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.
Psychopharmacology (Berl). 2019 Nov;236(11):3209-3219. doi: 10.1007/s00213-019-05273-5. Epub 2019 Jun 11.
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 REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00678730?term=NCT00678730&rank=1 ClinicalTrials.gov Identifier: NCT00678730.
儿茶酚-O-甲基转移酶（COMT）酶已被牵连到决定多巴胺能张力和 δ-9-四氢大麻酚（THC）在人类大脑中的作用。
本研究旨在评估（1）功能性多态性和（2）COMT 的急性药理学抑制对人类对 THC 的急性反应的影响。
子研究 I：在一项 2 天双盲、随机、安慰剂对照研究中，对 74 名健康受试者进行静脉内（IV）THC（0.05mg/kg）的作用研究，这些受试者的 COMT rs4680（Val/Met）多态性进行了基因分型。子研究 II：从子研究 I 中，COMT rs4680 同型纯合子（Val/Val 和 Met/Met）受试者接受 COMT 酶抑制剂托卡朋（200mg），然后在另外两天接受 IV THC 或安慰剂。在每个测试日定期获得主观、行为和认知数据。
子研究 I：Val/Val 个体对 THC 引起的注意力和工作记忆缺陷最敏感。相比之下，COMT 基因型并不影响 THC 的致幻和主观作用。子研究 II：托卡朋降低了 THC 引起的工作记忆缺陷，但不影响 THC 的致幻作用。托卡朋和 COMT 基因型（met/met）与报告的“柔和”感觉增加有关。
COMT rs4680 多态性与托卡朋对认知的相互作用，但不是对致幻和整体主观作用的影响，表明多巴胺能信号的调节可能选择性地影响健康个体中特定大麻素的作用。在针对这些作用的药物开发努力中，应考虑多巴胺能信号在大麻素认知作用中的作用。临床试验。注册：https://clinicaltrials.gov/ct2/show/NCT00678730？term=NCT00678730&rank=1 临床试验注册：NCT00678730。
