The Yin and Yang of Cannabis: A Systematic Review of Human Neuroimaging Evidence of the Differential Effects of Δ9-Tetrahydrocannabinol and Cannabidiol

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Abstract
Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have been the most investigated cannabinoids at the human and preclinical levels, although the neurobiological mechanisms underlying their effects remain unclear. Human experimental evidence complemented by observational studies suggests that THC may have psychotogenic effects while CBD may have antipsychotic effects. However, whether their effects on brain function are consistent with their opposing behavioral effects remains unclear. To address this, here we synthesize neuroimaging evidence investigating the acute effects of THC and CBD on human brain function using a range of neuroimaging techniques, with an aim to identify the key brain substrates where THC and CBD have opposing effects. After a systematic search, a review of the available studies indicated marked heterogeneity. However, an overall pattern of opposite effect profiles of the two cannabinoids was evident with some degree of consistency, primarily attributed to the head-to-head challenge studies of THC and CBD. While head-to-head comparisons are relatively few, collectively the evidence suggests that opposite effects of THC and CBD may be present in the striatum, parahippocampus, anterior cingulate/medial prefrontal cortex, and amygdala, with opposite effects less consistently identified in other regions. Broadly, THC seems to increase brain activation and blood flow, whereas CBD seems to decrease brain activation and blood flow. Given the sparse evidence, there is a particular need to understand the mechanisms underlying their opposite behavioral effects because it may not only offer insights into the underlying pathophysiological mechanisms of psychotic disorders but also suggest potentially novel targets and biomarkers for drug discovery.