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.
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.
Papers cited by this study that are also in Blossom
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.
(J Clin Psychopharmacol 2025;00:000-000) S erotonergic hallucinogens, or psychedelics, such as d-lysergic acid diethylamide (LSD), mescaline, 3,4-methylenedioxymethamphetamine (MDMA), and psilocybin, induce changes in sensory perception, emotion, thought, and sense of self, leading to remodeling of mental functions.These effects have been described as an altered state of consciousness, often including a mysticaltype experience.After decades of scientific marginalization, psychedelics are now being evaluated as potential therapeutic options for a wide variety of psychiatric conditions.Psychedelic agents have shown great therapeutic promise in depression, cancer-related distress, and addiction, as well as anxiety associated with life-threatening diseases.For example, one dose of psilocybin (25 mg) combined with psychological support in participants with a treatmentresistant episode of major depressive disorder (MDD) resulted in an incidence of response of 37% and remission rate of 29% at 3 weeks and a sustained response in 20% of participants at week 12.Existing antidepressants (eg, serotonin reuptake inhibitors and serotonin and norepinephrine reuptake inhibitors) are hindered by several therapeutic limitations. These include a slow onset of response, suboptimal response rates, adverse effects that can persist with chronic dosing (eg, weight gain, sexual dysfunction), discontinuation symptoms, and a necessity for chronic administration to relieve symptoms and prevent relapse.Serotonergic psychedelic compounds may offer a solution to some of these limitations by providing rapid and long-term antidepressant effects that are mediated by 5HT2A agonism.As well as mediating the subjective psychoactive effects of classic psychedelics, agonism of the 5-HT2A receptor is also presumed to mediate the antidepressant effects. The clinical utility of psilocybin is also not without limitations. For example, this agent induces a psychoactive state that may persist for 6 or more hours.During this time, health care professionals are required to supervise patients for safety reasons, which could divert valuable medical resources when scaled up for wider use, resulting in an expensive delivery model that may limit dissemination and utilization by those in need.RE104 (5-(3-(2-diisopropylaminoethyl)-1H-indol-4oxy)-oxopentanoic acid) hydrochloride) is an investigational prodrug of the synthetic psychedelic known as 4-hydroxy-N, N-diisopropyltryptamine or 4-OH-DiPT.Anecdotal reporting indicates dose-related psychoactive effects of oral 4-OH-DiPT that last < 3 hours.It should be noted, however, that the aqueous solubility of 4-OH-DiPT itself is very limited and thus, not readily suitable for direct subcutaneous administration. A prodrug of 4-OH-DiPT was created to improve stability, solubility and absorption relative to unmodified 4-OH-DiPT.Preclinical studies demonstrated rapid enzymatic cleavage of RE104 to the active metabolite 4-OH-DiPT in vivo. RE104 can be injected subcutaneously rather than taken orally, and thereby circumvents the potential issues related to gastrointestinal tract transit time and individual variability of metabolism and food intake. A subcutaneous (SC) formulation was chosen to promote complete absorption, enable rapid conversion to the active metabolite, and ensure a short and reproducible psychoactive experience with the drug that facilitates clinical application as a therapeutic agent. RE104 is in clinical development for postpartum depression (PPD) and other neuropsychiatric indications such as adjustment disorder.The clinical study presented herein is the first to formally evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of RE104 for injection in healthy participants.
