Abstract Background: Psychedelics are known to profoundly alter perception and self-referential processing, yet their specific effects on face recognition - a key aspect of social cognition remain underexplored. Objective: This study investigates the effects of an ayahuasca-inspired novel DMT/HAR (N,N-dimethyltryptamine/Harmine) formulation and Harmine alone on face recognition and self-referential processing, as measured by event-related potentials (ERPs). Methods: In a within-subject, double-blind, placebo-controlled design, 31 healthy male participants underwent EEG recording during a visual oddball task involving Self, Familiar, and Unknown Faces. The study compared the effects of a DMT/HAR formulation, harmine alone, and placebo on key visual ERP components: P1, N170, and P300. Results: DMT/HAR increased P1 amplitude and decreased N170 amplitude across all face categories, indicating enhanced early visual processing and disrupted face structural encoding. DMT/HAR also reduced P300 amplitude specifically for self-faces, diminishing neural differentiation between self and other faces. Conclusion: The DMT/HAR formulation significantly blurs the neural distinction between self and other faces, suggesting a potential mechanism by which psychedelics diminish attentional focus on self-referential information, thereby enhancing empathy and unity. These insights into serotonergic modulation of face recognition could inform therapeutic strategies for disorders characterized by altered self-processing.

MS, MK and DAD co-founded Reconnect Labs, an academic spin-off at the University of Zurich. MJM is a shareholder of Reconnect Labs. All other co-authors have no conflict of interest to declare related to this work.

NCT04716335

We gratefully acknowledge grant funding that supported this publication from a Frontiers Proposal Fellowship of the IMT School for Advanced Studies (D. Suay, 2021/2022), Italian Ministry of University and Research (D. Bottari, MUR; PRIN 2017 research grant. Prot. 20177894ZH), private donations of Fabian Hediger (M. J. Muller), the SNSF Swiss National Science Foundation (H. D. Aicher, Doc.CH Grant P0ZHP1_191935; M. Scheidegger & D. Meling, Spark CRSK-1_196833; D. A. Dornbierer, BRIDGE PoC 40B1-0_198689 ), from the Bioentrepreneur Fellowship UZH (D.A. Dornbierer, BIOEF-18-009), from the Forschungskredit PostDoc UZH (M. Scheidegger, Grant No. FK-18-052). The content is solely the responsibility of the authors and does not necessarily represent the official views of the funders.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics committee of University of Zurich gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors