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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.
Psychopharmacology (Berl). 2019 Nov; 236(11):3209-3219.P

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.

Authors+Show Affiliations

Department of Psychiatry, Yale University School of Medicine, 300 George St, Suite 901, New Haven, CT, 06510, USA. mohini.ranganathan@yale.edu. U.S. Department of Veterans Affairs, Clinical Neurosciences Division, VA Connecticut Healthcare System, 116A, 950 Campbell Avenue, West Haven, CT, 06511, USA. mohini.ranganathan@yale.edu. Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park St, New Haven, CT, 06519, USA. mohini.ranganathan@yale.edu.Department of Psychiatry, Yale University School of Medicine, 300 George St, Suite 901, New Haven, CT, 06510, USA. U.S. Department of Veterans Affairs, Clinical Neurosciences Division, VA Connecticut Healthcare System, 116A, 950 Campbell Avenue, West Haven, CT, 06511, USA. Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park St, New Haven, CT, 06519, USA.Department of Psychiatry, Yale University School of Medicine, 300 George St, Suite 901, New Haven, CT, 06510, USA. U.S. Department of Veterans Affairs, Clinical Neurosciences Division, VA Connecticut Healthcare System, 116A, 950 Campbell Avenue, West Haven, CT, 06511, USA. Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park St, New Haven, CT, 06519, USA.Department of Psychiatry, Yale University School of Medicine, 300 George St, Suite 901, New Haven, CT, 06510, USA. U.S. Department of Veterans Affairs, Clinical Neurosciences Division, VA Connecticut Healthcare System, 116A, 950 Campbell Avenue, West Haven, CT, 06511, USA. Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park St, New Haven, CT, 06519, USA.Department of Psychiatry, Yale University School of Medicine, 300 George St, Suite 901, New Haven, CT, 06510, USA.Department of Psychiatry, University of California San Diego School of Medicine, San Diego, 9500 Gilman Dr, La Jolla, CA, 92094, USA.Department of Psychiatry, Yale University School of Medicine, 300 George St, Suite 901, New Haven, CT, 06510, USA. U.S. Department of Veterans Affairs, Clinical Neurosciences Division, VA Connecticut Healthcare System, 116A, 950 Campbell Avenue, West Haven, CT, 06511, USA. Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park St, New Haven, CT, 06519, USA.

Pub Type(s)

Journal Article
Randomized Controlled Trial

Language

eng

PubMed ID

31187152

Citation

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, vol. 236, no. 11, 2019, pp. 3209-3219.
Ranganathan M, De Aquino JP, Cortes-Briones JA, 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 (Berl). 2019;236(11):3209-3219.
Ranganathan, M., De Aquino, J. P., Cortes-Briones, J. A., Radhakrishnan, R., Pittman, B., Bhakta, S., & D'Souza, D. 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
Ranganathan M, 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 (Berl). 2019;236(11):3209-3219. PubMed PMID: 31187152.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Ranganathan,Mohini, AU - De Aquino,Joao P, AU - Cortes-Briones,Jose A, AU - Radhakrishnan,Rajiv, AU - Pittman,Brian, AU - Bhakta,Savita, AU - D'Souza,Deepak C, Y1 - 2019/06/11/ PY - 2018/12/06/received PY - 2019/05/10/accepted PY - 2019/6/13/pubmed PY - 2020/1/29/medline PY - 2019/6/13/entrez KW - COMT KW - Cannabinoid KW - Cannabis KW - Dopamine KW - THC KW - Tolcapone SP - 3209 EP - 3219 JF - Psychopharmacology JO - Psychopharmacology (Berl.) VL - 236 IS - 11 N2 - 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. SN - 1432-2072 UR - https://www.unboundmedicine.com/medline/citation/31187152/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_ L2 - https://dx.doi.org/10.1007/s00213-019-05273-5 DB - PRIME DP - Unbound Medicine ER -