The study was approved and overseen by the Central Adelaide Local Health Network Human Research Ethics Committee . This committee is constituted and operated in accordance with the principles and requirements described in the Declaration of Helsinki
This study involved a total of 48 healthy participants (18 to 65 years of age, inclusive) with one or more prior recreational experiences with hallucinogenic or psychedelic compounds (excluding cannabis products) occurring more than 90 days before enrollment. Participants had not experienced any previous major adverse responses to a hallucinogenic or psychedelic drug (excluding cannabis) and did not have a current or history of a significant mental disorder as assessed by a Mini-International Neuropsychiatric Interview questionnaireand through interviews with a qualified clinical psychologist or psychiatrist. Key exclusion criteria included clinically significant cardiovascular, neurological, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, endocrine, or psychiatric disease; risk or history of suicidal behavior and/or suicidal ideation; personal or family history of psychotic or bipolar disorder; use of ayahuasca, kambó, yopo, ibogaine, psilocybin, dimethyltryptamine (DMT), 5methoxy-N,N-dimethyltryptamine (5-MeO-DMT), LSD, Syrian Rue, or other psychedelic agents, or use of amphetamines, opioids, or MDMA, within 90 days of screening. Additional exclusion criteria included the use of synthetic or naturally occurring cannabinoids from 28 days before study drug administration, and agreement not to use these through to end of study; a positive cotinine (a nicotine metabolite) test, alcohol breath test, or urine screen for drugs of abuse at screening and baseline; and the use of any psychoactive medication, haloperidol, any medication with monoamine oxidase (MAO) activity, or with an agent with precipitative potential for serotonin syndrome within 28 days. Participants were also excluded if they were pregnant, breastfeeding or had a positive pregnancy test at screening or on day -1; had positive results for serum hepatitis B surface antigen, hepatitis C antibody and human immunodeficiency virus testing at screening; had an eGFR at screening ≤ 60 mL/min/1.73 m 2 ; and had a positive test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; COVID-19) within 7 days of admission to the clinical research unit (CRU). Prohibited medications included prescription drugs taken within the 28 days or 5 half-lives (whichever was longer) before study drug administration, and/or use of over-the-counter medication in the 14 days or 5 half-lives (whichever was longer) before study drug administration. Exceptions included: hormonal contraceptives for women of childbearing potential ; up to 3000 mg paracetamol per day, or up to 1200 mg ibuprofen per day for a maximum of 3 days; and acute use of topical steroids.
This double-blind, randomized, placebo-controlled, single ascending dose phase 1 study included 6 cohorts of healthy participants (Study Protocol RE104-101 registered with Australian New Zealand Clinical Trial Registry as ACTRN12622000713796). The study comprised a screening period of up to 28 days followed by a treatment period, during which participants were admitted to the CRU 1 day before the dosing (d -1). On day 1, participants received the assigned SC starting dose of RE104 (starting at a dose of 5 mg in the first cohort) or placebo (Fig.) in a fed state after domiciling overnight and consuming a planned evening meal on day -1 and morning meal on day 1. Participants were discharged from the clinic on Day 2 (~24 hour post-dose) and returned to the clinic on day 10 for a follow-up visit. Ascending doses were tested in 6 placebo-controlled cohorts. Each cohort was planned to comprise 6 participants receiving RE104 and 2 receiving placebo (Fig.). A sentinel dosing strategy was utilized for the first 2 participants (n = 1 RE104; n = 1 placebo) for each dose level cohort tested. In the absence of clinically significant safety signals in sentinel participants, over a minimum 24-hour post-treatment observation period, the remaining 6 participants in the cohort (5 active treatment, 1 placebo) were then dosed. A safety review committee (SRC) reviewed safety and tolerability after completion of each cohort before moving on to the next dose level. In accordance with FDA guidelines for estimating the safe starting dose in initial clinical trials and using the noobserved-adverse-effect-level established in the RE104 nonclinical safety program, this phase 1 trial in healthy adult participants applied a 10-fold safety margin for the first cohort dosed with 5.0 mg of RE104 (FDA Guidance, 2005). The dose was then subsequently increased based on the data collected during the trial and evaluated by the SRC , which permitted dosing to continue up to 40 mg RE104. Participants in the first four cohorts received doses of 5, 10, 20, and 30 mg of RE104. Additional dose levels (cohorts 5 and 6) could be, and were, added based on emerging safety, tolerability, and PK assessments; these