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

Ludbrook and colleagues situate RE104 within a renewed clinical interest in serotonergic hallucinogens, noting that agents such as LSD, psilocybin and related compounds produce profound alterations in perception, mood and sense of self and have shown therapeutic promise in conditions including depression, cancer-related distress and addiction. The authors explain that existing antidepressant treatments have limitations (slow onset, chronic dosing, adverse effects) and that classic psychedelics, acting principally via 5-HT2A agonism, may offer more rapid and durable effects. They also highlight an operational challenge for clinical delivery: longer acute psychoactive states (eg, psilocybin lasting 6+ hours) require extended supervised monitoring, which poses practical and cost barriers to wider use. This study was designed to be the first formal human evaluation of RE104, a water‑soluble prodrug formulated for subcutaneous (SC) injection that converts to the active psychedelic 4-OH-DiPT. The authors describe the rationale for the prodrug and SC route—to improve solubility, promote rapid and reproducible absorption, and yield a shorter, predictable psychoactive experience suitable for therapeutic use. The principal aim was to characterise safety, tolerability, pharmacokinetics (PK) and exploratory pharmacodynamics (PD) of single ascending SC doses in healthy volunteers as a bridge to clinical development for postpartum depression and other indications.

This was a double‑blind, randomised, placebo‑controlled, single ascending dose Phase I study conducted in healthy adult volunteers. Six cohorts were planned with escalating single SC doses of RE104 (initially 5 mg, then 10, 20, 30, 35 and 40 mg), each cohort intended to include six active and two placebo participants; a sentinel dosing strategy (one active, one placebo) was used at each dose level with a safety review committee (SRC) assessing safety before dosing the remaining cohort participants. Midway through the 40 mg cohort the SRC reassigned half the participants to 30 mg due to tolerability concerns observed in early 40 mg recipients. Participants were admitted to the clinical research unit the day before dosing, dosed in a fed state on day 1, discharged ~24 hours post-dose and returned for follow-up on day 10. Eligible participants were adults aged 18–65 years with at least one prior recreational experience with a hallucinogenic or psychedelic compound (excluding cannabis), no prior major adverse reaction to such drugs, and no current or past significant psychiatric disorder as assessed by structured interview. Exclusion criteria included significant medical comorbidity, personal or family history of psychotic or bipolar disorder, recent use of a wide range of psychoactive substances or medications (specified windows), pregnancy or breastfeeding, and positive screens for certain infections or drugs. Concomitant medication restrictions and other standard safety exclusions applied. Primary endpoints were safety and tolerability measures: treatment‑emergent adverse events (TEAEs), vital signs, clinical labs, ECG, neurological exam, Columbia‑Suicide Severity Rating Scale (C‑SSRS), modified Observer's Assessment of Alertness/Sedation (MOAA/S), Rey Auditory Verbal Learning Test (RAVLT) and injection site reactions. Secondary endpoints characterised PK parameters of RE104 and its active metabolite 4‑OH‑DiPT (Cmax, Tmax, t1/2, AUC0‑t, AUC0‑inf, clearance and volume metrics) using LC‑MS/MS measurement and noncompartmental analysis. Exploratory PD assessments included a modified Drug Effect Questionnaire (DEQ) item assessing how “high” participants felt and the Mystical Experience Questionnaire (MEQ30); a “complete” mystical experience was predefined as >60% total MEQ30 score. Statistical analysis was descriptive; the sample size (6 active per dose) was typical for a first‑in‑human study rather than based on a formal power calculation. Safety analyses used the all‑treated population. PK parameters were derived by noncompartmental methods; dose proportionality was assessed with a power model. Blood sampling for PK included dense early timepoints (eg, 3, 7, 15, 30, 45, 60, 75, 90 minutes and at 2, 3, 4, 5, 6, 8, 12, 16 hours on day 1 and 24 hours on day 2). Preparatory psychological support and standardised set and setting procedures (preparatory session, music, eye cover, trained session monitors) were implemented for all participants.

