Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats
Kat F. Kiilerich, Joe Lorenz, Malthe B. Scharff, Nikolaj Speth, T Brandt, Julia Czurylo, Mengfei Xiong, Naja Støckel Jessen, Agata Casado-Sainz, Vladimir Shalgunov, Celia Kjærby, Grzegorz Satała, Andrzej J. Bojarski, Anders A. Jensen, Matthias M. Herth, Paul Cumming, Agnete Overgaard, Mikael Palner
January 5, 2023 preprint DOI: 10.31219/osf.io/gy6m9 via OpenAlex
Summary
AI-generated from the abstractRepeated low doses of psilocybin, a serotonergic psychedelic drug, were given to rats in a regimen that mimics human microdosing. The rats tolerated the doses well, showing no signs of anhedonia, anxiety, or altered movement. The treatment did not downregulate or desensitize the 5-HT2A receptor. It did impart resilience against stress from repeated injections and reduced self-grooming frequency, a proxy for compulsive actions. Additionally, it increased 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. These findings support anecdotal reports of benefits from psilocybin microdosing and suggest a possible physiological mechanism.
Study at a glance
| Characteristics | Experimental study |
|---|---|
| Population | Rats |
| Intervention | Psilocybin |
| Dose | low doses based on in vivo occupancy at rat brain 5-HT2A receptors |
| Topics | Psilocybin Serotonin |
| Keywords | Hallucinogen Anhedonia Psychology |
| Citations | 5 |
| Key finding | Repeated low doses of psilocybin in rats reduced stress-related behaviors and compulsive-like self-grooming, and increased 5-HT7 receptor expression and synaptic density in the paraventricular nucleus of the thalamus. |
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 often 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 using repeated low doses of psilocybin. Dosing is based on in vivo occupancy at rat brain 5-HT2A receptors. 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 receptor. 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 into the effects of repeated low doses of psilocybin. They further substantiate anecdotal reports of the benefits of psilocybin microdosing as a therapeutic intervention while pointing to a possible physiological mechanism.