Bridging the translational neuroscience gap: Development of the ‘shiftability’ paradigm and an exemplar protocol to capture psilocybin-elicited ‘shift’ in neurobiological mechanisms in autism

Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterised by differences in social communication, repetitive or restricted behaviours, and sensory atypicalities. Clinical trials seeking pharmacological treatments for core ASD features have largely failed, a problem the authors attribute not only to diagnostic heterogeneity but also to a lack of experimental paradigms that causally link neurochemical systems to brain function in humans. Most human neuroscience work in this area has relied on correlational approaches that cannot establish whether a given neurotransmitter system actually regulates a candidate brain mechanism. Whelan and colleagues introduce a “shiftability” paradigm intended to bridge this translational gap by deliberately perturbing neurochemical systems in vivo and measuring the resulting ‘shift’ in brain function across multiple organisational levels. The paper outlines the rationale for this experimental medicine approach, summarises methodological options, and presents an exemplar protocol (PSILAUT) that uses low doses of psilocybin as a serotonergic probe to test the hypothesis that 5HT-mediated regulation of sensory processing, local circuits and whole-brain networks differs between autistic and non-autistic adults. The broader goal is to create a pharmacological repository describing how different drugs change (or fail to change) brain mechanisms across individuals, thereby improving stratification for future clinical trials.

PSILAUT is described as a placebo-controlled, randomised, double-blind, repeated-measures, cross-over, case-control study. The investigators plan to recruit up to 70 adult participants (reporting 40 autistic and 30 non-autistic controls) who will each attend three dosing visits. On separate occasions participants will receive oral synthetic COMP360 psilocybin at one of two low doses (2 mg and 5 mg) or placebo. Dosing order will be pseudo-randomised to balance first-visit conditions but the low dose will always precede the higher dose to allow for safety-driven unblinding if needed. Screening will be via remote contact and written informed consent obtained; baseline characterisation will include an accepted expert ASD diagnosis (supplemented by standard diagnostic instruments where available) and questionnaires measuring core autistic features, sensory function and co-occurring psychopathology. Multimodal neurophysiological and neuroimaging measures form the core outcomes. MRI acquisitions on a 3.0 Tesla scanner will include structural imaging, resting-state functional MRI with multiband sequences (to permit dynamic functional connectivity analyses) and a face emotion processing task. Magnetic resonance spectroscopy using a HERMES sequence will target the dorsomedial prefrontal cortex to estimate GABA and glutamate–glutamine measures that index excitation/inhibition (E/I) balance. High-density (64-channel) EEG will be recorded at rest and during passive sensory paradigms: visual steady-state evoked potentials probing surround suppression, an auditory oddball paradigm measuring mismatch negativity (MMN) as an index of repetition suppression and deviance response, and a tactile paired-pulse inhibition task for sensory gating. Task-dependent EEG will measure event-related potentials such as the N170 to faces. Psychophysical tests (tactile detection threshold, amplitude discrimination), a cognitive battery (Reading the Mind in the Eyes test, probabilistic reversal learning, verbal fluency), the 5D-ASC questionnaire to index subjective drug effects, and peripheral measures including whole blood serotonin are also included. A wrist wearable will continuously record heart rate and heart-rate variability as autonomic arousal indices. Analytically, the design uses within-subject repeated measures so each participant serves as their own control. Both parametric and non-parametric statistics will test the primary hypotheses that psilocybin elicits modality-specific ‘shifts’ that differ by diagnostic group. The investigators plan to compute individual-level ‘shift’ metrics for each modality and examine associations with clinical measures (for example, questionnaire scores and whole blood serotonin), and to explore post-hoc multimodal relationships. Power considerations are based on prior pharmacological neuroimaging studies by the group that detected group differences with small samples (n < 20), and sample sizes for sensory tasks are justified with reference to medium effect detection at conventional power thresholds. Safety oversight and procedures for participant dropout and replacement are described at a protocol level; explicit exclusion criteria are not fully detailed in the extracted text.

The extracted text does not report empirical results; this paper presents a protocol and rationale rather than outcome data. Instead, the investigators state specific, testable expectations derived from prior literature and their own previous pharmacological challenge work. They predict that low-dose psilocybin will engage 5HT2A receptor-mediated mechanisms and produce measurable shifts in multiple modalities, including alterations in EEG oscillatory metrics (beta/gamma power, aperiodic activity) and local circuit proxies of E/I balance, changes in MRS-derived GABA and glutamate–glutamine markers, modulation of sensory suppression in visual (SSVEP surround suppression), auditory (repetition suppression/MMN) and tactile (paired-pulse inhibition) paradigms, and acute effects on resting-state and dynamic functional connectivity measured with fMRI and EEG. Task-dependent measures are expected to show altered dynamics of face-emotion processing (both fMRI and N170 ERP) and possible changes in cognitive tests sensitive to social cognition and flexibility. The authors also anticipate individual differences in pharmacological response and plan to relate observed shifts to baseline clinical and peripheral markers such as whole blood serotonin. No numerical effect sizes, confidence intervals or statistical outcomes are provided because no study data are reported.

Whelan and colleagues argue that the shiftability paradigm offers a way to move beyond correlational studies by directly testing whether perturbation of a neurochemical system produces predictable changes in brain mechanisms linked to autism. They position this experimental medicine approach as potentially more sensitive to individual neurobiological differences than standard case–control comparisons, and emphasise that measures targeting early or ‘foundational’ properties of brain organisation (sensory processing, local circuit E/I balance and network connectivity) may be stable across the lifespan and back-translatable to animal models. The authors acknowledge important limitations. The chosen pharmacological probe, psilocybin, is not entirely selective for 5HT2A receptors and binds multiple serotonin receptor subtypes, which complicates receptor-level interpretation. Practical constraints of the protocol—use of EEG caps, requirement to remain visually fixated, and repeat visits—may limit generalisability to autistic people with higher support needs or younger age groups; to mitigate this they include eye-tracking and focus on many passive tasks that require minimal behavioural response. The team also recognises participant drop-out risk in repeated-measures designs and states plans to replace participants as needed. They note that low doses (2 mg and 5 mg) are chosen to reduce the likelihood of marked psychedelic experiences while still engaging 5HT2A receptors, and that safety monitoring and a conservative dosing order are embedded in the protocol. In terms of implications, the investigators propose that pharmacological profiling using the shiftability approach could identify subgroups who do or do not show biologically meaningful responses to serotonergic modulation, thereby informing personalised-medicine strategies and improving the design of future clinical trials. They suggest that this approach could reduce the likelihood of failure in large-scale pharmacological trials that enrol participants on diagnostic criteria alone and do not assess mechanism.

The paper concludes that the shiftability paradigm aims to map how neurochemical systems modulate brain function across organisational scales and to identify individual differences between autistic and non-autistic adults. Using low-dose psilocybin as an exemplar serotonergic probe, the PSILAUT protocol seeks to reveal whether serotonergic regulation of sensory processing, local circuits and network dynamics differs by diagnostic group. The authors propose that results from such experimental medicine studies may improve understanding of neurodivergent brain biology, support more personalised approaches to pharmacological interventions, and help avoid costly, mechanism-insensitive clinical trials by enabling better stratification of likely responders and non-responders.