included 35 and 40 mg of RE104. Midway through the 40 mg cohort (cohort 6), half of the participants were reassigned to 30 mg by the SRC due to tolerability issues seen in the first 4 participants dose in the first cohort. The current standard in clinical psychedelic research is to facilitate adequate set and setting to ensure patient safety and optimal experience. "Set" and "setting" are concepts used to describe what the study participant brings to the psychedelic situation and what they find there."Set" refers to the conscious and unconscious parts of the individual leading up to the experience. This includes their beliefs, hopes, fears, traumas, personality, and temperament, as well as their expectations and fantasies about psychedelic experiences. In the context of clinical research, the study participant's attitude toward the research setting, the medication, cultural attributions to psychedelics, also constitute important parts of the study participant's set."Setting" refers to the physical space, environment, and context in which one experiences the drug's effects. Setting includes elements such as music, safety equipment, hospital, and inhabitants of the space (eg, session monitors, study staff, and study participants). The study participant's relationship with the session monitor and the study team is a primary aspect of the setting.To ensure an appropriate set all participants had a preparatory session before dosing that included psychoeducation about the possible range of experiences, potential adverse reactions, and techniques and interventions used to address them by trained session monitors. Before the study drug administration, the participants were provided with a set of headphones to listen to a pre-selected sequence of music and eye covers to ensure a setting with minimal sensory impact or disruptions. Administration of the study drug was performed under direct medical supervision and participants were accompanied by session monitors trained to provide safety oversight and support during the acute experience. Blood samples for plasma PK analysis of RE104 and 4-OH-DiPT were collected at the following timepoints: Predose; post-dose at 3, 7, 15, 30, 45, 60, 75, and 90 minutes and at 2, 3, 4, 5, 6, 8, 12, 16 (day 1); and at 24 hours (day 2). Quantification of RE104 and 4-OH-DiPT in human plasma was performed using liquid chromatography with tandem mass spectrometry (LC-MS/MS), as described in a previous publication.
The primary endpoints focused on the safety and tolerability of RE104. This included adverse events (AEs), vital signs, laboratory values, ECG, neurological examination, Columbia-Suicide Severity Rating Scale (C-SSRS), the modified Observer's Assessment of Alertness and Sedation Scale (MOAA/S), Rey auditory verbal learning test (RAVLT) and injection site tolerability. C-SSRS was assessed at screening and day -1 (to exclude participants with suicidal ideation before dosing) and the "since last visit" version was to be administered at subsequent visits (to monitor participants after dosing). The MOAA/S was used to monitor a participant's level of alertness and sedation.The secondary endpoints addressed the pharmacokinetic (PK) properties of single escalating doses of RE104 and 4-OH-DiPT. PK endpoints comprised maximum serum concentration (C max ), time to reach C max (T max ), time of last measurable concentration (T last ), half-life (t ½ ), area under the curve from time zero to infinity (AUC 0-inf ), AUC from time 0 to the last measurable concentration (AUC 0-t ), dosenormalized C max (C max /Dose), dose-normalized AUC (AUC/Dose), apparent elimination rate constant (K el ), apparent total body clearance (CL/F), and apparent volume of distribution (Vz/F). Several exploratory endpoints evaluating the initial PD effects of single escalating SC doses of RE104 were also assessed. This included the modified Drug Effect Questionnaire (DEQ), in which participants were asked to verbally Participants With RE104 5 mg TEAEs were defined as adverse events that commenced at or after the study drug administration. Treatment-related AEs were defined as AEs where the relationship to study drug was reported as respond to indicate how strongly they felt the drug effect and how high they felt on the scale of 0 to 10 after being administered the study drug.The Mystical Experience Questionnaire (MEQ 30) was used to assess mystical experience during a session across 4 domains of experience: mystical (including items concerning internal unity, external unity, noetic quality, and sacredness), positive mood, transcendence of time and space, and ineffability. The research shows that the presence and intensity of the mystical psychedelic experience is correlated with therapeutic efficacy in some studies, to include both symptom reduction and improved quality of lifealthough it has not been associated with symptom improvement in all research.A complete mystical experience is defined as > 60% of the total score (mystical, ineffability, positive mood, and transcendence of time and space domains).
