This double-blind, randomised, placebo-controlled Phase I study (n=48) evaluates the safety, pharmacokinetics, and psychoactive effects of RE104 (psilocybin analog; Luvesilocin; a prodrug of 4-OH-DiPT) in healthy adults with prior psychedelic experience. RE104 was well tolerated up to 40 mg with no serious adverse events, and plasma levels of its active form correlated with subjective drug effect and mystical experience scores. The compound produced psilocybin-like effects with a shorter duration (3–4 hours), supporting further therapeutic investigation.
Abstract of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RE104
“Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.“
Authors: Guy Ludbrook, Nathan Bryson, Beatrix Taylor, Jasna Hocevar-Trnka, Matthew W. Johnson, Joe Hirman, Glynn Morrish, Robert Alexander & Mark Pollack
Summary of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RE104
The authors introduce RE104 as a novel investigational psychedelic compound, developed as a prodrug of 4-hydroxy-N,N-diisopropyltryptamine (4-OH-DiPT), a synthetic tryptamine with serotonergic activity. RE104 is structurally designed to be rapidly converted in the body to 4-OH-DiPT, which then exerts psychedelic effects primarily through serotonin receptor activation, particularly at the 5-HT2A receptor. Unlike psilocybin, which has shown promise in treating depression but requires extended monitoring due to its long duration of action (typically 6–8 hours), RE104 is designed to offer a shorter, more manageable psychedelic experience lasting approximately 3–4 hours.
The study sets out to address the safety, tolerability, pharmacokinetics (how the drug is absorbed, distributed, metabolised, and excreted), and pharmacodynamics (the drug’s effect on the body) of RE104 in healthy adult participants. Psychedelics like psilocybin have been shown to produce therapeutic benefits that may be linked to the intensity and quality of the subjective psychedelic experience. However, clinical implementation is hindered by long durations and resource-intensive support structures. A compound like RE104 could offer a solution by shortening the treatment window while maintaining therapeutic intensity, thus improving scalability and cost-efficiency in clinical use.
This study marks the first formal human trial of RE104 and was designed as a Phase I investigation to assess its baseline safety and psychoactive properties. Prior to this study, limited preclinical research had suggested rapid metabolism of RE104 into its active metabolite, with potential for strong receptor activity and dose-dependent psychedelic effects. The trial aimed to evaluate these properties through a tightly controlled clinical setting, using both subjective experience measures and pharmacological testing.
Methods
Study Design and Participants
Find this paper
https://doi.org/10.1097/jcp.0000000000002047
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Cite this paper (APA)
Ludbrook, G., Bryson, N., Taylor, B., Hocevar-Trnka, J., Johnson, M. W., Hirman, J., ... & Pollack, M. (2022). Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RE104: A Double-Blind, Randomized, Single Ascending Dose Placebo-Controlled Study. Journal of Clinical Psychopharmacology, 10-1097.
Study details
Compounds studied
Psilocybin
Placebo
Topics studied
Safety
Healthy Subjects
Neuroscience
Study characteristics
Original
Placebo-Controlled
Double-Blind
Randomized
Bio/Neuro
Participants
48
Humans
Compound Details
The psychedelics given at which dose and how many times
Psilocybin 5 - 40mg | 1x
Linked Clinical Trial
A Double-Blind, Randomized, Placebo-Controlled Study to Investigate the Safety, Tolerability, and Pharmacokinetics of Single, Ascending, Subcutaneous Doses of FT-104 HCl In Healthy Volunteers Safety, Tolerability, and Pharmacokinetics of Subcutaneous FT-104 HCl (SAIL-101)This double-blind, randomized, placebo-controlled study (n=48) investigates the safety, tolerability, and pharmacokinetics of single, ascending, subcutaneous doses of psilocybin (FT-104 HCl) in healthy volunteers.