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Differential sensitivity to the acute psychotomimetic effects of delta-9-tetrahydrocannabinol associated with its differential acute effects on glial function and cortisol

Published online by Cambridge University Press:  27 October 2020

Marco Colizzi
National Institute for Health Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, and Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Italy
Nathalie Weltens
Laboratory for Brain-Gut Axis Studies (LaBGAS), Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Belgium
David J Lythgoe
Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
Steve CR Williams
Department of Neuroimaging, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
Lukas Van Oudenhove
Laboratory for Brain-Gut Axis Studies (LaBGAS), Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Belgium
Sagnik Bhattacharyya*
National Institute for Health Research (NIHR) Biomedical Research Centre, South London and Maudsley NHS Foundation Trust, and Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK
Author for correspondence: Sagnik Bhattacharyya, E-mail:



Cannabis use has been associated with psychosis through exposure to delta-9-tetrahydrocannabinol (Δ9-THC), its key psychoactive ingredient. Although preclinical and human evidence suggests that Δ9-THC acutely modulates glial function and hypothalamic-pituitary-adrenal (HPA) axis activity, whether differential sensitivity to the acute psychotomimetic effects of Δ9-THC is associated with differential effects of Δ9-THC on glial function and HPA-axis response has never been tested.


A double-blind, randomized, placebo-controlled, crossover study investigated whether sensitivity to the psychotomimetic effects of Δ9-THC moderates the acute effects of a single Δ9-THC dose (1.19 mg/2 ml) on myo-inositol levels, a surrogate marker of glia, in the Anterior Cingulate Cortex (ACC), and circadian cortisol levels, the key neuroendocrine marker of the HPA-axis, in a set of 16 healthy participants (seven males) with modest previous cannabis exposure.


The Δ9-THC-induced change in ACC myo-inositol levels differed significantly between those sensitive to (Δ9-THC minus placebo; M = −0.251, s.d. = 1.242) and those not sensitive (M = 1.615, s.d. = 1.753) to the psychotomimetic effects of the drug (t(14) = 2.459, p = 0.028). Further, the Δ9-THC-induced change in cortisol levels over the study period (baseline minus 2.5 h post-drug injection) differed significantly between those sensitive to (Δ9-THC minus placebo; M = −275.4, s.d. = 207.519) and those not sensitive (M = 74.2, s.d. = 209.281) to the psychotomimetic effects of the drug (t(13) = 3.068, p = 0.009). Specifically, Δ9-THC exposure lowered ACC myo-inositol levels and disrupted the physiological diurnal cortisol decrease only in those subjects developing transient psychosis-like symptoms.


The interindividual differences in transient psychosis-like effects of Δ9-THC are the result of its differential impact on glial function and stress response.

Original Article
Copyright © The Author(s), 2020. Published by Cambridge University Press

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