Acute psychotropic effects of 9-tetrahydrocannabinol (THC) associated with resting state brain function in the human insula: a pharmacological MRI study

Background: Cannabis produces a broad range of acute, dose-dependent psychotropic effects such as ‘feeling high’ and perceptual alterations. A limited number of neuroimaging studies have examined the acute impact of cannabis on resting state brain function, thereby mapping its psychotropic effects (van Hell et al., Int. J. Neuropsychopharmacol. (2011) 1377-88). Here we investigated the acute effects of ?9-tetrahydrocannabinol (THC), the main psychoactive ingredient of cannabis, on resting state brain function and their relationship with acute psychotropic effects.

Methods: Thirty-nine healthy male volunteers participated in a double-blind, randomised, placebo-controlled crossover pharmacological MRI study. Subjects underwent two 3T MRI sessions, receiving THC (6 mg) or placebo using a Volcano vaporizer. Acute subjective THC effects were assessed with composite visual analogue scales measuring perception, dysphoria and relaxation (Kleinloog et al., Int. J. Methods Psychiatr. Res. (2014) 245-56). Acute THC effects on resting state brain function were measured with Arterial Spin Labelling (ASL), which provides a quantitative measure of brain perfusion. ASL scans were preprocessed and analysed in SPM8, and THC effects on brain perfusion were assessed with a voxel-wise paired t-test (voxel size 2x2x2mm, FDR-corrected at cluster level, p<0.05). Multiple linear regression was performed with mean regional perfusion values as dependent and subjective effects as independent variables (THC minus placebo, p<0.05).

Results: Compared to placebo, THC induced a significant increase in the subjective rating of ‘perception’ (from 1.5±3.5 to 17.5±17.7, p<0.001) and a significant reduction in ‘relaxation’ (from -5.5±7.8 to -20.2±13.8, p<0.001). THC significantly increased perfusion in both left and right insula (653 voxels, p=0.003 and 1043 voxels, p<0.001, respectively), medial superior frontal cortex (555 voxels, p=0.005), and left middle orbital frontal gyrus (333 voxels, p=0.026). There were no brain areas showing a significant decrease in perfusion after THC administration. Subjective ratings of ‘perception’ (ß=0.629, p=0.014) and ‘relaxation’ (ß=0.540, p=0.020) were significantly related to THC effects on perfusion in the left insula.

Conclusions: THC significantly increased perfusion in bilateral insula and medial superior frontal cortex, indicating enhanced metabolism and thus elevated neural activity in the salience network. These results are in line with previous resting state studies, and suggest a THC-induced increase in awareness and anticipation of salient information (Craig, Nat. Rev. Neurosci. (2009), 59-70). This is consistent with the description of typical THC effects, including perceptual alterations, time distortion, and intensification of ordinary experiences such as eating and listening to music. Significant correlations between THC effects on perfusion in the insula and subjective measures of perception and relaxation further suggest that the main acute psychotropic effects of THC are mediated through recruitment of brain areas within the salience network.