Final statistical analyses were performed after database lock on April 28, 2023. The study sample size was not based on a formal power calculation but rather on generally acceptable participant numbers for a first-in-human study. A sample size of 6 healthy participants on active treatment at each dose level was thought sufficient to adequately meet the objectives of the study, to obtain initial safety and tolerability information, to estimate PK parameters, and to explore PD effects. No formal hypothesis testing was planned for this study. Statistical methods for the safety analyses were performed using the safety population (all-treated participants) and were primarily descriptive in nature. The plasma PK parameters of RE104 and its active entity 4-OH-DiPT were derived by noncompartmental analysis of the plasma concentration-time profiles. AUC 0-t was calculated according to the linear up/log down trapezoidal method using the measured concentration-time values above the lower limit of quantification (LLOQ). AUC 0-inf was calculated by combining AUC 0-t and extrapolated portion of the AUC (AUC ex- trap ). The half-lives of RE104 and 4-OH-DiPT were calculated as follows: t 1/2 = ln 2/λZ.
A total of 48 participants met the study eligibility criteria at screening. Of these, 36 participants were administered a single SC dose of RE104 and 12 participants were administered a single SC dose of matched placebo. The disposition of all study participants by treatment group is shown in Figure. All participants who received 30 mg RE104 were combined into a single treatment group and participants receiving placebo in any cohort were pooled to form a placebo group for comparison. Virtually all participants (97.9%) who were assigned to treatment and dosed went on to complete the study as planned; the exception was 1 participant who was dosed with 10 mg RE104 but was subsequently lost to follow-up (Fig.). All randomized study participants (n = 48; 100%) were treated and included in the Safety Analysis set, and all 36 participants who received RE104 were included in the PK analyses.
Demographic characteristics of age, sex, race and ethnicity were broadly consistent across all cohorts and treatment groups (Table). The median age across all participants at screening was 35 years and ranged from 18 to 60 years. Overall, 13/48 (27.1%) participants enrolled in the study were female. All female participants in this study were women of childbearing potential except one 59-year-old female participant in Cohort 6 (35 mg RE104) who was postmenopausal as confirmed by testing of FSH levels. The majority of participants were White and identified as being not of Hispanic or Latino ethnicity (both ≥ 91.7% per pooled RE104 or placebo treatment groups). Mean body weight and BMI were similar across all participants and all treatment groups.
Single SC administration of RE104 was generally safe and well-tolerated in healthy adult participants up to and including a dose of 30 mg, with no severe AEs, and no reports of significant or challenging experiences that were observed at the 2 higher doses tested (35 and 40 mg RE104). Across all participants, treatment-emergent adverse events (TEAEs) occurred in 22/36 (61.1%) of participants in the pooled RE104 group with 89 events, compared with 4/12 (33.3%) of participants with TEAEs in the pooled placebo group with 5 events (Table). Most TEAEs were mild to moderate in severity. Two participants had severe adverse events as outlined below. Regardless of severity, all TEAEs resolved. Two participants experienced adverse events of mild or moderate twitching (at 30 and 40 mg, respectively), both of which were resolved within 6 days. No participants experienced a serious AE (SAE) and no participants withdrew from the study early due to a TEAE. The frequency and number of TEAEs increased with administration of higher dose levels of RE104 (Table). Across all dose levels, the majority of TEAEs reported in participants treated with RE104 were assessed as treatmentrelated by the Investigator [79 out of 89 events were treatment-related in 21/22 (95.5%) of participants with TEAEs]. In contrast, TEAEs in half of all placebo-treated participants were assessed as treatment-related [2 out of 5 events were treatment-related events in 2/4 (50.0%) of participants with TEAEs]. The most frequent specific TEAEs in the pooled RE104 group (Table) were nausea (27.8%; 10/36 