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
Drug and Alcohol Dependence August 11, 2023 DOI: 10.1016/j.drugalcdep.2023.110925 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Re-analysis of three double-blind, placebo-controlled, within-subject pharmacological functional magnetic resonance imaging studies Peer reviewed |
|---|---|
| Sample size | 87 |
| Population | Healthy occasional cannabis users |
| Intervention | Δ9-tetrahydrocannabinol (THC) |
| Topics | Default mode network Cannabis |
| Keywords | Resting State FMRI Striatum Insula Prefrontal cortex Dopamine Cognition |
| Citations | 3 |
| Key points | THC robustly decreases connectivity in the salience network, and COMT genotype modulates both subjective effects and connectivity changes in the hippocampus-midbrain-striatum network. |
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.
Comparable studies
Other randomized controlled trials on cannabis, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Cannabidiol inhibits THC-elicited paranoid symptoms and hippocampal-dependent memory impairment Healthy participants | 2012 | Randomized controlled trial | n = 48 |
| Distinct Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing Healthy, English-native, right-handed men who had used cannabis 15 times or less in... | 2009 | Double-blind, randomized, placebo-controlled crossover trial | n = 15 |
| Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers Healthy male subjects | 2012 | Randomized controlled trial | n = 16 |
| Modulation of Mediotemporal and Ventrostriatal Function in Humans by Δ9-Tetrahydrocannabinol Healthy, native English-speaking, right-handed men of white race/ethnicity who had used... | 2009 | Randomized controlled trial | n = 15 |
| Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition Healthy volunteers with a history of light cannabis use | 2019 | Randomized, double-blind, within-subjects crossover | n = 14 |
Citations in the library
Cited by 4
- Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks Neuropsychopharmacology May 28, 2024
- Receptor-enriched analysis of functional connectivity (REACT) for understanding cannabinoid neuropsychopharmacology bioRxiv (Cold Spring Harbor Laboratory) June 5, 2025
- Brain Network Convergence of Abnormal Gray Matter and Functional Activity of Pathological Dissociative Symptoms. Psychiatry and Clinical Neurosciences August 29, 2026
- The relationship between recreational cannabis use, psychotic-like experiences, and the salience network in adolescent and young adult twins. Psychological Medicine October 7, 2025
Cites 18
- Psychedelic Effects of Ketamine in Healthy Volunteers Anesthesiology 1998
- Acute Effects of a Single, Oral dose of d9-tetrahydrocannabinol (THC) and Cannabidiol (CBD) Administration in Healthy Volunteers Current Pharmaceutical Design September 12, 2012
- The neuropsychopharmacology of cannabis: A review of human imaging studies Pharmacology & Therapeutics October 20, 2018
- Human Laboratory Studies on Cannabinoids and Psychosis. Biological Psychiatry April 1, 2016
- Dissociable effects of cannabis with and without cannabidiol on the human brain’s resting-state functional connectivity Journal of Psychopharmacology April 23, 2019
and 13 more in the library