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Send ORerdperirnstosfORredperisnotsnarterperpinritns@firstname.lastname@example.org Current Pharmaceutical Design, 2012, 18, 5131-5140 5131
A Critical Review of the Antipsychotic Effects of Cannabidiol: 30 Years of a Trans- lational Investigation
Antonio Waldo Zuardi1, José Alexandre S. Crippa1,2,*, Jaime E.C. Hallak1, Sagnik Bhattacharyya2, Zerrin Atakan2, Rocio Martín-Santos3, Philip K. McGuire2 and Francisco Silveira Guimarães4
1Department of Neuroscience and Behavior, Faculty of Medicine, University of São Paulo and National Institute for Translational Medicine (INCT-TM), Ribeirão Preto, SP – Brazil; 2Psychosis Clinical Academic Group, Department of Psychosis Studies, Institute of Psychiatry, King's College London; 3Department of Psychiatry, Institut Clínic Neurociencies, IDIBAPS, CIBERSAM, University of Barcelona, Barcelona, Spain and INCT-TM, Brazil, 4Department of Pharmacology, Faculty of Medicine, University of São Paulo”, Ribeirão Preto, SP - Brazil
Abstract: 9-tetrahydrocannabinol ( 9-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of 9- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volun- teers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of 9-THC involve the striatum and temporal cortex that have been traditionally associ- ated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psycho- sis, in general and in schizophrenia, in particular.
Keywords: Cannabidiol, CBD, cannabis, antipsychotic, psychosis. INTRODUCTION
The first evidence that cannabidiol (CBD), a non-psychoactive component of Cannabis sativa, could have antipsychotic properties was published in 1982 . This initial study investigated the inter- action between 9-tetrahydrocannabinol ( 9-THC), the main active constituent of the plant, and CBD in health volunteers. The co- administration of the two cannabinoids induced less anxiety and psychotomimetic symptoms than 9-THC alone. At that time it was suggested that CBD attenuation of 9-THC effects depended on a pharmacodynamic rather than pharmacokinetic interaction, since it had been shown that, at the CBD dose used, the drug did not change 9-THC levels in blood . The possible antipsychotic effect of CBD received further support later that year with the report of a higher frequency of acute psychotic episodes in patients admitted in psychiatric hospital after the use of a variety of cannabis virtually devoid of CBD . These initial results led to a series of studies that have established, from laboratory bench to patients, a clear link between CBD and antipsychotic activity. Therefore, the present article provides a critical review of the research evaluating antipsy- chotic potential of this cannabinoid.
EVIDENCE FROM ANIMAL MODELS
A summary of studies that have investigated the antipsychotic effects of CBD in animal models is shown in Table 1.
CBD produced effects similar to haloperidol, a typical antipsy- chotic drug, in apomorphine–induced stereotyped behavior and hyperlocomotion induced by both D-amphetamine and ketamine [4, 5]. Unlike haloperidol, CBD increased prolactin levels only at doses higher than those needed to block stereotyped behavior and did not cause catalepsy even at very high doses . This profile is similar
*Address correspondence to this author at the Department of Neurosciences and Behavior, Division of Psychiatry; Faculdade de Medicina de Ribeirão Preto; Universidade de São Paulo, Hospital das Clínicas - Terceiro Andar; Av. Bandeirantes, 3900; Ribeirão Preto, São Paulo, Brazil; Tel: +55-16- 36022201; Fax: +55-16- 36330866; E-mail: email@example.com
to clozapine, an atypical antipsychotic drug . Some discrepan- cies, however, have been observed in hyperlocomotion tests. Unlike ketamine, the increase in locomotor behavior induced by the more potent non-competitive antagonist of glutamate NMDA-receptors MK-801 was not attenuated by CBD . Also, Long et al,  failed to find a decrease in amphetamine-induced hyperlocomotion by acute doses of CBD, although chronic treatment with this drug was effective. Differences in rodent strains, CBD administration regime and the drug used to induce hyperlocomotion could help to explain these discrepancies.
Contradictory results were also observed regarding the effects of CBD in disruption of the prepulse inhibition (PPI) by MK-801. A study in mice found a significant reversal of PPI disruption  while in rats this effect was not observed . An increase in PPI response was also observed with acute and chronic administration of CBD in mice . Although this result is not indicative of an antipsychotic action, it suggests an effect that goes to the opposite direction from that produced by drugs that induce psychotic symp- toms. In addition, CBD was effective in attenuating social with- drawal induced by 9-THC in rats , but only partially effective to produce this same effect induced by MK-801 in mice . As pointed out above, differences in rodent species could be one of the reasons for these contradictory results.
Taken together, and even considering some conflicting results, preclinical data indicate that CBD does possess antipsychotic properties, having a profile compatible with atypical antipsychotics. Consistent with this suggestion, studies investigating changes in the expression of the proto-oncogene c-Fos showed that both CBD and clozapine, but not haloperidol, are able to increase this expression in the prefrontal cortex, while only haloperidol enhanced c-Fos expression in the dorsal striatum [10, 11].
Safety and side effect studies of CBD were required before human administration. Extensive in vivo and in vitro reports of
© 2012 Bentham Science Publishers
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