The 'PSILAUT' protocol: an experimental medicine study of autistic differences in the function of brain serotonin targets of psilocybin.

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.

Study at a glance

Abstract

The underlying neurobiology of the complex autism phenotype remains obscure, although accumulating evidence implicates the serotonin system and especially the 5HT2A receptor. However, previous research has largely relied upon association or correlation studies to link differences in serotonin targets to autism. To directly establish that serotonergic signalling is involved in a candidate brain function our approach is to change it and observe a shift in that function. We will use psilocybin as a pharmacological probe of the serotonin system in vivo. We will directly test the hypothesis that serotonergic targets of psilocybin - principally, but not exclusively, 5HT2A receptor pathways-function differently in autistic and non-autistic adults. The 'PSILAUT' "shiftability" study is a case-control study autistic and non-autistic adults. How neural responses 'shift' in response to low doses (2 mg and 5 mg) of psilocybin compared to placebo will be examined using multimodal techniques including functional MRI and EEG. Each participant will attend on up to three separate visits with drug or placebo administration in a double-blind and randomized order. This study will provide the first direct evidence that the serotonin targets of psilocybin function differently in the autistic and non-autistic brain. We will also examine individual differences in serotonin system function. This work will inform our understanding of the neurobiology of autism as well as decisions about future clinical trials of psilocybin and/or related compounds including stratification approaches. NCT05651126.