This Phase IIa open-label proof-of-concept trial (n=10) investigated GH001, an inhaled formulation of 5-MeO-DMT (up to 6, 12, and 18 mg), in women with postpartum depression. All patients responded and achieved remission by day 8, with effects first seen two hours after the final dose. It was well tolerated, with headache the most common mild to moderate side effect.
Papers cited by this study that are also in Blossom
Reckweg, J., Mason, N. L., van Leeuwen, C. et al. · Frontiers in Pharmacology (2021)
Objective
Postpartum depression (PPD) is a debilitating mood disorder with peripartum onset. Current treatment options are limited in PPD. GH001 is a synthetic inhalation formulation of the psychoactive molecule mebufotenin (5-MeO-DMT). This trial investigated the preliminary efficacy and safety of GH001 in adult females with PPD.
Methods
This phase 2a, proof-of-concept, open-label trial enrolled women aged 18–45 years (March 2023 to August 2024) with a Mini-International Neuropsychiatric Interview–confirmed diagnosis of major depressive disorder with peripartum onset. Patients had Montgomery-Asberg Depression Rating Scale (MADRS) scores of ≥28 at baseline. GH001 was administered as an individualized dosing regimen of up to 3 escalating doses (6, 12, and 18 mg) on day 1. The primary end point was the change in MADRS total score from baseline to day 8. Secondary end points included antidepressant response (≥50% reduction), remission (MADRS total score ≤10), and safety and tolerability of GH001.
Results
Ten patients were enrolled. Mean baseline MADRS total score was 36.7 (SD = 4.8). Mean MADRS total score change from baseline to day 8 was −35.4 points (SD = 5.5; P < .0001). All patients achieved response and were in remission on day 8, which was first observed 2 hours after their final dose on day 1. Inhalation of GH001 was well tolerated, and no serious adverse events (AEs) were reported. All treatment-emergent AEs were mild or moderate, with headache as the most frequently reported AE.
Conclusion
GH001 demonstrated rapid and significant improvements in depressive symptoms and remission of PPD with an acceptable safety profile and parallel improvements across secondary end points.
Postpartum depression is described as a common and potentially serious peripartum mood disorder that can affect maternal wellbeing, child development, and family functioning. The paper notes that existing treatments are often limited by slow onset, incomplete remission, and side effects, while the only FDA-approved medication for postpartum depression, zuranolone, is rapid-acting but appears to have relatively limited uptake in practice. The authors also frame mebufotenin (5-MeO-DMT) as a potent serotonin agonist with a short plasma half-life, and note that earlier inhaled mebufotenin studies in treatment-resistant depression suggested rapid antidepressant effects. Against that background, Johnson and colleagues set out to examine the preliminary efficacy, safety, tolerability, and functional effects of inhaled mebufotenin (GH001) in adult women with postpartum depression. This was presented as the first clinical trial of mebufotenin in this population, with additional exploratory interest in breastfeeding exposure through breast milk measurements.
This was a Phase 2a, proof-of-concept, open-label clinical trial conducted from March 2023 to August 2024. Women aged 18-45 years were enrolled if they had a Mini-International Neuropsychiatric Interview-confirmed diagnosis of major depressive disorder with peripartum onset and a baseline Montgomery-Åsberg Depression Rating Scale (MADRS) score of at least 28. The extracted text indicates that 10 patients were enrolled and that all completed the trial. The study population had moderate to severe symptoms, with a mean baseline MADRS score of 36.7. The intervention was GH001, a synthetic inhalation formulation of mebufotenin, delivered with the Volcano Medic 2 vapourisation system. Patients received an individualised dosing regimen on day 1 of up to three escalating doses: 6 mg, 12 mg, and 18 mg, with one-hour intervals between doses. A second or third dose was given only if the previous dose was tolerated and the target psychoactive effect had not yet been achieved, based on the investigators’ judgement and safety observations. Patients were trained in the inhalation technique beforehand and were supervised by qualified healthcare professionals. The trial included psychological support as standard care, but no planned psychotherapeutic intervention before, during, or after dosing. Patients were discharged on day 1 once assessments were complete and they were judged ready for discharge using the Clinical Assessment of Discharge Readiness. The primary outcome was change in MADRS total score from baseline to day 8. Secondary outcomes included MADRS change at 2 hours after the final dose and on day 2, response (at least 50% reduction in MADRS), remission (MADRS of 10 or less), Clinical Global Impression-Severity, and maternal functioning measured with the Barkin Index of Maternal Functioning (BIMF). Safety assessments included treatment-emergent adverse events, vital signs, ECG, spirometry, laboratory tests, sedation, dissociative symptoms, suicidality, psychiatric symptoms, cognition, and discharge readiness. Psychoactive effects were assessed with the Peak Experience Scale, the Challenging Experience Questionnaire, and the Mystical Experience Questionnaire. As an exploratory endpoint, the researchers measured mebufotenin, bufotenine, and 5-methoxyindole-3-acetic acid in breast milk from lactating participants. For the primary endpoint, the authors used a 1-sample t-test with a 1-sided significance level of 0.025. Secondary and exploratory outcomes were summarised descriptively. The trial had originally been powered for 15 patients, but recruitment stopped early and the final sample was 10.
