AB-PINACA. Critical Review Report

AB-PINACA (N-[(2S)-1-amino-3-methyl-1-oxobutan-2-yl]-1-pentyl-1H-indazole-3-carboxamide), originally developed by Pfizer Inc. as a synthetic cannabinoid receptor agonist (SCRA), has been encountered outside medical settings as a synthetic constituent and found in herbal smoking mixtures that are sold under a variety of brand names. It is common for retailers to purchase bulk quantities of the synthetic substance and add the synthetic material to plant matter that is then distributed onto the market. However, AB-PINACA is also available in powdered form as a “research chemical”. The identification of AB-PINACA was reported first in 2012 by Japan and more forensic detections began to emerge in other countries in 2013. Data from law enforcement suggest that AB-PINACA was one of the most prevalent substances in the United States of America in 2014, which dropped again in the following years. A small number of in vitro and in vivo studies are currently available but the data indicate that AB-PINACA binds to and activates human CB1 and CB2 receptors at low nanomolar concentrations, and that it induces a number of biological responses also triggered by the naturally occurring phytocannabinoid Δ9-THC. In tetrad assays (locomotor suppression, antinociception, hypothermia, and catalepsy), for example, AB- PINACA was shown to be 2- to 14-fold more potent than Δ9-THC and the effects were rimonabant-reversible. In some in vitro assays, AB-PINACA acted as a full agonist with slight selectivity for the hCB2 receptor. AB-PINACA also fully substituted for Δ9-THC in the drug discrimination paradigm and was 1.5-fold more potent than the training drug, which suggests that AB-PINACA may have abuse liability similar to Δ9-THC and/or other internationally controlled synthetic cannabinoid receptor agonists. Reports indicate an increasing trend for SCRAs being implicated in mini epidemics that have been associated with severe adverse drug effects including deaths. Reported adverse drug reactions associated with a range of SCRAs frequently include gastrointestinal (e.g. nausea/hyperemesis), neurological (e.g. hallucination, agitation, anxiety, paranoia, confusion, delusions, catatonia, lethargy, psychosis (including susceptible individuals)), cardiovascular (e.g. tachycardia, hypertension) and renal (e.g. acute kidney failure) features. The total number of cases reported in the scientific literature that make a causal link with AB-PINACA is very small. Intoxications and deaths associated with AB-PINACA have been reported but very few details are available. ‘Driving Under the Influence’ cases linked to AB-PINACA intoxication and ‘Drug Recognition Expert’ exams revealed significant impairment. Although not specific to just AB-PINACA, there are indications that socially vulnerable and stigmatized drug users for example found in homeless and prison populations, are increasingly associated with problematic use of SCRA products. Heavy use of SCRAs has been associated with problematic withdrawal symptoms even though further research is needed to investigate the underlying mechanisms. Epidemiological data, such as prevalence of use, abuse and dependence information specifically related to AB-PINACA could not be identified