana smoking. Smokers are subject to:

·         Coughing and phlegm production on most days;

·         Wheezing and other chest sounds;

·         Acute and chronic bronchitis;

·         Injury to airway tissue, including edema (swelling), increased vascularity, and increased mucus secretion;    

·         Impaired function of immune system components (alveolar macrophages) in the lungs.

Moore, B.A., et al. Respiratory effects of marijuana and tobacco use in a U.S. sample. Journal of General Internal Medicine 20(1):33-37, 2005. [Full Text]

Tashkin, D.P. Smoked marijuana as a cause of lung injury. Monaldi Archives for Chest Disease 63(2):93-100, 2005. [Abstract]

Hashibe, M., et al. Marijuana use and aerodigestive tract cancers: a population-based case control study. Cancer Epidemiology, Biomarkers & Prevention (In Press).

Source:NIDA Notes > Vol. 21, No. 1  Oct.2006

 

 

 

 

The human brain is also a system of subsystems and there is now overwhelming evidence that the development of the human brain continues well into adolescence up to age 20. We know that the brain is vulnerable to toxic substances that can cause cognitive dysfunctions in adults. There is substantial literature on the consequences of acute and chronic marijuana exposure in adults, including measures of cognitive and behavioral effects, as well as some measures of alterations in brain function, primarily in the domains of learning and memory. There have been relatively few studies, however, of the effects of exposure to marijuana during development,
Some have reported that a delay in adolescent brain development is common when alcohol and or other drug usage including marijuana – begins at a young age. Some frequent users feel a lack of initiative and concern about the future, find it hard to become or stay motivated, and think things will take care of them selves, (Wapner, Roger, 1995). As a result, the normal maturation process is interrupted. Development of coping skills, a code of ethics, acceptance of responsibility, and other signs of maturity frequently cease or regress. A frequent user’s emotional development may be delayed when he starts using, and may take much longer to develop once the user has become clean and sober for an extended period of time. Drug misuse usually leads to denial. Denial is one of the hallmarks of chemical dependency. Frequent users not only deny that their drug use is a problem; they may begin using denial to pretend other problems do not exist either. Forgotten birthdays, missed social engagements, and unmet commitments are all no big deal . (Wapner, Roger, 1995)
Jonathon Shedler and Jack Block (University of California, Berkeley) have done extensive studies of teenagers, which included abstainers, occasional users, and frequent users. Frequent users are described (by family and peers) as not dependable or responsible, not productive or able to get things done, guileful and deceitful, opportunistic, unpredictable and changeable in attitudes and behavior, unable to delay gratification, rebellious and nonconforming, prone to push and stretch limits, self-indulgent, not ethically consistent, not having high aspirations, and prone to express hostile feelings directly. (Shedler and Block, 1990)
Marijuana Effects
The specific effects of marijuana, however, vary greatly, depending on the quality and dosage of the drug, the personality and mood of the user, the user s past experiences with the drug, the social setting, and the user s expectations.
Considerable consensus exists however among regular users that when marijuana is smoked and inhaled, a state of slight intoxication results. This state is one of mild euphoria distinguished by increased feelings of well-being, heightened perceptual acuity, and pleasant relaxation, often accompanied by a sensation of drifting or floating away. Sensory inputs are intensified. Often a person’ s sense of time is stretched or distorted, so that an event that lasts only a few seconds may seem to cover a much longer span. Short-term memory may also be affected, as one notices that a bite has been taken out of a sandwich but does not remember having taken it. For most users, pleasurable experiences, including sexual intercourse, are reportedly enhanced. When smoked, marijuana is rapidly absorbed and its effects appear within seconds to minutes but seldom last more than 2 to 3 hours (Butcher, Mineka, & Hooley, 2004).
Marijuana may lead to unpleasant as well as pleasant experiences. For example, if a person uses the drug while in an unhappy, angry, suspicious, or frightened mood, these feelings may be magnified. With higher dosages and with certain unstable or susceptible individuals, marijuana can produce extreme euphoria, hilarity, and over talkativeness, but it can also produce intense anxiety and depression as well as delusions, hallucinations, and other psychotic-like experiences. Evidence suggests a strong relationship between daily marijuana use and the occurrence of self-reported psychotic symptoms (Tien & Anthony, 1990).

One study exploring past substance use history in incarcerated murderers reported that among men who committed murder, marijuana was the most commonly used drug. One-third indicated that they used the drug before the homicide, and two-thirds were experiencing some effects of the drug at the time of the murder (Spunt et al., 1994).
Marijuana does not lead to extreme physiological dependence, as heroin does. It can, however, lead to psychological dependence, in which the person experiences a strong need for the drug whenever he or she feels anxious or tense. In fact, recent research has reported that many marijuana use abstainers reported having withdrawal-like symptoms such as nervousness, tension, sleep problems, and appetite change (Budney, Hughes, et al., 2001; Kouri and Pope, 2000). One recent study of substance abusers reported that marijuana users were more ambivalent and less confident about stopping use than were cocaine abusers (Budney, Radonovich, et al., 1998).
Self Diagnosis
1. Does your periodic marijuana use and intoxication interfere with your performance at work or school?
2. Is your periodic marijuana use and intoxication physically hazardous in situations such as driving a car?
3. Do you or have you had legal problems as a consequence of arrests for marijuana possession?
4. Do you or have you had arguments with spouses or parents over the possession of marijuana in the home or its use in the presence of children?
If you answered Yes to any one of the above you may meet criteria for a diagnosis of Cannabis Abuse and I would recommend that you undergo an alcohol/ substance abuse evaluation by a Certified Substance Abuse Counselor (CSAC) and comply with all treatment recommendations.
If you are having psychological or physical problems associated with compulsively using marijuana, such as:

1. Craving;
2. Withdrawal symptoms;
3. Irritability;
4. Sleeplessness; and/ or
5. Anxiety
- when trying to quit, then a diagnosis of Cannabis Dependence should be considered rather than Cannabis Abuse. Likewise, I would recommend that you undergo an alcohol/ substance abuse evaluation by a Certified Substance Abuse Counselor (SAC) and comply with all treatment recommendations.
Multiple Addictions
In 2001, marijuana was a contributing factor in more than 110,000 emergency department visits in the United States. In a survey of drug-related visits to the emergency room (DAWN Report, 2001), 16 percent of drug-related visits were for marijuana abuse. Many of these emergency room visits, as one might suspect, involved the use of other substances along with marijuana. If you had trouble answering Yes to one of the above self-diagnosis questions, because you have used alcohol and/ or other drugs along with marijuana and you cannot contribute your problems to marijuana alone, then you may meet the criteria for Poly-substance Dependence and or Poly-behavioral Addiction, see below. other addictions co-exist, the initial therapeutic intervention for any addiction needs to include an assessment for other addictions. National surveys revealed that very high correlation exists between cannabis abuse and/ or other substance abuse and behavioral addictions.
Poor Prognosis
We have come to realize today more than any other time in history that the treatment of Cannabis Dependence and other lifestyle diseases and behavioral addictions related to gambling, food, sex, and/ or religion, (etc.) are often a difficult and frustrating task for all concerned. Repeated failures abound with all of the addictions, even with utilizing the most effective treatment strategies. But why do 47% of patients treated in private addiction treatment programs (for example) relapse within the first year following treatment (Gorski, T., 2001)? Have addiction specialists become conditioned to accept failure as the norm? There are many reasons for this poor prognosis. Some would proclaim that addictions are psychosomatically- induced and maintained in a semi-balanced force field of driving and restraining multidimensional forces. Others would say that failures are due simply to a lack of self-motivation or will power. Most would agree that lifestyle behavioral addictions are serious health risks that deserve our attention, but could it possibly be that patients with multiple addictions are being under diagnosed (with a single dependence) simply due to a lack of diagnostic tools and resources that are incapable of resolving the complexity of assessing and treating a patient with multiple addictions?
Diagnostic Delineation
Thus far, the DSM-IV-TR has not delineated a diagnosis for the complexity of multiple behavioral and substance addictions. It has reserved the Poly-substance Dependence diagnosis for a person who is repeatedly using at least three groups of substances during the same 12-month period, but the criteria for this diagnosis do not involve any behavioral addiction symptoms. In the Psychological Factors Affecting Medical Condition s section (DSM-IV-TR, 2000); maladaptive health behaviors (e.g., unsafe sexual practices, excessive alcohol, drug use, and over eating, etc.) may be listed on Axis I, only if they are significantly affecting the course of treatment of a medical or mental condition. Since successful treatment outcomes are dependent on thorough assessments, accurate diagnoses, and comprehensive individualized treatment planning, it is no wonder that repeated rehabilitation failures and low success rates are the norm instead of the exception in the addictions field, when the latest DSM-IV-TR does not even include a diagnosis for multiple addictive behavioral disorders. Treatment clinics need to have a treatment planning system and referral network that is equipped to thoroughly assess multiple addictive and mental health disorders and related treatment needs and comprehensively provide education/ awareness, prevention strategy groups, and/ or specific addictions treatment services for individuals diagnosed with multiple addictions. Written treatment goals and objectives should be specified for each separate addiction and dimension of an individuals life, and the desired performance outcome or completion criteria should be specifically stated, behaviorally based (a visible activity), and measurable.
New Proposed Diagnosis
To assist in resolving the limited DSM-IV-TRs diagnostic capability, a multidimensional diagnosis of Poly-behavioral Addiction, is proposed for more accurate diagnosis leading to more effective treatment planning. This diagnosis encompasses the broadest category of addictive disorders that would include an individual manifesting a combination of substance abuse addictions, and other obsessively-compulsive behavioral addictive behavioral patterns to pathological gambling, religion, and/ or sex / pornography, etc.). Behavioral addictions are just as damaging – psychologically and socially as alcohol and drug abuse. They are comparative to other life-style diseases such as diabetes, hypertension, and heart disease in their behavioral manifestations, their etiologies, and their resistance to treatments. They are progressive disorders that involve obsessive thinking and compulsive behaviors. They are also characterized by a preoccupation with a continuous or periodic loss of control, and continuous irrational behavior in spite of adverse consequences.
Poly-behavioral addiction would be described as a state of periodic or chronic physical, mental, emotional, cultural, sexual and/ or spiritual/ religious intoxication. These various types of intoxication are produced by repeated obsessive thoughts and compulsive practices involved in pathological relationships to any mood-altering substance, person, organization, belief system, and/ or activity. The individual has an overpowering desire, need or compulsion with the presence of a tendency to intensify their adherence to these practices, and evidence of phenomena of tolerance, abstinence and withdrawal, in which there is always physical and/ or psychic dependence on the effects of this pathological relationship. In addition, there is a 12 – month period in which an individual is pathologically involved with three or more behavioral and/ or substance use addictions simultaneously, but the criteria are not met for dependence for any one addiction in particular (Slobodzien, J., 2005). In essence, Poly-behavioral addiction is the synergistically integrated chronic dependence on multiple physiologically addictive substances and behaviors (e.g., using/ abusing substances – nicotine, alcohol, & drugs, and/or acting impulsively or obsessively compulsive in regards to gambling, food binging, sex, and/ or religion, etc.) simultaneously.
Multidimensional Treatment
Since chronic lifestyle diseases and disorders such as diabetes, hypertension, alcoholism, drug and behavioral addictions cannot be cured, but only managed – how should we effectively manage poly-behavioral addiction?
The Addiction Recovery Measurement System (ARMS) is proposed utilizing a multidimensional integrative assessment, treatment planning, treatment progress, and treatment outcome measurement tracking system that facilitates rapid and accurate recognition and evaluation of an individual s comprehensive life-functioning progress dimensions. The ARMS hypothesis purports that there is a multidimensional synergistically negative resistance that individual s develop to any one form of treatment to a single dimension of their lives, because the effects of an individual ‘s addiction have dynamically interacted multi-dimensionally. Having the primary focus on one dimension is insufficient. Traditionally, addiction treatment programs have failed to accommodate for the multidimensional synergistically negative effects of an individual having multiple addictions, (e.g. nicotine, alcohol, and obesity, etc.). Behavioral addictions interact negatively with each other and with strategies to improve overall functioning. They tend to encourage the use of tobacco, alcohol and other drugs, help increase violence, decrease functional capacity, and promote social isolation. Most treatment theories today involve assessing other dimensions to identify dual diagnosis or co-morbidity diagnoses, or to assess contributing factors that may play a role in the individual s primary addiction. The ARMS theory proclaims that a multidimensional treatment plan must be devised addressing the possible multiple addictions identified for each one of an individual s life dimensions in addition to developing specific goals and objectives for each dimension.
Conclusion
This article was not written with the intent to demonize or glorify the most widely used illicit and top US cash crop (U.S. growers produce nearly $35 billion worth of marijuana annually, making the illegal drug the country’s largest cash crop, bigger than corn and wheat combined, an advocate of medical marijuana use said in a study released on 18 Dec. 06, WASHINGTON), Reuters. Nor was it written to advocate the use or non-use of marijuana whether legally for medicinal purposes or illegally.
There are numerous articles readily available that already accomplish that mission. It is my hope though, that the 10 to 15 percent of individuals that have multiple complex problems involving marijuana usage will find the help that they need. Considering the wide range of addictive behaviors in our world today, one should always take into account an individual s ethnic, cultural, religious, and social background prior to making any clinical judgments, and it would be wise to not over-pathologize in this area. However, since successful treatment outcomes are dependent on thorough assessments, accurate diagnoses, and comprehensive individualized treatment planning – Poly-behavioral Addiction needs to be identified to effectively treat the complexity of multiple behavioral and substance addictions.
Sources:
National Institute on Drug Abuse, Marijuana Facts Parents Need to Know, September 2004, What is Marijuana, How is Marijuana Used?
Substance Abuse and Mental Health Services Administration, Results from the 2005 National Survey on Drug Use and Health: National Findings, September 2006
Substance Abuse and Mental Health Service Administration, Initiation of Marijuana Use: Trends, Patterns and Implications, July 2002.
National Institute on Drug Abuse and University of Michigan, Monitoring the Future 2005 Data From In-School Surveys of 8th-, 10th-, and 12th-Grade Students, December 2005
Centers for Disease Control and Prevention, Youth Risk Behavior Surveillance United States, 2005, June 2006
National Institute on Drug Abuse and University of Michigan, Monitoring the Future National Survey Results on Drug Use, 1975 2005, Volume II: College Students & Adults Ages 19 45 (PDF), 2006
Bureau of Justice Statistics, Drug Use and Dependence, State and
Federal Prisoners, 2004, October 2006
National Institute on Drug Abuse, InfoFacts: Marijuana, April 2006
National Institute on Drug Abuse, Research Report Series Marijuana Abuse, October 2001.
Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network, 2004: National Estimates of Drug-Related Emergency Department Visits, April 2006
Substance Abuse and Mental Health Services Administration, Mortality Data from the Drug Abuse Warning Network, 2001 (PDF), January 2003.
Substance Abuse and Mental Health Services Administration, Treatment Episode Data Set (TEDS) Highlights 2004 (PDF), February 2006
Federal Bureau of Investigation, Crime in the United States, 2005, September 2006
National Drug Intelligence Center, National Drug Threat Assessment 2007, October 2006
Bureau of Justice Statistics, Drug Use and Dependence, State and Federal Prisoners, 2004, October 2006
United States Sentencing Commission, 2005 Sourcebook of Federal Sentencing Statistics, June 2006
National Drug Intelligence Center, National Drug Threat Assessment 2007
James Slobodzien, Psy.D. CSAC, is a Hawaii licensed psychologist and certified substance abuse counselor who earned his doctorate in Clinical Psychology. The National Registry of Health Service Providers in Psychology credentials Dr. Slobodzien. He has over 20-years of mental health experience primarily working in the fields of alcohol/ substance abuse and behavioral addictions in medical, correctional, and judicial settings. He is an adjunct professor of Psychology and also maintains a private practice as a mental health consultant.

A large multi-cohort analysis has investigated factors affecting long-term response to potent antiretroviral therapy. Four to six years after starting anti-HIV treatment, higher rates of AIDS and mortality were seen in injection drug users and in those who had had AIDS-defining events or CD4 cell counts less than 25 cells/mm3 before starting therapy. The study, conducted by the Antiretroviral Therapy Cohort Collaboration, was published in the December 15th issue of the Journal of Acquired Immune Deficiency Syndromes.

Previous studies have found that rates of AIDS-related illness and death are higher in people who begin antiretroviral therapy with lower CD4 cell counts. Poorer response has also been found in injection drug users (IDUs) compared to other patients. However, most studies to date have looked at response over relatively short time periods. In this study, the Antiretroviral Therapy Cohort Collaboration (an international alliance of investigators from sixteen cohort studies of people with HIV – see www.art-cohort-collaboration.org) analysed data from 20,379 HIV-positive adults who had been on anti-HIV drugs for up to six years.

Participating cohorts were included if they had enrolled at least 100 treatment-naïve patients, 16 years of age or older, who had begun treatment with a combination of at least three antiretroviral agents. People with baseline viral loads less than 1000 copies/ml were excluded as possibly not treatment-naïve. This yielded a total of 20,379 patients from twelve European and North American cohorts. (A prognostic model based on this same data set was recently published – see the aidsmap report here)

Baseline characteristics were as follows: median age, 36; median CD4 cell count 224 cells/mm3; median month of therapy initiation, February 1999. Before treatment initiation, 2737 patients (23%) had already had a diagnosis of AIDS; 3231 (16%) were presumed infected due to IDU.

Of the initial regimens, 66% were NRTI/PI, 24% NRTI/NNRTI, 7% NRTI only, 2% triple-class; and 2% other (NRTI-sparing, or including T-20). The majority of participants (88%) began on a three-drug regimen.

Over a total of 61,798 person-years of follow-up, 1844 participants developed at least one AIDS-defining event, and 1005 died. AIDS-defining events and deaths were analysed by: baseline CD4 cell count (<25, 25 to 49, 50 to 99, 100 to 199, 200 to 349, and >350 cells/mm3), baseline viral load (<100,000 or ≥100,000 copies/ml), presumed mode of transmission (IDU or other), and AIDS diagnosis before baseline (yes or no).

Consistent with previous studies, lower baseline CD4 cell counts were consistently the strongest predictor of poorer outcomes. The effect was strongest for the lowest baseline counts, and tended to decline with length of time on therapy for all strata of CD4 count.

Beginning therapy at a baseline CD4 cell count between 200 and 349 continued to show a benefit until the four-year mark. Compared to those beginning at >350 cells/mm3 (the comparator group), the hazard ratio for progression to AIDS at one to two years on therapy was 1.5 (95% confidence interval [CI]: 1.0 to 2.3), 1.4 at two to three years (95% CI: 1.0 to 2.1), and 1.0 at four to six years (95% CI: 0.6 to 2.0). For each time period, hazard ratios were progressively higher for each lower CD4 stratum. For baseline CD4 counts <25 cells/ mm3, the hazard ratio for developing AIDS was 3.7 at one to two years (95% CI: 2.2 to 6.1), 2.4 at two to four years (95% CI: 1.5 to 3.8), and 2.3 at four to six years (95% CI: 1.0 to 2.3). At four to six years, the hazard ratio for mortality was 2.5 (95% CI: 1.2 to 5.5) for baseline CD4 counts <25 cells/ mm3.

For people presumed infected through IDU, at four to six years on HAART, the hazard ratio for AIDS was 1.6 (95% CI: 0.8 to 3.0) and the hazard ratio for mortality was higher at 3.5 (95% CI: 2.2 to 5.5). Note that cause of death was not analysed and was not necessarily directly due to HIV; mortalities due to hepatitis-related liver disease, overdose, trauma and other causes were not excluded. Mortality rates were still lower than would be expected in the absence of anti-HIV therapy.

Diagnosis of AIDS before the initiation of anti-HIV treatment also continued to predict AIDS-defining events at four to six years, with a hazard ratio of 2.3 (95% CI: 1.2 to 4.4); the predictive value for mortality ceased to be significant. HIV viral load (greater than, or less than, 100,000 copies/ml) was not a significant predictor of progression or death at any time point.

The study was limited by declining numbers of patients in follow-up after longer periods on antiretroviral treatment. At the end of the fourth year of anti-HIV therapy, 6838 participants were still being followed (23% of the original cohort); only 791 (4%) were followed for more than six years. As most original patients were still being followed up at the time of analysis, the researchers "do not believe that informative censoring is likely to be an important source of bias." However, results may have been confounded by socioeconomic and other factors which caused people to begin treatment late in the course of HIV progression. Larger hazard ratios for mortality than for development of AIDS were seen in several groups, which may be evidence of such confounding. Also, race and ethnicity were not included in the analysis due to lack of sufficient data.

The researchers concluded that "rates of AIDS and death were persistently higher in patients infected [through injection drug use]", and that "although the prognostic value of baseline CD4 count and a prior AIDS diagnosis declined with time, patients who were severely immunodeficient when they started therapy experienced higher rates of AIDS and death up to 6 years later." They believe these results may "strengthen the case for screening for HIV, because delaying treatment… has long-term disadvantages."

Reference
Antiretroviral Therapy Cohort Collaboration. Importance of baseline prognostic factors with increasing time since initiation of highly active antiretroviral therapy: collaborative analysis of cohorts of HIV-1–infected patients. J Acquir Immune Defic Syndr 46 (5):607-615, 2007.

Source: Wednesday, January 2, 2008

http://www.aidsmap.com/en/news/8ACEB690-26EB-4583-BF14-A4353CE335EC.asp

“Drug [including alcohol] addictions are medical diseases which deserve parity in national healthcare programmes…” states scientist and professor Carlton Erickson, as he reveals the neurobiological research.
Although this article was first printed in Addiction Today journal in 2002, the vast majority of alcohol and drug workers remain unaware of these vital facts. Read on…
Public and professional stigma against addictive diseases is a major social problem when dealing with conditions which have traditionally been dealt with by behavioural and spiritually-based programmes. Reducing this stigma is critical, as negative attitudes damage the level and quality of patient care – and funding for prevention, education and research.
For far too many years, the “field” of drug addiction treatment and prevention has drifted aimlessly, based on insufficient research evidence that addictions are brain diseases and about the pharmacology of addicting drugs. Much of the confusion is based on an incomplete understanding of the differences between intentional drug abuse and pathological drug dependence, the “new term for addiction”.
There is also a great deal of misinformation about the pharmacology of addicting drugs. This picture is changing rapidly, based on new neuroscience (brain) research which strongly indicates that the pleasure pathway – the medial forebrain bundle – of the brain is affected by all addictions, particularly in the pharmacological qualities of euphoria, craving and a theoretical concept of “drug need”.
This is the psychological correlate of behavioural “impaired control”. The neuroanatomical and neurochemical bases of drug need have yet to be demonstrated in the laboratory. But the research technology, such as brain scans, is now at hand to test the theories.
Everyone who cares about the victims of addiction must become more scientifically literate about the implications of new research findings, and ‘spread the news’ that biomedical research is on the threshold of proving what recovering people already know – that drug dependencies are medical diseases which deserve parity in present and future national healthcare programmes. Drug dependence must also be ‘handled’ differently from drug abuse in terms of responsibility and culpability in law enforcement.
This article covers the latest research on the neurobiology of dependence, including how the brain’s pleasure pathway works. It covers the differences between chemical abuse and chemical dependency, the latest therapies for drug dependency, and research methodologies which promise even more exciting breakthroughs in understanding “addictions” in the future. This information has important implications for prevention and education of the public about the true causes of drug problems, and how society can best deal with such problems.

SOLUTIONS
The solution. First, get rid of “Spam”: an acronym for stigma, prejudice, anger and misunderstanding. All of these lead to myths – widely-held, inaccurate beliefs – as compared to research-generated facts.
And there are some dangerous myths in this world. These include the myths that club drugs and marijuana are not addicting… that everyone who uses cocaine or heroin is addicted… that caffeine is highly addicting… that the form of a drug and how it is taken affects its “addiction potential”… and that alcoholics can stop drinking, since all they have to do is go to AA meetings.

TWO CRITICAL DEFINITIONS.

It is vital that professionals carry out assessments to distinguish between chemical abuse and dependence. As the cover story by Norman Hoffman in the last issue of Addiction Today emphasises, assessment directly affects what type of treatment is most effective for each client, and thus their care plan, choice of treatment unit and outcome results. To distinguish between the two is the most humane, most cost-effective and most professional course of action.
Chemical abuse is intentional overuse of substances in cases of celebration, anxiety, despair or ignorance. It is about people making bad choices about the use of drugs. It declines with adverse consequences, supply reduction or change in drug-use environment. Drug abusers have a major economic impact on society; for example, it is estimated that property theft to fund drug habits accounts for at least £2billion a year in the UK.
The criteria for chemical abuse, according to the DSM-IV diagnostic and statistical manual, are:
1) a maladaptive pattern of drug use leading to impairment or distress, presenting as one or more of the following over a 12-month period –
• recurrent use leading to failure to fulfill obligations
• recurrent use that is physically hazardous
• recurrent drug-related legal problems, and
• continued use despite social/interpersonal problems
2) the symptoms have never met the criteria for chemical dependence.
Dependence is “impaired control” over drug use, probably caused by a dysfunction in the brain’s pleasure pathway. This is the disease of addiction, an “I can’t stop without help” disease. It requires formal therapy and/or 12 steps and might require anti-craving drug therapy. The DSM-IV criteria for chemical dependence are:
1) a maladaptive pattern of drug use, leading to impairment or distress, presenting as three or more of the following over a 12-month period –
• tolerance to the drug’s actions
• withdrawal (generally, physical withdrawal)
• drug is used more than intended
• there is an inability to control drug use
• effort is expended to obtain the drug
• important activities are replaced by drug use, and
• drug use continues despite negative consequences
2) two types of dependence can occur –
• physiological dependence, including tolerance and withdrawal, and
• non-physiological dependence, excluding tolerance and withdrawal.
The terms “physical addiction” and “psychological addiction” are no longer valid, since the DSM-IV term includes both psychological and physical components.

DOES DRUG ABUSE LEAD TO DEPENDENCE?
A five-year follow-up of 1,300 men and women (Schuckit et al 2001) found that only 3% of abusers met criteria for dependence five years after being diagnosed as abusers. But many people believe that abuse usually leads to dependence. Instead, the two conditions appear to be separate; abuse may be a milder disorder not usually progressing to dependence.

RISK OF DEPENDENCE.
Data from the National Co-morbidity Survey of 8,100 men and women aged 15-24 years old (Wagner & Anthony 2002) showed that different drugs are associated with different rates of dependence. In the 10 year study, 15-16% of cocaine users become dependent, 12-13%of alcohol users and 8% of marijuana users. Of those who became dependent on cocaine, 5-6% became dependent in the first year of use. Fully 80% of people who became dependent on cocaine over the 10 years had become dependent in the first three years. These are only single studies which deserve more replication, but they are interesting in that they begin to break down some myths that people have about the onset of dependence in users and abusers.

EARLY vs LATE ONSET.
So, although it “looks” as if most people evolve from abuse to dependence, people can become dependent during their first year of using drugs, including alcohol. People in recovery seem to understand that some people become “instantly” dependent with the very first use of the drug; most reports concern early onset with the use of alcohol and cocaine. There is only one explanation, and it lies in the physiology of the medial forebrain bundle, or MFB, also known as the mesolimbic dopamine system.
The neurobiological model of “impaired control” characteristics.
A key point is that the “dependence” brain areas are in the part of the brain that governs unconscious thought. Dependence is not a “lack of will power” because
• the main problem with dependence lies in the MFB
• problems with the frontal cortex portion of the MFB produce a pathological impairment of decision-making.
Dependence is not mainly under conscious control.

BASIC NEUROBIOLOGY: NEUROTRANSMITTERS INVOLVED IN DEPENDENCE.

Dependence is probably due to a functional dysregulation – meaning: they aren’t working right! – of one or more neurotransmitter chemicals in the MFB. These include dopamine (which is affected by cocaine, amphetamines or alcohol), serotonin (alcohol or LSD), endorphins (alcohol or opioids such as heroin), gamma-aminobutyric acid (alcohol or benzodiazepines – antianxiety agents), glutamate (alcohol) and acetylcholine (nicotine or alcohol).
The dysregulation could be related to too much or too little neurotransmission, abnormal breakdown of neurotransmitters or abnormal receptor function. How does it come about? Is it due to genetic ‘malfunctions’, to drug-induced changes, or to other aspects of the environment? Neurobiological research points to genetics and drug-induced changes as being primary causes of dependence, whereas the environment is a major, though secondary, contributor to drug abuse and thus dependence.

THE RATIONALE BASED ON GENETICS.Abnormal genes lead to abnormal proteins. This results in abnormal transmitter-synthesising enzymes, abnormal transmitter-breakdown enzymes, or abnormal receptors. This is the cause of neurotransmitter dysregulation in the pleasure pathway. Impaired control appears to be due to this brain-chemistry disruption. It is the reason that scientists and clinicians now believe that dependence is a chronic medical brain disease.

SUMMARY.
Addicting drugs seem to ‘match’ the transmitter system that is not normal. To treat such individuals, detoxification – weaning people off the drug of choice – is the first step. Then, ideally, abstinence-based treatments are attempted, which traditionally have the greatest chance of success. But abstinence is not for everyone, so more treatment choices are becoming available through scientific research. For some, continued use of a similar drug (such as methadone for heroin- dependent people) or the initial drug (nicotine patches for people who stop smoking) is the choice, because some people report that they “need” a chemical to “feel normal” – in other words, to overcome the non-normal transmitter system.

TODAY’S TREATMENT OPTIONS.
More options create greater chances for helping people. Today’s options include some or all of the following:
• traditional – 12-step programmes/abstinence
• talk – inpatient/outpatient/aftercare
• misunderstood but useful – harm reduction, including methadone
• new – brief motivational counselling, cognitive behavioural therapy, motivational enhancement therapy, ‘significant others’ therapy, vouchers
• medical treatment – new medications to enhance abstinence, anticraving medications, methadone, buprenorphine, vaccines, drugs to alleviate withdrawal.
So, if addictions are a medical disease, why do we treat them behaviourally? What is the similarity between behavioural or talk therapies and pharmacotherapies in the way they work? Simple. Behavioural therapies probably change brain chemistry! If this is a brain disease, and people get better in behaviourally-based therapies, then brain chemistry has to change. Recent brain-scan research is confirming this rational conclusion.

DISRUPTING NERVE CELLS: EXPLANATION.

The basis of chemical dependence is dysregulation of nerve cell transmission – (see picture on the right) and there is an excellent description of this on the author’s university website here. Also, most drugs used to treat mental disorders, including chemical dependence, have their most basic action on individual nerve cells
Carlton Erickson PhD is a research scientist who has been studying the effects of alcohol on the brain for over 30 years. He is the Pfizer Centennial Professor of Pharmacology and director of the Addiction Science Research and Education Center, College of Pharmacy, University of Texas. He has published over 150 scientific and professional articles, has co-edited and co-authored books and is associate editor of the scientific journal Alcoholism: Clinical and Experimental Research. He is also a recipient of the Betty Ford Center Visionary Award 2000. He has spoken to about 70,000 professionals and people in recovery since 1978 and presents every two years at the UK/European Symposium on Addictive Disorders.
Source : www.addictiontoday.org. Sept. 17th 2008

By Mary Brett

In the last few years increasing concern has been expressed about the association of cannabis with mental illness. The number of cannabis users is going up. In the USA in some age groups, almost as many people are smoking cannabis as cigarettes. Children are starting to use the drug at an increasingly early age, more and more studies are emerging which link cannabis use with psychological and social problems, demand for treatment for cannabis users is rising and there is a change in the THC content of some cannabis varieties. Selectively bred strains such as skunk and nederweed have much greater percentages of THC than did the marijuana of the sixties and seventies.

Jan Ramstrom, the Swedish psychiatrist and expert on substance abuse who wrote Adverse Health Consequences of Cannabis Use (2003) said, “ At present we find ourselves in a curious situation where researchers and clinicians are becoming even more concerned, while the general public, not least in Europe, seems to grow less concerned”.

He also said, “It is worth mentioning that the opiates (heroin etc), apart only from the development of dependence, produce far fewer toxic psychiatric complications than do cannabis preparations”

Two fundamentally different psychotic manifestations are involved.

Toxic psychosis:
Cannabis-induced psychotic disorder, recognised as a diagnostic unit in the DSM 1V (Diagnostic and Statistical Manual of Mental Disorders) is caused by the toxic effects of the drug and involves a group of brain damage syndromes. The symptoms are caused by cannabis consumption and subside when drug use ceases. The use of anti-psychotic medicines to eliminate any residual symptoms means most patients make a full recovery unless he or she resumes the taking of cannabis or indeed other drugs. Symptoms of delirium often dominate, i.e. bewilderment and memory disturbance. Paranoia, hallucinations and aggression alternating with euphoria also occur. There is usually an absence of any heredity factor.

Functional psychosis:
“Functional” in this sense applies to the absence of organic damage. Cullberg 2000, said that there probably is some organic damage, possibly taking the form of some subtle vulnerability as yet unknown. This category covers schizophrenia and schizophrenia-like psychosis which usually runs a chronic course. Symptoms of delirium are absent and there is often a feeling of outside interference with thought. Often the person has a “premorbid personality” with extreme reserve, loss of interest and bizarre suspicious ideas.

To quote Jan Ramstrom again, “…what we are dealing with here are the most profound disturbances known to psychiatry; even when they are short-lived, such disturbances can leave marks on those affected and on their families which may remain for many years or even be of life-long duration.…..there is both an abuse condition and a serious mental disorder. These “dual disorders” are among the most difficult to assess in the whole of psychiatry. Moreover, conditions of this type not rarely make demands on the most costly resources available in the field of psychiatric care”.

Early Studies.
Papers as early as the 1970s saw researchers connecting cannabis consumption with psychosis.

1972. Tennant and Groesbeck studied American soldiers in Europe and found large numbers abusing drugs mostly hashish. Between 1968 and 1971, the number of acute psychotic reactions, not necessarily leading to schizophrenia increased from 16 in 1968 to 77 in 1971, an almost 5-fold increase in 4 years. They concluded that hashish smoking was the major contributor.

1974. Chopra and Smith described 200 patients admitted to a Calcutta psychiatric hospital between 1963 and 1968 with psychotic symptoms following cannabis use. Most cases were preceded by the ingestion of large quantities. One third had no previous psychiatric history and the symptoms were the same regardless of their history. The most potent cannabis preparations resulted in psychotic reactions in the shortest period of time.

1974. DA Treffert allowed 4 schizophrenic patients, all on anti-psychotic medicine to act as their own controls. Having been warned not to, all of them smoked cannabis occasionally. All of them experienced deterioration in their condition, sometimes with very serious consequences. This clearly demonstrated that there was a direct association between relapses into pot smoking and serious deterioration in the schizophrenia condition.

1974. Breakey and others pointed to some sort of association between drug use, including cannabis, and the onset of schizophrenic illness. He considered that cannabis and other drugs could precipitate latent schizophrenia, but also thought that cannabis could do this in cases where the illness would not occur otherwise. They based this conclusion on the fact that the drug induces schizophrenia on average 4 years earlier than the onset in other types of schizophrenia. The onset was also more sudden, and the premorbid personality always better than a comparative group of non-drug using schizophrenics.

1976. Thacore and Shukla made a clear attempt to demonstrate the occurrence of a specific cannabis-provoked functional psychosis.

Other papers around this time, giving support to the findings include, Talbott and Teague 1969, Weil 1970, Bernardson and Gunne 1972 and Harding and Knight 1973.

So even as long ago as the early seventies some researchers were trying to ring alarm bells about the possible psychological problems of cannabis use.

The eighties brought another crop of papers on the subject.

1981. MB Holmberg found that 10% of 16 year-old consumers of large quantities of drugs, almost exclusively cannabis, by the age of 27, would have a record of psychosis. This was much higher than the 3% in the normal population.

1985. Bier and Haastrup looked at psychological admissions over one year in a Copenhagen hospital. Thirty patients had cannabis-provoked psychosis. They then estimated that 15 in a population of 100,000 would be admitted each year with psychosis either precipitated or caused by cannabis.

1986. Negrette and others concluded that interaction between cannabis smoking and schizophrenia had the following characteristics. Cannabis smokers have more relapses, more hospital visits, the positive symptoms of schizophrenia are more dramatic and the patients are less susceptible to neuroleptic medication.

1986. Ghodse said there was clear evidence from countries where heavy cannabis use is common, that cannabis causes a short-term toxic psychosis. This was supported by laboratory experiments.

Among the large body of reports from researchers and clinicians at this time are the following: Palsson, Thulin and Tunving 1982, Rottamburg et al 1982, Tsuang et al 1982, Carney 1984, Brook 1984, Tunving 1985 and Hollister 1986.

However the most important publication at this time was the large study of Swedish conscripts by Andreasson, Allebeck et al in 1987.

Forty-five thousand conscripts had their drug-taking details taken at entry, aged 18 or 19. The levels of schizophrenia were then recorded over the next 15 years. Those on admission who claim to have taken cannabis on more than 50 occasions were found to be 6 times more likely to be diagnosed with schizophrenia in the following 15 years than those who had never consumed the drug. When confounding factors were taken into account, the risk became smaller but remained statistically significant.

Although the study attracted some criticisms, Negrette, the doyen in this field judged the connection to be reasonable taking other previous studies into account, while accepting there were some weaknesses. Andreasson in 1989 and Allebeck in 1993 strengthened their position by further research. They examined the medical records of 112 cannabis-dependent and schizophrenic patients. The findings in all significant respects confirmed the original study.

Further support came from the analysis of records of 100 schizophrenic patients between 1973 and 1977 randomly chosen by Dalman et al in 2002. A large measure of consistency was established with respect to regions, hospitals and timescale as well as the diagnostic criteria for schizophrenia, DSM-1V.

Over twenty years later in 2002, Zammit and others re-analysed the results. In the light of new research into the development of schizophrenia, they were able to discount more of the original objections.

Research continued in the nineties.

1990. Tien and Anthony conducted an epidemiological analysis of drug and alcohol use and concluded that there was an association between cannabis use and psychosis. Daily use over a year suggested a 2.4 times greater risk than non-users, any use related to a risk of 1.3 times. The daily risk figure remained significant after adjustment for other substance abuse and baseline psychiatric diagnosis.

1991. Chaudry et al studied cannabis psychosis following bhang ingestion. Bhang drinkers in Pakistan were found to have mania and paranoid features. Treated with anti-psychotic medicines, the majority recovered completely in 5 days. None had residual symptoms.

1991. Johnson, from his own long experience and a review of the current literature, estimated that 10% of all of those who had used cannabis more than once, experienced either delirium or psychosis. Later estimates confirmed this figure, notably Thomas in 1996 who sent questionnaires to young new Zealanders. Johns as recently as 2001 supported this claim.

1995. Wylie observed a group of British consumers of Dutch cannabis with a high THC content. He recorded a “wave of psychosis and confusional states”. The risk therefore becomes greater the more often cannabis is used and the greater its strength.

1998. Hall concluded that cannabis can cause psychotic like symptoms during intoxication, can lead to a “cannabis psychosis” to increase the relative risk of schizophrenia, and affect the clinical course of established schizophrenia.

Other studies which deserve mention are: Thornicroft 1990, Eikmeir et al 1991, Mathers et al 1991, Rolfe et al 1993, Kristensen 1994, McBride and Thomas 1995, Castle and Ames 1996, Hambrecht and Hafner 1996 and Fowler 1998.

A paper by J Giedd et al in 1999 on development of the adolescent brain must be mentioned here. They conclude that the brain does not finish its development till the mid twenties or beyond. So the warning is that drug abuse could alter the normal course of the maturing of the brain in the teenage years. Research by Giedd on this subject is on-going.

Since the year 2000 there has been a flood of publications. 2002. Louise Arsenault et al assessed 1100 New Zealand children at 11, 15, 18 and 26. Young adults smoking cannabis at the age of 15 were at a greater risk of developing schizophrenia or a schizophrenia-like illness by the age of 26. The risk was 10% times compared to 3% for non-users. Use at 15 was a stronger risk factor for schizophreniform disorder than use by the age of 18.

2002. The Nemesis Study by Van Os et al studied 4045 psychosis-free Dutch people and 59 who had a psychotic disorder, taken at random from 60 localities. They concluded that it must be considered proven that smoking cannabis can provoke a functional (non-toxic) schizophrenia-like psychosis. They replicated the Swedish study of Andreasson. It was of shorter duration and had fewer participants, but not the weaknesses. There was a baseline assessment and 2 follow up sessions, after 1 and 3 years, by questionnaire and clinical interviews. The study showed that individuals using cannabis at baseline were almost 3 times more likely to manifest psychotic symptoms at follow up. After confounding factors were taken into account the risk remained significant. A dose-response relationship was also found. The risk factor for the heaviest users rose to 6.8. They concluded: “cannabis use is an independent risk factor for the emergence of psychosis in psychosis-free persons and that those with an established vulnerability to psychotic disorders are particularly sensitive to its effects, resulting in poor outcome”.

2002. Nunez and Gurpegui compared 26 patients with cannabis-induced psychosis to 35 with acute schizophrenia. All used cannabis, they were repeatedly urine tested. They concluded that cannabis when continuously and heavily used can induce a psychotic disorder distinct from acute schizophrenia.

2002. Hiroshi Ujike found genetic abnormalities in the genes for the cannabinoid receptors on the brain cells of schizophrenics compared to non-schizophrenics. This implies a potential malfunction of their marijuana-linked circuitry, perhaps making them more vulnerable to schizophrenia.

Many people have argued and it seems logical that if the use of cannabis has increased then so must the incidence of schizophrenia.

2003. Boydell et al found that there was indeed a continuous and statistically significant rise in the incidence of schizophrenia between 1965 and 1997. It had doubled over the last 3 decades. The increase was greatest in people under 35.

2003. The Christchurch Health and Development Study. Fergusson et al looked at 1200 children from birth to the age of 21. The cannabis-dependent youngsters developed psychotic symptoms more often than those who were non-dependent. Individuals with cannabis-dependence disorder at 18 had a 3.7-fold increased risk of psychosis than those with no dependence disorder. At 21 the risk fell to 2.3 times.

They conclude that: “the findings are clearly consistent with the view that heavy cannabis use may make a causal contribution to the development of psychotic symptoms since they show that, independently of pre-existing psychotic symptoms and a wide range of social and contextual factors, young people who develop cannabis dependence show an elevated rate of psychotic symptoms”.

Another paper on the development of the brain appeared at this time.

2003. Chambers et al reviewed literature regarding the neurocircuitry underlying motivation, impulsivity and addiction. They focused on studies investigating adolescent neurodevelopment.

They found that adolescent neurodevelopment occurs in brain regions associated with motivation, impulsivity and addiction. These developmental processes may advantageously promote learning drives for adaptation to adult roles but may also confer greater vulnerability to the addictive actions of drugs. This has significant implications for understanding adolescent behaviour, addiction vulnerability and the prevention of addiction in adolescence and adulthood.

2004. Veen et al. One hundred and thirty-three Dutch patients with schizophrenia were interviewed. There was a strong association between the use of cannabis and an earlier age of first psychotic episode in male schizophrenics. On average they were 6.9 years younger than non-using patients.

2004. D’Souza et al. Various doses of THC were administered to 22 healthy subjects, screened for any vulnerability to schizophrenia. Some of them developed symptoms resembling schizophrenia for 30 minutes to 1 hour. There were no side effects after 1, 3 and 6 months. The study findings go along with several other lines of evidence that suggest a contribution of cannabis and/or abnormalities in the brain cannabinoid receptor system to the pathophysiology of schizophrenia.

2004. Arendt et al. Findings: 1439 heavy cannabis users seeking treatment for abuse problems in Denmark were compared to 9122 abusers of other substances.

Conclusion: Co-morbid psychiatric disorders are common among heavy cannabis users seeking treatment. Some psychiatric disorders occur more frequently in this group compared to users of other substances.

2005. Isaac and Holloway did their research in PICUs (Psychiatric Intensive Care Units). There was a high rate of cannabis abuse (71.3%) among the PICU population. Patients with cannabis abuse spent longer as their psychosis was more severe. They were also younger at first hospital admission. The conclusion was that cannabis abusers have more severe psychotic illness especially in schizophrenia. There are additional problems of weight gain.

2004. Frischer et al from Keele University monitored 3% of the population of England and Wales. The number of people using drugs and having mental illness rose by 62% between 1993 and 1998. (230 GP practices were looked at). Men accounted for 79% and women 44%.

The average age affected fell from 38 to 34. The number of cases of 25 to 34 year olds more than doubled. Drug abuse and psychosis were up by 147%, paranoia by 144% and schizophrenia by 128%.