participants), sinus tachycardia (25.0%; 9/36 participants), restlessness (19.4%; 7/36 participants), headache (16.6%; 6/36 participants), and agitation (11.1%; 4/36 participants). Restlessness and agitation were only reported in participants treated with the higher dose levels (30 mg and above) of RE104. Nausea occurred at the highest frequency in participants treated with 40 mg RE104 (66.7%; 2/3 participants). In participants treated with RE104, diarrhea occurred in 8.3% (3/36) of participants and vomiting and abdominal pain in 5.6% (2/36) of participants. No TEAEs of nausea, diarrhea or vomiting or abdominal pain were reported by participants in the pooled placebo group. Psychiatric disorder TEAEs were more frequently observed in participants treated with the highest dose of RE104 (40 mg). All psychiatric TEAEs in participants treated with RE104 were related to the study drug. No psychiatric TEAEs were reported by participants in the pooled placebo group. Psychiatric TEAEs reported included restlessness (19.4%; 7/36 participants); and agitation (11.1%; 4/36 participants) were only reported in participants treated with the higher dose levels of RE104. All other psychiatric TEAEs each occurred in 1 participant only, including dysphoria (35 mg RE104), anxiety (20 mg RE104), mixed emotional and conduct disturbance (30 mg RE104), hallucination (35 mg RE104), fear and irritability (both reported with 40 mg RE104). Two participants had TEAEs of agitation, which were severe and occurred in the highest RE104 dose groups (35 and 40 mg) on day 1. Both events were considered by the investigator to be related to the study drug. In one participant, a 59-year-old female, moderate agitation began 40 minutes after receiving 35 mg of RE104, which became more severe over the subsequent hour despite administration of nonpharmacologic supportive grounding techniques. The event resolved ~2 hours post-dose shortly after receiving administration of the 1 mg intravenous midazolam. In the other participant, a 26-year-old female, mild agitation began 10 minutes after receiving 40 mg of RE104, and worsened in severity by 35 minutes, which persisted for an additional 25 minutes despite administration of supportive grounding techniques, finally resolving shortly after administration of 2 mg of intravenous midazolam. In both cases, the events resolved on the same day as dosing and both participants completed the study per protocol. Injection site reactions (ISRs) occurred in 7/36 (19.4%) participants treated with a single SC injection of 20 , 30, 35, and 40 mg of RE104, and in 1 placebo participant. The frequency of ISRs did not increase with increasing RE104 dose. All ISRs were mild and transient, and none were considered by the investigator to be clinically significant. None of the investigated safety laboratory parameters demonstrated any clinically significant change from baseline, and none met the criteria for reporting as a TEAE. There were no clinically significant ECG abnormalities noted at any time in any treatment group. No participants receiving RE104 had a Fridericia's corrected QT interval (QTcF) > 500 msec, although 1 placebo participant had a QTcF > 500 msec. There were no individual changes in QTcF > 60 msec. Nonsignificant ECG abnormalities occurred at a similar frequency in all cohorts receiving RE104, with no worsening compared with the frequency A B observed at screening/baseline and all resolved spontaneously. The frequency of nonclinically significant ECG abnormalities in the pooled placebo group was comparable to that observed with the pooled RE104 treatment group. The C-SSRS score showed no increase during the study, indicating no apparent increased risk for suicide and suicidal behavior. Assessments of MOAA/S at all timepoints were largely normal regardless of treatment (RE104 or placebo) or dose of RE104 administered, with participants responding to their names spoken in a normal tone [mean score of 5 (SD 0) and median score of 5 (minimum/ maximum = 5)]. Regardless of the treatment (RE104 or placebo) or RE104 dose administered, no clinically significant changes occurred in RAVLT recall score or in the total RAVLT score at day 10 compared with assessments conducted at day -1 and baseline. There were no clinically significant effects on vital signs that were considered treatment-related, including blood pressure effects, laboratory values, or ECG findings during the study.
