Associate editor: M.G. Belvisi
Phytocannabinoids as novel therapeutic agents in CNS disorders

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Abstract

The Cannabis sativa herb contains over 100 phytocannabinoid (pCB) compounds and has been used for thousands of years for both recreational and medicinal purposes. In the past two decades, characterisation of the body's endogenous cannabinoid (CB) (endocannabinoid, eCB) system (ECS) has highlighted activation of central CB1 receptors by the major pCB, Δ9-tetrahydrocannabinol (Δ9-THC) as the primary mediator of the psychoactive, hyperphagic and some of the potentially therapeutic properties of ingested cannabis. Whilst Δ9-THC is the most prevalent and widely studied pCB, it is also the predominant psychotropic component of cannabis, a property that likely limits its widespread therapeutic use as an isolated agent. In this regard, research focus has recently widened to include other pCBs including cannabidiol (CBD), cannabigerol (CBG), Δ9tetrahydrocannabivarin (Δ9-THCV) and cannabidivarin (CBDV), some of which show potential as therapeutic agents in preclinical models of CNS disease. Moreover, it is becoming evident that these non-Δ9-THC pCBs act at a wide range of pharmacological targets, not solely limited to CB receptors. Disorders that could be targeted include epilepsy, neurodegenerative diseases, affective disorders and the central modulation of feeding behaviour. Here, we review pCB effects in preclinical models of CNS disease and, where available, clinical trial data that support therapeutic effects. Such developments may soon yield the first non-Δ9-THC pCB-based medicines.

Introduction

This review focuses on the emerging potential of phytocannabinoids (pCBs) to act as novel therapeutic agents in CNS disorders, in particular, as assessed by the use of preclinical in vivo animal models of CNS disease and available clinical trial data. Cannabis has been used medicinally and recreationally for thousands of years with early documentation of medicinal use in Chinese pharmacopoeias (Li & Lin, 1974) and the Indian Atharva Veda which accords cannabis status as one of five sacred plants (Touw, 1981). Early texts on herbal medicines were summarised by Dioscorides in ~60 A.D. and by Galen, who wrote of cannabis in the 2nd century A.D. in his De facultatibus alimentorum, “The leaves of this plant cure flatus – some people squeeze the fresh (seeds) for use in ear-aches. I believe that it is used in chronic pains”. Cannabis appeared in the 1788 New England Dispensatory, which retained large elements of Dioscorides herbal pharmacopoeia. Work of the 19th century Irish physician, William O'Shaughnessy, introduced medicinal use of cannabis to the UK (O'Shaughnessy, 1840), benefiting from the ascribed analgesic, anti-inflammatory, anti-emetic and anti-convulsant properties of the plant. However, medicinal use of cannabis fell out of favour in the early 20th century, largely due to concerns about psychoactivity and effects on behaviour, motor co-ordination and memory and learning; such concerns led to cannabis being removed from the British Pharmacopoeia in 1932 (Ashton, 2001, Kalant, 2001, Robson, 2001). However, it was still possible for UK physicians to prescribe cannabis for specific medicinal uses up to 1973, until prohibition by the Misuse of Drugs Regulation; in the current iteration of this Act, cannabis is classified in Schedule 1, meaning that therapeutic use is effectively prohibited (Moffat, 2002).

Despite these restrictions, interest in the pharmacology and potential therapeutic use of pCBs was engendered by the isolation of Δ9-THC and the subsequent discovery of other pCBs (Gaoni and Mechoulam, 1971, Mechoulam, 2005). Thereafter, the development of synthetic CB receptor ligands, such as Pfizer's CP55,940 in the 1980s, led to the identification of specific Δ9-THC binding sites in the human CNS (Herkenham et al., 1990) and the identification and cloning of the first CB receptor, CB1 (Matsuda et al., 1990). These findings contributed to the discovery of the endocannabinoid (eCB) system (ECS) (a term introduced by Di Marzo & Fontana, 1995), which comprises the cannabinoid (CB) receptors, eCBs as their endogenous ligands and the proteins responsible for eCB synthesis and degradation. Shortly thereafter, a second, principally peripheral, cannabinoid CB2 receptor was identified in 1993 (Munro et al., 1993). Around the same time, arachidonic acid-derived, endogenous CB receptor ligands were identified, with the discovery of arachidonylethanolamide (AEA; Devane et al., 1992) and 2-arachidonylglycerol (2-AG) (Mechoulam et al., 1995, Sugiura et al., 1995). The first eCB degrading enzyme to be cloned was fatty acid amide hydrolase (FAAH; Cravatt et al., 1996), with a number of further degradation and synthetic enzymes being identified shortly afterwards (Patricelli & Cravatt, 2001); these enzymes have become a major target for therapeutic manipulation (Di Marzo, 2008, Di Marzo, 2009). The discovery and characterisation of the ECS subserved a resurgence of interest in the pharmacological effects of the individual pCBs (Pertwee, 2008, Izzo et al., 2009).