They said, “A long-term, well funded, innovative campaign aimed at publicising the real mental health risks associated with drugs including cannabis needs to be in place as soon as possible”.

2004. Stephanis et al looked at 3500 19-year olds in Greece. Conclusions: These results add credence to the hypothesis that cannabis contributes to the population level of expression of psychosis. In particular, exposure early in adolescence may increase the risk for the sub-clinical positive and negative dimensions of psychosis, but not for depression.

2005. Favrat et al. Clinical trials of THC on psychomotor function and driving performance were conducted on 8 occasional cannabis users with no history of psychosis. Low doses were used. Two young men reacted badly. One 22 year-old showed severe anxiety and psychotic symptoms 90 minutes later, and was unable to do the tests. The other, also 22, was unable to do the tests for several hours, and experienced very unpleasant symptoms.

The doses were administered under clinical conditions and were much lower than would normally be found in a modern joint. The importance of this research is that oral administration of the THC caused significant psychotic reactions. Oral medicines are becoming increasingly available and doctors should be aware of these findings.

2005. Ferdinand. The “Zuid Holland” Study, a 14 year follow up study of 1580, initially 4 to16 year olds, drawn randomly from the Dutch population. (Because cannabis use is generally condoned in Holland, false negative reports of cannabis use may occur less frequently. This adds to the value of this study). Findings: Cannabis use in individuals who did not have psychotic symptoms before they began using cannabis, predicted future psychotic symptoms, the risk was almost 3 times greater. Also psychotic symptoms in those who had never used cannabis before the onset of psychotic symptoms also predicted future cannabis use.

Conclusion: The results either imply a common vulnerability with varying order of onset or a bi-directional causal relationship between cannabis use and psychosis.

2005. Van Os et al. Nearly 2500 young people between the ages of 14 and 24, with or without predisposition to psychosis were studied. Adjustment was done for confounding factors such as alcohol, cigarettes and other drugs. There was a dose-response relationship with increasingly frequent use of cannabis.

Conclusions: Cannabis use in young people moderately increased the risk of developing psychotic symptoms. The risk for onset of symptoms was much higher in young people with a predisposition for psychosis. Predisposition psychosis at baseline did not predict cannabis use at follow up. This rejects the self-medication hypothesis i.e. that psychotic patients take drugs to relieve the symptoms of the illness.

2005. Fergusson et al. This was a 25 year longitudinal study of 1055 New Zealand children from birth. Conclusions: “Even when all factors were taken into account, there was a clear increase in rates of psychotic symptoms after the start of regular use, with daily users of cannabis having rates that were over150% those of non-users. These findings add to a growing body of evidence from different sources, all of which suggest that heavy use of cannabis may lead to increased risks of psychotic symptoms and illness in susceptible individuals”.

Several review articles have also appeared in the last few years.

2001. Johns. Conclusion: “Heavy cannabis misuse leads to the risk of psychotic episodes and aggravates the symptoms and course of schizophrenia. For any psychiatric patient, risk management and care planning is incomplete without a thorough assessment of substance abuse”. 2003. Degenhardt and Hall. Conclusion: “Cannabis use does not appear to be causally related to the incidence of schizophrenia but its use may precipitate disorders in persons who are vulnerable to develop psychosis and worsen the course of the disorder among those who have already developed it”.

2004. Arsenault et al. A review of 5 papers was undertaken: The Swedish Conscript cohort, Andreasson 1987 and Zammit et al 2002. The Dutch Nemesis Sample, Van Os 2002. The Christchurch Study, Fergusson et al 2003. The Dunedin Study, Arsenault 2002. The overall conclusion: “A twofold increase in the relative risk for later schizophrenia. At the population level, elimination of cannabis smoking would reduce the incidence of schizophrenia by around 8% assuming a causal relationship. Cannabis is a component cause for psychosis, part of a complex constellation of factors”.

2004. Rey et al. Conclusion: The weight of evidence points in the direction of early and regular use of cannabis having substantial negative effects on psychosocial functioning and psychopathology.

2004. Drewe et al. This article appeared in response to the potential legalization of cannabis in Switzerland. Conclusion: “An increase in consumption would be expected therefore there would probably be an increase in the prevalence of psychosis, not only acute toxic but also chronic psychosis. Schizophrenic psychoses would be expected to be triggered at an earlier age so there could be deleterious consequences not only for many currently healthy individuals but for disablement pensions”.

2004. Raphael and Wooding. Conclusion: “Of primary importance is the fact that cannabis use does have a number of significant associated harms. It is not a soft or safe option and its notable co-morbidity with psychotic and non-psychotic illnesses make it a significant and growing public health issue – a fact increasingly reflected in both the national and international scientific literature”.

Other reviews deserving mention include: Leweke et al 2004, Witton and Murray 2004, John Macleod et al 2004 and Smit et al 2004.

Professor Robin Murray of the Institute of Psychiatry, London, drew attention to the fact in 2003 that recent evidence had demonstrated that THC increases the release of dopamine, thus increasing its level in the brain. Psychotic symptoms in conditions like schizophrenia are mediated by dopamine.

Two important papers are awaiting publication in scientific journals.

Caspi et al. in a paper to be published in Biological Psychiatry, have found variants in a gene (COMT) which is involved in dopamine transmission. It was found to moderate the influence of adolescent cannabis use on the development of adult psychosis. One in four people carries this gene. The research was carried out on 803 men and women born in Dunedin, New Zealand in 1972 and 1973. They were enrolled at birth. The gene comes in 2 variants, methionine and valine, and everyone has two copies of the gene. If a person inherits 2 methionine types, the rate of psychotic illness is 3%, the normal rate for non-users. However if a person has 2 valine variants, the rate rises to 15% for those who have used cannabis in their teens. Dr Caspi said, “Research has shown that the valine gene variant and cannabis affect the brain’s dopamine system in similar fashion, suggesting that they deliver a “double dose” that can be damaging”.

Markus Leweke and others from the University of Cologne in Germany addressed The International Cannabis and Mental Health Conference in Melbourne in August 2004.

The brain’s “natural cannabis” is a substance called anandamide. Much higher levels of this chemical were found in the brains of schizophrenics experiencing their first psychotic episode and before they had embarked on medication for their condition, and also the brains of people with psychotic symptoms and a strong susceptibility to schizophrenia.

Surprisingly the more severe the schizophrenia, the lower the levels of anandamide. They postulated that anandamide may actually be produced to control psychotic symptoms and dampen them down. THC binds to anandamide receptors. It makes these receptor sites less sensitive and may disrupt the system in other ways as well.

An article appeared in New Scientist in August 2004.

In 2004 Marijuana and Madness was published by Cambridge University Press. The editors were, Professor David Castle of The Mental Health Research Unit, Melbourne, and Professor Robin Murray of The Institute of Psychiatry in London.

Twenty-nine contributors to 13 chapters are listed. Many of them have been mentioned in this article. The review from the journal “Addiction” says:

“Each chapter is well written and well presented…There is little doubt that the chapters are expertly written…Marijuana and madness illustrates clearly the benefits of a multi-disciplinary perspective in providing the tools for answering a complex question”.

Mary Brett, retired biology teacher and former Head of Health Education Dr Challoner’s Grammar School Amersham Bucks. May 9th 2005.

The high prevalence of co-morbidity between drug use disorders and other mental illnesses does not mean that one caused the other, even if it appeared first. In fact, establishing causality or directionality is difficult for several reasons. Some symptoms of a mental disorder may not be recognized until the illness has substantially progressed, and imperfect recollections of when drug use/abuse started can also present timing issues. Still, three scenarios deserve consideration:
1. Drugs of abuse can cause abusers to experience one or more symptoms of another mental illness. The increased risk of psychosis in some marijuana abusers has been offered as evidence for this possibility.
2. Mental illnesses can lead to drug abuse. Individuals with overt, mild, or even subclinical mental disorders may abuse drugs as a form of self-medication. For example, the use of tobacco products by patients with schizophrenia is believed to lessen the symptoms of the disease and improve cognition (“Smoking and Schizophrenia: Self-Medication or Shared Brain Circuitry?”).
3. Both drug use disorders and other mental illnesses are caused by overlapping factors such as underlying brain deficits, genetic vulnerabilities, and/or early exposure to stress or trauma.
All three scenarios probably contribute, in varying degrees, to how and whether specific comorbidities manifest themselves.
Overlapping Conditions– Shared Vulnerability
High Prevalence of Drug Abuse and Dependence Among Individuals With Mood and Anxiety DisordersHigh Prevalence of Mental Disorders Among Patients With Drug Use Disorders

Higher Prevalence Smoking Among Patients With Mental Disorders

Because mood disorders increase vulnerability to drug abuse and addiction, the diagnosis and treatment of the mood disorder can reduce the risk of subsequent drug use. Because the inverse may also be true, the diagnosis and treatment of drug use disorders may reduce the risk of developing other mental illnesses and, if they do occur, lessen their severity or make them more amenable to effective treatment. Finally, because more than 40 percent of the cigarettes smoked in this country are smoked by individuals with a psychiatric disorder, such as major depressive disorder; alcoholism; post-traumatic stress disorder (PTSD); schizophrenia; or bipolar disorder, smoking by patients with mental illness contributes greatly to their increased morbidity and mortality.
Data in top two graphs reprinted from the National Epidemiologic Survey on Alcohol and Related Conditions (Conway et al., 2006).
Data in bottom graph from the 1989 U.S. National Health Interview Survey (Lasser et al., 2000).
Common Factors
Overlapping Genetic Vulnerabilities. A particularly active area of comorbidity research involves the search for genes that might predispose individuals to develop both addiction and other mental illnesses, or to have a greater risk of a second disorder occurring after the first appears. It is estimated that 40-60 percent of an individual’s vulnerability to addiction is attributable to genetics; most of this vulnerability arises from complex interactions among multiple genes and from genetic interactions with environmental influences. In some instances, a gene product may act directly, as when a protein influences how a person responds to a drug (e.g., whether the drug experience is pleasurable or not) or how long a drug remains in the body. But genes can also act indirectly by altering how an individual responds to stress or by increasing the likelihood of risk-taking and novelty-seeking behaviors, which could influence the development of both drug use disorders and other mental illnesses. Several regions of the human genome have been linked to increased risk of both, including associations with greater vulnerability to adolescent drug dependence and conduct disorders. The rate of smoking in patients with schizophrenia has ranged as high as 90 percent.
Involvement of Similar Brain Regions.
Some areas of the brain are affected by both drug use disorders and other mental illnesses. For example, the circuits in the brain that use the neurotransmitter dopamine–a chemical that carries messages from one neuron to another– are typically affected by addictive substances and may also be involved in depression, schizophrenia, and other psychiatric disorders.
Indeed, some antidepressants and essentially all antipsychotic medications target the regulation of dopamine in this system directly, whereas others may have indirect effects. Importantly, dopamine pathways have also been implicated in the way in which stress can increase vulnerability to drug addiction. Stress is also a known risk factor for a range of mental disorders and therefore provides one likely common neurobiological link between the disease processes of addiction and those of other mental disorders.
The overlap of brain areas involved in both drug use disorders and other mental illnesses suggests that brain changes stemming from one may affect the other. For example, drug abuse that precedes the first symptoms of a mental illness may produce changes in brain structure and function that kindle an underlying propensity to develop that mental illness. If the mental disorder develops first, associated changes in brain activity may increase the vulnerability to abusing substances by enhancing their positive effects, reducing awareness of their negative effects, or alleviating the unpleasant effects associated with the mental disorder or the medication used to treat it.
Smoking and Schizophrenia: Self- Medication or Shared Brain Circuitry?
Patients with schizophrenia have higher rates of alcohol, tobacco, and other drug abuse than the general population. Based on nationally representative survey data, 41 percent of respondents with past-month mental illnesses are current smokers, which is about double the rate of those with no mental illness. In clinical samples, the rate of smoking in patients with schizophrenia has ranged as high as 90 percent.
Various self-medication hypotheses have been proposed to explain the strong association between schizophrenia and smoking, although none have yet been confirmed. Most of these relate to the nicotine contained in tobacco products: Nicotine may help compensate for some of the cognitive impairments produced by the disorder and may counteract psychotic symptoms or alleviate unpleasant side effects of antipsychotic medications. Nicotine or smoking behavior may also help people with schizophrenia deal with the anxiety and social stigma of their disease.
Research on how both nicotine and schizophrenia affect the brain has generated other possible explanations for the high rate of smoking among people with schizophrenia: The presence of abnormalities in particular circuits of the brain may predispose individuals to schizophrenia; increase the rewarding effects of drugs like nicotine; or reduce an individual’s ability to quit smoking. The involvement of common mechanisms is consistent with the observation that both nicotine and the medication clozapine (which also acts at nicotine receptors) can improve attention and working memory in an animal model of schizophrenia. Clozapine is effective in treating individuals with schizophrenia. It also reduces their smoking levels. Understanding how and why patients with schizophrenia use nicotine is likely to help us develop new treatments for both schizophrenia and nicotine dependence.
The Influence of Developmental Stage
Adolescence–A Vulnerable Time. Although drug abuse and addiction can happen at any time during a person’s life, drug use typically starts in adolescence, a period when the first signs of mental illness commonly appear. It is therefore not surprising that co-morbid disorders can already be seen among youth. Significant changes in the brain occur during adolescence, which may enhance vulnerability to drug use and the development of addiction and other mental disorders. Drugs of abuse affect brain circuits involved in reward, decision making, learning and memory, and behavioral control, all of which are still maturing into early adulthood. Thus, understanding the long-term impact of early drug exposure is a critical area of co-morbidity research.
The brain continues to develop into adulthood and undergoes dramatic changes during adolescence. One of the brain areas still maturing during adolescence is the prefrontal cortex– the part of the brain that enables us to assess situations, make sound decisions, and keep our emotions and desires under control. The fact that this critical part of an adolescent’s brain is still a work in progress puts them at increased risk for poor decisions (such as trying drugs or continuing abuse). Thus, introducing drugs while the brain is still developing may have profound and long-lasting consequences.
The high rate of co-morbidity between drug abuse and addiction and other mental disorders argues for a comprehensive approach to intervention that identifies, evaluates, and treats each disorder concurrently.
Early Occurrence Increases Later Risk. Strong evidence has emerged showing early drug use to be a risk factor for later substance abuse problems; additional findings suggest that it may also be a risk factor for the later occurrence of other mental illnesses. However, this link is not necessarily a simple one and may hinge upon genetic vulnerability, psychosocial experiences, and/or general environmental influences. A recent study highlights this complexity, with the finding that frequent marijuana use during adolescence can increase the risk of psychosis in adulthood, but only in individuals who carry a particular gene variant (see sidebar, “The Influence of Adolescent Marijuana Use on Adult Psychosis Is Affected by Genetic Variables”).
The Influence of Adolescent Marijuana Use on Adult Psychosis Is Affected by Genetic Variables

Percentage of Individuals Meeting Diagnostic Criteria for Schizophreniform Disorder at Age 26

Source: Caspi A, Moffitt TE, Cannon M, et al., 2005.
The above figure shows that variations in a gene can affect the likelihood of developing psychosis in adulthood following exposure to cannabis. The Catechol-O-Methyltransferase gene regulates an enzyme that breaks down dopamine, a brain chemical involved in schizophrenia. It comes in two forms: Met and Val. Individuals with one or two copies of the Val variant have a higher risk of developing schizophrenic-type disorders if they used cannabis during adolescence (dark bars). Those with only the Met variant were unaffected by cannabis use. These findings hint at the complexity of factors that contribute to co-morbid conditions; however, more research is needed.
Source: NIDA Jan.2009

CASE REPORT

Cannabinoid hyperemesis syndrome: Clinical diagnosis of an underrecognised manifestation of chronic cannabis abuse

Siva P Sontineni, Sanjay Chaudhary, Vijaya Sontineni, Stephen J Lanspa
Online Submissions: wjg.wjgnet.com World J Gastroenterol 2009 March 14; 15(10): 1264-1266
wjg@wjgnet.com World Journal of Gastroenterology ISSN 1007-9327
doi:10.3748/wjg.15.1264 © 2009 The WJG Press and Baishideng. All rights reserved.
Siva P Sontineni, Sanjay Chaudhary, Vijaya Sontineni,
Stephen J Lanspa, Department of Medicine, Creighton
University, Suite 5850, 601 N 30th Street, Omaha, NE 68131,
United States
Author contributions: Sontineni SP provided the patient’s data,
organized, conceptualized and contributed to the manuscript
writing and final approval; Chaudhary S collected the patient
data, reviewed the literature and contributed to the manuscript
writing; Sontineni V reviewed the literature and compiled the
references; Lanspa SJ supervised, provided critical review
and obtained financial support from the division; All authors
approved the final manuscript.
Correspondence to: Siva P Sontineni, MD, Department
of Internal Medicine, 601 N 30th St Suite 5850, Creighton
University Medical Centre, Omaha, NE 68131,
United States. ssontineni@gmail.com
Telephone: +1-402-4158319 Fax: +1-402-2804220
Received: October 25, 2008 Revised: February 8, 2009
Accepted: February 15, 2009
Published online: March 14, 2009

Abstract

Cannabis is a common drug of abuse that is associated with various long-term and short-term adverse effects.
The nature of its association with vomiting after chronic abuse is obscure and is underrecognised by
clinicians. In some patients this vomiting can take on a pattern similar to cyclic vomiting syndrome with
a peculiar compulsive hot bathing pattern, which relieves intense feelings of nausea and accompanying
symptoms. In this case report, we describe a twentytwo year-old-male with a history of chronic cannabis
abuse presenting with recurrent vomiting, intense nausea and abdominal pain. In addition, the patient
reported that the hot baths improved his symptoms during these episodes. Abstinence from cannabis led
to resolution of the vomiting symptoms and abdominal pain. We conclude that in the setting of chronic
cannabis abuse, patients presenting with chronic severe nausea and vomiting that can sometimes be
accompanied by abdominal pain and compulsive hot bathing behaviour, in the absence of other obvious
causes, a diagnosis of cannabinoid hyperemesis syndrome should be considered.
© 2009 The WJG Press and Baishideng. All rights reserved.

INTRODUCTION
Cannabis has been used recreationally for millennia and is the third most commonly used drug after tobacco
and alcohol[1,2]. Research into the neurobiology of the compound has led to the discovery of an endogenous
cannabinoid system. The therapeutic potential of cannabinoids has been recognized and these compounds are
utilized as anti-emetics[3-5]. Recently, a distinct syndrome in chronic cannabis abusers characterized by recurrent
vomiting associated with abdominal pain and a tendency to take hot showers has been increasingly recognised.
This clinical manifestation is paradoxical to the previously identified therapeutic role of cannabinoids as antiemetics.
We describe the case of a young male seeking repeated emergency room care with recurrent nausea
and vomiting.

CASE REPORT
A 22-year male presented with recurrent episodes of nausea, refractory vomiting, and colicky epigastric pain
for one week. The symptoms were characterized by treatment-resistant nausea in the morning, continuous
vomiting, and colicky epigastric abdominal pain. Each episode lasted 2 to 3 h and increased with food intake.
He often had two or more episodes a day during the symptomatic period. He had been treated for the severe
nausea and vomiting in the emergency room on two occasions in the preceding two months. He also reported
having learned to help himself by taking a hot bath each time the symptoms appeared, which dramaticallyimproved his symptoms. This habit had become a compulsion for him for symptom relief with each episode
of hyperemesis. On physical examination his mucous membranes were dry, his pulse rate was 102/min and
blood pressure was 140/100 with positive orthostasis. The remainder of the physical examination was unremarkable.
His complete blood count and comprehensive metabolic panel were unremarkable. In addition, serum
amylase and lipase levels were within the normal range. His urine drug screen was positive for tetrahydrocannabinol
(THC). Abdominal X-ray series and ultrasonography were within normal limits.
Oesophagogastroduodenoscopy revealed Grade 2 distal oesophagitis and hiatal hernia. On further interviewing,
he admitted to consistent marijuana abuse for the past 6 years, often smoking cannabis every hour or
two on a daily basis. The patient and his mother did not recall any significant past illnesses or recurrent vomiting
when he was a child. He was treated with intravenous fluids with steady improvement in symptoms, and metoclopramide,
pantoprazole and morphine for the abdominal pain. It was explained that marijuana was the cause
of his symptoms and he was advised not to resume marijuana abuse. On subsequent follow-up, he had abstained from cannabis and remained symptom-free.

DISCUSSION
Cannabis is one of the most commonly abused drugs worldwide. Over the past decade, marijuana has
remained the most commonly used illicit substance with close to 50% of high school seniors admitting use at
some time[1]. It is estimated that each year 2.6 million individuals in the USA become new users and most are
younger than 19 years of age[6].
The long-term and short-term toxicity of cannabis abuse is associated with pathological and behavioural
effects. However, cannabis has also been suggested to have therapeutic properties with anticonvulsive,
analgesic, antianxiety and anti-emetic activities. Cannabis has also been used to treat anorexia in patients with
acquired immunodeficiency syndrome[3-5]. The actions of cannabis are mediated by specific cannabinoid
receptors. The first of the cannabinoid receptors-CB-1- was identified in 1990 and this finding revolutionized the
study of cannabinoid biology. Since then, a multitude of roles for the endogenous cannabinoid system has been
proposed. A large number of endogenous cannabinoid neurotransmitters or endocannabinoids have been
identified, and the CB-1 and CB-2 cannabinoid receptors have been characterized[7]. The CB-1 receptors exert
a neuromodulatory role in the central nervous system and enteric plexus[8]. Cannabinoid type 2 receptors
have an immunomodulatory effect and are located on tissues such as microglia[5]. The presence of other
receptors, transporters, and enzymes responsible for the synthesis or metabolism of endocannabinoids are
being recognised at an extraordinary pace. Cannabinoids have a wide variety of effects on the body systems and
physiologic states (Table 1) due to their actions on the receptors as well as direct toxic effects.
The anti-emetic effect of cannabinoids is largely mediated by CB-1 receptors in the brain and the
intestinal tract, although some of their effect may also be receptor-independent. However, in this report,
we were presented with the paradoxical effect of hyperemesis in a susceptible chronic cannabis abuser.
Such a paradoxical response has previously only been demonstrated following acute toxicity to an intravenous
injection of crude marijuana extract[9]. Proposed mechanisms of cannabinoid hyperemesis include
toxicity due to marijuana’s long half-life, fat solubility, delayed gastric emptying, and thermoregulatory and
autonomic disequilibrium via the limbic system[10].
Cannabinoids are known to impair peristalsis in a dosedependent manner[11,12], which can theoretically override
the centrally mediated anti-emetic effects, thus leading to hyperemesis. It is not known why the hyperemesis
syndrome surfaces after several years of cannabis abuse. The effects of cannabinoids on the functions of the
thermoregulatory and autonomic mechanisms of the brain can lead to behavioural changes[10]. Such effects
might be the underlying mechanism for the compulsive hot bathing behaviour. There is also a supposition that
the syndrome could represent a type of cyclic vomiting.
Cyclic vomiting syndrome (CVS) in adults is now very well recognized, and it has been proposed that marijuana
contributes to CVS[13]. However, unlike the other forms of CVS, patients with cannabinoid hyperemesis are not
likely to have a history of migraine or other psychosocial stressors and the peculiar behaviour of hot showers is
Cognitive and mental health
Impaired memory
Impaired attention, organization and integration of complex information
Association with schizophrenia
Increased risk for depression
Pulmonary
Carcinogenic effect
Obstructive lung disease
Increased propensity toward infections
Acute and chronic bronchitis
Behavioural
Weapon possession and physical fighting
Unwanted and unprotected sexual encounters
Unwanted pregnancies
School dropout
Amotivational syndrome
Impairment of driving skill and coordination
Endocrine
Decreased testosterone, sperm motility and production, disruption of
ovulatory cycle
Pregnancy
Low birth weight
Problems with attention, memory and higher cognitive function
Cardiovascular
Stroke
Dose-dependent increase in HR
Orthostasis
Decreased exercise tolerance
Precipitation of angina or myocardial infarction unique to this syndrome.

Allen et al[10] first noted this condition in a group of nineteen patients from Australia with chronic
cannabis abuse and cyclical vomiting illness. An earlier case report by de Moore et al[17] described a chronic
cannabis abuser with psychogenic vomiting, which was complicated by spontaneous pneumomediastinum.
Subsequent reports have identified similar clinical presentations[7-9,18]. Given the high prevalence of chronic
cannabis abuse worldwide and the paucity of reports in the literature, clinicians need to be more attentive to the
clinical features of this underrecognised condition.

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pneumomediastinum. Aust N Z J Psychiatry 1996; 30: 290-294
18 Chang YH, Windish DM. Cannabinoid hyperemesis relieved
by compulsive bathing. Mayo Clin Proc 2009; 84: 76-78
S- Editor Li LF L- Editor Kerr C E- Editor Yin DH
Essential for diagnosis:
History of regular cannabis use for years
Major clinical features of syndrome
Severe nausea and vomiting
Vomiting that recurs in a cyclic pattern over months
Resolution of symptoms after stopping cannabis use
Supportive features
Compulsive hot baths with symptom relief
Colicky abdominal pain
No evidence of gall bladder or pancreatic inflammation
Table 2 Clinical diagnosis of cannabinoid hyperemesis

Source: 1266 ISSN 1007-9327 CN 14-1219/R World J Gastroenterol March 14, 2009 Volume 15 Number 10
www.wjgnet.com

There were 1810 deaths from benzodiazepine overdose 1990–1996 according to Home Office Statistics and there are an estimated 1600 benzodiazepine-related traffic accidents with 110 deaths each year in the UK.
C.H. Ashton, Emeritus Professor of psychopharmacology, Newcastle UniversityThe current number of benzo addicts in the UK is estimated at one and a half million although no official figures exist. Many more people are ingesting benzos and are on their way to addiction. Many other ex-addicts have withdrawn but remain damaged. There is no treatment for benzo damage. Post-benzo sufferers are often left to struggle alone, stigmatised and excluded by the Health Service that made them ill.
Mick Behan, Parliamentary Researcher, Submission to the Health Select Committee Enquiry into the Influence ofthe Pharmaceutical Industry 2004

“It is estimated that 1.5 million people’s lives have been destroyed by involuntary tranquilliser addiction leading to long periods of mental ill health. A man whom I met recently had been on tranquillisers for 45 years. Those people want to work, but cannot do so. As far as I am aware, the only primary care trust that has introduced a withdrawal programme is Oldham. Will the Secretary of State encourage his Department and the Department of Health to
study the Oldham model with the aim of getting some of those people off prescription drugs and back to work? That would improve their quality of life, and would reduce the benefits bill as well.”
Jim Dobbin (Heywood and Middleton) (Lab/Co-op) Hansard 31 March 2008

Manslaughter by gross negligence
“Negligence is generally defined as failure to exercise a reasonable level of precaution given the circumstances and so may include both acts and omissions. The defendants in such cases are often people carrying out jobs that require special skills or care, such as doctors who fail to meet the standard which could be expected from them and cause death. In R v Bateman (1925) 19 Cr App.R. 8, the Court of Criminal Appeal held that gross negligence
manslaughter involved the following elements:

1. the defendant owed a duty to the deceased to take care
2. the defendant breached this duty
3. the breach caused the death of the deceased
4. the defendant’s negligence was gross, that is, it showed such a disregard for the life and safety of others as to amount to a crime and deserve punishment.”

Negligence
“Failure to exercise the care toward others which would reasonably be expected of a person in the circumstances,or taking action which a reasonable person would not. Failure to exercise care, resulting in injury to others.”

On 23 February 2009 the Archer report on the 4,800 or so haemophiliacs who were infected with hepatitis C (and around 1,200 who were also infected with HIV) through blood transfusions in the late 1970s and early 1980s was made public. The report plainly sets out the pattern of negligence and injustices of successive governments.
The inquiry was privately funded by donations and received no support from government, either financial or through evidence. At the time of the inquiry’s launch, in February 2007, there had been 1,757 deaths and the number is increasing. The inquiry was set up by Lord Morris of Manchester and chaired
by the former solicitor general, Lord Archer. The report runs to 113 pages and Lord Archer told the press conference that the infection of the haemophiliacs was “the worst treatment disaster in the history of the NHS” and a “horrific human tragedy”. But has there been an even greater disaster with nearly fifty years of tranquilliser over-prescribing by doctors?
As with tranquillisers, the blood scandal campaigners have been religiously rejected by the Department of Health over the years and although some have received a small degree of compensation (tranquilliser victims have received none), little has in fact been done to help them or their families. Some UK families have had nothing because their HIV-infected breadwinners died before 2003. Others live anxious and needy lives because they have been unable to work. Canada and Ireland on the other hand acted much more quickly with more generous financial help and assistance with mortgages and insurance. The report has urged the government to offer a more substantial compensation package with survivors and their families but the Department of Health has so far offered only sympathy and a promise to look at the findings. No-blame assistance could be given though it is nearly 20 years since Virginia Bottomley, as health minister, promised that the needs of haemophiliacs would be kept under constant review. That review has sunk without trace.
The Department of Health also looked at the findings of the 2004-5 Health Select Committee report on the Pharmaceutical Industry, which included criticism of the provision for prescribed Tranquilliser addicts, but then rejected almost all of them. Sympathy is cheap but action and recognition costs money and impacts on the image of the NHS and politicians. The DoH is blame averse and addicted to the avoidance of responsibility and the recognition of avoidable scandals. Charles Dickens summed it up very well:
‘Regard our place [The Circumlocution Office] from the point of view that we only ask you to leave us alone and we are as capital a Department as you will find anywhere…It’s like a limited game of cricket. A field of outsiders are always going to bowl in at the Public Service, and we block the balls…Clennam asked what became of the bowlers? The airy young Barnacle replied, that they grew tired, got dead beat, got lamed, got their backs broken,
died off, gave it up, went in for other games.’ Charles Dickens, Little Dorrit, pp 736, 737

The reality of Benzodiazepines
Benzodiazepines are much more than a question of harm done by the medical profession. There is the crucial fact that successive governments of both parties allowed them to do it. Government and medical dismissal of patient experience as relatively minor and short-term is nothing more than a repetition of false assertions, the original source of which (if it was ever known), has been lost. What cannot be rationally doubted, is the fact that benzodiazepines are frequently seriously
damaging—something which might not be immediately apparent, judging by the truly enormous quantities that doctors have prescribed over the years, both in the UK and in other countries. There were warnings from very early in the life of these drugs that this was so, but the drug companies successfully fought off the findings for nearly thirty years until benzodiazepines were old news. Benzodiazepines might well help some people in the short-term, owing to their properties as hypnotics, anticonvulsants, muscle relaxants, amnesics and anxiolytics. But benzodiazepines have potentially incredibly serious adverse effects made even worse by polypharmacy, excessive dosages and long-term use. Benzodiazepines were largely sold to doctors as being much less toxic than their predecessors the barbiturates but they are a long way from being safe drugs. High doses of benzodiazepines lead to over-sedation. Benzodiazepines impact on the ability to think, make decisions,
and to remember. They make it much harder to learn new information. There are people who have withdrawn from benzodiazepines who find they have lost whole years and decades of their lives. In the elderly, these effects can lead to a false diagnosis of Alzheimer’s disease. In spite of this fact, many occupants of old people’s homes and in the community are regularly prescribed benzodiazepines. The primary effect of benzodiazepines is one of addiction. With regular use for only a few months
or even weeks the body comes to depend on them both psychologically and physically for normal
functioning. As a consequence of this dependence, tolerance develops, so that larger doses are needed to produce the same initial effects. There is clear evidence showing that hypnotic effects are no longer effective after a few weeks and anxiolytic effects after only a few scant months. People unknowingly continue taking them mainly to prevent withdrawal effects. If dosage is insufficient once tolerance has
developed, or if the drug is completely stopped, withdrawal symptoms then develop. This is an important reason why the long-term prescribed feel so ill all the time. The Department of Health stubbornly and perversely ignores this basic scientific truth and has illogically introduced an instalment prescription plan. Quite how doling out prescriptions over days will benefit addicted patients is a question it refuses to
answer. It looks like action and to government that is probably enough of a recommendation, but doctors tempted to give it a try, may well find the ‘problem’ becoming much more noticeable in their surgeries as a result. At present there are over a million long-term prescribed benzodiazepine users in the UK. Several
studies, including those carried out by Newcastle University, have shown from computerised prescribing records, that there are 180 or so such patients in every GP practice. These long-term patients, while continuing their drug use, often suffer from adverse effects and from withdrawal effects afterwards —for
a sizeable proportion this is permanent. Long-term use is commonly accompanied by increasingly diverse illnesses.
“Withdrawal symptoms can last months or years in fifteen percent of long-term users. In some people chronic use has resulted in long-term, possibly permanent disability.” C.H. Ashton 2003

Professor C.H. Ashton, unlike those who advise government behind the scenes, ran an effective benzodiazepine withdrawal clinic from 1982–1994 at Newcastle University. She has described the morbidity in the first 50 consecutive patients who attended. They had been taking prescribed “therapeutic” doses of benzodiazepines for between five and twenty years and had decided to withdraw because they did not feel well while taking the drugs. Of these, 20% suffered from agoraphobia and/or
panic attacks, 10% had had neurological investigations (three for Multiple Sclerosis) and 18% had had gastrointestinal investigations. Backing up the argument that long-term benzodiazepines lead to other prescriptions, she said that 62% of the first group had been prescribed other psychotropic drugs since starting benzodiazepines, the most common being antidepressants. In addition, 28% had been prescribed two benzodiazepines, thereby doubling the addiction potential and the possibility of side effects. Professor Ashton has said categorically that the symptoms which led to the investigations and the polypharmacy, were not the reason for starting benzodiazepines, but developed during long-term use. She has said on several occasions, that there is a likelihood that health for everyone does not
necessarily return to normal after prescriptions cease.

“From the current evidence it appears that the symptoms that are most likely to be long-lasting are anxiety and insomnia, cognitive impairment, depression, various sensory and motor phenomena, and gastrointestinal problems. Tranquilliser drugs undoubtedly cause thought deficits and impair coping abilities. There may be an extended period after the taking of benzodiazepines has ceased when former patients find stressful situations difficult to deal
with, though of course many still taking the drugs have the same experience as well. Something as basic as queuing in a shop, or answering the phone, can often seem a frightening and stressful situation. Complete recovery may require the individual to learn new strategies to replace the years of coping through drugs. For some people whose economic and social circumstances, have been severely impacted, this learning may prove to be
inordinately difficult and sometimes impossible.”
C.H. Ashton, 2003
On any patient leaflet you will find advice saying that anxiety occurring after withdrawal is due to pre-existing symptoms recurring. Indeed it is normally cited by the profession as a reason why most doctors continue prescriptions. Patients who were not prescribed the drugs for clinical anxiety (and that is the majority) know that the self-serving ‘symptoms recurring argument’ is untrue. This can be a Catch
22 situation. Depression is common in long-term benzodiazepine users and patient experience points to the drugs being the cause. Depression also appears when patients withdraw. There may be pharmacological reasons for this but who would not be depressed by the realisation of what had been done to them by what they thought was a safe medicine? Depressive symptoms may appear for the very first time after withdrawal—often some weeks later, and may be severe and protracted for a long
time. Suicide has been reported in some studies. Government maintains a supreme indifference to this benzodiazepine research. Instead it continues a parrot-like repetition of the need to prevent addiction occurring in the first place, ignoring the plight of many thousands of people disabled through medical prescribing.
It will be difficult for most people to believe that members of a highly regarded profession could inflict such damage, but the fact is that most doctors have an affinity with potions, and with the rise of drug company influence, they developed an affinity with the manufacturers of them.

“Doctors prescribe by nature. I had a patient who told me that her doctor had warned her that if she came off her medication she might die. I just saw another patient who was on seventy tablets a day. There are doctors out there who are absolutely committed to prescribing, and if the patient doesn’t get better, they just up the dose.”
Dr Robert Lefever, Director of the Promis Recovery Centre in Kent

It was the psychopharmacalogical era beginning in the late fifties that led to the explosion of medically-induced ill health. Benzodiazepines were pushed by their manufacturers as appropriate for virtually anything. Doctors followed the logic of this advert religiously: “In the face of ill health there is anxiety and where there is anxiety either as a complicating factor or as a cause of illness itself, there is a place for LIBRIUM.”
Today, in spite of this undeniable fact, the UK Department of Health rigidly maintains an illusion that the drugs are always prescribed for clinical anxiety and therefore suffering patients fall within the psychiatric sphere of responsibility. That way, it can say that any psychological problems while taking benzodiazepines or following withdrawal, are due to pre-prescription symptoms returning. They will not engage with the fact that patients, who were given the drugs for other reasons, are as likely to experience the same psychological difficulties as those who were given them for clinical anxiety. Physical side-effects are ignored. It has been claimed that benzodiazepines are the most researched drugs in the world but much of the early research was basic and superficial to say the least, and would not meet today’s standards.

Long-term research has never taken place, either then or subsequently. Patients who took the drugs for years—many for decades—therefore have their claims of health damage ignored and rejected in the face of zero scientific evidence that it did not happen. Between the introduction of benzodiazepines and 2004, Home Office and other figures suggest 17,000 deaths associated with benzodiazepines but as with all official statistics, they may well be an underestimate. In reply to a question from the Parliamentary Health Committee in 2004, Professor Alasdair Breckenridge, the Chairman of the UK drugs regulator stated that he thought there had been
approximately 170 deaths. As Professor Heather Ashton said at the time, this represented 1% of the total and was a gross under-representation on the part of the regulator. There are people who have taken the drugs and claim to have experienced no untoward effects or problems during ingestion or in withdrawal. On one side of the argument about the benefit of benzodiazepines and possible symptoms, there is Professor David Nutt of Bristol University, who believes the downside of benzodiazepines has been over-emphasised and that medics are being unduly
constrained in their use. Nutt outlines his position on benzodiazepines in his paper “The Psychopharmacology of Anxiety”. He recommends prescribing practices that directly contradict the 1988 CSM Guidelines on prescribing and what the Department of Health says is its position. Professor Nutt takes every opportunity to air these views, most recently in a lecture to students and medical staff at Newcastle University. Professor Heather Ashton agrees that some people can withdraw from benzodiazepines with few if any symptoms and that there are probably many reasons why. Personality may play a part and this ultimately has a physical basis, shaped by genetics and environment which determines the “wiring up” of the brain—e.g. the synaptic connections which mediate the ways that individuals have learnt to cope
with anxiety and stress. There is evidence that anxious people have fewer GABA/benzodiazepine receptors in the emotional areas of the brain than more stolid people—so perhaps those without withdrawal symptoms had more GABA receptors to utilise. They may not develop so much benzodiazepine tolerance (down-regulation of GABA/benzodiazepine receptors) and so suffer less rebound of GABA under activity related to withdrawal symptoms. The distribution and sensitivity of these
receptors may vary so that some people may have more physical symptoms in withdrawal while others experience more psychological symptoms. She also says that the nature of withdrawal may depend partly on the type of benzodiazepine used. Withdrawal symptoms are usually worse in those using short acting
and/or potent benzodiazepines such as lorazepam, alprazolam, and clonazepam even if these are withdrawn slowly
A crucial ingredient, seldom if ever, ever mentioned in relation to benzodiazepine withdrawal, is the factor of polypharmacy, which Professor Ashton agrees may also play a part. She says that over 60% of the long-term dependent she saw in her National Health Service Withdrawal Clinic, had also been prescribed other drugs, usually antidepressants, along with the benzodiazepines. Antidepressants, antipsychotics, and morphine-based painkillers, all have side-effects themselves—with symptoms not dissimilar to benzodiazepine withdrawal. Any discussion by anyone on the subject of benzodiazepine withdrawal is therefore necessarily incomplete, if it does not take into account the fact that for many people, benzodiazepine prescriptions led to other drug prescriptions—many of them producing physical dependence. It is often a situation of withdrawing from multi-drug use, rather than single drug use. So, the experience of people who have taken (or who are still taking) benzodiazepines and indeed other mind-altering drugs, varies. There are a number of reasons for the individuality of response, not least, differences in human physical make-up, length of prescription and differences in personal circumstances. A person working in a job, which does not require high-level intellectual thought, or constant decision-making, for instance, may find it altogether easier to avoid the impact of benzodiazepines on cognition.
But there needs to be some sort of true representation for the stories of the very large numbers of UK citizens whose existence has been needlessly harmed and sometimes destroyed by prescribed benzodiazepine addiction. Benzodiazepines are not the only treatment to destroy health and lives as the recent Vioxx disaster and the haemophilia scandal testify. There are strong common elements between
the stories—pharmaceutical company deceit, regulatory inaction, and dogged medical belief in benefit, is common to all. But it is the scale of benzodiazepine prescribing and its longevity that makes this story unique. Benzodiazepines have been prescribed in their billions to millions of patients, based on a jigsaw
of poor and non-existent research, pharmaceutical power, amateur regulation, medical ignorance and disdain, and organised government cover-up.
How are statistics of large benefit and little harm arrived at? What rigorous investigation is it based on? Is it, for instance, based on the absence of complaint to doctors, regulators or drug companies? Is it based on collected endorsements from patients? Or is based on neither of these? Is it, in fact, not a statistic at all—merely another plank in the house built by the indoctrinators? But the desire to believe is strong. It is a sad but observable fact that we look beyond positive claims and assurances only after we have personally met the hidden downside of drugs that ‘help millions’, through our own experience.

Socio-economic cost of benzodiazepine addiction
Benzodiazepines have been a near 50 year horror story for tens of thousands of people in the UK but this medical disgrace has never been addressed. Weak, belated and spasmodic warnings have been issued over the years and they have had the unfortunate side-effect for patients, of allowing government and the benzodiazepine manufacturers to further draw a veil over the historic and ongoing impact of
inappropriate prescribing in the public mind. It is possible to make an argument that much of the medical profession does not fully realise what it has done, given the speed of consultations, the failure of regulators to pass on the horror stories they
have been told, and the distance between the patient in the doctor’s surgery and the patient’s actual life outside it. But above all, it is the chemical ability of benzodiazepines to produce apparent mental instability and engender a belief, not only in doctors but also in patients, that this drug-produced harm is genuine illness that has led to the greatest medical damage. The belief has been fostered among
doctors (and unwittingly by the patients), that the drugs and consequent ones have been necessary. It is simply not true that benzodiazepine injury has ever been addressed.
There are still far too many prescribed addicts in the UK and thousands of former addicts who took the drugs long-term, and as a result are living with ruined health which cannot be rebuilt. Many are living in poverty because of the effects of benzodiazepines. Whole lives have been lost and cannot be relived. Families have
disintegrated, never to reunite. The real severity of benzodiazepine damage has never been officially recognised. In the face of it the Department of Health believes that repeated utterance of statements such as ‘we take the problem seriously’ or ‘our priority is to prevent addiction occurring in the first place’ makes it true for actual and
former patients and is adequate support for those badly in need of it. The debate on benzodiazepines has largely centred on addiction versus efficacy, but addiction
can be seen as only part of the picture—mostly important in relation to the fact that once addicted, patients keep taking them— the far more serious side of the issue centres around what continued addiction often leads to, and its dire effects on general health, thinking abilities, and life. There are extensive costs to the patient and to society, caused by benzodiazepines but not studied by medicine, because their nature is not seen as medical. There are costs produced by benzodiazepines which are medical but which have never been researched, and which are therefore not
recognised by medicine

There are costs to the National Health Service of medical investigations for symptoms which are in reality a result of the effects of benzodiazepines. These costs must be very high indeed, if patient reporting is taken into account, but they are officially unquantified. Investigations for MS, ME, IBS, Arthritis and Thyroid deficiency and other ‘ghost illnesses’ are common—usually the results are negative.
For people taking benzodiazepines and particularly the elderly, there is a much increased risk of accidents. The cause of the accidents, whether occurring in the home, on the road, at work or in a care home is routinely not recognised, but has a cost for the individual beyond the cost to the NHS. There is a great deal of evidence that the unborn are severely affected by the addiction of the mother. The link between benzodiazepines and foetal harm was denied in Parliament in 1999 but it
undoubtedly occurs.
“The developing foetus can be congenitally malformed; it can have heart attacks in the womb. We also know that the newborn baby born to somebody taking benzodiazepines will have difficulty breathing and they would have floppy muscles—what doctors call a ‘floppy baby’ and they may be unduly cold because the temperature regulation, which is so important to a baby, is disrupted…Well I think if any doctor is prescribing benzodiazepines to a pregnant woman, he should check his indemnification status because it is in fact illegal prescribing.”
Robert Kerwin, Professor of Psychopharmacology at the Maudesley Hospital in London, ‘Face the Facts’, BBC Radio 4 1999

Prescribed benzodiazepines can lead to loss of control over actions which means in practice that drug-induced violence occurs in the home involving partners and children. Unwanted pregnancies are another side-effect of the drugs. Inhibition reduction leads to anti-social acts such as theft and vandalism. People end up in gaol because the impact on thought and emotion is not recognised. As Professor Ashton says:
“Benzodiazepines can occasionally cause paradoxical aggression and have been associated with baby-battering, wife-beating and grandma-bashing. They can also cause depression and can precipitate suicide in depressed patients. They should not be used in depression although they are still commonly prescribed long-term for depressed and anxious patients. They can also cause emotional blunting and apathy, with inability to cope with the needs of children and family, an effect bitterly regretted by many long-term users.”

