A systematic review of adverse events arising from the use of synthetic cannabinoids and their associated treatment

Robert J. Tait, et al


Context: Synthetic cannabinoids (SCs) such as “Spice”, “K2”, etc. are widely available via the internet despite increasing legal restrictions. Currently, the prevalence of use is typically low in the general community (<1%) although it is higher among students and some niche groups subject to drug testing. Early evidence suggests that adverse outcomes associated with the use of SCs may be more prevalent and severe than those arising from cannabis consumption.

Objectives: To identify systematically the scientific reports of adverse events associated with the consumption of SCs in the medical literature and poison centre data.

Method: We searched online databases  and manually searched reference lists up to December 2014. To be eligible for inclusion, data had to be from hospital, emergency department, drug rehabilitation services or poison centre records of adverse events involving SCs and included both self-reported and/or analytically confirmed consumption.

Results: From 256 reports, we identified 106 eligible studies including 37 conference abstracts on about 4000 cases involving at least 26 deaths. Major complications include cardiovascular events (myocardial infarction, ischemic stroke and emboli), acute kidney injury (AKI), generalized tonic-clonic seizures, psychiatric presentations (including first episode psychosis, paranoia, self-harm/suicide ideation) and hyperemesis. However, most presentations were not serious, typically involved young males with tachycardia (≈37–77%), agitation (≈16–41%) and nausea (≈13–94%) requiring only symptomatic care with a length of stay of less than 8 hours.

Conclusions: SCs most frequently result in tachycardia, agitation and nausea. These symptoms typically resolve with symptomatic care, including intravenous fluids, benzodiazepines and anti-emetics, and may not require inpatient care. Severe adverse events (stroke, seizure, myocardial infarction, rhabdomyolysis, AKI, psychosis and hyperemesis) and associated deaths manifest less commonly. Precise estimates of their

incidence are difficult to calculate due to the lack of widely available, rapid laboratory confirmation, the variety of SC compounds and the unknown number of exposed individuals. Long-term consequences of SCs use are currently unknown. Keywords: Emergency medical services, street drugs, drug overdose, mental disorders, drug-related side effects and adverse reactions


The prevalence of SC consumption is low in the general population.   However, the risk of requiring medical attention following use of SC seems to be greater than that for cannabis consumption.  Our systematic review of adverse events found that typically events were not severe, only required symptomatic or supportive care and were of short duration.

Nevertheless, a number of deaths have been attributed either directly or indirectly to SC consumption, together with other major adverse sequelae, including a significant number with persistent effects including new on-set psychosis with no family history of psychosis

We did not include popular media reports or the grey literature in the search, which would probably reveal further cases but would be less likely to contain reliable medical information. We were unable to determine the exact number of cases in the scientific literature due to the potential overlap between poison centre data and hospital reports. We could not even definitively establish the number of deaths attributed to SC consumption. Of the 28 531 ED visits in 2011 recorded in the DAWN database, 119 (0.4%) led to death potentially related to SC use

Our review of published cases identified only 22 fatal cases in the USA through to the end of 2014. As not all presentations especially for psychiatric problems or palpitations will include assessment of SC use, SC presentations may currently be seriously underreported. This suggests that the magnitude of the health burden due to SC use is considerably greater than that currently documented. Most of the data were based on self-reported consumption of SC, with no simple screening test available yet for clinicians.

Some of the information on adverse effects of SCs arises from poison centre data. Wood et al. outlined the strengths and weakness of poison centre data for novel psychoactive substances.  In brief, poison centres may detect new and unfamiliar exposures, but the rates of detection may decline with familiarity with the substances involved. In addition, the data depend upon voluntary reporting, often lack analytical confirmation, and may not discern which symptoms to attribute to a given substance, in cases of poly-drug exposure. Similarly, novel adverse events and events involving new SCs are more likely to be reported or published in the medical literature.

The consumption of cannabis affects the cardiovascular system and increases the risk of myocardial infarction.  Similarly, cannabis has been implicated in ischemic stroke, especially multifocal intracranial stenosis among young adults.   Cannabis use, ischemic stroke, and multifocal intracranial vasoconstriction, a prospective study in 48 consecutive young patients. The potential mechanisms include cardiac ischemia due to increased heart rate, postural hypotension, impaired oxygen supply arising from raised carboxyhemoglobin levels, especially in conjunction with tobacco smoking, and catecholamine-mediated pro-arrhythmic effects.  Marijuana as a trigger of cardiovascular events: speculation or scientific certainty? It is thus perhaps unsurprising that similar adverse outcomes have occurred following the use of SCs given their increased potency at CB1 receptors. Whether these compounds have significant direct effects on other receptors is still unknown.

