2026 ECNP Congress

PS01-1202

Boundary conditions of psychedelic plasticity: Empathy and mentalizing networks remain stable after DMT and harmine in experienced meditators

Klemens Egger — M. Rassouli, D. Meling, H.D. Aicher, J. Mueller, J. Jareño Redondo, T. Singer, M. Scheidegger · University Hospital of Psychiatry Zurich, Department of Adult Psychiatry and Psychotherapy, Zurich, Switzerland

2026 ECNP Congress

Introduction

Psychedelics and meditation have each been associated with enhanced prosocial functioning [1], yet their combined effects on neural systems supporting empathy, compassion, and Theory of Mind (ToM) remain unclear. While prior work has demonstrated alterations in large-scale brain network organization following psychedelic administration and meditation practice [2–4], it remains unresolved whether these changes translate to process-specific socio-affective functions under task demands. Moreover, it is unclear whether such effects persist beyond acute states or interact with pre-existing expertise in contemplative practice. The present study investigated whether psychedelic-augmented meditation modulates neural and behavioral indices of empathy, compassion, and ToM using the EmpaToM fMRI paradigm in experienced meditators.

Methods

In a randomized, double-blind, placebo-controlled retreat study, 40 experienced meditation practitioners underwent task-based functional magnetic resonance imaging (fMRI) before and after a 3-day meditation retreat. Participants received either an ayahuasca-inspired oral formulation containing N,N-dimethyltryptamine (DMT) and harmine (120 mg/120 mg total dose, administered in four divided doses) or placebo on the second day of the retreat. Socio-affective and socio-cognitive processes were assessed using the EmpaToM fMRI paradigm, which orthogonally manipulates emotional valence (negative vs. neutral) and inference type (ToM vs. non-ToM) within a 2×2 factorial design [5]. Behavioral outcomes (empathy, compassion, and ToM performance) were analyzed using linear mixed-effects models. Task-evoked neural responses were analyzed using first-level GLMs and second-level mixed-effects models, with voxelwise correction for multiple comparisons (pFDR<.05).

Results

At baseline, the EmpaToM task robustly replicated canonical activation patterns, including anterior insula and anterior cingulate engagement during empathic processing, and medial prefrontal and temporoparietal regions during ToM. Behavioral data showed expected modulation by emotionality, confirming task validity. Participants exhibited elevated task-based compassion relative to reference samples, while self-reported compassion was comparatively lower, indicating a dissociation between behavioral and self-report measures in our sample of trained meditators. Contrary to our hypothesis, no significant Drug × Time interactions were observed for behavioral measures of empathy, compassion, or ToM performance (all p>.15). Similarly, whole-brain and region-of-interest analyses revealed no significant effects of DMT+harmine, meditation, or their interaction on task-evoked neural responses. Activation patterns remained highly stable across sessions and conditions. Covariate analyses including age, sex, meditation experience, and prior psychedelic use did not alter these findings.

Conclusions

Psychedelic-augmented meditation with DMT+harmine did not modulate task-evoked neural or behavioral markers of empathy, compassion, or ToM in experienced meditators within an early post-acute window. These findings suggest that core socio-affective and cognitive systems, when engaged under structured task demands, exhibit substantial stability despite pronounced subjective and network-level effects of psychedelics. Rather than indicating absence of psychedelic effects, the results delineate boundary conditions for socio-affective plasticity and highlight a dissociation between transient DMt+harmine-induced experiential changes and consolidated socio-affective and cognitive processing architectures. Together, these findings emphasize the importance of considering measurement level, timing of assessment, and participant characteristics when interpreting psychedelic effects on social cognition and emotion. Future studies should target both acute and subacute time windows, include diverse populations, and employ complementary paradigms to better capture dynamic and ecologically valid aspects of social cognition.

References

  1. Simonsson C, Chambers R, Hendricks PS, et al. Classic Psychedelic Use and Current Meditation Practice. Mindfulness (N Y) 2023; 14: 763–768.
  2. Egger K, Meling D, Polat F, et al. Meditation, psychedelics, and brain connectivity: A randomized controlled resting-state fMRI study of N,N -dimethyltryptamine and harmine in a meditation retreat. Imaging Neuroscience; 3. Epub ahead of print 29 September 2025. DOI: 10.1162/IMAG.a.907.
  3. Tang YY, Hölzel BK, Posner MI. The neuroscience of mindfulness meditation. Nat Rev Neurosci 2015; 16: 213–225.
  4. Wall MB, Harding R, Zafar R, et al. Neuroimaging in psychedelic drug development: past, present, and future. Mol Psychiatry 2023; 28: 3573–3580.
  5. Kanske P, Bockler A, Trautwein FM, et al. Dissecting the social brain: Introducing the EmpaToM to reveal distinct neural networks and brain-behavior relations for empathy and Theory of Mind. Neuroimage 2015; 122: 6–19.