Benzodiazepines cause job loss either whilst taking them or while attempting to withdraw. Not everyone loses their job of course but a significantly large number do, and it is not surprising, given the deadening effects of the addiction and the high number and severity of possible withdrawal effects. This effect on the individual and on families is totally ignored by government. In 2004 the Chief Medical
Officer, Professor Liam Donaldson, reminded doctors of their continuing over-prescribing. He referred to the cost to the NHS of the drugs themselves, but made no mention of the costs to the individual. There is a large financial impact to the state generally, which benzodiazepine addiction is responsible for. People who are unable to work pay no taxes or national insurance. Their spending power is curtailed and therefore they pay less VAT. Addicted and unemployed the benzodiazepine dependent make very little contribution to the economy. Although many iatrogenic benzodiazepine addicts are to all intents and purposes disabled, few receive disability benefits. Thousands do receive incapacity benefit at a lower figure, because of the length of their ‘illness’, and this is of course a drain on the national economy. Many iatrogenic victims have not worked for decades. Perhaps the biggest loss for a proportion of the dependent (and who knows how big this proportion is) is the loss of choice. They cannot choose to buy a house or might lose a house because of
the drug effects. They cannot take holidays or buy a new car. They cannot socialise or take up hobbies because of induced anxiety and the inability to concentrate and think clearly. Some discover after they have withdrawn from the drugs that they never left the house or indeed a room, for years because of benzo-induced agoraphobia—prisoners because of drug prescriptions. There is much exhortation from government these days about the need to build up personal pensions to maintain a secure lifestyle in retirement—we are all living longer and the state is becoming
more hard-pressed to finance pensioners. There are thousands, addicted for decades to benzodiazepines, who feel assaulted anew when they hear that message. Through state avoidance of responsibility for health protection, they had no chance to build up a personal pension, leaving them entirely dependent on the state for the future. What a supreme irony it is then, that at a time when the state is telling everyone that the state pension is completely inadequate and that they should save for a personal one, there are many condemned to poverty through state inactivity and denial.
The most insidious effect of the drugs in the estimation of many is the effect the drugs have had on their family. The family was not prescribed the drugs but it was as certainly and indelibly marked as the taker. The lack of emotional response due to benzodiazepines is something a child does not understand and may never understand, even as an adult. The life chances of children of the unemployed
and sick iatrogenic addict are necessarily reduced and their emotional needs may remain unsatisfied, leading to problems for them later in life. It can be very difficult afterwards to re-establish relationships between a formerly addicted parent and children. Where does the patient find closure in the face of orchestrated denial, lack of government recognition and help, and a spirit within the medical profession that sees each new drug as a wonder drug, taking decades each time before it exercises control? The three components of continuing good health are psychological, physical and social. Benzodiazepines have a three-pronged negative effect on health—the effects of taking of them, the realisation afterwards of the impact they had on a life and the realisation for the individual that they are powerless to achieve recognition. It is a deep and genuine kind of grief which is not in the annals of medicine. Within the present political, legal and medical structures, there is little hope of closure.

A Selection of Informed Comments on Tranquillisers
“Thousands of people could not possibly invent the bizarre symptoms caused by therapeutic use of benzodiazepines and reactions to their withdrawal. Many users have to cope, not only with a frightening range of symptoms, but also with the disbelief and hostility of their doctors and families. It is not uncommon for patients to be “struck off” if they continue to complain about withdrawal symptoms. Even when doctors are concerned and understanding about the problem, they often have little knowledge of withdrawal procedure, even less about
treatment…”
Trickett S, Withdrawal from Benzodiazepines, Journal of the Royal College of General Practitioners 1983; 33: 608

“The medical profession took nearly 20 years from the introduction of benzodiazepines to recognise officially that these minor tranquillisers and hypnotics were potentially addictive. The ‘happiness pills’, which had been propping up a fair proportion of the adult population since the early 1960s, were found to have an unexpectedly bitter aftertaste: doctors and patients alike were unprepared for the problems of dependence and withdrawal that are
now known to be common even with normal therapeutic doses.”
Editorial (Anon), The Benzodiazepine Bind, The Lancet, 22 September 1984, 706

“There’s certainly a problem, the NHS are concerned. The NHS spends about £40 million per annum on these drugs. There are a substantial number of people who do suffer from this problem long-term. I know that the withdrawal symptoms can be agonising for some people and can be very difficult indeed.”
John Patten, Health Minister, 1984

“In the UK, 11.2% of all adults take an anti-anxiety drug at some time during any one year. But over a quarter of these people (3.1% of all adults) are chronic users, taking such medication every day. Even at a conservative estimate, 20% of these will develop symptoms when they attempt to withdraw. That means a quarter of a million people in the UK. The sooner the medical profession faces up to its responsibilities towards these iatrogenic
addicts, the sooner it will regain the confidence of the anxious members of our community.”
M.H. Lader, Anna C. Higgitt, Management of benzodiazepine dependence, Update 1986, Brit J Addiction, 1986, 81, 7–10

“The benzodiazepines are probably the most addictive drugs ever created and the vast army of enthusiastic doctors who prescribed these drugs by the tonne have created the world’s largest drug addiction problem.”
Dr Vernon Coleman, ‘The Drugs Myth’, 1992

Dear Mr Haslam,
Thank you for your recent letter regarding Benzodiazepine Tranquillisers. Dawn Primarolo and myself have been taking up cases and have advised on how best the groups involved might organise a parliamentary lobby and keep attention on these issues. We have also tried to assist through both Parliamentary Questions and raising the matter on the floor of the House, in pushing the Government to accept its own responsibilities and to take action now to ensure that it does not happen again.

This is something we will be returning to both in the House and in terms of our own future policy development. I am passing your letter to Paul Boateng who, as the legal affairs spokesman, has specific responsibility for the litigation side of what is a national scandal.
David Blunkett MP, Shadow Secretary of State for Health,
24 February 1994

“…the risks [of benzodiazepines] were always obvious and…the providers of medicine between them, readily let this happen.”
Charles Medawar, Social Audit, Power and Dependence 1991

They [benzodiazepines] are very effective at relieving anxiety, but we now know that they can be addictive after only four weeks regular use. When people try to stop taking them they may experience unpleasant withdrawal symptoms which can go on for some time. These drugs should be only used for short periods, perhaps to help during a crisis. They should not be used for longer-term treatment of anxiety.
The Royal College of Psychiatrists, July 2001

“Benzos are responsible for more pain, unhappiness and damage than anything else in our society.”
Phil Woolas MP, Deputy Leader of the House of Commons and Local Government Minister, Oldham Chronicle, February 12 2004

Parallels
“My family believe my brother was murdered, and I stick by that.”
Brother of Blood Transfusion Victim, Daily Telegraph, February 23, 2009
Interviewer: I don’t want to sensationalise this Susan but, in the last couple of minutes, you’ve actually accused doctors of murder. Campaigner Sue Bibby: Well I think that they do have a case to answer – it would be very nice if one or two of them would actually stand up and speak.
Talk Radio UK Interview on Tranquillisers with Mike Dicken and Susan Bibby
December 5, 1998

Is one scandal greater than the other, a larger case of inertia and unconcern? A scandal is a scandal, both are sizeable and have involved a large number of deaths, both have involved government inaction, but the 48 year benzodiazepine scandal must be seen as the greater if only for its longevity and absence of recognition. The heyday of vast tranquilliser over-prescribing took place in the 1970s and 1980s. The 4,800 or so haemophiliac victims received their contaminated blood at that time. But the tranquilliser scandal rolled on and new addicts are still, without warnings, being created today.

“The Department of Health fails even to collect figures that might be considered unpalatable.”
Alice Miles, The Times, July 4 2007

“[Benzodiazepines] have been prescribed for sports injuries, muscle spasms, premenstrual tension, exam nerves, depression, general malaise and much else…”
Professor C.H. Ashton, Bristol and District Tranquilliser Project AGM, October 2005

The benzodiazepine story has many unique qualities and the Department of Health has developed a policy of no-admission and steadfast denial. Instead of action it has:
•Routinely insisted that its priority is “to prevent addiction occurring in the first place” in the face of much evidence of injury and the fact that those injuries have been occurring for nearly half a century. Crucially, it also maintains that doctors must be free to exercise clinical judgement, even when that judgement (as in the case of David Nutt) is likely to increase addiction and harm.

•It has made no effort to commission research into the wide variety of injuries reported by patients and sticks rigidly to the message that tranquilliser addiction is a mental health problem when in fact it is a problem of chemical addiction with physical responses to that addiction.

•It has left campaigners to provide detailed information on the scale and nature of the problem but has not accepted it; neither has it made any attempt to investigate and provide its own data.

•It has always insisted that treatment and withdrawal assistance is available when it has been shown to be non-existent and in the knowledge that prescribers who addicted patients have little interest in the addiction or the expertise to assist.

•It has consistently evaded all responsibility for the situation, preferring historically to blame it on prescribers, though lately it has moved towards the blaming of patients and stigmatising them as drug misusers. Medical and government defence of the benzodiazepine scandal has moved through several stages, not necessarily in this order and not necessarily one at a time. Sometimes previous positions are
resurrected:

•The drugs are not addictive
•And if they are, it is because of an addictive personality
•Patients ask for them
•Patients bully doctors into prescribing
•The drugs are cheap to provide for government
•Doctors have no time to assist in withdrawal/doctors find it very difficult
•There are no alternatives to pills in UK healthcare
•Aware or former iatrogenic addicts are merely seeking compensation
•It’s all down to defective genes
•It’s all in the past, it was regrettable but we have learned lessons
•Patients abuse the drugs and must be controlled
•Benzo campaigners select their evidence

In 1988 the Committee on the Safety of Medicines issued 4 week prescribing Guidelines to doctors but these were never seriously followed up and the CSM had no remit to discover whether they were being followed. There was no plan to audit the number of patients on individual prescriber lists who had already exceeded the Guidelines and offer withdrawal assistance. Hence there are tens of thousands of
people today who have been taking tranquillisers for decades without knowledge that their life is being harmed.

“GPs will be asked to trawl through their patients’ records to identify those most at risk of developing cardiovascular disease and call them in for an assessment, the National Institute for Health and Clinical Excellence proposed today.
The Guardian in June 2007

Hearing the victims of the haemophilia scandal speak is like a rerun of the tranquilliser scandal: “I would just like to see someone apologise, but they won’t do it because they think they will be subject to criminal actions.” “One of the reasons the government had been so successful in keeping the whole thing silent was because there
were so few people willing to stand in public and campaign.” “People say move on with your life, but that’s hard if you have had no resolution and you are surviving on £59 a
week.” “We need an apology, just the acknowledgement that this happened and it shouldn’t have happened. I don’t think they realise how much that means to people.”
“People need to be able to live comfortably without having to go cap in hand to the local authority or a fund whenever they need the slightest thing. All we are asking for is to be able to live with decency and dignity.”

Tranquilliser victims
“[But] for a large proportion of those on incapacity benefit—half of them claiming for five years or longer—the benefit is a (cheap) compensation for the fact that they have no future. And never will have…”
Yvonne Roberts, Where’s the Benefit? The Guardian, February 6 2008

Tranquilliser victims have received no recognition, no support, no apologies, no compensation and no closure—and this in spite of the fact that so many of them cannot work, have no pensions or security and live with ruined health because there is no agonist for the damage inflicted. Many victims do receive state benefits and the government refuses to investigate how many of those on benefits are there because of the drugs, but benefits are not large and do not represent security. In fact because the Department of Works and Pensions, reliant on Department of Health information, does not take benzodiazepine injury seriously, the victims live constantly with the fear of losing those benefits. The Archer report acknowledges how the extraordinary financial burden of long term ill-health had been placed upon people who had lost their jobs, lost their insurance and, as has so often been the case, lost the breadwinners in their families. There has been no such acknowledgement in the case of tranquillisers. In this horror story the victims have been left to their own devices.

•Government has allowed health, social and economic destruction through addiction to take place and still allows it.
•Government knows what has happened and avoids recognition of it.
•Government has left many to wither on benefits and has made no attempt at rehabilitation.
•Government now believes as part of its political struggle with other parties that such people can continue to remain unrecognised and can be viewed in exactly the same light as every other benefit claimant.

Tranquilliser Quotes

“…apart from people’s physical health going down (although luckily, some people seem to be able to stand up to that), they are described by their families as being “Jekyll and Hyde”. Agoraphobia (not being able to go out) is a very, very common symptom which very few people actually have before they’re given the drugs – sometimes they might have it, but mostly they don’t have it until they’ve been put on the drugs. This of course makes them [the
patients] incapable of doing anything much. They can’t go out to the local shops, they can’t look after their children properly; they are very distressed by this and feel it’s their own fault. Usually they go back to the GP and the GP will say: “Oh you’re an anxious personality and that’s what’s wrong with you,” and they usually give them more benzodiazepines, or other antidepressant drugs as well.
Sue Bibby Talk Radio UK Interview with Mike Dicken and Susan Bibby December 5, 1998

“In fact the drug was poisoning my central nervous system. Emotionally I felt numb…Those pills cheated me of myadult life – I lived like a robot…”

“….After 30 years of tranquillisers mixed with a variety of anti-depressants, the mother-of-six says the drugs have left her physically and mentally handicapped. Over the years Mrs Dixon’s health has deteriorated and she has suffered a host of problems including panic attacks, muscle weakness, mood swings, bowel problems, nausea and severe pelvic pain. Her condition has left her unable to leave her home for the past 10 years and watch her children
and 20 grandchildren growing up….”

“One Barnet woman, who wanted to remain anonymous, says she was left housebound after being addicted to benzodiazepines for more than 20 years. She was originally prescribed the drugs for a stomach upset, but now suffers thyroid problem, asthma, ME and leg pain so severe she can hardly walk – all of which she attributes to the drugs.”
Hendon & Finchley Times August 2003

“I was prescribed Lorazepam at 16. I am now aged 44 and have been off tranquillisers for two years, after a GP suggested that I had perhaps been on them too long! After suffering most of my life with Agoraphobia and Panic Attacks, I cannot believe that this drug is still manufactured. It is high time the drug companies were held accountable and something positive was done. How many people have to lose their quality of life and battle so hard, with little help to regain it, before someone says stop.”
The Tranquilliser Trap, May 2001

“If the government knows these drugs to be harmful why are they allowing them to be dispensed? Why have they not implemented resources to help patients come off the drugs? It takes more than a guideline…the problem will not go away…indeed it will not ‘die’ off which is one method some GPs are using to reduce their prescriptions, i.e. they are waiting for those patients who have been addicted for 20+ years to die because it is easier to give a 2
minute prescription rather than seeing a demanding patient for 20 minutes a visit every day until they get what they demand.”
The Tranquilliser Trap, May 2001

“I believe I am one of the longest addicts of Lorazepam, I started taking them in 1974 following a car accident and finished taking them in 2000 (26 years). I was 18 when I was first prescribed them and the effect upon my life has been devastating, like others I thought I was going out of my mind, a fact my doctor was only too willing to agree with…I am forty five and I can’t remember what it was like when I was 18, I can’t remember a time when my life was
not governed by fear. I may function in society, but that does not mean I can lead a normal life. However I find that the medical profession believes that now I no longer take these drugs that I am back to full fitness…I was offered no support from anywhere and yet if I was a Heroin addict, I would have had masses of help and support.” The Tranquilliser Trap, May 2001

“There are people out there…who are hooked, unknowingly, unwillingly, and they feel that society has ‘chucked them overboard’. They feel they no longer belong anywhere. They feel they’ve lost such a lot, that they can no longer regard themselves as fully human.”The Tranquilliser Trap, May 2001

Source: Published in Daily Dose 4th April 2009 Colin Downes-Grainger 25 .02.2009

BackgroundStreet drugs known as ‘ecstasy’ have been sold for
about 20 years in the UK. The active substance that
such tablets contain – or purport to contain – is
3,4-methylenedioxymethamphetamine (MDMA).
Shortly after consumption, MDMA releases
chemicals in the brain that tend to bring about
a sense of euphoria, exhilaration and increased
intimacy with others. It is thought to be the third
most commonly used illegal drug in the UK after
cannabis and cocaine, with estimates suggesting
that between 500,000 and 2 million tablets are
consumed each week. Most people who take
ecstasy also use other legal and illegal drugs,
sometimes at the same time. Ecstasy is commonly
taken in nightclubs and at parties and is very often
associated with extended sessions of dancing.
Along with the pleasurable effects sought by users
of MDMA, it has become clear that the drug can
cause a range of unintended harms. In the short
term, a range of adverse events have been reported
– some fatal – and consumption of MDMA may
also have long-term consequences, especially with
regard to users’ mental health.
Objectives
This review aims to address the question: ‘What
are the harmful health effects of taking ecstasy
(MDMA) for recreational use?’ It does not examine
the harmful indirect and/or social effects, such as
effects on driving and road traffic accidents and
the consequences of any effect MDMA may have on
sexual behaviour.

Previous research syntheses
(Level I evidence)
For each identified Level I synthesis, it was difficult
to ascertain the exact methods adopted and
evidence included. Three reviews reported worse
performance for ecstasy users compared to controls
in a variety of neurocognitive domains (attention,
verbal learning and memory, non-verbal learning
and memory, motor/psychomotor speed, executive
systems functioning, short- and long-term
memory). A fourth study reviewed self-reported
depressive symptoms and found that ecstasy users
had increased levels compared to controls. The
final synthesis was primarily concerned with the
acute intoxication effects of ecstasy rather than
health harms. In all analyses, the effect sizes seen
were considered to be small.
Controlled observational
studies (Level II evidence)
Of the 110 controlled observational studies
included, there was one prospective study, the
Netherlands XTC Toxicity (NeXT) study, which
recruited a cohort of participants likely to start
using ecstasy and followed them for a year. Those
who started using ecstasy were then compared to
a group of matched controls who had remained
ecstasy-naïve. Ecstasy-exposed participants had
poorer performance in some memory tests,
although the absolute test scores for both cohorts
were comfortably within the normal range.
Other tests suggested an association between
ecstasy exposure and certain aspects of sensation seeking,
but there was no evidence of an effect on
depression or impulsivity. The cumulative dose of
ecstasy consumed was small (median 3–6 tablets).
The remaining Level II evidence consisted of cross sectional
studies only. Data were directly pooled
for seven individual outcomes. Six were common
measures of immediate and delayed verbal recall,
in which ecstasy users performed significantly
worse than polydrug controls. Effect sizes appeared
to be small, with the mean scores for each group
falling within the normal range for the instrument
concerned. No difference was seen between ecstasy
users and polydrug and drug-naïve controls in the
remaining measure, IQ.
A total of 915 outcome measures were grouped
into broad outcome domains as suggested in
the literature and after consultation with expert
advisers. For 16 of these meta-outcomes, there
were sufficient data for meta-analysis: immediate
and delayed verbal and visual memory, working
memory, sustained and focused attention, three
measures of executive function (planning, response
inhibition and shifting), perceptual organisation,
self-rated depression, memory, and anxiety and
impulsivity measured objectively and subjectively.
Ecstasy users performed significantly worse than
polydrug controls on all outcome domains with
the exception of executive function (response
inhibition and shifting) and objective measures of
impulsivity. Fewer comparisons were possible with
drug-naïve controls, with statistically significant
effects seen for verbal and working memory and
self-rated measures of depression, memory and
impulsivity. With both control groups, former
ecstasy users frequently showed deficits that
matched or exceeded those seen among current
users.
The small effect sizes seen were not consistently
modified by any study-level demographic variables.
There was little evidence of a dose–response
effect: studies reporting heavier average use
of ecstasy did not provide more extreme effect
measures than those consisting of lighter users,
and there was no demonstrable effect of length
of abstinence from ecstasy. When assessing the
impact of inter-arm differences on results, no
consistent effect was seen for imbalances in age
or gender. However, in several cases, it appeared
that imbalances in intelligence between cohorts
may have been important. Use of other drugs also
appeared to modify effects: alcohol consumption
proved the most consistent effect modifier, with
increased exposure in ecstasy-exposed populations

apparently reducing the magnitude of deficits
across a range of neurocognitive outcomes.
For the remaining outcome domains, there
were insufficient data for quantitative synthesis
and the results were summarised narratively.
For psychopathological symptoms, there was a
significant deficit for ecstasy users compared to
polydrug controls in the obsessive–compulsive
domain only, with greater deficits seen in
comparison to drug-naïve controls. In a few studies,
ecstasy users have been shown to have higher
levels of subjectively rated aggression than drug naïve
controls. It was not possible to draw clear
conclusions about the possible effects of ecstasy
consumption on dental health, loneliness, motor
function or sleep disturbance.
Case series and case reports
(Level III evidence)
Registry data from the np-SAD and GMR are not
directly comparable due to differences in data
sources and recording of drug use. The GMR
(1993–2006) suggests that there were, on average,
17 deaths a year where ecstasy was recorded as the
sole drug involved (2.5% of all deaths ascribed to a
single drug) and another 33 per year where it was
reported as co-drug use. Ecstasy-associated deaths
appear to have increased up to 2001 but to have
stabilised thereafter. In the 10 years to 2006, the
np-SAD recorded an average of 50 drug-related
deaths in which ecstasy was present (69 in 2006; 5%
of the total for the year). Ecstasy was believed to be
the sole drug implicated in an average of 10 deaths
annually over the same time period. According to
this registry, the typical victim of an ecstasy death
is an employed white male in his twenties, who
is a known drug user co-using a number of other
substances. Nearly half of ecstasy-related deaths
occur on a Saturday or Sunday night.
Published case series and case reports document
a wide range of fatal and non-fatal acute harms,
often very selectively. Two major syndromes
are most commonly reported as the immediate
cause of death in fatal cases: hyperthermia (with
consequences including disseminated intravascular
coagulation, rhabdomyolysis and acute liver and
renal failure) and hyponatraemia (commonly
presenting with confusion and seizures due to
cerebral oedema). Ecstasy users presenting with
hyponatraemia have invariably consumed a large
amount of water. We found 41 deaths relating to
hyperthermia reported in the literature and 10
from hyponatraemia (all women).
Other acute harms associated with fatal cases
include cardiovascular dysfunction, neurological
dysfunction (seizures and haemorrhage) and
suicide. Acute renal failure and sub acute liver
failure can occur without association with
hyperthermia. All these presentations were also
seen in non-fatal cases, alongside an additional
range of symptoms including acute psychiatric
effects, urinary retention and respiratory
problems including pneumothorax and
pneumomediastinum.
There are difficulties in estimating taken dose
of MDMA from the available literature, and it is
not clear why some people seem to have acute,
even fatal, reactions to doses that are commonly
tolerated in others.
Discussion
The evidence we identified for this review
provides a fairly consistent picture of deficits in
neuro-cognitive function for ecstasy users compared
to ecstasy-naïve controls. Although the effects
are consistent and strong for some measures,
particularly verbal and working memory, the effect
sizes generally appear to be small: where single
outcome measures were pooled, the mean scores of
all participants tended to fall within normal ranges
for the instrument in question and, where multiple
measures were pooled, the estimated effect sizes
were typically in the range that would be classified
as ‘small’.
However, there are substantial shortcomings in the
methodological quality of the studies analysed.
Because none of the studies was blinded, observer
or measurement bias may account for some of
the apparent effect. There is a suggestion of
publication bias in some analyses, and we saw clear
evidence of selective reporting of outcomes.
Selection bias is an inevitable problem: due to the
observational nature of all relevant evidence, there
is no guarantee that the cohorts being compared
were not subject to differences in areas other than
exposure to ecstasy. This effect will have been
exaggerated in those studies comparing ecstasy exposed
participants to drug-naïve controls; in
these instances, it is impossible to isolate the effect
of ecstasy exposure from the impact of other
substances. Within-study imbalances in intelligence
and the use of other substances, particularly
alcohol, appeared to explain some of the effects
seen. We suggest that the apparently beneficial
Methods
The following databases were searched using
a comprehensive search syntax: MEDLINE,
EMBASE, PsycINFO (run 19 September 2007)
and Web of Knowledge (run 7 October 2007).
The search outputs were considered against pre specified
inclusion/exclusion criteria; the full text
of all papers that could not confidently be excluded
on title and abstract alone was then retrieved and
screened. Only studies published in English were
included. Meeting abstracts were included only
if sufficient methodological details were given
to allow appraisal of study quality. Studies were
categorised according to a hierarchy of research
design, with systematic research syntheses (Level
I evidence) being preferred as the most valid and
least open to bias. Where Level I evidence was
not available, controlled observational studies
(Level II evidence) were systematically reviewed. If
neither Level I nor Level II evidence was available,
uncontrolled case series and case reports (Level
III evidence) were systematically surveyed. Data
extraction was undertaken by one reviewer and a
sample checked by a second.
Synthesising Level II evidence posed substantial
challenges due to the heterogeneity of the included
studies, the number and range of outcome
measures reported, the multiplicity of comparisons
(differing ecstasy exposures, differing comparator
groups) and outcomes, repeated measures and
the observational nature of the data. Analyses
were stratified for current and former ecstasy
users, with separate analyses for control groups
using other illegal drugs but not ecstasy (polydrug
controls) or controls naïve to illegal drugs (drug naïve
controls). Random-effects meta-analyses were
used throughout. Heterogeneity was also explored
through study-level regression analysis (meta regression).
Where a sufficient number of studies
had reported identical outcomes, they were meta analysed
on their original scale. Other outcome
measures were grouped into broad domains
and effect sizes expressed as standardised mean
differences in order to combine data derived from
multiple instruments. Objective and self-reported
outcome measures within each domain were
analysed separately.
For the Level III evidence, only narrative synthesis
was possible.
Results
Of 4394 papers identified by our searches, 795
were reviewed in full and 422 met the inclusion
criteria. Five systematic syntheses, 110 controlled
observational studies and 307 uncontrolled
effect of alcohol consumption may be explained
in two ways: either alcohol may mitigate the
hyperthermic effects of ecstasy in the acute setting,
attenuating damage to the brain, or ecstasy users
who co-use alcohol may represent a population of
more casual ecstasy takers than those who tend not
to drink.
Although the NeXT study suggests that small
deficits in memory may be secondary to ecstasy
exposure, all other included studies were
cross-sectional in nature; without evidence of
the temporal relationship between exposure
and outcome, it is difficult to draw any causal
inferences.
We did not find any studies directly investigating
the quality of life of participants, and we found
no attempts to assess the clinical meaningfulness
of any inter-cohort differences. The clinical
significance of any exposure effect is thus
uncertain; it seems unlikely that these deficits
significantly impair the average ecstasy user’s
everyday functioning or quality of life. However,
our methods are unlikely to have identified
subgroups that may be particularly susceptible
to ecstasy. In addition, it is difficult to know how
representative the studies are of the ecstasy-using
population as a whole. Generalising the findings is
therefore problematic.
Ecstasy is associated with a wide range of
acute harms, but remains a rare cause of death
when reported as the sole drug associated with
death related to drug use. Hyperthermia and
hyponatraemia and their consequences are the
commonest causes of death, but a wide range of
other acute fatal and non-fatal harms are reported.
Due to the poor quality of the available evidence, it
is not possible to quantify the risk of acute harms in
any meaningful way.
Research recommendations
Large, population-based, prospective studies are
required to examine the time relationship between
ecstasy exposure and neuro-cognitive deficits and
psychopathological symptoms.
Further research synthesis of the social and other
indirect health harms of ecstasy would provide a
more complete picture. Similar synthesis of the
health harms of amphetamines generally would
provide a useful comparison.
Future cross-sectional studies will only add to the
evidence-base if they are large, as representative as
possible of the ecstasy-using population, use well validated
outcome measures, measure outcomes
as objectively as possible with researchers blind
to the ecstasy-using status of their subjects, report
on all outcomes used, and provide complete
documentation of possible effect modifiers.
Cohorts should be matched for baseline factors,
including IQ and exposure to alcohol.
The heterogeneity of outcome measures used by
different investigators is unhelpful: consensus on
the most appropriate instruments to use should be
sought. Investigators should collect data directly
reflecting the quality of life of participants and/or
attempt to assess the clinical meaningfulness of any
inter-cohort differences.
A registry of adverse events related to illegal
intoxicants presenting to medical services (akin to
the ‘yellow card’ system for prescription medicines)
would enable useful estimation of the incidence of
harmful effects of ecstasy in comparison to other
substances.
Future case reports of acute harms of ecstasy are
unlikely to contribute valuable information to the
evidence-base. Where novel findings are presented,
care should be taken to report toxicological
findings confirming the precise identity of the
substance(s) consumed by the individual(s) in
question.

Source: Rogers G, Elston J, Garside R, Roome C, Taylor
R, Younger P, et al. The harmful health effects
of recreational ecstasy: a systematic review of
observational evidence. Health Technol Assess
2009;13

Approximately 36% of East Asians (Japanese, Chinese, and Koreans) show a characteristic physiological response to drinking alcohol that includes facial flushing , nausea, and tachycardia [1] . This so-called alcohol flushing response (also known as “Asian flush” or “Asian glow”) is predominantly due to an inherited deficiency in the enzyme aldehyde dehydrogenase 2 (ALDH2) [2]. Although clinicians and the East Asian public generally know about the alcohol flushing response (e.g., http://www.echeng.com/asianblush/), few are aware of the accumulating evidence that ALDH2-deficient individuals are at much higher risk of esophageal cancer (specifically squamous cell carcinoma) from alcohol consumption than individuals with fully active ALDH2. This is particularly unfortunate as esophageal cancer is one of the deadliest cancers worldwide [3], with five-year survival rates of 15.6% in the United States, 12.3% in Europe, and 31.6% in Japan [4] Our goal in writing this article is to inform doctors firstly that their ALDH2-deficient patients have an increased risk for esophageal cancer if they drink moderate amounts of alcohol, and secondly that the alcohol flushing response is a biomarker for ALDH2 deficiency. Because of the intensity of the symptoms, most people who have the alcohol flushing response are aware of it. Therefore clinicians can determine ALDH2 deficiency simply by asking about previous episodes of alcohol-induced flushing. As a result, ALDH2-deficient patients can then be counselled to reduce alcohol consumption, and high-risk patients can be assessed for endoscopic cancer screening. Based on the sizes of the Japanese, Chinese, and Korean populations and the expected frequency of ALDH2-deficient individuals in each [1], we estimate that there are at least 540 million ALDH2-deficient individuals in the world, representing approximately 8% of the population. In a population of this size, even a small reduction in the incidence of esophageal cancer could result in a substantial reduction in esophageal cancer deaths worldwide.

Summary Points

ALDH2 eficiency resulting from the ALDH2 Lys487 allele contributes to both the alcohol flushing response and an elevated risk of squamous cell esophageal cancer from alcohol consumption.
Knowledge of the flushing response is useful clinically, as it allows doctors to identify their ALDH2-deficient patients in a simple, cost-effective, and non-invasive manner.
Doctors should counsel their ALDH2-deficient patients to limit alcohol consumption and thereby reduce the risk of developing esophageal cancer.
In view of the approximately 540 million ALDH2-deficient individuals in the world, many of whom now live in Western societies, even a small percent reduction in esophageal cancers due to a reduction in alcohol drinking would translate into a substantial number of lives saved.

A Primer on the Genetics of Alcohol Metabolism

Ethanol is first metabolized primarily by alcohol dehydrogenase (ADH) into acetaldehyde (Figure 2), a mutagen and animal carcinogen that causes DNA damage and has other cancer-promoting effects [5–7]. Acetaldehyde is subsequently metabolized to acetate, mainly by the enzyme ALDH2 [8]. In East Asian populations there are two main variants of ALDH2, resulting from the replacement of glutamate (Glu) at position 487 with lysine (Lys) [9]. The Glu allele (also designated ALDH2*1) encodes a protein with normal catalytic activity, whereas the Lys allele (ALDH2*2) encodes an inactive protein. As a result, Lys/Lys homozygotes have no detectable ALDH2 activity. Because the Lys allele acts in a semi-dominant manner, ALDH2 Lys/Glu heterozygotes have far less than half of the ALDH2 activity of Glu/Glu homozygotes; in fact, the reduction in ALDH2 activity in heterozygotes is more than 100-fold [8].

Alcohol consumed by ALDH2-deficient individuals is metabolized to acetaldehyde, which accumulates in the body due to absent ALDH2 activity and results in facial flushing, nausea, and tachycardia [2]. These unpleasant effects are the result of diverse actions of acetaldehyde in the body, including histamine release [10]. Because of the intensity of this unpleasant response, ALDH2 Lys/Lys homozygotes are unable to consume significant amounts of alcohol. As a result, they are protected against the increased risk of esophageal cancer from alcohol consumption [11]. This observation also provided evidence for a causative role for ethanol in esophageal cancer, and a key role for acetaldehyde in mediating this effect [11].
ALDH2 Lys/Glu heterozygotes experience a less severe manifestation of the flushing response due to residual but low ALDH2 enzyme activity in their cells. As a result, some are able to develop tolerance to acetaldehyde and the flushing response and become habitual heavy drinkers, due in part to the influence of societal and cultural factors (see below). Therefore, paradoxically, it is the more common low-activity ALDH2 heterozygous genotype that is associated with greatest risk of esophageal cancer from drinking alcohol.

Evidence That ALDH2 Deficiency Increases the Risk of Alcohol-Related Squamous Cell Esophageal Cancer
Following the first study [12], which was conducted in the Japanese population, case control studies in Japan and Taiwan have consistently demonstrated a strong link between the risk of esophageal squamous cell carcinoma and alcohol consumption in low-activity ALDH2 heterozygotes, with odds ratios (ORs) ranging from 3.7 to 18.1 after adjustment for alcohol consumption. Moreover, most studies show ORs of over 10 for increased risk in heterozygotes who are heavy drinkers [13,14]. An independent meta-analysis has also confirmed an increased risk, even among moderate drinking heterozygotes [11]. In the Japanese and Taiwanese studies, a strikingly high proportion (58%–69%) of the excessive risk for esophageal cancer is attributable to drinking by low-activity ALDH2 heterozygous individuals [13,14].
Consistent with the results of case control studies, prospective studies in cancer-free alcoholics have also shown that the relative hazard for future upper aerodigestive tract (UADT) cancers in low-activity ALDH2 heterozygotes is approximately 12 times higher than in individuals with active ALDH2 [15]. (The UADT includes the oral cavity, pharynx, larynx, and esophagus.) In addition, alcohol consumption in low-activity ALDH2 heterozygotes has been associated with other cancer-related outcomes, including the presence of multiple areas of esophageal dysplasia (i.e., premalignant lesions) and multiple independent UADT cancers [13].
It is important to note that ALDH2 deficiency does not influence esophageal cancer risk in non-drinkers [11]. Furthermore, the magnitude of the ALDH2-associated esophageal cancer risk depends on the relative importance of alcohol versus other risk factors in a given population. In rural areas of China, where there is a high rate of esophageal cancer but alcohol drinking plays a less important role than in Japan and Taiwan, there is a more modest positive association (ORs, 1.7 to 3.1) between low-activity ALDH2 heterozygotes and esophageal cancer risk (e.g., [16]).
Acetaldehyde Is Responsible for Facial Flushing and Esophageal Cancer Risk in ALDH2-Deficient Individuals Top
Acetaldehyde is responsible for the facial flushing and other unpleasant effects that ALDH2-deficient individuals experience when they drink alcohol [10]. Importantly, there is now direct evidence that ALDH2-deficient individuals experience higher levels of acetaldehyde-related DNA and chromosomal damage than individuals with fully active ALDH2 when they consume equivalent amounts of alcohol, providing a likely mechanism for the increased cancer risk. A study in Japanese alcoholics [17] showed that the amount of mutagenic acetaldehyde-derived DNA adducts (Figure 4) in white blood cells was significantly higher in ALDH2-deficient heterozygotes than in individuals with active ALDH2 (Table 1). In this study, while the two groups were matched for alcohol consumption, the ALDH2-deficient group consumed slightly less alcohol on average than the controls. Also, ALDH2 heterozygotes who drank alcohol had higher levels of white blood cells with chromosomal damage than drinkers with active ALDH2 [18]. Because of these as well as other data, the 2007 International Agency for Research on Cancer Working Group on alcohol and cancer specifically noted the substantial mechanistic evidence supporting a causal role for acetaldehyde in alcohol-related esophageal cancer [19].

Five Key Papers in the Field
Harada et al., 1981 [2] The first documentation of the relationship between ALDH deficiency and the flushing reaction.

Yoshida et al., 1984 [9] Identification of the amino acid variant responsible for ALDH deficiency.

Yokoyama et al., 1996 [12] The first evidence demonstrating that ALDH2-deficient individuals have a dramatically elevated risk of esophageal cancer when they drink alcohol.

Yokoyama et al., 2003 [25] Demonstrates that an updated flushing questionnaire containing two simple questions is approximately 90% sensitive and specific for identifying ALDH2-deficient individuals.

Baan et al., 2007 [19] Summary of the conclusions from the 2007 International Agency for Research on Cancer Working Group on the Consumption of Alcoholic Beverages. This is the first report to conclude that ethanol in alcoholic beverages is carcinogenic to humans. The report also adds the female breast and colorectum to the list of sites for alcohol-related carcinogenesis and notes substantial mechanistic evidence linking acetaldehyde to esophageal cancer risk based on studies from ALDH2-deficient individuals.

While the UADT is exposed to acetaldehyde from alcoholic beverages [20] and tobacco smoke, increasing evidence points to the metabolism of ethanol by microorganisms in the oral cavity as an important source of acetaldehyde in saliva and, by extension, in the esophagus. Acetaldehyde levels in saliva are 10–20 times higher than in blood, due to the local formation of acetaldehyde by oral microorganisms [21]. Importantly, ALDH2 heterozygotes had two to three times the acetaldehyde levels in their saliva compared to fully active ALDH2 individuals after a moderate dose of oral ethanol [22].

Social and Cultural Factors Modulate Alcohol Drinking by ALDH2 Heterozygotes

Alcohol consumption is a social activity, and as such can be strongly influenced by cultural and social forces. In Japan, where the risk of alcohol-related esophageal cancer in ALDH2 heterozygotes has been most well documented, going out drinking after work with colleagues is an essential element of Japanese business society, and the idea of group harmony is particularly powerful. The percentage of heavy drinking men who are low-activity ALDH2 heterozygotes has risen substantially in the last few decades, in parallel with the proliferation of business society in Japan and increases in per capita alcohol consumption. Harada et al. [23] first reported that the frequency of inactive ALDH2 was very low (only 2%) in Japanese alcoholics in 1982. In a later study using archival DNA samples, Higuchi et al. [24] determined that in 1979, 3% of Japanese alcoholics were ALDH2 heterozygotes, compared with 8% in 1986 and 13% in 1992. In a more recent study, approximately 26% of heavy drinking (consuming more than about 400 g of ethanol per week) men in Tokyo were ALDH2 Lys487 heterozygotes [35]. In other East Asian countries, estimates of the percentage of alcoholics who are low-activity ALDH2 heterozygotes range from 17% in Taiwan in 1999 [26] to 4% in Korea in 2007 [27]. Taken together, these observations indicate that the inhibitory effect of heterozygous ALDH2-deficiency on alcohol consumption can be strongly influenced by local social and cultural factors which may change over time.

There are many East Asians now living in Western societies, particularly at universities and in metropolitan areas. A sub-population of special concern is ALDH2-deficient university students who may face peer pressure for heavy drinking and binge drinking. Furthermore, anecdotal evidence indicates that some young people view the facial flushing response as a cosmetic problem and use antihistamines in an effort to blunt the flushing while continuing to drink alcohol [28]. This practice is expected to increase the likelihood of developing esophageal cancer.

Education and Early Detection Can Reduce the Global Health Burden of Esophageal Cancer

Clinicians who treat patients of East Asian descent need to be aware of the risk of esophageal cancer from alcohol consumption in their ALDH2-deficient patients. Importantly, clinicians can determine whether an individual of East Asian descent is ALDH2 deficient simply by asking whether they have experienced the alcohol flushing response. In the Japanese population, ALDH2 deficiency can be identified accurately based on the answers to a flushing questionnaire consisting of two questions (see Box 1) about previous episodes of facial flushing after drinking alcohol [25]. The two questions can be easily included as part of a standard clinical interview. In a Japanese male population, the flushing questionnaire had a 90% sensitivity and 88% specificity [25] and a positive predictive value of 87% (based on the tabulated data in [25]). The flushing questionnaire gave a similarly high sensitivity (88%) and specificity (92%) when administered to Japanese women [29].

Clinical Tests To Assess ALDH2 Deficiency Due To the ALDH2 Lys487 Allele
1. The Flushing Questionnaire

The flushing questionnaire consists of two questions: (A) Do you have a tendency to develop facial flushing immediately after drinking a glass (about 180 ml) of beer?; (B) Did you have a tendency to develop facial flushing immediately after drinking a glass of beer in the first one or two years after you started drinking? For both questions, the choice of answers are: yes, no, or unknown.
If an individual answers yes to either question A or B, they are considered to be ALDH2 deficient [25]. The addition of question B is important because some individuals can become tolerant to the facial flushing effect.
The questionnaire that was tested referred to a small (about 180 ml) glass of beer. However, it seems likely that similar results would be obtained if the question were asked about beer or other beverages containing a similar amount of alcohol (about two-thirds of a glass of wine or shot of hard liquor).

2. The Ethanol Patch Test

The ethanol patch test is performed as follows: 0.1 ml of 70% ethanol is pipetted onto a 15 × 15 mm lint pad fixed on an adhesive tape. The patch is attached to the inner surface of the upper arm for a 7-minute period and then removed. A patch area that shows erythema 10–15 minutes after removal is judged as positive. The sensitivity, specificity, and positive predictive value for inactive ALDH2 are more than 90% in Japanese youth [34].

Once ALDH2-deficient patients have been identified, they should be informed about their elevated risk of developing esophageal cancer risk from drinking alcohol. As can be seen from Figure 5, ALDH2 deficiency increases esophageal cancer risk at all three drinking levels, but the slope of the line relating alcohol consumption to esophageal cancer risk is steeper in ALDH2-deficient individuals. Clinicians might therefore use this graph to explain the increased risk when counseling their ALDH2-deficient patients to reduce alcohol consumption.

Alcohol consumption amounts: low, 1–8.9 units/week; moderate, 9–17.9 units/week; high, ≥18 units/week; where 1 unit = 22 g of ethanol. The referent (OR = 1) is never/rare drinkers (<1 unit/week) of either genotype. Odds ratios were adjusted for age, frequency of drinking strong alcohol beverages, pack-years of smoking, and intake of fruit and green-yellow vegetables, based on a multiple logistic regression model. Error bars are 95% confidence intervals. The graph is based on the data in [25].
doi:10.1371/journal.pmed.1000050.g005
The ORs in Figure 5 are adjusted for smoking. However, patients should also be informed that smoking further increases the esophageal cancer risk in a synergistic manner with alcohol [30]. As noted above, cigarette smoking dramatically increases acetaldehyde levels in saliva, and ALDH2-deficient individuals have a reduced capacity to clear salivary acetaldehyde.
For patients at high risk of esophageal cancer, doctors should also consider endoscopy for early cancer detection. A health risk assessment tool to select candidates for endoscopic cancer screening, including data on alcohol flushing as well as alcohol consumption, smoking, and dietary habits, is currently being developed and validated [31]. Using a version of the health risk assessment that includes the flushing questionnaire as a major component, it has been estimated that approximately 58% of esophageal cancers in the Japanese population could be detected by screening only the individuals with the top 10% risk scores [31].
When detected early, esophageal cancer can be treated by endoscopic mucosectomy, a standard and relatively non-invasive procedure. However, once the cancer has grown large enough to penetrate the submucosal layer, the likelihood of lymph node metastasis increases significantly [32]. Only about 20% of esophageal cancer patients survive three years after diagnosis [3], emphasizing the importance of disease prevention.
ALDH2-deficient university students may have their first experiences with heavy drinking while at university. Therefore, it is particularly important for university health professionals to be aware of the relationship between ALDH2 deficiency, facial flushing, and alcohol-related cancer risk. Informing ALDH2-deficient young people of their risk of esophageal cancer from alcohol drinking represents a valuable opportunity for cancer prevention. However, most of the data on the accuracy of the flushing questionnaire have come from individuals over 40 years old. To assess ALDH2 deficiency in young people with little experience of alcohol consumption, an ethanol patch test (see Box 1) can be used [13]. In the patch test, ethanol is applied to the skin, where it is metabolized to acetaldehyde. (Both ADH and ALDH can be detected in skin fibroblasts [33].) If the acetaldehyde is not further metabolized to acetate, it causes vasodilation, which is detected visually as localized erythema. Like the flushing questionnaire, the ethanol patch test is simple and inexpensive to perform, and the sensitivity, specificity, and positive predictive value for inactive ALDH2 have been shown to be more than 90% in Japanese youth [34].