Reckweg, J. T., Mason, N. L., Theunissen, E. L. et al. · Frontiers in Psychology (2025)
Barrett, F. S., Bradstreet, M. P., Leoutsakos, J. M. S. et al. · Journal of Psychopharmacology (2016)
Barrett, F. S., Johnson, M. W., Griffiths, R. R. · Journal of Psychopharmacology (2015)
Vogt, S. B., Ley, L., Erne, L. et al. · Translational Psychiatry (2023)
Strassman, R. J., Qualls, C .R. · JAMA Psychiatry (1994)
Reckweg, J., Uthaug, M. V., Szabo, A. et al. · Journal of Neurochemistry (2022)
Ten women with postpartum depression were enrolled. The mean age was 31.6 years, the mean duration of the current depressive episode was 30.9 weeks, and the mean parity was 2. Most participants were not taking antidepressants for the current episode, although 60% had previously received pharmacotherapy for earlier major depressive episodes. Baseline symptom burden was substantial, with a mean MADRS score of 36.7, a mean Clinical Global Impression-Severity score of 4.8, and a mean BIMF score of 68.8 out of 120, suggesting marked functional impairment. Dosing was completed in all participants: one received 6 mg, seven received 6 + 12 mg, and two received 6 + 12 + 18 mg. The primary endpoint was met. MADRS scores fell by a mean of 35.4 points from baseline to day 8, with a 95% confidence interval of -39.32 to -31.48 and P < .0001, corresponding to an approximate 96% relative reduction in symptom severity. Significant reductions were also seen as early as 2 hours after the final dose and on day 2. All 10 participants showed large reductions in depressive symptoms at all post-dose time points reported. Response and remission were each achieved by 100% of participants at 2 hours, day 2, and day 8. Clinical severity also improved, with mean CGI-S changes of about -3.7 to -3.8 points across the follow-up visits. Maternal functioning improved as well. Among the eight participants with BIMF data, the total score increased by a mean of 34.1 points by day 8, which the authors describe as an approximate 56% improvement. Improvements were seen across most functional areas, particularly in psychological wellbeing. For psychoactive effects, 7 of 10 participants reached a Peak Experience threshold on the Peak Experience Scale, but the Challenging Experience Questionnaire and Mystical Experience Questionnaire did not show consistent effects. Safety findings were generally favourable. Thirteen treatment-emergent adverse events occurred in 8 of 10 participants, most of them mild; only one participant had a moderate event. Headache was the most common adverse event, occurring in 5 participants. No serious, severe, or flashback-related adverse events were reported, and no one withdrew from the study. The authors report transient increases in blood pressure and heart rate after dosing that resolved within 20-60 minutes, without clinically significant trends in laboratory values, respiratory measures, or other vital signs. After psychoactive effects had subsided, there was no notable worsening on sedation, dissociation, or cognition measures. Suicidal ideation on the C-SSRS decreased from 3 participants at baseline to none at discharge, day 2, or day 8, and all participants were judged ready for discharge on the dosing day. In the exploratory breast milk analysis, four lactating participants were assessed. Mebufotenin was detectable at 1 hour after dosing but declined to below quantification, or close to it, by about 8 hours and was below quantification on days 2 and 8. Bufotenine was below quantification in all breast milk samples. 5-MIAA was also transiently detectable and was below quantification by day 8.
Johnson and colleagues interpret the findings as showing that a single-day inhaled GH001 regimen produced rapid and large antidepressant effects in women with moderate to severe postpartum depression, with the primary endpoint achieved and remission observed very early in treatment. They emphasise that the speed of symptom improvement appears faster than that reported for zuranolone and, in cross-study comparison, faster than brexanolone. They also note that the magnitude of the MADRS change compares favourably with earlier GH001 studies in treatment-resistant depression and bipolar II depression. The authors present the improvement in CGI-S, BPRS, and BIMF as supportive of a broader clinical effect, not just a change in one depression scale. They highlight the absence of serious adverse events, the lack of sedation or cognitive impairment after the acute psychoactive phase, and the fact that all participants were discharged the same day as evidence that this inhaled regimen may be feasible in clinical settings. They also interpret the breast milk results as suggesting that mebufotenin and its metabolite are rapidly cleared, potentially allowing only a brief interruption of breastfeeding around dosing. In positioning the results against earlier work, the authors contrast GH001 with SSRIs and zuranolone, noting the slower onset and other practical limitations of those treatments. They also suggest that GH001’s pharmacology, short half-life, and ultra-short psychoactive duration may fit with postpartum depression management approaches, if future trials confirm these findings. At the same time, they are careful to note important limitations: the study was small, open-label, lacked a control arm and blinding, had only one week of follow-up, and enrolled a predominantly White sample in which most participants were not taking concurrent antidepressants. They state that these factors limit the ability to attribute the observed improvements solely to GH001 and reduce generalisability. The authors also note that psychotherapeutic intervention was not part of the design, which they argue reduces expectancy-related confounding, and they call for larger, placebo-controlled trials with longer follow-up to confirm efficacy and safety. They further suggest future studies should examine mother-infant relationship outcomes and whether intermittent retreatment might be sufficient, drawing cautiously on earlier GH001 extension data in treatment-resistant depression.
The authors conclude that GH001 given as a single-day individualised inhaled regimen was well tolerated in adult women with postpartum depression and was associated with large improvements in depressive symptoms and maternal functioning over the short follow-up period. They state that these preliminary findings justify further investigation in larger, randomised, placebo-controlled trials with longer follow-up to determine longer-term efficacy and safety.