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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

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Abstract

Rationale

The catechol-O-methyl transferase (COMT) enzyme has been implicated in determining dopaminergic tone and the effects of delta-9-tetrahydrocannabinol (THC) in the human brain.

Objective

This study was designed to evaluate the effect of (1) a functional polymorphism and (2) acute pharmacological inhibition of COMT on the acute response to THC in humans.

Methods

Sub-study I: The effect of intravenous (IV) THC (0.05 mg/kg) was investigated in 74 healthy subjects genotyped for the COMT rs4680 (Val/Met) polymorphism in a 2-test-day double-blind, randomized, placebo-controlled study. Sub-study II: COMT rs4680 homozygous subjects (Val/Val and Met/Met) from sub-study I received the COMT enzyme inhibitor tolcapone (200 mg) followed by IV THC or placebo on two additional test days. Subjective, behavioral, and cognitive data were obtained periodically on each test day.

Results

Sub-study I: Val/Val individuals were most sensitive to THC-induced attention and working memory deficits. In contrast, the psychotomimetic and subjective effects of THC were not influenced by COMT genotype. Sub-study II: Tolcapone reduced THC-induced working memory deficits, but not THC’s psychotomimetic effects. Tolcapone and COMT genotype (met/met) were associated with an increased report of feeling “mellow.”

Conclusions

The interaction between COMT rs4680 polymorphisms and tolcapone on the cognitive, but not on the psychotomimetic and overall subjective effects of THC, suggests that modulation of dopaminergic signaling may selectively influence specific cannabinoid effects in healthy individuals. The role of dopaminergic signaling in the cognitive effects of cannabinoids should be considered in drug development efforts targeting these effects.

Clinicaltrials.gov registration

https://clinicaltrials.gov/ct2/show/NCT00678730?term=NCT00678730&rank=1

ClinicalTrials.gov Identifier: NCT00678730.

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Acknowledgments

We also acknowledge support from the (1) Department of Veterans Affairs, (2) National Institute of Drug Abuse, and (3) National Institute of Alcoholism and Alcohol Abuse.

Funding

Funding and support from R01 DA12382 (Deepak Cyril D’Souza, M.D.), VA Connecticut Healthcare System (VACHS), NARSAD Young Investigator Award 2008 (Savita Bhakta, M.D.) and National Institutes of Mental Health (NIMH) R25 MH071584, “Integrated Mentored Patient-Oriented Research Training (IMPORT) in Psychiatry” (Joao P. De Aquino, M.D.), and Dana Foundation David Mahoney program and CTSA Grant Number UL1 TR001863 from the National Center for Advancing Translational Science (NCATS) (Rajiv Radhakrishnan, M.D.). Deepak Cyril D’Souza has received in the past 3 years and currently receives research grant support administered through Yale University School of Medicine from Pfizer Inc.

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Correspondence to Mohini Ranganathan.

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Fig. S1

Study Design. Schedule of testing for sub-studies I and II. Sub-study I included 74 individuals of 3 genotypes (Val/Val, Val/Met, Met/Met). THC was administered at time point 0. Sub-study II included 22 homozygote (10 Val/Val, 22 Met/Met) individuals. Tolcapone was administered at time point -90 minutes. THC was administered at time point 0. Subjective and behavioral measures were collected before and after THC administration time points -30, 0 ,+60 and +300 minutes. Cognitive testing was done once approximately 30 minutes after THC administration. (PDF 157 kb)

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Ranganathan, M., De Aquino, J.P., Cortes-Briones, J.A. 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 236, 3209–3219 (2019). https://doi.org/10.1007/s00213-019-05273-5

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