Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (−)‐ trans ‐Δ 9 ‐tetrahydrocannabinol (Δ 9 ‐THC), (−)‐cannabidiol (CBD) and (−)‐ trans ‐Δ 9 ‐tetrahydrocannabivarin (Δ 9 ‐THCV), interact with cannabinoid CB 1 and CB 2 receptors. Δ 9 ‐THC, the main psychotropic constituent of cannabis, is a CB 1 and CB 2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB 1 /CB 2 receptor agonists in CB 1 ‐ and CB 2 ‐expressing cells or tissues, the manner with which it interacts with CB 2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Δ 9 ‐THCV behaves as a potent CB 2 receptor partial agonist in vitro . In contrast, it antagonizes cannabinoid receptor agonists in CB 1 ‐expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Δ 9 ‐THCV also interacts with CB 1 receptors when administered in vivo , behaving either as a CB 1 antagonist or, at higher doses, as a CB 1 receptor agonist. Brief mention is also made in this review, first of the production by Δ 9 ‐THC of pharmacodynamic tolerance, second of current knowledge about the extent to which Δ 9 ‐THC, CBD and Δ 9 ‐THCV interact with pharmacological targets other than CB 1 or CB 2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

Abbreviations:

AM251 N‐(piperidin‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide CBD (−)‐cannabidiol CHO Chinese hamster ovary CP55940 (−)‐cis‐3‐[2‐hydroxy‐4‐(1,1‐dimethylheptyl)phenyl]‐trans‐4‐(3‐hydroxypropyl)cyclohexanol EAE experimental autoimmune encephalomyelitis GABA γ‐aminobutyric acid GTPγS guanosine‐5′‐O‐(3‐thiotriphosphate) HU‐210 (6aR)‐trans‐3‐(1,1‐dimethylheptyl)‐6a,7,10,10a‐tetrahydro‐1‐hydroxy‐6,6‐dimethyl‐6H‐dibenzo[b,d]pyran‐9‐methanol O‐4394 synthetic Δ9‐tetrahydrocannabivarin R‐(+)‐WIN55212 (R)‐(+)‐[2,3‐dihydro‐5‐methyl‐3‐(4‐morpholinylmethyl)pyrrolo‐[1,2,3‐de]‐1,4‐benzoxazin‐6‐yl]‐1‐naphthalenylmethanone SR141716A N‐(piperidin‐1‐yl)‐5‐(4‐chlorophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide hydrochloride SR144528 N‐[(1S)‐endo‐1,3,3‐trimethyl bicyclo [2.2.1] heptan‐2‐yl]‐5‐(4‐chloro‐3‐methylphenyl)‐1‐(4‐methylbenzyl)‐pyrazole‐3‐carboxamide THC tetrahydrocannabinol THCV tetrahydrocannabivarin TRPV1 transient receptor potential vanilloid receptor 1

