A phase 1/2 trial to assess safety and efficacy of a vaporized 5-methoxy-N,N-dimethyltryptamine formulation (GH001) in patients with treatment-resistant depression

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a serotonergic tryptamine that acts primarily at 5-HT1A and 5-HT2A receptors and, when inhaled, produces very rapid (seconds) but short-lived (minutes) psychoactive effects. Naturalistic use and observational surveys of 5-MeO-DMT (including toad-venom sources and synthetic preparations) have reported subjective improvements in well-being and reduced depressive symptoms in some users. Other serotonergic tryptamines (for example psilocybin and DMT) have shown antidepressant effects in clinical trials, but it remains unknown whether 5-MeO-DMT can produce therapeutic benefit in major depressive disorder, what dose(s) are required, and how best to manage the considerable inter-individual variability in acute effects. The authors set out to investigate safety and potential antidepressant efficacy of GH001, a vapourised pharmaceutical-grade formulation of 5-MeO-DMT, in patients with treatment-resistant depression (TRD). The trial comprised a Phase 1 component testing single doses (12 mg and 18 mg) with safety as the primary endpoint, and a Phase 2 component testing an individualized dosing regimen (IDR) of up to three escalating doses (6 mg, 12 mg, 18 mg within a single day) with the primary efficacy endpoint of remission (MADRS ≤ 10) at day 7. The IDR was motivated by short duration of 5-MeO-DMT effects and the aim to adapt dosing to individual response while limiting unnecessary high exposure.

The trial was conducted at Maastricht University (The Netherlands) with appropriate ethics and regulatory approvals and was registered on clinical trial registries. Recruitment occurred across the Netherlands and Belgium through multiple channels. Eligible participants met DSM-5 criteria for single-episode or recurrent major depressive disorder (without psychotic features) and fulfilled study criteria for TRD, including insufficient response to at least two adequate pharmacological courses or one pharmacological plus one evidence-based psychotherapy within the current episode. Additional entry requirements included a MADRS score ≥ 28 at screening (with ≤ 20% improvement allowed before dosing) and a PGI-S score ≥ 4. Exclusion criteria included current or past psychotic disorders, bipolar disorder (or immediate family history), several other psychiatric diagnoses judged to render participation unsuitable, past significant adverse reaction or non-response to psychedelic/dissociative drugs, significant medical contraindications, and suicidality as assessed clinically. Participants on psychoactive medications underwent taper and washout prior to dosing. The extracted text does not fully report some baseline participant characteristics that were said to be summarised in a table. Phase 1 was an open-label, single-arm, single-dose design with two groups (n = 4 per group) receiving 12 mg or 18 mg GH001 via inhalation. Phase 2 was an open-label, single-arm IDR design (n = 8) in which participants could receive up to three escalating doses (6 mg, then 12 mg, then 18 mg) spaced 3 hours apart within a single day; dose escalation was contingent on not having achieved a predefined ‘peak experience’ (PE), tolerability, and agreement by participant and clinician. A proprietary Peak Experience Scale (PE Scale) averaged three 0–100 visual analogue items (intensity, loss of control, profoundness); a PE was defined as an average score ≥ 75. Participants were informed that doses were active but were not told the specific identity or amount until study completion. No formal psychotherapeutic interventions (preparation, guided session, integration) beyond standard consent, a comfortable environment, and availability of medical/psychological support were provided. GH001 (synthetic GMP 5-MeO-DMT) was administered via the Volcano Medic Vaporization System; participants inhaled the generated aerosol in a single breath and were instructed to hold their breath for 10 s. The Phase 1 primary endpoint was safety and tolerability, evaluated by adverse events, laboratory tests, vital signs, ECG, psychiatric safety scales (BPRS, C-SSRS, CADSS) and cognitive tests (PVT, DSST). The Phase 2 primary endpoint was efficacy measured as proportion of patients in remission (MADRS ≤ 10) at day 7. MADRS assessments were performed at screening, baseline, 2 h, 1 day and 7 days post-dose; at 2 h the sleep item was carried forward from baseline. MADRS interviews were conducted remotely by raters who did not witness dosing. Secondary endpoints included mean MADRS change at each post-dose time point and proportion with response (≥ 50% MADRS reduction) at day 7. Safety monitoring included continuous AE recording from after screening to study completion and coding with MedDRA version 22. No formal sample size calculation was performed for Phase 1; Phase 2 set n = 8 to provide ≥ 90% power (actual ≈ 96%) for a one-sided exact binomial test against a null remission probability ≤ 1% assuming a true remission probability of 50% with α = 0.025. Two-sided exact mid-p 95% confidence intervals were reported for remission probability. Paired t-tests compared mean MADRS scores at each post-dose time point with baseline. The study safety group (SSG), including independent experts, reviewed safety data after each part of the study.

