Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of Subcutaneous RE104: A Double-Blind, Randomized, Single Ascending Dose Placebo-Controlled Study.
Guy Ludbrook, Nathan Bryson, Beatrix Taylor, Jasna Hocevar-Trnka, Matthew W Johnson, Joe Hirman, Glynn Morrish, Robert Alexander, Mark H Pollack
Journal of Clinical Psychopharmacology July 21, 2025 DOI: 10.1097/jcp.0000000000002047 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Double-blind, randomized, placebo-controlled, phase 1 study Peer reviewed |
|---|---|
| Sample size | 48 |
| Population | Healthy adult participants with prior experiences with hallucinogenic or psychedelic compounds |
| Intervention | RE104 |
| Dose | 5 to 40 mg |
| Topics | Psilocybin |
| Keywords | 4‑substituted tryptamines Re104 Hallucinogens Pharmacokinetics This 4-substituted tryptamine 4-substituted tryptamines Predictable absorption Safety Well-tolerated Psychedelic effects effects Mystical experiences Shorter experience Shorter than psilocin Lasting 3-4 hours Favorable therapeutic profile Dose-finding dose-finding approach Correlated with dose |
| Citations | 2 |
| Key points | Single subcutaneous doses of RE104 up to 40 mg were safe and well-tolerated, produced dose-related psychedelic effects lasting 3 to 4 hours, and showed a favorable safety profile similar to psilocybin but with shorter duration. |
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.
Comparable studies
Other randomized controlled trials on psilocybin, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety | 2016 | Randomized controlled trial | n = 51 |
| Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Patients with cancer-related anxiety and depression | 2016 | Double-blind, placebo-controlled, crossover trial | n = 29 |
| Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance Hallucinogen-naïve adults reporting regular participation in religious or spiritual... | 2006 | Double-blind study | n = 36 |
| Trial of Psilocybin versus Escitalopram for Depression Selected group of patients with depression | 2021 | Randomized controlled trial | |
| Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder Adults aged 21 to 75 years with major depressive disorder, not currently using... | 2020 | Randomized controlled trial | n = 24 |
Citations in the library
Cited by 5
- Factors Associated with Intentions to Use Psilocybin for Mental Health in Relation to Psychotherapy, Psychiatric Medications, and Natural/Synthetic Options Journal of Psychoactive Drugs September 1, 2026
- The purpose of the psychosocial protocol in the psychedelic-assisted therapy: A scoping review Journal of Psychopharmacology June 26, 2026
- Short- and Long-Acting Psychedelics: Structure-Activity Relationships, Pharmacology, and Implications for Neuropsychiatric Therapeutics. ACS Chemical Neuroscience June 17, 2026
- Next-Generation Psychedelic Drug Development ACS Chemical Neuroscience September 15, 2026
- A randomized crossover trial comparing the acute physiological and psychological effects of botanical formulations of oral psilocybin, oral psilocin, and sublingual psilocin. Journal of Psychopharmacology August 29, 2026
Cites 37
- Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial Journal of Psychopharmacology November 30, 2016
- Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial Journal of Psychopharmacology November 30, 2016
- Human hallucinogen research: guidelines for safety. Journal of Psychopharmacology July 1, 2008
- Psychedelics Promote Structural and Functional Neural Plasticity Cell Reports June 1, 2018
- Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression. New England Journal of Medicine November 3, 2022
and 32 more in the library