Synthetic Cannabinoid Receptor Agonists: a heterogeneous class of novel psychoactive substance with emerging risk of psychosis

What is already known on this topic

Concerns grow over the harms of novel psychoactive substances (NPS), and their profile was raised further in the UK when plans for new legislation banning their use were announced in May 2015. The widespread reporting of ‘legal high’ mortality figures has previously been criticised as misleading owing to the overinclusivity of this term,1 and specific data on the toxicity profile of these drugs is relatively scarce. The review by van Amsterdam and colleagues brings together such evidence specifically for the NPS subtype of Synthetic Cannabinoid Receptor Agonists (SCRAs, known as ‘Spice’), focusing on psychosis-like effects given the biological plausibility of this risk conferred by their full cannabinoid receptor agonism.2

Methods of the study

The authors searched PubMed for English, French, German or Dutch language papers and hand searched reference lists of retrieved papers. Synonyms for synthetic cannabinoids and adverse effects were used. The 250 papers retrieved formed the basis for a descriptive review of the history, profile and reasons for use of SCRAs, highlighting their heterogeneity before focusing on adverse effects. There was no meta-analysis of data, which was not explicitly addressed but indeed would have been inappropriate given the heterogeneity encountered.

What this paper adds

• ‘Spice’ products vary widely between brands and batches with respect to the combination and concentration of SCRAs and inclusion of other psychoactive substances such as caffeine. Active components may be unevenly distributed within a single product.

• The most commonly reported acute adverse effects across ‘Spice’ products are tachycardia, agitation, drowsiness and hallucinations. No formally confirmed fatal overdoses of SCRAs have been described. There is suggestion that younger users may be particularly vulnerable, though it is unclear from presented data whether this is simply representative of the demographic profile of use.

• Data from a variety of sources, including US poison centres, case reports and studies based in in-patient or emergency department settings suggest psychotic symptoms may occur at a clinically relevant rate following SCRA use. Such symptoms took a variety of forms, occurred at a variety of time points, and ranged from acute new-onset episodes to relapse of pre-existing illness. Prospective or comparative studies with cannabis are not available and as such the relative risk cannot be estimated.

Limitations

The review does not claim to be fully systematic. While the type and quality of some individual included studies is described and cited as a limitation, there is no standardised critical appraisal of studies for inclusion. The search strategy used is pragmatic rather than exhaustive, (only a single database and no specific reference to psychosis in its search string). One can argue as to the objectivity of a non-systematic review and therefore its ability to deliver valid conclusions. However, in this case the obvious heterogeneity and limitations of available primary evidence make it unlikely that a fully systematic approach would have yielded significant additional value.

What next in research

There are significant challenges to understanding the real-world harms of this rapidly evolving group of drugs. Improving the reliability of detection itself requires novel approaches,3 and access to screening tests is currently inconsistent across centres. The significant variation described not just within the umbrella of NPS but here between superficially interchangeable SCRA products further highlights need for standardised definition and reporting. Developing networks of poison information centres with systematic reporting between regions and countries has been suggested as one way to meet these challenges.4 This needs to be alongside studies in which the presence of such a substance is confirmed by laboratory testing rather than patient reporting alone. Research in prison populations is surprisingly lacking despite wide acknowledgement that ‘Spice’ is now a drug of choice in this setting.5 Given the barriers to robust clinical data collection, furthering knowledge of the pharmacological profile of individual drugs is also of merit—for example, recent profiling of benzofurans (marketed as ‘Benzo Fury’) shows receptor profiles associated with heart valve fibrosis, hallucinogenesis and vasoconstriction.6

Do these results change clinical practice and why?

The authors provide a measured overview of the field, discussing the potential significant risks of SCRAs suggested by pharmacological and clinical literature. For clinicians, the heterogeneity described means screening for ‘legal high’ use is not in itself adequate, and we must enhance the accuracy of our recording of the use of specific agents. From a harm-minimisation perspective, the variable composition of these products and associated risks must be highlighted to patients. Though the magnitude of risk of psychosis is unknown, this seems likely to be at a clinically relevant level and as such SCRAs must be added to the list of aetiological factors considered in new presentation and relapse. Likewise, the reported occurrence of agitation would also warrant consideration (and study) of SCRA use as a possible modifiable risk factor for violence.