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. 2022 Jun;36(6):732-744.
doi: 10.1177/02698811221092506. Epub 2022 May 20.

Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain

Matthew B Wall  1   2   3 , Tom P Freeman  2   4 , Chandni Hindocha  2 , Lysia Demetriou  1   3   5 , Natalie Ertl  1   3 , Abigail M Freeman  2 , Augustus Pm Jones  6 , Will Lawn  2 , Rebecca Pope  2 , Claire Mokrysz  2 , Daniel Solomons  3 , Ben Statton  7 , Hannah R Walker  6 , Yumeya Yamamori  6 , Zixu Yang  3 , Jocelyn Ll Yim  6 , David J Nutt  3 , Oliver D Howes  7   8   9 , H Valerie Curran  2 , Michael Ap Bloomfield  6
Affiliations

Individual and combined effects of cannabidiol and Δ9-tetrahydrocannabinol on striato-cortical connectivity in the human brain

Matthew B Wall et al. J Psychopharmacol. 2022 Jun.

Abstract

Background: Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are the two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have opposite effects. The brain effects of these drugs alone and in combination are poorly understood. In particular, the striatum is implicated in the pathophysiology of several psychiatric disorders, but it is unclear how THC and CBD influence striato-cortical connectivity.

Aims: To examine effects of THC, CBD, and THC + CBD on functional connectivity of striatal sub-divisions (associative, limbic and sensorimotor).

Method: Resting-state functional Magnetic Resonance Imaging (fMRI) was used across two within-subjects, placebo-controlled, double-blind studies, with a unified analysis approach.

Results: Study 1 (N = 17; inhaled cannabis containing 8 mg THC, 8 mg THC + 10 mg CBD or placebo) showed strong disruptive effects of both THC and THC + CBD on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum network which was not present in the THC + CBD condition. In Study 2 (N = 23, oral 600 mg CBD, placebo), CBD increased connectivity in the associative network, but produced only relatively minor disruptions in the limbic and sensorimotor networks.

Outcomes: THC strongly disrupts striato-cortical networks, but this effect is mitigated by co-administration of CBD in the limbic striatum network. Oral CBD administered has a more complex effect profile of relative increases and decreases in connectivity. The insula emerges as a key region affected by cannabinoid-induced changes in functional connectivity, with potential implications for understanding cannabis-related disorders, and the development of cannabinoid therapeutics.

Keywords: CBD; Cannabinoids; THC; cannabis; fMRI; resting-state.

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Conflict of interest statement

Declaration of conflicting interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: M.B.W. and N.E.’s primary employer is Invicro LLC., a private company which performs contract research work for the pharmaceutical and bio-technology industries. L.D. was also previously employed by Invicro while some of the work in this submission took place but is now in an academic position at the University of Oxford. C.H. was employed by GW Pharmaceuticals during the revise and resubmit process. Her substantive contribution to this publication occurred before employment at GW pharmaceuticals. M.A.P.B. is a director of Bloomfield Health Limited, a mental health company which is not involved in the cannabinoid industry. All other authors declare no other conflicts of interest.

Figures

Figure 1.
Figure 1.
Drug effects on brain-wide connectivity with the limbic striatum in study 1. Contrast is placebo > THC. Clusters represent a significant decrease in functional connectivity with the limbic striatum in the active drug condition. (a) Significant clusters on 3D cortical surface renders. (b) The limbic striatum seed-region. (c) Significant clusters on axial slices. The THC + CBD condition showed no significant effects for this seed-region.
Figure 2.
Figure 2.
Drug effects on brain-wide connectivity with the associative striatum in Study 1. Contrasts are placebo > active drug. Clusters represent a significant decrease in functional connectivity with the associative striatum in the active drug conditions. (a) Significant clusters (blue) in the placebo > THC + CBD comparison on 3D cortical renders. (b) Significant clusters (green) in the placebo > THC comparison on 3D cortical renders. (c) The associative striatum seed-region. (d) Significant clusters in both comparisons ((a) and (b); same colours) overlaid together on axial slices.
Figure 3.
Figure 3.
Drug effects on brain-wide connectivity with the sensorimotor striatum in study 1. Contrasts are placebo > active drug. Clusters represent a significant decrease in functional connectivity with the sensorimotor striatum in the active drug conditions. (a) Significant clusters (blue) in the placebo > THC + CBD comparison on 3D cortical renders. (b) Significant clusters (green) in the placebo > THC comparison on 3D cortical renders. (c) The sensorimotor striatum seed-region. (d) Significant clusters in both comparisons ((a) and (b); same colours) overlaid together on axial slices.
Figure 4.
Figure 4.
Mean connectivity within each network, across the three drug conditions. Significant effects were seen in the limbic striatum network (placebo vs THC: t(16) = 2.69, p = 0.04) and in the sensorimotor striatum network (placebo vs THC + CBD: t(16) = 2.93, p = 0.025; placebo vs THC: t(16) = 3.07, p = 0.019). *p < 0.05 (Tukey’s-corrected for multiple comparisons).
Figure 5.
Figure 5.
Drug effects on brain-wide connectivity with the associative (red), limbic (yellow) and sensorimotor (pink) striatum in Study 2. CBD: cannabidiol; PL: placebo. Both relative increases (CBD > PL) and decreases (PL > CBD) are shown, depending on the pattern of significant results in the three analyses. Effects on sensorimotor striatum connectivity were only seen in the left cerebellum, and are therefore not visible on the top panel, which only shows inflated views of the cortex.
See this image and copyright information in PMC

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