A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol

Ethan Russo

a,b,c,

*

, Geoffrey W. Guy

a

a

GW Pharmaceuticals, Porton Down Science Park, Salisbury, Wiltshire SP4 0JQ, UK

b

University of Washington School of Medicine, Seattle, WA, USA

c

University of Montana Department of Pharmaceutical Sciences, MT, USA

Received 15 August 2005; accepted 18 August 2005

Summary

This study examines the current knowled ge of physiological and clinical effects of tetrahydrocannabinol (TH C) and can nab idi ol (CB D) and pre sen ts a rat ion ale for the ir com bin ati on in pha rma ceu tic al pre par ati ons . Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as ant i-i nﬂa mma tor y sub sta nce s ind epe nde nt of cyc lo- oxy gen ase (CO X) inh ibi tio n. CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permi tted the admi nistra tion of highe r dose s of THC, provid ing evidence for clinic al efﬁcacy and safe ty for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturba nces, periphera l neuro path ic pain , brach ial plexu s avuls ion sympt oms, rheumatoi d arthr itis and int rac tab le can cer pa in. Pro spe cts for fut ure app lic ati on of who le can nab is ext rac ts in neu rop rot ect ion , dru g dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efﬁcacy while reducing adverse events is supported.

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c

2005 Elsevier Ltd. All rights reserved.

Introduction

Can nab ino ids ref er to a het ero mor phi c gro up of molecu les that demonstra te activ ity upon cannab- inoid receptors and are characterised by three vari- eties: endogenous or endocannabinoids, synthetic canna binoid s, and phytoc anna binoid s, which are natural terpenophenolic compounds derived from

Cannabis

spp. In recent years, scientists have provided eluci- dat ion of the mec han isms of act ion of can nab is and THC with the discovery of an endocannabinoid ligand, arachidonylethanolamide, nicknamed anan- damide, from the Sanskrit word

ananda,

or ‘‘bliss’’ [1] . An an da mi de in hi bi ts cy cl ic AM P me di at ed thr oug h G-p rot ein cou plin g in tar get cel ls. Ear ly

0306-9877/$ - see front matter

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c

2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.08.026 * Corresponding author. Present address. 2235 Wylie Avenue, Missoula, MT 59802, USA. Tel.: +1 406 542 0151; fax: +1 406 542 0158.

E-ma il addr esses :

66,