Δ9‐THC can both activate and block cannabinoid receptors Because Δ9‐THC has relatively low cannabinoid receptor efficacy, classical pharmacology predicts that its ability to activate these receptors will be particularly influenced by the density and coupling efficiencies of these receptors. It is, for example, possible that there are some CB 1 ‐ or CB 2 ‐expressing cells or tissues in which Δ9‐THC does not share the ability of higher efficacy agonists to activate CB 1 or CB 2 receptors because the density and coupling efficiencies of these receptors are too low. These will be populations of cannabinoid receptors in which Δ9‐THC might instead antagonize agonists that possess higher CB 1 or CB 2 efficacy when these are administered exogenously or released endogenously. It is noteworthy, therefore, that both the density and coupling efficiencies of CB 1 receptors vary widely within the brain. For example, in rat, CB 1 receptor density is much higher in substantia nigra pars reticulata, entopeduncular nucleus, globus pallidus and lateral caudate–putamen than in amygdala, thalamus, habenula, preoptic area, hypothalamus and brain stem and CB 1 coupling to G proteins is markedly more efficient in hypothalamus than in frontal cortex, cerebellum or hippocampus (reviewed in Pertwee, 1997; Childers, 2006). Moreover, CB 1 receptors in mouse hippocampus are more highly expressed by GABAergic interneurons than glutamatergic principal neurons (Monory et al., 2006). CB 1 receptors are also distributed within the mammalian brain in a species‐dependent manner. Thus for example, compared to rat brains, human brains express more CB 1 receptors in the cerebral cortex and amygdala and less in the cerebellum, a finding that may explain why motor function seems to be affected more by CB 1 receptor agonists in rats than humans (Herkenham et al., 1990). There is also evidence that a species difference in the relative sensitivities of GABA‐ and glutamate‐releasing neurons to CB 1 receptor agonism may explain why, following administration of the high‐efficacy CB 1 receptor agonist, R‐(+)‐WIN55212, signs of anxiety decrease in mice but increase in rats (Haller et al., 2007). In view of the rather low‐expression levels and/or coupling efficiencies of CB 1 receptors in some central neurons, it is not altogether unexpected that Δ9‐THC has been found to behave as a CB 1 receptor antagonist in some experiments. For example, Patel and Hillard (2006) found that Δ9‐THC shares the ability of the CB 1 ‐selective antagonists, SR141716A and N‐(piperidin‐1‐yl)‐5‐(4‐iodophenyl)‐1‐(2,4‐dichlorophenyl)‐4‐methyl‐1H‐pyrazole‐3‐carboxamide (AM251), to induce signs of anxiogenic activity in a mouse model in which CP55940 and R‐(+)‐WIN55212 each displayed anxiolytic‐like activity. Evidence has also been obtained from one investigation that Δ9‐THC can oppose R‐(+)‐WIN55212‐induced stimulation of guanosine‐5′‐O‐(3‐thiotriphosphate) ([35S]GTPγS) binding to rat cerebellar membranes (Sim et al., 1996), and from others that it can attenuate inhibition of glutamatergic synaptic transmission induced in rat or mouse cultured hippocampal neurons by R‐(+)‐WIN55212 or 2‐arachidonoylglycerol (Shen and Thayer, 1999; Kelley and Thayer, 2004; Straiker and Mackie, 2005). In one of these investigations, performed with mouse cultured ‘ataptic’ hippocampal neurons (Straiker and Mackie, 2005), the results obtained also suggested that Δ9‐THC can inhibit depolarization‐induced suppression of excitation, and hence presumably that it may inhibit endocannabinoid‐mediated retrograde signalling in at least some central neuronal pathways. The extent to which and precise mechanisms through which the heterogeneity of the cannabinoid CB 1 receptor population within the brain shapes the in vivo pharmacology of Δ9‐THC and causes it to behave differently from agonists with higher CB 1 or CB 2 efficacy warrants further investigation. So too does the hypothesis that Δ9‐THC may sometimes antagonize responses to endogenously released endocannabinoids, not least because there is evidence that such release can modulate the signs and symptoms of certain disorders and/or disease progression (reviewed in Pertwee, 2005b; Maldonado et al., 2006). Although this modulation often seems to be protective, there is evidence that it can sometimes produce harmful effects that, for example, give rise to obesity or contribute to the rewarding effects of drugs of dependence. (−)‐trans‐Δ9‐Tetrahydrocannabinol can also produce antagonism at the CB 2 receptor. Thus, Bayewitch et al. (1996) have found Δ9‐THC (0.01–1 μM) to exhibit only marginal agonist activity in COS‐7 cells transfected with human CB 2 (hCB 2 ) receptors when the measured response was inhibition of cyclic AMP production stimulated by 1 μM forskolin. Instead, Δ9‐THC behaved as a CB 2 receptor antagonist in this bioassay at both 0.1 and 1 μM with an apparent K B value against HU‐210 of 25.6 nM. More recently, Kishimoto et al. (2005) found that Δ9‐THC (1 μM) shares the ability of the CB 2 ‐selective antagonist, N‐[(1S)‐endo‐1,3,3‐trimethyl bicyclo [2.2.1] heptan‐2‐yl]‐5‐(4‐chloro‐3‐methylphenyl)‐1‐(4‐methylbenzyl)‐pyrazole‐3‐carboxamide (SR144528), to abolish 2‐arachidonoylglycerol‐induced migration of human leukaemic natural killer cells.

The CB 2 receptor pharmacology of Δ9‐THCV (−)‐trans‐Δ9‐Tetrahydrocannabivarin targets not only CB 1 but also CB 2 receptors, and indeed, like Δ9‐THC, appears to bind equally well to both these receptor types (Table 1). Moreover, as in experiments performed with mouse brain membranes, so too in experiments with hCB 2 ‐CHO cell membranes, eΔ9‐THCV has been found to antagonize CP55940 in the [35S]GTPγS‐binding assay in a surmountable manner (Thomas et al., 2005). In contrast to the brain membrane data, however, results obtained from the experiments performed with hCB 2 ‐CHO cell membranes indicate that the mean apparent K B value of eΔ9‐THCV for its antagonism of CP55940 (10.1 nM) is significantly less than its hCB 2 K i value for displacement of [3H]CP55940 from these membranes (Table 1). At the concentration at which it produces this antagonism (1 μM), or indeed at 10 μM, eΔ9‐THCV administered by itself does not affect [35S]GTPγS binding to the hCB 2 ‐CHO cell membranes (RG Pertwee and A Thomas, unpublished), suggesting that in contrast to CBD (Thomas et al., 2007), the unexpectedly high potency that eΔ9‐THCV displays as a CB 2 receptor antagonist in vitro does not stem from any ability to counteract CP55940‐induced stimulation of [35S]GTPγS binding non‐competitively through a direct inhibitory effect on CB 2 receptor signalling. Although Δ9‐THCV may not be a CB 2 receptor inverse agonist, evidence has emerged recently that it is a CB 2 receptor partial agonist. This came from experiments with eΔ9‐THCV in which the measured response used to indicate CB 2 receptor activation was inhibition of forskolin‐induced stimulation of cyclic AMP production by hCB 2 ‐CHO cells (Gauson et al., 2007). This is a bioassay that detects cannabinoid receptor activation with greater sensitivity than the [35S]GTPγS‐binding assay, probably because adenylate cyclase is located further along the cannabinoid receptor signalling cascade than G protein (reviewed in Pertwee, 1999; Howlett et al., 2002). Additional experiments are now required to establish whether Δ9‐THCV also activates CB 2 receptors in vivo. If it does, then it will be important to determine whether Δ9‐THCV is effective against chronic liver diseases, there being evidence that one effective strategy for managing these disorders in the clinic may be to administer a medicine that simultaneously blocks CB 1 receptors and activates CB 2 receptors (Mallat et al., 2007).

