A phase 2 uncontrolled, open-label study of intranasal BPL-003 (5-methoxy-N,N-dimethyltryptamine) in patients with treatment-resistant depression

Design and setting: This completed cohort was the first of four in an ongoing open-label Phase 2a trial (NCT05660642). A single intranasal 10 mg dose of BPL-003 (5-MeO-DMT benzoate, dry powder) was administered with psychological support. The trial was conducted at King's College London's Institute of Psychiatry, Psychology and Neuroscience and at Hammersmith Medicines Research in London. The protocol had appropriate regulatory and ethics approvals and adhered to Good Clinical Practice. Participants and eligibility: Adults aged 18–75 years with MDD (DSM‑5) classified as moderate-to-severe on the Montgomery–Åsberg Depression Rating Scale (MADRS) and meeting TRD criteria (failure to respond adequately to at least two antidepressant trials) were eligible. Participants were required to be otherwise medically stable by history, examination, ECG and laboratory tests. Key exclusions included medical conditions increasing cardiovascular risk from sympathomimetic effects, current or past psychotic or bipolar disorders, recent (within 12 months) substance use disorder (other than nicotine or caffeine), prior non-response to ketamine/esketamine or to adequate electroconvulsive therapy, and use of classic psychedelics within 6 months. The extracted text notes a supplemental table with the full eligibility list. Intervention and psychological support: After screening (up to 56 days), participants underwent a washout of conventional antidepressant drugs (up to 6 weeks) such that no participant was taking antidepressants for at least 2 weeks prior to dosing. Standardised, manualised, non-directive psychological support was provided: three preparatory sessions (Days −12, −7 and −3), a supervised dosing session and three integration sessions on Days 2, 8 and 15. Dosing involved a single spray (10 mg) delivered into one nostril using a dry powder device; participants were resident at the site from the day before or the morning of dosing until at least 4 hours post-dose. The lead therapist and a support assistant were present during dosing and for 90 minutes afterwards. Assessments and endpoints: The primary endpoints were safety and tolerability assessed by adverse events (AEs/TEAEs), laboratory tests, vital signs, ECG, physical (including nasal) examinations, suicidal ideation/behaviour assessed with the Columbia‑Suicide Severity Rating Scale (C‑SSRS), and readiness for discharge measured by the Readiness for Discharge Questionnaire (RDQ). Exploratory endpoints included the Mystical Experience Questionnaire (MEQ‑30), pre-treatment expectancy measured with the Stanford Expectation of Treatment Scale (SETS), and PK (plasma 5‑MeO‑DMT at pre-dose, 5, 15 and 60 minutes). Depression-related outcomes included clinician-rated MADRS and CGI‑S, and participant-reported QIDS‑SR‑16, PGIC, Sheehan Disability Scale (SDS) and Snaith–Hamilton Pleasure Scale (SHAPS). Follow-up visits occurred every 2 weeks to Day 85 post-dose. Pharmacokinetics and analysis populations: Blood for PK was assayed by validated LC–MS/MS with a lower limit of quantification <0.5 ng/mL. Statistical analysis was exploratory and descriptive only; no formal hypothesis testing or sample-size calculation was performed. Defined analysis populations were the safety analysis set (SAS), intent-to-treat (ITT), per-protocol (PP) and PK concentration population. Analyses were performed using SAS Version 9.4.

