Attached is a submission from Professor Stuart Reece to the Food and Drug Administration in USA for forwarding to the World Health Organization relating to the re-scheduling of cannabis

FDA Federal Register Submission for WHO Review and Consideration – Colorado Teratogenicity Patterns Illustrated

Email from Stuart Reece April 2018

This is an exchange on Drug Watch International with questions from Roger Morgan and responses from Dr Stuart Reece (in bold italics)

Hi Stuart

In reflecting on the studies referred to by Peggy Mann from 40 or 50 years ago, combined with your recent research, I believe we need to do some more research.  I have the following questions:

1. What is involved evaluating the chromosomes in cells of humans?  Do you take a chunk of flesh, or ???? No.  Would most universities have the capability to do this? No.

If you wanted to do this properly studies would involve the following.  I think they need to be detailed and extensive in view of the now massive populations risks which are presented.  You are actually talking about something which may be devastating – if 12% of Coloradan babies are impact PRIOR to legalization then “Houston, Houston we have a problem…  This is Apollo 13 calling.”

1. Cell culture studies – many cells, neurons, sperm and eggs, gut cells skin cells
2. Several species – white rabbit and hamsters model humans best.
3. Human cell lines – many
4. Human cells – skin cells, cheek cells, transformed white blood cells – lymphoblastoid cells – EBV infected lymphocytes taken from blood samples
5. Human sperm

1. A key change would be to apply next generation sequencing to these cells and tissues so:
   1. DNA
   2. RNA
   3. Proteins
   4. DNA methylation
   5. Histone changes – nuclear proteins looking for
   6. Epigenetic changes
   7. Epitranscriptomic changes
   8. Metabolome changes
   9. The interaction between the metabolome and the epigenome
   10. Profile the immune change including cytokines in detail – these are very important and far reaching and cause aging and germ cell damage – cytokines – TH17 cells etc…
   11. Compare the immune and growth factor changes seen in cannabis exposed patients with old folks and compare the way they reproduce clinical aging.

1. Look at pregnancies prospectively.  Look at the sperm of males – sequence them do genetic and epigenetic studies.  Then study their babies and see if they carry the same abnormalities after birth…  See how the correlate with the various congenital anomalies.

2)  What are the implications if the cannabis consumers only have half of the 46 chromosomes that are normal in humans?  Not true.  Physical and mental abnormalities in offspring …. and future generations?..   Chromosomal anomalies will do this yes – and chromosomal shattering processes which cannabis can induce.  Cannabis changes cell division process causing chromosomal shattering and also epigenetic changes – changes in the signalling along the DNA on how the genes are used and expressed.

3)  Will the chromosome levels return to normal if a person quits consuming cannabis?   Short answer – not studied yet.

Long answer – yes I think there will be a degree of repair.  However I also think it is unlikely ever to return to normal. Especially after heavy use because some of the epigenetic imprinting is permanent – obviously from studies which have been done.

4)  Cannabis is known to cause mutations to sperm and ova which can affect a fetus even before pregnancy.  If they stop using, will everything return to normal?  Same as above. Serious concerns.  Depends on level of exposure.  Depends on time between cannabis and making babies…   I do not mean to imply that one or two joints as a young person and babies ten years later is bad.  Nothing suggests that.  But heavy cannabis use such as we are seeing more and more if – and Deborah Hasin from Mailman School of Public Health  in 2017 said USA has an extra 500,000 of in legal states – that is a big problem for later reproduction.

I think the evidence that young people of reproductive age should not go near cannabis for genotoxic reasons is now very strong indeed, and so too do all of my collaborators including my biostatistical friends.

Consider:

1. 12.6% of Coloradan had major congenital anomalies in 2013 PRIOR to legalization
2. The rate of cannabis use by people over 12 years in Colorado was 14% in 2013
3. The rate of cannabis use by all pregnant women in California in 2015 was 8% on testing
4. The rate of cannabis use by mothers less than 20 years in California was 24% in 2015.

So about as many babies are being born deformed AS ARE BEING EXPOSED TO CANNABIS.

So clearly a very high percentage of cannabis exposed babies are experiencing major congenital anomalies.

This should send shivers down our spine – not only that cannabis use is rolling out but that cannabis use is aimed primarily at young adults the very group who should be keeping well away from it.

We need to define these risks much better at the population level by careful studies.

Sperm would be easy to collect and study and define and then correlate with subsequent foetal outcomes.

Thanks and God bless – and spare us all,

Stuart.

