The CB1 Neutral Antagonist Tetrahydrocannabivarin Reduces Default Mode Network and Increases Executive Control Network Resting State Functional Connectivity in Healthy Volunteers

Abstract

Background: The cannabinoid cannabinoid type 1 (CB1) neutral antagonist tetrahydrocannabivarin (THCv) has been suggested as a possible treatment for obesity, but without the depressogenic side-effects of inverse antagonists such as Rimonabant. However, how THCv might affect the resting state functional connectivity of the human brain is as yet unknown.

Method: We examined the effects of a single 10mg oral dose of THCv and placebo in 20 healthy volunteers in a randomized, within-subject, double-blind design. Using resting state functional magnetic resonance imaging and seed-based connectivity analyses, we selected the amygdala, insula, orbitofrontal cortex, and dorsal medial prefrontal cortex (dmPFC) as regions of interest. Mood and subjective experience were also measured before and after drug administration using self-report scales.

Results: Our results revealed, as expected, no significant differences in the subjective experience with a single dose of THCv. However, we found reduced resting state functional connectivity between the amygdala seed region and the default mode network and increased resting state functional connectivity between the amygdala seed region and the dorsal anterior cingulate cortex and between the dmPFC seed region and the inferior frontal gyrus/medial frontal gyrus. We also found a positive correlation under placebo for the amygdala-precuneus connectivity with the body mass index, although this correlation was not apparent under THCv.

Conclusion: Our findings are the first to show that treatment with the CB1 neutral antagonist THCv decreases resting state functional connectivity in the default mode network and increases connectivity in the cognitive control network and dorsal visual stream network. This effect profile suggests possible therapeutic activity of THCv for obesity, where functional connectivity has been found to be altered in these regions.

Keywords: Cannabinoids; default mode; fMRI; obesity; resting state; reward.

Figure 1.

Coronal, sagittal, and axial slices showing the amygdala seed region and functional connectivity maps for the difference between placebo and tetrahydrocannabinol (THCv) groups, overlaid on the default mode network. The right graph displays the % blood-oxygenation-level-dependent signal change extracted from the region of significant treatment effect. Precuneus: − 8 -72 24 and p = 0.0009 for the placebo group and THCv group.

Figure 2.

Coronal, sagittal, and axial slices showing the amygdala seed region and functional connectivity maps for the difference between placebo and tetrahydrocannabinol (THCv) groups, overlaid on the executive control network. The right graph displays the % blood-oxygenation-level-dependent signal change extracted from the region of significant treatment effect. Dorsal anterior cingulate cortex: 6 4 52 and p = 0.00001 for the placebo group and THCv group.

Figure 3.

Coronal, sagittal, and axial slices showing the right dorsal medial prefrontal cortex seed region and functional connectivity maps for the difference between placebo and tetrahydrocannabinol (THCv) groups, overlaid on the right dorsal visual stream network. The right graph displays the % blood-oxygenation-level-dependent signal change extracted from the region of significant treatment effect. inferior frontal gyrus/medial frontal gyrus: 52 28 22 and p = 0.003 for the placebo group and THCv group.

Figure 4.

Graph of the % blood-oxygenation-level-dependent signal change extracted from the region of significant treatment effect: precuneus [− 8 -72 24 p = 0.0009] and correlated with body mass index (BMI) score for placebo and tetrahydrocannabinol (THCv).