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

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.

The acute effects of cannabidiol on emotional processing and anxiety: a neurocognitive imaging study.

RATIONALE: There is growing interest in the therapeutic potential of cannabidiol (CBD) across a range of psychiatric disorders. CBD has been found to reduce anxiety during experimentally induced stress in anxious individuals and healthy controls. However, the mechanisms underlying the putative anxiolytic effects of CBD are unknown. OBJECTIVES: We sought to investigate the behavioural and neural effects of a single dose of CBD vs. placebo on a range of emotion-related measures to test cognitive-mechanistic models of its effects on anxiety. METHODS: We conducted a randomised, double-blind, placebo-controlled, crossover, acute oral challenge of 600 mg of CBD in 24 healthy participants on emotional processing, with neuroimaging (viewing emotional faces during functional magnetic resonance imaging) and cognitive (emotional appraisal) measures as well as subjective response to experimentally induced anxiety. RESULTS: CBD did not produce effects on brain responses to emotional faces and cognitive measures of emotional processing, or modulate experimentally induced anxiety, relative to placebo. CONCLUSIONS: Given the rising popularity of CBD for its putative medical benefits, these findings question whether further research is warranted to investigate the clinical potential of CBD for the treatment of anxiety disorders.

The effects of acute cannabidiol on cerebral blood flow and its relationship to memory: An arterial spin labelling magnetic resonance imaging study.

BACKGROUND: Cannabidiol (CBD) is being investigated as a potential treatment for several medical indications, many of which are characterised by altered memory processing. However, the mechanisms underlying these effects are unclear. AIMS: Our primary aim was to investigate how CBD influences cerebral blood flow (CBF) in regions involved in memory processing. Our secondary aim was to determine if the effects of CBD on CBF were associated with differences in working and episodic memory task performance. METHODS: We used a randomised, crossover, double-blind design in which 15 healthy participants were administered 600 mg oral CBD or placebo on separate days. We measured regional CBF at rest using arterial spin labelling 3 h after drug ingestion. We assessed working memory with the digit span (forward, backward) and n-back (0-back, 1-back, 2-back) tasks, and we used a prose recall task (immediate and delayed) to assess episodic memory. RESULTS: CBD increased CBF in the hippocampus (mean (95% confidence intervals) = 15.00 (5.78-24.21) mL/100 g/min, t14 = 3.489, Cohen's d = 0.75, p = 0.004). There were no differences in memory task performance, but there was a significant correlation whereby greater CBD-induced increases in orbitofrontal CBF were associated with reduced reaction time on the 2-back working memory task ( r= -0.73, p = 0.005). CONCLUSIONS: These findings suggest that CBD increases CBF to key regions involved in memory processing, particularly the hippocampus. These results identify potential mechanisms of CBD for a range of conditions associated with altered memory processing, including Alzheimer's disease, schizophrenia, post-traumatic stress disorder and cannabis-use disorders.

The acute effects of cannabidiol on the neural correlates of reward anticipation and feedback in healthy volunteers.

BACKGROUND: Cannabidiol has potential therapeutic benefits for people with psychiatric disorders characterised by reward function impairment. There is existing evidence that cannabidiol may influence some aspects of reward processing. However, it is unknown whether cannabidiol acutely affects brain function underpinning reward anticipation and feedback. HYPOTHESES: We predicted that cannabidiol would augment brain activity associated with reward anticipation and feedback. METHODS: We administered a single 600 mg oral dose of cannabidiol and matched placebo to 23 healthy participants in a double-blind, placebo-controlled, repeated-measures design. We employed the monetary incentive delay task during functional magnetic resonance imaging to assay the neural correlates of reward anticipation and feedback. We conducted whole brain analyses and region-of-interest analyses in pre-specified reward-related brain regions. RESULTS: The monetary incentive delay task elicited expected brain activity during reward anticipation and feedback, including in the insula, caudate, nucleus accumbens, anterior cingulate and orbitofrontal cortex. However, across the whole brain, we did not find any evidence that cannabidiol altered reward-related brain activity. Moreover, our Bayesian analyses showed that activity in our regions-of-interest was similar following cannabidiol and placebo. Additionally, our behavioural measures of motivation for reward did not show a significant difference between cannabidiol and placebo. DISCUSSION: Cannabidiol did not acutely affect the neural correlates of reward anticipation and feedback in healthy participants. Future research should explore the effects of cannabidiol on different components of reward processing, employ different doses and administration regimens, and test its reward-related effects in people with psychiatric disorders.