Source: Email to Drug Watch International www.drugwatch.org April 2018

The following is an extract from an email by Stuart Reece to Drug Watch International (DWI)

It seems to me that the main pillars of this argument rest on the following primary evidentiary supports:

1. AGEING (spelt “aging” in the USA)  is often defined as an accumulation of deleterious changes over time.  What is the toxicopathology of cannabis characterized by?? An accumulation of deleterious changes over time – which is obviously the same;
2. The multi-system and panorganismal nature of the cannabis related changes is strong clinical evidence that rather than a process limited just to one organ – such as the brain – what we are actually seeing is indicative of a deeper change across all cells, which likely manifests in certain organ specific ways.  This is the list of organ damage below.
3. A concatenation of age-defining illnesses:

1. The arterial toxicity of cannabis is a very big deal because it is one of the major hallmarks of ageing – most people in industrialized nations die from stroke or heart attack, and arterial ageing is the major surrogate for organismal / biological ageing.  So arterial ageing – far from being a curiosity in the cannabis literature – assumes massive importance in general medical terms
2. The association of cannabis with ten cancers is massive.  Cancer is also an age defining disease.  So one cannot say that cancer is associated with cannabis and so what – this is a very big deal indeed.  Cancer is one of the major age defining diseases
3. Immunopathy.  By stimulating the immune system cannabis increases one of the major ageing pathways.  The pro-inflammatory actions of     cannabis are now well documented.  In ageing medicine this is described as “inflamm-aging.”  It is a major pathway to ageing and age related disease, and is known to be linked with high death rates.  Cannabis is usually described as being immunosuppressive.  But we are learning that the immune system is a very complex place.  It is like a trampoline mat.  If it goes down in one place it will go up in another.  Hence patients with immune compromising disorders like rheumatoid arthritis and systemic lupus get immune complications and autoimmune diseases – including cancer.
4. Negative effect on stem cell division.  Obviously we need our stem cells healthy so that we can stay healthy.  Cannabis advocates cannot have their cake and eat it too.  They propose it as a cancer remedy because it stops cell division.  Well if you accept that argument then you must also accept that its effect on cell division is negative which has a catastrophic implication for general stem cell health in all tissue beds
5. The effects on children.  If children are born with mental compromise, paediatric cancers, and foetal malformations then that is a sign of infantile induction of ageing both by definition – since cancer defines age related disease – and since this is obviously an accumulation of deleterious ages in the paediatric age group.
6. Genotoxicity. The association of cannabis with both cancer, congenital malformations, mental retardation in offspring and congenital cancers becomes strong presumptive evidence for genotoxicity.  This is one of the best described pathways to cellular and organismal ageing.  Congenital cancers (rhabdomyosarcoma, leukaemia and neuroblastoma) are ALWAYS due to genetic defects inherited from parents or earlier generations
7. Epigenotoxicity.  As you are aware it is now a matter of record that cannabis has now well documented epigenetic changes (Szutorisz 2018; Neuroscience Behav Rev 85: 93).  The epigenetic levels is one of the strongest hypothesized levels for ageing.  In truth it interacts strongly with the metabolome (since that supplies its substrates) and the genome (since epigenetics seems to often determine sites of DNA cutting and gene splicing both in normal cells and in cancer).  The epigenetic signature of cannabis has even been traced through sperm (Lombard).  Hence ageing has an epigenetic signature and so too does cannabis.  Whilst the two have NOT been formally compared to my knowledge, in view of the above it seems more than likely that significant overlap will be found. Indeed cannabis induced changes in some major epigenetic enzymes, particularly Sirt2 – likely the best age-documented enzyme ever – were documented by Quinn (2008; Neuropsychopharmacology 33:1113).  Inheritable epigenetic immunotoxicity was also documented by Lombard C (2011; JPET 339:607)

Source: Email from Stuart Reece to Drug Watch International drug-watch-international@googlegroups.com February 2018

The implications of these findings on the propagation of cannabis genotoxicity and epigenotoxicity to the next generation extremely significant.

Prior to this research, the field was aware of the effects in the male but the work in females is more recent.

To access the full document:

1. Click on the link below.
2. An image  – the front page of the full document will appear.
3. Click on the image to open the full document.

HUMAN REPRO AND GENOTOXICITY ARTICLE

There are several principal pathways to inheritable genotoxicity, mutagenicity and teratogenesis induced by cannabis which are known and well established at this time including the following. These three papers discuss different aspects of these effects.

1. Stops Brain Waves and Thinking
The brain has both stimulatory and inhibitory pathways.  GABA is the main brain inhibitory pathway. Brain centres talk to each other on gamma (about 40 cycles/sec) and theta frequencies (about 5 cycles/sec), where the theta waves are used as the carrier waves for the gamma wave which then interacts like harmonics in music.  The degree to which the waves are in and out of phase carries information which can be monitored externally.  GABA (γ-aminobutyric acid) inhibition is key to the generation of the synchronized firing which underpins these various brain oscillations. These GABA transmissions are controlled presynaptically by type 1 cannabinoid receptors (CB1R’s) and CB1R stimulation shuts them down. This is why cannabis users forget and fall asleep.

