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
Summary
Compellingly, repeated low doses of the serotonergic hallucinogen Psilocybin imparted stress resilience and reduced compulsive behaviors in rats, without causing anhedonia. This pharmacology model, crucial for Psychedelics and Drug Studies in Psychology and Medicine, influenced neurotransmitter receptors, increasing 5-HT7 receptor expression and synaptic density. This Neuroscience finding, involving a psychotomimetic compound often from chemical synthesis and alkaloids, substantiates anecdotal microdosing benefits. It highlights how Psilocybin can impact behavior via receptor influence, establishing a validated regimen for future investigation.
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.