Pharmacological and behavioral effects of tryptamines present in psilocybin-containing mushrooms

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 compounds 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. HIGHLIGHTSO_LIBaeocystin, norbaeocystin, and aeruginascin may have similar therapeutic value to psilocybin, but are understudied C_LIO_LICompound stability varied widely, with dephosphorylated forms showing lowest stability C_LIO_LIRates of metabolism by alkaline phosphatase and monoamine oxidase were similar across compounds C_LIO_LIBlood brain barrier penetration was limited to dephosphorylated forms of psilocybin, baeocystin, and norbaeocystin C_LIO_LIRat behavioral testing suggested norbaeocystin may have therapeutic utility similar to psilocybin, without causing hallucinations C_LI