2. Blocks GABA Pathway and Brain Formation
GABA is also a key neurotransmitter in brain formation in that it guides and direct neural stem cell formation and transmission and development and growth of the cerebral cortex and other major brain areas. Gamma and theta brain waves also direct neural stem cell formation, sculpting and connectivity. Derangements then of GABA physiology imply that the brain will not form properly.  Thin frontal cortical plate measurements have been shown in humans prenatally exposed to cannabis by fMRI. This implies that their brains can never be structurally normal which then explains the long lasting and persistent defects identified into adulthood.

3. Epigenetic Damage
DNA not only carries the genetic hardware of our genetic code but it also carries the software of the code which works like traffic lights along the sequence of DNA bases to direct when to switch the genes on and off. This is known as the “epigenetic code”. Fetal alcohol syndrome is
believed to be due to damage to the software epigenetic code. The long lasting intellectual, mood regulation, attention and concentration defects which have been described after in utero cannabis exposure in the primary, middle and high schools and as college age young adults
are likely due to these defects. Epigenetics “sets in stone” the errors of brain structure made in (2) above.

4. Arterial Damage
Cannabis has a well described effect to damage arteries through (CB1R’s) (American Heart Association 2007) which they carry in high concentration (Nature Reviews Cardiology 2018). In adults this causes heart attack (500% elevation in the first hour after smoking), stroke,
severe cardiac arrhythmias including sudden cardiac death; but in developing babies CB1R’s acting on the developing heart tissues can lead to at least six major cardiac defects (Atrial- ventricular- and mixed atrioventricular and septal defects, Tetralogy of Fallot, Epstein’s deformity amongst others), whilst constriction of various babies’ arteries can lead to serious side effects such as gastroschisis (bowels hanging out) and possibly absent limbs (in at least one series).

5. Disruption of Mitotic Spindle
When cells divide the separating chromosomes actually slide along “train tracks” which are long chains made of tubulin. The tubulin chains are called “microtubules” and the whole football-shaped structure is called a “mitotic spindle”. Cannabis inhibits tubulin formation,
disrupting microtubules and the mitotic spindle causing the separating chromosomes to become cut off in tiny micronuclei, where they eventually become smashed up and pulverized into “genetic junk”, which leads to foetal malformations, cancer and cell death. High rates of
Down’s syndrome, chromosomal anomalies and cancers in cannabis exposed babies provide clinical evidence of this.

6. Defective Energy Generation & Downstream DNA Damage
DNA is the crown jewel of the cell and its most complex molecule. Maintaining it in good repair is a very energy intensive process. Without energy DNA cannot be properly maintained. Cannabis has been known to reduce cellular energy production by the cell’s power plants,
mitochondria, for many decades now. This has now been firmly linked with increased DNA damage, cancer formation and aging of the cells and indeed the whole organism. As it is known to occur in eggs and sperm, this will also damage the quality of the germ cells which go into forming the baby and lead directly to damaged babies and babies lost and wasted through spontaneous miscarriage and therapeutic termination for severe deformities.

7. Cancer induction
Cannabis causes 12 cancers and has been identified as a carcinogen by the California Environmental Protection agency (2009). This makes it also a mutagen. 4 of these cancers are inheritable to children; i.e. inheritable carcinogenicity and mutagenicity. All four studies in
testicular cancer are strongly positive (elevation by three fold). Carcinogen = mutagen = teratogen.

8. Colorado’s Teratology Profile
From the above described teratological profile we would expect exactly the profile of congenital defects which have been identified in Colorado(higher total defects and heart defects, and chromosomal defects) and Ottawa in Canada (long lasting and persistent brain
damage seen on both functional testing and fMRI brain scans in children exposed in utero) where cannabis use has become common. Gastroschisis was shown to be higher in all seven studies looking at this; and including in Canada, carefully controlled studies. Moreover in
Australia, Canada, North Carolina, Colorado, Mexico and New Zealand, gastroschisis and sometimes other major congenital defects cluster where cannabis use is highest. Colorado 2000-2013 has experienced an extra 20,152 severely abnormal births above the rates prior to
cannabis liberalization which if applied to the whole USA would equate to more than 83,000 abnormal babies live born annually (and probably about that number again therapeutically aborted); actually much more since both the number of users and concentration of cannabis have risen sharply since 2013, and cannabis has been well proven to be much more severely genotoxic at higher doses.

9. Cannabidiol is also Genotoxic
Cannabidiol tests positive in many genotoxicity assays, just as tetrahydrocannabinol does.

10. Births defects registry data needs to be open and transparent and public.
At present it is not. This looks too much like a cover up.

Source:  By Professor Dr. A. S Reece
(Edith Cowan University & University of Western Australia) 2019