Associate editor: M.G. BelvisiPhytocannabinoids as novel therapeutic agents in CNS disorders
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
References (319)
- et al.
Activation of the CB1 cannabinoid receptor protects cultured mouse spinal neurons against excitotoxicity
Neurosci Lett
(2001) - et al.
Supply and demand for endocannabinoids
Trends Neurosci
(2011) - et al.
Effects of the cannabinoid receptor agonist CP 55,940 and the cannabinoid receptor antagonist SR 141716 on intracranial self-stimulation in Lewis rats
Life Sci
(2001) - et al.
Dronabinol as a treatment for anorexia associated with weight loss in patients with AIDS
J Pain Symptom Manage
(1995) - et al.
Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats
Eur Neuropsychopharmacol
(2008) - et al.
Marijuana effect expectancies: relations to social anxiety and marijuana use problems
Addict Behav
(2008) - et al.
Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials
Lancet
(2007) - et al.
Effects of marihuana cannabinoids on seizure activity in cobalt-epileptic rats
Pharmacol Biochem Behav
(1982) - et al.
Multiple sclerosis
Lancet
(2008) - et al.
Effects of cannabidiol on behavioral seizures caused by convulsant drugs or current in mice
Eur J Pharmacol
(1982)
Controlled clinical trial of cannabidiol in Huntington's disease
Pharmacol Biochem Behav
Immunohistochemical localization of anabolic and catabolic enzymes for anandamide and other putative endovanilloids in the hippocampus and cerebellar cortex of the mouse brain
Neuroscience
Cannabinoid signalling
Life Sci
Decreased depression in marijuana users
Addict Behav
Cannabinoid-induced motor incoordination through the cerebellar CB(1) receptor in mice
Pharmacol Biochem Behav
Involvement of the cerebellar adenosine A1 receptor in cannabinoid-induced motor incoordination in the acute and tolerant state in mice
Brain Res
The endocannabinoid system: its general strategy of action, tools for its pharmacological manipulation and potential therapeutic exploitation
Pharmacol Res
Anandamide, an endogenous cannabinomimetic eicosanoid: 'killing two birds with one stone'
Prostaglandins Leukot Essent Fatty Acids
Excitotoxicity in a chronic model of multiple sclerosis: Neuroprotective effects of cannabinoids through CB1 and CB2 receptor activation
Mol Cell Neurosci
Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington's disease transgenic mice
Neuroscience
Neuroprotective strategies involving ROS in Alzheimer disease
Free Radic Biol Med
Single application of a CB1 receptor antagonist rapidly following head injury prevents long-term hyperexcitability in a rat model
Epilepsy Res
Antidepressant-like effect of delta9-tetrahydrocannabinol and other cannabinoids isolated from Cannabis sativa L
Pharmacol Biochem Behav
Neuroprotective effect of (−)delta9-tetrahydrocannabinol and cannabidiol in N-methyl-D-aspartate-induced retinal neurotoxicity: involvement of peroxynitrite
Am J Pathol
Chemical constituents of marijuana: the complex mixture of natural cannabinoids
Life Sci
Cannabidiol inhibits inducible nitric oxide synthase protein expression and nitric oxide production in beta-amyloid stimulated PC12 neurons through p38 MAP kinase and NF-kappaB involvement
Neurosci Lett
Behavioral analysis of marijuana effects on food intake in humans
Pharmacol Biochem Behav
Effects of smoked marijuana on food intake and body weight of humans living in a residential laboratory
Appetite
Rates of psychiatric comorbidity among U.S. residents with lifetime cannabis dependence
Am J Drug Alcohol Abuse
The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alpha-1-beta glycine receptor function
Pharmacology
Anticonvulsant effect of cannabidiol
S Afr Med J
CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies
Br J Pharmacol
Therapeutic action of cannabinoids in a murine model of multiple sclerosis
J Neurosci
Pharmacology and effects of cannabis: a brief review
Br J Psychiatry
The seed and the soil: effect of dosage, personality and starting state on the response to delta 9 tetrahydrocannabinol in man
Br J Clin Pharmacol
Cannabinoids control spasticity and tremor in a multiple sclerosis model
Nature
Sativex: clinical efficacy and tolerability in the treatment of symptoms of multiple sclerosis and neuropathic pain
Expert Opin Pharmacother
Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients
Neuropsychopharmacology
Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide
Br J Pharmacol
Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease
Brain
9 -Tetrahydrocannabinol effect on audiogenic seizure susceptibility
Psychopharmacologia
The plant cannabinoid delta9-tetrahydrocannabivarin can decrease signs of inflammation and inflammatory pain in mice
Br J Pharmacol
Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator
Chem Res Toxicol
Therapeutic uses of cannabis
Endocannabinoids inhibit transmission at granule cell to Purkinje cell synapses by modulating three types of presynaptic calcium channels
J Neurosci
Emerging role of the cannabinoid receptor CB2 in immune regulation: therapeutic prospects for neuroinflammation
Expert Rev Mol Med
Hypnotic and antiepileptic effects of cannabidiol
J Clin Pharmacol
Inhibition of an equilibrative nucleoside transporter by cannabidiol: a mechanism of cannabinoid immunosuppression
Proc Natl Acad Sci U S A
Cultured rat microglial cells synthesize the endocannabinoid 2-arachidonylglycerol, which increases proliferation via a CB2 receptor-dependent mechanism
Mol Pharmacol
Cannabis for dyskinesia in Parkinson disease: a randomized double-blind crossover study
Neurology
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