The comparatively short period for which SC have been available and used in the general community means that long-term outcomes are currently unknown. However, the occurrence of AKI has implications for future health with a meta-analysis estimating a nearly nine-fold increase in the risk of developing chronic kidney disease, and a three-fold increase in the risk of end stage renal disease, compared to those who have not had AKI.   Thus, even low prevalence events with apparently limited duration, like AKI, have the potential to result in significant health costs following the resolution of acute symptoms. The other effects with long-term potential health consequences are initiation or exacerbation of psychiatric disorders, particularly psychosis. These are extremely debilitating and disabling conditions with large societal and health impacts for patients, families and the health system.

Clinical implications

SC intoxication appears to be a distinct and novel clinical entity. Use of SCs can cause more significant clinical effects than marijuana. There also appear to be qualitative differences in the nature of the symptoms with which patients present. The sheer number of SCs available and the rate at which they continue to change confound examinations of the scale and extent of the problem.   More recent formulations (in the UK termed “Third Generation”) are typically more potent that earlier SCs and seem to be associated with greater harms.  Trecki and colleagues report that the incidence of clusters and severity of adverse events involving SCs appears to be increasing.   This increase could be due to greater familiarity with presentations, better coordination between public health authorities and laboratories or the characteristics of newer SCs.   The overall effects of SC can resemble those of cannabis, but other than anxiety and paranoia these are not usually the symptoms associated with acute hospital presentation. Instead, patients seem to present in EDs because of behavioural abnormalities (agitated behaviour, psychosis, anxiety) or symptoms associated with acute critical illness. The latter includes seizures (which if prolonged can lead to rhabdomyolysis and hyperthermia), AKI, myocardial ischaemia and infarction in demographic groups where this would be most unusual. The majority of mild intoxications only require symptomatic treatment and generally do not require hospital admission. Severe intoxications, involving seizures, severe agitation or mental health disturbances, arrhythmias and significant chest pain, should be admitted to hospital for further investigation.

The lack of an antidote to SCs, analogous to that for opioid overdose, complicates management, as does the unpredictable effects and lack of a clear toxidrome to distinguish SCs from other recreational drugs.   The differential diagnosis requires the elimination of diverse conditions including hypoglycaemia, CNS infection, thyroid hyperactivity, head trauma and mental illness.  Benzodiazepines are usually sufficient to control agitation: while the use of haloperidol has also been described.  Caution is advised in undifferentiated agitation. Benzodiazepine failure should prompt consideration of definitive airway control. In addition to intravenous fluids for dehydration, the primary goals are protecting the airway, preventing rhabdomyolysis and to monitor for either cardiac or cerebral ischemia.

Traditionally, most recreational drug overdoses have been easily explicable based on clinical presentation alone. From an epidemiological perspective, this position should be revisited. Both the Welsh Emerging Drugs and Identification of Novel Substances (WEDINOS) and the Australian Capital Territory Novel Substances (ACTINOS) projects, routinely analyse raw product samples in the possession of patients, associated with severe or unusual presentations. This protocol has been able to characterize novel products well before their identification by law enforcement, arguably generating important information, not just for the patient concerned but also for population health services.


Data from poison centres and drug monitoring systems in Europe, the UK, the USA, and Australia illustrate trends of increased use of SCs. The number of unique SCs appears to continue growing, but the SCs seem to share common characteristics within the class. The most common effects include tachycardia, agitation and nausea; these generally respond to supportive care. However, physicians should be aware of the severe cardiovascular, cerebrovascular, neurological, psychiatric and renal effects, which occur in a minority of cases.

Differences among compounds in the class are difficult to assess. Methods to detect, identify and confirm new SCs lag behind the appearance of these drugs. Further, many of the cases depend upon self-report of the patients, whose information may be unreliable or inaccurate. Improving the availability of advanced laboratory resources will improve our ability to recognize SCs with higher risk of severe toxicity.

Source:  Extracts from Clinical Toxicology  Volume 54, 2016 – Issue 1  Nov.2015

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