Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction

D’Souza, Deepak Cyril; Abi-Saab, Walid Michel; Madonick, Steven; Forselius-Bielen, Kimberlee; Doersch, Anne; Braley, Gabriel; Gueorguieva, Ralitza; Cooper, Thomas B.; Krystal, John Harrison

doi:10.1016/j.biopsych.2004.12.006

Cited by 617Cannabis and Cannabinoid ResearchSchizophrenia research and treatmentPsychedelics and Drug Studies

Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction

D’Souza, Deepak Cyril, Abi-Saab, Walid Michel, Madonick, Steven, Forselius-Bielen, Kimberlee, Doersch, Anne, Braley, Gabriel, Gueorguieva, Ralitza, Cooper, Thomas B. +1 more·2005·Biological Psychiatry

DOI 10.1016/j.biopsych.2004.12.006

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Abstract

Background Recent advances in the neurobiology of cannabinoids have renewed interest in the association between cannabis and psychotic disorders.Methods In a 3-day, double-blind, randomized, placebo-controlled study, the behavioral, cognitive, motor, and endocrine effects of 0 mg, 2.5 mg, and 5 mg intravenous Delta-9-tetrahydrocannabinol (Delta-9-THC) were characterized in 13 stable, antipsychotic-treated schizophrenia patients. These data were compared with effects in healthy subjects reported elsewhere.Results Delta-9-tetrahydrocannabinol transiently increased 1) learning and recall deficits; 2) positive, negative, and general schizophrenia symptoms; 3) perceptual alterations; 4) akathisia, rigidity, and dyskinesia; 5) deficits in vigilance; and 6) plasma prolactin and cortisol. Schizophrenia patients were more vulnerable to Delta-9-THC effects on recall relative to control subjects. There were no serious short- or long-term adverse events associated with study participation.Conclusions Delta-9-tetrahydrocannabinol is associated with transient exacerbation in core psychotic and cognitive deficits in schizophrenia. These data do not provide a reason to explain why schizophrenia patients use or misuse cannabis. Furthermore, Delta-9-THC might differentially affect schizophrenia patients relative to control subjects. Finally, the enhanced sensitivity to the cognitive effects of Delta-9-THC warrants further study into whether brain cannabinoid receptor dysfunction contributes to the pathophysiology of the cognitive deficits associated with schizophrenia.

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In the laboratory, administration of THC increases psychotic symptoms in people with schizophrenia.
“In the laboratory, administration of THC increases psychotic symptoms in people with schizophrenia [53].”
From Cannabis, cannabinoids and health: a review of evidence on risks and medical benefits (2025) · cites this paper as [53]
There is evidence to suggest a positive association between cannabis use and development of psychosis, in people susceptible to psychotic disorders.
“There is evidence to suggest a positive association between cannabis use and development of psychosis, in people susceptible to psychotic disorders.117–119”
From Clinical Practice Guidelines for Cannabis and Cannabinoid-Based Medicines in the Management of Chronic Pain and Co-Occurring Conditions (2024) · cites this paper as [118]

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The Endocannabinoid System as an Emerging Target of Pharmacotherapy
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Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia
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Cannabis
Vale, A. (2003) · Medicine · doi:10.1383/medc.31.10.40.27812

Authors: D’Souza, D. C., Abi-Saab, W. M., Madonick, S., Forselius-Bielen, K., Doersch, A., Braley, G., Gueorguieva, R., Cooper, T. B., & Krystal, J. H.
Affiliations: Yale University (US)
University of Connecticut (US)
Connecticut Mental Health Center (US)
Nathan Kline Institute for Psychiatric Research (US)
Corresponding author: D’Souza, Deepak Cyril
ORCID: D’Souza, Deepak Cyril
Gueorguieva, Ralitza
Cooper, Thomas B.
Krystal, John Harrison
Venue: Biological Psychiatry
Publisher: Elsevier BV
Published: 2005-03
Volume: 57
Issue: 6
Pages: 594-608
ISSN: 0006-3223 (ISSN-L)
DOI: 10.1016/j.biopsych.2004.12.006
OpenAlex: W1964167179
Cited by: 617
References: 168
Citations by year: 2026: 10 · 2025: 16 · 2024: 25 · 2023: 24 · 2022: 30 · 2021: 23 · 2020: 30 · 2019: 22 · 2018: 35 · 2017: 43 · 2016: 31 · 2015: 28 · 2014: 26 · 2013: 32 · 2012: 32
FWCI: 18.50
Type: journal article
Language: en
Open access: closed
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Biological Psychiatry (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (5k02aa000261-04)
National Institute on Alcohol Abuse and Alcoholism (K02 AA00261-04)
National Institute of Mental Health (R01 MH61019-02, R01MH061019, P50 MH44866-15, P50MH044866)
National Institute on Drug Abuse (R01DA12382-01, R01DA012382)
Topics: Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
Social Sciences › Psychology › Clinical Psychology › Psychedelics and Drug Studies
Keywords: delta-9-tetrahydrocannabinol, schizophrenia, cannabis, psychosis, cognitive impairment, learning and recall, akathisia, dyskinesia, prolactin, cortisol, sustained attention
MeSH terms: Adult, Arousal, Cognition, Dose-Response Relationship, Drug, Double-Blind Method, Endocrine System, Female, Humans, Injections, Intravenous, Male, Middle Aged, Motor Activity, Neuropsychological Tests, Perception, Psychiatric Status Rating Scales, Psychotic Disorders, Psychotropic Drugs, Mental Recall, Schizophrenia, Dronabinol, Verbal Learning, Akathisia, Drug-Induced

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Delta-9-tetrahydrocannabinol effects in schizophrenia: Implications for cognition, psychosis, and addiction

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