Clinical trials of pharmacological approaches targeting the core features of autism have failed. This is despite evidence from preclinical studies, genetics, post-mortem studies and correlational analyses linking peripheral and central markers of multiple candidate neurochemical systems to brain function in autism. Whilst this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is very little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. As a result, our understanding of how neurochemical differences contribute to neurodiversity is limited and impedes our ability to translate findings from animal studies into humans. Here, we begin by introducing our shiftability paradigm, an approach to bridge the translational gap in autism research. We then provide an overview of the methodologies used and explain our most recent choice of psilocybin as a pharmacological probe of the serotonin system in vivo. Finally, we provide a summary of the protocol for PSILAUT, an exemplar shiftability study which uses psilocybin to directly test the hypothesis that the serotonin system functions differently in autistic and non-autistic adults.

Please see Acknowledgements.

https://clinicaltrials.gov/ct2/show/NCT05651126

Please see Acknowledgments.

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