RE104 was absorbed rapidly, with a T lag of 0 hour and median T max values ranging from 0.25 to 0.50 hour across dose groups. After reaching peak levels, plasma RE104 concentrations seemed to decline in a mono-exponential manner in all dose groups (Fig.). RE104 exposure, based on geometric mean C max , AUC 0-t , and AUC 0-inf , increased with dose, and was dose-proportional over the dose range studied (5 to 40 mg) (Table). Geometric mean (geometric CV%) C max , AUC 0-t , and AUC 0-inf values ranged from 149.756 (63%) to 1781.941 (19.9%) ng/mL, 134.8 (64.9%) to 1814 (15.8%) h*ng/mL, and 135.6 (64.6%) to 1814 (15.8%) h*ng/mL, respectively. Plasma RE104 t ½ (mean values ranging from ~0.43 to 0.64 h), T last (median values ranging from ~4.000 to 6.183 h), and clearance (mean values ranging from ~22 to 42 L/h) were generally similar for all doses. Dose proportionality of plasma RE104 exposure PK parameters (ie, AUC 0-inf , AUC 0-t , and C max ) was assessed using a power model. The 95% CI for the slope of the power models for AUCs and C max included 1 and the slope estimates were between 0.8 and 1.25, suggesting dose proportionality over the dose range studied (5 to 40 mg). 4-OH-DiPT appeared rapidly in plasma, with a T lag of 0.000 hour and median T max values ranging from 1.000 hour to 1.250 hours across dose groups. After reaching peak levels, plasma 4-OH-DiPT concentrations seemed to decline in a mono-exponential manner in all dose groups (Fig.). Geometric mean (geometric CV%) C max , ranged from 17.175 (30.5%) to 274.200 (9.2%) ng/mL, whereas AUC 0-t and AUC 0-inf values ranged from 75.29 (60.1%) to 1376 (54.5%) h*ng/mL, and 79.89 (59.4%) to 1405 (57.1%) h*ng/ mL, respectively (Table). Plasma 4-OH-DiPT t ½ (mean values ranging from ~2.72 to 4.12 h) and T last (median values ranging from 12.00 to 24.00 h) were generally similar for all doses. Dose proportionality of plasma 4-OH-DiPT exposure PK parameters (Table) was assessed using a power model. The 95% CI for the slope of the power models for AUCs and C max included 1 and the slope estimates were between 0.8 and 1.25, suggesting dose proportionality over the dose range studied (5 to 40 mg).
Modified Drug Effect Questionnaire Initial PD response to RE104 was determined using the modified DEQ to assess subjective experience of the strength of substance effects.Results of the modified DEQ [Item 2/ are you high right now? (DEQ-high)] over time demonstrated a strong RE104 dose-dependent effect (Fig.). For doses ≥ 30 mg RE104 peak modified DEQ-high scores ranged from 6.44 (at 1.5 h post-dose for 30 mg RE104) to 10 (at 1 h post-dose with 40 mg RE104). The mean time to peak score across these 3 highest RE104 dose levels was 1.2 hours. The mean experience duration, based on a modified DEQ-high response score of > 3, ranged from 2.7 to 4.2 hours with doses ≥ 30 mg. For all doses, with the exception of 40 mg, modified DEQ-high scores decreased to ≤ 1.5 by the 4-hour post-dose timepoint; for the 40 mg RE104-treated participants, this decrease was reached by the next assessment timepoint (at 6 h). The mean experience duration for 30 mg was 3.6 hours, and all participants at that dose had a score of ≤ 1 at 4 hours post-dose. Only 1 participant in the pooled placebo group reported a modified DEQ-high score > 3 (at 2 h post-dose on Day 1), with a duration of experience of 1 hour. Similar trends were observed with results for the modified DEQ [Item 1/feel /do you feel a drug effect right now?(DEQ-feel)] (data not shown).
Initial PD response to RE104 data was determined using the MEQ 30 to measure and assess individual episodes of mystical experience. MEQ 30 responders were defined as individuals reporting a "complete" mystical experience (defined as > 60% of MEQ 30 in the total score), a threshold which is considered to be predictive of clinical efficacy.A dose-related increase in frequency of MEQ responders was observed, with 66.7%, 83.3%, and 100% of participants in the 30, 35, and 40 mg RE104 treatment groups, respectively (Fig.).
