2026 ECNP Congress

PS04-4220

Serotonin system stimulation and empathy: a comparative investigation of psilocybin, MDMA, and methylphenidate

Lydia Belinger — E.J.E. Engeli, N.M. Rieser, L. Becciolini, M. Herdener, K.H. Preller · University Hospital of Psychiatry Zurich, Department of Adult Psychiatry and Psychotherapy, Zürich, Switzerland

2026 ECNP Congress

Background

Social cognition is proposed as a central mechanism underpinning the therapeutic effects of psychedelics and MDMA, which is particularly relevant in light of findings that deficits in social functioning play a key role in a range of psychiatric disorders [1]. Both psychedelics and MDMA are known to acutely modulate social perception and behavior [2], with the serotonin (5-hydroxytryptamine, 5-HT) system playing a critical role in these processes [3–5]. To date, there is limited evidence of long-lasting effects, and the associated neuropharmacological mechanisms as well as time-dependent alterations are not yet sufficiently understood. Addressing this gap is critical for optimizing therapeutic applications.

Aims

We investigated if stimulating the serotonin system with psilocybin and MDMA leads to lasting changes in social cognition compared to the non-serotonergic control substance methylphenidate. While the present study assessed multiple domains of social cognition, here we focus specifically on changes in empathy.

Methods

The study employed a randomized, double-blind, placebo-controlled, parallel-group design, with 120 healthy participants receiving a single dose of MDMA (100 mg), psilocybin (15 mg), or methylphenidate (60 mg) under standardized conditions. Empathy was assessed at baseline and four weeks after the substance intake using the Multifaceted Empathy Test (MET). The MET is a valid and reliable computer-based assessment tool that measures both cognitive and emotional facets of empathy [6]. Specifically, it assesses cognitive empathy, explicit emotional empathy, and implicit emotional empathy in reaction to photographs of individuals in positively and negatively valenced emotionally charged situations. The statistical analyses included repeated-measures ANOVA and subsequent post-hoc comparisons, with a significance level of p < 0.05.

Results

Preliminary analyses identified substance-specific and valence-selective effects on implicit emotional empathy. Psilocybin produced a significant reduction in implicit emotional empathy for negative stimuli four weeks after substance administration (p < 0.05). No significant changes were observed for MDMA or methylphenidate, or for cognitive or explicit emotional empathy in any group (p > 0.05).

Conclusions

The results suggest that psilocybin may induce sustained and valence-specific alterations in distinct domains of empathy, rather than a uniform pro-social enhancement. The observed reductions in implicit empathy to negative stimuli may reflect changes in emotion regulation processing, although this interpretation requires further investigation. Importantly, these findings demonstrate that psilocybin can modulate empathic processing up to one month after administration. Further research into these lasting effects could deepen our understanding of social-cognitive mechanisms in psychedelic interventions and serve as a foundation for the development of new treatment approaches for social impairments associated with psychiatric disorders.

Funding and Conflicts of Interest: The trial was funded by the Tiny Blue Dot Foundation (grant ID 61796544), which had no further influence on the trial design, data collection, analysis, or the interpretation of the data. K.H. Preller is an employee of Boehringer Ingelheim GmBH & CO KG and works as Chief Scientist and Board Member of Directors for the Heffter Research Institute. The remaining authors have nothing to disclose.

References

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  3. Wen, A., Singhal, N., Jones, B. D., Zeifman, R. J., Mehta, S., Shenasa, M. A., Blumberger, D. M., Daskalakis, Z. J., & Weissman, C. R. (2024). A systematic review of study design and placebo controls in psychedelic research. Psychedelic Medicine, 2 (1), 15–24. https://doi.org/10.1089/psymed.2023.0028
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  5. Nayak, S. M., & Zahid, Z. (2025). Out of control: Blinding, dose response, and psychosocial controls in psychedelic trials. Journal of Psychopharmacology, 02698811251368367. https://doi.org/10. 1177/02698811251368367
  6. Dziobek, I., Rogers, K., Fleck, S., Bahnemann, M., Heekeren, H. R., Wolf, O. T., & Convit, A. (2008). Dissociation of cognitive and emotional empathy in adults with Asperger syndrome using the Multifaceted Empathy Test (MET). Journal of autism and developmental disorders, 38(3), 464-473. https://doi.org/10.1007/s10803-007-0486-x