Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system ? A systematic review, John M McPartland et al., 2014

Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review

John M McPartland, Marnie Duncan, Vincenzo Di Marzo and Roger G Pertwee

British Journal of Pharmacology, 2015, 172, 737-753.

Doi : 10.1111/bph.12944


Based upon evidence that the therapeutic properties of Cannabis preparations are not solely dependent upon the presence of Δ9-tetrahydrocannabinol (THC), pharmacological studies have been recently carried out with other plant cannabinoids (phytocannabinoids), particularly cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV). Results from some of these studies have fostered the view that CBD and THCV modulate the effects of THC via direct blockade of cannabinoid CB1 receptors, thus behaving like first-generation CB1 receptor inverse agonists, such as rimonabant. Here, we review in vitro and ex vivo mechanistic studies of CBD and THCV, and synthesize data from these studies in a meta-analysis. Synthesized data regarding mechanisms are then used to interpret results from recent pre-clinical animal studies and clinical trials. The evidence indicates that CBD and THCV are not rimonabant-like in their action and thus appear very unlikely to produce unwanted CNS effects. They exhibit markedly disparate pharmacological profiles particularly at CB1 receptors: CBD is a very low-affinity CB1 ligand
that can nevertheless affect CB1 receptor activity in vivo in an indirect manner, while THCV is a high-affinity CB1 receptor ligand and potent antagonist in vitro and yet only occasionally produces effects in vivo resulting from CB1 receptor antagonism. THCV has also high affinity for CB2 receptors and signals as a partial agonist, differing from both CBD and rimonabant. These cannabinoids illustrate how in vitro mechanistic studies do not always predict in vivo pharmacology and underlie the necessity of testing compounds in vivo before drawing any conclusion on their functional activity at a given target.

Abbreviations : 2-AG, sn-2 arachidonoyl glycerol; AEA, anandamide; CBD, cannabidiol; CV, coefficient of variation; DAGL, diacylglycerol lipase; FAAH, fatty acid amide hydrolase; FsAC, forskolin-stimulated adenylate cyclase; MAFP, methylarachidonoyl fluorophosphonate; MAGL, monoacylglycerol lipase; PMSF, phenylmethyl sulfonyl fluoride; THCV, Δ9-tetrahydrocannabivarin



Isolating and identifying the ‘primary active ingredient’ in Cannabis (the plant) and cannabis (the plant product) stymied chemists for over 150 years. Finally, Gaoni and Mechoulam (1964) isolated and defined
Δ9-tetrahydrocannabinol (THC). THC and biosynthetically related and structurally similar plant cannabinoids are now called phytocannabinoids to distinguish them from structurally dissimilar but pharmacologically analogous endocannabinoids (see below) and synthetic cannabinoids (synthocannabinoids).

THC exerts most of its physiological actions via the endocannabinoid system. The endocannabinoid system consists of (i) GPCRs for THC, known as cannabinoid receptors; (ii) endogenous cannabinoid receptor ligands; and (iii) ligand metabolic enzymes. The salient homeostatic roles of the endocannabinoid system have been roughly portrayed as ‘relax, eat, sleep, forget, and protect’ (Di Marzo et al., 1998). When malfunctioning, the endocannabinoid system can contribute to pathological states (Russo, 2004; Di Marzo, 2008).

All vertebrate animals express at least two cannabinoid receptors. The CB1 receptor principally functions in the nervous system but is expressed in many cells throughout the body. CB2 receptors are primarily associated with cells governing immune function, such as splenocytes, macrophages, monocytes, microglia, and B- and T-cells. Recent evidence demonstrates the presence of CB2 receptors in other cells, often up-regulated under pathological conditions (reviewed in Pertwee et al., 2010).

The paradigmatic endocannabinoid ligands are N-arachidonylethanolamine (anandamide, AEA) and
2-arachidonoylglycerol (2-AG). One of AEA’s key biosynthetic enzymes is N-acyl phosphatidyl-ethanolamine phospholipase D. The chief biosynthetic enzymes of 2-AG are two isoforms of diacylglycerol lipase: DAGLα and DAGLβ. The primary catabolic enzymes of AEA and 2-AG are fatty acid
amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) respectively. COX-2 can also catabolize AEA and 2-AG (Kozak et al., 2002).

Synthetic THC (dronabinol) became clinically available in the 1980s for indications including anorexia and weight loss in people with AIDS, and for nausea and vomiting associated with cancer chemotherapy. Off-label uses include migraine, multiple sclerosis, sleep disorders and chronic neuropathic pain. However, the therapeutic window of THC is narrowed by side effects. In clinical trials, dronabinol precipitated dysphoria, depersonalization, anxiety, panic reactions and paranoia (Cocchetto et al., 1981).

Psychological side effects occur more frequently with THC than with whole cannabis (Grinspoon and Bakalar, 1997). Only six years after Raphael Mechoulam successfully isolated THC, one of the authors of this article determined that THC did not act alone in cannabis (Gill et al., 1970). Other constituents in cannabis work in a paradoxical capacity of mitigating the side effects of THC, but improving the therapeutic activity of THC.

Cannabidiol (CBD) and Δ9-tetrahydrocannabivarin (THCV)

At last count, 108 phytocannabinoids have been characterized in various chemovars of the plant (Hanuš, 2008). The other phytocannabinoids of greatest clinical interest are CBD and THCV. THC and CBD are ‘sister’ molecules, biosynthesized by nearly identical enzymes in Cannabis – expressions of two alleles at a single gene locus (de Meijer et al., 2003). THC and CBD are C21 terpenophenols with pentyl alkyl tails,
whereas THCV is a C19 propyl-tailed analogue of THC. Cannabis biosynthesizes these compounds as carboxylic acids, for example, THC-carboxylic acid (2-COOH-THC). When heated, dried or exposed to light, the parent compounds are decarboxylated.

Fundamentally, THC mimics AEA and 2-AG by acting as a partial agonist at CB1 and CB2 receptors (Mechoulam et al., 1998). But rather than simply substituting for AEA and 2-AG, cannabis and its many constituents work, in part, by ‘kickstarting’ the endocannabinoid system (McPartland and Guy, 2004). CBD, in particular, gained attention early in this regard. Several landmark studies published in the previous century have shown interactions between CBD and THC (see Box 1).