This phase 1 study represents the first formal evaluation of the safety, tolerability, PK, and PD effects of the investigational therapy RE104 and its active entity 4-OH-DiPT in healthy adult volunteers. Safety evaluation, the primary objective of this study, demonstrated that SC doses of RE104, up to and including 40 mg, were safe, with mostly mild-to-moderate, transient TEAEs that are typical of those associated with the pharmacology of psychedelic serotonergic agonists. No participants experienced a SAE and no participants withdrew from the study early due to a TEAE. The overall safety profile of RE104 seems to be consistent with those reported for other serotonergic agonists including anxiety, nausea, headaches, and physical or psychological discomfort. The TEAEs observed are likely related to its mechanism of action rather than pleiotropic effects.No new safety signals were observed compared with the nonclinical toxicology findings for RE104 and the established clinical profile for classical psychedelics, like psilocybin.The safety of various psychedelic compounds including psilocybin was recently reviewed by Holze et al.The administration of psilocybin, LSD, and mescaline resulted in moderate blood pressure and heart rate elevations. In this study, sinus tachycardia events were asymptomatic and resolved spontaneously. In those participants who experienced sinus tachycardia, the mean duration was 74.8 minutes (range 43 to 120 min) for 30 mg RE104 (n = 4), 173.3 minutes (range 28 to 303 min) for 35 mg RE104 (n = 3) and 109.0 minutes (range 59 to 159 min) for 40 mg RE104 (n = 2). Mean heart rate increases were 23.5 beats per minute (BPM) (8 to 37 BPM) for 30 mg RE104, 31.3 BPM (24 to 42 BPM for 35 mg RE104 and 45.0 BPM (41 to 49 BPM) for 40 mg RE104 at 1 hour and less thereafter. The effects on heart rate and blood pressure were deemed not clinically significant. Laboratory safety parameters after RE104 did not show any clinically significant change from baseline, and none met the criteria for a TEAE. In the present study in healthy participants, RE104 was not associated with an increase in suicidality as assessed by C-SSRS score. RE104 was absorbed rapidly after SC administration and, after reaching peak levels, plasma RE104 declined in a mono-exponential manner with a concomitant formation of 4-OH-DiPT in all dose groups. RE104 and 4-OH-DiPT exposures seemed to be dose-proportional over the dose range 5 to 40 mg, with mean plasma t½ of RE104 and 4-OH-DiPT ranging from 0.43 to 0.64 hour and 2.72 to 4.12 hours, respectively, and clearance was generally similar for all doses. The appearance of 4-OH-DiPT was observed in the first blood sample taken at 5 minutes. Plasma levels of 4-OH-DiPT roughly correlated with the clinical assessment of drug effect by the DEQ and MEQ, with maximum drug effect occurring at the plasma peak T max levels (1 to 1.25 hour) and duration of the subjective acute experience resolved by < 4 hours for participants on ≤ 30 mg RE104. These responses were evident both in terms of whether participants felt high and whether participants provided responses meeting the threshold for a complete mystical experience after administration of RE104. The PK profile of the active entity of RE104, 4-OH-DiPT, was generally aligned with the PD profile, as demonstrated by the modified DEQ coinciding with the peak plasma concentration T max and PD effects. However, the subjective drug effect declined faster than the plasma levels of 4-OH-DiPT. Within this study, doses ≤ 30 mg were generally better tolerated than the higher doses of 35 and 40 mg RE104, which led to acute, severe agitation as seen in 2 participants, 1 at 35 mg and 1 at 40 mg. Similar challenging experiences have been reported to occur with other classical psychedelics including psilocybin,particularly at higher exposures. On the basis of tolerability, a single SC injection of 30 mg RE104 was selected as the target therapeutic dose and is currently under investigation in a randomized, active dosecontrolled, phase 2 trial in adult women with moderate-tosevere PPD. This dose was not associated with any serious AEs or reports of significant or challenging experiences (as noted at the 2 higher doses evaluated) and was sufficient to achieve a complete mystical experience in a majority of participants (6/9, 67%), suggesting an appropriate balance of safety, tolerability and potential for therapeutic effect, and supporting selection of this dose for future clinical proof-of-concept study.At this dose, the mean acute experience duration was 3.6 hours, a convenient interval for clinical safety monitoring, representing