Participants and disposition: Twelve participants were enrolled between February 2023 and February 2024. All 12 completed the trial and were included in the SAS and ITT populations; 11 were included in the PP population and 10 in the PK population. Two participants were excluded from PK analyses due to cannula malfunction. One participant was excluded from the PP population for major protocol deviations (ongoing suicidal ideation at screening and undisclosed regular high-dose psychedelics/ketamine use). Baseline characteristics: The extracted text reports the mean number of prior antidepressant trials as 3.3 lifetime (range 2–5) and 3.2 in the current episode (range 2–5). Detailed demographics are in a supplemental table that appears in the source but is not fully reproduced in the extracted text. Safety and tolerability: Ten of 12 participants (83.3%) experienced 26 TEAEs: 12 were mild, 13 moderate and one severe (treatment-related increased systolic blood pressure). The most frequent TEAEs were nausea (4 participants, 33.3%), nasal discomfort (4 participants, 33.3%), vomiting (3 participants, 25.0%) and suicidal ideation (2 participants, 16.7%). Nine participants (75.0%) experienced 18 TEAEs judged treatment-related (eight mild, nine moderate, one severe). Most treatment-related TEAEs (16/18) began and resolved on the day of dosing. Transient increases in systolic and diastolic blood pressure and heart rate peaked at 10 minutes post-dose and returned near baseline by 60 minutes. Peak post-dose systolic blood pressure ranged from 148 to 226 mmHg; the single severe event (226 mmHg) occurred in a participant with elevated pre-dose blood pressure, was asymptomatic, resolved during observation and required no intervention. There were no serious TEAEs or withdrawals. One participant experienced an adverse event of special interest—moderate auditory pseudo-hallucinations on Day 2 lasting 1 day—which was considered probably related but not clinically significant. No clinically significant laboratory, nasal physical or ECG abnormalities were reported. Readiness for discharge: 10 of 12 participants were ready for discharge at the first RDQ assessment (nominal 90 minutes post-dose); median time to discharge readiness was 98.4 minutes (range 95–167). Pharmacokinetics: In the PK population (N = 10), 5‑MeO‑DMT was measurable in all participants at 5 minutes post-dose (mean 18.4 ng/mL, range 4.15–42.5). Mean concentrations were 21.1 ng/mL at 15 minutes (range 9.5–38.4) and fell to a mean of 3.8 ng/mL (range 1.0–7.0) by 60 minutes. Depression-related clinical outcomes (PP unless stated): On the MADRS, mean baseline total score was 27.5 (moderate). Mean decreases from baseline across all post-dose timepoints (Days 2–85) ranged from 12.2 to 13.0 points. Mean total MADRS was 14.8 on Day 2 and 14.5 on Day 85. On Day 2, six participants (54.5%) had a ⩾50% decrease from baseline and four (36.4%) were in remission (MADRS ⩽10). Across post-dose assessments, ten participants (90.9%) met the criterion of a ⩾50% decrease at one or more timepoints, and seven participants (63.6%) were in remission at one or more timepoints. CGI‑S scores declined from a mean of 4.3 at baseline to 2.5 on Day 2 and remained ⩽3 (mildly ill) for the study duration. QIDS‑SR‑16 scores fell from a mean baseline of 14.1 to about 7.0 on Day 8 and remained ≤7.7 through follow-up (highest individual score during Days 29–85 was 21). On the PGIC at Day 85, 9 of 10 analysed participants (90%) reported improvement; 5 (50% of those analysed) reported much or very much improvement. Mean change in PGIC at Day 85 was −1.6. Function and anhedonia: The mean SDS total score decreased from 18.0 at baseline to 9.7 at Day 29, with mean decreases of 8.7–10.0 points (48%–53%) maintained through Days 29–85. SHAPS scores showed large reductions from a baseline mean of 8.4, with mean changes ranging −4.7 to −6.5 on Days 29, 57 and 85; the Day 85 mean SHAPS score was 1.5, below the threshold indicating absence of anhedonia. Subjective experience and expectancy: MEQ‑30 total scores ranged from 0.53 to 5 (mean 2.7); 3 participants (25%) met criteria for a complete mystical experience (⩾60% on all four subscales). SETS scores showed higher positive than negative expectancies (mean positive 2.9, negative 1.9); two participants with the most favourable expectancy scores were among those with complete mystical experiences and were strong clinical responders.

Roberts and colleagues interpret the findings as showing rapid reductions in depressive symptoms from the day after a single 10 mg intranasal dose of BPL-003 given with psychological support, with effects that were sustained over 12 weeks in most participants. The safety and tolerability profile observed was consistent with the prior Phase I study in healthy volunteers: TEAEs were predominantly mild or moderate and clustered on the day of dosing, with nausea and nasal discomfort most common. Transient sympathetic activation (increased heart rate and blood pressure) peaked around 10 minutes post-dose and generally normalised by 60 minutes; one participant had a severe transient systolic blood pressure elevation that was asymptomatic and resolved without intervention. Two participants experienced treatment-emergent suicidal ideation that the investigators considered clinically significant but unlikely related to study treatment; both had a history of suicidal ideation prior to enrolment and recovered during the trial. The authors note consistent, clinically meaningful improvements across clinician-rated (MADRS, CGI‑S) and participant-reported measures (QIDS‑SR‑16, PGIC, SDS, SHAPS), with a high proportion of participants meeting response (⩾50% reduction) and remission criteria at one or more post-dose timepoints. MEQ‑30 data indicated that only a quarter of participants had a complete mystical experience, and clinical improvement was not limited to those individuals, suggesting that multiple mechanisms (for example, psychological flexibility, ego-dissolution, mindfulness-related processes and potential neuroplasticity effects) might contribute to benefit. The short duration of BPL-003's acute effects and the observed median readiness-for-discharge time of about 98 minutes could favour feasibility and resource efficiency in clinical implementation. The authors explicitly acknowledge important limitations: the small sample size, open-label uncontrolled design and lack of blinding make it impossible to determine causality or to separate drug effects from expectancy, the psychological support model, and contextual factors. Participants tended to have more positive than negative expectancies on the SETS, which could bias outcomes. The sample was predominantly male, middle-aged and white, limiting generalisability. Because the study was exploratory and not powered for inferential statistics, formal significance testing was not performed. The authors state that adequately powered, randomised, controlled trials with more representative samples are required to confirm efficacy and safety; such trials are planned.

Roberts and colleagues conclude that a single intranasal 10 mg dose of BPL-003 administered with psychological support was well tolerated in this small Phase 2a TRD cohort, with PK and safety findings consistent with prior healthy volunteer data. Preliminary clinical observations indicated rapid and sustained improvement in depressive symptoms over a 12‑week follow-up. The authors suggest BPL-003 may warrant further investigation as a potential treatment option for TRD and that these results support progressing to larger, randomised, controlled clinical trials.