Phytocannabinoids as novel therapeutic agents in CNS disorders

^a School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6UB, United Kingdom
^b School of Psychology and Clinical Language Sciences, University of Reading, Whiteknights, Reading, RG6 6UB, United Kingdom

http://dx.doi.org/10.1016/j.pharmthera.2011.09.002, How to Cite or Link Using DOI

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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.

Abbreviations

AD, Alzheimer’s disease;
AED, anti-epileptic drugs;
AEA, arachidonylethanolamide;
2-AG, 2-arachidonylglycerol;
CBC, cannabichromene;
CBD, cannabidiol;
CBDV, cannabidivarin;
CB, cannabinoid;
CBG, cannabigerol;
CBN, cannibinol;
DAGLα, diacylglycerol lipase α;
eCB, endocannabinoid;
FAAH, fatty acid amide hydrolase;
FST, forced swim test;
GPCR, G-protein-coupled receptor;
HD, Huntington’s disease;
6-OHDA, 6-hydroxydopamine;
iNOS, inducible nitric oxide synthase;
IN, interneuron;
LPS,lipopolysaccharide;
MES, maximal electroshock;
MAGL, monoacyl glycerol lipase;
MS, multiple sclerosis;
NO, nitric oxide;
NRS, numerical rating scale;
PD, Parkinson’s disease;
pCB, phytocannabinoid;
PC,Purkinje cell;
rCBF, regional cerebral blood flow;
SAD, seasonal affective disorder;
SCE, standardised cannabis extract;
SPST, stressful public-speaking test;
TST, tail suspension test;
Δ⁹-THC, Δ⁹-tetrahydrocannabinol;
Δ⁹-THCV, Δ⁹tetrahydrocannabivarin;
TRP, transient receptor potential;
TH+,tyrosine hydroxylase positive

Keywords

Cannabinoids;
Endocannabinoid system;
CB₁ receptors;
Electrophysiology;
Epilepsy;
Feeding

Figures and tables from this article:

: Fig. 1. Biosynthesis of major phytocannabinoids.; Figure options

: Fig. 2. Effect of phytocannabinoids on SR141716A binding in mouse cerebellum membranes. Competition binding assays for phytocannabinoids in comparison to standard synthetic CB₁ ligands against 1 nM [³H]SR141716A. B) Δ⁹-THCV has micromolar affinity and CBD and CBG have millimolar affinity for CB₁ receptors. Data courtesy of Dr Imogen Smith.; Figure options

: Fig. 3. Effect of Δ⁹-THCV in mouse cerebellar brain slices. A) In patch clamp recording from IN-PC synapses, Δ⁹-THCV(58 μM) increased frequency of miniature inhibitory postsynaptic currents and blocked agonist effects of WIN55,212-2 (WIN55; 5 μM). B) In MEA recording from cerebellar slices (i), WIN55 (5 μM)-induced increases in PC spike firing were significantly reversed by Δ⁹-THCV (5–40 μM) (ii); *p < 0.05 (Mann–Whitney U-test).; Figure options

: Fig. 4. CBD has a multi-modal action. Scheme showing some identified molecular targets and potential modes of actions for CBD in central neurons.; Figure options

Table 1. Summary of human case studies and clinical trials employing cannabinoids or cannabis in which a pro- or anti-convulsant effect was observed. The limited nature of some sources occasionally renders information regarding study design, dosage routes, compound purity and origin unavailable. Extant and pertinent information has been included below.