Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug

A.W. Zuardi, J.A.S. Crippa, J.E.C. Hallak, F.A. Moreira and F.S. Guimarães

Brazilian Journal of Medical and Biological Research, 2006, 39, 421-429

ISSN 0100-879X Review

Abstract
A high dose of Δ9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of Δ9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic
actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.

Keywords : Cannabidiol, Δ9-Tetrahydrocannabinol, Cannabinoid, Anxiety, Antipsychotic, Schizophrenia

 

Introduction
The use Cannabis sativa (cannabis) extracts as medicine was described in China and India (1) before the birth of Christ. The therapeutic use of cannabis was introduced in Western medicine in the first half of the 19th century and reached its climax in the last two decades of the same century. At the turn of the century, several pharmaceutical companies were marketing cannabis extracts and tinctures which were prescribed by doctors for many different complaints including pain, whooping cough and asthma, and as a sedative/hypnotic agent (2). However, the use of cannabis as a medicine almost completely disappeared at about the middle of the 20th century. The main reasons for this disappearance were the variable potency of cannabis extracts, the erratic and unpredictable individual responses, the introduction of synthetic and more stable pharmaceutical substitutes such as aspirin, chloral hydrate
and barbiturates, the recognition of important adverse effects such as anxiety and cognitive impairment, and the legal restrictions to the use of cannabis-derived medicines (2). Today this situation has changed considerably. The main active psychotropic constituent of cannabis, Δ9-tetrahydrocannabinol (Δ9-THC), was isolated, identified and synthesized in the 1960’s. Almost three decades later, cannabinoid receptors in the brain were described and cloned and the endogenous cannabinoids were isolated and identified (3). As a result of these discoveries the interest in cannabis research has remarkably increased. For instance, the number of publications using the key word “brain”, compiled by the ISI Web of Knowledge, increased 26 times from 1960-1964 to 2000- 2004, while the number of publications about ‘cannabis’ increased 78.5 times during the same period. As a consequence, the research on the use of cannabis as medicine has been renewed.

Although Δ9-THC is commonly accepted as the main factor responsible for the effects of cannabis, several reports have demonstrated that other components of the plant influence its pharmacological activity (4). One of these components is cannabidiol (CBD), which may constitute up to 40% of cannabis extracts (5) and is devoid of the typical psychological effects of cannabis in humans (6). Studies on the interaction between Δ9-THC and CBD have produced apparently contradictory results (7). Although potentiation of the effects of Δ9-THC has been observed (8,9), this phenomenon probably involves pharmacokinetic interactions since CBD is a potent inhibitor of hepatic drug metabolism (10) and increases Δ9-THC concentrations in the brain (11). Several studies, however, have reported antagonism of the effects of Δ9-THC when both compounds are administered simultaneously to animals (12,13) or humans (6,14). CBD (1 mg/kg) co-administered with Δ9- THC (0.5 mg/kg) significantly reduced the anxiety and the psychotomimetic symptoms induced by the latter drug in healthy volunteers (6). Since the dose of CBD used in that study did not change Δ9-THC levels in blood (15), it was suggested that CBD blocked the effects of Δ9-THC by some intrinsic pharmacological properties. Actually, when administered alone CBD produced its own effects, including hypnotic (16), anticonvulsive (17), neuroprotective (18), and hormonal (increased corticosterone and cortisol levels) effects (19,20). These effects led to the hypothesis that CBD could have anxiolytic and/or antipsychotic effects.

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