Despite the therapeutic potential afforded by the discovery of the ECS, licensed pCB-based medicines have largely been restricted to the use of Δ9-THC in a subset of chronically ill patients. Synthetically produced Δ9-THC and its analogues are used clinically as dronabinol and nabilone, both used for attenuation of cancer chemotherapy-induced nausea and vomiting and appetite stimulation in HIV/AIDS patients. The widespread use of Δ9-THC is limited by psychoactivity and the associated abuse potential. Δ9-THC is a partial agonist at CB1 receptors whilst, by contrast, the anti-obesity agent, rimonabant, was the first clinically licenced CB1 receptor antagonist. However, as a result of psychiatric side effects (depression and suicidality) reported following usage of higher doses (Christensen et al., 2007), rimonabant sales were suspended in 2008. Sativex (an approximately 1:1 mixture of Δ9-THC:CBD) is the first medicine derived from whole cannabis plant extracts to be licenced (at present in the UK, Canada, Spain, Germany, Denmark and New Zealand); specifically, to treat pain and spasticity in multiple sclerosis (MS) patients (Perras, 2005, Barnes, 2006). Most pertinently, the introduction of Sativex provided a precedent for the licenced therapeutic use of pCBs, a theme that will be further investigated here. The combination of CBD and Δ9-THC in Sativex is considered to reduce unwanted effects of Δ9-THC (Russo & Guy, 2006), most likely by CBD inhibiting the metabolism of Δ9-THC to the more psychoactive 11-OH-Δ9-THC (Bornheim & Grillo, 1998), and there is evidence that CBD can oppose Δ9-THC effects in vivo (Vann et al., 2008, Malone et al., 2009). Thus, Sativex is an important development as it reduces Δ9-THC central actions to produce a drug which is more tolerable and less prone to abuse (Schoedel et al., 2011). In this regard, it is also possible that Δ9-THC efficacy could be enhanced by ‘entourage’ effects of other pCBs present in the Δ9-THC and CBD extracts of which Sativex is comprised (Russo, 2011). Overall, the investigation of alternative, non-Δ9-THC pCBs which lack psychotropic effects, but retain pharmacological activity, and the elucidation of their mechanisms of action has increasingly become a focus of the pharmaceutical industry and their potential to combat CNS disease is the major focus of this review.

Section snippets

Synthesis and production of phytocannabinoids

pCBs are lipid-soluble chemicals present in the resin secreted from trichomes that are abundantly produced by female plants of the Cannabis sativa herb. It is worth highlighting that pCBs are not so named because they share a common pharmacological target site or mechanism of action to eCBs and synthetic CBs, but due to their shared chemical structure. Within the plant, pCBs are synthesised from fatty acid precursors via a series of transferase and synthase enzymes (Fig. 1). The two major pCBs,

The endocannabinoid system (ECS)

The detailed characterisation of the ECS, including the molecular determination of CB receptors and the metabolic pathways and actions of eCBs, initially provided a useful framework to discuss pCB actions. CB receptor activity can be modulated directly by ligand binding, or indirectly, via modulation of eCB levels (for example by enzyme inhibition). CB1 and CB2 receptors are seven-transmembrane spanning proteins of the rhodopsin G-protein-coupled receptor (GPCR) family A, sharing 44% sequence

Historical background

Cannabis has played a historical role in the treatment of hyperexcitability disorders, a prominent example being epilepsy, where the first evidence of therapeutic use was attributed to the Arabic scholar al-Mayusi in 1100 AD (Lozano, 2001), although additional evidence to support such use can be found in both Ayurvedic and Islamic medicine (Russo, 2005, Russo, 2007). Cannabis use was again noted in the 15th century, when the historian Ibn al-Badri wrote that when “the epileptic son of the

Conclusions

The demonstration that Cannabis sativa contains numerous pCBs in addition to the major psychoactive Δ9-THC component, provides the impetus to support a solid body of preclinical studies focussing on therapeutic development of non-Δ9-THC pCBs. Work in animal models of diseases is now being extended to an increasing number of clinical trials in human CNS disease. The latter, in particular, has been fuelled by the introduction of the first SCE- and, by extension, pCB-, based medicine, Sativex. As

Acknowledgments

The authors wish to thank researchers within the laboratory, in particular Dr Imogen Smith, Mr Nicholas Jones and Mr Jon Farrimond for data and input to the work. BJW thanks Dr Ethan Russo for valuable discussion and difficult to obtain manuscripts associated with cannabis effects upon epilepsy. BJW also thanks Prof. Elizabeth Williamson and Prof. Raphael Mechoulam for first kindling his interest in phytocannabinoid pharmacology. AJH thanks Prof. Javier Fernandez-Ruiz for a pre-publication view

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