Neurobiological mediators of clinical outcomes in psychedelic-assisted therapies

Psychedelic-assisted therapies have demonstrated rapid and often sustained clinical benefit across depression, PTSD, and other conditions. Neuroimaging, electrophysiological, and molecular studies increasingly link these effects to structural and functional neuroplasticity, supported by theoretical frameworks such as the Entropic Brain Hypothesis and REBUS. In parallel, clinical and qualitative research emphasizes the centrality of the subjective, phenomenological experience to therapeutic outcome. These two literatures — neurobiological and phenomenological — have largely developed in parallel, with few studies directly testing how they relate within the same patient sample. Consequently, whether neurobiological changes are causally responsible for clinical improvement, merely predictive of it, or simply co-occurring alongside a distinct psychological process remains an open and clinically consequential question.This research topic aims to advance understanding of the causal and explanatory role neurobiological change plays in producing clinical outcomes following psychedelic-assisted interventions. Specifically, we seek studies addressing whether neuroplasticity markers (assessed via PET, EEG, fMRI, or molecular biomarkers) mediate therapeutic change, predict treatment response, or accompany clinical improvement— and to what extent subjective and phenomenological factors contribute independently of, or interact with, these biological mechanisms. Recent developments make this question newly tractable. Emerging non-hallucinogenic psychoplastogens/neuroplastogens — compounds engaging overlapping downstream plasticity pathways (e.g., 5-HT2A/TrkB/mTOR signaling) while producing minimal or no subjective psychedelic experience — offer a natural comparator for isolating the relative contributions of neuroplasticity versus phenomenology. Similarly, cross-compound comparisons (classic serotonergic psychedelics versus ketamine, ibogaine, and related rapid-acting agents) provide additional leverage on which neurobiological features are necessary versus incidental to outcome. We welcome contributions applying formal mediation/moderation modeling, longitudinal multi-timepoint designs, and methodological frameworks suited to disentangling these relationships, alongside theoretical work situating findings within a broader mechanistic and phenomenological context.This topic welcomes studies integrating neurobiological and clinical/psychological data within the same cohort, though single-domain studies with clear cross-domain implications are also encouraged.We invite contributions addressing themes including:• Formal mediation or moderation analyses linking neurobiological measures (PET, EEG, fMRI, molecular biomarkers) to clinical or psychological outcomes• Comparative studies across different psychedelic compounds or treatment protocols• Comparisons between hallucinogenic psychedelics and non-hallucinogenic psychoplastogens/neuroplastogens• Methodological or theoretical frameworks for testing mediation, or for harmonizing biomarkers across studies• Studies examining the independent or interactive contribution of subjective/phenomenological experience to therapeutic outcome• Longitudinal, multi-timepoint designs pairing repeated neurobiological and clinical measuresWe welcome the following article types:• Original Research• Study Protocol• Systematic Review• Mini Review• Hypothesis and TheoryMartin Williams is Executive Director of Psychedelic Research in Science & Medicine. The other Topic Editors declare no competing interests with regard to the Research Topic subject. Topic editors: Denis Pavăl, Martin L Williams Source: https://www.frontiersin.org/research-topics/84481/neurobiological-mediators-of-clinical-outcomes-in-psychedelic-assisted-therapies