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 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.

A scoping review of the effects of mushroom and fungus extracts in rodent models of depression and tests of antidepressant activity

“…The species used in all of the animal models were limited to rats and mice: we did not find instances of other rodent species that have been utilized as antidepressant screens ( Kramer et al, 1998 ; Alo et al, 2019 ). Fourteen of the studies used rats ( Matsuzaki et al, 2013 ; Minami et al, 2013 ; Tan et al, 2016 ; Liu C. et al, 2017 ; Song et al, 2017 ; Wang et al, 2017 ; Huang et al, 2020 ; Nascimento et al, 2020 ; Lin et al, 2021a ; Zhang L. et al, 2021 ; Lin et al, 2021b ; Anuar et al, 2022 ; Cheng, 2023 ; Rakoczy et al, 2023 ), while the remaining 36 studies used mice to test for antidepressant-like effects ( Zhou et al, 2005 ; Nishizawa et al, 2007 ; Koo et al, 2008 ; Singh et al, 2014 ; Tianzhu et al, 2014 ; Socala et al, 2015 ; Yao et al, 2015 ; Gupta et al, 2016 ; Huang et al, 2016 ; Nakamichi et al, 2016 ; Song et al, 2016 ; Xu, 2016 ; Bao et al, 2017 ; Liu Y. et al, 2017 ; Lin et al, 2017 ; Chiu et al, 2018 ; Mahmoudi et al, 2018 ; Ryu et al, 2018 ; Jin et al, 2019 ; Li et al, 2019 ; Song et al, 2020 ; Li H. et al, 2021 ; Li TJ. et al, 2021 ; Zhang T. et al, 2021 ; Chong et al, 2021 ; Hossen et al, 2021 ; Park et al, 2021 ; Singh et al, 2021 ; Zhao et al, 2021 ; Chou et al, 2022 ; Mi et al, 2022 ; Xin et al, 2022 ; Yu et al, 2022 ; Ezurike et al, 2023 ; Zhao et al, 2023 ; Hernandez-Leon et al, 2024 ).…”

“…The duration of drug treatment varied significantly across the studies, from acute doses with behavioural testing 30 min later ( Socala et al, 2015 ; Mahmoudi et al, 2018 ; Jin et al, 2019 ; Zhang T. et al, 2021 ; Hossen et al, 2021 ; Park et al, 2021 ; Hernandez-Leon et al, 2024 ), up to 92 days of continuous administration ( Anuar et al, 2022 ). Of the 50 studies, 13 were acute (treatment over a span of <24 h) ( Matsuzaki et al, 2013 ; Socala et al, 2015 ; Yao et al, 2015 ; Gupta et al, 2016 ; Lin et al, 2017 ; Mahmoudi et al, 2018 ; Jin et al, 2019 ; Zhang T. et al, 2021 ; Hossen et al, 2021 ; Park et al, 2021 ; Singh et al, 2021 ; Rakoczy et al, 2023 ; Hernandez-Leon et al, 2024 ), six were sub-acute (1–7 days) ( Nishizawa et al, 2007 ; Song et al, 2016 ; Bao et al, 2017 ; Nascimento et al, 2020 ; Song et al, 2020 ; Yu et al, 2022 ), and the remaining 31 studies involved chronic treatment (>7 days). The mean duration of treatment for the chronic studies was 30.4 (±16.7) days for the longest treated group in each study (some studies had varying durations of treatment depending on the group).…”

“…The modal and median periods of treatment for chronic studies were both 28 days. Rats were more likely to be treated chronically, with only two of the 14 rat studies involving acute treatment ( Matsuzaki et al, 2013 ; Rakoczy et al, 2023 ).…”

“…Twenty one of the 50 studies did not use an animal model of depression per se , and tested antidepressant activity solely with standalone antidepressant screens. This included 18 studies which used the FST and 10 that used the TST (seven studies used both); only two of these 21 studies used rats ( Matsuzaki et al, 2013 ; Rakoczy et al, 2023 ).…”

“…( Lin et al, 2017 ), and the mushroom extracts psilocybin and norbaeocystin (three doses over 24 h, 1 mg/kg, i.g.) ( Rakoczy et al, 2023 ). No antidepressant effect was observed for Collybolide (a fungal metabolite; 2 mg/kg, i.p.)…”