Exposure‐Response Analysis to Assess the Concentration‐QTc Relationship of Psilocybin/Psilocin
Clinical Pharmacology in Drug Development – April 06, 2020
Source: OpenAlex
Summary
Psilocybin, a potent hallucinogen, shows promise as a medicine for major depressive disorder, with heart safety being a key focus in its pharmacology. Analysis revealed that even at a clinical dose of 25 mg, the mean QT interval change was only 2.1 milliseconds. Even at a supraclinical concentration of 60 ng/mL, the mean change remained low at 9.1 milliseconds. This low proarrhythmic risk is crucial for Psychedelics and Drug Studies, building on insights from traditional medicine and the chemical synthesis of such alkaloids. The short four-hour half-life prevents drug accumulation, supporting its therapeutic application.
Abstract
Abstract Psilocybin is being developed for treating major depressive disorder. Psilocybin is readily dephosphorylated to psilocin upon absorption. The potential for psilocin proarrhythmic effect was assessed using a concentration‐QTc interval (C‐QTc) analysis from an open‐label single ascending dose study of psilocybin. Psilocybin doses ranged from 0.3 to 0.6 mg/kg. This trial showed a significant but shallow C‐QTc relationship. At the clinical dose of 25 mg, the mean psilocin maximum concentration is 18.7 ng/mL, and the associated mean (upper 90% confidence interval of mean) QTcF change is 2.1 (6.6) milliseconds. Given the short half‐life of psilocin of about 4 hours, there would be no accumulation after monthly oral doses used in clinical trials. The upper limit of the 90% confidence interval of the model‐predicted mean ΔQTcF crossed 10 milliseconds at a psilocin concentration of 31.1 ng/mL. At a supraclinical psilocin maximum concentration of about 60 ng/mL, ΔQTcF remains low, with a mean (upper limit of the 90% confidence interval) of 9.1 (17.9) milliseconds. This analysis enabled the characterization of the C‐QTc relationship and prediction of QTc prolongation at the expected clinical and possible higher psilocybin doses.