Pharmacological and behavioural effects of tryptamines present in psilocybin‐containing mushrooms

Jun 2, 2024British journal of pharmacology

Drug and behavior effects of tryptamines found in psilocybin mushrooms

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Abstract

All compounds showed nearly identical rates of dephosphorylation and metabolism, indicating potential for similar biological activity.

The dephosphorylated forms of baeocystin and norbaeocystin crossed a blood-brain barrier mimetic to a similar degree as psilocybin.
Norbaeocystin activated the 5-HT receptor with similar efficacy to psilocin and norpsilocin in cell imaging assays.
Psilocybin uniquely induced head twitch responses in rats, signaling its hallucinogenic potential.
Norbaeocystin, like psilocybin, improved outcomes in the forced swim test, suggesting potential antidepressant effects.
All compounds exhibited minimal changes to renal and hepatic health metrics, indicating favorable safety profiles.

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BACKGROUND AND PURPOSE: Demand for new antidepressants has resulted in a re-evaluation of the therapeutic potential of psychedelic drugs. Several tryptamines found in psilocybin-containing "magic" mushrooms share chemical similarities with psilocybin. Early work suggests they may share biological targets. However, few studies have explored their pharmacological and behavioural effects.

EXPERIMENTAL APPROACH: We compared baeocystin, norbaeocystin and aeruginascin with psilocybin to determine if they are metabolized by the same enzymes, similarly penetrate the blood-brain barrier, serve as ligands for similar receptors and modulate behaviour in rodents similarly. We also assessed the stability and optimal storage and handling conditions for each compound.

KEY RESULTS: In vitro enzyme kinetics assays found that all compounds had 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 crossed a blood-brain barrier mimetic to a similar degree as the dephosphorylated form of psilocybin, psilocin. The dephosphorylated form of norbaeocystin was found to activate the 5-HTreceptor with similar efficacy to psilocin and norpsilocin in in vitro cell imaging assays. Behaviourally, only psilocybin induced head twitch responses in rats, a marker of 5-HT-mediated psychedelic effects and hallucinogenic potential. However, like psilocybin, norbaeocystin improved outcomes in the forced swim test. All compounds caused minimal changes to metrics of renal and hepatic health, suggesting innocuous safety profiles. 2A2A

CONCLUSIONS AND IMPLICATIONS: Collectively, this work suggests that other naturally occurring tryptamines, especially norbaeocystin, may share overlapping therapeutic potential with psilocybin, but without causing hallucinations.

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Pharmacological and behavioural effects of tryptamines present in psilocybin‐containing mushrooms

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