In a new study from the University of Southern Denmark, researchers have shed light on the effects of microdosing psilocybin, the active component in psychedelic mushrooms, in rats. The study offers preliminary evidence that small, regular doses of psilocybin could potentially offer therapeutic benefits, particularly in reducing stress-induced anhedonia (the inability to feel pleasure) and compulsive behaviors, without inducing significant anxiety or schizophrenic-like symptoms. The findings have been published in Molecular Psychiatry.
Psilocybin, long known for its psychedelic effects, has recently caught the attention of the scientific community for its potential in treating various psychiatric disorders. Previous studies have primarily focused on the effects of high doses of psilocybin, often used in combination with psychotherapy, to treat conditions like depression and addiction. Patients undergoing such treatments experience a controlled psychedelic episode in a supportive setting, which is then integrated into their therapy.
However, less was known about the impact of taking psilocybin in much smaller, sub-psychedelic doses, commonly referred to as ‘microdosing.’ This practice, popularized by high-performance cultures in places like Silicon Valley, has been claimed to improve mental clarity and well-being without the intense psychedelic experiences. The researchers aimed to scientifically investigate these claims and expand our understanding of psilocybin’s potential therapeutic uses.
“I have always been interested in psychedelic drugs and the serotonergic system. I did my master thesis developing radiotracers for positron emission imaging of 5-HT2A receptors. Microdosing caught my attention when I was a postdoc at Stanford University in 2012-2015,” said study author Mikael Palner, an associate professor at The Department of Clinical Research at University of Southern Denmark.
“It was a lot in the media and I knew a few people in the tech industries that were talking about it. When colleague of mine, Martin Korsbak Madsen, carried out a study in humans where they measured the 5-HT2A receptor binding of psilocybin and correlated this to the psychedelic experience, it really paved the way for a good microdosing study in rats, with a new way to define microdoses that are more scientific. Below 20% binding to the 5-HT2A receptor did not induce psychedelic effects in humans.”
The study involved 78 Long Evans rats in various experimental setups. The rats were housed under controlled conditions, and some were kept on a restrictive diet to maintain motivation for certain tests. The researchers first established what constituted a ‘microdose’ of psilocybin. They did this by administering varying doses of the substance and measuring its occupancy of a specific type of serotonin receptor in the brain (5-HT2A receptors) using positron emission tomography (PET) scans.
A dose that occupied less than 20% of these receptors without inducing overt behavioral changes was considered a microdose. This was determined to be 0.05 mg/kg of psilocybin.
Further, the team examined psilocybin’s impact on different serotonin receptors, assessing the drug’s affinity and activation potential. The behavioral effects of psilocybin microdosing were then evaluated. Rats were given a microdose every other day for 24 days, and their behaviors, such as anxiety levels, reaction to stress, and compulsive actions, were observed in both familiar and novel environments. Postmortem analyses were also conducted to examine changes in receptor expressions and synaptic protein levels.
In controlled settings, the microdosed rats did not exhibit increased anxiety or symptoms akin to schizophrenia, which are sometimes concerns with psychedelic substances. Intriguingly, a reduction in compulsive self-grooming behavior was observed. This suggests a potential impact on stress-related or compulsive behaviors.
Even in new environments, microdosed rats showed no significant increase in anxiety. They did not exhibit altered exploration behaviors in the elevated plus maze or open-field tests.
One of the most interesting findings was the increased resistance to stress-induced anhedonia. Rats receiving microdoses maintained a steady preference for sucrose, indicating that they did not lose the ability to feel pleasure, a common symptom in certain mental health disorders like depression.
“In our study we compared a group that got psilocybin injections to a group that got saline injections,” Palner said. “I was surprised that these repeated injection of saline was enough to induce anhedonia in our animals, that was not our initial hypothesis. The animals that got psilocybin did not show the same anhedonic behavior.”
The study also found no evidence of behavioral desensitization to psilocybin. This means the rats’ responses to the substance remained consistent throughout the treatment period, which is important for considering its long-term therapeutic use.
Notably, the study observed an increase in 5-HT7 receptor expression and synaptic vesicle protein 2A levels in the paraventricular thalamic nucleus of the brain. This suggests that microdosing might induce changes in synaptic connections and receptor expressions, potentially underpinning the observed behavioral changes.
“Small doses of psilocybin do have effects on the rat brain and behavior,” Palner told PsyPost. “In particular, it seems to induce stress resilience, which may be one reason why people report so varied results. Stress is a predisposition for many mental disorders and will exaggerate symptoms.”
One significant limitation is that the study was conducted on rats, not humans. While rats are a common model for understanding human biology and behavior, there are intrinsic differences between species that may affect how these findings translate to human treatments. Additionally, exploring the long-term effects and sustainability of any therapeutic benefits will be essential before considering psilocybin microdosing as a viable treatment option.
“This is a study in rats, and rats are not humans,” Palner explained. “Especially trying to say anything about mental health from studies in rats should be taken lightly. But that said, I hope it can guide future human studies. Secondly, we did not look at any possible side-effects, increased plasticity in the brain long-term may not be a good thing, and could make you vulnerable to other disorders or diseases. Otherwise, natural selection would have given us a much longer teenage period where the brain is especially adaptable.”
“I would really like to emphasize that while some people will see microdosing of psilocybin as a natural thing, it is still a drug, and we do not currently know a lot about side-effects from long term repeated use.”
The study, “Repeated low doses of psilocybin increase resilience to stress, lower compulsive actions, and strengthen cortical connections to the paraventricular thalamic nucleus in rats“, was authored by Kat F. Kiilerich, Joe Lorenz, Malthe B. Scharff, Nikolaj Speth, Tobias G. Brandt, Julia Czurylo, Mengfei Xiong, Naja S. Jessen, Agata Casado-Sainz, Vladimir Shalgunov, Celia Kjaerby, Grzegorz Satała, Andrzej J. Bojarski, Anders A. Jensen, Matthias M. Herth, Paul Cumming, Agnete Overgaard, and Mikael Palner.
