Your COMT gene variant determines how much THC impairs your working memory | Research

The takeaway

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.

Genetics researchers, cannabis neuroscientists, and anyone interested in why THC affects people differently.

Val/Val carriers most sensitive to THC cognitive impairment

What the researchers 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.

Why it 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 numbers in context

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 the study worked

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.

What this study cannot 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.

How to read the evidence

Moderate: double-blind, randomized, placebo-controlled design with genotype stratification, but moderate sample size.

When this study was published

Published in 2019.

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.

Questions still open

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?

Common 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.

Read the original research

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

View on PubMed ↗Publisher’s paper ↗

Citation

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