Task-independent acute effects of delta-9-tetrahydrocannabinol on human brain function and its relationship with cannabinoid receptor gene expression: a neuroimaging meta-regression analysis

A single dose of delta-9-tetrahydrocannabinol (THC) alters brain activation signals in a widespread network of regions, with some areas showing increased and others decreased activity. The magnitude of these changes is directly related to the local expression of the cannabinoid type-1 (CB1) receptor, but not the type-2 (CB2) receptor. THC increased activation in the anterior cingulate, superior frontal cortices, middle temporal and occipital gyri, striatum, amygdala, thalamus, and cerebellum crus II, while decreasing it in the middle temporal gyrus, superior temporal gyrus, angular gyrus, precuneus, cuneus, inferior parietal lobule, and cerebellum lobule IV/V. A dose-response relationship was observed in certain brain regions.

Study at a glance

Abstract

Abstract Background The neurobiological mechanisms underlying the effects of delta-9-tetrahydrocannabinol (THC) remain unclear. Here, we examined the spatial acute effect of THC on human on regional brain activation or blood flow (hereafter called ‘activation signal’) in a ‘core’ network of brain regions that subserve a multitude of processes. We also investigated whether the neuromodulatory effects of THC are related to the local expression of its key molecular target, cannabinoid-type-1 (CB1R) but not type-2 (CB2R) receptor. Methods A systematic search was conducted of acute THC-challenge studies using fMRI, PET, and arterial spin labelling in accordance with established guidelines. Using pooled summary data from 372 participants, tested using a within-subject repeated measures design under experimental conditions, we investigated the effects of a single dose (6-42mg) of THC, compared to placebo, on brain signal. Findings As predicted, THC augmented the activation signal, relative to placebo, in the anterior cingulate, superior frontal cortices, middle temporal and middle and inferior occipital gyri, striatum, amygdala, thalamus, and cerebellum crus II and attenuated it in the middle temporal gyrus (spatially distinct from the cluster with THC-induced increase in activation signal), superior temporal gyrus, angular gyrus, precuneus, cuneus, inferior parietal lobule, and the cerebellum lobule IV/V. Using post-mortem gene expression data from an independent cohort from the Allen Human Brain atlas, we found a direct relationship between the magnitude of THC-induced brain signal change, indexed using pooled effect-size estimates, and CB1R gene expression, a proxy measure of CB1R protein distribution, but not CB2R expression. A dose-response relationship was observed with THC dose in certain brain regions. Interpretation These meta-analytic findings shed new light on the localisation of the effects of THC in the human brain, suggesting that THC has neuromodulatory effects in regions central to many cognitive tasks and processes, with greater effects in regions with higher levels of CB1R expression.