How Many Cancers Could Be Prevented by Reducing Alcohol Consumption in ALDH2-Deficient Individuals?
Finally, it is important to consider how many esophageal cancer cases might be prevented if ALDH2-deficient individuals reduced alcohol consumption. To address this question, the tabulated data of [35] were used to recalculate the population-attributable risk by Bruzzi’s method [36]. The results of this calculation indicate that if moderate or heavy drinking ALDH2 heterozygotes were instead only light drinkers, 53% of esophageal squamous cell carcinomas might be prevented in the Japanese male population.

Source: PLoS Med 6(3): e1000050. doi:10.1371/journal.pmed.1000050
Published: March 24, 2009

 

Effects on Neurocognitive Functioning
Maternal cannabis use during pregnancy has subtle effects on offspring’s neurocognitive functioning.

Beginning at age three to four, children of mothers who used cannabis heavily while pregnant have demonstrated deficits in memory, verbal and perceptual skills, and verbal and visual reasoning after adjusting for potentially confounding variables (Day et al., 1994; Fried & Watkinson, 1990).

Impaired performance in verbal and quantitative reasoning and short-term memory has also been found among six-year-old children whose mothers reported smoking one or more marijuana cigarettes per day, after controlling for significant covariates (Goldschmidt, Richardson, Willford, & Day, 2008).

In children around the age of nine, prenatal cannabis exposure has been linked with impaired abstract and visual reasoning, poor performance on tasks reflecting
executive functioning (i.e., visual-motor integration, nonverbal concept formation, and problem solving), and deficits in reading, spelling, and achievement, independent of various covariates (Fried, Watkinson & Gray, 1998; Fried & Watkinson, 2000; Goldschmidt, Richardson, Cornelius, & Day, 2004; Richardson, Ryan, Willford, Day & Goldschmidt, 2002)

Vulnerability in visual-cognitive functioning has been shown to persist into early adolescence among those offspring heavily exposed to cannabis (Fried, Watkinson, & Gray, 2003). Findings from brain imaging studies of young adults aged 18–22 indicate that in utero cannabis exposure negatively impacts the neural circuitry involved in aspects of executive functioning, including response inhibition and visuospatial working memory (Smith, Fried, Hogan, & Cameron, 2004, 2006).

These findings are particularly noteworthy as they demonstrate the long-term impairing effects of prenatal exposure to cannabis on offspring’s neurocognitive functioning.Global intelligence does not appear to be impacted by prenatal cannabis exposure (Fried et al., 1998, 2003).

When children reach age six, the effects of maternal cannabis use during pregnancy become much more evident. Compared to offspring of non-users, children born to cannabis users— particularly heavy users—have been found to be more hyperactive, inattentive, and impulsive (Fried, Watkinson, & Gray, 1992; Leech, Richardson, Goldschmidt, & Day, 1999), even after controlling for extraneous variables.

At age 10, prenatally exposed children display increased hyperactivity, inattention, and impulsivity, and show increased rates of delinquency and externalizing problems as reported by their mothers and teachers, compared to those children who were not exposed prenatally to cannabis (Fried et al., 1998; Goldschmidt, Day, & Richardson, 2000).

In children aged 13–16, however, some aspects of attention (i.e., flexibility, encoding and focusing) appear to no longer be affected by cannabis exposure (Fried et al., 2003).

There is accumulating evidence that suggests prenatal cannabis exposure may contribute to the initiation and frequency of subsequent substance use during
adolescence. Porath and Fried (2005) reported that 16- to 21-year-old offspring (particularly males) of cannabis users were at increased risk, in a dose-related
manner, for the initiation of cigarette smoking and cannabis use, and daily cigarette smoking, compared to offspring of non-using mothers, independent of potential prenatal confounds. Similar results were noted by Day, Goldschmidt, and Thomas (2006); compared to offspring of non-users, youth of mothers who heavily used cannabis while pregnant not only reported using this substance more frequently at age 14, but they also initiated use at an earlier age. This result was significant even after controlling for potential confounds.

Effects on Mental Health
There is emerging evidence linking in utero cannabis exposure to depressive and anxious symptomatology. After controlling for prenatal exposure to other drugs and risk factors for childhood depression, offspring of maternal cannabis users expressed significantly more depressive and anxious symptoms at age 10 compared to children of non-users (Gray, Day, Leech, & Richardson, 2005; Leech, Larkby, Day, & Day, 2006).

Mechanisms of Action
The mechanisms responsible for the effects of prenatal cannabis exposure are not well understood. Cannabinoids are able to cross the placental barrier and may affect the expression of key genes for neural development, leading to neurotransmitter and behavioural disturbances (Gomez et al., 2003). The presence of cannabinoid receptors in the placenta and fetal brain may also mediate adverse actions of prenatal cannabis exposure (Park, Gibbons, Mitchell, & Glass, 2003), as these receptors are associated with aspects of brain functioning including cognition and memory (Kumar, Chambers, Pertwee, 2001). Animal studies have documented that cannabinoids can lead to changes in dopamine activity and impaired functioning of the hypothalamus-pituitaryadrenal axis (Kumar et al., 2001), which may affect mood and neurobehavioural outcomes in offspring. It is also possible that an underlying genetic factor may account for both the lifestyle habits of the pregnant mother (i.e., cannabis use) and her child’s neurodevelopment and behaviour.

Conclusions and Implications
Evidence does suggest that prenatal exposure to cannabis (particularly heavy exposure) has subtle adverse effects, beginning at approximately three years of age, on subsequent cognitive functioning, behaviour, substance use, and mental health in offspring. Cannabis-related deficits in the cognitive domain could impair a child’s academic functioning and may require educational remediation, enrichment or placement to help protect against future learning problems.

Prevention efforts directed towards reducing maternal cannabis use during pregnancy could have significant effects in reducing such cognitive impairment. Prevention and intervention programs aimed at reducing prenatal cannabis exposure could also help reduce the percentage of youth who experience mental health conditions and other comorbid problem behaviours, such as substance use and delinquency. It has been reported that at least half of all pregnancies in North America are unplanned (Walker, Rosenberg, & Balaban, 1999). That, combined with the fact that nearly 7% of American women of childbearing age (15–44 years) reported past-month use of marijuana and hashish in 2005 (SAMHSA, 2006) indicates the potential risk for offspring to be prenatally exposed to cannabis.

Cannabis use is a preventable prenatal risk factor; the findings reviewed from the literature suggest that it is prudent to advise pregnant women, and women thinking of becoming pregnant, of the risks associated with cannabis use during pregnancy.

Source Clearing the Smoke on Cannabis . Maternal Cannabis Use During Pregnancy http://www.ccsa.ca/ 2009

Jordan Diplock, Irwin Cohen, and Darryl Plecas
School of Criminology and Criminal Justice,
University College of the Fraser Valley, Abbotsford, British Columbia, Canada
Abstract
The truth about the risks and harms associated to personal marijuana use is rarely a feature of the ongoing debate over the legal status of the drug, with advocates on both sides at fault. Some consensus over the potential harms needs to be reached before any meaningful discussion can occur on this issue. This article reviews research published between 2000 and 2007 and suggests that there are many risks associated to marijuana use with regards to impairment, academic and social development, general and mental health, and continued drug use. Although some findings highlight very serious concerns for users, the numbers that become adversely affected by marijuana use do not represent the majority of users. A debate on the legal status of marijuana based on the facts about the risks and harms of this drug will greatly aid in determining the appropriate actions to address personal marijuana use around the world.
Keywords: Academic Performance; Gateway; Harms; Health; Impairment; Marijuana; Mental Health; Risks
Introduction
The debate over the personal use of marijuana in North America and around the world is extremely contentious with supporters for decriminalization and legalization, and others who assert the importance of strict prohibition. The exceptionally adversarial nature of this debate is likely one of the main obstacles to determining the most appropriate way to address marijuana use within society. As a result of interested parties remaining resolute in their particular positions, the marijuana debate often becomes characterized by selective reporting or the misuse or misinterpretation of the available information. In addition, the popular debate rarely transcends ideological arguments on marijuana’s potential harms. With proponents of legalization championing marijuana as a benign drug and prohibitionists stressing its dangerousness, the debate often fails to consider the totality of the empirical research evidence. The purpose of this review is to discuss the harms associated with marijuana use from an objective viewpoint to provide a basis for the development of further research on how to best address the issues of marijuana use.
As research on marijuana use and its effects is constantly providing additional information, the full extent of the effects of marijuana on users will likely not be known conclusively in the near future. This should not be regarded negatively, as it is the nature of research that future studies improve upon the methodologies and results of previous research. For example, in 1997, The Independent, a popular British newspaper, was a strong supporter of the decriminalization of marijuana in the United Kingdom. In part, this support led to a pro-cannabis march that pressured the government to downgrade the classification of marijuana . Ten years later, that newspaper printed a public apology for its leadership role in the legalization campaign with a headline stating “If only we had known then what we can reveal today”. This example demonstrates the importance of considering new evidence and being willing to refine one’s position based on the best available information. By reviewing the current research on the potential harms associated with marijuana use, this review intends to synthesize the best evidence to inform the debate.
Ensuring that one considers the most current research on marijuana use is not only important because of the changing nature of academic research, but also because the drug under study has changed over the years. In other words, marijuana does not refer to cannabis with a particular level of -Tetrahydrocannabinol (THC). Over time, the level of THC in marijuana has changed; typically, it has increased. However, because there have been very few studies on the changes in potency of marijuana over the years, it cannot be confirmed conclusively that marijuana users in the 1970s were typically consuming a different drug than today’s users. The information that does exist suggests that, on average, marijuana users today are exposed to higher levels of THC than in past decades. Research on potency trends of seized marijuana between 1980 and 1997 concluded that average THC levels of marijuana seized in the United States increased from less the 1.5% in 1980 to approximately 3% in the early 1990s, to over 4% in 1997 . Moreover, in an article published by the Drug Enforcement Administration (DEA), Newell reported that average THC concentrations in marijuana from 36 samples seized in the state of Florida in 2002 were over 6%. These levels were determined to be at par with the averages reported by the Marijuana Potency Monitoring Project . In Canada , the Royal Canadian Mounted Police [RCMP] reported that on average seizures of marijuana in Canada had THC concentrations over 10%. Seizures in Europe of imported marijuana typically had THC levels between 2% and 8%, but the potency of hydroponically-grown “skunk” may be as high as double that of the imported marijuana . However, it must be kept in mind that the nature of marijuana production and distribution is such that a regular user would likely be exposed to marijuana of various different concentration levels of THC. As the majority of marijuana production remains the industry of criminals, many of whom use hydroponic operations and compete with each other to produce the most and the ‘best’ marijuana, there is no reason to believe that the quality of street marijuana has remained consistent over time.
In addition to levels of THC, the understanding of the number of different constituents of marijuana and their potential to interact with each other changes over time. ElSohly and Slade reported that the number of known natural compounds in marijuana increased from 423 to 489 between 1980 and 2005. Of those numerous chemicals, 70 were Cannabinoids, 9 of which were discovered since 1980 . The changes in knowledge about the complex chemical makeup of marijuana further complicate the study of the potential dangers of its use.
Because marijuana is used around the world by approximately 160 million people, there has been a great deal of research conducted on its effects on users . The use of marijuana results in a variety of changes within the user’s body that can have a range of effects . Given this, the focus of this review is limited to the research evidence on potential harms associated with marijuana use in the areas of: impairment; academic and social development; general physical health; mental health; and continuing drug use. Although there is also a substantial body of research on the medical use of marijuana for particular patients, a review and discussion of the research on medical marijuana is not included in this study. This exclusion is not meant to suggest that marijuana is universally accepted as a safe or effective treatment for any illness, as Voth has clearly demonstrated that the wider debate over the use of marijuana extends into the issue of the drug’s medical use. The discussion presented in this review will concentrate on the use of marijuana within the general population and the empirical evidence for how marijuana use effects the general population in the five previously listed areas.

Methodology
To ensure that this review considered the most current research, information was collected from articles published from 2000 to 2007. Articles were identified by searching a number of databases, including Medline, Pub.Med, PsychINFO, and Google Scholar. To ensure a more complete search, a variety of keywords were combined with ‘marijuana’ to search the databases. In particular, these keywords related to the five aforementioned areas. An extremely partial list of keywords included ‘impairment’, ‘academics’, ‘heart disease’, ‘respiratory’, ‘cancer’, ‘psychosis’, and ‘gateway’.
Once an article was identified, it was assessed for appropriateness based on a review of the article’s title and abstract. One potential limitation of this review was that only full-text-available articles written in English were considered for this review. However, in order to expand the number of articles considered, both original research studies and articles that reviewed topics related to the harms of marijuana use were included. In order to ensure objectivity in the selection process, the inclusion or rejection of articles occurred without consideration of authorship or the conclusions or recommendations made by the authors. Given this, the articles considered in this review represented the continuum of current research on the harms that may be associated with marijuana use. Because of the scope of this topic and the amount of literature on marijuana use, the articles included in this review do not represent all available research on the effects of marijuana use. However, because many of the articles included in this review included extensive reviews of previous literature, the areas of focus for this review were well represented.
Finally, when considering the evidence presented in this review, it is critical to keep in mind that many of the studies based their results and conclusions on self-reported effects of marijuana use by the users themselves. While self-report studies are extremely valuable, they are susceptible to a variety of methodological problems, such as social desirability effects, errors in memory, exaggeration, and deception, which must be considered when evaluating results or conclusions . In addition, it is also extremely difficult to link or establish a direct causal relationship between drug use and other specific behaviours as it is likely that behaviours or outcomes are the result of multiple factors, rather than exclusively one factor, such as drug use.
Marijuana Related Impairment
One of the important debates in the research literature is the effect of marijuana use on cognitive and motor skills. Several studies have focused on determining whether there are any negative effects on cognitive or motor skills within hours of marijuana use . A number of studies have more specifically focused on the effect of marijuana use on abilities related to operating a motor vehicle . In addition to studies of short-term impairment, research has been conducted on long-term impairments associated with prolonged marijuana use .
Short-term Impairment
Impairment immediately after the consumption of marijuana may be a concern for users and the community at large. Short-term impairment has generally been assessed anywhere from 5 – 10 minutes to several hours after use. Testing the effects of marijuana on working and episodic memory determined that focusing attention and response accuracy were impaired immediately after smoking marijuana, even marijuana with less than 4% THC. The authors concluded that the marijuana resulted in difficulty maintaining a coherent train of thought and disruptions to selective filtering processes, both of which impaired memory. Similarly, another study reported that acute marijuana intoxication was accompanied by impairment of brain function related to goal-oriented activities. Further, it was suggested that marijuana consumption inhibited impulse and anger control in some users implying a possible link between marijuana use and violent or antisocial behaviour in some individuals . However, impaired attention was not found in a study of marijuana’s effects on auditory focused attention tasks where participants responded to a tone by pressing a button as quickly as possible. Results of an examination of brain functioning hours after using marijuana found that heavy marijuana users did not present impaired abilities on simple spatial working memory tasks, as deficits were compensated for by employing regions of the brain not commonly used during such tasks.
Although the research reported that short-term cognitive impairment could occur among marijuana users, the level of impairment and its seriousness was not significant. However, this does not suggest that there are no or few short-term risks of impairment. Instead, this conclusion may be due to the small sample sizes of only 10 to 12 participants in the studies examined . In effect, the sample sizes in these studies limited the ability to draw any firm conclusions about the range or seriousness of short-term cognitive impairments associated with marijuana consumption.
Researchers also examined the relationship between marijuana induced cognitive impairment and common abilities, activities, or behaviours, such as operating a motor vehicle. Ramaekers and co-workers concluded that decision-making, planning, tracking, reaction time, and impulse control were impaired by high-potency marijuana. Although the 20 subjects were considered only light users, substantial impairment of executive and motor functioning for a period of at least six hours was found. Although the 13% THC level in the marijuana used in this study was higher than the averages reported by the DEA and RCMP , this study demonstrated that serious impairment lasting for many hours was common when consuming high potency forms of marijuana.
Operating a motor vehicle can be dangerous at any time. However, doing so while impaired by marijuana significantly increases the risks of accident. Although some studies revealed that recent marijuana use was a causal factor for only a small proportion of accidents, short-term marijuana impairment does contribute to serious motor vehicle accidents To better determine marijuana impairment among drivers, standardized field sobriety tests have been designed to detect impairment by marijuana in a manner similar to alcohol. Research on field tests concluded that, as expected, impairment increases with the level of THC . Even low levels of THC can moderately impair driving abilities, but driving is severely impaired when either higher levels of THC marijuana is consumed or marijuana with lower levels of THC is consumed with even small amounts of alcohol . Considering the research examined for this review on the relationship between marijuana consumption and impairment, there appears to be a strong consensus that marijuana use has a negative and potentially harmful effect on driving.
Long-term Impairment
There are few studies on the long-term impairment of chronic marijuana consumption compared to the acute effects of marijuana use. Still, some researchers examined the potential for impairment as a result of long-term use, even during periods of abstinence . From the results of one study of older participants (33-50 years old), it appeared that, although heavy marijuana users showed impaired cognitive abilities after a week of abstinence, there were no noticeable impairments after twenty-eight days of abstinence . When compared to a control group, long-term marijuana using teens (aged 16 – 18) had equivalent task performance on a go/no-go task after twenty-eight days of abstinence . However, marijuana users committed more errors on cognitive tests and showed increased brain processing effort during the inhibition task . When comparing early-onset users to late-onset users, even after twenty-eight days of abstinence, early-onset frequent marijuana users had a greater likelihood of suffering a range of cognitive functioning impairments, in particular verbal IQ, compared to late-onset and non-users .
One interesting finding about long-term marijuana users was that there was an increase in brain activity in more regions of the brain when performing a variety of cognitive tests when compared to non-users. The researchers concluded that this finding was the result of the brain working harder and differently to overcome the deficits resulting from the marijuana use . In addition to working harder and differently, significantly increased blood volumes in various regions of the brain have been discovered , even after a period of abstinence of six to thirty-six hours. The researchers indicated that it remained unknown how these changes affected brain functioning and whether these changes were permanent, long-lasting, or temporary. However, these findings do suggest that there is a potential for some type of long-term brain impairment. Nonetheless, with the exception of impairments caused by psychosis and other mental illnesses discussed later in this review, when considering the totality of the research literature on the relationship between marijuana use and long-term cognitive or motor impairment, there appears to be little evidence to support the assertion that serious impairment is a likely result from long-term marijuana use, especially after a period of abstinence.
The Effects of Marijuana Use on Academic and Social Development
As marijuana is the drug of choice for many young people, it is necessary to understand whether marijuana has any negative effects on academic performance and the transition from adolescence to adulthood. The evidence for both immediate impairment and the possibility of longer-term impairment supports the notion that marijuana use may have negative consequences on the development of young users. In a consideration of academic performance and graduation, a number of studies have focused on the relationship between marijuana use and absenteeism , I.Q. , and academic achievement . By examining the lifestyles of adults who reported being heavy marijuana users in their youth, other researchers have attempted to assess the effects of marijuana use on social development . The following section provides a discussion of the literature in these areas.
Marijuana and School Performance
There are many factors that contribute to academic achievement, such as general intelligence, interest/curiosity, motivation, lifestyle, and social relationships/networks. Since the adolescent human brain is still developing, it is possible that recreational marijuana use may disrupt ‘normal’ development, which may manifest in, among other things, poorer school performance. Survey research revealed that students who were absent on the day of a school-based survey were more likely to use marijuana, alcohol, and cigarettes than students who were present. Although it is unsupportable to conclude that one specific day of absence from school was caused by or related to marijuana use, this study provides some small support for the more impressive findings of Lynskey and Hall’s review of cross-sectional studies on marijuana and school-related issues. Their review of over 50 research studies concluded that marijuana appeared to have a strong relationship with absenteeism, lack of retention, and not graduating.
An examination of the relationship between academic achievement and drug use in a diverse sample of 18,726 students concluded that marijuana use, when examined alone, was statistically significantly related to lower standardized test scores in math, science, reading, and social studies. Average scores on the math comprehension test for marijuana users were further below the mean than on any other test, while reading comprehension appeared to be affected the least. However, when marijuana was combined with alcohol or cigarettes, the results were much less robust. In effect, both regular smoking and alcohol intoxication explained much more of the variance, thus reducing the influence of marijuana on test scores. The explanation provided for this finding was the relatively small number of students who reported ever being under the influence of marijuana at school compared to the number of students who regularly used alcohol and/or cigarettes at school . Similarly, a study by Diego and colleagues found that grade point averages decreased as the reported frequency of marijuana use increased. Marijuana use had a larger negative correlation with grade point average as frequency of use increased than alcohol or cigarettes. While these findings suggested a link between marijuana use and academic achievement, the research could not establish a direct causal relationship or the direction of the relationship. Nonetheless, for the most part, social scientists agree that marijuana use is detrimental to school performance .
Since marijuana has been linked to short-term impairment and a decrease in school performance, some researchers have studied the effects of marijuana on IQ (29). However, measuring the direct effects of marijuana use on IQ has been difficult as there is rarely a baseline measure of a subject’s IQ prior to their initiation into marijuana use. One longitudinal study that had baseline measures of IQ prior to the subject ever using marijuana reported a statistically significant decrease in IQ score among individuals who smoked five or more marijuana cigarettes per week. On average, a 4.1 point decrease was measured between the time the subject was 9 – 12 years old (no prior use) and 17 – 20 years old (current and/or past use). However, when considering the degree of marijuana use for the sample of 70 marijuana users, only those characterised as heavy users showed any decreases in IQ compared to slight users, former users, and non-users who demonstrated increases in IQ . These results suggested that marijuana use has an effect on general intelligence but is more severe for regular and chronic marijuana users.
Marijuana Use and Later Social Development
Success in adulthood is related to a wide range of developmental and social variables throughout childhood and adolescence. It has been hypothesised that many of these contributing dynamics could be negatively affected by the use of marijuana. For example, some people contend that one of the possible outcomes of marijuana use is chronic low motivation. In effect, the hypothesis is that marijuana use among young people contributed to the development of low motivation which has long-term effects on school and employment performance. In their research, however, Lynskey and Hall concluded that there was little evidence to support the low motivational syndrome hypothesis because the majority of supportive evidence was based on older uncontrolled studies of case histories and observational reports, while controlled field or laboratory studies did not find compelling evidence of such a syndrome. Moreover, long-term (over 20 years), regular marijuana use among males was not associated with any specific negative socio-demographic effects such as alcohol or nicotine abuse or dependence, hospitalizations, and health-related quality of life .
However, other researchers have found several adverse associations between marijuana use and social development. A study of the relationship between marijuana use in 2,842 high school students and later occupational attainment concluded that marijuana had some differential negative associations with occupational attainment for males and females . Specifically, for males, self-reported abstinence or low frequency use of marijuana had no effect on occupational attainment, although high prestige jobs typically had a greater percentage of non-users or former low frequency users. However, for male users, after a certain threshold level was passed, success in occupational attainment decreased with increased early marijuana use. The threshold for this relationship in this study was ambiguous as the linear relationship began with the category associated to between 3 and 39 occasions of marijuana use in one year. Among females, early marijuana use was found to have strong negative outcomes on occupational attainment, but the pattern was different from that of males, lacking the easily identifiable threshold and negative linear relationship .
Green and Ensminger examined the effects of marijuana use on a variety of social variables among a cohort of 530 African Americans. Frequent adolescent marijuana use was associated with poorer academic achievement, a lack of stable employment, and family dysfunction. These results suggested that using marijuana 20 or more times during adolescence was associated with being unemployed, unmarried, and becoming a parent while unmarried. Early marijuana use was also linked to dropping out of school and continued marijuana use as an adult . Although this study was specific to African Americans, when considered with other studies on occupational attainment and school performance, these results contribute to the body of literature indicating that marijuana use among young people can have a detrimental outcome on their future. However, these findings do not confirm a causal relationship between marijuana use and poor performance in school or life. Still, the evidence does suggest that, even in the absence of a direct causal link, the use of marijuana during adolescence, for many young people, is often accompanied by other factors, such as the development of delinquent peer associations or a general lack of commitment to pro-social activities and institutions, which can lead to problems with social development.
General Health Consequences of Marijuana Use
The use of marijuana introduces foreign substances into the body and produces a number of chemical changes in the user’s brain and body. Given this, there is a large amount of literature focusing on the physical effects of marijuana. To begin, there is little evidence to suggest that marijuana use poses a serious risk for an overdose death or its infrequent use is related to the development of long-term health problems . Given this research, the majority of health-related studies focused on the potential harmful health outcomes associated with long-term and heavy marijuana use. One of the most widely studied issues is the relationship between smoking marijuana and the development of respiratory ailments .
In addition, the short-term and long-term effects of marijuana use on the circulatory system have also been extensively studied . Other researchers have focused on potential reproductive harms , the effects of marijuana use on the immune system , and the risks for cancers . There is also a burgeoning research literature on the degree to which marijuana users can develop a dependency and experience withdrawal symptoms . The following section will review the research literature on these important issues.
Respiratory Ailments Related to Marijuana Use
The most common way of using marijuana is by smoking it. A direct consequence of this method of consumption is that smoke must enter the airways and lungs of the user. As a result, researchers are interested in the amount and type of harm that smoking marijuana has on the respiratory system of users. This is particularly important because marijuana smoke contains many of the same poisons found in tobacco smoke. Given this, research has focused on determining whether the respiratory outcomes of smoking marijuana are similar or worse than those associated with smoking tobacco . Taylor et al. reported that respiratory symptoms were significantly more prominent in marijuana-dependent users than in non-users. The sample consisted of 21 year old subjects from the 1970s who self-reported short histories of smoking marijuana . The associated self-reported respiratory problems included wheezing, shortness of breath after exercise, nocturnal chest tightness, and early morning phlegm and mucus. These symptoms, which are typically indicative of chronic bronchitis, were also found to be associated with smoking marijuana in other research .
In their review of the research literature, Taylor and Hall argued that marijuana should be considered as damaging to the airways as tobacco and that there was a strong possibility that smoking marijuana was a contributing factor to the development of chronic lung disease. Further research concluded that long-term marijuana smoking was also associated with an increase in airflow obstruction and obstructive lung disease. A comparison of the effects of marijuana cigarettes to tobacco cigarettes concluded that one marijuana cigarette can have the obstructing effects on the lungs equal to that of two to five tobacco cigarettes. Lower lung density and increased total lung capacity were also recorded for marijuana smokers, but macroscopic emphysema was not found to be a common symptom . These findings suggested that serious negative respiratory outcomes should be expected for regular marijuana smokers, regardless of the marijuana’s THC levels, even among youth or young adults.
Since many of the detrimental effects on the respiratory system are the direct result of smoking, there have been several studies examining whether vaporizers provide a less harmful way to consume marijuana . Based on self-reported respiratory symptoms after using vaporizers to inhale marijuana cannabinoids, Earleywine and Barnwell concluded that vaporizers did provide some measure of safety, especially as the amount of marijuana inhaled increased. Hazekamp et al. reached a similar conclusion.
While the use of vaporizers may reduce or eliminate some of the respiratory ailments for users, the THC in marijuana may pose a respiratory risk. In response to the presence of THC, human airways experience cellular changes, especially to mitochondrial energetics, which are responsible, in part, for the health of cells and their energy production . Sarafina et al. described these changes as deleterious effects, as changes to the mitochondria of lung cells affects the viability and functioning of those cells. These changes were more significant with higher concentrations of THC and longer exposure times . In effect, as a result of THC in the lungs and airways, the risk of adverse pulmonary conditions is substantially increased by the potential for damage to the airway epithelial cells .
Potential Harms of Marijuana Use on the Heart and Circulatory System
One direct outcome from using marijuana is an immediate increase in heart rate. It is estimated that marijuana use increases the heart rate 20% to 50% immediately following consumption . This has led researchers to examine the short and long-term implications of marijuana use on the heart and the circulatory system. The majority of research in this area relies on case studies . Although the conditions documented in the research literature may be serious, it must be kept in mind that there is little evidence to suggest that the outcomes discussed in the case studies are typical or the norm for marijuana users.
Based on their case study of a 34-year-old man who reported heart fluttering and near syncope after marijuana use, Rezkalla and coworkers suggested that marijuana was a likely contributor to the decrease in coronary blood flow and ventricular tachycardia experienced by their subject. Another study described two cases; one in which a man with a history of heart problems suffered arrhythmia precipitated by marijuana use, the second described a young patient who suffered an onset of myocardial infarction. The researchers concluded that marijuana was a serious concern for those who may be predisposed to heart-related illnesses. Similarly, Caldicott et al. documented the case of a young patient who suffered a heart attack after marijuana use, despite having no other identifiable risk factors for a cardiac event.
Findings may be more informative when referring to larger samples that identify cardiac risks associated with marijuana use. One study concluded that, although it was less common than other stressors, marijuana use was a trigger for myocardial infarction . In this study , the risk of onset of myocardial infarction increased approximately five-fold in the first hour after use.
The conclusion of existing research is that marijuana use may, in rare instances, trigger a heart attack. However, it is important to recognise that the evidence in support of this conclusion may be confounded by the subject’s participation in a wide range of other unhealthy habits that may also contribute to a greater or lesser degree to a heart attack. Still, there is some evidence to conclude that marijuana is harmful to the heart and researchers, such as Aryana and Williams (, have stated a belief that heart problems related to marijuana use may be more common than is currently recognized. In addition, they warned that as the population of marijuana users aged, continued use may increase the risk for a number of adverse cardiovascular issues, such as tachyarrhythmia, acute coronary syndrome, vascular complication, and congenital heart defects .
Consequences of Marijuana Use on Reproduction and Pregnancy
There is a growing body of literature on the effects of drug use on sperm and egg development and the short and long-term outcomes for the foetus. This literature focuses on the relationship between drug use and implications for fertility and healthy, successful pregnancy. For example, several studies have investigated the effects of marijuana use on male sperm fertility and female hormones . Scheul et al. found that the presence of THC in the reproductive fluids of both males and females could inhibit the ability of sperm to complete fertilization. Other research reported that THC inhibited male fertility by binding to sperm cells and impairing sperm functions. In females, marijuana was found to disrupt the endocrine system and produce an estrogenic effect, which can have detrimental effects on specific elements of the female reproductive system . It should be noted, however, that the effects were more the result of the contaminants of smoking the drug than the psychoactive chemicals . In addition, marijuana use negatively affected female reproductive hormones which could lead to delayed ovulation . In considering these studies, the conclusion is that marijuana use may have some negative effects on human reproduction and that these outcomes are increased for those already at risk for infertility or other reproductive conditions.
Research also examined the degree to which marijuana use by pregnant mothers affected the unborn foetus and whether maternal marijuana use led to negative outcomes for the child. Kuczkowski reported that THC crosses the placental barrier, but that there was no confirmation that it had a teratogenic effect. In other words, there is no evidence that marijuana use by a pregnant mother contributes or causes birth defects or malformations. However, research by Wang et al. determined that some impairment was present in foetuses exposed to marijuana. This finding led the researchers to conclude that some long-term emotional and behavioural implications existed for children exposed to marijuana while in the womb.
Fried and Smith’s review of literature concluded that the effects of prenatal exposure to marijuana were subtle, with little evidence supporting growth or behavioural effects prior to age three. Others concluded that there was a statistically significant association between prenatal exposure to marijuana and later use; however, they concluded that there were many other potential factors that could have contributed to later marijuana use among those exposed to the drug while in the womb. One common theme among the research conducted to date was that they all called for more study on this issue. Although further research is needed in this area, to date, no substantial dangers have been confirmed to be associated to smoking marijuana while pregnant. However, marijuana smoke contains hazardous chemicals and materials, many of which exist in tobacco smoke. Therefore, just as health providers caution that tobacco should not be used by pregnant mothers, the caution should extend to marijuana use.
Marijuana Use as a Potential Threat to the Immune System
THC from marijuana may act upon the immune system similarly to the way it does on cells in the reproductive system . If the immune system is compromised by the use of marijuana, there may be significant implications for health care systems around the world . The relationship between marijuana use and deficiencies of the immune system is based, in part, on the findings that THC inhibits the ability of T-cells and alveolar macrophages to protect the body from foreign pathogens . Alveolar macrophages are a main defence against infections in the lungs. A review of the research literature in this area by Copeland et al. suggested, however, that it might require high doses of THC to substantially impair immune system functioning. Still, when considering the number of respiratory problems associated with smoking marijuana, and the possibility of serious carcinogenic properties in the drug, compromising the immune system may further compound the harms of marijuana use, especially among those already suffering from weakened immune systems.
Cancer Causing Effects of Marijuana
Because marijuana smoke contains many of the same harmful carcinogens as tobacco smoke, there is a possibility that marijuana use may be associated with the onset of various types of cancers, especially lung cancer as the most common method of consuming marijuana is by smoking it . To date, however, the research does not support the association between marijuana use and cancer. In their study, Hashibe and colleagues failed to find substantial evidence for an association between marijuana use and lung or upper areodigestive tract cancers. A review of research on lung cancer and marijuana use by Mehra et al. revealed many of the methodological difficulties in attributing outcomes specifically to smoking marijuana. For example, in many instances, marijuana users also smoke tobacco, there is the challenge of determining proper thresholds for marijuana use, and the research has typically included only small sample sizes. Mehra et al. suggested that because the plausibility of an association between marijuana smoking and cancer is so apparent, improved studies are required to test this possible link. Other research has reached similar conclusions about the link between marijuana use and cancer . Although a 1999 study by Zhang and colleagues reported a potential for marijuana use to increase the risk of squamous cell carcinoma of the head and neck, the evidence for a link between marijuana use and head and neck cancers has been limited and conflicting . In a recent study, marijuana was not found to increase the risk of head and neck cancer, although the duration of use under study might have been too limited to rule out the possibility of a longer-term effect . Another large-sample study concluded that marijuana was not associated to oral squamous cell carcinoma. There was also no link between maternal or paternal marijuana use and risk of childhood acute myeloid leukaemia .
Although there is currently no evidence to confirm that marijuana use increases the risk for any type of cancer, there will likely be continued research. Already, there are many researchers who believe that the changes to a variety of cells in the body caused by marijuana use may contribute to the development of cancers including lung cancer, oral cancers, and breast cancer .
Marijuana Dependency and Withdrawal
Despite the commonly held belief that marijuana use does not lead to addiction, existing research has often referred to a dependency on the drug . Although many people use marijuana on a regular basis, Looby and Earleywine reported that fewer than half of all daily users exhibited the behaviours necessary to meet the established criteria for being classified as drug dependent. These criteria include tolerance, withdrawal, taking the drug for longer periods of time or larger doses than intended, inability to stop or reduce use, increasing the time spent obtaining the drug and recovering from its effects, ignoring other important activities, and continuing use despite undesirable consequences. The authors argued that frequent use does not necessarily result in dependence, but that it may be a contributing factor. Their research suggested that negative effects of marijuana use, such as dissatisfaction with life, low motivation, and unhappiness, were more related to dependence on the drug than regular use . When considering the results of this research with findings from Copersino et al. on withdrawal symptoms, strong support is established for the idea that a proportion of frequent marijuana users suffer negative effects resulting from a dependency.
In terms of factors that most likely contribute to the development of a marijuana dependency, Hall reported that initiation to drug use at an early age was the most significant. However, in terms of public policy, if THC levels are indeed increasing and continue to increase, there will likely be a growing number of users who find themselves dependent on marijuana. Furthermore, as the National Institute on Drug Abuse’s definition of addiction focuses on the “uncontrollable, compulsive craving, seeking and use of drugs”, the physical effects of dependency and withdrawal may be only part of the problem, as addiction can occur without physical signs of dependency. This may prove more problematic if future research establishes additional negative health consequences of long-term use as users may experience more difficulty abstaining from use even in the face of exacerbating social and health problems.
Marijuana Use and Mental Health
In addition to some potentially serious physical health problems, marijuana use has also been associated with mental health problems. The link between marijuana use and psychosis or later schizophrenia has possibly received the most attention in the research literature. This body of research focuses on the role of marijuana in triggering psychosis the risk of developing schizophrenia among those who suffered marijuana-induced psychoses, the dangers of marijuana use for those already suffering from psychosis , and a number of hypotheses on whether marijuana use contributes to the presence of psychoses or schizophrenia or whether mental health issues contribute to the onset of marijuana use To a lesser degree, researchers have also investigated the relationship between marijuana use and depression and anxiety .
Marijuana-Precipitated Psychosis and Schizophrenia
An association between marijuana use and the onset of psychosis recently emerged as a serious concern. Given this, it is necessary to understand the potential for marijuana to contribute to psychosis and what proportion of marijuana users are at risk for developing psychosis. Research suggests that 8% to 10% of all cases of psychosis may be triggered by the use of marijuana Others concluded that marijuana use was linked to psychosis independent of any previous mental pathology. Given this, there is a growing consensus that, although it is relatively rare, marijuana induced psychosis is a potential threat to users, specifically to those who are already vulnerable for this type of mental affliction In order to explain this relationship, Caspi et al. reported that there may be an interaction between the chemicals typically present in marijuana and a number of ‘susceptible’ genes in the user that contributes to the onset of marijuana-induced psychosis and schizophrenia.
Research findings suggested that if marijuana use triggered psychosis, it might be a risk factor for schizophrenia in determining whether those who suffered from an episode of marijuana-induced psychosis were at risk of developing later schizophrenia, a group of such individuals was compared to a group of people referred for schizophrenia-spectrum disorders for the first time who had no history of marijuana psychosis . Although suffering from some recognized methodological problems, this study found that marijuana-induced psychosis was an important risk factor for developing schizophrenia and that it often had an earlier age of onset compared to those who self-reported no marijuana use. In partial support, Solowij and Michie found similarities between the cognitive effects of marijuana use and the cognitive endophenotypes of schizophrenia. This suggested that there was little reason to believe that marijuana is a direct cause of schizophrenia, but that marijuana likely aggravates pre-existing susceptibilities to schizophrenia . This hypothesis may explain why those prone to suffering from marijuana-related psychosis are also more susceptible to later schizophrenia.
One of the complications for fully understanding marijuana’s association with psychosis and later schizophrenia is that people with mental illness may continue to use the drug. The effects of marijuana use in patients who had recently suffered from psychosis were studied to determine whether symptoms were prolonged and worsened by the drug . Findings suggested that those who continued to use marijuana were at a greater risk of having more symptoms and a continuous course of mental illness . It could not be confirmed from the study, however, if marijuana caused the symptoms to worsen or the degree to which marijuana directly contributed to the symptoms.
There were a number of relational hypotheses tested in the research literature . The most common hypotheses were that: marijuana use caused psychosis and schizophrenia without any existing predisposition; marijuana use triggered the onset of these symptoms in people who were previously vulnerable; marijuana use exacerbated the symptoms in those already suffering; and those already suffering from these symptoms were more likely to self-medicate with marijuana. Although the current state of the research does not support the hypothesis that the relationship between marijuana and psychotic symptoms is one of self-medication , other hypotheses found more support.
The strongest support was for the second and third hypotheses. However, the causal hypothesis remains debatable. Degenhardt and Hall found that cases of schizophrenia in the general population did not rise with an increase in reported marijuana use, thus weakening the case for the causal hypothesis. Although further research is needed to more fully understand the causal association between marijuana use and psychosis, based on the research to date, psychosis and later schizophrenia as a result of marijuana use is a risk for a small portion of the marijuana using population.
Depression and Anxiety Among Marijuana Users
Although psychosis and schizophrenia were researched more than other mental health issues associated with marijuana use, there is a body of research on other issues such as depression, anxiety, and violence. Research found that increased marijuana use among high school students was associated with increased self-reports of depression. However, others found that past-year marijuana use was not a significant predictor of future development of depression. Similarly, research by Bonn-Miller et al. found that marijuana use was a predictor of anxiety symptoms, but not of depression. Again, it remains a challenge to determine whether marijuana use is a cause of these symptoms or if the symptoms play a contributing role in marijuana use.
Marijuana’s Role in Continuing Drug Use
The discussion of potential harms of marijuana use presented thus far indicated that marijuana poses a number of potential risks to the general population of users and some specific negative outcomes for a relatively small subgroup. The risk or actual harms associated with marijuana use can be seriously compounded by the use of other drugs and can become overshadowed by the dangers associated with becoming addicted to ‘harder drugs’. Moreover, there has long been the suggestion that marijuana can act as a ‘gateway’ for much harder drug use. It would appear that the probability that marijuana acts as a gateway to other illicit drugs is much higher than the other way around . According to Fergusson and Horwood , when adjusting for other common covariate factors such as childhood, family, and life-style factors, regular marijuana use (fifty or more times in a year) was strongly related to the onset of further illicit drug use. However, others found that the opportunities presented by the lifestyle accompanying marijuana use were just as likely as the actual use of marijuana to predict the use of other illicit drugs. Currently, there is no evidence to prove or disprove that any biological effects of marijuana use increases the likelihood of using other illicit drugs, although researchers continue to test this hypothesis . Based on twin studies, it is well established that marijuana use is a strong predictor of future illicit drug use regardless of the familial and environmental similarities between twins .
Still, since the majority of marijuana users do not continue on to other illicit drugs , it is important to understand what factors distinguish between those who do and those who do not go on to use harder drugs. The appropriate policy and control responses may be very different depending on whether the relationship was based on the biological effects of marijuana use or on the lifestyles that accompanied marijuana and other illicit drug use. Currently, it can be concluded that, for those who use marijuana, there is a risk of using other illicit drugs. However, without a better understanding of what causes or correlates with an increased risk, it is impossible to determine what effects changes to marijuana’s current legal status would have on patterns and rates of drug use.
Conclusions
The debate over the most appropriate policy to have with respect to the personal use of marijuana has generally been polarized because of differing positions on the drug’s harms. In addition to the unknown extent of the potential for harm caused by existence and interaction of over 800 natural chemical components of marijuana, including 70 cannabinoids, it can be concluded that marijuana does pose some considerable confirmed risks to users. Some concern over marijuana is merited by findings regarding its ability to create short-term impairment, specifically on driving ability. Academic performance and social development appear to be negatively affected by marijuana use, but the causal role that the drug plays in the lack of future success of young people remains unconfirmed. As expected, smoking the drug contributes to considerable harm to the lungs and airways. Even though the use of vaporizers removes the contaminants of combustion and reduces some major respiratory problems, THC exposure to the lungs appears to be unhealthy. The immune system is also compromised by the use of marijuana, specifically the ability of the lungs to defend against foreign pathogens. Although cancers, heart problems, and threats to human reproduction are not common among marijuana users, most experts contend that further investigation is required, and the potential for risk should not be dismissed. The development of psychosis and later schizophrenia should also remain a concern for a small proportion of those who use marijuana. Dependency and regular, long-term use of the drug are also factors that likely exacerbate the potential for the majority of the harms previously identified in this review. Of course, these harms are often compounded by the fact the marijuana users have an increased likelihood of continuing on to other illicit drugs.
It is important to remain cognizant of the fact that the harms associated with marijuana use, though very serious in some cases, are not experienced by the majority of users, although prolonged regular use will generally put a person at a greater risk than occasional use. The debate over marijuana use requires advocates of both decriminalization and prohibition to concede that marijuana is neither harmless, nor is it particularly dangerous to the majority of users. It should be acknowledged by all that the lives of a small proportion of the population will be seriously disrupted by marijuana use.
With an understanding of the potential harms associated to marijuana use forming the basis of the debate, politicians, policymakers, and citizens can begin to answer the important questions that will form the basis for discussing policy options. For example, what can be learned from other jurisdictions about ways to respond to the social and personal harms associated with marijuana use? What lessons can be learned from the experiences with alcohol that might apply to marijuana? Are there other or better approaches than prohibition to manage the problems that marijuana use creates? Further research will also be required to better understand whether decriminalization promotes increased use. In other words, would the decriminalization of marijuana create better opportunities to regulate the drug, or would it result in greater social harm?
To date, the research evidence shows that marijuana has a number of associated harms. In some cases, these harms are worse than those associated with regulated substances such as alcohol or tobacco. Based on the course of research, it is likely that future studies will further refine our understanding of the harms of marijuana use. However, because marijuana continues to be a popular recreational drug, it is necessary that researchers disseminate their latest findings in a wide range of ways in order for the public to have the best information at their disposal about the harms and risks associated with using marijuana.

