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Modulation of Mediotemporal and Ventrostriatal Function in Humans by 9-Tetrahydrocannabinol

A Neural Basis for the Effects of Cannabis sativa on Learning and Psychosis

Sagnik Bhattacharyya, MD; Paolo Fusar-Poli, MD; Stefan Borgwardt, MD; Rocio Martin-Santos, MD, PhD; Chiara Nosarti, PhD; Colin O’Carroll, PhD; Paul Allen, PhD; Marc L. Seal, PhD; Paul C. Fletcher, PhD, FRCPsych; José A. Crippa, MD, PhD; Vincent Giampietro, PhD; Andrea Mechelli, PhD; Zerrin Atakan, FRCPsych; Philip McGuire, PhD, FRCPsych

Arch Gen Psychiatry. 2009;66(4):442-451.

Context  Cannabis sativa use can impair verbal learning, provoke acute psychosis, and increase the risk of schizophrenia. It is unclear where C sativa acts in the human brain to modulate verbal learning and to induce psychotic symptoms.

Objectives  To investigate the effects of 2 main psychoactive constituents of C sativa, 9-tetrahydrocannabinol (9-THC) and cannabidiol, on regional brain function during verbal paired associate learning.

Design  Subjects were studied on 3 separate occasions using a block design functional magnetic resonance imaging paradigm while performing a verbal paired associate learning task. Each imaging session was preceded by the ingestion of 9-THC (10 mg), cannabidiol (600 mg), or placebo in a double-blind, randomized, placebo-controlled, repeated-measures, within-subject design.

Setting  University research center.

Participants  Fifteen healthy, native English-speaking, right-handed men of white race/ethnicity who had used C sativa 15 times or less and had minimal exposure to other illicit drugs in their lifetime.

Main Outcome Measures  Regional brain activation (blood oxygen level–dependent response), performance in a verbal learning task, and objective and subjective ratings of psychotic symptoms, anxiety, intoxication, and sedation.

Results  9-Tetrahydrocannabinol increased psychotic symptoms and levels of anxiety, intoxication, and sedation, whereas no significant effect was noted on these parameters following administration of cannabidiol. Performance in the verbal learning task was not significantly modulated by either drug. Administration of 9-THC augmented activation in the parahippocampal gyrus during blocks 2 and 3 such that the normal linear decrement in activation across repeated encoding blocks was no longer evident. 9-Tetrahydrocannabinol also attenuated the normal time-dependent change in ventrostriatal activation during retrieval of word pairs, which was directly correlated with concurrently induced psychotic symptoms. In contrast, administration of cannabidiol had no such effect.

Conclusion  The modulation of mediotemporal and ventrostriatal function by 9-THC may underlie the effects of C sativa on verbal learning and psychotic symptoms, respectively.

Author Affiliations: Section of Neuroimaging (Drs Bhattacharyya, Fusar-Poli, Borgwardt, Martin-Santos, Allen, Mechelli, Atakan, and McGuire) and Cognition Schizophrenia and Imaging Laboratory (Dr Nosarti), Division of Psychological Medicine and Psychiatry, Department of Biostatistics (Dr Giampietro), and Department of Psychology (Dr Mechelli), Institute of Psychiatry, King's College London, London, and Brain Mapping Unit, Department of Psychiatry, University of Cambridge, Cambridge (Dr Fletcher), England; Section of Psychiatry, Department of Psychobehavioral Health Sciences, University of Pavia, Pavia, Italy (Dr Fusar-Poli); Psychiatric Outpatient Department, University Hospital Basel, Basel, Switzerland (Dr Borgwardt); Pharmacology Research Unit, Municipal Institute for Medical Research–Hospital del Mar, and Psychiatric Department, Institute of Neuroscience, Hospital Clinico, Institut d’Investigacions Biomèdiques August Pi I Sunyer–Centro de Investigación Biomédica en Red en el área de Salud Mental (CIBER-SAM), Barcelona, Spain (Dr Martin-Santos); Department of Neuroscience, Columbia University, New York, New York (Dr O’Carroll); Melbourne Neuropsychiatry Centre, The University of Melbourne, National Neuroscience Facility, Carlton, Australia (Dr Seal); and Department of Neurosciences and Behavior, Faculty of Medicine of Ribeirão Preto, University of São Paulo, and Inct Translational Medicine, São Paulo, Brazil (Dr Crippa).

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