In recent years, the scientific community has turned its attention back to the potential of psychedelics as therapeutic agents, with psilocybin, a naturally occurring substance found in certain mushrooms, at the forefront of this research. A new study published in the journal Molecular Psychiatry suggests possible benefits of using psilocybin-containing mushroom extract over its chemically synthesized counterpart for the treatment of psychiatric disorders such as depression, PTSD, obsessive-compulsive disorders, and anxiety.
“My colleagues and I are very interested in the potential of psychedelics to treat serious, treatment resistant psychiatric disorders such as depression, PTSD, OCD and even schizophrenia,” said study author Bernard Lerer, a professor of psychiatry and director of the Hadassah BrainLabs Center for Psychedelic Research at Hebrew University.
“There are many anecdotal and clinical reports which suggest that extract of psilocybin-containing mushrooms may have unique effects that are qualitatively and quantitatively different from chemical psilocybin, and also some preclinical studies. This observation has important clinical implications and we wanted to test it empirically in a laboratory study.”
Current clinical research predominantly utilizes chemically synthesized versions of psilocybin. However, psilocybin-containing mushrooms contain a complex mixture of psychoactive and non-psychoactive compounds that could synergistically influence their therapeutic effects. This phenomenon, known as the “entourage effect,” suggests that the therapeutic potential of a psychedelic substance may not solely be due to its primary active ingredient (e.g., psilocybin) but also to the contribution of other compounds present in the natural source.
The entourage effect is a concept previously recognized in cannabis research, where the combined action of cannabinoids and other compounds in the plant is believed to produce more significant therapeutic effects than any single compound alone. By comparing the effects of naturally derived mushroom extract to those of chemically synthesized psilocybin, the researchers sought to uncover whether the presence of these additional compounds in the extract could offer benefits not observed with psilocybin alone.
The research was conducted using adult male C57BL/6J mice, divided into groups receiving either the mushroom extract, chemically synthesized psilocybin, or a control saline solution. Both forms of psilocybin were administered at a dose designed to be therapeutically relevant, based on equivalent dosing models between mice and humans.
To assess the immediate behavioral effects and potential neuroplasticity induced by psilocybin, the researchers employed the head twitch response (HTR) assay, a well-established method for studying the acute effects of psychedelics in mice.
Additionally, the study delved deeper into the biochemical and molecular changes potentially underpinning the therapeutic effects of psilocybin. This included analyzing the expression levels of specific synaptic proteins in the brain, which serve as markers of neuroplasticity, and conducting metabolomic analysis to explore broader metabolic changes in the frontal cortex following treatment.
When examining the effects on synaptic protein levels — a proxy for neuroplastic changes associated with long-term therapeutic benefits — the researchers found significant differences. The levels of certain synaptic proteins, such as GAP43, PSD95, synaptophysin, and SV2A, were more pronouncedly increased in various brain regions by the mushroom extract compared to synthesized psilocybin.
These proteins are crucial for synaptic growth, development, and plasticity, suggesting that mushroom extracts may promote a more robust neuroplastic response than psilocybin alone. This finding is particularly relevant to the therapeutic context, as enhanced neuroplasticity is believed to underlie the long-term benefits of psilocybin treatment for psychiatric disorders.
Furthermore, the metabolomic analysis revealed distinct metabolic changes in the frontal cortex of mice treated with the mushroom extract versus those given synthesized psilocybin or a control solution. The analysis identified specific metabolic pathways that were differentially affected by the mushroom extract, including those involved in purine metabolism, arginine and proline metabolism, and others.
These changes suggest that the mushroom extract induces a unique metabolic state in the brain, which could contribute to its therapeutic effects. Notably, the presence of additional compounds in the mushroom extract, beyond psilocybin itself, might be responsible for these distinct metabolic and protein expression patterns, hinting at a complex “entourage effect” where multiple components act synergistically.
“Our findings need to be confirmed in human studies but they do suggest that there may be therapeutic advantages to psilocybin-containing mushroom extract over chemically synthesized psilocybin, when both are administered at the same psilocybin dose,” Lerer told PsyPost.
Interestingly, the researchers observed that both the mushroom extract and synthesized psilocybin induced the head twitch response in mice, and there was no notable difference in the behavioral response between the two treatments. This finding indicates that, at a basic behavioral level, the acute effects of the substances are similar.
“We were surprised by the fact that there were no differences in the acute effect on the head twitch response between chemical psilocybin and psilocybin-containing mushroom extract while the differences emerged in terms of longer term effects on synaptic proteins and metabolomics,” Lerer said. “This has important potential clinical relevance.”
Rodents provide a highly controlled environment for experiments. Their genetic background can be precisely defined, reducing variability and enhancing the reproducibility of results. This is crucial for studies investigating complex biological processes like those affected by psychedelic compounds. Rodents also share a surprising degree of genetic and physiological similarity with humans.
While rodent studies are crucial for advancing our understanding of potential psychiatric treatments and the underlying biological mechanisms, they represent an initial step in a comprehensive research process. The findings must be interpreted with caution when applied to humans.
“As in any preclinical study, translation to humans is the major challenge,” Lerer said. “One cannot assume that mouse findings will be applicable to humans. One needs to do empirical studies.”
“Our long-term goals in this research is to understand what underlies the differences we observed between mushroom extract and chemical psilocybin. We believe that additional components of the extract, besides psilocybin and psilocin, are playing a role and our objective is to identify these components and understand what they are doing and how they do it.”
“This is a fascinating line of research with important clinical implications,” Lerer added. “We look forward to taking it from mice to humans.”
The study, “Effect of chemically synthesized psilocybin and psychedelic mushroom extract on molecular and metabolic profiles in mouse brain,” was authored by Orr Shahar, Alexander Botvinnik, Amit Shwartz, Elad Lerer, Peretz Golding, Alex Buko, Ethan Hamid, Dani Kahn, Miles Guralnick, Karin Blakolmer, Gilly Wolf, Amit Lotan, Leonard Lerer, Bernard Lerer, and Tzuri Lifschytz.
