The serotonin system, particularly the 5HT2A receptor, may differ in autistic and non-autistic brains, but previous studies only show correlations. This registered clinical trial (NCT05651126) will directly test whether serotonergic signaling functions differently by using low doses (2 mg and 5 mg) of psilocybin as a pharmacological probe. In a double-blind, randomized, placebo-controlled case-control design, autistic and non-autistic adults will undergo functional MRI and EEG to measure how neural responses shift with psilocybin. The study aims to provide the first direct evidence of differential serotonin system function in autism and inform future clinical trials.
Clinical trials for drugs targeting core autism features have failed, despite evidence linking various neurochemical systems to brain function in autism. The field has relied on association studies, but the only way to directly establish a neurotransmitter's role in a brain function is to experimentally change it and observe a shift. There is little direct experimental evidence on how neurochemical systems modulate information processing in the living human brain, limiting translation from animal studies. The authors introduce a "shiftability" paradigm to bridge this gap, using psilocybin as a pharmacological probe of the serotonin system in vivo. They present the protocol for 'PSILAUT', a study testing whether the serotonin system functions differently in autistic and non-autistic adults.