, Volume 236, Issue 11, pp 3209–3219 | Cite as

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

  • Mohini RanganathanEmail author
  • Joao P. De Aquino
  • Jose A. Cortes-Briones
  • Rajiv Radhakrishnan
  • Brian Pittman
  • Savita Bhakta
  • Deepak C. D’Souza
Original Investigation



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.


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.


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.


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.”


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. registration Identifier: NCT00678730.


COMT THC Cannabis Cannabinoid Dopamine Tolcapone 



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 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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official view of NIH.

Supplementary material

213_2019_5273_MOESM1_ESM.pdf (157 kb)
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)
213_2019_5273_MOESM2_ESM.docx (92 kb)
ESM 1 (DOCX 92 kb)


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Copyright information

© This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply 2019

Authors and Affiliations

  • Mohini Ranganathan
    • 1
    • 2
    • 3
    Email author
  • Joao P. De Aquino
    • 1
    • 2
    • 3
  • Jose A. Cortes-Briones
    • 1
    • 2
    • 3
  • Rajiv Radhakrishnan
    • 1
    • 2
    • 3
  • Brian Pittman
    • 1
  • Savita Bhakta
    • 4
  • Deepak C. D’Souza
    • 1
    • 2
    • 3
  1. 1.Department of PsychiatryYale University School of MedicineNew HavenUSA
  2. 2.U.S. Department of Veterans Affairs, Clinical Neurosciences DivisionVA Connecticut Healthcare SystemWest HavenUSA
  3. 3.Clinical Neuroscience Research UnitConnecticut Mental Health CenterNew HavenUSA
  4. 4.Department of PsychiatryUniversity of California San Diego School of MedicineLa JollaUSA

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