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 mgkg) was investigated in 74 healthy subjects genotyped for the COMT rs4680 (ValMet) polymorphism in a 2-test-day double-blind, randomized, placebo-controlled study. Sub-study II COMT rs4680 homozygous subjects (ValVal and MetMet) 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 ValVal 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 THCs psychotomimetic effects. Tolcapone and COMT genotype (metmet) 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 httpsclinicaltrials.govct2showNCT00678730termNCT00678730rank1 ClinicalTrials.gov Identifier NCT00678730.