Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RE104: A Double-Blind, Randomized, Single Ascending Dose Placebo-Controlled Study.

A single subcutaneous dose of RE104, a prodrug of the synthetic psychedelic 4-OH-DiPT, was generally safe and well-tolerated in 48 healthy adults with prior psychedelic experience. Doses from 5 to 40 mg produced no serious adverse events or deaths; most side effects were mild to moderate and occurred under supervision. The drug appeared rapidly in the blood, with peak levels reached in 1.0 to 1.25 hours and a half-life of 2.72 to 4.12 hours. Exposure increased proportionally with dose. Plasma levels correlated with drug effects and mystical experiences, and higher doses produced more complete mystical experiences. The psychoactive experience lasted 3 to 4 hours, shorter than psilocybin, suggesting a favorable therapeutic profile.

Study at a glance

Abstract

This study is the first to formally evaluate in humans the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of RE104, a prodrug of the synthetic psychedelic known as 4-hydroxy-N,N-diisopropyltryptamine or 4-OH-DiPT. This double-blind, randomized, placebo-controlled, phase 1 study of single subcutaneous (SC) doses of RE104 (5 to 40 mg) included 6 cohorts and a total of 48 healthy adult participants with prior experiences with hallucinogenic or psychedelic compounds. SC doses of RE104 were generally safe up to 40 mg with no serious adverse events (AEs) or deaths. Most AEs occurred acutely under supervision and were mild to moderate. The Columbia-Suicide Severity Rating Scale score did not increase during the study, and the Assessment of Alertness and Sedation Scale was largely normal at all timepoints regardless of dose. RE104 exposure, based on Cmax, AUC0-t, and AUC0-inf, increased with dose from 5 to 40 mg RE104. 4-OH-DiPT appeared rapidly in plasma (median Tmax ranged from 1.0 to 1.25 hours across dose groups). Mean plasma 4-OH-DiPT t½ ranged from 2.72 hours to 4.12 hours. PKs appeared linear at the doses examined. Plasma levels of 4-OH-DiPT correlated with the Drug Effect Questionnaire and Mystical Experience Questionnaire (MEQ). Dose-related increases were observed in frequency of the MEQ 30 "complete mystical experience" responders. Single SC doses of RE104 resulted in a psychoactive experience and a favorable safety profile similar to psilocybin but with a shorter duration of psychoactive effect (3 to 4 hours). Results suggest a potential for therapeutic effect, warranting further study.