Your COMT gene variant determines how much THC impairs your working memory
People with the Val/Val COMT genotype were most sensitive to THC-induced attention and working memory deficits, and pharmacologically inhibiting COMT with tolcapone reduced THC's cognitive effects but not its psychosis-like effects.
Quick Facts
What This Study Found
Val/Val individuals showed the greatest THC-induced working memory and attention deficits. COMT genotype did not influence THC's psychotomimetic or subjective effects. Tolcapone (a COMT inhibitor) reduced THC-induced working memory deficits but not psychotomimetic effects, suggesting dopaminergic signaling selectively mediates cognitive but not psychotic effects of THC.
Key Numbers
74 subjects in sub-study I. Val/Val most sensitive to THC-induced cognitive deficits. Tolcapone 200 mg reduced THC working memory impairment. Neither COMT genotype nor tolcapone affected psychotomimetic effects.
How They Did This
Two sub-studies. Sub-study I: 74 healthy subjects genotyped for COMT Val/Met received IV THC (0.05 mg/kg) or placebo in a double-blind crossover. Sub-study II: Val/Val and Met/Met homozygous subjects received tolcapone 200 mg followed by IV THC or placebo on two additional days.
Why This Research Matters
This helps explain why some people experience significant cognitive impairment from cannabis while others do not. COMT genotype may be a useful predictor of vulnerability to THC's cognitive effects.
The Bigger Picture
This study elegantly separates the cognitive and psychotic effects of THC, showing they operate through different neurochemical pathways. This has implications for developing drugs that could protect against THC's harms.
What This Study Doesn't Tell Us
IV THC administration does not replicate typical cannabis use. Sample size was moderate. Only one COMT polymorphism was studied. Tolcapone has limited clinical use due to liver toxicity concerns.
Questions This Raises
- ?Could COMT genotyping help identify people at greatest cognitive risk from cannabis?
- ?Would other dopamine-modulating drugs also protect against THC's cognitive effects?
- ?Does COMT genotype predict long-term cognitive outcomes in regular cannabis users?
Trust & Context
- Key Stat:
- Val/Val carriers most sensitive to THC cognitive impairment
- Evidence Grade:
- Moderate: double-blind, randomized, placebo-controlled design with genotype stratification, but moderate sample size.
- Study Age:
- Published in 2019.
- Original Title:
- Highs and lows of cannabinoid-dopamine interactions: effects of genetic variability and pharmacological modulation of catechol-O-methyl transferase on the acute response to delta-9-tetrahydrocannabinol in humans.
- Published In:
- Psychopharmacology, 236(11), 3209-3219 (2019)
- Authors:
- Ranganathan, Mohini(13), De Aquino, Joao P(12), Cortes-Briones, Jose A(5), Radhakrishnan, Rajiv, Pittman, Brian, Bhakta, Savita, D'Souza, Deepak C
- Database ID:
- RTHC-02250
Evidence Hierarchy
Participants are randomly assigned to treatment or placebo groups to test cause and effect.
What do these levels mean? →Frequently Asked Questions
What is the COMT gene?
COMT (catechol-O-methyltransferase) is an enzyme that breaks down dopamine in the prefrontal cortex. The Val/Met polymorphism affects how quickly dopamine is cleared: Val/Val clears it fastest, Met/Met slowest.
Why did tolcapone help cognition but not psychosis?
This suggests THC's cognitive effects depend on dopaminergic signaling (which tolcapone modulates) while its psychosis-like effects operate through different pathways, possibly direct CB1 receptor activation.
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Cite This Study
https://rethinkthc.com/research/RTHC-02250APA
Ranganathan, Mohini; De Aquino, Joao P; Cortes-Briones, Jose A; Radhakrishnan, Rajiv; Pittman, Brian; Bhakta, Savita; D'Souza, Deepak C. (2019). Highs and lows of cannabinoid-dopamine interactions: effects of genetic variability and pharmacological modulation of catechol-O-methyl transferase on the acute response to delta-9-tetrahydrocannabinol in humans.. Psychopharmacology, 236(11), 3209-3219. https://doi.org/10.1007/s00213-019-05273-5
MLA
Ranganathan, Mohini, et al. "Highs and lows of cannabinoid-dopamine interactions: effects of genetic variability and pharmacological modulation of catechol-O-methyl transferase on the acute response to delta-9-tetrahydrocannabinol in humans.." Psychopharmacology, 2019. https://doi.org/10.1007/s00213-019-05273-5
RethinkTHC
RethinkTHC Research Database. "Highs and lows of cannabinoid-dopamine interactions: effects..." RTHC-02250. Retrieved from https://rethinkthc.com/research/ranganathan-2019-highs-and-lows-of
Access the Original Study
Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkTHC research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.