Cannabinoid research in the 2010s

Cannabis sativa is possibly the plant with the longest history of cultivation by man (Russo, 2007). It has long been exploited for its fibre; as a biomass converter, it has exceptional utility. For most people, however, there is the association of cannabis with ‘recreational drugs’, which has lead to the profusion of names associated with the plant and extracts thereof (marijuana, hashish, bhang, weed, grass, etc.). The ‘modern’ scientific era of cannabis research was prompted by the discovery of the major psychoactive ingredient in cannabis extracts (Gaoni and Mechoulam, 1964). This was, of course, Δ9-tetrahydrocannabinol or THC. Raphael Mechoulam has numerous publications, filled with seminal observations, including the identification of the two ‘best’ candidates for endogenous cannabinoid molecules: anandamide (Devane et al., 1992) and 2-arachidonoylglycerol (Mechoulam et al., 1995). He has become something of an icon in the cannabis field, with this issue of BJP containing a series of original articles prompted by a symposium held in Jerusalem in November 2010 to celebrate his 80th birthday. The first issue, entitled ‘Cannabinoids in Biology and Medicine’, containing primarily reviews, was published in August 2011 (http://onlinelibrary.wiley.com/doi/10.1111/bph.2011.163.issue-7/issuetoc). Current research in cannabinoid-related areas is vibrant, with the added focus of TRPV1 ion channels, PPAR nuclear receptors and the ‘orphan’ G-protein coupled receptors, GPR18, GPR55 and GPR119, as molecular targets of cannabinoids and cannabinoid-like molecules. Furthermore, the identification of endogenous agonists at cannabinoid receptors which lead to the demonstration of multiple routes for synthesis and transformation of these endocannabinoids has added to the molecular targets available for potential exploitation. The involvement of ‘big pharma’ in cannabinoid research has been intermittent, with Pfizer and Sterling-Winthrop providing the very useful synthetic compounds CP55940 and WIN55212-2 in the 1970s and 1980s, respectively, without being able to translate these pharmacological successes into therapeutic solutions. The limiting factor for these compounds appears to have been the psychoactivity evoked through activation of CNS CB1 cannabinoid receptors. In the 2000s, Sanofi-Aventis achieved a measure of success with the CB1 cannabinoid receptor antagonist/inverse agonist rimonabant (Acomplia®, SR141716A; Sanofi-Aventis, Paris, France) as one of the few pharmacotherapeutic alternatives for obesity. This success was short lived, however (approval was for 2006–2009 in Europe, not approved in the US), through adverse CNS effects in a significant minority of patients. In the clinical setting, therefore, cannabinoids are currently represented by THC itself (dronabinol, Marinol®; Solvay Pharmaceuticals, Brussels, Belgium), a THC analogue (nabilone, Cesamet®; Valeant Pharmaceuticals International, Mississauga, Canada) and THC in combination with other cannabinoids derived from the cannabis plant, notably cannabidiol (Sativex®; GW Pharmaceuticals, London, UK). So where is cannabinoid research likely to go in the 2010s? The answer, as with many other fields of pharmacological/therapeutic interest, lies in the symposia and meetings focused on cannabinoids.