Individual and combined effects of Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) on striato-cortical connectivity in the human brain

Abstract

Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) are two major constituents of cannabis with contrasting mechanisms of action. THC is the major psychoactive, addiction-promoting, and psychotomimetic compound, while CBD may have somewhat 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. Across two placebo-controlled, double-blind studies, we examine the effects of THC, CBD, and THC+CBD on the functional connectivity of striatal sub-divisions (associative, limbic, and sensorimotor) using resting-state functional Magnetic Resonance Imaging (fMRI) and seed-based functional connectivity analyses. Study 1 (N=17; inhaled 8mg THC, 8mg THC+10mg CBD, placebo) showed strong disruptive effects of both THC and THC+CBD conditions on connectivity in the associative and sensorimotor networks, but a specific effect of THC in the limbic striatum, which was alleviated in the THC+CBD condition such that it did not differ from placebo. In Study 2 (N=23, oral 600mg CBD, placebo) CBD increased connectivity in the associative network, but relatively minor decreases/disruptions were found in the limbic and sensorimotor. In conclusion, THC strongly disrupts striato-cortical networks, and this effect is selectively mitigated in the limbic striatum when co-administered with CBD. When administered alone, 600mg oral CBD 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.

Associations between regular cannabis use and brain resting-state functional connectivity in adolescents and adults

“…Results from these analyses are shown in supplementary figures 2 and 3, with the derived ROI masks shown in supplementary figure 4. The overall pattern seen for all the networks in these group-mean analyses conforms to previous work(Wall, et al, 2019) (Wall et al, 2020), so these analyses also serve to validate the acquisition and analysis methods used.…”

Delta-9-Tetrahydrocannabinol, Cannabidiol, and Acute Psychotomimetic States: A Balancing Act of the Principal Phyto-Cannabinoids on Human Brain and Behavior

“…More recently, a regional specificity in THC-CBD interaction relevant to alleviation of psychotomimetic response has been demonstrated by Wall et al (67). Using resting state functional magnetic resonance imaging, the authors noted that CBD:THC combination resulted in alleviation of THC induced functional connectivity disruption, specifically in the limbic sub-division of the striatum but not in the associative and sensorimotor sub-striatal networks (67). Taken together, the findings suggest that restoring cortical-striatal balance of glutamatergic tone may be a potential underlying mechanism of CBD action in attenuating THC-induced acute psychotomimetic response.…”

“…In contrast, striatal glutamate increase has been shown in human studies to be a marker of THC-induced acute psychotomimetic response (66). More recently, a regional specificity in THC-CBD interaction relevant to alleviation of psychotomimetic response has been demonstrated by Wall et al (67). Using resting state functional magnetic resonance imaging, the authors noted that CBD:THC combination resulted in alleviation of THC induced functional connectivity disruption, specifically in the limbic sub-division of the striatum but not in the associative and sensorimotor sub-striatal networks (67).…”