Source: Journal of Global Drug Policy and Practice Vol. 3. Issue 2 Summer 2009

More Author Affiliations: ORYGEN
Research Centre (Drs Yu¨ cel,
Whittle, and Lubman) and
Melbourne Neuropsychiatry
Centre, Department of
Psychiatry, The University of
Melbourne and Melbourne
Health (Drs Yu¨ cel, Whittle,
Fornito, and Pantelis),
Melbourne, Australia; School of
Psychology and Illawarra
Institute for Mental Health,
University of Wollongong,
Wollongong, Australia
(Dr Solowij and
Ms Respondek); and
Schizophrenia Research
Institute, Sydney, Australia
(Dr Solowij).
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recent structural magnetic resonance imaging (MRI) studies
have also reported contradictory findings, ranging from
no global or regional changes in brain tissue volume or
composition14-16 to gray and white matter density changes,
either globally17 or in focal regions, most notably in the
hippocampal and parahippocampal areas.18,19 However,
these previous studies used imaging techniques with relatively
coarse spatial and anatomical resolution and typically
focused on samples with multiple substance use or
comorbid psychiatric disorders and on only moderate levels
of cannabis use (ie, _2 joints per day). Indeed, despite
strong evidence of neurotoxicity in the animal literature,
6-9 to our knowledge, no neuroimaging study has
examined the neurobiologic sequelae of long-term heavy
cannabis use while controlling for the important confounds
of polydrug abuse and co-occurring psychiatric
disorders.
In this study, we used high-resolution 3-T MRI to assess
volumetric changes in 2 cannabinoid-rich regions
of the brain (the hippocampus and the amygdala) known
to be susceptible to the neurotoxic effects of cannabis exposure
in a sample of long-term heavy users carefully
screened for polysubstance abuse and mental disorders.
Given the growing literature regarding an association between
cannabis use and the development of psychosis20
and cognitive impairment,16,21 we also assessed for subthreshold
psychotic symptoms and verbal learning ability
in this otherwise psychologically healthy sample.
METHODS
PARTICIPANTS
Male cannabis users with long histories of regular and heavy
cannabis use (n=15) and nonusing healthy male volunteers
(n=16) matched on age, estimated premorbid intelligence (National
Adult Reading Test),22 years of education, and state and
trait anxiety (Spielberger State-Trait Anxiety Inventory)23 were
recruited from the general community via a variety of advertisements
(Table). Cannabis users had lower Global Assessment
of Functioning scale scores and greater depressive symptoms
(as measured using the Hamilton Depression Rating Scale)24
than the comparison group; however, there were no current
or lifetime histories of diagnosable medical, neurologic, or psychiatric
conditions as assessed using the Structured Clinical Interview
for DSM-IV Axis I Disorders, Patient Edition.25 All the
control subjects also underwent a Structured Clinical Interview
for DSM-IV Axis I Disorders, Non-Patient Edition.25 Subthreshold
psychotic symptoms were probed using the Scale for the
Assessment of Positive Symptoms26 and the Scale for the Assessment
of Negative Symptoms.27 Regarding alcohol use, the
groups did not differ in levels of current consumption, lifetime
use, or history of abuse or dependence; and no participant
drank more than 24 standard alcoholic drinks per week.
Significantly more cannabis users were also tobacco smokers
(_2=22.9, P_.001) (Table). For all users, cannabis was the primary
drug of abuse, with only limited experimental use of other
illicit drugs (generally _10 lifetime episodes).
PROCEDURE
Participants were assessed on 2 occasions, usually 1 week apart.
In the first test session, participants completed demographic,
clinical, and substance use history assessments. In the second
test session, they completed the Rey Auditory Verbal Learning
Test (RAVLT) and underwent structural MRI.
Participants were asked to abstain from using substances for
at least 12 hours before each test session, and cannabis users
reported abstaining from cannabis for a mean of 21.3 hours before
the first test session (median, 14 hours; range, 10-72 hours)
and a mean of 19.8 hours before the second test session (median,
17 hours; range, 12-48 hours). Urine samples were obtained
from users on 4 occasions and from controls on 2 occasions
to corroborate self-reported abstinence. Specifically, for
cannabis users, samples were obtained on the evening before
each test session and on the day of testing. For controls, samples
were collected only on the day of testing. Examination of these
samples demonstrated that all but 1 cannabis user had cannabinoid
metabolites (11-nor-_9-tetrahydrocannabinol-9-
carboxylic acid creatinine normalized) detected in urine samples
from the first test session, and levels were generally high
(evening: median, 467 ng/mg [range, 0-2320 ng/mg]; day of
testing: median, 447 ng/mg [range, 0-11 293 ng/mg]). From the
second test session, 2 users returned a 0 reading; otherwise,
cannabinoid metabolite levels were again high (evening: median,
456 ng/mg [range, 0-3511 ng/mg]; day of testing: median,
389 ng/mg [range, 0-4470 ng/mg]). The levels of urinary
cannabinoid metabolites generally corroborate the selfreported
patterns of heavy cannabis use in the sample. All but
2 control subjects returned a 0 reading for cannabinoid metabolites
across both test sessions. The 2 controls with positive
urine samples reported only minimal and very occasional
exposure to cannabis. The median level of cannabinoid metabolites
in controls at the first test session was 0 ng/mg (range,
0-184 ng/mg) and at the second test session was 0 ng/mg (range,
0-180 ng/mg).
STRUCTURAL MRI
The MRI data were obtained using a 3-T scanner (Intera; Phillips
Medical Systems NA, Bothell, Washington) at the Symbion
Clinical Research Imaging Centre, Prince of Wales Medical
Research Institute, Sydney. A 3-dimensional volumetric
spoiled gradient–recalled echo sequence generated 180 contiguous
coronal slices. The imaging parameters were as follows:
echo time, 2.9 milliseconds; repetition time, 6.4 milliseconds;
flip angle, 8°; matrix size, 256_256; and 1-mm3 voxels.
Hippocampal, amygdala, whole brain, and intracranial volumes
were measured using established reliable protocols28-31
and were delineated by a trained rater (S.W.) masked to group
information. Specifically, the hippocampal boundaries were as
follows: posterior, the slice with the greatest length of continuous
fornix; medial, the open end of the hippocampal fissure
posteriorly, the uncal fissure in the hippocampal body, and the
medial aspect of the ambient gyrus anteriorly; lateral, the temporal
horn of the lateral ventricle; inferior, the white matter inferior
to the hippocampus; superior, the superior border of the
hippocampus; and anterior, the alveus was used to differentiate
the hippocampal head from the amygdala. The anterior border
was the most difficult to identify consistently and was aided
by moving between slices before and after the index slice. The
amygdala boundaries were as follows: posterior, the appearance
of amygdala gray matter above the temporal horn; superolateral,
the thin strip of white matter that separates the amygdala
from the claustrum and the tail of the caudate; medial, the
angular bundle, which separates the amygdala from the entorhinal
cortex; superomedial, the semilunar gyrus; inferior, the
hippocampus; inferolateral, the temporal lobe white matter and
the extension of the temporal horn; and anterior, the slice anterior
to the appearance of the optic chiasm. Whole brain volumes
were estimated using the Brain Extraction Tool method32
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to separate brain from nonbrain tissue. After brain/nonbrain
segmentation, each voxel was classified into gray matter, white
matter, or cerebrospinal fluid using FAST Model statistical software.
33 Only gray and white matter were used in the estimate
of whole brain volumes. The intracranial cavity was delineated
from a sagittal reformat of the original 3-dimensional data
set. The major anatomical boundary was the dura mater below
the inner table, which was generally visible as a white line.
Where the dura mater was not visible, the cerebral contour was
outlined. Other landmarks included the undersurfaces of the
frontal lobes, the dorsum sellae, the clivus, and the posterior
arch of the craniovertebral junction.
Interrater and intrarater reliabilities were assessed by means
of the intraclass correlation coefficient (ICC) (absolute agreement)
using 15 brain images from a separate MRI database established
specifically for this purpose and that has previously
been delineated by another expert rater. For the hippocampus,
interrater ICC reliabilities were 0.92 (right) and 0.91 (left)
and intrarater ICC reliabilities were 0.98 (right) and 0.95 (left).
For the amygdala, interrater ICC reliabilities were 0.85 (right)
and 0.88 (left) and intrarater ICC reliabilities were 0.93 (right)
and 0.97 (left). Once reliability was established, the rater (S.W.)
delineated the regions of interest for the images acquired from
the present study.
STATISTICAL ANALYSES
Whole brain volume, age, educational level, and estimated IQ
were not significantly different between the 2 groups and were,
therefore, not used as covariates (Table). Regional gray matter
volumes for the hippocampus and amygdala were corrected for
the effect of the intracranial cavity using a previously described
formula34 and were analyzed using analyses of variance,
with hemisphere (left or right) and region (hippocampus
and amygdala) as within-subject factors and group as the
between-subject factor. Main effects and interactions were evalu-
Table. Demographic, Clinical, Drug Use, and MRI Volumetric Measures
Measure
Long-term Cannabis Users
(n=15)
Nonusing Control Subjects
(n=16) P Valuea
Age, mean (SD), y 39.8 (8.9) 36.4 (9.8) .31
IQ, mean (SD) 109.2 (6.3) 113.9 (8.1) .09
RAVLT score, mean (SD)
Sum of 5 learning trials 43.8 (8.8) 57.4 (10.1) _.001
20-min delay 8.9 (4.1) 12.3 (3.7) .009b
Educational level, mean (SD), y 13.4 (3.2) 14.8 (3.7) .28
GAF scale score, mean (SD) 72.0 (11.2) 80.8 (9.4) .02
HAM-D score, mean (SD) 5.87 (3.2) 2.56 (1.9) _.001b
STAI, mean (SD)
State anxiety 34.3 (9.8) 32.9 (9.4) .67
Trait anxiety 39.3 (9.7) 39.0 (8.2) .92
SAPS score, mean (SD) 8.1 (7.9) 0.6 (1.2) _.001b
SANS score, mean (SD) 11.7 (8.5) 1.4 (1.4) _.001b
Cannabis use
Duration of regular use, mean (SD) [range], yc 19.7 (7.3) [10-32] NA NA
Age started regular use, mean (SD) [range], yc 20.1 (6.9) [12-34] NA NA
Current use, mean (SD), d/mod 28 (4.6) NA NA
Current use, mean (SD), cones/mod,e 636 (565) NA NA
Cumulative exposure, past 10 y, mean (SD)f 77 816 (66 542) NA NA
Cumulative exposure, lifetime, mean (SD)f 186 184 (210 022) 12.7 (12.2) _.001
Estimated episodes of use, median (range) 62 000 (4600-288 000) 11 (0-30) _.001
Alcohol use, mean (SD), standard drinks/wk 9.6 (6.1) 6.8 (5.0) .19
Tobacco use, mean (SD), cigarettes/d 16.5 (8.9) 7.5 (9.2) .20
Brain volumes, mean (SD), mm3
Intracranial cavity 1 546 237 (94 018) 1 607 590 (136 386) .14
Whole brain 1 310 780 (90 778) 1 374 123 (105 673) .09
Hippocampus .002g
Left hemisphere 2849 (270) 3240 (423)
Right hemisphere 2949 (244) 3348 (400)
Amygdala .01g
Left hemisphere 1766 (98) 1878 (190)
Right hemisphere 1601 (143) 1744 (158)
Abbreviations: GAF, Global Assessment of Functioning; HAM-D, Hamilton Depression Rating Scale; MRI, magnetic resonance imaging; NA, not applicable;
RAVLT, Rey Auditory Verbal Learning Test; SAPS, Scale for the Assessment of Positive Symptoms; SANS, Scale for the Assessment of Negative Symptoms;
STAI, State-Trait Anxiety Inventory.
aTwo-tailed t test unless otherwise indicated.
bMann-Whitney test.
cRegular use was defined as at least twice a month.
dCannabis users had used at this level for most of their drug-using history.
eA cone is the small funnel into which cannabis is packed to consume through a water pipe in a single inhalation. Without the loss of sidestream smoke, the
quantity of tetrahydrocannabinol delivered by this method is estimated as equating 3 cones to 1 cigarette-sized joint. Thus, the cannabis users in this study
smoked the equivalent of 212 joints per month, or approximately 7 joints per day.
fExpressed as cones for users and as episodes for controls. Estimates of lifetime exposure beyond 10 years in these very long-term users became skewed and
unreliable; hence, the 10-year estimate was used in correlational analyses.
gRegion_group analysis of variance.
(REPRINTED) ARCH GEN PSYCHIATRY/VOL 65 (NO. 6), JUNE 2008 WWW.ARCHGENPSYCHIATRY.COM
696
©2008 American Medical Association. All rights reserved.
Downloaded from www.archgenpsychiatry.com , on June 3, 2008
ated using Greenhouse-Geisser–corrected degrees of freedom,
with _=.05. Effect sizes, expressed as Cohen d, are also reported
for pairwise contrasts. Only effects involving group (cannabis
users vs nonusers) and associations with cannabis use
parameters are reported because this was the primary focus of
the present study. Group comparisons of performance on the
RAVLT and measures of subthreshold psychotic symptoms
(using the Scale for the Assessment of Positive Symptoms and
the Scale for the Assessment of Negative Symptoms) were conducted
using independent-samples t tests or Mann-Whitney tests
for nonnormally distributed data. Pearson product moment correlational
analyses were conducted to examine the behavioral
(ie, symptom and cognitive) relevance of any identified group
differences in regional brain volumes and the association
between these brain changes and parameters of cannabis use.
These analyses were necessarily exploratory given the limited
sample size.
RESULTS
GROUP CONTRASTS
In the analysis of regional gray matter volumes, there
was a significant main effect of group (F1,29=12.98,
P=.001) and a region_group interaction (F1,29=6.25,
P=.02). This result and the post hoc pairwise analyses
demonstrated reduced hippocampal volumes in cannabis
users (F1,29=11.14, P=.002 corrected; a reduction of
12.1% in the left and 11.9% in the right hippocampus
relative to controls), with a very large effect size (Cohen
d: left hippocampus, 1.17; and right hippocampus,
1.27) (Figure 1). Cannabis users also had smaller
amygdala volumes (F1,29=7.31, P=.01 corrected; a
reduction of 6.0% in the left amygdala and 8.2% in the
right amygdala relative to controls), with large effect
sizes (Cohen d: left amygdala, 0.80; and right amygdala,
0.99). The region _ group interaction reflects that the
overall reduction in hippocampal volume was relatively
(and significantly) greater than the reduction in amygdala
volume (12.0% in the hippocampus vs 7.1% in the
amygdala). In the analysis of subthreshold psychotic
symptoms, cannabis users reported significantly higher
positive symptoms (Scale for the Assessment of Positive
Symptoms; z=−3.57, P_.001) and negative symptoms
(Scale for the Assessment of Negative Symptoms;
z=−3.66, P_.001) than nonusing controls. Regarding
verbal learning, cannabis users displayed significantly
poorer performance than controls on the RAVLT measures
(sum of words recalled across the 5 learning trials:
z=−3.97, P_.001; and free recall after a 20-minute
delay: z=−2.61, P=.009).
CORRELATIONAL ANALYSES
There was a significant inverse association between left
hippocampal volume and cumulative cannabis exposure
during the previous 10 years (r=−0.62, P=.01; accounting
for 38% of the variance in left hippocampal volume)
(Figure 2A). When 1 participant with relatively
higher cumulative cannabis exposure and small hippocampal
volume was excluded, 22% of the variance was
still accounted for despite falling short of significance in
the reduced sample (r=−0.47, P=.09). There was also an
association between left hippocampal volume and positive
symptoms (r=−0.77, P_.001) (Figure 2B) and between
positive symptoms and cumulative cannabis exposure
(r=0.52, P=.048) (Figure 2C). The associations
between left hippocampal volume and cumulative cannabis
exposure and between left hippocampal volume and
positive symptoms remained after controlling for the effects
of global functioning (Global Assessment of Functioning
scale) and depressive symptoms (Hamilton Depression
Rating Scale). No other associations were found
between other brain volumetric measures, cannabis use,
and psychotic symptoms, and they did not vary as a function
of alcohol or tobacco use. Measures of RAVLT performance
did not correlate with hippocampal or amygdala
volumes in either controls or cannabis users.
COMMENT
To our knowledge, this is the first human study of longterm
heavy cannabis users to demonstrate marked
exposure-related hippocampal volume reductions.
These findings corroborate previous animal research,6-9
suggesting that long-term heavy cannabis use is associated
with significant and localized hippocampal volume
reductions that relate to increasing cumulative cannabis
exposure. In addition, the present findings are consis-
tent with the view that cannabis use increases the risk
of psychotic symptoms and informs the debate concerning
the potential long-term hazardous effects of cannabis
in this regard. The bilateral reduction in amygdala
volume is a novel but not unexpected finding given the
dense concentration of cannabinoid receptors in this
region.35
Although these findings are consistent with those of
a previous study,18 it is difficult to directly compare these
results with those of other human studies given that past
work used MRI with lower magnetic field strength and
spatial resolution and did not conduct region-of-interest–
based analyses (eg, performed whole-brain voxel-based
analyses18). Tzilos et al14 conducted the only other study,
to our knowledge, that investigated cannabis users with
a relatively long history of use (specifically, an average
duration of use of 22.6 years, or 18.9 years of daily use)
and their study is, therefore, most comparable with the
present study. Although they found no effects of longterm
cannabis use on hippocampal volume, the authors
acquired their images at a lower field strength and with
a coarser spatial resolution (1.5 T with 3-mm-thick slices
vs 3 T with 1-mm-thick slices in the present study), an
important consideration given the size of the brain structures
investigated. Moreover, their region of interest was
less specific to the hippocampus relative to the present
measure because they also included the parahippocampal
gyrus. Furthermore, there was a relatively large age
discrepancy between their users and controls (38.1 vs 29.5
years), and the minimum duration of exposure to cannabis
was considerably lower in their sample (as little as
1 year of cannabis exposure), but, overall, their sample
reported an average of 20 100 lifetime episodes of use.
In contrast, the minimum duration of exposure to cannabis
in the present sample was 10 years, with an average
of 62 000 episodes of use. Thus, despite a similar mean
duration of use, the present sample used more than 3 times
as much cannabis, which may explain the finding of a
dose-response relationship between hippocampal volume
and cumulative cannabis use. Further highresolution
MRI work is necessary to characterize precisely
the dosage of cannabis required for significant brain
changes to occur.
The pattern of use in the present sample is consistent
with heavy cannabis use patterns that have previously
been reported in other Australian studies. For example,
Copeland and colleagues36 reported median daily intake
of 8 cones (the small funnel into which cannabis is packed
to consume through a water pipe in a single inhalation)
in an Australian sample of cannabis users seeking treatment
for cannabis dependence, ranging up to 125 cones
per day in the heaviest user, with 11% reporting cannabis
smoking throughout the day. The heaviest user herein
reported smoking 80 cones per day (approximately 25
joints smoked throughout the day). This pattern of cannabis
use is not dissimilar to the heaviest cannabis users
from other studies of non–treatment-seeking samples of
Australian cannabis users.37,38
Despite the large magnitude of effects observed, it remains
unclear whether these volumetric reductions
reflect neuronal or glial loss, a change in cell size, or a
reduction in synaptic density (eg, dendritic arborization),
all of which have been reported in rodent studies.
6-9 For example, Scallet and colleagues9 found striking
tetrahydrocannabinol-induced residual decreases in
the mean volume of hippocampal neurons and their nuclei
and a 44% reduction in the number of synapses up
to 7 months after the last exposure to tetrahydrocannabinol.
Moreover, Landfield and colleagues7 administered
tetrahydrocannabinol 5 times a week for 8 months
(approximately 30% of the rat lifespan, and comparable
in frequency and duration to the present sample) and
found significant tetrahydrocannabinol-induced decreases
in neuronal density in the hippocampus. Such
findings may help explain the mechanisms underlying
gross hippocampal and amygdala volume loss seen in this
sample of long-term heavy cannabis users.
Left Hippocampal Volume, mm3
In the present study, hippocampal volume in the cannabis-
using group was inversely correlated with cumulative
exposure to the drug in the left, but not right, hemisphere.
Previous functional imaging studies16,39 have found
reduced left hippocampal activation during cognitive performance
in cannabis users, and there is evidence to suggest
that hippocampal abnormalities in psychiatric disorders
such as schizophrenia are more prominent in the
left hemisphere.40 These findings converge to suggest that
the left hippocampus may be particularly vulnerable to
the effects of cannabis exposure and may be more closely
related to the emergence of psychotic symptoms. In this
context, it is interesting that we found a significant inverse
correlation between left hippocampal volume and
positive symptoms. Cannabis use was also positively correlated
with positive symptoms, suggesting that there are
complex associations among exposure to cannabis, hippocampal
volume reductions, and psychotic symptoms.
Given these relationships, it is possible that the exposurerelated
hippocampal reduction may reflect heavy cannabis
use in response to preexisting or developing psychotic
symptoms. However, there is limited empirical
support for long-term self-medication of subthreshold psychotic
symptoms with cannabis and stronger support for
the induction of psychotic symptoms subsequent to cannabis
exposure.20 As such, it seems more likely that prolonged
heavy use of cannabis induced subthreshold psychotic
symptoms and that both of these factors are
associated with hippocampal volume loss. These symptoms
were subthreshold because these cannabis-using participants
were carefully screened for current and past history
of mental disorders. Furthermore, the fact that the
mean age of the present cannabis-using sample was nearly
40 years suggests that these symptoms are unlikely to reflect
a prodrome. One speculation is that the present participants
were less genetically vulnerable to developing
a psychotic disorder subsequent to cannabis use,41,42 allowing
them to smoke heavily for many years. Future longitudinal
work assessing the emergence of hippocampal
reductions and psychotic symptoms with continued exposure
to cannabis, and how these are related to polymorphic
variations in susceptibility genes for psychotic
disorders, will prove useful in better characterizing these
relationships.
Given that cannabis users had significantly greater depressive
symptom scores than controls and that there is
an association between depression and hippocampal volume
reduction,43 it could also be argued that depressive
symptoms may be another mediating factor in the relationship
between cannabis use and hippocampal volume
reduction. However, there are a variety of important
considerations that make this unlikely. First, there
was no significant association between hippocampal volumes
and depressive symptom scores. Second, the relationship
between left hippocampal volume and quantity
of cannabis used was maintained after statistically
controlling for depressive symptoms. Finally, the overwhelming
evidence suggests that hippocampal reductions
in major depressive disorder tend to occur in the
more persistent forms of the disorder (eg, multiple episodes,
repeated relapses, or long illness duration).43,44 This
was not the case in the present sample of cannabis users,
who scored less than 6.0 on the Hamilton Depression
Rating Scale, had never been diagnosed as having
major depression, and did not seek treatment for any depressive
disorder.
Cannabis users showed poorer performance on measures
of verbal learning, consistent with previous findings.
Although some functional imaging studies have
found reduced left hippocampal blood flow and activation
during verbal (and visual) learning tasks in cannabis
users, we found no correlation between RAVLT
performance measures and hippocampal volume in either
controls or cannabis users. It is likely that anatomical volume
is a less sensitive measure than brain activation for
identifying correlations with behavioral performance. This
is a particularly pertinent consideration given that the
performance measures on the RAVLT are likely to reflect
the operation of numerous cognitive processes not
necessarily related to hippocampal function. Future work
using experimental tasks designed to more specifically
probe memory functions mediated by the hippocampus
may be useful in this regard.
The bilateral reduction in amygdala volume is a novel
but not unexpected finding given the dense concentration
of cannabinoid receptors in this region.35 There were
no cognitive, psychotic, or depressive symptom associations
with reduced volume in the amygdala. However,
this region has been significantly implicated in cannabinoid-
associated emotional and reward-related learning
and memory processes.47,48 Given that these aspects of
learning have not been examined in human cannabis users,
they would seem to serve as a potentially informative
avenue forward to help elucidate the functional relevance
of such volumetric reduction in the amygdala.
The relationship between long-term cannabis use and
brain abnormalities is complex. Although a limitation of
this study may be the residual effects of cannabis in light
of the fact that the cannabis users in this study were required
to be cannabis free for only 12 to 24 hours before
MRI, such issues are likely to be more pertinent for studies
examining more dynamic aspects of brain functioning
(eg, activations and cognition).49 The present structural
findings are unlikely to relate to the recent effects
of cannabis use because we are unaware of any evidence
that suggests that the hippocampus and amygdala can
change in volume by 6% to 12% in short periods. However,
although we maintain that the present results reflect
brain changes associated with long-term heavy cannabis
use rather than the consequences of recent exposure,
further longitudinal work is required to assess whether
such changes are reversible across more protracted periods
of abstinence.
Another limitation of this study is the relatively small
sample size, although the sample was exceptionally unique
in that participants were very long-term and heavy cannabis
users (mean of 5-7 joints per day for _10 years)
without polydrug use or co-occurring neurologic or diagnosable
mental disorders. As such, we conducted the
first, to our knowledge, “pure” examination of the effects
of heavy and protracted exposure to cannabis in humans.
The large effect sizes of the main findings suggest
that these results are robust and reproducible. These findings
are further strengthened by the observed dose-
response relationships between hippocampal volume reductions
and cumulative cannabis use.
There is ongoing controversy concerning the longterm
effects of cannabis on the brain.  These findings
challenge the widespread perception of cannabis as having
limited or no neuroanatomical sequelae. Although
modest use may not lead to significant neurotoxic effects,
these results suggest that heavy daily use might indeed
be toxic to human brain tissue. Further prospective,
longitudinal research is required to determine the
degree and mechanisms of long-term cannabis-related
harm and the time course of neuronal recovery after abstinence.
Correspondence: MuratYu¨ cel, PhD,MAPS,ORYGENResearch
Centre, 35 Poplar Rd (Locked Bag 10), Melbourne,

 

A summary of recent scientific findings on the real and adverse impacts of marijuana.

For Further information please contact

Michael Robinson
Executive Director
Drug Free Australia
PO Box H135
Hurlstone Park NSW 2193
Phone 02 9591 8850
Email : info@drugfreeaustralia.org.au

The following summary is a collation of material from a wide source of medical reviews and scientific journals with emphasis on reputable scientific studies rather than editorial commentaries. The following has been collated into the following points for a concise guide

The over-riding principle on which to decide what is in the patient’s best interests must be medical science over rumour or anecdotal opinion.

OVERVIEW

While supporters of marijuana use put forward anecdotal stories and psuedo-science of rumours, myths and snake-oil hype,

… the seriously ill, trusting in the care of medical professionals demand the highest standards of medicine be adhered to, not diverted from.

… Medicine must be based on science.

… As a proposed medical substance, marijuana should be subject to the same level of scientific scrutiny as any other new medicine being suggested for use, when it is it fails the test.

In short, modern medicine is based on fact, not fiction!

15 Reasons to reject marijuana use for the seriously ill include

1) Unacceptable Side Effect Profile.

At the symptom level the toxicity of the oral formulation is almost prohibitive with most cannabis naive patients reporting unacceptable side effects including psychological dysphoria “bad trips.”

This study contains the very interesting observations as follows:

“Although there is an aura that marijuana is a “safe” drug, the untoward psychological (eg. panic, anxiety, depression, psychosis) and medical complications (eg. bronchitis, malignancies, sexual dysfunction) associated with its use are well documented.”

Source: Levin FR “Pharmacotherapy for Marijuana Dependence: A Double blind, placebo
controlled pilot study of divalproex sodium.” Am J Addiction 13: 21-23 (2004)

one journal addressed the clinical consequences of marijuana use. The introductory paper stated

… “that in addition to marijuana abuse/dependence, marijuana use is associated in some studies with impairment of cognitive function in the young and old, fetal and developmental consequences, cardiovascular effects…, respiratory/pulmonary complications… impaired immune function…and risk of developing head, neck, and/or lung cancer. ….” The summary stated further that “…research presented at this workshop suggests that marijuana use is not without health hazards and, within the limits of the available data, is associated with significant adverse consequences affecting almost every physiological system.”

Source: Journal of Clinical Pharmacology 2002;42:7S-10S

….a letter from NIDA’s Marijuana Research Center dated January of 2001 stated that

it had more than 15,000 research papers in its marijuana bibliography. However, it must be noted that because of the many negative consequences associated with marijuana smoking there is a reluctance to do clinical trials on humans. Further, because it remains an illicit drug there is also reticence to spend limited research dollars to determine the interaction of an illicit drug with prescription pharmaceuticals. Nevertheless, research on compounds found in marijuana is ongoing and has lead to the development of a number of prescription drugs with several others currently being accessed. However, smoking marijuana as a medicinal remedy is an unnecessary danger to patients …

Source: Reference: J Clin Pharmacol 2002;42:7S-10S, Khalsa et al
Risk of Heart Attacks increase 4 fold within 1 hour of smoking cannabis

Harvard School of Public Health and Boston’s Beth Israel Deaconess Medical Center that smoking “Marijuana Raises Heart Risks.” The study on which this was based was also published in July of 2001.

Source:Mittleman et al, Triggering Myocardial Infarction by Marijuana, Circulation, (103), 2001.

Now, a report in Forensic Science International, by researchers Bachs & Mørland, of the National Institute of Forensic Toxicology in Oslo, Norway, report on six cases of “cardiovascular death in young adults” …….., the authors reference several other cases of cardiovascular incidents related to cannabis use. The studies reported in this article indicate that using marijuana can increase the risk of stroke and bleeding in the brain, which can result in death.

Source: Thomas Geller, MD; Laura Loftis, MD; David S. Brink, MD; Pediatrics, March 2004
Link to Mental Illness including depression and psychotic episodes tripled by cannabis use

There are now more and more research studies that link mental illness to cannabis use. The following studies are all useful sources

Sources: American Journal of Psychiatry, March 2004
Van Us J, Dutch Study, American Journal of Epidemiology, 2002.
“Cannabis Abuse as a Risk Factor for Depressive Symptoms”
Am J. Psychiatry, 158:12, December 2001. Bovasso

Cancers, Lung Infections and Lung Damage.
“The constituents of cannabis and tobacco smoke include a similar range of pro-inflammatory and carcinogenic substances.”
“The way marijuana is inhaled as opposed to the way tobacco is inhaled means that smoking a ‘joint’ of cannabis results in exposure to significantly greater amounts of combusted material than with a tobacco cigarette.” Regarding the use of waterpipes (bongs) to ameliorate smoking hazards, the paper states: “There appears to be no significant reduction in risk with this modified inhalation technique. There is also a link between psychiatric illness and cannabis use, indicating that this particular subgroup may be at particular risk of respiratory disease with prolonged exposure to both tobacco and cannabis smoke.”

Reference: Internal Medicine Journal 2003;33:310-313, Taylor and Hall.

Smoking marijuana just once or twice a day for a number of years could lead to serious lung disease.

Source: Reported in Join Together March 2000 from Thorax, Journal of British Thoracic Society.
Smoking marijuana can cause cancer

“many people may think marijuana is harmless, but it is not”, Zhang said in a statement. “The carcinogens in marijuana are much stronger than those in tobacco. the big message here is the marijuana, like tobacco, can cause cancer.” Zhang studied 173 patients diagnosed with head and neck cancer, and compared them to 176 cancer free control patients. Those who said they habitually smoked marijuana were more likely to be in the group with head and neck cancers. And the more they smoked , the bigger the risk.

Source: Dr Zhag , Jonsson cancer center University of California,
Reported in journal of cancer Epidemiology Biomarker and prevention Dec 1999.

Researchers report in the July 2000 issue of the “Journal of Immunology” that tetrahydrocannabinol (THC), the major psychoactive component of marijuana, can promote tumor growth by impairing the body’s anti-tumor immunity system.
Source: Roun et al. Biological Psychology Laboratory at Maclean Hospital Limited in haemorrhage Notes Vol. 15, No. 1

Aggravation of pain and muscle spasticity (the opposite of treatment for those suffering AIDS, M.S., Asthma)

Marijuana will not stop Multiple Sclerosis Pain

In findings that contradict earlier research, a team of scientists reports that marijuana does not improve the often painful symptoms of multiple sclerosis (MS). .A previous study in mice indicated that marijuana might help to relieve these painful spasms. However, the amount of the drug used in mice would not be tolerated in humans, the researchers explain. While their study included just 16 patients, it is the largest randomized, controlled clinical trial to investigate the use of marijuana to treat MS.

“Compared to placebo, neither THC nor plant-extract treatment reduced spasticity,” Dr. Joep Killestein from the VU Medical Center in Amsterdam, the Netherlands, told Reuters Health.

Source: Neurology 2002;58:1404-1407.

Smoking can double risk of MS

Smokers are 181 times more likely to develop multiple sclerosis than non smokers according to Dr Trond Riise.

Professor Riise said: “This is the first time that smoking has been established as a risk factor.., hopefully these results will help us learn more about what causes Ms by looking at how smoking affects the onset of the disease.

Source: Dr Trond Riise,University of Bergen Norway reported by ASH Oct 2003

“… since anandamide acts on nerves in the trachea and lungs and is quickly eliminated from the body, an inhaler could potentially control the cough without any side effects. Piomelli says don’t smoke marijuana for asthma, because it could trigger lung constriction and make the problem worse.
Source: Piomelli et al. University of California. Published in Nature . Nov 2000.
2) Inadequate Empirical Evidence

The level of the evidence for its use for the various indications seems to be based at best on preliminary or pilot data. All too often support for marijuana is on anecdotal comment and not scientifically valid data but commonly little more than opinion or anecdotal material.

3) Lack of Comparative Data

This is particularly obvious in the case of the indication for vomiting where there are no comparative trials with the standard serotonin-3 antagonists such as drugs of the ondansetron family. In the case of pain relief, the effects of cannabis appear to be about the same as a moderate dose of codeine, with the notable addition of generally unacceptable side effects.

4) Complexity of the Endocannabinoid System

There are at least two major cannabis receptors and probably three. Their pharmacology is not completely worked out. It is well known that a high concentration of receptors exists on both neurones in the hypothalamus and all of the immune cells of the body. One of the key target groups for whom “medical marijuana” is frequently recommended is AIDS patients. Hence the generally immunosuppressive effects of the cannabinoids should be of major concern in such patients whose immunocompromise is known to be finally lethal.

A third element of this system if the enteric nervous system, which has as many neurones as the brain and spinal cord namely 100 million. Cannabis receptors have been defined in this nervous system, and disorders of bowel function are well known in cannabis addicted patients. This should also worry us – that there is another 100 million neurones whose cannabinoid sensitivies and pharmacology is largely unexplored.

It is also of interest that one of the family of several endocannabinoid molecules 2-acylglycerol, has been noted to change cellular specificity and apparent phenotype of cultured cells from adipocyte to fibroblast. Such radical changes of cellular phenotype imply that usual safety studies will be difficult to guarantee if cellular perturbations of such major degree are involved.

5) Immunosuppression

This immunosuppression is a huge issue in its own right. It is matter of enormous clinical and theoretical interest and implications, and has begun to be explored in great detail in the laboratories of north America. Indeed a senior professional organization has now been formed in the USA to examine this in its own right as it relates to both cannabis and other illicit agents. It is called the Society for Neuroimmune Pharmacology. The effects of this are in fact counter productive indicating that the whole plant marijuana product should never be administered to anyone, let alone someone who is already sick or immune compromised.

Study Finds Marijuana Ingredient Promotes Tumour Growth, Impairs Anti-Tumour Defences

Researchers report in the July 2000 issue of the “Journal of Immunology” that tetrahydrocannabinol (THC), the major psychoactive component of marijuana, can promote tumour growth by impairing the body’s anti-tumour immunity system. While previous research has shown that THC can lower resistance to both bacterial and viral infections, this is the first time that its possible tumour-promoting activity has been reported.

The authors also suggest that smoking marijuana may be more of a cancer risk than smoking tobacco. The tar portion of marijuana smoke, compared to that of tobacco, contains higher concentrations of carcinogenic hydrocarbons, including benzapyrene, a key factor in promoting human lung cancer. And marijuana smoke deposits four times as much tar in the respiratory tract as does a comparable amount of tobacco, thus increasing exposure to carcinogens.

Source: Roun et al. Biological Psychology Laboratory at Maclean Hospital Limited in haemorrhage Notes Vol. 15, No. 1

Cannabis increases tumour growth via several mechanisms including:

1) tars contain many chemicals which are directly tumour stimulating (anthracene’s, nitrosamines, hydrocarbon: higher tar content than
cigarettes);

2) immunosuppressive, reduces immune surveillance and anti-tumour activities of lymphocytes and natural killer cells;

3) altered cytokine production such that permissive cytokines are produced rather than immunostimulatory ones;

4) altered prostaglandin production.

Furthermore these effects occur both by receptor (CB1 and CB2) mediated and receptor independent mechanisms.

All of which means that you CANNOT in good conscience give THC to either AIDS patients or cancer patients, or recommend cannabis for human use.

Source:The PubMed studies

6)
Availability of non-psychoactive congeners

(i.e. there are currently better alternatives and scientific research continues to develop better medicines)

Both cannabidiol and dexanabinol (HU-210) share many of the supposedly beneficial effects of THC but are not psychoactive. As this area is better studied it is likely that many such agents are likely to be made available. With the unacceptably high level of side effects noted in these patients, it would appear to be thoroughly premature to precipitately launch into the making of THC available at this time. A multitude of studies have demonstrated currently available medicines are superior to cannabis.

Source:NeuroReport, Vol. 13, No. 5, 16 April 2002.
Source: Eija Kalso, Associate professor. Pain Clinic, Helsinki University Hospital, Finland BMJ.3212-3.. July 7th 2001

7) Unacceptability of the smoked form of delivery

The toxicity of the smoked form to the aerodigestive tracts, including its association with chronic bronchitis and emphysema and asthma has been agreed upon by major colleges of thoracic medicine worldwide including the Australian and New Zealand Thoracic Society and the British Lung Foundation. Cancer of the mouth, throat, tongue, larynx pharynx have also been noted. Interestingly a high rate of bladder cancer has been noted in some series as cannabinoids are excreted by the urinary route.

Smoking can double risk of MS

Smokers are 181 times more likely to develop multiple sclerosis than non smokers according to Dr Trond Riise.

Source:Dr Trond Riise,University of Bergen Norway reported by ASH Oct 2003
Passive inhalation of cannabis smoke
The blood samples from the passive subjects taken up to 3 hrs. after the start of exposure to cannabis smoke showed a complete absence of cannabinoids. In contrast, their urine samples taken from passive sample up to 6 hrs. after exposure showed significant concentrations of cannabinoid metabolites (less than or equal to 6.8 ng ml-1). These data, taken with the results of other workers, show passive inhalation of cannabis smoke to be possible.

Souce:Law B, Mason PA, Moffat AC, King LJ, Marks V. PMID: 6149279 [PubMed - indexed for MEDLINE]
Cannabis Poisoning
A paediatrician Dr John Goldsmith has come out publicly with a survey he has done in North Island Hospital in NZ. emergency units where babies under the age of 2.5 years are admitted for cannabis poisoning .

Source: Dr John Goldsmith North Island Hospital ,New Zealand, 2002

Unacceptability of the oral form of Delivery
As it is not easily possible to titrate the oral dose exactly a very high rate of unpleasant and dysphoric side effects has been noted. This would appear also to be a sub-optimal route of delivery.

9) The Complexity of bringing drugs to market

The complexity and cost of bringing drugs to market has been noted many times, and is said to cost up to the billions of dollars. Furthermore this is understood never to have been done in Australia. Hence it is only prudent for Australian regulatory authorities including Governments to await formal pharmaceutical trials in nations and entities which have recognized pharmaceutical industries such as Europe and North America. It is prudent not to attempt to bypass this process for litigant as well as compassionate reasons. To inflict upon sick people, the adverse effects of marijuana could be interpreted by the public and the courts as a negligent act of the government who have an over riding responsibility to protect the public from claims that cannot and have not been sustained in evidence.

10) Aging and Stem Cells

With all the recent debate in relation to embryonic stem cells, the central, pivotal and essential role of stem cells which occur in the adult organism appears to have been radically overlooked. Obviously patients addicted to many drugs look prematurely and severely aged. Experimental studies have established for many years that all the illicit drugs of abuse cause single cell programmed death. This appears to occur in an additive and indeed multiplicative manner. One of the worst offenders is THC. It is also established that all the illicit drugs cause an inhibition of stem cell growth. This is well described in the brain and hypothalamus, but also affects other tissues. The combined effects of increased rate of cell death, and reduced rate of cell renewal may potentially be very serious and urgently require further study. This should concern many Governments given the increasing burden of aging on health budgets in many nations. The very real prospect of accelerated aging – especially of vulnerable patients such as those suffering from AIDS should precipitate a major community outcry against all but the most scrupulous clinical use of the appropriately researched cannabinoids.

11) Basic Neuropharmacophysiology

THC actually acts to inhibit synaptic transmission. Receptors exist on the PRE-synaptic side of the synapse and appear to act to turn off neurotransmission. This is known to scientists as “retrograde neurotransmission.” This is of course entirely consistent with the clinical syndrome we see of so-called “dope-heads.” This of course is the major reason it is used – the “downer” or sedative effect.

But the basis of its neuropharmacology should give us great pause indeed, for we appear to be shutting down the brain functions. It should also be added that there is a very close relationship between the opiate and cannabinoid receptor at the molecular level on the cell membrane. Both are 7-transmembrane loop-helix-loop GTP coupled plasma membrane receptors, coupled to inhibitory effects on adenyl cyclase and DNA transcription in the cell nucleus via similar intracellular transduction cascades.

Both are associated with immunosuppression, programmed cell death, and stem cell inhibition. Both occur in similar parts of the brain particularly in the hypothalamus and limbic circuits; both appear to share significant cross-talk at the plasma membrane level. In other words the so-called “gateway hypothesis” which was demonstrated and proven in the Christchurch New Zealand cohort, and was thought to be based on social and values based activities, almost certainly extends also to the molecular and cell membrane level.

12) Sundry Toxicities

Toxic effects on the following systems are accepted even by major cannabis advocates such as Wayne Hall.:

‘In fact the serious adverse effects of Cannabis have been known for some time now. Including adolescent developmental problems, permanent cognitive impairment as well as involvement in and the development of psychosis’.

Source:Hall W, Solowij N, “Long-term Cannabis use and Mental Health” 1997 British Journal of Psychiatry, August,1997 171:107-8

‘Caused disturbance to neural connectivity. However, it seems Cannabis can precipitate or exacerbate a schizophrenic tendency in a characteristic manner’.
Source:Hall W, Solowij N, “Long-term Cannabis use and Mental Health” 1997 British Journal of Psychiatry, August, 171:107-8
Hall A, Degenhardt, “Cannabis and Psychosis” Australian National Drug and Alcohol Research Centre, Presented
at The Inaugural International Cannabis and Psychosis Conf. 1999, Melbourne 16-17 February 1999

Chronic Symptoms of Cannabis Psychosis
‘Patients are left with the well-recognised and permanent symptoms of memory loss, apathy, loss of motivation and, paranoid ideation. ….. there is accumulating evidence of the psychological consequences of using Cannabis’.

Source: Hall W, Solowji N, Lemon J, The health and psychological consequences Monograph Series no 25.
Canberra:Australia Government Publishing Service, 1994 of Cannabis use. Nat. Drug Strategy
a) Driving

More than one in five drivers who died on NZ roads 1995-1997 had been smoking cannabis in the-hours before they crashed. The study found 82 of a sample of 386 drivers had cannabis in their bloodstreams and 54 per cent of the cannabis smokers were over the legal alcohol limit.

Source: Institute of Environmental Science and Research (ESR) in New Zealand. Jan 2000.

Marijuana use can render the user unfit to drive for more than 24 hours and adversely affect cognitive impairment for up to 28 days
Source: Bolla, K.I., et al. Dose-related neurocognitive effects of marijuana use. Neurology 59(9):1337-1343, 2002.

b) Gene toxicity
Genetic anomalies tied with marijuana—activated brain chemicals appear linked to schizophrenia, Japanese researchers report.
This result provides genetic evidence that marijuana use can result in schizophrenia or a significantly increased risk of schizophrenia.
The researchers described their findings in the scientific journal Molecular Psychiatry.

