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Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats

Molecular Psychiatry volume 28, pages 3829–3841 (2023)Cite this article

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Abstract

Psilocybin (a classic serotonergic psychedelic drug) has received appraisal for use in psychedelic-assisted therapy of several psychiatric disorders. A less explored topic concerns the use of repeated low doses of psychedelics, at a dose that is well below the psychedelic dose used in psychedelic-assisted therapy and often referred to as microdosing. Psilocybin microdose users frequently report increases in mental health, yet such reports are often highly biased and vulnerable to placebo effects. Here we establish and validate a psilocybin microdose-like regimen in rats with repeated low doses of psilocybin administration at a dose derived from occupancy at rat brain 5-HT2A receptors in vivo. The rats tolerated the repeated low doses of psilocybin well and did not manifest signs of anhedonia, anxiety, or altered locomotor activity. There were no deficits in pre-pulse inhibition of the startle reflex, nor did the treatment downregulate or desensitize the 5-HT2A receptors. However, the repeated low doses of psilocybin imparted resilience against the stress of multiple subcutaneous injections, and reduced the frequency of self-grooming, a proxy for human compulsive actions, while also increasing 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These results establish a well-validated regimen for further experiments probing the effects of repeated low doses of psilocybin. Results further substantiate anecdotal reports of the benefits of psilocybin microdosing as a therapeutic intervention, while pointing to a possible physiological mechanism.

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Fig. 1: Pharmacokinetics of low doses of psilocybin.
Fig. 2: Repeated low doses of psilocybin reduces compulsive behavior of rats in a familiar open-field environment.
Fig. 3: Repeated low doses of psilocybin does not induce deficits in pre-pulse inhibition (PPI) of the startle reflex in the rat.
Fig. 4: Repeated low doses of psilocybin increases resiliance to stress-induced anhedonia, but does not change trait anxeity in rats in a novel environments.
Fig. 5: No tolerance from repeated low doses of psilocybin.
Fig. 6: Repeated low doses of psilocybin increases receptor levels and synaptic density in the paraventricular thalamic nucleus (PVT) of the rat.

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Data availability

All data and statistical analysis, can be found at our Open Science Framework website https://osf.io/gy6m9/.

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Acknowledgements

Psilocybin and psilocin were kindly provided by Prof. Dr. Tomáš Páleníček (Prague Psychiatric Center) and [3H]Cimbi-36 by Prof. Dr. Christer Halldin (Karolinska Institute). Professor DM Gitte M. Knudsen, head of the Neurobiology Research Unit, Copenhagen University Hospital, offered her support and guidance for students and researchers throughout the project.

Funding

Lundbeck Foundation (R192-2015-1591). Lundbeck Foundation (R194-2015-1589). Independent Research Fund Denmark (5053-00036B), Independent Research Fund Denmark (0169-00030B), Savværksejer Jeppe Juhls og Hustrus Ovita Juhls Mindelegat. Købmand i Odense Johann og Hanne Weimann født Seedorffs Legat.

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Authors and Affiliations

  1. Neurobiology Research Unit, Copenhagen University Hospital, Copenhagen, Denmark

    Kat F. Kiilerich, Joe Lorenz, Malthe B. Scharff, Nikolaj Speth, Mengfei Xiong, Naja S. Jessen, Agata Casado-Sainz, Agnete Overgaard & Mikael Palner

  2. Clinical Physiology and Nuclear Medicine, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Tobias G. Brandt, Julia Czurylo, Naja S. Jessen & Mikael Palner

  3. Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Mengfei Xiong, Vladimir Shalgunov, Anders A. Jensen & Matthias M. Herth

  4. Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Copenhagen, Denmark

    Vladimir Shalgunov & Matthias M. Herth

  5. Center for Translational Neuromedicine, University of Copenhagen, Copenhagen, Denmark

    Celia Kjaerby

  6. Department of Medicinal Chemistry, Maj Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland

    Grzegorz Satała & Andrzej J. Bojarski

  7. Department of Nuclear Medicine, Bern University Hospital, Bern, Switzerland

    Paul Cumming

  8. School of Psychology and Counselling, Queensland University of Technology, Brisbane, QLD, Australia

    Paul Cumming

  9. Department of Nuclear Medicine, Odense University Hospital, Odense, Denmark

    Mikael Palner

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  1. Kat F. Kiilerich
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Contributions

Conceptualization: JL, AO, MP. Methodology: KFK, JL, NSJ, TGB, JC, MS, NS, MX, WR, NRR, AC, VS, CK, GS, AB, AAJ, MMH, MP. Investigation: KFK, JL, NSJ, TGB, JC, MS, NS, MX, WR, NRR, AC, VS, GS, AB, AAJ, MMH, MP. Visualization: MP. Funding acquisition: MP. Project administration: MP. Supervision: NRR, CK, MMH, AO, MP. Writing – original draft: KFK, JL, PC, MP. Writing – review & editing: KFK, JL, NSJ, TGB, JC, MS, NS, MX, WR, NRR, AC, VS, GS, CK, AB, AAJ, MMH, PC, AO, MP.

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Correspondence to Mikael Palner.

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MP has an ongoing research collaboration with Compass Pathways LTD and holds stock in Compass Pathways LTD. AAJ is co-founder and co-owner of the company Lophora ApS. The other authors declare no competing interests.

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Kiilerich, K.F., Lorenz, J., Scharff, M.B. et al. Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats. Mol Psychiatry 28, 3829–3841 (2023). https://doi.org/10.1038/s41380-023-02280-z

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