Journal of Medicinal Chemistry
November 20, 2023
Kaveh Matinkhoo, Lisa Yu, David Press et al.
18 citations
Psilocybin's therapeutic benefits for depression and anxiety are limited by the long duration of its psychedelic effects, driven by sustained exposure to its active metabolite psilocin. To address this, researchers synthesized and screened 28 new chemical entities, introducing various cleavable groups at the 4-hydroxy position of the indole core to alter metabolic processing. Several novel prodrugs showed altered pharmacokinetic profiles and reduced pharmacological exposure compared to psilocybin, suggesting they could maintain long-term therapeutic benefits while shortening the psychedelic experience.
Current Biology
December 9, 2025
Sarah G. Cook, Stephanie J. Lee, Emma Ference et al.
3 citations
Psilocybin activates the hypothalamic-pituitary-adrenal (HPA) axis by stimulating corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN). This activation is more pronounced in female mice and depends on serotonergic 5-HT2A and 5-HT2C receptors. The 5-HT2A receptor effects involve direct post-synaptic depolarization of CRHPVN neurons and increased presynaptic glutamate release. Psilocybin also alters how CRHPVN neurons respond to environmental changes, leading to a surprising decrease in activity that contrasts with typical stress responses. This context-specific modulation may be a key mechanism for recalibrating maladaptive stress reactivity, supporting the influence of setting on the psychedelic experience.
bioRxiv (Cold Spring Harbor Laboratory)
May 18, 2023
Sheetal A. Raithatha, Jillian M. Hagel, Kaveh Matinkhoo et al.
1 citation
preprint
Psilocybin, the prodrug of psilocin found in magic mushrooms, shows therapeutic promise for depression and anxiety but produces a psychoactive episode lasting up to 6 hours, which limits clinical use. Researchers engineered a library of 28 novel prodrug derivatives of psilocin by modifying the 4-carbon position of the indole ring. In vitro screening in human serum and cellular fractions identified 15 prodrugs that produced psilocin, notably ester and thiocarbonate-based compounds. Pharmacokinetic studies in mice showed these prodrugs yielded psilocin levels comparable to psilocybin but with reduced overall exposure and no detectable psilocin at 24 hours. Five prodrugs induced head twitch responses approaching or exceeding psilocybin, and two provided long-term anxiety relief in stressed mice. These candidates may shorten the psychedelic experience while retaining therapeutic benefits.
Research Square
March 10, 2023
Xue Chen, Jing Li, Lisa Yu et al.
An enzyme from cane toad (Rhinella marina), named RmNMT, efficiently produces N,N-dimethylated indolethylamines, including psychedelic compounds like N,N-dimethyltryptamine. Unlike similar enzymes in mammals and fungi, RmNMT is highly efficient and promiscuous, enabling the bioproduction of new-to-nature indolethylamine derivatives. N,N-Dimethylated indolethylamines showed reduced binding and activation at 5-HT1A and 5-HT2A receptors compared to primary amines, yet only these tertiary amines induced hallucinogenic behavior in mice, suggesting metabolic stability is key. This discovery establishes a platform for producing and screening novel indolethylamines for potential psychiatric medicines.