The neuropsychopharmacology of cannabis: A review of human imaging studies

Abstract

The laws governing cannabis are evolving worldwide and associated with changing patterns of use. The main psychoactive drug in cannabis is Δ⁹-tetrahydrocannabinol (THC), a partial agonist at the endocannabinoid CB₁ receptor. Acutely, cannabis and THC produce a range of effects on several neurocognitive and pharmacological systems. These include effects on executive, emotional, reward and memory processing via direct interactions with the endocannabinoid system and indirect effects on the glutamatergic, GABAergic and dopaminergic systems. Cannabidiol, a non-intoxicating cannabinoid found in some forms of cannabis, may offset some of these acute effects. Heavy repeated cannabis use, particularly during adolescence, has been associated with adverse effects on these systems, which increase the risk of mental illnesses including addiction and psychosis. Here, we provide a comprehensive state of the art review on the acute and chronic neuropsychopharmacology of cannabis by synthesizing the available neuroimaging research in humans. We describe the effects of drug exposure during development, implications for understanding psychosis and cannabis use disorder, and methodological considerations. Greater understanding of the precise mechanisms underlying the effects of cannabis may also give rise to new treatment targets.

Keywords: Addiction; Cannabis; Cognition; Development; Neuroimaging; Psychosis.

Fig. 1

The distribution of CB₁Rs across the human brain. These axial (left), coronal (middle) and sagittal (right) views schematically depict regions of medium and high endocannabinoid type 1 receptor (CB₁R) concentration. This was extrapolated from mean labelling densities as described by Glass et al. (1997). [³H]CPP55,940 binding >80 fmol/mg was defined as high and 40-80 fmol/mg was defined as medium. Regions with high CB₁R concentration include (in alphabetical order): amygdala (not in view), cerebellum, cingulate gyrus, dorsal motor nucleus of the vagus, entorhinal cortex, globus pallidus, hippocampal formation, middle frontal gyrus, substantia nigra, and Wernicke’s area. Regions with medium CB₁R concentration include (in alphabetical order): auditory cortex (right), caudate nucleus, mediodorsal nucleus of the thalamus, motor cortex, occipitotemporal gyrus, putamen, somatosensory cortex, and visual cortex. Montreal Neurological Institute coordinates (x,y,z) are shown above.

Fig. 2

THC and retrograde endocannabinoid signalling at the synaptic cleft. The cannabinoids 2-arachidonoylglycerol and anandamide are produced endogenously by neurons and act at endocannabinoid type 1 receptors (CB₁Rs) on adjacent synaptic terminals. CB₁R activity leads to retrograde suppression of excitation in glutamatergic nerve terminals and retrograde suppression of inhibition in GABAergic nerve terminals. Δ⁹-tetrahydrocannabinol (THC) disrupts this signalling process.