Clinical Summary: Inhaled Mebufotenin (GH001) for Adult Patients With Postpartum Depression: A Phase 2a Open-Label Clinical Trial
Postpartum depression is common and can be persistent, while existing pharmacologic options may have delayed onset or practical limitations. In this phase 2a, single-arm, open-label trial, inhaled mebufotenin (GH001) was evaluated in adult female outpatients with moderate-to-severe postpartum depression using a single-day individualized dosing regimen.
Who was studied
- 10 female outpatients aged 18–45 years
- Met diagnostic criteria for major depressive disorder with peripartum onset
- >4 weeks postpartum at dosing and ≤12 months postpartum at screening
- Required baseline MADRS total score ≥28
- Mean (SD) age: 31.6 (5.2) years
- Mean (SD) duration of current depressive episode: 30.9 (12.9) weeks
- Mean (SD) baseline MADRS: 36.7 (4.8)
- Mean (SD) baseline CGI-S: 4.8 (0.79)
- Mean (SD) baseline BIMF total score: 68.8 (15.6) of 120 (n=8)
- Phase 2a, proof-of-concept, single-arm, open-label trial
- Screened at 3 sites in the United Kingdom and the Netherlands; enrolled from 1 site in the United Kingdom
- Enrollment from March 2023 to August 2024
- Primary endpoint: mean change in MADRS total score from baseline to day 8
- Follow-up visits included day 2 and day 8
- All 10 patients completed the trial
- No planned psychotherapeutic intervention before, during, or after dosing
How it was done
- Preparation. GH001 was administered by pulmonary inhalation using the Volcano Medic 2 Vaporization System. Before dosing, patients were trained in inhalation technique and prepared for possible psychoactive effects by the trial physician.
- Individualized dosing. Patients received up to 3 escalating doses on a single day: 6 mg, then 12 mg, then 18 mg, with a 1-hour interval between doses.
- Escalation decision. A second or third dose was given if the previous dose was well tolerated according to the trial physician’s judgment and if the patient had not achieved an intense psychoactive effect, defined as a mean Peak Experience Scale score ≥75.
- Disposition. Patients were discharged on the day of dosing after completing assessments and once judged discharge-ready using the Clinical Assessment of Discharge Readiness.
Dosing patterns were 6 mg alone in 1 patient, 6 + 12 mg in 7 patients, and 6 + 12 + 18 mg in 2 patients.
What happened
The primary endpoint was met. Mean (95% CI) MADRS total score change from baseline to day 8 was −35.4 points (−39.32 to −31.48; P<.0001), corresponding to an approximate 96% relative reduction from baseline. Significant MADRS reductions were also observed at 2 hours postdose and on day 2 (P<.0001 for both).
All 10 patients achieved both response and remission at 2 hours postdose, day 2, and day 8. CGI-S improved at all measured time points, with mean (SD) changes from baseline of −3.7 (0.82) at 2 hours postdose, −3.8 (0.79) at day 2, and −3.8 (0.83) at day 8. Maternal functioning improved, with mean (SD) BIMF total score increase of 34.1 (16.10) points at day 8 (n=8), an approximate 56% improvement.
Seven of 10 patients (70.0%) achieved a peak experience. Median (range) clinician-reported duration of psychoactive effects after individual doses was 22.0 (5–62) minutes after 6 mg, 25.0 (7–37) minutes after 12 mg, and 25.0 (10–40) minutes after 18 mg, with no clear dose response.
Safety
Thirteen TEAEs occurred in 8 of 10 patients (80.0%) and were mostly mild in severity (87.5%); 1 patient reported a TEAE with moderate severity. Headache was the most commonly reported TEAE (5/10 patients); all other TEAEs occurred in a single patient each. No serious TEAEs, severe TEAEs, or flashbacks were reported, and no patient withdrew.
Transient increases in blood pressure and heart rate were observed after dosing and returned spontaneously to baseline within 20–60 minutes. There were no notable or consistent changes in hematology, chemistry, urinalysis, spirometry, body weight, respiratory rate, SpO2, or body temperature, and no clinically significant abnormal laboratory shifts were identified. After psychoactive effects subsided, there was no worsening on clinician-rated dissociation or sedation measures and no consistent evidence of cognitive impairment on CANTAB tasks.
Suicidal ideation on the C-SSRS decreased from 3 patients (30.0%) at baseline to 0 at discharge, day 2, and day 8. All patients were deemed ready for discharge within the dosing day.
Breast milk analysis
Among lactating patients (n=4), mebufotenin in breast milk ranged from 0.24 to 3.11 ng/mL at 1 hour postdose and declined to below the limit of quantification (0.025 ng/mL) to 0.04 ng/mL at approximately 8 hours postdose; all levels were below the limit of quantification on days 2 and 8. Bufotenin was below the limit of quantification at all time points. 5-MIAA ranged from 13.9 to 28.5 ng/mL at 1 hour, declining to below the limit of quantification to 0.90 ng/mL at approximately 8 hours and below the limit of quantification on day 8.
What it means
These findings are preliminary. Important limitations include the small sample size (N=10), short follow-up of 1 week, lack of a control arm, and no blinding, which limit attribution of symptom change exclusively to GH001. Generalizability may also be limited because the study population was predominantly White (90%) and 9 of 10 patients were not receiving pharmacotherapy for the current depressive episode. Cross-study comparisons with other postpartum depression treatments should be made cautiously because of differences in trial populations, methods, and outcome measures.
Based on: Johnson M, Aceves Baldo P, Arbe E, et al. Inhaled mebufotenin (GH001) for adult patients with postpartum depression: a phase 2a open-label clinical trial. JCP. 2026;87(3):25m16284.