Forty‑eight participants were randomised and dosed: 36 received single SC doses of RE104 and 12 received placebo. All treated participants were included in the safety set; all 36 active participants were included in PK analyses. Almost all (97.9%) completed the study; one participant dosed with 10 mg RE104 was lost to follow‑up. Median age was 35 years (range 18–60) and 13/48 (27.1%) were female; the cohort was predominantly White and non‑Hispanic/Latino. Safety and tolerability: Across pooled RE104 recipients, 22/36 (61.1%) experienced TEAEs (89 events total) versus 4/12 (33.3%) in the pooled placebo group (5 events). Most TEAEs were mild or moderate and resolved. No deaths or serious adverse events (SAEs) occurred, and no participant withdrew due to a TEAE. Two participants experienced severe agitation—one after 35 mg and one after 40 mg RE104—both considered related to study drug; both events resolved on the day of dosing following non‑pharmacologic measures and administration of intravenous midazolam (1 mg in one case, 2 mg in the other). The most frequent TEAEs in the pooled RE104 group were nausea (27.8%; 10/36), sinus tachycardia (25.0%; 9/36), restlessness (19.4%; 7/36), headache (16.6%; 6/36) and agitation (11.1%; 4/36). Gastrointestinal events (diarrhoea 8.3%; vomiting/abdominal pain 5.6%) occurred only in RE104 recipients. Psychiatric TEAEs (eg, restlessness, agitation, dysphoria, anxiety, hallucination) were more frequent at higher doses (35–40 mg). Injection site reactions occurred in 7/36 (19.4%) active participants and in 1 placebo recipient; all were mild and transient. No clinically significant laboratory changes or ECG abnormalities were observed; no RE104 recipient had QTcF > 500 ms. C‑SSRS scores did not increase and MOAA/S scores indicated participants remained responsive at assessed timepoints. RAVLT scores showed no clinically meaningful changes at day 10 versus baseline. Pharmacokinetics: RE104 was absorbed rapidly (Tlag 0 hr) with median Tmax 0.25–0.50 hr and mean plasma t1/2 ≈ 0.43–0.64 hr. Geometric mean RE104 Cmax ranged from 149.756 ng/mL to 1781.941 ng/mL across doses; AUC0‑t ranged from 134.8 to 1814 h·ng/mL and AUC0‑inf ranged from 135.6 to 1814 h·ng/mL. Power model assessments yielded slope estimates between 0.8 and 1.25 with 95% CIs including 1, consistent with dose proportionality over 5–40 mg. The active metabolite 4‑OH‑DiPT appeared rapidly (Tlag 0 hr) with median Tmax 1.00–1.25 hr and mean t1/2 ≈ 2.72–4.12 hr. Geometric mean 4‑OH‑DiPT Cmax ranged from 17.175 to 274.200 ng/mL; AUC0‑t ranged from 75.29 to 1376 h·ng/mL and AUC0‑inf from 79.89 to 1405 h·ng/mL. Dose proportionality for 4‑OH‑DiPT exposures was also supported by power model results. Pharmacodynamics: Subjective drug effects measured by the modified DEQ showed a clear dose dependence. For doses ≥ 30 mg peak DEQ‑high scores ranged from 6.44 (30 mg at 1.5 hr) to 10 (40 mg at 1 hr), with mean time to peak ≈ 1.2 hr. Mean duration of experience defined by DEQ‑high > 3 ranged from 2.7 to 4.2 hours for doses ≥ 30 mg; for 30 mg mean duration was 3.6 hours and all participants at 30 mg had DEQ‑high ≤ 1 at 4 hours post‑dose. Plasma 4‑OH‑DiPT concentrations roughly correlated with DEQ and MEQ measures, with maximal subjective effect coinciding with metabolite Tmax, though subjective effects declined faster than plasma levels. On the MEQ30, the proportion of participants reporting a ‘‘complete’’ mystical experience (>60% MEQ total) increased with dose: 66.7% at 30 mg, 83.3% at 35 mg and 100% at 40 mg (per reported cohort data).

The investigators interpret these results as supporting a favourable safety and tolerability profile for single SC doses of RE104 in healthy volunteers, with most adverse events being mild or moderate, transient and consistent with the known effects of serotonergic psychedelics. They note no SAEs and no study withdrawals attributable to TEAEs. Two instances of acute severe agitation occurred at the highest doses tested (35 and 40 mg) and resolved with supportive care and benzodiazepine administration; on the basis of tolerability the team selected 30 mg as the target therapeutic dose for subsequent Phase II testing. Pharmacokinetic findings demonstrated rapid absorption of RE104 after SC dosing, rapid appearance of the active metabolite 4‑OH‑DiPT (median Tmax ~1–1.25 hr) and mean metabolite half‑life in the range of ~2.7–4.1 hours. The authors report dose‑proportional exposure across the 5–40 mg range. Pharmacodynamic assessments showed dose‑dependent subjective effects on the DEQ and an increasing frequency of complete mystical experiences on the MEQ30 at higher doses; peak subjective effects roughly coincided with metabolite Tmax, and the subjective acute experience duration at 30 mg was approximately 3.6 hours, shorter than typical reports for psilocybin. The authors position RE104 as potentially advantageous for clinical delivery because the shorter acute psychoactive window (3–4 hours at therapeutic doses) could reduce supervision time compared with longer‑acting psychedelics. They discuss mechanistic hypotheses—principally 5‑HT2A agonism and possible downstream neuroplasticity pathways (TrkB, mTOR) described for other psychedelics—but emphasise these mechanisms remain to be established for RE104 in humans. Limitations acknowledged include the absence of an active comparator for PD effects and limited participant diversity (majority White and male). The authors report that RE104 30 mg is proceeding into a randomised, active dose‑controlled Phase II trial in women with moderate‑to‑severe postpartum depression and that additional studies, including a lactation transfer study and investigations in other indications, are planned. They conclude that single SC doses of RE104 produce an acute subjective experience with a safety profile broadly similar to psilocybin but with a shorter duration of acute effect, supporting further clinical evaluation.