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
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.
ClinicalTrials.gov Identifier: NCT00678730.
KeywordsCOMT 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.
- Behan ÁT, Hryniewiecka M, O'tuathaigh CM, Kinsella A, Cannon M, Karayiorgou M, Gogos JA, Waddington JL, Cotter DR (2012) Chronic adolescent exposure to delta-9-tetrahydrocannabinol in COMT mutant mice: impact on indices of dopaminergic, endocannabinoid and GABAergic pathways. Neuropsychopharmacology 37:1773–1783CrossRefGoogle Scholar
- Bossong MG, van Hell HH, Schubart CD, van Saane W, Iseger TA, Jager G, van Osch MJ, Jansma JM, Kahn RS, Boks MP (2019) Acute effects of ∆ 9-tetrahydrocannabinol (THC) on resting state brain function and their modulation by COMT genotype. Eur NeuropsychopharmacolGoogle Scholar
- Brunner E, Domhof S, Langer F (2002) Nonparametric analysis of longitudinal data in factorial designs. Wiley, New YorkGoogle Scholar
- Caspi A, Moffitt TE, Cannon M, McClay J, Murray R, Harrington H, Taylor A, Arseneault L, Williams B, Braithwaite A (2005) Moderation of the effect of adolescent-onset cannabis use on adult psychosis by a functional polymorphism in the catechol-O-methyltransferase gene: longitudinal evidence of a gene X environment interaction. Biol Psychiatry 57:1117–1127CrossRefGoogle Scholar
- Chen J, Lipska BK, Halim N, Ma QD, Matsumoto M, Melhem S, Kolachana BS, Hyde TM, Herman MM, Apud J, Egan MF, Kleinman JE, Weinberger DR (2004) Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genet 75:807–821CrossRefGoogle Scholar
- Cosker E, Schwitzer T, Ramoz N, Ligier F, Lalanne L, Gorwood P, Schwan R, Laprévote V (2017) The effect of interactions between genetics and cannabis use on neurocognition. A review. Prog Neuro-Psychopharmacol Biol PsychiatryGoogle Scholar
- D’Souza DC, Braley G, Blaise R, Vendetti M, Oliver S, Pittman B, Ranganathan M, Bhakta S, Zimolo Z, Cooper T (2008) Effects of haloperidol on the behavioral, subjective, cognitive, motor, and neuroendocrine effects of Δ-9-tetrahydrocannabinol in humans. Psychopharmacology 198:587–603CrossRefGoogle Scholar
- Henquet C, Rosa A, Krabbendam L, Papiol S, Fananas L, Drukker M, Ramaekers JG, van Os J (2006) An experimental study of catechol-o-methyltransferase Val158Met moderation of delta-9-tetrahydrocannabinol-induced effects on psychosis and cognition. Neuropsychopharmacology 31:2748–2757CrossRefGoogle Scholar
- Hirvonen M, Nagren K, Rinne J, Pesonen U, Vahlberg T (2009) COMT Val158Met genotype does not alter cortical or striatal dopamine D2 receptor. Availability in vivo Mol Imaging BiolGoogle Scholar
- Lazenka MF, Tomarchio AJ, Lichtman AH, Greengard P, Flajolet M, Selley DE, Sim-Selley LJ (2015) Role of dopamine type 1 receptors and dopamine-and cAMP-regulated phosphoprotein Mr 32 kDa in Δ9-tetrahydrocannabinol–mediated induction of ΔFosB in the mouse forebrain. J Pharmacol Exp Ther 354:316–327CrossRefGoogle Scholar
- Munafò MR, Smith GD (2018) Robust research needs many lines of evidence. Nature Publishing GroupGoogle Scholar
- Muñoz-Arenas G, Paz-Bermúdez F, Báez-Cordero A, Caballero-Florán R, González-Hernández B, Florán B, Daniel Limón I (2015) Cannabinoid CB1 receptors activation and coactivation with D2 receptors modulate GABAergic neurotransmission in the globus pallidus and increase motor asymmetry. Synapse 69:103–114CrossRefGoogle Scholar
- O'Tuathaigh CMP, Clarke G, Walsh J, Desbonnet L, Petit E, O'Leary C, Tighe O, Clarke N, Karayiorgou M, Gogos JA, Dinan TG, Cryan JF, Waddington JL (2012) Genetic vs. pharmacological inactivation of COMT influences cannabinoid-induced expression of schizophrenia-related phenotypes. Int J Neuropsychopharmacol 15:1331–1342CrossRefGoogle Scholar
- Ranganathan M, Radhakrishnan R, Addy PH, Schnakenberg-Martin AM, Williams AH, Carbuto M, Elander J, Pittman B, Sewell RA, Skosnik PD (2017) Tetrahydrocannabinol (THC) impairs encoding but not retrieval of verbal information. Prog Neuro-Psychopharmacol Biol Psychiatry 79:176–183CrossRefGoogle Scholar
- Shafa R (2009) Poster 3: Comt-inhibitors may be a promising tool in treatment of marijuana addiction. Am J Addict 18:322Google Scholar
- Temple EC, Driver M, Brown RF (2014) Cannabis use and anxiety: is stress the missing piece of the puzzle? Front Psychol 5:168Google Scholar
- Tunbridge EM, Dunn G, Murray RM, Evans N, Lister R, Stumpenhorst K, Harrison PJ, Morrison PD, Freeman D (2015) Genetic moderation of the effects of cannabis: catechol-O-methyltransferase (COMT) affects the impact of Δ9-tetrahydrocannabinol (THC) on working memory performance but not on the occurrence of psychotic experiences. J Psychopharmacol 29:1146–1151CrossRefGoogle Scholar
- Vaessen TSJ, de Jong L, Schäfer AT, Damen T, Uittenboogaard A, Krolinski P, Nwosu CV, Pinckaers FME, Rotee ILM, Smeets APW (2018) The interaction between cannabis use and the Val158Met polymorphism of the COMT gene in psychosis: a transdiagnostic meta–analysis. PLoS One 13:e0192658CrossRefGoogle Scholar
- Vinkers CH, Van Gastel WA, Schubart CD, Van Eijk KR, Luykx JJ, Van Winkel R, Joels M, Ophoff RA, Boks MP, Genetic R, Investigators OUP, Bruggeman R, Cahn W, de Haan L, Kahn RS, Meijer CJ, Myin-Germeys I, van Os J, Wiersma D (2013) The effect of childhood maltreatment and cannabis use on adult psychotic symptoms is modified by the COMT Val(1)(5)(8)Met polymorphism. Schizophr Res 150:303–311CrossRefGoogle Scholar