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Psychedelic studies in nonhuman primates: Past and future

Molecular Psychiatry (2025)Cite this article

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Abstract

Studies of serotonergic or ‘classic’ psychedelics in nonhuman primates (NHPs) have provided valuable information about the drugs’ effects on the brain and behavior in closely related species to humans. Psychedelics induce characteristic changes to both spontaneous and operant behaviors in NHPs, though variability exists in the different effects reported by different studies; this variability could be due to factors like differences across drugs, differences in dose ranges across studies, and inter-individual variability in drug responsiveness. Several effects of psychedelics in NHPs mirror those in humans, including development of tolerance to psychedelic effects and low abuse liability, though evidence is mixed on whether psychedelics cause visual hallucinations in NHPs. NHP studies have also examined psychedelic mechanisms of action, supporting and connecting existing findings from human and rodent studies. Here we review the knowledge gained from psychedelic research in NHPs encompassing multiple psychedelic compounds in several NHP species. We conclude by highlighting NHPs’ potential to serve as preclinical models of psychedelic effects on psychiatric conditions and suggesting several directions for future research to ensure the accuracy and effectiveness of an NHP psychedelic model.

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Fig. 1: Chemical structures of classic serotonergic psychedelics.
Fig. 2
Fig. 3: Brain areas identified as areas of psychedelic action in humans, NHPs, and rodents.

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Acknowledgements

This work was supported by NIH grants R01MH128217 (A.C.K.), R01MH137047 (A.C.K.), and One Mind – COMPASS Rising Star Award (A.C.K.), and by the National Institute for Mental Health (R01 MH128190; SW.C.C.).

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Authors and Affiliations

  1. Department of Psychology, Yale University, New Haven, CT, USA

    Jamie C. Masthay & Steve W. C. Chang

  2. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

    Alex C. Kwan

  3. Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA

    Alex C. Kwan

  4. Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA

    Alex C. Kwan

  5. Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    Steve W. C. Chang

  6. Kavli Institute for Neuroscience, Yale University School of Medicine, New Haven, CT, USA

    Steve W. C. Chang

  7. Wu Tsai Institute, Yale University School, New Haven, CT, USA

    Steve W. C. Chang

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  1. Jamie C. Masthay
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  2. Alex C. Kwan
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Contributions

JCM conceptualized the review, conducted the literature review, created figures, and wrote the manuscript. ACK contributed to the literature review, created figures, and wrote the manuscript. SWCC conceptualized the review, contributed to the literature review, and wrote the manuscript.

Corresponding author

Correspondence to Steve W. C. Chang.

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Competing interests

ACK has been a scientific advisor or consultant for Boehringer Ingelheim, Empyrean Neuroscience, Freedom Biosciences, and Xylo Bio. ACK has received research support from Intra-Cellular Therapies. The other authors declare no competing financial interests.

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Masthay, J.C., Kwan, A.C. & Chang, S.W.C. Psychedelic studies in nonhuman primates: Past and future. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03240-5

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