Source:Hiroshi Ujike,Okayama university Japan- Reported in UPI Science News, New York 2002

c) Hormonal and reproductive toxicities
d) Likely effect on cancer

e) Amotivational syndrome

f) Depression

Frequent Marijuana Use Associated With Depression and Anxiety in Teen Girls

Teens, especially girls, who use marijuana frequently are more likely to suffer from depression and anxiety, say Australian researchers.
Teens who used marijuana weekly or more often had twice the risk of experiencing depression and anxiety. The risk of depression and anxiety was greatest among females who used marijuana daily – they had five times the risk of being depressed or anxious than their non-using peers.

Source: George C. Patton; Carolyn Coffey; John B. Carlin; Louisa Degenhardt; Michael Lynskey; Wayne Hall;
British Medical Journal, November 23, 2002
g) Psychosis
its effect to exacerbate supposedly underlying tendencies is agreed upon: several recent papers, including some from Netherlands, also document the occurrence of this severe disorder in patients without pre-existing personal or family history. In this connection it is worth noting that in the laboratory psychosis can be predictably produced in 100% of animals by the combined use of amphetamines and cannabis.

Marijuana and Schizophrenia

In one of the earliest studies that associates marijuana use with schizophrenia, 45,570 Swedish conscripts were asked to report their frequency of cannabis use. Over the 15 year follow up period, conscripts who had used cannabis more than 50 times before conscription had a six times higher risk for development of schizophrenia than non-users. Those who used cannabis 11 to 50 times had a three-fold increase in risk.

Source: Quoted in Taylor H: Analysis of the Medical Use of Marijuana and its Societal Implications.
Journal of the American Pharmaceutical Association 1998; 38: 220-7
h) Cardiovascular

Vasoconstriction occurs in many tissue beds, along with a faster heart rate. This has been associated with heart attack in some recent series, and organ infarction. It is of particular concern in the long term to think that such changes are likely occurring in the brain, along with accelerated cell death. The studies reported in this article indicate that using marijuana can increase the risk of stroke and bleeding in the brain, which can result in death.

Source: Thomas Geller, MD; Laura Loftis, MD; David S. Brink, MD; Pediatrics, March 2004
13) Comments on specific indications:

a) Where it is recommended to be used with prochlorperazine for vomiting. It is likely inferior to ondansetron etc. Side effect profile unacceptable. Seldom used clinically even where it is available to be prescribed.

b) Pain relief. Equal to codeine, plus the nasty side effects. codeine and other alternatives preferred.

c) Appetite stimulation. Minimal effect in published studies. However may be associated with other functions later on. Seems to be associated with morbid obesity developing in a number of heavy users in later decades. (This would appear to include several well-known cannabis advocates). Given that we known that obesity itself is a terrible health disadvantage, this alone should give us great cause. Overweight is also associated with at least 12 cancers, and according to a New England Med J article in 2003, the overall elevated cancer risk in the overweight is 156% of normal, with up to 450% for some tumours such as liver.

The authors reported that “participants reported ‘negative’ subjective effects… [irritable, miserable, bad drug effects, negative mood states] during days after smoking marijuana, but not after oral THC.” They noted that previous studies had found that both dronabinol and smoked marijuana increased “total daily calorie intake and produced abstinence symptoms upon discontinuation of their use.” [NOTE: caloric intake does not remedy wasting syndrome]
The doses of dronabinol and smoked marijuana used in the study were based on the researchers’ previous studies in which they found 20 mg of dronabinol had similar effects to marijuana cigarettes with a potency of 3.1% THC.

In conclusion, the authors note “This finding may have important clinical implications because it suggests that oral delta-9 THC is as effective as smoked marijuana…”

d) M.S. Likely to be acting as an immunosuppressant which should worry us enormously especially in AIDS patients.

e) Epilepsy. Some studies demonstrate also pro-epileptic effects. However there are lots of anticonvulsant drugs on the market currently which have a lesser side effect profile than THC.

f) Glaucoma. It is said that the intra-ocular pressure is lowered after systemic administration only at doses which depress the heart action. Very good drugs already exist for this disorder. A topically applied eye drop may have a role. Whether THC or one of the non-psychoactive cannabinoids would be most suitable remains to be determined.

Reference: Hart et al, Psychopharmacology (2002) 164:407-415

MARIJUANA SMOKING VS. CANNABINOIDS FOR GLAUCOMA THERAPY: A REVIEW

Abstract

This review encompasses the clinical effects, including toxicological data, of marijuana and many constituent compounds on the eye and the remainder of the body.

A perspective is given on the use of marijuana and the cannabinoids in the treatment of glaucoma. The conclusion is reached that although it is undisputed that smoking of marijuana plant material causes an intraocular pressure fall in 60 to 65% of users, continued use at a rate needed to control glaucomatous intraocular pressure leads to substantial systemic pathological changes. Development of drugs based upon the cannabinoid molecule or its agonists, for use as topical or oral antiglaucoma medications, seems to be worthy of further pursuit. Among the latter chemicals are some that have no known adverse psychoactive side effects.

Source: Keith Green, Ph.D., D.Sc., Department of Ophthalmology, Department of Physiology & Endocrinology,
Medical College of Georgia, Augusta, Georgia
14) Addictive and Habit Forming Potential
The addictive capacity of cannabis is now accepted and has been established in the scientific literature at least since the publication of the DSM IV of the American Psychiatric Association in 1994; and has been verified many times in papers since that time. The fact that this is now accepted throws into question its clinical use, for the drug itself is associated with uncontrolled use. Combined with its gateway action in terms of introducing the user to other drugs, this should be a point of major concern for all regulatory authorities, simply because addiction implies that it is not able to be regulated in the normal manner of other therapeutic agents.

15) The T.G.A.

If marijuana is in fact effective, economical and ultimately appropriately suitable to be prescribed to patients then it should pass the demands of Australia’s medical regulatory bodies …. including The Therapeutic Administration. Botanical or crude plant marijuana has not.

Refer to Cannabis with care? Booklet for further details on this concern as well as others

Copies available from Drug Free Australia. PO Box H135 Hurlstone Park NSW 2193
Or email info@drugfreeaustralia.org.au

Here is just one of the many examples of Australian and International professional bodies who oppose marijuana use.

AMERICAN ACADEMY PEDIATRICS STATEMENT

American Academy of Pediatrics Vol. 113 No. 6 June 2004 p.1825 – 1826

Recommendations

1. The American Academy of Pediatrics opposes the legalization of marijuana.

2. The American Academy of Pediatrics supports rigorous scientific research regarding the use of cannabanoids for the relief of symptoms not currently ameliorated by existing legal drug formulations.

CONCLUSION.

In short true compassion for our ill patients necessitates and indeed morally obliges appropriate and disciplined medical care for them.

The normal physiological action of cannabinoids in terms of the inhibition of brain function by retrograde neurotransmission is of major concern to all those concerned with preserving and promoting the neurological and normal brain function of adolescents and young adults, and thus maximizing the neurological potential and intellectual property of the on-coming generation.

If cannabinoids are shown to have a place in evidence based medical therapeutics in the future then, given the well established high side effect profile of these agents, and their horrific long term cumulative toxicities, it is appropriate that patients only be exposed after careful and replicated disciplined and independently controlled clinical trials with appropriate dose forms, or appropriate agents, most likely not THC itself.

It is also appropriate that comparative studies with established and accepted safe agents also be performed.

Issues of genotoxicity, weight gain, immunosuppression, impaired concentration while driving, gateway action at both the molecular and social level, premature aging including suppression of stem cell activity and renewal, and depression of brain function and neurogenesis and psychological toxicity appear to be particularly germane and of very real clinical concern, and the subject of on-going research at this time.

By Ann Stoker, B.A., NDPA.

CANNABIS – INFORMATION

Cannabis information for parliamentary briefings, leaflets and general articles needs to be clearly stated and simple – but with scientific references to source materials. The general public, and young people in particular, have been, and are being, given misinformation, insufficient information or totally incorrect information in many of the leaflets issued by other agencies. Most of these leaflets repeat messages from large organisations such as DrugsScope, (an organisation which was formed from the merging of two other groups ISDD and SCODA) or Connexions. ISDD had been disseminating out of date information for years yet an offer of help with updating the ISDD information on cannabis by a biology teacher specialising in the subject was refused.

HARMFULNESS OF CANNABIS

Given the known harmfulness of cannabis it would be unethical to try to replicate some of the small scale studies which showed significant harm from the use of the substance, The claim that millions worldwide use cannabis is no reason to ignore the harm which the small studies identify, and there are other quite large scale studies showing different elements of possible harm. In the USA there were 77,000 admissions to hospital emergency rooms in 1998 due to the use of cannabis. In the last year or two more and more psychiatrists and doctors have been publicising the fact that thousands of people are suffering from mental illness due to their use of cannabis. In the National Health Service in Britain there is a ‘yellow card scheme’ where GPs who come across even a few examples of contra-indications to prescribed drugs send in the card to flag up ‘caution’. These cautions are taken very seriously since the widespread prescribing of certain drugs could result in another situation Like thalidomide if not identified early on. This scheme could be adopted to note any physical or mental illness which doctors believe is due to their patient’s use of cannabis. We should take notice of any studies showing harm in so many areas from the use of cannabis. The fact that thousands may use and have no apparent adverse effects is of no consequence – many pharmaceutical drugs are withdrawn from general use when they harm a few – even though they may help many others. Professor Gabriel Nahas writes very eloquently on this very point:

The protagonists of the free availability of cannabis who are convinced that this drug does not constitute a serious health hazard will claim that those who wish to ban cannabis must produce convincing reasons before we restrict the individual’s right to choose (Schofield. 1971) – This view is a transposition of a legal concept regarding man’s innocence until proven guilty into the field of medicine, where a different viewpoint prevails in respect to drug usage. indeed, physicians have to take a guarded view of all drugs. which are considered guilty until proven innocent. The state which has the mandate to protect the health of the people, must hold a view similar to that of the physician.
Professor G. Nahas ‘Marijuana – Deceptive Weed’ 1975 Published by Raven Press

It is clear therefore that saying ‘millions use cannabis’ or ‘ I use and it never did me any harm’ is the same as saying that millions drink alcohol and they are not all alcoholics. True. But many are – and the younger they are when they begin to use alcohol the more likely they are to become problem drinkers. Cannabis is no different and more and more research is being published which shows that early onset use of cannabis and other illegal drugs leads to more problematic and chaotic drug use in later life.

MILLIONS USE CANNABIS WORLDWIDE

The often quoted figures that millions’ use cannabis world-wide or’ 2 -6 million have used cannabis in the UK – are themselves very misleading. Several years go the figure of 2 million users in the UK was bandied about – now one reads ‘Up to 6 million users’. Firstly, where is the hard evidence? The activity is illegal and therefore difficult to portray accurately. Were they users in their youth and are they now non-users ? Have these users tried the drug once, twice or many times ? Did they use daily, weekly, monthly, three times a year or once every five years? Did they smoke ditchweed, grass, ganja, resin, sinsemilla, skunk or chaw? These questions are important because the very real harms from the use of cannabis will vary from person to person and are dependent upon the age of onset of use, the length of time used, the frequency of use, the type and purity of the drug used, the strength of the drug used. Thus it is not possible to compare a 50 year old intelligent male who has occasionally smoked an 0.5% THC joint at parties – from the age of 18 – perhaps a total of 100 low potency joints in his life, to an unemployed and alienated young man of 18 who started smoking 0.5% THC joints at 13 years of age and was a daily smoker of skunk (15 – 27% THC) by 15 – which could be well over 700 joints in 2 years. The risks to their health, their education, their employment prospects, their family and social life and their relationships with the opposite sex will be very different.

IS CANNABIS ADDICTIVE?

There is plenty of research that shows cannabis to be an addictive substance. The following authors have all written affirmatively on the subject of addiction.

One of the single most important reasons why there has been an upsurge in the use of illegal drugs by Western youth is the mistaken belief that marijuana is a ‘soft’ drug. not physically addictive, and mood-altering rather than mind altering. Studies of the characteristics of drugs and patterns of their use and the observations of patients, doctors, teachers and ex-drug users have made it clear how misleading these assumptions have been.
Elaine Walters Marijuana – An Australian Crisis’ 1993

Cannabis is readily available on the streets. Were it to be legalised the addiction rate would inevitably he greater. The following quotation concerned narcotics but the point is made that greater availability of drugs leads to greater addiction.
‘The addiction rate to narcotics among the medical profession is estimated to be 30-50 times greater than that of the general population. These statistics suggest that easy availability and the inherent addictive properties of narcotics are important factors…….
Nils Bejerot, ‘Addiction. An Artificially Induced Drive’ published by Charles Thomas. USA

Like all addictive substances, cannabis is not easy to give up. Some believe that it is more difficult to stop all use of cannabis than it is to stop the use of most other drugs.
A marked and rapid tolerance to most of the physiological and neuropsvchological effects of THC occurs. Withdrawal symptoms occur after cessation of heavy daily cannabis administration. As is the case for other drug dependencies, there is no pharmacological cure for cannabis dependency. Therefore, as for treatment of other dependencies, that of cannabis should employ methods that aim at abstinence from the drug so as to foster a drug-free life. Long-term cannabis smokers are difficult to treat because of their denial of the progressive and subtle negative effects of their dependency.
Gabriel G. Nahas, MD. Ph.D. D.Sc. ‘A Manual on Drug Dependence’ 1992
published by Essential Medical Information Systems. Durant. USA
In a study including people who used both cocaine and marijuana, many stated that giving up the use of marijuana was in some ways more difficult than giving up cocaine.
Strategies for breaking marijuana dependence. Zweben & O 1992 (2):165-71
Published in Journal Psychoactive Drugs
Clinically there is no doubt that psychological dependence on marijuana can and does occur. It is the drug of choice of many of the adolescents in our clinic. … Symptoms of psychological dependence parallel those seen in classic adult-onset alcoholism, and, in fact, such a model seems to serve very well for marijuana dependence. Symptoms such as increasing use to the point of tolerance, solitary use, surreptitious use, symptomatic use, blackouts, personality change when intoxicated, inability to control the amount used, preoccupation with use, inappropriate use, and use despite adverse consequences are seen regularly in our adolescent patients… irritability, anorexia, insomnia, and intensive drug seeking behaviour upon cessation of marijuana use (with) relief of these by return to marijuana use.
…a major clinical issue (is that) many children are referred to paediatricians, child psychiatrists and other health care workers for problematic behaviours and the child is not recognised as an extensive marijuana user.., because health care personnel often do not inquire about such drug use, or if they do inquire the child will minimize the extent of use.. there is extensive enabling behaviour , of both an active and passive nature, among school officials, parents and some professionals who deal with children. There appears to be a need for research and education regarding this behaviour if we are to increase our effectiveness in identifying those individuals whose drug use is problematic and in intervening as early as possible.

Marijuana and Youth – Clinical Observations on Motivation and Learning. pages 98-99 Robert Niven M.D.
Published by the National Institute on Drug Abuse. 1982
The prevalence and severity of psychiatric problems and addiction associated with cannabis, has resulted in ‘marijuana-related-dysfunctioning’ being one of the most frequent admission diagnoses in drug treatment facilities.
TheCannabis Connection by Elaine Walters Australia. 1989
Surveys indicate that the percentages of excessive consumers of illegal dependence producing drugs are related to the respective addictive properties of the drugs. Experts have concluded that marijuana addiction frequency, though not as high as cocaine or heroin, is far higher than alcohol. Still when someone has become dependent on marijuana the addiction is as severe and difficult to treat.
Ibid
In 1968 the official classification of psychiatric disorders did away with the term addiction, replacing it with dependence… The result of a sudden termination in use of the drug of addiction, the withdrawal reaction, is well known in the cases of heroin and alcohol. That it occurs with the marijuana discontinuation, to a different degree, is not generallv appreciated.
Bitter Grass – The Cruel Truth About Marijuana by Roy Hanu Hart M.D. Published by Psychoneurologia Press
in Cooperation with the American Academy of Psychiatry &Neurology (AAPN). Kansas.

The pharmacological classification of dependence-producing drugs is as follows:

Toxicity to brain cells (neuropsychological toxicity) with impairment of mental functions and changed perception of reality (‘spaced out’)
A primary pleasure reward from chemical effects on the Limbic Area of the brain, (‘the pleasure centre’).
Craving, compulsion and repetitive self-administration.
Tolerance with daily use; a progressively greater dose needed to get a high.
Mental and/or physical damage from acute or chronic use.

There is also a summary of dependence in decreasing order of severity:

Opiates.
Major psychostimulants – cocaine, amphetamines.
Psychodepressants – Alcohol if greater than 30 mls. per day.
barbiturates. benzodiazepines.
Cannabis (is a psychodepressant but also a stimulant and a hallucinogenic – depending on type used, eg grass, resin or chaw). Hallucinogens – LSD, PCP, Magic mushrooms etc.
Volatile solvents (e.g. aerosols, glue, acetone etc.)
Minor psychostimulants (caffeine etc.)

Source: Marijuana. Elaine Walters Assoc.Printers. AustraliaISBN 0 646 15066 9

Using the above definitions, and just a few extracts from scientific and medical writings, it is clear that cannabis is both physically and psychologically addictive – as any worker in a drug rehabilitation centre could confirm. Relativists say it’s not a problem because it’s only psychologically addictive – in fact psychological addiction is a bigger problem than physical. It is immaterial as to whether cannabis is physically or psychologically addictive (some would say both); there is research to show that cannabis is one of the most difficult drugs to give up and relapse following de-tox. is very common. That is addiction.

LINKS WITH LEGALISERS

Provided the assertions can be backed up by references to source materials, it is essential that cannabis details are truthful – even if they are considered by some to be ‘hard-hitting’. It has been suggested that NDPA should ‘play down’ the harmfulness of cannabis, and not to become involved in the ‘debates’ over legalisation issues. This would be a very short-sighted strategy – the legalisers hide behind pseudo-scientific groups and big money organisations (Drug Policy Alliance, Lindesmith Institute etc.) and will themselves be citing ‘technical’ papers written by their own members (Nadelmann, Zimmer, John Morgan etc. etc.) – who clearly have an axe to grind. Without pointing up the connections between the legalisation movement and some of the misinformation being published (and posted on the Internet), young people may well accept at face value the ‘facts’ they are given by such people.

It needs to be made clear that when reading any research about drugs in general and cannabis in particular, the credentials and affiliations of the authors should be checked carefully. Even ‘evaluations’ can be biased. Scientists or academics who are members of legalisation bodies do produce ‘research’ which puts an attractive and acquiescent spin on drug use. Many of these have publicly admitted that they themselves use illegal drugs. Scientists and medics who publicise studies which show the opposite may belong to anti-legalisation groups – and some have joined these groups because they have first hand experience in their professional capacities of the problems caused by drug use. In between these two dichotomous groups are a large body of professionals with no affiliations to anti or pro-legalisation groups, and who, year after year. add to the body of knowledge about drugs, especially cannabis. The University of Mississippi has over 15,000 research papers about cannabis ‘and none of them give it a clean bill of health.

The following are some quotations from the proceedings of the Second International Symposium ‘Cannabis. Physiopathology, Epidemiology, Detection’, organized by the National Academy of Medicine in Paris in April 1992. This congress consisted of 53 renowned scientists from all over the world who presented papers on cannabis.

‘At a time when strong voices are advocating the relegalisation of illicit drugs, and public health is threatened by the progression of illicit drug consumption, the City of Paris is proud to support outstanding scientific studies which should help to promote prevention programmes for your youth. ….(scientists) are now seeking methods to curtail the use and trivialisation of substances which pollute the internal milieu of man’s brain and physical health and especially that of future generations. Such is our hope and our goal’.
Jacques Chirac. Mayor of Paris. Former Prime Minister of France.
‘And today, all the clinical symptomatology of cannabis intoxication described so accurately by Moreau, (in 1845), and which has been confirmed by many other psychopharmacologists, is being reinvestigated and correlated with biochemical and neurophysiological markers of the brain. Such studies will be discussed in this colloquium which should be another landmark in our understanding of the human brain.’
Henri Baruk. Prof. Honoraire de La Faculte de Medecin

The general conclusions of this international conference were as follows:

1. The toxicity of cannabis is today well established, experimentally and clinically. This drug adversely effects the central nervous system, the lung, immunity and reproductive function.
2. Epidemiological studies have reported that the use of ‘hard drugs’ rarely occurs among subjects who have never consumed cannabis.

3. Consequently, the participants to this colloquium rebut the distinction made between soft and hard drugs.

4. The trivialisation (decriminalization) of cannabis use, where it has occurred, has resulted in a considerable increase of its consumption and of its subsequent damaging effects.

5. It is important to foster a campaign of information and prevention bearing both on the legal aspects and the health consequences of cannabis consumption.

Professor Henri Balon. President. French National Academy of Medicine. April 1992.

The continued increase in the use of illegal drugs, by young people in particular, is a cause for great concern. As Elaine Walters (Australia) wrote so cogently in 1993:
Experience shows that one cannot be in favour of legalisation, and hope to discourage drug use by youth. In the USA during the period in which eleven states decriminalised marijuana half of high school seniors were using, or had experimented with marijuana and 11% became intoxicated daily. ….Drug legalisation will result in more people experimenting with drugs, more experimenters becoming regular users and more regular users becoming addicts.
‘Marijuana – An Australian Crisis’ Elaine Walters 1993.

Many young people receive out of date information from leaflets widely distributed by schools, health promotion units, youth clubs, young peoples’ counselling services etc. They read in newspapers, or watch on television, pseudo debates about ‘de-criminalisation of cannabis’, they are told that they should make their own ‘informed choices’ about use or non-use and that they should ensure that they use ‘responsibly’.

‘The dramatic increase in illegal drug use among adolescents and young adults indicates that drug education programmes in schools need to be reviewed …relevant, accurate and up-to-date information is an important part of the whole approach. No choices should be given to young people about illegal drugs, and their use cannot be regarded as a civil right or privilege. ‘Just Say No’ is a clear and concise message. ….Young people should be taught how to evaluate advertisements, and how to recognise promotion of drug use in music videos, records and other commercialised forms of entertainment. Drug use and under-age drinking among adolescents should not be regarded as ‘normal’. Neither should it be regarded as a psychological problem. It is a behavioural problem which requires correction, intervention and common sense from parents, teachers and members of the community.
Ibid.

We must give the public, and especially young people, information about cannabis which is clear, up-to-date and unequivocal. NDPA acknowledges this need and will continue to provide such information.

By Mary Brett, Head of Health Education, Dr.Challoners Grammar School, Amersham. Bucks.

Paper presented at the Maxie Richards Foundation Conference Glasgow Oct 2003.
Cannabis or marijuana, is our commonest illegal drug, currently used in Britain by around 3.2 million people. Most of them are totally unaware of its damaging effects, especially on the brain.

There are now in excess of 15,000 scientific papers on cannabis. None of the ones I have read say it is a safe drug, and I am assured it is the same for the rest.

We need to know how this damage is caused, and will start with the cells of the brain. Messages pass along the nerve fibres as minute electrical impulses and cross the gap, the synapse, between nerve cells in the form of chemicals called neurotransmitters. These are the brain’s natural drugs and there are dozens of them Each neurotransmitter molecule has a particular shape that fits into its own receptor site on the next cell, as a key fits into a lock.

The mind-altering drugs that people take operate at these synapses. They either mimic the neurotransmitter by shape, increase the rate at which they are released block them or prevent them from being re-absorbed. They take control point out to my pupils that no person can do that, no parent, no teacher or friend. But drugs can.

The psychoactive ingredient in cannabis is a substance called tetrahydrocannabinol, THC for short. It mimics a neurotransmitter called anandamide, from the Sanskrit word, ananda, which means bliss, Receptor sites for anadamide, and therefore THC, exist in many regions of the brain and in other organs of the body. So the actions of cannabis are many and varied.

In the brain, CBI receptors are in the cerebral cortex. In the sensory areas, sound and colour perception are distorted. Muscle coordination and psychomotor skills like driving are impaired in the motor areas, judgement, reasoning and logical thought are also affected. They are also present in the hippocampus where memory and the appreciation of time and space are situated, There are other areas with receptors, but the lack of them in the brain stem which controls automatic functions like respiration, is thought to explain the absence of overdosing. In the rest of the body the receptors are called CB2 receptors.

But it is in .the limbic region of the brain, a circular area in the centre, which suffers the greatest impact from cannabis. This is the seat of the emotions, and its activity determines our moods, whether we are happy or sad anxious or peaceful. Anxiety, depression, panic attacks and even paranoia can be triggered if it is disturbed. It also houses the ‘pleasure ‘or ‘reward’ system. Many drugs affect this area to give a high e.g. cocaine, ecstasy, amphetamines, alcohol and nicotine. Cannabis is no exception. The reason people give for taking cannabis is to get a high or a feeling of euphoria. All these drugs release the neurotransmitter, dopamine. However, THC acts on the CB1 receptors more strongly and for a longer time than anandamide so the effects are enhanced, THC has to be entirely eliminated from the body whereas anandamide is quickly recycled.

One experience of a high leads to another and another. Tolerance develops, receptors need more stimulation and more are produced. Dependence occurs, both psychological and physical. Withdrawal symptoms have been seen, shaking, insomnia, irritability, anxiety and aggression. Not so dramatic as the ‘cold turkey’ of heroin withdrawal since the fat-soluble cannabis remains so long in the body.
Fifty per cent of the THC from a joint will still be there five to six days later and ten per cent after a month, traces can be detected in the hair and urine for weeks after that. Compare this with water-soluble alcohol which disappears at the rate of one unit an hour, the amount in half a pint of beer a glass of wine etc.

In September, 2002, out of the six million drug addicts in the United States, sixty per cent were dependent on cannabis, and more youngsters were being treated there for marijuana dependence than for alcohol. An Australian researcher, Professor Wayne Hall, estimates that of those who ever try cannabis, ten per cent will become addicted, roughly the same as for alcohol.

There is no foolproof cure for any type of addiction.

The effects on the brain are not limited to addiction. People don’t always get the desired euphoria they are seeking. The most common adverse effect is anxiety or even panic. Symptoms can range from restlessness to loss of control to paranoia and fears of impending death. Although these are usually short-lived, occasionally they persist for several weeks.

An American paper in 2001 using nearly 2,000 participants, reported a four-fold increased risk of major depression. The same risk factor emerged in an Australian study of daily teenage female users. A paper in the British Journal of Psychiatry May 2002, found the increased risk for depression was 26 times in teenagers who use cannabis, alcohol and tobacco.

Acute psychosis can occur. A ten-year experiment with decriminalization in Alaska was terminated in 1991 by a public referendum after over 2,.000 people had to be hospitalized and treated in the previous two years for cannabis psychosis. The four to six week treatments were carried out at the taxpayers expense, fuelling anger and resentment. I personally know of six people in some way connected with my school, who have young relatives or friends who have become psychotic due to cannabis use.

A friend of mine lost a son to drugs 2 years ago. He had started using cannabis at the age of fifteen at his public school. And as so often happens progressed through all the other drugs and spent the last few years of his life in care homes and psychiatric institutions. He died of a particularly pure dose of heroin at the age of 45. Shortly before he died, he told his mother he could handle any drug now except cannabis. It made him paranoid and terrified him.

Swedish studies which followed the progress of over 50,000 conscripts, aged eighteen to twenty-five, over fifteen years, discovered that the risk of developing schizophrenia was increased by a factor of six for those who had used cannabis more than fifty times. This was when the concentration of THC was much lower than it is today. In the sixties, the average THC content was 0.5%, now at 5%, it is ten times stronger. Skunk and nederweed, selectively bred varieties from Holland can have THC contents of anything from 9% to 27%. This is a very different drug from the one that fuelled the ‘hippy’ generation.

Other studies have confirmed these findings of mental illness, and one from New Zealand by Dr Louise Arsenault of the Institute of Psychiatry in London in 2002, found a correlation with cannabis and violence. Young males were five times more likely to be violent than non-users, the increased risk for alcohol was three. So much for the cry of the pro-legalisers that youngsters are better off stoned and peaceful than drunk and violent. Whether cannabis actually causes schizophrenia is still to be discovered, but it certainly triggers and exacerbates the condition in vulnerable people. It is interesting to note that increased dopamine activity is implicated in schizophrenia, and other dopamine releasing drugs like amphetamines and cocaine can cause a schizophrenic psychosis. Could this give us a clue as to how cannabis operates?

In a Swedish investigation into suicides, users of alcohol, amphetamines and heroin were compared with marijuana users. More cases occurred in cannabis users than in any other group and the methods used were more violent, No other group jumped from high buildings or murdered others before taking their own lives. There have been several tragic tales in the press in the last year or so, of young people committing suicide after taking cannabis. Maybe people don’t die of an overdose, a common cry of the pro-legalisers but in 1999, in the United States, out of 664 marijuana related deaths, in 187 of them the only drug involved was marijuana.

There is increasing suggestive evidence, both from animal experiments and scans of the human brain, that some cells may die. Brain cells are never replaced. Permanent brain damage is a distinct possibility. It would be slow, subtle, insidious but cumulative.

High densities of CB1 receptors in the cortex and hippocampus cause concentration and the learning and memory processes to be badly impaired. The persistence of THC in the membranes for a long time, compounds the problems. As a schoolteacher, this is the area that causes me most concern.

Even on one or two joints a month, a cannabis personality develops. Users become inflexible, can’t plan their day properly, their problem-solving skills deteriorate, they can’t take criticism and they feel misunderstood. School grades take a nosedive and they often miss out on their chosen university places. At the same time they are lonely and miserable, Trying to talk sense to them becomes a futile exercise. Few children, using cannabis even occasionally, will achieve their full potential.

A few years ago, a former pupil came to see me. He was in his last year of a degree in pharmacology and wanted to do his dissertation on cannabis. Having been a user of cannabis while at school, he had only just managed to scrape into university with C and D grades Most of his friends didn’t make it. “What stopped you”, I asked. He looked surprised. “You did”, he said, “I could quote every word you ever said about cannabis, and all of it came true.”. He also managed to stop some of his friends. He got a first for his dissertation, spent a year with a friend of mine, a toxicologist as a technician, did an MSc in neurology, and is now researching brain diseases towards a PhD.

Because CB1 receptors are in the motor area of the cortex, psychomotor performance and muscle control are affected. People should not drive. Airline pilots, on flight simulators could not land their planes properly even up to and beyond twenty-four hours after a joint and had no idea that anything was amiss. If you have a joint today, you should not be driving tomorrow. Cannabis has been implicated in more vehicle accidents in some American surveys than alcohol, although ten times as many people drink. One ‘spliff’ is thought by some experts to have the same effect as the amount of alcohol needed to just exceed the drink-drive limit.

THC, by dissolving in the fatty cell membranes, expands them, it is a partial anaesthetic, and so interferes with their structures and alters other receptor sites. The transmission of other neurotransmitters is therefore disrupted. It is a multi-faceted drug.

CB2 receptors are found in the cells of our immune system and THC disrupts the copying of DNA into new cells being made in the body. Fewer white blood cells are produced and some are abnormal. As a result, people are more likely to fall ill, their sickness will be prolonged and more severe. AIDS patients, with an already weakened immune system would be well advised to steer clear of this drug.

The heart also contains CB2 receptors. The heart rate is increased and blood pressure rises. A report from an Athens hospital in 2000, found three young men, heavy cannabis users, average age twenty-five, with heart attacks that could not be explained away except by their use of cannabis. A report in 2002 found that middle-aged people were 5 times more likely to have a heart attack in the hour following the smoking of a joint.

Cannabis smoke contains more of some of the carcinogens found in tobacco smoke and deposits three to four times as much tar in the airways. Even 20 years ago, lung biopsies of young French and American soldiers were finding pre cancerous cells, not usually found till middle age in tobacco users. As well as lung cancers, rare head and neck cancers are now being seen in young cannabis users, not found in tobacco smokers till the average age of sixty-four.

Doctors in Sweden are advised to suspect cannabis use when young people present with bronchitis, the link is so common.

Cannabis smoke burns at a higher temperature, the smoke is inhaled deeper and held longer in the lungs. One joint in cancer terms is thought to be the equivalent of five cigarettes. The British Lung Foundation was planning recently to start warning young pot-smokers of these dangers by text messages. Collapsed lungs, lungs shot through with holes and young people needing transplants are all part of the sorry saga.

Sperm have very high concentrations of CB2 receptors, and the female uterus is rich in anandamides, so it is hardly surprising that cannabis can have significant effects on the reproductive process. THC also interferes with the production of the sex hormones.

Human sperm have consistently been seen to be lower in numbers, and with decreased mobility. Surveys on young male pot-smoking patients, twenty years ago in Kingston Hospital, Jamaica, found 20% complaining of impotence and 35% with a sperm count so low, it would render them sterile. And that was when the strength of cannabis was a tenth of what it is today.

A very recent report from Buffalo in The States, showed sperm of cannabis users were less likely to be able to fertilise eggs. The sperm were swimming too fast too soon and burning themselves out long before they could reach the eggs. It also confirmed the significantly reduced numbers of sperm and seminal fluid in cannabis smokers.

In the late seventies and early eighties, a rash of papers found various abnormalities and even stillbirths in the offspring of mice and rats exposed to cannabis. Some of this older research has been criticized for various reasons but in 1994, the eminent cannabis researcher, Australian Professor Wayne Hall said, ‘It would be unwise to exclude cannabis as a cause of malformations until larger studies incorporating better controls have been carried out’.

One thing that is consistent in the research of today and twenty years ago, is the reduction in weight and length of the baby, the equivalent of smoking ten to fifteen cigarettes a day. Low birth weight relates in later life to diabetes, heart disease and high blood pressure. These babies also had mild symptoms of withdrawal. Three studies in the nineties linked cannabis use to a ten-fold increase in cases of one form of leukaemia, and increases in two other forms of childhood cancer.

In December, 2002, one in every eight babies born in The Princess Royal Maternity Hospital in Glasgow, had been exposed to cannabis before birth. Seventy-five per cent of babies exposed to drugs in the womb have medical problems later in life compared to twenty-seven per cent who are not exposed.

Just as I was preparing this talk about a month ago, I met a woman whose daughter had become schizophrenic from cannabis use. She then became pregnant and had a baby at the age of seventeen. She begged her mother to take in the little boy as she could not look after him herself. Grandparents have very few rights so they had to fight through the courts which took most of their savings. The baby suffered from epilepsy for some time after it was born, her daughter will be on medication for life.

The progress of babies born to cannabis-using mothers is being followed in a long-running investigation in Ottawa by Peter Fried and others:

The parents reported above average problems with behaviour, decreased attention and more impulsiveness. Fried has also warned of the delayed maturing of the visual system.

Deficiences in neurological behaviour are not really apparent till the age of four. This is when children start using their ‘executive functions’ (the ability to plan things and solve problems). By the age of 12 these problems were still apparent. Fried also warns that today’s stronger varieties will almost certainly make things worse.

Other researchers have come up with supporting evidence. In two studies of three year-olds, one found the results of intelligence tests to be below normal, the other, investigating sleep patterns, found more problems, more arousals and low sleep efficiency.

I would like now, to address a few of the controversies surrounding cannabis.

The first is the medical argument.

In 1979, a pot-using American lawyer, Keith Stroup, said, “We will use the medical marijuana argument as a red herring to give pot a good name”. In the early nineties, Richie Cowan his successor at NORML, the National Organization for the Reform of the Marijuana Laws, echoed this by saying, “Medical marijuana is our strongest suit. It is our point of leverage which will move us toward the legalisation of marijuana for personal use. This campaign is still ongoing.

There may well be some ingredients in the cannabis plant that may prove beneficial in medicine. But that is the point — the ingredients. Medicines, by law, have to be pure single chemicals so that their actions are predictable and controllable. Heroin and cocaine fall into this category. THC is already available as Nabilone in Britain and Marinol in the USA. The pro-legalisers don’t tell you this — they want their joints. These prescription drugs however are unpopular with doctors because of their side effects. Currently the BMA is testing some of the other cannabinoids, there are around sixty of them in the plant, and no one should have a problem with this. It is estimated that people suffering from glaucoma would need six joints a day to maintain reduced pressure in the eyeball. Hardly useful members of the community. It’s like saying to someone, “take up smoking to get your weight down”. Nicotine suppresses the appetite. Any GP giving this advice would be severely censured.

In November 1996, Proposition 200 permitted physicians in Arizona to prescribe marijuana with no limitation on the age of the patient or the disorder involved. Two months later, in January, 1997, a poll revealed that 85% of the voters believed it should be changed, 60% wanted it repealed and 70% said it gave kids the impression that it was OK to smoke pot. In 1998, 109 distinguished scientists from all over the world, held a conference in New York on medical marijuana. In 1999 their conclusions, published in Marijuana and Medicine, stated, ‘Marijuana or THC do not qualify as safe or effective medications which aim at restoring or maintaining physiological functions of cells, organs and organisms .They have no place in a modern pharmacopoeia from which cannabis was eliminated in the first part of the century’.

A more recent ‘ploy’ of the pro-legalisers is the promotion of hemp. Hemp is cannabis. They claim its needed for everything from ropes to cloth and newsprint. In reality it’s twice the price of the finest linen, paper from trees is much cheaper and ropes rot, and are not so strong as the synthetic ones we use today. Why? — It is a very simple chemical process to extract the 0.25% THC from hemp, purify and concentrate it to a very powerful 40% which they call CHAW.

There is a strong movement for the legalization of cannabis. So who are these people?

Most are users, or their children are. Some, like Richard Branston, would make a lot of money selling it, Others are libertarians. “We can do what we like with our bodies, it’s no one else’s business”. That’s fine as long as it doesn’t affect or interfere with anyone else. But, stoned drivers can and do kill others. Addicts get treatment at taxpayers’ expense. Stoned workers are inefficient and unproductive, and yes, passive smoking does occur. And where’s the liberty in making yourself a slave to a toxic drug for life?

Another controversy is the gateway theory. “Does cannabis lead onto other drugs’ ? Well it can! Lots of surveys in America by Denise Kandel point to this being the case. Level of usage is closely correlated. She found that, of those using mar between 10 and 100 times in their lifetime, 51% went on to harder drugs. From 100 to 1,000, it rose to 79%, and over 1,000 times it was 90%. Studies more recently from Australia and New Zealand, always controlled for confounding factors, have found that weekly users are sixty times more likely to progress, and the trend is confirmed by research on twins.Of course not everyone will go down this route, but almost one hundred per cent of heroin users started on cannabis.

People often compare the cannabis situation today with prohibition in the 30’s. The comparison is false. An attempt was made then to make a drug that was legal, illegal A drug that was used by most of the population, could be used without damage to health and had been around for centuries.

Cannabis is currently illegal, and even when it was legal, was only used by a minority of individuals. Use over the centuries has always been patchy. Regular use of cannabis today is around 8 to 9%, not the 30 to 40% of people who have tried it. How many children try smoking? — 90%? We’re stuck with tobacco and alcohol, If introduced now, they would almost certainly be controlled drugs. We are desperately campaigning to stop people from smoking and abusing alcohol, do we really need another easily obtainable legal drug to add to the misery caused by the other two? Pulling the genie back in the bottle is not an easy task.

In fact, from a health point of view, prohibition was a spectacular success. Alcohol consumption declined, deaths from cirrhosis of the liver fell by one third, cases of alcohol-induced psychosis plummeted. Child neglect, juvenile delinquency and alcohol-related divorces all dropped by 50%.

Now I want to tell you, at least in my view, why we are in such a mess with drugs.

Parents must naturally assume that drug education in schools strongly discourages children from starting to use drugs. They could not be more wrong.

The vast majority of drug educators teach harm reduction and have done so for the past fifteen years or so, Harm reduction has its legitimate place when dealing with known users to try to limit the damage with the aim of getting them to stop. They can be encouraged to ‘chase the dragon’ inhale the fumes from heroin rather than inject it, and so avoid all the blood-borne diseases like AIDS and hepatitis. It has no place in the classroom where around 90% of pupils have no intention of following that way of life.

One of the favourite phrases of harm reductionists is “informed choice There should be no choice — drugs are illegal. Surely teachers of all people should be seen to be upholding the law. And anyway, they are currently not being informed properly, especially about cannabis, to make a choice, more on this later.

Harm reductionists don’t tackle” drugs, they accommodate them. Adults are opting out and abrogating their responsibilities. The first duty of parents, and indeed all adults, is the protection of vulnerable youngsters from anything that puts them in danger. We don’t let our offspring cross a busy road till they are old enough, or run towards a fire and burn themselves, why abandon them to drugs? Nor do we let them choose to break the law in other ways, e.g. speeding or petty pilfering.

It’s not surprising in this climate of acceptance, that drug use is rising, Preventing children from starting to use drugs is, after all not the aim of harm reduction, Children need rules and regulations. The only way they feel safe and secure is when they have boundaries to kick against. They often use their parents as an excuse when they want to opt out. “Dad would kill me”, is a phrase frequently overheard. They have no time for teachers who can’t control a class or try to be trendy. Often the boys who come back to see me after they have left are the ones I have had to discipline most severely.

I never say, “Don’t do drugs” or “just say no”. I simply point out, in biological terms, what can happen to their brains and bodies. I add to that all the social, family, emotional, educational and employment consequences of that way of life and they begin to appreciate its futility of it. Nor am I above a bit of emotional blackmail. I remind the boys that when they were pregnant, their mothers would have been fanatical about what they put into their bodies in case it harmed their unborn child. How devastating must it be for parents to have to sit back and watch their offspring ruining their brains and bodies with toxic chemicals.

Prevention does work. The most spectacular success of a prevention programme was seen in the United States between 1979 and 1991. This was the famous “Just say no” campaign. Don’t let anyone tell you it didn’t work. Parents got fed up with the trendy excuses for drug taking and collaborated with teachers, the police, social and youth workers, customs and excise and the children themselves, to foster the idea that drug-taking is not normal and was indeed harmful, and it worked ! The number of drug users fell from 23 to 14 million, a reduction of 60%, use of cannabis and cocaine halved, daily cannabis taking fell by 75%.

In surveys at the time, the most common reason for abstaining from, or quitting cannabis use was 70% with concerns over physical and psychological damage. Parental disapproval played a large part with a surprising 60%, as did the law, 40%. In 1991, they thought they had licked the problem and took their eyes off the ball. Inevitably usage once again rose, but now, under a new preventionist drug tsar, John Walters, once again it is on the decline.

The Swedes have always had excellent prevention programmes in place, and their whole culture is anti-drug. Sweden has a very low level of drug use.

Harm reduction literature consistently trivializes cannabis. Schools are bombarded with harm reduction literature, some of it is unbelievable and quite shocking. Here are some examples of the Manchester-based charity, Lifeline’s approach. Their leaflet on cannabis shows how a joint is rolled, The last line reads, “A lot of people who are now both parents and grandparents smoked cannabis during the sixties and seventies The first piece of advice they give to kids when their parents find out they are using drugs is ‘Don’t get caught in the first place”. Other street-wise pamphlets are full of graphic pictures of sex and four-letter words.

When I gave evidence to the Home Affairs Select Committee on cannabis, I showed them some of this stuff. They were, to give them their due, collectively shocked, and initiated an inquiry into their funding, which incidentally comes from central government and health authorities. The Sunday Telegraph at that time, took up the story. The latest catalogue had “self-funded” beside many of the pamphlets, so it would appear that something has been done, it would have been nice to have been told.

Drug scope, currently advising the government on all aspects of drugs, distribute a cannabis leaflet with two young men in a field of marijuana, on the policeman’s helmet of one it says, ‘Have fun, take care. They consistently deny that cannabis is physically addictive in spite of abundant scientific evidence to the contrary, and fail to mention some of its effects, while playing down the significance of others. They demand conclusive proof of the long-term effects. We don’t have conclusive proof that cigarettes cause lung cancer, but because of animal experiments and statistical correlations we accept the fact. Why is it different with cannabis? They don’t want anyone arrested for the possession of small quantities of drugs — any drugs! Needless to say, they are enthusiastically endorsing David Blunkett’s ill-advised proposal to down grade cannabis. On Radio 4 on the 27th May this year, Roger Howard, then Head of DrugScope, called for the reclassification of ecstasy and LSD as well as cannabis.

For a government that banned beef-on-the-bone with its infinitesimal risk of causing CJD, it is incomprehensible that they are contemplating a move that will inevitably result in more people using a substance proved to be harmful ‘We must err on the side of caution’, said a government spokesman at the time, Indeed we must, Have we learned nothing from the lawsuits brought by tobacco users?

Since David Blunkett’s ill-advised announcement to down grade cannabis, taking of the drug by 14 to 15 year olds has shot up 50%, from 19 to 29%.