a 50% reduction in acute psychoactive experience duration relative to historical, although not direct comparative evidence with psilocybin (6 to 8 hour).The molecular mechanisms of RE104 in achieving its pharmacodynamic effects are unclear. However, agonism of the 5-HT2A receptor presumably mediates not only the hallucinogenic effects but also the antidepressant effects of serotonergic psychedelics.In addition, various psychedelic compounds have been shown to promote neuritogenesis, spinogenesis, and synaptogenesis as evidenced by increased dendritic arbor complexity, promote dendritic spine growth, and stimulate synapse formation in the rat cortex.The structural changes in the pre-frontal cortex after psychedelics are not only associated with serotonin 5-HT 2A receptor agonism but also a stimulation of the signaling pathways involved tropomyosin receptor kinase B (TrkB) (functioning as a receptor for brain-derived neurotrophic factor) and mammalian target of rapamycin (mTOR).It remains to be determined whether such effects occur in humans and mediate the antidepressant response, or whether RE104 shares these mechanisms of action. Limitations of the current trial include the absence of an active comparator for the pharmacodynamic effects and a lack of diverse study participants (the majority of participants were White, identified as being not of Hispanic or Latino ethnicity, and male). Future studies will include the evaluation of a broader patient population to assess the safety and efficacy of targeted indications. This study in healthy adult volunteers showed that a single SC dose of RE104 at 30 mg was generally well-tolerated with robust pharmacodynamic (PD) effects that indicate potential for therapeutic effect in treatment trials, given that the intensity and quality of the subjective drug experience may be predictive of treatment response to psilocybin therapy in depression.RE104 at 30 mg is currently being evaluated for efficacy and safety when administered under health care provider supervision in patients with PPD. In addition, a clinical lactation study is underway to assess the extent of transfer of RE104 and its major metabolites into breast milk to further characterize the safety profile of RE104 in this population. Additional studies are planned for RE104 to include other neuropsychiatric indications, such as adjustment disorder in medically ill patients. In conclusion, single SC doses of RE104 resulted in an acute subjective experience and a favorable safety profile similar to that reported with psilocybin but with a shorter duration of acute psychoactive effect (3 to 4 h). Results from this study suggests that a single SC injection of RE104 30 mg is well-tolerated and manifests a potential for therapeutic effect, warranting further study.
Create a free account to open full-text PDFs.
Vollenweider, F. X., Vollenweider-Scherpenhuyzen, M. F. I., Bäbler, A. et al. · NeuroReport (1998)
Kometer, M., Schmidt, A., Bachmann, R. et al. · Biological Psychiatry (2012)
Hibicke, M., Gobbi, G. · Journal of Neuroscience (2020)
Griffiths, R. R. · Journal of Psychopharmacology (2008)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
Gasser, P., Holstein, D., Michel, Y. et al. · Journal of Nervous and Mental Disease (2014)
Zafar, R., Siegel, M., Harding, R. et al. · Frontiers in Psychiatry (2023)
Andersen, K. A. A., Carhart-Harris, R. L., Nutt, D. J. et al. · Acta Psychiatrica Scandinavica (2020)
Goodwin, G. M., Aaronson, S. T., Alvarez, O. et al. · New England Journal of Medicine (2022)
Galvão-Coelho, N. L., Marx, W., Sinclair, J. et al. · Psychopharmacology (2021)
Reiff, C. M., Richman, E. E., Nemeroff, C. B. et al. · American Journal of Psychiatry (2020)
Schindowski, E. M., Jungwirth, J., Schuldt, A. et al. · EClinicalMedicine (2023)
Johnson, M. W., Hendricks, P. S., Barrett, F. S. et al. · Pharmacology and Therapeutics (2019)
Carbonaro, T. M., Hurwitz, E., Johnson, M. W. · Psychopharmacology (2017)
Knight, G., Rucker, J., Cleare, A. J. et al. · Frontiers in Psychiatry (2022)
Davis, A. K., Streeter Barrett, F., Cosimano, M. P. et al. · Journal of Psychopharmacology (2022)
Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)
Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)
Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S. et al. · Journal of Psychopharmacology (2016)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)
Nutt, D. J., Erritzoe, D., Carhart-Harris, R. L. · Cell (2020)
Rickli, A., Moning, O. D., Hoener, M. C. et al. · European Neuropsychopharmacology (2016)
Gatch, M. B., Hoch, A., Carbonaro, T. M. · ACS Pharmacology and Translational Science (2020)