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Human Laboratory Studies on Cannabinoids and Psychosis

  • Mohamed Sherif
    Affiliations
    Schizophrenia and Neuropharmacology Research Group, VA Connecticut Healthcare System, West Haven

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author
  • Rajiv Radhakrishnan
    Affiliations
    Schizophrenia and Neuropharmacology Research Group, VA Connecticut Healthcare System, West Haven

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author
  • Deepak Cyril D’Souza
    Affiliations
    Schizophrenia and Neuropharmacology Research Group, VA Connecticut Healthcare System, West Haven

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
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  • Mohini Ranganathan
    Correspondence
    Address correspondence to Mohini Ranganathan, M.D., Psychiatry Service, 116A, VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT 06516.
    Affiliations
    Schizophrenia and Neuropharmacology Research Group, VA Connecticut Healthcare System, West Haven

    Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut

    Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut
    Search for articles by this author
Published:February 01, 2016DOI:https://doi.org/10.1016/j.biopsych.2016.01.011

      Abstract

      Some of the most compelling evidence supporting an association between cannabinoid agonists and psychosis comes from controlled laboratory studies in humans. Randomized, double-blind, placebo-controlled, crossover laboratory studies demonstrate that cannabinoid agonists, including phytocannabinoids and synthetic cannabinoids, produce a wide range of positive, negative, and cognitive symptoms and psychophysiologic deficits in healthy human subjects that resemble the phenomenology of schizophrenia. These effects are time locked to drug administration, are dose related, and are transient and rarely necessitate intervention. The magnitude of effects is similar to the effects of ketamine but qualitatively distinct from other psychotomimetic drugs, including ketamine, amphetamine, and salvinorin A. Cannabinoid agonists have also been shown to transiently exacerbate symptoms in individuals with schizophrenia in laboratory studies. Patients with schizophrenia are more vulnerable than healthy control subjects to the acute behavioral and cognitive effects of cannabinoid agonists and experience transient exacerbation of symptoms despite treatment with antipsychotic medications. Furthermore, laboratory studies have failed to demonstrate any “beneficial” effects of cannabinoid agonists in individuals with schizophrenia—challenging the cannabis self-medication hypothesis. Emerging evidence suggests that polymorphisms of several genes related to dopamine metabolism (e.g., COMT, DAT1, and AKT1) may moderate the effects of cannabinoid agonists in laboratory studies. Cannabinoid agonists induce dopamine release, although the magnitude of release does not appear to be commensurate to the magnitude and spectrum of their acute psychotomimetic effects. Interactions between the endocannabinoid, gamma-aminobutyric acid, and glutamate systems and their individual and interactive effects on neural oscillations provide a plausible mechanism underlying the psychotomimetic effects of cannabinoids.

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