Connexions, an organization now charged by the government to give advice to schools on such matters as careers, counselling and drugs, recently sent drug leaflets to my school, They were written in trendy ‘street-cred’ language by ‘The Clued-up Posse’ a group of kids from Kirkcaldy, Fife. The one on cannabis contained virtually no information on the dangers of pot, but masses on risk reduction. My sixth form thought it was patronizing, useless and positively encouraging of drug use. They also pointed out that it mimicked a Rizla packet. What sort of message does that send out? I made a fuss and The Sunday Telegraph, The Daily Mail and even The Sun took up the story. The leaflet has now been withdrawn.
Talking of messages, this is a worksheet from a book specially written for PHSE in schools. No comment!

Then we have all the blatant promotion of cannabis with logos on T-shirts, jackets and bags and on the front of magazines like Ministry. We have pop-stars and even MPs openly boasting about using cannabis, and songs that glorify drugs. Pro-legalisation articles vastly outnumber those against in the national press, and information about where to get cannabis seeds and paraphernalia is freely available in magazines and on the web. Propaganda like this makes my job a never-ending uphill struggle.

Drugs are illegal because they are dangerous, not dangerous because they are illegal.

The war on drugs has not failed. It has yet to be fought. And it must start with children. Remove the demand and you remove the problem.

I want to finish with two quotes.

Dr Robert Dupont, founder of the National Institute for Drug Abuse in The United States said, ‘I have been apologizing to the American people for the last ten years for promoting the decriminalization of cannabis, I made a mistake. Marijuana combines the worst effects of alcohol and tobacco and has other ill-effects that neither of these two have”.

He also said, ‘In all of history, no young people have ever taken marijuana regularly on a mass scale. Therefore our youngsters are in effect making themselves guinea pigs in a tragic experiment. Thus far our research clearly suggests we will see horrendous results’.

Why has there not been a study to investigate the effect that marijuana may have on the rate at which the immune system degrades in patients who are HIV positive?

Brain Damage Produced by Cocaine

This document has concentrated on the harmful effects of marijuana, because this drug is the fundamental cause of the drug epidemic. Nevertheless, it is prudent to review evidence that cocaine also does serious damage to the human brain, so that youngsters will have all the more reason to reject cocaine.

As reported in 1990, brain scans were employed at Brigham and Women’s Hospital in Boston, Massachusetts to measure blood flow in the brains of cocaine users. Radioactive iodine was injected into the blood, and a three-dimensional projection of the emission from the iodine in the brain was obtained from single photon-emission computed tomography (SPECT). The SPECT display was sensitive to the rate of blood flow in different regions of the brain.

The results were displayed in a dramatic video tape, prepared by English and Holman . The brain scans for all of the regular cocaine users, even those who took cocaine lightly, showed voids in the brain where blood flow was very low. The brain scan of one subject, who used cocaine heavily, had so many voids his brain image looked like Swiss cheese. Yet, this heavy cocaine user was still a functioning individual, who held a full-time job, and so might superficially seem to be using cocaine safely.

This study proved that cocaine cannot be used in moderation. Even in light cocaine users, cocaine drastically reduces blood flow in significant regions of the brain, and so must seriously harm the brain. A copy of this video tape ought to be shown in all drug education programs.
Up to a few years ago, both cocaine and marijuana were widely claimed to be ‘safe, non-addictive drugs’ by many so-called drug abuse ‘experts’. Medical evidence proves that it is physically impossible for anyone to use either marijuana or cocaine in moderation because regular use of either drug, even in modest amounts, produces serious brain damage.

Conclusions

Mark Twain once said: “It ain’t what you don know that hurts you. It’s what you do know that ain’t so.” This is an ideal motto to characterize our failure to stop the drug epidemic.

In the late 1960’so many so-called “experts” on drug abuse expounded the Marijuana Myth, claiming that marijuana is a soft drug, very much less dangerous than heroin, and no more harmful than alcohol.

The Marijuana myth is based on a gross misinterpretation of the effects of marijuana which fails to recognize that THC the psychoactive ingredient in marijuana, is strongly fat soluble, and so is extremely slow acting. Although THC is highly potent, it appears to be mild because it acts so slowly.

The facts show that all arguments supporting the Marijuana myth are fallacious. Scientific medical evidence proves that marijuana is a very dangerous drug, at least as harmful as heroin.

Marijuana itself causes serious damage to the brain and to other elements of the body. Besides, it is a deceptive trap that often lures an unsuspecting casual user into escalating drug abuse, which typically includes other illegal psychoactive drugs and heavy alcohol drinking.

The Marijuana myth was broadly accepted by the public, and this led to extensive marijuana use, particularly by the young. Drug education programs were set up to combat the resultant drug epidemic. However, most of these programs have endorsed the Marijuana Myth, and fail because they are faced with an impossible task. ‘They try to teach kids to keep away from drugs, while supporting the claim that marijuana is no more harmful than alcohol.

Drug educators often teach that “All psychoactive drugs, including alcohol, are equally bad”. But the kids know that many people use alcohol without harm, and this often includes the drug educator himself. Since marijuana and alcohol are equally bad’, the kids frequently conclude that marijuana is no worse than alcohol, and like alcohol can be taken safely if used in moderation.

Regardless of how strongly one preaches “Say No to drugs!”, some kids will experiment with pot if they believe it is relatively harmless. They make the classic statement ‘Since my parents (or other adults that I know) are able to drink alcohol without harm, I should be able to smoke a little pot safely’.

The fat-soluble THC gradually builds up in the bodies of the kids experimenting with pot, and drags them into a trap. More and more kids are drawn, into this maelstrom, as the pot smokers induce others to try their harmless drug, often to provide money to support their steadily escalating desire for pot and other drugs.

Eventually, the damage that marijuana is doing to the pot smokers becomes apparent to their associates and so the other kids learn from direct experience to leave marijuana alone. It is my belief that direct experience is what is saving most young people from drug abuse, not drug education. Unfortunately, this direct experience requires that the lives of the pot smokers be sacrificed in order to educate the rest.

The Marijuana myth is widely believed today for many reasons. Regular pot smokers form a strong body of foot soldiers who are quick to support their favourite drug. Behind them is the disguised propaganda, spread by the very sophisticated and rich leaders illegal drug dealing. These efforts of confusion are magnified by a great many others, who, out of ignorance, are very reluctant to think that their concept of marijuana can be so fallacious.

Many people have experimented lightly with marijuana and luckily escaped without serious harm. They do not want to admit that they played around with a very dangerous drug. How can the harmless ‘grass’ they toyed with be as damaging as is charged? Obviously, they feel, anyone who says that marijuana is highly dangerous must be exaggerating.

A fallacious claim often made to support the Marijuana Myth is that many responsible people have been able to smoke marijuana for long periods without apparent harm. The answer to this claim is that it is very difficult to determine in a specific case how much marijuana a person has smoked, and how much harm it has caused. Remember that the primary damage that marijuana does to the brain occurs in the deep limbic region which controls the emotions. Consequently, a person can appear to be intellectually competent, yet be severely damaged emotionally by his use of marijuana.

A few years ago, Abbie Hoffman wrote a book extolling the virtues of marijuana and telling the readers how to deceive a drug test. Superficially it might appear that marijuana had not harmed him. However, a little later he committed suicide.

The potency of available pot has increased enormously since the 1960 from 1% THC (or less) to as high as 25% today. Hence, the destruction from marijuana is now progressing at a much faster rate. School children today are being seriously harmed by marijuana, even at early grades. It is essential that we discard the gross misconceptions of this drug and give an honest picture a drug education classes.

When our young people are taught the scientific truths about marijuana very few will touch it and our drug epidemic will end.

 

 

By John-Manuel Andriote 

In Parts of Washington’s Gay Community, Crystal Methamphetamine Is Starting to Take a Toll — and Creating a Demand for Treatment

Chad Upham had been the kind of kid any parent would be proud of — an Eagle Scout, a good child who didn’t cause problems in his fundamentalist Christian family. He didn’t touch a beer until he was 21.

Jump forward to an early Monday morning this past July. Upham, now 27, had been up all night after another weekend of drugs and sexual hookups with strangers he met online.

But instead of pushing his limits for indulgence again, he made a different choice. Around 3 a.m., Upham sent an e-mail to his friends and family with some unexpected news.

“Over the past four months,” he wrote, “I have become a regular user of crystal methamphetamine.” He added, “I acknowledge, without shame, a concern for my mental, physical and emotional health.”

While meth abuse is well-established in the U.S. heartland and increasing in New York and Los Angeles, it has had a low profile in the Washington area, where crack cocaine and marijuana are still the targets of most anti-drug programs run by law enforcement and public health agencies.

But meth use is increasing in portions of the gay community, according to local health officials, area addiction and mental health practitioners, and specialists in gay health issues. The District’s Whitman-Walker Clinic, which provides HIV/AIDS and other health services to a largely gay clientele, reports that 75 percent of its new drug treatment clients list crystal meth as their primary drug of abuse. Five Crystal Meth Anonymous groups meet near Dupont Circle, a neighborhood with many gay residents. Two and a half years ago there were none. Suburban treatment centers report an increase in meth-related referrals, including some in teenagers. The D.C. government has just awarded its first grant for an anti-meth public education campaign, which will target the gay community.

The Post reported in July that police in Southern Maryland had found a small methamphetamine lab in the bathroom of a La Plata townhouse — along with a cache of weapons, including grenades and seven rifles, some with bayonets. But that close-in lab is an exception. Federal drug authorities said in a 2002 report that the few meth labs in this region are located in the rural Shenandoah Valley.

Methamphetamine is a homemade, highly impure version of amphetamine, a stimulant that was widely abused in the 1950s through the 1970s. Its main ingredient is distilled from the pseudoepinephrine found in many over-the-counter cold and allergy medications.

Commonly known as crystal, crystal meth and Tina, meth is a potent, highly addictive drug that some experts say can cause long-term neurological and cardiovascular damage. The drug supercharges the central nervous system, causing the brain to churn out dopamine. This neurotransmitter affects brain processes that control movement, emotional response and the ability to feel pleasure and pain.

“Someone said [meth] is like smoking a cigarette, having an orgasm and eating chocolate all at the same time,” said Amy Bullock-Smith, clinical program manager for the Whitman-Walker Clinic’s addiction services, “and all that lasting about 12 hours.”

Meth induces euphoria almost immediately after the odorless, bitter-tasting powder is smoked, the most common way meth is used. It takes a few minutes to feel the same rush from snorting, swallowing, injecting or, less commonly, dissolving it in water and taking it as an enema. This is followed by six to eight hours, and sometimes as much as 24 hours, of increased energy, suppressed appetite and other stimulating effects.

Meth labs can be set up in homes, motels, apartments, trailers, houseboats, cars — anywhere that heat and basic lab tools can be used to cook down cold and allergy medications to extract their active ingredients. Other chemicals used to make meth — according to news reports and numerous Web sites that offer “recipes” — include iodine crystals, red phosphorous from the strike pad on matchbooks, muriatic acid, acetone, methanol and drain cleaner.

A Local View

Aside from its growing use in gay clubs, meth has made little impact in local jurisdictions, officials say.

In its most recent drug threat assessment report, published in 2002, the Department of Justice’s National Drug Intelligence Center described meth abuse as “limited” in Maryland, “a low but increasing threat to Virginia,” particularly southwestern Virginia, and “not yet a serious problem in the District.”

The department said that most meth available in this area was produced in southwestern states or Mexico. It was distributed to users by teenagers and young adults, mostly at nightclubs and raves, large dance parties usually held in warehouses or open fields.

Over the past five years there has been a surge in the number of gay men in the Washington area seeking treatment for meth abuse. Kevin Shipman, manager for special populations in the District’s Addiction Prevention and Recovery Administration, notes that the number of meth referrals to the Whitman-Walker Clinic’s outpatient drug programs is five times higher this year than in 2000.

Local substance abuse treatment programs for adolescents report seeing small but growing numbers of youthful meth abusers.

At the Inova Kellar Center, senior case manager Mary Ellen Ruff said this mental health center in Fairfax is seeing a lot of adolescents who have experimented with meth, though she does not have specific figures. She blames the drug’s accessibility, pointing out that teens “don’t have to go downtown to get it, but can buy it from their neighbors.” She said some teens who abuse attention-deficit hyperactivity disorder (ADHD) drugs — kids without the disorder who get the drugs illegally and use them as stimulants — move up to crystal meth.

Whitman-Walker’s Bullock-Smith said the men turning to her clinic for help with meth addiction are typical of Washington’s professional caste — Type A personalities in fast-paced jobs that require a lot of mental energy. “It’s not necessarily the folks who want to party all the time,” she said.

She points out that people with untreated ADHD seem especially attracted to meth because, much like legally prescribed stimulants such as Ritalin (methylphenidate), the drug paradoxically calms and focuses them. Researchers have suggested that, like crystal meth, methylphenidate amplifies the brain’s release of dopamine, thereby improving attention and focus in individuals who have weak dopamine signals.

Because the drug’s effects can include a supercharged libido, extended periods of high energy and sleeplessness and a much-reduced ability to make sound judgments, unprotected and promiscuous sex is a high risk. Recent studies from San Francisco and Chicago confirm that gay meth abusers are at significantly heightened risk for becoming infected with HIV and other sexually transmitted infections.

A 2003 study in the American Journal of Drug and Alcohol Abuse found that meth users are likely to experience increased respiration and blood pressure, irregular heartbeat and insomnia.

A report in Psychological Medicine in 2003 said that long-term users may experience paranoia, hallucinations, tremors, mood disturbances, repetitive motor activities, homicidal or suicidal thoughts and irreversible damage to small blood vessels that increase the risk of stroke. Children of meth users frequently are at risk for neglect and abuse, the authors found.

Researchers reported in the American Journal of Psychiatry in 2001 that prolonged exposure to even low doses of meth can damage up to 50 percent of the brain’s dopamine-producing cells.

Those who overdose on meth experience hyperthermia and convulsions that, if not treated, can result in death.

“While some people enjoy the short-term benefits,” said Bullock-Smith, “it’s the long-term effects, like the psychosis, that bring them to me.”

Breaking Tina’s Spell

The National Institute on Drug Abuse says the only treatment known to be effective for methamphetamine addiction is cognitive behavioral therapy to modify thinking and behaviors and to increase skills in coping with stressors. The agency says that meth recovery groups, such as Crystal Meth Anonymous, appear to help sustain drug-free recovery, though relapse rates are high.

As for the brain damage meth causes, researchers Gene-Jack Wang and colleagues at the Brookhaven National Laboratory in Upton, N.Y., have offered evidence that some areas of the brain begin to heal after abstaining for as little as two months. Other damage is longer-lasting.

George Kolodner, a board-certified addiction psychiatrist and medical director of the Kolmac Clinic in Silver Spring, said his clinic saw an increase in crystal meth users beginning about two years ago, but the trend has not accelerated since then. He said meth users are the most difficult patients to treat because there is no medication to prevent craving or treat the protracted post-use symptoms, such as dysphoria, or depressed mood.

“With other substances,” said Kolodner, “we can help people get off and keep off by decreasing their cravings. With meth and cocaine, we don’t have that.”

Randy Pumphrey, executive director of the Washington Psychiatric Institute’s Lambda Center, which provides substance abuse services to gay people, said that in the past four years meth has increased from being “something we saw every once in a while” to the third most commonly abused substance, after alcohol and crack, among new clients.

If someone is dependent, said Pumphrey, “they are going to need a period apart from their environment — and also need hospitalization” to deal with the paranoia, severe depression or even homicidal feelings that can accompany the detox process.

After this acute phase, Pumphrey said, patients usually participate in a daytime treatment program for several weeks before joining an extended support program such as Whitman-Walker’s six-month evening program for recovering addicts.

Kolodner said the relative newness of meth-specific support groups is a challenge to treatment because few have been in recovery long enough to serve as mentors.

Bullock-Smith explains that Whitman-Walker’s three-phase ddiction recovery program requires a substantial commitment. To graduate, clients must attend one to three meetings a week at the clinic, participate in an outside 12-step group, have a sponsor, undergo breathalyzer and urinalysis tests to verify that they are not using, see a therapist, have a psychiatric evaluation and complete “lots of homework.”

Let’s Talk About It

A committee including the police department and other District agencies, substance abuse professionals, youth organizations, nightclub owners and recovering addicts began to meet this summer to plan a response to what they view as a growing meth crisis.

Like community-level anti-meth efforts in other cities, the D.C. Crystal Meth Working Group is planning a campaign aimed at educating the nonusing public, preventing meth abuse among gay men and offering treatment referrals to current users. The District health department has provided a $42,000 grant for the group to work with Whitman-Walker on the campaign.

This is a good start, said group member Bruce Weiss, executive director of the Sexual Minority Youth Assistance League, which serves gay, lesbian, bisexual and transgendered youth. The group will seek $1 million from the D.C. government and try to ensure that fighting meth is included in the five-year plan of the task force advising the mayor on anti-drug priorities.

Community activist Christopher Dyer, who chairs the group’s social marketing campaign subcommittee, said the campaign’s slogans, “Let’s Talk About Crystal Meth” and “Crystal Meth Sucks,” will be launched in nightclubs with posters, pins and T-shirts.

Another group member, Ed Bailey, co-owner of Nation, a Southeast Washington dance club, said major club owners across the country support anti-meth campaigns like this one. The drug has cut into their business because people typically do not drink alcohol when they are using meth, he said. Over time they also become increasingly isolated and don’t go to clubs.

Since deciding to live meth-free after one too many sleepless, drug-driven weekends, Chad Upham said he depends mainly on Crystal Meth Anonymous groups and constructive activities with family and friends to support his recovery. Although he saw a doctor for a standard checkup, he — unlike some of his recovering friends — isn’t taking any medications to treat anxiety or depression.

Upham is discovering that Tina continues to tempt.

“I am thinking desirously about the people, places and things that were associated with my using,” he said. Running into a person he knew from those “hot days and nights” revives thoughts of “all that fun.”

But he pulls himself back to his new reality — denying the drug, listening to his family, co-workers and new friends in the support groups he attends several nights a week.

They have “embraced me in my weakness,” said Upham, “continually saying that I am brave, courageous and strong for taking the steps to get and stay healthy and live independent of drugs for satisfaction.”

Source: The Washington Post Tuesday, November 8, 2005

John-Manuel Andriote, author of “Victory Deferred: How AIDS Changed Gay Life in America,” is a Washington journalist. To comment on this article, send e-mail tohealth@washpost.com.

 © 2005 The Washington Post Company

© HNN INTERNATIONAL CENTRE. SWEDEN Oct.2002

Did you know that….

• The Drug Abuse Warning Network (DAWN), a system for monitoring the health impact of drugs, estimated that, in 2001, marijuana was a contributing factor in more than 110,000 emergency department visits in the United States, with about 15 per cent of the patients between the ages of 12 and 17, and almost two-thirds male.

• In 1999, the US National Institute of Justice’s Arrestee Drug Abuse Monitoring Program (ADAM), which collects data from 34 sites on the number of adult arrestees testing positive for various drugs, found that, on average, 39 per cent of adult male arrestees and 26 per cent of adult female arrestees tested positive for marijuana.

• ADAM collected data on juvenile arrestees in nine sites and found that marijuana was the most commonly used drug among these youths. On average, 53 per cent of juvenile male and 38 per cent of juvenile female arrestees tested positive for marijuana.

• Through its effects on the brain and body, marijuana intoxication can cause accidents. Studies show that approximately 6 to 11 per cent of fatal accident victims test positive for THC. In many of these cases, alcohol is detected as well.

• In a study conducted by the US National Highway Traffic Safety Administration, a moderate dose of marijuana alone was shown to impair driving performance; however, the effects of even a low dose of marijuana combined with alcohol were markedly greater than for either drug alone. Driving indices measured included reaction time, visual search frequency (driver checking side streets), and the ability to perceive and/or respond to changes n the relative velocity of other vehicles.

• Marijuana use has been shown to increase users’ difficulty in trying to quit smoking tobacco. This was recently reported in a study comparing smoking cessation in adults who smoked both marijuana and tobacco with those who smoked only tobacco. The relationship between marijuana use and continued smoking was particularly strong in those who smoked marijuana daily at the time of the initial interview, 13 years prior to the follow up interview.

• A study of 450 individuals found that people who smoke marijuana frequently but do not smoke tobacco have more health problems and miss more days of work than non-smokers do. Many of the extra sick days used by the marijuana smokers in the study were for respiratory illnesses.

• A study comparing 173 cancer patients and 176 healthy individuals produced strong evidence that smoking marijuana increases the likelihood of developing cancer of the head or neck, and that the more marijuana smoked, the greater the increase. A statistical analysis of the data suggested that marijuana smoking doubled or tripled the risk of these cancers.

• Marijuana has the potential to promote cancer of the lungs and other parts of the respiratory tract because it contains irritants and carcinogens. IN fact, marijuana smoke contains 50 per cent to 70 per cent more carcinogenic hydrocarbons than does tobacco smoke. It also produces high levels of an enzyme that converts certain hydrocarbons into their carcinogenic form, levels that may accelerate the changes that ultimately produce malignant cells.

• Some adverse health effects caused by marijuana may occur because THC impairs the immune system’s ability to fight off infectious diseases and cancer. IN laboratory experiments that exposed animal and human cells to THC or other marijuana ingredients the normal disease-preventing reactions of many of the key types of of immune cells were inhibited. IN other studies, mice exposed to THC or related substances were more likely than unexposed mice to develop bacterial infections and tumours.

• One study has indicated that a person’s risk of heart attack during the first hour after smoking marijuana is four times his or her usual risk. The researchers suggest that a heart attack might occur, in part, because marijuana raises blood pressure and heart rate and reduces the oxygen-carrying capacity of blood.

• Students who smoke marijuana get lower grades and are less likely to graduate from high school, compared with their non-smoking peers. In one study, researchers compared marijuana smoking and non-smoking 12th-graders’ scores on standardized tests of verbal and mathematical skills. Although all of the students had scored equally well in 4th grade, the smokers’ scores were significantly lower in 12th grade than the non-smokers scores were.

• Several studies have associated workers’ marijuana smoking with increased absences, tardiness, accidents, workers’ compensation claims, and job turnover. A study among municipal workers found that employees who smoked marijuana on or off the job reported more ‘withdrawal behaviors’ – such as leaving work without permission, day-dreaming, spending work time on personal matters, and shirking tasks – that adversely affect productivity and morale.

• Because marijuana compromises the ability to learn and remember information, the more a person uses marijuana the more her or she is likely to fall behind in accumulating intellectual, job, or social skills. Moreover, research has shown that marijuana’s adverse impact on memory and learning can last for days or weeks after the acute effects of the drug wear off. For example, a study of 129 college students found that among heavy users of marijuana, those who smoked the drug at least 27 of the preceding 30 days, critical skills related to attention, memory, and learning were significantly impaired, even after they had not used the drug for at least 24 hours. The heavy marijuana users in the study had more trouble sustaining and shifting their attention and in registering, organising, and using information than did the study participants who had used marijuana no more than 3 of the 30 previous days. As a result, someone who smokes marijuana once daily may be functioning at a reduced intellectual level all of the time.

• More recently, the same researchers showed that a group of long-term heavy marijuana users’ ability to recall words from a list was impaired 1 week following cessation of marijuana use, but returned to normal by 4 weeks. An implication of this finding is that even after long-term heavy marijuana use, if an individual quits marijuana use, some cognitive abilities may be recovered.

• Another study produced additional evidence that marijuana’s effects on the brain can cause cumulative deterioration of critical life skills in the long run. Researchers gave students a battery of tests measuring problem-solving and emotional skills in 8th grade and again in 12th grade. The results showed that the students who were already drinking alcohol plus smoking marijuana in 8th grade started off slightly behind their peers but that the distance separating these two groups grew significantly by their senior year in high school. The analysis linked marijuana use, independently of alcohol use, to reduced capacity for self-reinforcement, a group of psychological skills that enable individuals to maintain confidence and persevere in the pursuit of goals.

• Research has shown that babies born to women who used marijuana during their pregnancies display altered responses to visual stimuli, increased tremulousness, and a high-pitched cry, which may indicate problems with neurological development. During infancy and preschool years, marijuana-exposed children have been observed to have more behavioural problems and to perform tasks of visual perception, language comprehension, sustained attention, and memory more poorly than non-exposed children do. In school, these children are more likely to exhibit deficits in decision-making skills, memory and the ability to remain attentive.

• Long-term marijuana use can lead to addiction for some people; that is, they use the drug compulsively even though it often interferes with family, school, work, and recreational activities.

• According to the 2001 US National Household Survey on Drug Abuse, an estimated 5.6 million Americans age 12 or older reported problems with illicit drug use in the past year. Of these, 3.6 million met diagnostic criteria for dependence on an illicit drug. More than 2 million met diagnostic criteria for dependence on marijuana/hashish. IN 1999, more than 220,000 people entering drug abuse treatment programs reported that marijuana was their primary drug of abuse.

• Along with craving, withdrawal symptoms can make it hard for long-term marijuana smokers to stop using the drug. People trying to quit report irritability, difficulty sleeping, and anxiety. They also display increased aggression on psychological tests, peaking approximately 1 week after they last used the drug.

By Mary Brett

There are several problems associated with the investigation of possible links between cannabis use and any carcinogenic effects it may have on human cells.

There are now some 140,000 or so scientific research papers on tobacco, while those on cannabis still amount only to about a tenth of that number. It is a relatively young science and, like tobacco, its side effects are usually not apparent for decades.

Cannabis smoking has only been widespread in Western society since the early 1970s and there would presumably be a 20 to 30 year latency period between the initiation of smoking and the development of cancer as is the case with tobacco.

Cannabis smokers often mix tobacco with their cannabis so they run all the well-documented risks of developing cancer associated with tobacco smoke. Relatively few of them smoke cannabis alone so any consequences and therefore causes are almost impossible to separate out. Marijuana smokers are more likely to under report their smoking, if they report it at all.

Large samples are required for case-control studies to take place. It is very difficult to get reliable information about an illegal substance from a large number of people. Questions about cannabis smoking are rarely asked of lung cancer patients.

On the other hand the similarities between tobacco and cannabis are many, the main difference being the presence of nicotine in tobacco and the 60 or so cannabinoids in cannabis (Hoffman et al 1975, Tashkin et al 1997, BMA 1997). So similar side effects may be expected.

Cannabis smoke contains 4 to 5 times as much tar as tobacco smoke so the amount of tar deposited in the lungs daily in a cannabis smoker is comparable to that of a tobacco smoker with a 20 a day habit (Benson et al, 1995).

Also the tar from cannabis contains 50% more of some of the carcinogens found in tobacco, notably benzpyrene, a potent carcinogen and a key factor in the promotion of lung cancer (Hoffman et al 1997, Tashkin et al 1997, Novotny et al 1976, Leuchtenberger et al 1983).

For lung cells to become cancerous, a particular combination of cell-growth regulating genes (oncogenes) must become activated or undergo mutation (suppressor genes of tumours).

Marijuana smoke has been reported to produce chromosome aberrations in bacteria as demonstrated by the Ames test (Busch et al 1979 and Wehner et al 1980).

Biopsies of bronchial mucosa have yielded interesting results. Abnormal proliferation of cells (goblet and reserve), transformation of normal ciliated cells to squamous metaplasia (skin-like cells), accumulation of inflammatory cells and abnormal cell nuclei have all been observed (Gong et al 1987, Fliegel et al 1997, Barsky et al 1998). A much higher proportion of these abnormalities was seen in marijuana smokers compared to non-smokers, the number was similar to that of tobacco smokers. Smokers of both tobacco and marijuana exhibited the highest number of all, suggesting the two have an additive effect. Precursors of the development of lung cancer in tobacco smokers include squamous metaplasia and abnormal nuclei (Auerbachet al 1961). Confirmation of these observations also came in 1980 from FS Tennant when he examined US servicemen who were heavy hashish smokers. The mutagenic properties of cannabis smoke were previously recorded in papers in the seventies (Magus and Harris 1971 and Hoffman et al 1975). Human lung explants, exposed to marijuana smoke resulted in DNA and chromosomal alterations (Van Hoozen et al 1997).

Oncogenes and tumour suppressive genes, when mutated, produce proteins which cause cells to multiply rapidly and uncontrollably, resulting in tumours. Two of these proteins were found to be markedly increased in cannabis smokers compared to tobacco or non-smokers, the effects of tobacco and cannabis being additive (Roth et al 1998). The mutagenic effects of marijuana smoke have also been observed by Chiesara and Rizzi 1983, Gilmore et al 1971, Herha and Obe 1974 and Stenchever et al 1974.

Benzpyrene can cause alteration of a gene, P53, one of the commonest tumour suppressor genes if acted on by a chemical particle, CYP1A1. THC has been shown to increase production of this particle so making possible the development of respiratory cancer. P53 is thought to play a part in 75% of lung cancers and it is expressed in 11% of cannabis and tobacco smokers (Dinissenko et al 1996, Marques-Magallanes et al 1997).

The immune system has a role to play in the development of cancer. Alveolar macrophages protect the lungs from infection, they also kill tumour cells. Marijuana and tobacco smokers produce two or three times as many of these cells as non-smokers. The effects of smoking both being additive (Barbers et al 1987). The macrophages in both tobacco and marijuana smokers were larger and had more inclusions, probably due to the ingestion of smoke particles (Beals et al 1989). A more recent paper by Baldwin et al in 1997 found significant impairment of the macrophage cells of both tobacco and marijuana smokers. These cells have been shown to have cannabis receptors (Bouaboula et al 1993). Anti-tumour immunity depends on antigen-presenting dendritic cells being able to stimulate the proliferation of T lymphocytes that identify and destroy tumour cells. In in-vitro studies in which dendritic cells and T lymphocytes were incubated with or without THC, the THC suppressed the T cell proliferation in a dose-dependent manner (Roth et al 1997). Two earlier papers on this subject were written in 1975, Peterson et al and Nahas et al. DNA alterations have been seen in the lymphocytes of pregnant marijuana smokers and their newborns. This study is particularly important as tobacco smokers were excluded (Ammenheuser et al 1998). Cannabis smoking also depressed pro-inflammatory cytokine production. Cytokines regulate macrophage function so this may account for the impairment of their ability to kill tumour cells (Baldwin et al 1997).

Painting tar from marijuana smoke on the skins of mice produced lesions correlated with malignancies (Cottrell 1973).

There are a significant number of reports of human cancers which may be linked to the smoking of marijuana. FM Taylor in 1988 examined adults with upper respiratory tract cancer over a period of 4 years. Of 6 men and 4 women, average age 33.5 years, nine had carcinomas of the lungs tongue or larynx, five were heavy cannabis smokers, two smoked it regularly, one had possibly used other drugs and two were non cannabis smokers. It was complicated by the fact that six were heavy alcohol users and six were smokers of tobacco. He concluded that regular marijuana use was a potent factor especially in the presence of other risk factors. He conceded that alcohol and tobacco may have played a part, but pointed out that the peak incidence for cancers due to tobacco or alcohol is in the seventh decade of life. All of these victims were much younger.

In 1989 Caplan and Brigham reported two cases of tongue cancer. One was a man of 37 the other a man of 52. Both were heavy cannabis users, neither smoked tobacco or drank alcohol. Endicott and Skipper in 1991 conducted a 2-centre USA retrospective study. Twenty-six patients of age 41 or less were diagnosed with throat or head tumours. The normal average age for tumours of this type is 57. All 26 were current or former marijuana smokers.

PJ Donald in 1993 examined patients with cancer of the head and throat over a 20-year period. He found 22 patients of age 40 or under on diagnosis, with squamous cell cancer. Their average age was 26. Nineteen of them were cannabis smokers, 16 being heavy users. In 13 the tumour was in the tongue or elsewhere in the oral cavity. Only half of them smoked tobacco.

110 private patients with lung cancer were studied. Nineteen (17%) of them were under 45. Thirteen of these had smoked marijuana of whom 12 reported current tobacco use. No tobacco-only smoking patients under 45 were noted (Sridhar et al 1994).

An epidemiological study to examine a possible association between cancer and marijuana was published in 1997 by Sidney and colleagues. 65,000 health plan members aged between 15 and 49 in 1979 to 1985 were followed for the development of new cancers till 1993. 182 tobacco-related cancers were detected, of which 97 were in the lungs. The study revealed no risk factors for cancers for lifetime or current use of marijuana.

The major limitation in this exercise is that those who were heavy or long-term users of cannabis were not followed up for long enough to detect cancers. Another criticism is that there may not have been sufficient of these long-term or heavy users to make the study effective. It must be remembered that most marijuana users quit before the level of exposure is sufficient to initiate the development of cancer and cannabis smoking has only been widespread in the USA since the 70s.

The most prominent name and authority on cannabis and diseases of the respiratory system is that of Dr Donald Tashkin. He has researched the topic since the early seventies.

In 1993 he listed the factors suggesting that cannabis smoking may be associated with an increased risk of respiratory tract cancers.

1. Cannabis smoke has 50% more of certain carcinogens than tobacco smoke, especially the highly carcinogenic benz-pyrene.

2. Four times as much tar is produced by a cannabis cigarette than a tobacco one.

3. Experiments on animals have shown that cannabis smoke or tar from it is carcinogenic.

4. Heavy cannabis consumers have significantly higher numbers of cellular changes consistent with the preliminary stages of cancer.

5. There have been several reports of young cannabis-using people exhibiting the development of cancer. Tumours have appeared 10 to 30 years earlier than those who smoked tobacco alone.

In a review paper in 2002 he added that examination of the mucous membranes in long-term smokers suggests that THC weakens the immune defences against tumour cells.

In November 2002 the British Lung Foundation produced a paper “A Smoking Gun? The Impact of Cannabis Smoking on Respiratory Health”. One of their recommendations was: “ The British Lung Foundation recommends a public health education campaign aimed at young people to ensure that they are fully aware of the increased risk of pulmonary infections and respiratory cancers associated with cannabis smoking”.

In September 2003 The Thoracic Society of Australia and New Zealand produced a position paper in The Internal Medicine Journal on the respiratory health effects of cannabis (Taylor and Hall). They also called for a campaign. “Public Health Education should dispel the myth that cannabis smoking is relatively safe by highlighting that the adverse respiratory effects of smoking cannabis are similar to those of smoking tobacco…that the respiratory hazards of smoking cannabis are significant…almost all studies indicate that the effects of cannabis and tobacco smoking are additive and independent”.

In June 2005 Roth and Tashkin of UCLA, the two leading authors of many papers linking cannabis and cancer for over 10 years, described an epidemiological study at the meeting of the International Cannabinoid Research Society in Tampa, Florida. This paper has yet to appear on the ICRS website. Tashkin reported that they had failed to substantiate the link. Needless to say the press immediately issued banner headlines like “Marijuana is safer than tobacco”. However it has emerged that the study lacked statistical power. Tashkin and Roth explained that they had very few patients smoking more than 6 joints a day, a very mild level of consumption. Had they had more moderate and heavy smokers, their outcomes would almost certainly have been different. The study was originally designed to have 3 controls for each cancer case, in reality the ratio was around 0.7. Statistics are powerful but not powerful enough to account for gross flaws in sampling errors and study design.

In 1981 the WHO report on cannabis use said, “It is instructive to make comparisons with the study of effects of other drugs, such as tobacco or alcohol. With these drugs, “risk factors” have been freely identified, although full causality has not yet been established. Nevertheless such risk factors deserve and receive serious attention with respect to the latter drugs. It is puzzling that the same reasoning is often not applied to cannabis”… “To provide rigid proof of causality in such investigations is logically and theoretically impossible, and to demand it is unreasonable”.

Mary Brett, biologist and former head of health education, Dr Challoner’s Grammar School (boys) Chesham Road, Amersham, Bucks. HP6 5HA, UK 17th July 2005 References are available for this paper – please send a s.a.e. to NDPA

by Jane Wheatley

Our correspondent hears testimony to the link between cannabis and psychosis

Judy Mylne woke with a start and glanced at her bedside clock; it was 3am. She went to the window and looked out over the quiet street of terraced houses: in the middle of the road her son James was Rollerblading, up and down, up and down, between the rows of parked cars. He must have woken her as he went out, she thought, leaning her forehead against the cool glass, watching him, feeling sick and afraid.

At first when James had started behaving oddly, being difficult, she’d put it down to normal teenage moodiness, probably exacerbated by his parents’ divorce when he was 16.  He’d always been very good at art, won prizes; you had to make allowances for artistic souls didn’t you? But now, two years later, it was a lot more worrying. He would rant at his mother obsessively about such things as the power of purple; friends avoided him, tutors on his art foundation course said they couldn’t teach him. “He’s a mess,” they told Judy.

One evening he dropped his Walkman on the floor, stamped on it and screamed: “I’m going to kill myself and take you with me.” He head-butted the wall, put his fist through a door and, with blood pouring from head and hand, ran out on to the street. The next day Judy took him to their GP, who referred him to a psychiatrist, to whom James admitted that he had been smoking cannabis regularly. By now he was hearing voices and thought people were following him. One night Judy came home from dinner to find James packing a few random objects into a bag inside a nest of twisted coat hangers. He said he was going to walk to Nepal in the morning.

“I thought: ‘My God, he’s really, really ill’,” Judy recalls. She closed the door quietly, fetched two sleeping pills, dissolved them in a glass of Coca-Cola and took it to him. Then she packed a bag and went to a friend’s house. In the morning she rang her GP, the psychiatrist, her older stepsons and her ex-husband. “I’m not going back to the house,” she told them, “you must go and get James and take him somewhere safe.”

James’s father, a barrister, was in court and asked leave to speak to the judge in his chambers. There he explained that his son had been taking drugs and was possibly psychotic. The judge looked at him: “My son has the same problem,” he said. “Go, and take as long as you need.” 

There but for fortune, it seems, go any of us with teenage children.

Though most people use cannabis without any obvious harm, most of us know of someone — our own child or a friend’s, a friend of a friend’s — who has got into trouble smoking weed, often skunk, which has higher levels of THC, the compound that gets you stoned.

The most extreme cases, such as James, develop a psychosis (schizophrenia or bipolar disorder) from which they may or may not recover. And it is no respecter of class, education or background. Dr Zerrin Atakan, a psychiatrist, sees severe cases at her clinic at London’s Maudsley Hospital: “Sadly many of these young people had been bright, sensitive, happy children,” she says. “Parents often feel dreadfully guilty for allowing them to smoke weed, because in their day, it was relatively harmless.”

Dr Atakan’s patients have usually been smoking from a young age, while the brain is still developing: “We know now that this is a significant risk factor in the development of psychosis. In an ideal world, no one would smoke before the age of 18.”

So, does cannabis cause psychosis? Almost certainly not by itself.

Cannabis-related psychosis is a relatively new feature in the landscape of mental illness and there is little reliable data on it. One study found that people who use cannabis before the age of 15 are at least four times more likely to develop schizophrenia, but all of them probably had a predisposition for psychosis in the first place — sometimes, though not always, indicated by a family history of mental health problems.

A new Australian review of current evidence found that 42 per cent of patients with psychosis had used cannabis. Yet, despite much greater use of skunk during the Nineties, there has been no significant increase in the incidence of psychosis in the past 30 years. Why not? David Kavanagh, of the University of Queensland, is one of the authors of the review:  

 “While cannabis may not cause psychosis, there is no doubt that it will trigger psychosis much earlier in vulnerable young people. This is very important because the period of late adolescence is critical for the completion of education and the development of social, emotional and sexual competence and a psychotic episode during this period is extremely disrupting.

“We also know that cannabis use tends to worsen subsequent symptoms and triggers further episodes.” British researchers believe that, because cannabis use by children is a recent phenomenon, the effects have yet to show in the figures and that there will be an increase in schizophrenia in this current decade. In one study of 2,500 young people, the effect of cannabis use was much stronger in those with a predisposition for psychosis (23.8 per cent) than in those without (5.6 per cent). But even when there is no known family history of mental illness, some children may be genetically more vulnerable than their peers, or have a personality that does not handle cannabis very well, and the Government has ordered a review of the evidence for this. There are genetic tests, but they are expensive and unlikely to be ordered until the damage is done. So how do you tell?

“Well, it’s not written on the forehead,” says Dr Atakan, wryly. Marjorie Wallace, founder of the mental health charity SANE, agrees that you cannot know who is vulnerable: “It’s like watching children playing Russian roulette; one of them is going to be a victim.”

Wallace has worked with schizophrenic young people for 20 years: is there a classic type? “Well, yes,” she concedes, “usually male, often more inward-looking, artistic and sensitive. Often very promising but then he starts to drop out of college, loses friends and slides quietly into isolation. After one psychotic breakdown, there is treatment and partial recovery but then he’ll go back to cannabis, substituting it for his medication.” The key, says Dr Atakan, is early intervention: “There is a prodromal phase of psychotic illness that parents can look out for: a teenager might be a bit more withdrawn, excitable, suspicious, touchy, anxious; he might develop an extreme interest or obsession with one thing, ignoring everything else and avoiding social contact. untreated psychosis — is critical, yet people are baffled and don’t know how to ask for help.”   Like many parents, Judy Mylne did not relate her son’s behaviour to drugs. “I think I was in denial,” she says now. By the time the family rescue squad was called in, he was in full-blown psychosis. He spent a month in the secure Nightingale Clinic, where he was put on a heavy dose of the antipsychotic drug Risperdal and underwent group therapy. He came home and, under the watchful eye of his mother, gradually reduced his dosage. He came off medication entirely in the summer of 2004. This year he completed his art degree, embarked on an MA and is successfully selling his art work.
 
James was lucky: he had a mother who stuck by him and, when the crisis hit, there was money to pay for instant professional help. After the medical insurance ran out, there was high-quality psychiatric support at his local Hammersmith Hospital. But services across the rest of the country are patchy, to say the least. How can parents and teenagers get the help that they need?   Eddie Greenwood is the clinical services director of the mental health charity Rethink; he says that, because governments have been so slow to recognise the causal link between cannabis and psychosis, there is a dearth of provision for young sufferers: “Primary care diagnostic services are often poor. A GP may refer a young person to a community mental health team, but they are unlikely to have a case worker experienced in dual diagnosis — that is, a combination of psychosis and substance abuse.”
The Government is now urging NHS trusts to develop early intervention teams for young people with first-onset psychosis. “But the demand wildly outstrips supply,” says Greenwood, “and the problem is going to get worse before it gets better. ”

“This is the time to seek help. What we call D.U.P. — duration of

Last Christmas, says Judy, she asked him if he would come and help her to get the tree. “He asked me if I’d had a tree when he was in the clinic and who was at home for Christmas Day. I told him, just me and his sister. ‘Oh, Mum,’ he said, ‘I’m so sorry!’” Judy felt like punching the air. “I thought: ‘Yes! Insight, empathy, at last.’ And humour has returned, too. For four years, I hadn’t heard him laugh.”

At the moment, a young person presenting with psychotic symptoms is likely to be sent by his GP for assessment and then referred to a psychiatrist who may prescribe antipsychotic drugs and send him home. For families in rural and under-resourced areas, this could be disastrous. “If you leave these people with arm’s-length treatment, they will just deteriorate,” cautions Greenwood. “The key is active engagement: getting an intervention programme organised around the young person’s needs.”

Dr Atakan agrees: “Where these specialist services exist, they are resourced to supply psychological support as well as medical. Treatment is a contentious issue; it is not ethical to prescribe antipsychotics to young people who may not be psychotic. It’s a complex area.” And cannabis may be a useful scapegoat for families not wanting to face the stigma of mental illness. David Kavanagh: “When a young person develops a psychotic disorder, family members naturally search for reasons. The young person may be blamed for bringing it on himself by smoking. Not only may this not be true, but such hostile criticsm increases the likelihood of further episodes.” Last month, after pressure from police and some drugs charities, the Advisory Council on the Misuse of Drugs considered reclassifying cannabis as a Class B drug. But they are expected to recommend no change on the grounds that there is not enough new evidence to link it with mental illness. The council was also asked to consider giving a higher classification for skunk — “a more potent form of cannabis” — but this is thought to be unworkable. Dr Atakan would rather see cannabis legalised: “The present system is so bad; at least if it were legalised, some control mechanisms could be applied. At the moment it is in the hands of the dealers and it is in their interest to sell strong skunk. It needs to be regulated, like cigarettes, but most importantly there should be a thorough education campaign starting in primary school.”

Marjorie Wallace is dubious. “Until we know more about these new forms of cannabis, with their high THC levels and their effect on the young brain, we should not be giving out the message that this is a soft drug.”

