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Whelan et al. 2024 — PSILAUT: psilocybin as a probe of serotonin function in autism

🔬ResearchPeer-reviewed

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Citation

Whelan, T.P., Daly, E., Puts, N.A., Smith, P., Allison, C., Baron-Cohen, S., Malievskaia, E., Murphy, D.G.M., & McAlonan, G.M. (2024). “The ‘PSILAUT’ protocol: an experimental medicine study of autistic differences in the function of brain serotonin targets of psilocybin.” BMC Psychiatry, 24:319. doi:10.1186/s12888-024-05768-2. Open Access. Trial registration: NCT05651126.

What this paper is

This is a study protocol, not a results paper. PSILAUT is a case-control study at King’s College London using low-dose psilocybin (2 mg and 5 mg, compared to placebo) as a pharmacological probe to test whether 5HT₂A receptor pathways function differently in autistic versus non-autistic adult brains. It sits at the intersection of psychedelic neuroscience, serotonin pharmacology, and autism research. The paper describes design, methods, and measures; results are not yet published.

What they are testing

The core hypothesis: serotonergic targets of psilocybin — principally 5HT₂A receptor pathways — function differently in autistic brains. This is not a trial of psilocybin as a treatment for autism. It is a “shiftability” study: give a pharmacological probe, observe whether the brain’s response shifts differently in autistic versus non-autistic people, and infer something about the baseline function of the system being probed.

Key design features

  • Participants: up to 70 adults; target n = 30 autistic, n = 30 non-autistic, matched by age and sex, half female in each group. Autistic participants are without intellectual disability and without co-occurring psychotic illness.
  • Design: double-blind, placebo-controlled, crossover. Each participant attends 3 visits receiving either placebo, 2 mg, or 5 mg of synthetic COMP360 psilocybin in pseudo-randomised order (low dose always before high).
  • Measures across organisational levels: MRS (GABA/glutamate balance), resting-state fMRI, face-emotion fMRI task, EEG (resting-state + auditory oddball + visual processing), psychophysics, cognitive tasks. The multi-level design means they can probe circuit-level, network-level, and task-level differences simultaneously.
  • Low doses deliberately: 2 mg and 5 mg are subperceptual or barely perceptual — chosen to reveal serotonin system function without causing a full psychedelic experience. This is a methodological choice, not a limitation; the point is pharmacological probing, not phenomenological investigation.

Why the serotonin system matters for autism

The protocol’s background section marshals the evidence:

  • Polymorphisms in genes for serotonin synthesis, transporters, and receptors are associated with autism.
  • Elevated whole-blood serotonin levels are reported in roughly one-third of autistic individuals.
  • The 5HT₂A receptor is specifically implicated: it is involved in dendritic maturation, neuronal differentiation, and regulation of brain-derived neurotrophic factor during development. It is densely expressed in sensorimotor integration regions and in the default mode network.
  • The HT2RA gene is a candidate gene associated with autism.
  • Lower cortical 5HT₂A receptor binding has been correlated with social communication differences in autism — but no study has directly tested whether these pathways function differently, which is what PSILAUT sets out to do.

Community engagement

Before designing the study, 331 autistic adults were surveyed. 41% were “very interested” and 28% “somewhat interested” in psilocybin research. 25% were not interested. The team explicitly states they would not have proceeded without clear community support, and they framed the study as exploratory rather than therapeutic from the start.

Relevance to this wiki

PSILAUT connects to this work in two ways:

  1. Serotonin and sensory processing. If 5HT₂A pathways shape how sensory information is weighted and integrated — and there is accumulating evidence that they do — then understanding autistic differences in these pathways deepens the mechanistic account behind the hypo/hyperresponsivity patterns that this wiki documents in practice. The protocol explicitly measures sensory-level responses (EEG auditory oddball, psychophysics) alongside higher-order network connectivity.

  2. The neurodiversity framing. The study is carefully positioned as investigating difference, not deficit. It asks “does this system work differently?” not “is this system broken?” — which aligns with the approach taken here. The community engagement process models what participatory research should be: autistic people had a genuine veto over whether the research happened.

Limitations and caveats

  • No results yet. This is a protocol paper. The findings, when published, will be the ones to cite.
  • Excludes autistic people with ID. This is necessary for informed consent and safety in a psilocybin study, but it means the findings will not directly apply to autistic people with intellectual disability. Whether serotonin system differences in autistic adults without ID can be extrapolated to those with ID is an open question.
  • Low doses only. The study will not address what happens at psychedelic doses. This is deliberate but limits what can be said about the phenomenological overlap between psychedelic states and autistic experience (for that, see Predictive processing and autism).
  • Psilocybin is not 5HT₂A-specific. Psilocin (the active metabolite) also binds 5HT₇, 5HT₂B, 5HT₁D, 5HT₆, 5HT₅, 5HT₂C, and 5HT₁B receptors. The authors acknowledge this but argue 5HT₂A is the principal target.

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