Pharmacological and behavioral effects of tryptamines present in psilocybin-containing mushrooms
Ryan J. Rakoczy, Grace N. Runge, Abhishek K. Sen, Oscar Sandoval, Quynh Nguyen, B. Roberts, Jon H. Sciortino, William E. Gibbons, Lucas M. Friedberg, J. Andrew Jones, Matthew S. Mcmurray
bioRxiv (Cold Spring Harbor Laboratory) October 23, 2023 preprint DOI: 10.1101/2023.10.19.563138 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Comparative pharmacological and behavioral study |
|---|---|
| Population | Rats |
| Interventions | baeocystin norbaeocystin aeruginascin psilocybin |
| Topics | MDMA Psilocybin |
| Keywords | Tryptamines Hallucinogen Pharmacology |
| Key points | Norbaeocystin improved outcomes in the forced swim test in rats, similar to psilocybin, but did not induce head twitch responses, suggesting therapeutic potential without hallucinations. |
Abstract
ABSTRACT Demand for more efficacious antidepressants, particularly those with a rapid onset of action, has resulted in a reevaluation of psychedelic drugs for their therapeutic potential. Several tryptamines found in psilocybin-containing ‘magic’ mushrooms share chemical similarities with psilocybin, and early work suggests they may also share receptor targets. However, few studies have explored their pharmacological and behavioral effects. To accomplish this, we compared baeocystin, norbaeocystin, and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, penetrate the blood brain barrier, serve as ligands for similar centrally located receptors, and modulate behavior in rodents similarly. We first assessed the stability and optimal storage and handling conditions for each compound. In vitro enzyme kinetics assays then found that all compounds shared nearly identical rates of dephosphorylation via alkaline phosphatase and metabolism by monoamine oxidase. Further, we found that only the dephosphorylated products of baeocystin and norbaeocystin could cross a blood brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. Behaviorally, only psilocybin was found to induce head twitch responses in rats, a marker of 5HT2A agonism and indicator of the compound’s hallucinogenic potential. However, like psilocybin, norbaeocystin was also found to improve outcomes in the forced swim test. All compounds were found to cause minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. Collectively, this work suggests that other naturally-occurring tryptamines, especially norbaeocystin, may share the same therapeutic potential as psilocybin, but without causing hallucinations. HIGHLIGHTS Baeocystin, norbaeocystin, and aeruginascin may have similar therapeutic value to psilocybin, but are understudied Compound stability varied widely, with dephosphorylated forms showing lowest stability Rates of metabolism by alkaline phosphatase and monoamine oxidase were similar across compounds Blood brain barrier penetration was limited to dephosphorylated forms of psilocybin, baeocystin, and norbaeocystin Rat behavioral testing suggested norbaeocystin may have therapeutic utility similar to psilocybin, without causing hallucinations
Comparable studies
Other preclinical and animal studies on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice | 2021 | Observational cohort | |
| Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice | 2021 | Experimental study | |
| Psychedelics reopen the social reward learning critical period Mice | 2023 | Experimental study in mice | |
| Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice | 2020 | Experimental study with dose-response experiments | |
| Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice | 2013 | Experimental study |
Citations in the library
Cited by 2
- A scoping review of the effects of mushroom and fungus extracts in rodent models of depression and tests of antidepressant activity Frontiers in Pharmacology June 3, 2024
- From molecules to meaning: unpacking the antidepressant mechanisms of psychedelic drugs. Expert Review of Clinical Pharmacology June 11, 2025
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and 26 more in the library