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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number110925
JournalDrug and Alcohol Dependence
Early online date12 Aug 2023
Publication statusPublished - 1 Oct 2023

Bibliographical note

Funding Information:
This work was supported by multiple funds. The study at UCL was funded by Drug Science , Channel 4 Television , and the Beckley Foundation . The study at UM was funded by a research grant from ZonMW , the Netherlands (grant number 31160206 ) awarded to JR. The study at UMCU was performed within the framework of Top Institute Pharma , Project number T5-107 .


  • Brain-imaging
  • Functional networks
  • Pharmacogenetics
  • Psychosis
  • Resting state fMRI
  • Tetrahydrocannabinol

ASJC Scopus subject areas

  • Toxicology
  • Pharmacology
  • Psychiatry and Mental health
  • Pharmacology (medical)


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