Cannabinoid modulation of amygdala reactivity to social signals of threat in humans

Abstract

The cannabinoid (CB) system is a key neurochemical mediator of anxiety and fear learning in both animals and humans. The anxiolytic effects of delta(9)-tetrahydrocannabinol (THC), the primary psychoactive ingredient in cannabis, are believed to be mediated through direct and selective agonism of CB(1) receptors localized within the basolateral amygdala, a critical brain region for threat perception. However, little is known about the effects of THC on amygdala reactivity in humans. We used functional magnetic resonance imaging and a well validated task to probe amygdala responses to threat signals in 16 healthy, recreational cannabis users after a double-blind crossover administration of THC or placebo. We found that THC significantly reduced amygdala reactivity to social signals of threat but did not affect activity in primary visual and motor cortex. The current findings fit well with the notion that THC and other cannabinoids may have an anxiolytic role in central mechanisms of fear behaviors and provide a rationale for exploring novel therapeutic strategies that target the cannabinoid system for disorders of anxiety and social fear.

Figure 1.

THC effects on self-report measures. Mean “feel drug” (DEQ) (A), “drug high” (DEQ) (B), and “high” (VAS) (C) scores over time after oral administration of THC (solid line; open circles) or PBO (dashed line; closed circles). Means are based on DEQ data from 14 subjects and VAS data from 15 subjects. Error bars represent SEM. *p < 0.05, two-tailed.

Figure 2.

THC effects on amygdala activation. A, B, Statistical t maps overlaid on a canonical brain rendering (MNI coronal y-plane = 0) showing right lateral amygdala activation to threat (>nonthreat) faces is present during the PBO session but absent during the THC session. C, Statistical t map overlaid on a canonical brain rendering (MNI coronal y-plane = 0) showing greater threat-related amygdala reactivity in the PBO relative to the THC session (PBO > THC). For additional information, see Results. Statistical t score scale is shown at the bottom of the brain rendering. R, Right.