                                                   *     *     *     *     *

“Sometimes I felt that people were talking about what I was thinking about”.  From the age of 14, I was smoking cannabis at weekends; by 18, I was smoking almost every night and doing some chemicals and pills at the weekends (LSD, ketamine, MDMA and cocaine). But, in comparison to others, I wasn’t doing many Class A drugs; I believe it was the consistent and accelerated use of cannabis that led to my diagnosis of drug-induced psychosis in 2000.   Out of about 25 drug users I knew then, three people, including myself, were creative, sensitive individuals — and not as bright as everyone else. I believe we were particularly vulnerable to the effects of cannabis. One of them, my best friend, jumped off a multistorey car park two years ago. The main difference between him and me was that I stopped taking drugs in 2001 and he didn’t. The thing about having something wrong with your mental state is that you can never escape it. When you can’t help yourself, you get angry, frustrated and sad about yourself. I would fleetingly remember my old self, when everything was fine and I was having so much fun — until it hurt too much. I wanted to be that person again. I believed that people were talking about me in public — and what was worse, what they were saying seemed to feed into the tangled web of delusional beliefs that  I had about my life. Sometimes I felt that people were talking about what I was thinking about. As a result, I thought I was some special character in a world that everyone knew of.

Paranoia is fundamentally egotistic and every conspiracy theory serves in some way to aggrandise the believer. My research into Buddhism has shone light on this and given me hope and help. I have recently been told by a doctor that my case is a great success. Certainly I feel one hundred times better than I did four years ago.

JAMES MYLNE

A search on Cannabis Psychosis produced 444 references. Here are the first 10.

 1:  Ferdinand RF, van der Ende J, Bongers I, Selten JP, Huizink A, Verhulst FC. Related Articles, Links  Cannabis-psychosis pathway independent of other types of psychopathology. Schizophr Res. 2005 Nov 15;79(2-3):289-95. Epub 2005 Aug 25. PMID: 16125368 [PubMed - in process]

2:  Verdoux H, Tournier M, Cougnard A. Related Articles, Links  Impact of substance use on the onset and course of early psychosis. Schizophr Res. 2005 Nov 1;79(1):69-75. Epub 2005 Jan 11. PMID: 16198239 [PubMed - in process]

3:  Broome MR, Woolley JB, Tabraham P, Johns LC, Bramon E, Murray GK, Pariante C, McGuire PK, Murray RM. Related Articles, Links  What causes the onset of psychosis? Schizophr Res. 2005 Nov 1;79(1):23-34. PMID: 16198238 [PubMed - in process]

4:  Green B, Young R, Kavanagh D. Related Articles, Links  Cannabis use and misuse prevalence among people with psychosis. Br J Psychiatry. 2005 Oct;187:306-13.PMID: 16199787 [PubMed - in process]

5:  Viveros MP, Llorente R, Moreno E, Marco EM. Related Articles, Links  Behavioural and neuroendocrine effects of cannabinoids in critical developmental periods.Behav Pharmacol. 2005 Sep;16(5-6):353-62.  PMID: 16148439 [PubMed - in process]

6:  Long LE, Malone DT, Taylor DA. Related Articles, Links  Cannabidiol Reverses MK-801-Induced Disruption of Prepulse Inhibition in Mice.Neuropsychopharmacology. 2005 Jul 27; [Epub ahead of print] PMID: 16052245 [PubMed - as supplied by publisher]

7:  Clough AR, d’Abbs P, Cairney S, Gray D, Maruff P, Parker R, O’Reilly B. Related Articles, Links  Adverse mental health effects of cannabis use in two indigenous communities in Arnhem Land, Northern Territory, Australia: exploratory study.Aust N Z J Psychiatry. 2005 Jul;39(7):612-20.
PMID: 15996143 [PubMed - in process]

8:  Henquet C, Murray R, Linszen D, van Os J. Related Articles, Links  The environment and schizophrenia: the role of cannabis use.  Schizophr Bull. 2005 Jul;31(3):608-12. Epub 2005 Jun 23. PMID: 15976013 [PubMed - in process]

9:  Maki P, Veijola J, Jones PB, Murray GK, Koponen H, Tienari P, Miettunen J, Tanskanen P, Wahlberg KE, Koskinen J, Lauronen E, Isohanni M.

Related Articles,

 Predictors of schizophrenia–a review.

Br Med Bull. 2005 Jun 9;73:1-15. Print 2005.

PMID: 15947217 [PubMed - in process]

10:  van Os J, Henquet C, Stefanis N. Related Articles, Links  Cannabis-related psychosis and the gene-environment interaction: comments on Ferdinand et Al. 2005.  Addiction. 2005 Jun;100(6):874-5. No abstract available. PMID: 15918820 [PubMed - indexed for MEDLINE]

 Links

Where to get help:

         www.ukcia.org

          www.rethink.org
       
        www.knowcannabis.org.uk   www.turning-point.co.uk

       

 

The Maudsley Hospital provides a programme for people wishing to cut down their cannabis intake.

Further reading: Marijuana and Madness, edited by David Castle and Robin Murray. Cambridge University Press.

 Source:  The Times November 14, 2005

 

Margret Drewe, Jürgen Drewe, Anita Riecher-Rössler
Psychiatric Outpatient Department and Clinic for Pharmacology und Toxicology,University Hospital Basel, Switzerland

Legalisation of cannabis use in Switzerland has recently been debated by the Swiss Parliament. Although legalisation has not yet been decided upon, it is still the subject of impassioned public discussion. If cannabis use is legalised, an increase in consumption is to be expected. One of the manifold negative consequences for mental health will probably be an increase in the prevalence of psychoses – not only acute, toxic psychosis but also chronic psychoses. Schizophrenic psychoses are expected to be triggered at an earlier age and to be negatively influenced in their course. This eventuality could have deleterious consequences not only for many currently healthy individuals predisposed to psychosis, but also for the disability pension.

 

In Switzerland cannabis is a widely used drug due to its psychotropic effects. It enjoys an almost legally accepted status. The National Health Inquiry (Schweizerische Gesundheitsbefragung 2002) showed that the recreational use of cannabinoids increased significantly during the period 1992–2002. In 2002, 225,000 persons in the 15–64 age group consumed cannabinoids, corresponding to 4.7% of the Swiss population. The proportion of consumers increased in the under-40 age group from 12.2% in 1992 to 21.7% in 2002. In 2002 between 36% and 24.4% of men and women respectively of the 15–24 age group reported that they had consumed cannabis at least once [1]. It may be speculated that the prevalence of cannabis consumption would increase further if consumption were legalised in Switzerland, as the Swiss Parliament has debated. Hence the implications for mental health are of importance. Besides its disturbing effects on psychomotor performance and driving ability [2], development of psychological and physical dependence on cannabis and other drugs [3–5], impairment of cognitive function (memory, attention) [6], changes in personality such as loss of motivation, as described by the term “amotivational syndrome” [7], as well as development of depression and psychosis [5], are reported in the literature. With respect to psychosis, a distinction must be drawn between dose-dependent toxic, so-called drug-induced psychoses and schizophrenic psychoses. The existence of the usually reversible toxic psychoses has been well described [5, 8], but there is still controversy as to whether acute or chronic cannabis consumption can lead to the development of chronic, especially schizophrenic psychoses. In the Mannheim ABC Schizophrenia Study the last author of this paper demonstrated that first-admitted patients with schizophrenia showed a twofold higher prevalence of drug abuse (predominantly cannabis) compared with healthy controls [9, 10]. Experience in our Basel FEPSY – (Früherkennung von Psychosen – Early Detection of Psychosis) project show a similar disproportionate use of cannabis: approximately 75% of our newly diagnosed patients with schizophrenia reported regular use of cannabis (at least several times per month). We shall therefore discuss the evidence in the literature for a causal relationship between the use of cannabis and the development of (chronic) schizophrenic psychoses. We are aware that the kind of relationship between cannabis consumption and development of schizophrenic psychoses is highly controversial [11]: one view is that cannabis use is secondary to psychiatric disorders, or caused by other, concomitantly consumed drugs, or is even due to confounding factors (both cannabis use and psychosis are caused by one or more as yet unknown factors).

A different view is that of a causal or modulating effect (in vulnerable patients) of cannabis use for the development of psychoses. And an integrative view, supported by our own earlier data [9], postulates that both kinds of interaction are possible. In what follows, our criteria for deciding between these views are similar to other authors’ [11, 12]:

Summary

Introduction – Cannabis and risk of psychosis

1) Is there biological evidence of an interaction between the cannabis and the dopaminergic system in cerebral tissue?

2) Is there a statistical association between cannabis use and psychosis and, more specifically,

3) Is there a temporal relationship between antecedent cannabis use and later onset of psychotic symptoms, and, finally

4) Is there a dose-response relationship for cannabis use and development of schizophrenic psychoses?

The importance of dopamine balance in specific brain areas for the development of psychoses has been sufficiently demonstrated, being the basis of the dopamine-antagonistic therapy with neuroleptic drugs. Cannabis may affect this balance by its active psychotropic components, such as tetrahydrocannabinol (THC) and its metabolite 11-OH-THC. It increases dopaminergic activity in relevant areas of the mesolimbic system, possibly by blockade of GABAergic neuronal activity [4, 13]. Cannabis exerts these effects by binding to specific receptors (mainly the CB1-receptor), which interact with local dopamine D2-receptors [14]. Both receptor genes show a significant homology in regulatory parts [15]. Interactions between the two receptors were reported for the striatum of rats and monkeys [16]. The most extensive expression of CB1-receptors is found be important for the development of schizophrenia, namely the mesolimbic and mesocortical dopaminergic system [4]. Further, it has been proposed that genetic mutations of the CB1-receptor gene are accompanied by an increased risk of developing cannabis abuse in schizophrenic patients [17]. The finding of increased blood concentrations of anandamide, an endogenous CB1-receptor agonist, in a group of schizophrenic patients [18] corroborates these findings.

Neurobiological background

Can cannabis consumption lead to short-lasting, “toxic” psychoses?

In the literature there are many case reports on acute psychiatric symptoms after the consumption of sometimes high doses of cannabis, showing the clinical picture of short, reversible toxic psychosis with organic features such as confusion or disorientation. In India, 200 patients were hospitalised after consumption of exceptionally high doses of cannabis because of severe psychiatric symptoms (confusion, emotional lability, disorientation, depersonalisation, paranoid symptoms) [19]. The symptoms lasted for some days, but longer in patients with a history of psychiatric disorders.

Can cannabis consumption also lead to non-toxic psychoses/psychotic symptoms?

In a large-scale enquiry in 1000 persons in New Zealand aged between 18 and 35, 38% reported cannabis consumption. 22% of these subjects reported anxiety and panic attacks and 15% psychotic symptoms following cannabis use. Women reported panic attacks significantly more often than men [20]. In Germany, 36,000 US soldiers were questioned about cannabis consumption. 5120 admitted consuming cannabis at least 3 times weekly. Psychiatric symptoms such as panic attacks or toxic psychoses following consumption of a single high dose of cannabis were reported by 720 soldiers [21]. Van Os and co-workers investigated the effect of cannabis in 4045 healthy subjects and 59 psychotic patients [22]. In a 3-year follow-up investigation the consumers showed a 2.8-fold higher risk (95% CI: 1.2–6.5) of developing psychotic symptoms than non-consuming controls. In the group of patients with pre-existing psychotic symptoms, the risk was 24.2-fold (95% CI: 5.4–107.5) It emerged that the severity of In this study more than 50% of psychotic episodes could be related to consumption of cannabis. The authors concluded that cannabis consumption increases the risk of developing psychotic symptoms in healthy subjects and worsens the prognosis in psychotic patients. The impact of cannabis consumption on the risk of developing psychoses has also been investigated in other studies. Thus, in the National Survey of Mental Health and Well-Being (NSMHWB) [23], a representative poll (N = 10641) showed that cannabis abuse was accompanied by a significant 2.8-fold (95% CI: 1.4–5.9) increased risk of developing psychosis. However, these studies did not further investigate the type of psychosis.

Clinical studies

Can cannabis consumption cause a schizotypal personality?

Cannabis consumption is associated with a schizophrenia-like personality. Several authors show that young consumers and previous consumers have higher scores on schizotypy, and psychoticism scales even when they do not show other psychiatric symptoms. They also show deficits in attentional inhibition and decreased reaction time compared to never-users [24, 25]. The causal relationship of this association is, however, not yet clear: do these personality traits predispose to cannabis abuse or does cannabis abuse induce these changes of personality?

Can cannabis consumption also trigger or even cause schizophrenic psychoses?

A historical cohort study in more than 50,000 Swedish conscripts over an observation period of some 27 years investigated the importance of cannabis consumption for the development of schizophrenia and psychoses [26]: young men who reported previous cannabis consumption on more than 50 occasions at the outset of the observation period showed a 6.7-fold (95% CI: 4.5–10.0) increased risk of later hospitalisation for schizophrenia and other psychoses. The latter author also reported very interesting results in the ABC study (Age, Beginning and Course of Schizophrenia): this study investigated 276 first-time hospitalised schizophrenic patients (232 with first episode) [27, 28]. Twice the number of patients reported a lifetime history of substance abuse than healthy controls – 14.2% versus 7% [9, 29]. Of these patients 88% consumed cannabis, in approx. 60% of whom cannabis consumption preceded even the first still very unspecific symptoms of schizophrenia [29], on average by about 4.5 years [9]. In 35% of cases the first unspecific symptoms were reported to have occurred in the same month as the start of drug consumption. Cannabis-consuming patients were significantly younger than non-consuming patients. The authors therefore concluded that cannabis consumption may have precipitated (triggered) the onset of schizophrenia in predisposed (vulnerable) patients and aggravated the symptoms [29, 30]. However, there may also be a subgroup of patients who have started to use cannabis to attenuate the first [9, 31, 32]. (pre-)psychotic symptoms as a form of self-therapy.

In a recent reanalysis of five large (N = 1011 to 50,053 patients) studies [22, 26, 33–35] Smit et al. pointed out that in these studies there was a clear temporal relationship of antecedent cannabis use before first psychiatric symptoms were observed[11]. Effects of other concomitantly used drugs were excluded and the effects of other confounders were taken into account in four of these studies. In two of them [22, 26] a dose-dependent increase in psychosis risk was observed. As the authors pointed out, this does not imply that psychotic patients “do not use cannabis as a form of ‘self-medication’, but these results do imply that cannabis use increases the risk of later schizophrenia even when self-medication can be ruled out as an explanation” [11]. Verdoux et al. [36] found that young undergraduate students with high vulnerability to development of psychosis reported more unusual perceptions and feelings of thought influence after cannabis consumption than subjects with low vulnerability. Interestingly, they could not find evidence of increased use of cannabis following the occurrence of psychotic experiences. This contradicts the self-medication model in the psychotic stage but not necessarily in the still unspecific prodromal stage. Young age appears to increase the risk of developing psychotic symptoms following cannabis use. In a prospective longitudinal study Arseneault et al. [34] investigated whether adolescent cannabis use is a risk factor for adult schizophreniform disorders. The study was performed in 1037 adolescents from New Zealand and showed that cannabis consumption at age 15 years significantly increased the risk of developing schizophrenia(4.5-fold, 95% CI: 1.1–18.2) up to age 26. However, cannabis consumption at age 18 increased the risk only 1.7-fold (95% CI: 0.7–4.2). These results were corroborated by a birth cohort in 1265 children [35] studied to age 21. The authors showed that subjects fulfilling DSM-IV criteria for cannabis dependence had elevated rates of psychotic symptoms as compared to individuals without cannabis dependence – at age 18 the increase was 3.7-fold (95% CI: 2.8–5.0) and at age 21 2.3- fold (95% CI: 1.7–3.2). This significant increase was still present when data were adjusted for pre-existing symptoms or other background factors. Despite this close association of cannabis use with schizophrenia, the causal relationship between cannabis consumption and schizophrenic psychosis is still controversial. On the one hand, many studies show an increased risk of developing schizophrenia in patients consuming cannabis; on the other hand, in a simulation Degenhardt [37] showed that a causal relationship would have led to a significant increase in the incidence of schizophreniain Australia, which has, however, not been observed [8]. A possible explanation for the lack of evidence of an increase in schizophrenia rates in epidemiological studies may be a reporting bias: in clinical studies, which usually find this association, exposed patients have been systematically studied for psychiatric disturbances in one or more follow-up investigations. This has led to detection of mild psychotic symptoms, which outside clinical studies may not have been detected (underreporting). Also, the proportion of cannabis-induced schizophrenia may be small and, therefore, an increase inschizophrenia rate attributed to cannabis use may not be easily detectable. On the other hand, Boydell et al. [38] recently reported a continuous and statistically significant increase in the incidence of schizophrenia from the London area for the period 1965–1997. Interestingly, this increase was most marked in people under 35 years of age and was not gender-specific. Furthermore, it is conceivable that cannabis is not causal in a narrow sense, but merely triggers the outbreak of schizophrenic psychoses in individuals with a specific (genetic) vulnerability for this disease. Cannabis use would then simply result in earlier manifestation of schizophrenia in these vulnerable patients rather than an increased incidence. Evidence for this has just been published [39]. This alone would also be relevant, since it has important implications for the mental and educational development of these patients. If the onset of first symptoms is earlier, have not usually completed their professional education and have not developed a sufficient social network. Earlier onset due to a “cannabis trigger” may therefore be associated with a worse prognosis of schizophrenia, especially regarding its psychosocial course.

Can cannabis consumption worsen the progression of schizophrenia?

The productive symptoms of psychosis are amplified by concomitant consumption of cannabis. Compliance with antipsychotic treatment and utilisation of rehabilitation programmes are impaired [29]. Schizophrenia patients with cannabis use suffer from more frequent and earlier relapse episodes [40, 41]. Because of the dopaminergic effects of cannabis it can be speculated that cannabis-consuming patients suffering from schizophrenia may need higher doses of antipsychotic (anti-dopaminergic) medication. Psychotic patients with cannabis consumption are usually younger, predominantly male and show more criminal behaviour [42]. On the basis of our criteria, the following conclusions can be drawn:

– Cannabis consumption modulates dopamine concentrations in certain brain areas, and can thus induce or modulate the development of psychotic symptoms and psychosis.

– Cannabis in high doses may induce acute, reversible (toxic) psychoses.

– Cannabis may also induce the manifestation of schizophrenic psychoses in vulnerable patients (“dopaminergic stress”) or at least trigger an earlier onset in this population.

– Young age is an additional risk factor for the development of psychoses.

– Concomitant cannabis consumption may affect the progression of schizophrenic psychoses and worsen the prognosis.

– Cannabis consumption is associated with a schizotypical personality, the causal relationship of which is not yet clear.

– Cannabis consumption can also lead to other psychiatric disorders, including depression and may result in a severe loss of energy and cognitive disturbances.

Conclusions

To obtain more definite answers to the questions of causality, dose-effect relationship, the severity and time course of these effects, the importance of other confounding factors, and, finally, the size of the impending burden for the individual and the society, we urgently need additional prospective longitudinal studies. Nevertheless, at this stage of research we can and should, depending on our view, already sound a note of warning, especially as the potency of the substances used and the prevalence of abuse and dependence are apparently growing [43]. Increased cannabis consumption in our society could have deleterious consequences for many so far healthy individuals, not only because of the negative influences on education and work performance due to impairment of cognitive function and loss of energy, but also due to the “psychotogenic” properties of cannabis. Healthy individuals with a currently “hidden” predisposition to psychosis could develop full blown psychosis. In individuals vulnerable to schizophrenia the outbreak of this disorder could be triggered at an earlier age and negatively influenced in its course. This would not only have severe psychosocial consequences for the individual and his family. As schizophrenia is already one of the most expensive diseases, this could also have negative consequences for the national economy – inter alia due to the high level of disability pensions at a very young age. What conclusions can be drawn? Politicians, health professionals and teachers should more intensively pinpoint the potential health risks of cannabis use, in particular for young adolescents. Information campaigns should be launched in the media. Although complete prohibition of cannabis may be neither enforceable nor successful in our society, legalisation of cannabis could – on the other hand – send the wrong message concerning the potential harm done by its use. It goes without saying that people who are already dependent need our help and should not be criminalised; but methods of controlled use for dependent persons have also been found for other substances and drugs. Our main focus should in any case be on the prevention of new cases of cannabis dependence.

Correspondence:

Prof. Anita Riecher-Rössler, MD Psychiatric Outpatient Department University Hospital / Universitätsspital Basel Petersgraben 4 CH-4031 Basel E-Mail: ariecher@uhbs.ch

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By Timothy Wilens, M.D. The overlap between attention-deficit/ hyperactivity disorder and alcohol or drug abuse or dependence (referred to here as substance use disorders [SUDs]) in adolescents has been an area of increasing clinical, research and public health interest. Appearing in early childhood, ADHD affects from 6% to 9% of children and adolescents worldwide (Anderson et al., 1987) and up to 5% of adults (Kessler, in press). Longitudinal data suggest that childhood ADHD persists into adolescence in 75% of cases and into adulthood in approximately one-half of cases (for review, see Weiss, 1992). Substance use disorders usually appear in adolescence or early adulthood and affect between 10% to 30% of U.S. adults and a less defined, but sizable, number of juveniles (Kessler, 2004). The study of comorbidity between SUDs and ADHD is relevant to both research and clinical practice in developmental pediatrics, psychology and psychiatry with implications for diagnosis, prognosis, treatment and health care delivery. Overlap Between ADHD and SUD Structured psychiatric diagnostic interviews assessing ADHD and other disorders in substance-abusing groups have indicated that from one-third to one-half of adolescents with SUDs have ADHD (DeMilio, 1989; Milin et al., 1991). For example, aggregate data from government-funded studies of mainly cannabis-abusing youth indicate that ADHD is the second most common comorbidity with from 40% to 50% of both girls and boys manifesting full criteria for ADHD. Data largely ascertained from adult groups with SUDs also show an earlier onset and more severe course of SUD associated with ADHD (Carroll and Rounsaville, 1993; Levin and Evans, 2001). ADHD as a Risk Factor or Precursor for SUD The association of ADHD and SUDs is particularly compelling from a developmental perspective as ADHD appears to manifest itself earlier than the SUD; therefore, the SUD is an unlikely risk factor for ADHD. Thus, it is important to evaluate to what extent ADHD is a precursor of SUDs. Prospective studies of children with ADHD have provided evidence that the group with conduct or bipolar disorders co-occurring with ADHD have the poorest outcome with respect to developing SUDs and major morbidity (Biederman et al., 1997; Mannuzza et al., 1993). As part of an ongoing prospective study of ADHD, it was found that differences in the risk for SUDs in adolescents with ADHD (mean age=15) compared to controls without ADHD were accounted for by comorbid conduct or bipolar disorders (Biederman et al., 1997). However, it also has been shown that the age of risk for SUD onset in adolescents without comorbid ADHD is approximately 17 years in girls and 19 years in boys (Biederman et al., in press-a; Milberger et al., 1997b). These findings were confirmed by Katusic and associates (2005) and Molina and Pelham (2003), who have shown elevated risk of SUDs in adolescents with ADHD. ADHD treatment and SUD. Clarification of the critical influence of ADHD treatment in youth on later SUDs remains hampered by methodological issues. Since prospective studies in youth with ADHD are naturalistic, and hence not randomized for treatment, attempts to disentangle positive or deleterious effects of treatment from the severity of the underlying condition(s) are hampered by serious confounds. Whereas concerns of the abuse liability and potential kindling of specific types of abuse (e.g., cocaine) secondary to early stimulant exposure in children with ADHD have been raised (Drug Enforcement Administration, 1995; Vitiello, 2001), the preponderance of clinical data do not appear to support such a contention. To reconcile findings in this important area, my group completed a meta-analysis of the literature (Faraone and Wilens, 2003; Wilens et al., 2003). We included studies examining the later risk of SUDs in children exposed to stimulant pharmacotherapy, identifying two studies into adolescence and five studies into adulthood. We found that stimulant pharmacotherapy did not increase the risk for later SUDs. In fact, we found that stimulant pharmacotherapy protected against later SUDs (odds ratio of 1.9) and that the effect was stronger in adolescents relative to adults (Wilens et al., 2003). It is notable that the magnitude of risk reduction (e.g., 50% reduction in risk) indicated that the ultimate risk of SUDs in treated individuals with ADHD may approximate the level of risk in individuals without ADHD (general population). SUD Pathways Associated With ADHD An increasing body of literature shows an intriguing association between ADHD and cigarette smoking. It has been previously reported that ADHD is a significant predictor for early initiation of cigarette smoking (before age 15) and that conduct and mood disorders comorbid with ADHD put youth at particularly high risk for early-onset smoking (Milberger et al., 1997a) data also suggest that one-half of smokers with ADHD go on to later SUDs (Biederman et al., in press-b). This is not surprising given that not only does smoking lead to peer group pressures and availability of illicit substances, but that nicotine exposure may make the brain more susceptible to later behavioral disorders and SUDs (Trauth et al., 2000). Furthermore, nicotinic-modulating agents are increasingly being evaluated for the treatment of ADHD (Wilens et al., in press-b). Of interest, prospective data funded by the National Institute on Drug Abuse suggest that stimulant treatment of ADHD reduces not only the time to onset but also the incidence of cigarette smoking (Monuteaux, 2004). The precise mechanism(s) mediating the expression of SUDs in ADHD remains to be seen. The self-medication hypothesis is compelling in ADHD considering that the disorder is chronic and often associated with demoralization and failure, factors frequently associated with SUDs in adolescents. Moreover, it has been found that among substance-abusing adolescents with and without ADHD, adolescents with ADHD reported using substances more frequently to attenuate their mood and to help them sleep. No evidence of differences in types of substances has emerged between substance-abusing teen-agers with or without ADHD (Biederman et al., 1997). In addition, the potential importance of self-medication needs to be tempered against more systematic data showing the strongest association between ADHD and SUDs is comorbidity and familial contributions, such as exposure to parental SUDs during vulnerable developmental phases. Diagnosis and Treatment Guidelines Evaluation and treatment of comorbid ADHD and SUDs should be part of a plan in which consideration is given to all aspects of the teen-ager’s life. Any intervention in this group should follow a careful evaluation of the adolescent including psychiatric, addiction, social, cognitive, educational and family evaluations. A thorough history of substance use should be obtained that includes past and current usage and treatments. Although no specific guidelines exist for evaluating the patient with an active SUD, in my experience at least one month of abstinence is useful in accurately and reliably assessing for ADHD symptoms. Semi-structured psychiatric interviews or validated rating scales of ADHD are invaluable aids for the systematic diagnostic assessments of this group. The treatment needs of individuals with SUDs and ADHD need to be considered simultaneously; however, the SUD needs to be addressed initially (Riggs, 1998). If the SUD is active, immediate attention needs to be paid to stabilization of the addiction(s). Depending on the severity and duration of the SUD, adolescents may require inpatient treatment. Self-help groups offer a helpful treatment modality for many with SUDs. In tandem with addiction treatment, adolescents with co-occurring SUDs and ADHD require intervention(s) for the ADHD as well as other co-occurring psychiatric disorders. Medication serves an important role in reducing the symptoms of ADHD and other concurrent psychiatric disorders. Effective agents for adolescents with ADHD include the stimulants, noradrenergic agents and catecholaminergic antidepressants (Wilens et al., 2002). Findings from a meta-analysis of 10 studies of open and controlled trials suggest that medications used in adolescents and adults with ADHD plus SUDs have only a meager effect on the ADHD, but have little effect on substance use or cravings (Riggs et al., 2004; Schubiner et al., 2002; Wilens et al., 2005). Of interest, no evidence exists that treating ADHD pharmacologically through an active SUD exacerbates the SUD. This is consistent with the work of Grabowski et al. (2004), who used stimulants to block cocaine and amphetamine abuse. Also consistent with these findings, earlier work by Volkow et al. (1998) demonstrated significant differences between binding at the dopamine transporter between methylphenidate and cocaine, suggesting a much smaller abuse risk for methylphenidate in contrast to cocaine. In ADHD adults with SUDs, the nonstimulant agents (atomoxetine [Strattera]), antidepressants (bupropion [Wellbutrin]), and extended-release or longer-acting stimulants with lower abuse liability and diversion potential are preferable (Riggs, 1998). While of particular interest because of the drug’s broad spectrum of activity in ADHD and lack of abuse liability (Heil et al., 2002), results from ongoing trials of atomoxetine in SUDs are not yet available. In individuals with SUDs and ADHD, frequent monitoring of pharmacotherapy should be undertaken–including evaluation of compliance with treatment, use of questionnaires (Gignac et al., 2005), random toxicology screens as indicated, and coordination of care with addiction counselors and other caregivers. Issues of diversion. Surprisingly, limited information is available on the inappropriate use of stimulants in terms of the magnitude of the problem and the characteristics of misuse in individuals for whom they are prescribed. Musser et al. (1998) surveyed 161 children with ADHD responding to methylphenidate in order to assess diversion. The authors reported that 16% of children had been approached to sell or give away their prescribed medication; however, the actual rates of diversion were not reported. Marsh et al. (2000), using a retrospective review of the medical charts of 240 adolescents with ADHD, reported that 12% had misused their methylphenidate, although the characteristics of those youth were not reported. Poulin (2001) surveyed 13,549 students in grades 7 through 12 and found that 8.5% had used nonprescribed stimulants in the year prior to the survey. Of those students who were receiving prescribed stimulants, 14.7% had given their medications and 7.3% had sold their medication to other students. Similar to other studies, those to whom the stimulants were diverted misused the stimulants in context with other substances of abuse. Similarly, we recently found that 11% of adolescents and young adults with ADHD diverted (sold) and 22% had misused their stimulants (e.g., escalated dose, used with other substances, became euphoric) (Wilens et al., in press-a). We also found that ADHD individuals with conduct disorder or SUDs accounted for the misuse and diversion and that there appeared to be more misuse and diversion of immediate-release compared to extended-release stimulants (Wilens et al., in press-a). Summary There is a strong literature supporting a relationship between ADHD and SUDs. Both family/genetic and self-medication influences may be operational in the development and continuation of SUDs in ADHD. Adolescents with ADHD and SUDs require multimodal interventions incorporating addiction and mental health treatment. Pharmacotherapy in individuals with ADHD and SUDs needs to take into consideration timing, misuse and diversion liability, potential drug interactions, and compliance concerns. While the existing literature has provided important information on the relationship of ADHD and SUDs, it also points to a number of areas in need of further study. The mechanism by which untreated ADHD leads to SUDs, as well as the risk reduction of ADHD treatment on cigarette smoking and SUDs, needs to be better understood. Given the prevalence and major morbidity and impairment caused by SUDs and ADHD, prevention and treatment strategies for these adolescents need to be further developed and evaluated. Acknowledgements This research was supported by National Institutes of Health grants R01 DA14419 and K24 DA016264 to Dr. Wilens. Dr. Wilens is director of Substance Abuse Services at Massachusetts General Hospital’s Pediatric Psychopharmacology Clinic and associate professor of psychiatry at Harvard Medical School. References Anderson JC, Williams S, McGee R, Silva PA (1987), DSM-III disorders in preadolescent children. Prevalence in a large sample from the general population. Arch Gen Psychiatry 44(1):69-76. Biederman J, Monuteaux M, Mick E et al. (in press-a), Young adult outcome of attention deficit hyperactivity disorder: a controlled 10 year prospective follow-up study. Psychol Med. Biederman J, Monuteaux M, Mick E et al. (in press-b), Is cigarette smoking a gateway drug to subsequent alcohol and illicit drug use disorders? A controlled study of youths with and without ADHD. Biol Psychiatry. Biederman J, Wilens T, Mick E et al. (1997), Is ADHD a risk for psychoactive substance use disorder? Findings from a four-year prospective follow-up study. J Am Acad Child Adolesc Psychiatry 36(1):21-29. Carroll KM, Rounsaville BJ (1993), History and significance of childhood attention deficit disorder in treatment-seeking cocaine abusers. Compr Psychiatry 34(2):75-82. DeMilio L (1989), Psychiatric syndromes in adolescent substance abusers. Am J Psychiatry 146(9):1212-1214. Drug Enforcement Administration (1995), Methylphenidate Review Document. Washington, D.C.: Office of Diversion Control, Drug and Chemical Evaluation Section. Faraone SV, Wilens T (2003), Does stimulant treatment lead to substance use disorders? J Clin Psychiatry 64(suppl 11):9-13. Gignac M, Wilens TE, Biederman J et al. (2005), Assessing cannabis use in adolescents and young adults: what do urine screen and parental report tell you? J Child Adolesc Psychopharmacol 15(5):742-750. Grabowski J, Shearer J, Merrill J, Negus SS (2004), Agonist-like, replacement pharmacotherapy for stimulant abuse and dependence. Addict Behav 29(7):1439-1464. Heil SH, Holmes HW, Bickel WK et al. (2002), Comparison of the subjective, physiological, and psychomotor effects of atomoxetine and methylphenidate in light drug users. Drug Alcohol Depend 67(2):149-156. Katusic SK, Barbaresi WJ, Colligan RC et al. (2005), Psychostimulant treatment and risk for substance abuse among young adults with a history of attention-deficit/hyperactivity disorder: a population based, birth cohort study. J Child Adolesc Psychopharmacol 15(5):764-776. Kessler R (in press), A recent replication of the National Comorbidity Study estimating the prevalence of adult ADHD among persons 18-44 in the US. Psychol Med. Kessler RC (2004), The epidemiology of dual diagnosis. Biol Psychiatry 56(10):730-737. Levin FR, Evans SM (2001), Diagnostic and treatment issues in comorbid substance abuse and adult attention-deficit hyperactivity disorder. Psychiatric Annals 31(5):303-312. Mannuzza S, Klein RG, Bessler A et al. (1993), Adult outcome of hyperactive boys. Educational achievement, occupational rank, and psychiatric status. Arch Gen Psychiatry 50(7):565-576. Marsh LD, Kay JD, Payne TP (2000), Methylphenidate misuse in substance abusing adolescents. Journal of Child and Adolescent Substance Abuse 9(3):1-14. Milberger S, Biederman J, Faraone SV et al. (1997a), ADHD is associated with early initiation of cigarette smoking in children and adolescents. J Am Acad Child Adolesc Psychiatry 36(1):37-44. Milberger S, Biederman J, Faraone SV et al. (1997b), Associations between ADHD and psychoactive substance use disorders. Findings from a longitudinal study of high-risk siblings of ADHD children. Am J Addict 6(4):318-329. Milin R, Halikas JA, Meller JE, Morse C (1991), Psychopathology among substance abusing juvenile offenders. J Am Acad Child Adolesc Psychiatry 30(4):569-574. Molina BS, Pelham WE (2003), Childhood predictors of adolescent substance use in a longitudinal study of children with ADHD. J Abnorm Psychol 112(3):497-507. Monuteaux MC (2004), A randomized, double-blind, placebo-controlled clinical trial of bupropion for the prevention of smoking in youth with attention-deficit/hyperactivity disorder. Presented at the National Cancer Institute’s Tobacco Investigators’ Meeting: Synthesizing Research for the Public’s Health. San Diego; June 2-4. Musser CJ, Ahmann PA, Theye FW et al. (1998), Stimulant use and potential for abuse in Wisconsin as reported by school administrators and longitudinally followed children. J Dev Behav Pediatr 19(3):187-192. Poulin C (2001), Medical and nonmedical stimulant use among adolescents: from sanctioned to unsanctioned use. CMAJ 165(8):1039-1044 [see comment]. Riggs PD (1998), Clinical approach to treatment of ADHD in adolescents with substance use disorders and conduct disorder. J Am Acad Child Adolesc Psychiatry 37(3):331-332. Riggs PD, Hall SK, Mikulich-Gilbertson SK et al. (2004), A randomized controlled trial of pemoline for attention-deficit/hyperactivity disorder in substance-abusing adolescents. J Am Acad Child Adolesc Psychiatry 43(4):420-429. Schubiner H, Saules KK, Arfken CL et al. (2002), Double-blind placebo-controlled trial of methylphenidate in the treatment of adult ADHD patients with comorbid cocaine dependence. Exp Clin Psychopharmacol 10(3):286-294. Trauth JA, Seidler FJ, Slotkin TA (2000), Persistent and delayed behavioral changes after nicotine treatment in adolescent rats. Brain Res 880(1-2):167-172. Vitiello B (2001), Long-term effects of stimulant medications on the brain: possible relevance to the treatment of attention deficit hyperactivity disorder. J Child Adolesc Psychopharmacol 11(1):25-34. Volkow ND, Wang GJ, Fowler JS et al. (1998), Dopamine transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate. Am J Psychiatry 155(10):1325-1331. Weiss G (1992), Child and Adolescent Psychiatric Clinics of North America: Attention-Deficit/Hyperactivity Disorder. Philadelphia: W.B. Saunders Company. Wilens TE, Biederman J, Spencer TJ (2002), Attention deficit/hyperactivity disorder across the lifespan. Annu Rev Med 53:113-131. Wilens TE, Faraone SV, Biederman J, Gunawardene S (2003), Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. Pediatrics 111(1):179-185. Wilens TE, Gignac M, Swezey A et al. (in press-a), Characteristics of adolescents and young adults with ADHD who divert or misuse their prescribed medications. J Am Acad Child Adolesc Psychiatry. Wilens TE, Monuteaux MC, Snyder LE, Moore H (2005), The clinical dilemma of using medications in substance abusing adolescents and adults with ADHD: what does the literature tell us? J Child Adolesc Psychopharmacol 15(5):787-798. Wilens TE, Verlinden MH, Adler LA et al. (in press-b), ABT-089, a neuronal nicotinic receptor modulator, for the treatment of ADHD in adults: results of a pilot study. Biol Psychiatry. Source: Psychiatric Times January 2006 Vol. XXV Issue 1

By LINDA CARROLL

Thirty years ago, scientists linked prenatal alcohol exposure with a perplexing pattern of birth defects including neurological problems, low birth weight, mental retardation and a set of facial malformations.

Up to that time, many doctors had assumed that alcohol was so harmless that it was sometimes administered intravenously to women who were thought to be at risk of losing their pregnancies.

But in recent decades, scientists have discovered that alcohol can be remarkably toxic — more than any other abused drug — to developing fetuses. New research with imaging techniques is helping experts uncover which parts of the developing brain are damaged by alcohol exposure.

By pinpointing the damaged areas, they are beginning to understand the origins of the problem behaviors and learning disabilities linked to alcohol.

Scientists are also homing in on a protein important to the developing brain that is affected by alcohol. It is possible, they say, that a medication can be created to protect the brains of developing fetuses, even if pregnant women cannot quit drinking.

It is not surprising that it has taken researchers so long to tease out the link between alcohol exposure and birth defects. For one thing, the effects of alcohol exposure seem to vary widely.

Some fetuses seem to escape unscathed, even when their mothers drink heavily, while others are severely damaged. No one knows why.

”It’s not like thalidomide, where anyone who took it had an affected child,” said Dr. Sandra W. Jacobson, a professor at Wayne State School of Medicine in Detroit, referring to the morning-sickness drug linked to birth defects in the late 1950′s and early 1960′s. ”There’s a range with alcohol. You might get the full-blown syndrome in 4 out of 100 heavy drinkers.”

There are also many babies who are affected, but not severely enough for the syndrome to be diagnosed. Some with fetal alcohol effects may appear relatively normal but have behavioral problems and learning deficits like those with the syndrome.

Further complicating matters is the question of how much alcohol it takes to cause harm. In the past few years, successive studies have shown an effect at increasingly lower levels. One study, published last year, found a small but significant effect on average in children born to women who consumed just a drink and a half a week.

”We were surprised by this,” said the lead author, Dr. Nancy Day, a professor of psychiatry at the Western Psychiatric Institute and Clinic in Pittsburgh. The women in the study were recruited from a prenatal clinic between May 1983 and July 1985.

”The children were in the normal range of growth,” Dr. Day said, ”but if you compare them to children whose mothers didn’t drink at all, they weighed less, were shorter and had smaller head circumferences.”

The effect of low levels of alcohol appears to be subtle, said Dr. James R. West, head of the department of anatomy and neurobiology at the Texas A&M medical school.

”Perhaps instead of having an I.Q. of 120, you might end up with 115,” he said. ”You might seem perfectly normal, but not have the motor skills to make the high school football team.”

Another factor making it difficult to tease out the impact of alcohol is its widespread effects on the developing brain and body.

”Alcohol is a dirty drug,” Dr. West added. ”It affects a number of different neurotransmitters, and all cells can take it up.” Compare this with cocaine, Dr. West said, which is taken up by only one neurotransmitter.

It is also difficult to identify the effects of alcohol because a woman’s drinking habits seem to make a big difference. Experts say it matters when a pregnant woman drinks, how often she drinks and what her pattern of drinking is: whether she drinks small amounts daily or periodically binges.

Drinking in the first trimester can lead to facial malformations, while in the second it can interrupt nerve formation in the brain, Dr. West said. During the third, it can kill existing neurons and interfere with nervous system development, he added.

Researchers have also determined that babies are more likely to be affected if mothers drink in a binge pattern, like five drinks one day rather than a single drink daily, Dr. Jacobson of Wayne State said.

Because alcohol affects so many sites in the brain, researchers have come to believe that alcohol is far worse for the developing fetus than any other abused drug.

Dr. Jacobson’s study included cocaine users who also used varying quantities of alcohol. ”We found more serious cognitive impairment in relation to alcohol than cocaine or other drugs, including marijuana and smoking,” Dr. Jacobson said.

The damage done to fetuses often has been wrongly connected to cocaine, many experts say.

”The consensus, I think, at this point is that most of the adverse effects that had been reported due to cocaine and crack use were from alcohol use,” said Dr. Kenneth R. Warren, the director of the office of scientific affairs at the National Institute on Alcohol Abuse and Alcoholism. ”It is the leading cause of birth defects due to an ingested environmental substance in this country.”

In 1973, researchers coined the phrase fetal alcohol syndrome to describe babies born with a certain pattern of neurologic and physiologic defects related to alcohol exposure in utero.

Early on, it was clear that exposed children were wired differently from normal ones and that they exhibited an array of disabilities.

Dr. Ann P. Streissguth, the director of the fetal alcohol and drug unit at the University of Washington and a professor at the medical school there, ticked off a list: ”These included attention problems, hyperactivity, learning problems — particularly in arithmetic — language problems, memory problems, fine and gross motor problems, poor impulse control, poor judgment, intellectual deficits and difficulty integrating past experience to plan and organize future behavior.”

Researchers wondered whether specific areas of the brain were being consistently harmed by alcohol exposure in utero. Poor judgment, for example, might point to damage to the frontal lobes. The lobes, as the control center of the brain, are involved in planning, organizing and inhibiting inappropriate responses, the researchers say.

Thirty years ago, the only way researchers could learn about the effects of alcohol on the brain was to study children who died shortly after birth.

”We knew from brain autopsies that in severe cases the brains were terribly disorganized,” said Dr. Edward P. Riley, the director of the Center for Behavioral Teratology at San Diego State University. Now, researchers use imaging techniques like M.R.I.’s to look at the damage caused by alcohol. Several recent studies using magnetic resonance imaging have shown damage to the corpus callosum, a band of nerve fibers that connects the left and right sides of the brain.

A report published in 2002 compared the brain scans of adults and children who had severe or mild alcohol-related disabilities with the scans of healthy counterparts. The researchers found that the corpus callosa were abnormally shaped in 80 percent of those who had been exposed to alcohol in utero.

Another study found that the corpus callosum was smaller and shifted forward in children and young adults with the syndrome. Using a technique known as diffusion tensor imaging to look closer at the corpus callosum, researchers at Emory University have seen abnormalities in the myelin, the substance that insulates nerve cells.

When the myelin is damaged, signals do not carry as crisply through the cells, said Dr. Claire D. Coles, director of the Fetal Alcohol Center at the Marcus Institute and a professor of psychiatry and behavioral sciences at Emory.

Another study published in 2002 found that frontal lobe structures were smaller in teenagers and young adults who had been exposed to alcohol prenatally.

By pinpointing which sections of the brain are most likely to be damaged by alcohol, scientists may find a way to block its effects.

Researchers recently recognized that some of alcohol’s effects were similar to those experienced by children born with defects in genes that control L1 adhesion cells. Fetal cells that are destined to grow into the brain and nervous system bind to one another with the help of adhesion molecules like L1, said Dr. Michael E. Charness, an associate professor of neurology at Harvard.

In laboratory experiments, Dr. Charness and his colleagues showed that alcohol could interfere with L1′s stickiness, thus hampering crucial cell-to-cell attachments. In an article published in The Proceedings of the National Academy of Sciences in July, they showed that a protein, NAP, could block alcohol’s effect on L1. When NAP was given to mice exposed to alcohol, the protein appeared to stave off neurological effects.

”The idea of giving drugs to pregnant women is controversial,” Dr. Charness said. ”Drugs may have their own risks.”

But, he said, there are areas of the world where fetal alcohol syndrome is a huge problem. In parts of South Africa, the incidence of the syndrome in first graders is around 4.5 percent, he said. ”The rate of drinking is high,” Dr. Charness added. ”And the women won’t stop drinking despite interventions. It might be reasonable to give them a drug that can prevent the more serious effects of alcohol.”