Development of an E. coli-based norbaeocystin production platform and evaluation of behavioral effects in rats
Alexandra M. Adams, Nicholas A. Anas, Abhishek K. Sen, Jordan D. Hinegardner-Hendricks, Philip J. O’dell, William J. Gibbons, Jessica E. Flower, Matthew S. Mcmurray, J. Andrew Jones
Metabolic Engineering Communications March 11, 2022 DOI: 10.1016/j.mec.2022.e00196 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Long-Evans rats |
| Interventions | Psilocybin Norbaeocystin |
| Topics | Psilocybin |
| Keywords | Tryptamine Metabolite In vivo Pharmacology Computational biology Hallucinogen Biochemistry Biotechnology |
| Citations | 21 |
| Key findings | Norbaeocystin did not elicit a pharmacological response in rats, suggesting it may not have strong affinity for the serotonin 2A receptor. |
Abstract
Interest in the potential therapeutic efficacy of psilocybin and other psychedelic compounds has escalated significantly in recent years. To date, little is known regarding the biological activity of the psilocybin pathway intermediate, norbaeocystin, due to limitations around sourcing the phosphorylated tryptamine metabolite for in vivo testing. To address this limitation, we first developed a novel E. coli platform for the rapid and scalable production of gram-scale amounts of norbaeocystin. Through this process we compare the genetic and fermentation optimization strategies to that of a similarly constructed and previously reported psilocybin producing strain, uncovering the need for reoptimization and balancing upon even minor genetic modifications to the production host. We then perform in vivo measurements of head twitch response to both biosynthesized psilocybin and norbaeocystin using both a cell broth and water vehicle in Long-Evans rats. The data show a dose response to psilocybin while norbaeocystin does not elicit any pharmacological response, suggesting that norbaeocystin and its metabolites may not have a strong affinity for the serotonin 2A receptor. The findings presented here provide a mechanism to source norbaeocystin for future studies to evaluate its disease efficacy in animal models, both individually and in combination with psilocybin, and support the safety of cell broth as a drug delivery vehicle.
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 21
- Indole Alkaloids from Psychoactive Mushrooms: Chemical and Pharmacological Potential as Psychotherapeutic Agents Biomedicines February 5, 2023
- The evolution and ecology of psilocybin in nature. Fungal Genetics and Biology June 1, 2023
- “Biosynthesis of psilocybin and its nonnatural derivatives by a promiscuous psilocybin synthesis pathway in Escherichia coli” Biotechnology and Bioengineering June 20, 2023
- Pharmacological and behavioural effects of tryptamines present in psilocybin‐containing mushrooms British Journal of Pharmacology June 2, 2024
- “In vivo biosynthesis of N,N-dimethyltryptamine, 5-MeO-N,N-dimethyltryptamine, and bufotenine in E. coli” Metabolic Engineering May 23, 2023
and 16 more in the library
Cites 12
- Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports October 13, 2017
- Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives Metabolic Engineering March 26, 2020
- In vivo production of psilocybin in E. coli Metabolic Engineering September 21, 2019
- Synthesis and Biological Evaluation of Tryptamines Found in Hallucinogenic Mushrooms: Norbaeocystin, Baeocystin, Norpsilocin, and Aeruginascin Journal of Natural Products February 20, 2020
- Fully automated head-twitch detection system for the study of 5-HT2A receptor pharmacology in vivo Scientific Reports October 3, 2019
and 7 more in the library