Send Reprints Orders on reprints@benthamscience.org 4966 Current Pharmaceutical Design, 2012, 18, 4966-4979 1873-4286/12 $58.00+.00 © 2012 Bentham Science Publishers Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers R. Martín-Santos 1,2,3 *, J.A. Crippa 1, 4 , A. Batalla 2 , S. Bhattacharyya 1 , Z. Atakan 1 , S. Borgwardt 1,5 , P.Allen 1 , M.Seal 1,6 , K.Langohr 3,7 , M. Farré 3 , AW.Zuardi 4 and P.K. McGuire 1 1 Department of Psychosis Studies, Institute of Psychiatry, King’s College London, UK; 2 Department of Psychiatry, Institut Clínic de Neurociències, Hospital Clínic, IDIBAPS, CIBERSAM, Barcelona and Department of Psychiatry and Clinical Psychobiology, Uni- versity of Barcelona, Spain; 3 Human Pharmacology and Neurosciences, Hospital del Mar Research Institute - IMIM, Barcelona, Spain; 4 Department of Neuroscience and Behavior, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Brazil and INCT Translational Medicine, Ribeirão Preto, Brazil; 5 Department of Psychiatry, UPK, University of Basel, Switzerland; 6 Melbourne Neuropsychiatry Centre, The University of Melbourne, Australia; 7 Department of Statistics and Operations Research, Polytechnic University of Catalonia, Barcelona, Spain Abstract: Rationale: Animal and humans studies suggest that the two main constituents of cannabis sativa, delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have quite different acute effects. However, to date the two compounds have largely been studied sepa- rately. Objective: To evaluate and compare the acute pharmacological effects of both THC and CBD in the same human volunteers. Methods: A randomised, double-blind, cross-over, placebo controlled trial was conducted in 16 healthy male subjects. Oral THC 10 mg or CBD 600 mg or placebo was administered in three consecutive sessions, at one-month interval. Physiological measures and symptom ratings were assessed before, and at 1, 2 and 3 hours post drug administration. The area under the curve (AUC) between baseline and 3 hours, and the maximum absolute change from baseline at 2 hours were analysed by one-way repeated measures analysis of variance, with drug condition (THC or CBD or placebo) as the factor. Results: Relative to both placebo and CBD, administration of THC was associated with anxiety, dysphoria, positive psychotic symptoms, physical and mental sedation, subjective intoxication (AUC and effect at 2 hours: p<0.01), an increase in heart rate (p<0.05). There were no differences between CBD and placebo on any symptomatic, physiological variable. Conclusions: In healthy volunteers, THC has marked acute behavioural and physiological effects, whereas CBD has proven to be safe and well tolerated. Keywords: Cannabis, -9-THC-tetrahydrocannabinol, cannabidiol, unique dose, pharmacological acute effects, humans, induced anxiety, induced psychosis, review. INTRODUCTION Cannabis sativa preparations (marijuana, hashish, and others) are the illicit drugs most widely used in young people [1]. The plant has around 400 different chemical constituents, but two of its major psychoactive compounds are delta-9-tetrahydrocannabinol (THC) [2] and cannabidiol (CBD) [3,4]. THC acts as a partial agonist at specific endogenous cannabi- noid receptors, termed CB1 and CB2, both members of the G- protein coupled receptor class [5]. The CB1 receptors are mainly expressed in the central nervous system, with a high density in the anterior cingulate, prefrontal cortex, medial temporal lobe and other areas [6] and are thought to mediate the majority of the effects of THC in the central nervous system. However, depending on the brain region, and whether the local CB1 receptors are expressed on neurons that release GABA or glutamate, THC can have either inhibitory or excitatory effects [7]. The acute administration of THC is associated with relaxation and enjoyment, but can also lead to unpleasant effects such as anxi- ety, psychotic symptoms, depression, apathy, and impairment of memory [8]. It has also been associated with impairments in *Address correspondence to this author at the Department of Psychiatry, Institut Clínic de Neurociències, Hospital Clínic, IDIBAPS, CIBERSAM, and Department of Psychiatry and Clinical Psychobiology, University of Barcelona, Villarroel, 170. 08036-Barcelona, Spain; Tel: 34 932275400; Fax: 34 932275538; E-mail: rmsantos@clinic.ub.es learning, motor coordination, slowed reaction time, impaired con- centration during complex tasks, deficits in some executive func- tions, and impairments in some aspects of verbal processing, such as verbal fluency [9,10]. THC administration can also produce an increase in heart rate and orthostatic hypotension. However, the acute effects of THC and their time of onset are subject to wide inter-individual variation and due to differences in route of admini- stration, rate of absorption, metabolism and the subject’s expecta- tion of its effects [11]. In contrast, CBD has a low affinity for CB1 receptors [12] and its molecular mechanism of action remains poorly understood. It may facilitate endocannabinoid signaling by inhibiting the cellular uptake and enzymatic hydrolysis of endocannabinoids [12]. It can also bind to CB1 and to serotonergic (5HT1A) receptors, inhibit adenosine uptake, and can activate vanilloid (TRPV1) receptors at micromolar concentrations [12-16]. CBD is pharmacologically active and can have anticonvulsant, sedative, anxiolytic [3,4,17,18] and antipsychotic effects [4, 19-25]. Unlike THC, CBD does not have acute effects on motor or cognitive performance [26, 27], nor does it have significant effects on pulse rate or blood pressure [28, 29]. Functional neuroimaging studies have confirmed the neuro- physiological effects of THC and CBD are distinct and opposite [30-34]. Moreover, co-administration of CBD and THC may alter the pharmacological effect of the THC, in that CBD potentiates some of THC’s desirable effects but attenuates some of its negative effects [29, 34-36]. However, it is difficult to establish which