Future directions It is now well established that Δ9‐THC is a cannabinoid CB 1 and CB 2 receptor partial agonist and that depending on the expression level and coupling efficiency of these receptors it will either activate them or block their activation by other cannabinoids. Further research is now required to establish in greater detail the extent to which the in vivo pharmacology of Δ9‐THC is shaped by these opposing actions both in healthy organisms, for example following a decrease in cannabinoid receptor density or signalling caused by prior cannabinoid administration, and in animal disease models or human disorders in which upward or downward changes in CB 1 /CB 2 receptor expression, CB 1 /CB 2 ‐receptor‐coupling efficiency and/or in endocannabinoid release onto CB 1 or CB 2 receptors have occurred in cells or tissues that mediate unwanted effects or determine syndrome/disease progression. The extent to which the balance between cannabinoid receptor agonism and antagonism following in vivo administration of Δ9‐THC is influenced by the conversion of this cannabinoid into the more potent cannabinoid receptor agonist, 11‐OH‐Δ9‐THC, also merits investigation. Turning now to CBD, an important recent finding is that this cannabinoid displays unexpectedly high potency as a CB 2 receptor antagonist and that this antagonism stems mainly from its ability to induce inverse agonism at this receptor and is, therefore, essentially non‐competitive in nature. Evidence that CB 2 receptor inverse agonism can ameliorate inflammation through inhibition of immune cell migration and that CBD can potently inhibit evoked immune cell migration in the Boyden chamber raises the possibility that CBD is a lead compound from which a selective and more potent CB 2 receptor inverse agonist might be developed as a new class of anti‐inflammatory agent. When exploring this possibility it will be important to establish the extent to which CBD modulates immune cell migration through other pharmacological mechanisms. There is also a need for further research directed at identifying the mechanisms by which CBD induces signs of inverse agonism not only in CB 2 ‐expressing cells but also in brain membranes and in the mouse isolated vas deferens. Important recent findings with Δ9‐THCV have been that it can induce both CB 1 receptor antagonism in vivo and in vitro and signs of CB 2 receptor activation in vitro at concentrations in the low nanomolar range. Further research is now required to establish whether this phytocannabinoid also behaves as a potent CB 2 receptor agonist in vivo. Thus, a medicine that blocks CB 1 receptors but activates CB 2 receptors has potential for the management of certain disorders that include chronic liver disease and also obesity when this is associated with inflammation. The bases for the ligand and tissue dependency that Δ9‐THCV displays as an antagonist of CB 1 /CB 2 receptor agonists in vitro also warrant further research. In addition, in view of the structural similarity of Δ9‐THCV to Δ9‐THC, it will be important to determine the extent to which Δ9‐THCV shares the ability of Δ9‐THC, and indeed of CBD, to interact with pharmacological targets other than CB 1 or CB 2 receptors at concentrations in the nanomolar or low micromolar range. It will also be important to establish the extent to which CB 1 ‐ and CB 2 ‐receptor‐independent actions contribute to the overall in vivo pharmacology of each of these phytocannabinoids and give rise to differences between the in vivo pharmacology of Δ9‐THC or Δ9‐THCV and other cannabinoid receptor ligands such as CP55940, R‐(+)‐WIN55212 and SR141716A. Finally, cannabis is a source not only of Δ9‐THC, CBD and Δ9‐THCV but also of at least 67 other phytocannabinoids and as such can be regarded as a natural library of unique compounds. The therapeutic potential of many of these ligands still remains largely unexplored prompting a need for further preclinical and clinical research directed at establishing whether phytocannabinoids are indeed ‘a neglected pharmacological treasure trove’ (Mechoulam, 2005). As well as leading to a more complete exploitation of Δ9‐THC and CBD as therapeutic agents and establishing the clinical potential of Δ9‐THCV more clearly, such research should help to identify any other phytocannabinoids that have therapeutic applications per se or that constitute either prodrugs from which semisynthetic medicines might be manufactured or lead compounds from which wholly synthetic medicines might be developed.

Acknowledgments The writing of this review was supported by grants from the National Institute on Drug Abuse (NIDA) (DA‐09789), the Biotechnology and Biological Sciences Research Council (BBSRC) and GW Pharmaceuticals.

Conflict of interest The author states no conflict of interest.