Cannabidiol: from an inactive cannabinoid to a drug with wide spectrum of action Canabidiol: de um canabinóide inativo a uma droga com amplo espectro de ação

Objective: The aim of this review is to describe the historical development of research on cannabidiol. Method: This review was carried out on reports drawn from Medline, Web of Science and SciELO. Discussion: After the elucidation of the chemical structure of cannabidiol in 1963, the initial studies showed that cannabidiol was unable to mimic the effects of Cannabis. In the 1970’s the number of publications on cannabidiol reached a first peak, having the research focused mainly on the interaction with delta9-THC and its antiepileptic and sedative effects. The following two decades showed lower degree of interest, and the potential therapeutic properties of cannabidiol investigated were mainly the anxiolytic, antipsychotic and on motor diseases effects. The last five years have shown a remarkable increase in publications on cannabidiol mainly stimulated by the discovery of its anti-inflammatory, anti-oxidative and neuroprotective effects. These studies have suggested a wide range of possible therapeutic effects of cannabidiol on several conditions, including Parkinson’s disease, Alzheimer’s disease, cerebral ischemia, diabetes, rheumatoid arthritis, other inflammatory diseases, nausea and cancer. Conclusion: In the last 45 years it has been possible to demonstrate that CBD has a wide range of pharmacological effects, many of which being of great therapeutic interest, but still waiting to be confirmed by clinical trials. Descriptors: Cannabidiol; Cannabis; Cannabinoids; History; Therapeutic uses Resumo Objetivo: O objetivo desta revisão é descrever a evolução histórica das pesquisas sobre o canabidiol. Método: Esta revisão foi conduzida utilizando-se bases de dados eletrônicas (Medline, Web of Science e SciELO). Discussão: Após a elucidação de sua estrutura química, em 1963, os estudos iniciais do canabidiol demonstraram que ele não foi capaz de mimetizar os efeitos da maconha. Na década de 70, o número de publicações sobre o canabidiol atingiu um primeiro pico, com as investigações centrando-se principalmente na sua interação com o delta9-THC e nos seus efeitos antiepiléptico e sedativo. As duas décadas seguintes apresentaram um menor nível de interesse e as propriedades terapêuticas potenciais do canabidiol investigadas foram, principalmente, as ansiolíticas, antipsicóticas e seus efeitos sobre as doenças motoras. Os últimos cinco anos têm demonstrado um notável aumento de publicações sobre o canabidiol, principalmente estimulado pela descoberta dos seus efeitos anti-inflamatório, anti-oxidativo e neuroprotetor. Estes estudos têm sugerido uma vasta gama de possíveis efeitos terapêuticos da canabidiol em várias condições, incluindo doença de Parkinson, doença de Alzheimer, isquemia cerebral, diabetes, náusea, câncer, artrite reumatóide e outras doenças inflamatórias. Conclusão: Nos últimos 45 anos, foi possível demonstrar uma vasta gama de efeitos farmacológicos do canabidiol, muitos dos quais são de grande interesse terapêutico, que ainda necessitam ser confirmados por estudos clínicos. Descritores: Canabidiol; Cannabis; Canabinóides; História; Usos terapêuticos 1 Department of Neurology, Psychiatry and Medical Psychology, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto (SP), Brazil Antonio Waldo Zuardi1 Correspondence Antonio Waldo Zuardi Av. Candido Pereira Lima, 745 – Jd. Recreio 14040-250 Ribeirão Preto, SP, Brasil E-mail: [email protected] Submitted: March 7, 2008 Accepted: April 17, 2008 Rev Bras Psiquiatr. 2008;30(3):271-80 SPECIAL ARTICLE 271 History of research on cannabidiol Rev Bras Psiquiatr. 2008;30(3):271-80 272 Introduction In the tip of secreting hairs located mainly on female-plant flowers and, in a smaller amount, in the leaves of cannabis plant, there are resin glands that have a considerable amount of chemically related active compounds, called cannabinoids. In some varieties of cannabis the main cannabinoid is the psychoactive component of the plant, delta9-tetrahydrocannabinol (delta9-THC). Cannabis varieties typically bred for fiber are nearly always relatively low in delta9-THC, cannabidiol (CBD) being the predominant cannabinoid in these plants.1 Although CBD was isolated from marijuana extract in 1940 by Adams et al.,2 for almost 25 years no further work has been reported, except for a few early works about its isolation. Only in 1963 its exact chemical structure was elucidated by Mechoulam and Shvo.3 Over the following few years Mechoulam’s group was responsible for the structure and stereochemistry determination of the main cannabinoids, which opened a new research field on pharmacological activity of cannabis constituents.4,5 The evolution of the number of publications on CBD since 1963, in comparison with