Department of Psychiatry, UMC Utrecht Brain Center, Utrecht University, Utrecht, the Netherlands; Department of Psychiatry, Parnassia Psychiatric Institute, Amsterdam, the Netherlands.
Department of Neuropsychology & Psychopharmacology, Maastricht University, Maastricht, the Netherlands.
Drug Alcohol Depend. 2023 Oct 1;251:110925. doi: 10.1016/j.drugalcdep.2023.110925. Epub 2023 Aug 12.
Cannabis produces various acute psychotropic effects, with marked individual differences. Cannabis use is a risk factor for developing psychotic disorders. The main component responsible for these effects is Δ9-tetrahydrocannabinol (THC). Here we investigated the neural basis of acute THC effects and its modulation by catechol-methyl-transferase (COMT) Val158Met genotype.
Resting state functional MRI data of healthy occasional cannabis users were combined and re-analyzed from three double-blind, placebo-controlled, within-subject pharmacological functional magnetic resonance imaging studies (total N=87). Functional connectivity after placebo and THC was compared in three functional networks (salience, executive and default mode network) and a network implicated in psychosis (the hippocampus-midbrain-striatum network). COMT genotype modulation of subjective effects and connectivity was examined.
THC reduced connectivity in the salience network, specifically from the right insula to both the left insula and anterior cingulate cortex. We found a trend towards decreased connectivity in the hippocampus-midbrain-striatum network after THC. COMT genotype modulated subjective effects of THC, with strongest dysphoric reactions in Met/Met individuals. In addition, reduced connectivity after THC was demonstrated in the hippocampus-midbrain-striatum network of Met/Met individuals only.
In this large multisite study we found that THC robustly decreases connectivity in the salience network, involved in processing awareness and salient information. Connectivity changes in the hippocampus-midbrain-striatum network may reflect the acute psychotic-like effects of THC. COMT genotype modulation of THC's impact on subjective effects and functional connectivity provides further evidence for involvement of prefrontal dopamine levels in the acute effects of cannabis.
大麻产生各种急性精神作用，个体差异明显。大麻使用是发展精神病障碍的风险因素。负责这些效果的主要成分是Δ9-四氢大麻酚（THC）。在这里，我们研究了急性 THC 效应的神经基础及其对儿茶酚-O-甲基转移酶（COMT）Val158Met 基因型的调节。
从三个双盲、安慰剂对照、内源性药物功能磁共振成像研究中（共 87 人）合并并重新分析了健康偶然大麻使用者的静息状态功能磁共振成像数据。在三个功能网络（突显网络、执行网络和默认模式网络）和一个与精神病有关的网络（海马体-中脑-纹状体网络）中比较了安慰剂和 THC 后的功能连接。检查了 COMT 基因型对主观效应和连接的调节作用。
THC 降低了突显网络的连接，特别是从右侧岛叶到左侧岛叶和前扣带皮层。我们发现，THC 后海马体-中脑-纹状体网络的连接有降低的趋势。COMT 基因型调节了 THC 的主观效应，Met/Met 个体的抑郁反应最强。此外，仅在 Met/Met 个体的海马体-中脑-纹状体网络中显示出 THC 后连接减少。
在这项大型多中心研究中，我们发现 THC 显著降低了突显网络的连接，突显网络参与处理意识和显著信息。海马体-中脑-纹状体网络的连接变化可能反映了 THC 的急性类精神病效应。COMT 基因型对 THC 对主观效应和功能连接的影响的调节提供了进一步的证据，表明前额叶多巴胺水平参与了大麻的急性效应。
