Acute effects of Δ9-tetrahydrocannabinol (THC) on resting state connectivity networks and impact of COMT genotype: A multi-site pharmacological fMRI study

Teuntje A D Pelgrim; Johannes G Ramaekers; Matthew B Wall; Tom P Freeman; Matthijs G Bossong

doi:10.1016/j.drugalcdep.2023.110925

Acute effects of Δ9-tetrahydrocannabinol (THC) on resting state connectivity networks and impact of COMT genotype: A multi-site pharmacological fMRI study

Drug Alcohol Depend. 2023 Oct 1:251:110925. doi: 10.1016/j.drugalcdep.2023.110925. Epub 2023 Aug 12.

Authors

Teuntje A D Pelgrim¹, Johannes G Ramaekers², Matthew B Wall³, Tom P Freeman⁴, Matthijs G Bossong⁵

Affiliations

¹ Department of Psychiatry, UMC Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands; Department of Psychiatry, Parnassia Psychiatric Institute, Amsterdam, the Netherlands.
² Department of Neuropsychology & Psychopharmacology, Maastricht University, Maastricht, the Netherlands.
³ Invicro London, Hammersmith Hospital, London, UK; Faculty of Medicine, Imperial College London, London, UK; Clinical Psychopharmacology Unit, University College London, London, UK.
⁴ Addiction and Mental Health Group (AIM), University of Bath, Bath, UK.
⁵ Department of Psychiatry, UMC Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands. Electronic address: M.G.Bossong@umcutrecht.nl.

PMID: 37598453
DOI: 10.1016/j.drugalcdep.2023.110925

Abstract

Background: Cannabis produces various acute psychotropic effects, with marked individual differences. Cannabis use is a risk factor for developing psychotic disorders. The main component responsible for these effects is Δ9-tetrahydrocannabinol (THC). Here we investigated the neural basis of acute THC effects and its modulation by catechol-methyl-transferase (COMT) Val158Met genotype.

Methods: Resting state functional MRI data of healthy occasional cannabis users were combined and re-analyzed from three double-blind, placebo-controlled, within-subject pharmacological functional magnetic resonance imaging studies (total N=87). Functional connectivity after placebo and THC was compared in three functional networks (salience, executive and default mode network) and a network implicated in psychosis (the hippocampus-midbrain-striatum network). COMT genotype modulation of subjective effects and connectivity was examined.

Results: THC reduced connectivity in the salience network, specifically from the right insula to both the left insula and anterior cingulate cortex. We found a trend towards decreased connectivity in the hippocampus-midbrain-striatum network after THC. COMT genotype modulated subjective effects of THC, with strongest dysphoric reactions in Met/Met individuals. In addition, reduced connectivity after THC was demonstrated in the hippocampus-midbrain-striatum network of Met/Met individuals only.

Conclusions: In this large multisite study we found that THC robustly decreases connectivity in the salience network, involved in processing awareness and salient information. Connectivity changes in the hippocampus-midbrain-striatum network may reflect the acute psychotic-like effects of THC. COMT genotype modulation of THC's impact on subjective effects and functional connectivity provides further evidence for involvement of prefrontal dopamine levels in the acute effects of cannabis.

Keywords: Brain-imaging; Functional networks; Pharmacogenetics; Psychosis; Resting state fMRI; Tetrahydrocannabinol.

Publication types

Randomized Controlled Trial
Research Support, Non-U.S. Gov't

MeSH terms

Brain
Cannabinoid Receptor Agonists / pharmacology
Cannabis*
Catechol O-Methyltransferase / genetics
Catechol O-Methyltransferase / pharmacology
Dronabinol / pharmacology
Genotype
Hallucinogens* / pharmacology
Humans
Magnetic Resonance Imaging

Substances

Dronabinol
Catechol O-Methyltransferase
Hallucinogens
Cannabinoid Receptor Agonists
COMT protein, human