publications on cannabis in general, is shown in Figure 1. Only a few pharmacological studies on CBD were reported before the early 1970’s, showing that CBD had no cannabis-like activity.6 The number of publications increased in this decade and reached a first peak around 1975. In this period, a Brazilian research group led by Carlini, gave an important contribution, especially about the interactions of delta9-THC with other cannabinoids, including CBD.7 Then, the number of publications declined and remained stabilized until a few years ago. The interest in studies about cannabis was renewed in the early 1990’s, by the description and cloning of specific receptors for the cannabinoids in the nervous system and the subsequent isolation of anandamide, an endogenous cannabinoid.8 Afterwards, the number of publications about cannabis has been continuously growing, but the reports on CBD remained stable until the early 2000’s. In the last five years there has been an explosive increase in publications on CBD, with the confirmation of a plethora of pharmacological effects, many of them with therapeutic potential. There are some recent and very good reviews on CBD.9-12 As historical aspects have so far not been yet emphasized, the aim of the present review is to describe the development of this research field which transformed our view about CBD from an inactive cannabinoid to a drug with multiple actions. Inactive cannabinoid that interact with delta9-THC (1970’s) The early pharmacological tests on isolated cannabinoids had evidenced that except for delta9-THC, no other major psychotomimetically active compounds were present in cannabis.13 During this period, several reports attested that CBD was unable to mimic the effects of cannabis both in animals14 and in humans,15,16 leading to the thought that it was an inactive cannabinoid. This thought began to change with the observation that the activity in animals of several samples of cannabis differed widely, a fact which could not be attributed only to the different delta9THC contents of the samples.17,18 It was then hypothesized that other cannabinoids, among them CBD, could be interfering with the delta9-THC effects. Many interactive studies between CBD and delta9-THC were accomplished by different groups, producing seemingly contradictory results both in animals,19-21 and in humans.22-24 Different schedules of drug administration used in these studies may help explain the contradictions. It seems that CBD administered before delta9-THC potentiates the effects of the latter compound. However, concomitant use of both compounds suggests that CBD antagonizes delta9-THC effects.25-27 This difference could be explained by pharmacokinetic or pharmacodynamic interactions between the two cannabinoids. CBD has been found to be a potent inhibitor of hepatic drug metabolism.28,29 Pre-treatment of mice with high doses of CBD causes an increase in delta9-THC level in the brain.30 Recently, evidence that CBD also inhibits the metabolic hydroxylation of delta9-THC in human volunteers31 has been obtained. This pharmacokinetic interaction could explain the increased effects of delta9-THC by CBD pretreatment. On the other hand, CBD is not able to change delta9-THC blood level with co-administration of both compounds in rats32 or humans volunteers.33 Therefore, it has been suggested that CBD can antagonize delta9-THC effects pharmacodynamically.34 Early evidence (1970’s) on CBD pharmacological activity 1. Antiepileptic action The first pharmacological actions of CBD described were the antiepileptic and the sedative ones. In 1973, a Brazilian group reported that CBD was active in reducing or blocking convulsions produced in experimental animals by a variety of procedures,35,36 which was confirmed by another group one year later.37 At the end of that decade, the same Brazilian group has tested CBD as a treatment for intractable epilepsy in 16 grandmal patients. Each patient received, in a double-blind procedure, 200 to 300 mg daily of CBD or placebo for as long as four and a half months. Throughout the experiment, the patients did not stop taking the antiepileptic drugs prescribed before the experiment (which had not eliminated their seizures). Only one of the eight patients getting CBD showed no improvement, while among the patients who received the placebo, 1 improved and 7 remained unchanged.38 In a less successful study, no significant improvement in seizure frequency was observed among 12 epileptic patients who received 200-300 mg of cannabidiol per day, in addition to standard antiepileptic drugs.39 No further clinical trials with CBD have been published since then. Therefore, the clinical efficacy of CBD on epilepsy is still uncertain. 2. Sedative action In the early 1970’s, suggestive evidence of a sedative action appeared, based on the observation that CBD reduced ambulation in