Sixteen participants completed the study (7 females, 9 males), aged 21–51 years (median 29.5). All were reported as white. Recruitment occurred between November 2019 and September 2021 with a pause for the COVID-19 pandemic. In Phase 1, 2 of 4 participants in the 12 mg group achieved a PE (PE Scale ≥ 75) and 0 of 4 in the 18 mg group did so. In Phase 2 (IDR), 7 of 8 participants achieved a PE: six achieved a PE after the second administration (6 mg followed by 12 mg) and one after the third administration (6 mg + 12 mg + 18 mg). The intensity of psychoactive effects increased with escalation in the IDR, and mean PE scores at participants’ maximum individual dose were higher than those in the single-dose Phase 1 groups. Remission (MADRS ≤ 10) at day 7 occurred in 2 of 4 participants (50%) in the 12 mg Phase 1 group, 1 of 4 (25%) in the 18 mg Phase 1 group, and 7 of 8 (87.5%) in the Phase 2 IDR group. The IDR result met the pre-specified primary endpoint (remission probability = 0.875; 95% CI = 0.473–0.997; mid-p 95% CI = 0.520–0.994; p < 0.0001 by exact binomial test). Reported mean MADRS changes from baseline to day 7 were −21.0 (−65%) for the 12 mg group, −12.5 (−40%) for the 18 mg group, and −24.4 (−76%) for the IDR group; the IDR reduction was reported as statistically significant (p < 0.0001). All observed remissions were apparent by day 1, and 6 of the 10 remissions were already observed at the 2 h assessment. Psychiatric safety assessments (BPRS) showed a marked reduction in overall psychiatric symptom scores over the treatment week. C-SSRS and CADSS evaluations did not show clinically significant changes at post-dose time points compared with baseline. Cognitive assessments (PVT and DSST) showed no evidence of impairment. No clinically significant changes were reported in vital signs, ECGs or laboratory safety parameters. Adverse drug reactions listed were mild or moderate and resolved spontaneously; no serious adverse events (SAEs) were reported. The SSG concluded that GH001 administration via inhalation was safe and well tolerated at the investigated single doses and the IDR.

The authors interpret the findings as indicating that inhaled GH001 can be administered safely in an outpatient setting and can produce rapid, large reductions in depressive symptoms in patients with treatment-resistant depression. The individualized dosing regimen (up to three doses on a single day) produced superior clinical outcomes compared with single-dose administration in this open-label cohort: 87.5% remission at day 7 in the IDR group versus 50% and 25% in the 12 mg and 18 mg single-dose groups, respectively. The antidepressant effect emerged very quickly: all remissions were observed by day 1 and more than half of remissions (6 of 10) were already evident at the 2 h assessment. The authors note that a 1-week endpoint is consistent with draft regulatory guidance for rapid-acting antidepressants. The investigators further highlight an apparent association between PE intensity and clinical outcome. Across the cohort, 9 participants experienced a PE and 8 of those 9 achieved remission; conversely, among the 7 participants without a PE only 2 achieved remission. The authors therefore present the PE-guided IDR as a pragmatic approach to manage inter-individual variability and to increase the likelihood of inducing a therapeutically relevant acute experience while avoiding unnecessarily high dosing. With respect to safety, no severe adverse effects or clinically significant changes in psychiatric safety scales, cognitive tests, vital signs, ECG or laboratory parameters were observed, and adverse reactions were mild or moderate and self-limiting. These safety observations are presented as consistent with prior GH001 data in healthy volunteers. The authors emphasise that dosing was delivered without extensive psychotherapeutic procedures (beyond standard consent, a comfortable setting and availability of support), which they note contrasts with other psychedelic development programmes. The authors acknowledge the limited sample size and the open-label design implicitly by concluding that the promising safety and signal of efficacy warrant further clinical research. They state that these results should be confirmed in a larger patient population in a randomised, controlled clinical trial to reliably establish efficacy and safety.