The mixed serotonin receptor agonist psilocybin reduces threat-induced modulation of amygdala connectivity

• We measured BOLD signals during a threat-inducing pictures task.
• Subjects were treated with psilocybin (a serotonergic hallucinogen) and placebo.
• We compared effective connectivity changes between psilocybin and placebo using DCM.
• We found that psilocybin decreased top-down connectivity from the amygdala to visual cortex.
• Results point at a neural mechanism underlying emotional shifts induced by psilocybin.

Stimulation of serotonergic neurotransmission by psilocybin has been shown to shift emotional biases away from negative towards positive stimuli. We have recently shown that reduced amygdala activity during threat processing might underlie psilocybin's effect on emotional processing. However, it is still not known whether psilocybin modulates bottom-up or top-down connectivity within the visual-limbic-prefrontal network underlying threat processing. We therefore analyzed our previous fMRI data using dynamic causal modeling and used Bayesian model selection to infer how psilocybin modulated effective connectivity within the visual–limbic–prefrontal network during threat processing. First, both placebo and psilocybin data were best explained by a model in which threat affect modulated bidirectional connections between the primary visual cortex, amygdala, and lateral prefrontal cortex. Second, psilocybin decreased the threat-induced modulation of top-down connectivity from the amygdala to primary visual cortex, speaking to a neural mechanism that might underlie putative shifts towards positive affect states after psilocybin administration. These findings may have important implications for the treatment of mood and anxiety disorders.