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

Abstract

Background: Treatment-resistant depression (TRD) is a substantial public health burden, but current treatments have limited effectiveness. The aim was to investigate the safety and potential antidepressant effects of the serotonergic psychedelic drug 5-MeO-DMT in a vaporized formulation (GH001) in adult patients with TRD.

Methods: The Phase 1 part (n = 8) of the trial investigated two single dose levels of GH001 (12 mg, 18 mg) with a primary endpoint of safety, and the Phase 2 part (n = 8) investigated an individualized dosing regimen (IDR) with up to three increasing doses of GH001 (6 mg, 12 mg, and 18 mg) within a single day, with a primary endpoint of efficacy, as assessed by the proportion of patients in remission (MADRS ≤ 10) on day 7.

Results: Administration of GH001 via inhalation was well tolerated. The proportion of patients in remission (MADRS ≤ 10) at day 7 was 2/4 (50%) and 1/4 (25%) in the 12 mg and 18 mg groups of Phase 1, respectively, and 7/8 (87.5%) in the IDR group of Phase 2, meeting its primary endpoint (p < 0.0001). All remissions were observed from day 1, with 6/10 remissions observed from 2 h. The mean MADRS change from baseline to day 7 was -21.0 (-65%) and - 12.5 (-40%) for the 12 and 18 mg groups, respectively, and - 24.4 (-76%) for the IDR.

Conclusion: Administration of GH001 to a cohort of 16 patients with TRD was well tolerated and provided potent and ultra-rapid antidepressant effects. Individualized dosing with up to three doses of GH001 on a single day was superior to single dose administration.Clinical Trial registration: Clinicaltrials.gov Identifier NCT04698603.

Keywords: 5-MeO-DMT; clinical trial; individualized dosing; psychedelics; treatment-resistant depression.

Conflict of interest statement

JRe and JRa are scientific consultants to GH Research. TT is an employee and shareholder of GH Research. The authors declare that this study received funding from GH Research. The funder had the following involvement in the study: study design, data analysis and preparation of the manuscript. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2023 Reckweg, van Leeuwen, Henquet, van Amelsvoort, Theunissen, Mason, Paci, Terwey and Ramaekers.

Figures

Figure 1

Upper panel (A) shows a diagram of participant flow. The lower panel (B) shows the flow of study assessments from pre-screening (Visit A) through Screening (Visit B), Baseline (Visit C1), after administration (Visit C2), 1 day follow-up (Visit D) to the 7 day follow-up (Visit E). Aside from the Montgomery-Åsberg Depression Rating Scale (MADRS), other scales included C-SSRS, BPRS, and CADSS, while the latter was limited to visits (C) pre and post, D and E. Vital signs included measures of heart rate and blood pressure as detailed in the Supplementary appendix. Measures of cognition included the PVT and DSST. All assessments at Visit C2 were taken between 1–3 h (D0-H2) after administration of GH001, as detailed in the Supplementary appendix. The peak experience (PE) rating was assessed through the Peak Experience Scale.

Figure 2

Mean (SE) and individual retrospective ratings of the acute psychedelic experience assessed with the Peak Experience Scale (PES) after single doses of 12 and 18 mg of GH001 and after the individualized dosing regimen (IDR).

Figure 3

Panel (A) shows remission, response and improvement rates after single doses of GH001 and after an individualized dosing regimen (IDR) of GH001. Panel (B) shows mean (SE) of the Montgomery-Åsberg Depression Rating Scale (MADRS) ratings at screening (S), at baseline before dosing (D0-B), at 2 h after dosing (D0-H2), and at 1 (D1) and 7 (D7) days follow-up in the Phase 1 part (single dose) and the Phase 2 part (IDR). Grey planes indicate remission as indicated by MADRS ≤ 10. Panel (C) shows mean (SE) MADRS change from baseline at D0-H2, D1, and D7.