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 psychedelic from the tryptamine class, that primarily acts as an agonist at the 5-HT1A and 5-HT2A receptors (1, 2), and that, when delivered via pulmonary inhalation, has a rapid onset (about 5–10 s) and a short duration (about 5–30 min) of psychoactive effects (2–5). 5-MeO-DMT is a naturally-occurring substance, and it has a long history of use in naturalistic contexts, where its ability to induce altered states of consciousness (4, 6), often described as ego-dissolution and feelings of unity and connectedness with the universe, has been applied for spiritual or self-exploratory purposes (2, 7). Additionally, observational studies and a web-based survey on the naturalistic or recreational use of toad venom containing 5-MeO-DMT or synthetic 5-MeO-DMT have described subjective improvements in participant-reported measures of satisfaction with life and psychological well-being in people without an underlying mental health condition and reductions of depressive symptoms in people with self-reported depression (5, 8, 9). Further, antidepressant properties of other tryptamines such as psilocybin and DMT have been suggested in clinical populations in clinical trials (10–12). It is, however, unknown if 5-MeO-DMT might elicit therapeutic effects in mental disorders, and which doses of 5-MeO-DMT are required to occasion a therapeutic outcome.

A promising target indication for psychedelic treatment (13, 14) is treatment-resistant depression (TRD) which occurs in approximately 30 to 60% of patients with major depressive disorder (15, 16). The range is due to a lack of consensus regarding the definition for TRD. In clinical trials, an inadequate therapeutic response to at least one pharmacotherapy, one pharmacotherapy and one psychotherapy, or two pharmacotherapies within the same depressive episode has been used (17). Novel treatment options for TRD are desired, as conventional treatments appear to fail. Serotonergic psychedelics could potentially address this unmet need (14).

This study aimed to investigate the safety and efficacy of GH001, a proprietary vaporized 5-MeO-DMT formulation (GH Research, Dublin, Ireland) in patients with TRD. In the Phase 1 part of the study, TRD patients received single doses of 12 mg or 18 mg of GH001, and in the Phase 2 part, patients received an individualized dosing regimen (IDR) of up to three increasing doses of 6 mg, 12 mg, and 18 mg of GH001 within a single day. The IDR was designed (7) to control the significant inter-personal dose–response variability, which has been described for 5-MeO-DMT (8) and other serotonergic psychedelics (18, 19). The IDR is enabled by the short half-life of GH001, by its short duration of psychoactive effects and by its lack of tachyphylaxis. The short duration of psychoactive effects of GH001, together with their ineffable nature, also facilitates administration without specific psychotherapeutic interventions (preparation, guided treatment session, integration) as an integrated part of the therapeutic modality, as often done in other psychedelic development programs with psychedelic drugs inducing prolonged psychoactive effects. In the GH001 program, preparation and support is provided as part of standard medical care, and consists of standard informed consent, provision of a comfortable dosing environment, and availability of medical and psychological support throughout the study.

The study was conducted at the Faculty of Psychology and Neuroscience, Maastricht University, The Netherlands. The study was approved by the Dutch Central Committee on Research Involving Human Subjects (CCMO) and the Medical Ethics Committee of the Academic Hospital of Maastricht and Maastricht University and conducted according to the principles of Good Clinical Practice (GCP) and the code of ethics on human experimentation established by the declaration of Helsinki (1964) and amended in Fortaleza (2013). The study was registered in the Dutch CCMO-register (NL70411.068.19), EudraCT (2018-004208-20), and clinicaltrials.gov↗ (NCT04698603).

The study comprised 16 participants (7 females, 9 males), aged 21 to 51 years (median = 29.5). All participants were white and no differences between gender identity and sex assigned at birth were reported. Demographic data is summarised in Table 1. Participants were enrolled between November 2019 and September 2021, with a break in recruitment between March 2020 and June 2020 due to the COVID-19 pandemic.

Mean (SE) and individual ratings of the Peak Experience Scale (PES) are shown in Figure 2. In the Phase 1 part, 2 out of 4 patients achieved a PE (i.e., PES rating ≥ 75) in the 12 mg dose group, and 0 out of 4 patients achieved a PE in the 18 mg dose group. In the Phase 2 part, applying the IDR, 7 out of 8 patients achieved a PE, whereby 6 patients achieved a PE after the second administration (6 mg + 12 mg), and one patient achieved a PE after the third administration (6 mg + 12 mg + 18 mg). The intensity of the psychoactive effects increased with increasing dosage amounts of the IDR in the Phase 2 part, and at the maximum individual dose level, the mean PE total score was higher than in the single dose groups of the Phase 1 part.

Mean (SE) MADRS ratings in the Phase 1 and Phase 2 parts of the study are shown in Figure 3. The proportion of patients with MADRS remission (MADRS ≤ 10) at day 7 was 2 out of 4 (50%) and 1 out of 4 (25%) in the 12 mg and 18 mg groups in the Phase 1 part, respectively, and 7 out of 8 (87.5%) in the IDR group in the Phase 2 part, meeting its primary endpoint (remission probability = 0.875; 95% CI = 0.473–0.997; Mid-p 95% CI = 0.520–0.994; p < 0.0001). Of the 10 patients in the study who had a remission at day 7, 8 achieved a PE. Of the 9 patients in the study who achieved a PE, 8 had a remission at day 7, whereby the 1 patient with a PE but no remission was a patient in the Phase 2 part of the study who had received all 3 GH001 doses, and thus had maximized the potential of the IDR. Of the 7 patients in the study who did not achieve a PE, 2 had a remission at day 7. Of the 10 remissions observed at day 7, all remissions were observed from day 1, with 6 of those 10 remissions observed from 2 h after the last dose. 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. Paired t-tests revealed a significant decrease in MADRS ratings at 2 h (t = −4.71; p = 0.0022), 1 day (t = −8.08; p < 0.0001), and 7 days (t = −5.31; p = 0.0011) after single dose administrations in the Phase 1 part, and at 2 h (t = −4.88; p = 0.0018), 1 day (t = −14.54; p < 0.0001), and 7 days (t = −9.98; p < 0.0001) after administration of the IDR in Part B. The time since initial diagnosis, the time in the current episode, the total number of antidepressive treatment courses in the current episode, and the baseline severity of depression did not correlate with the rate of MADRS remissions at day 7 or the mean MADRS change from baseline to day 7.

The assessment of the BPRS, while formally a safety assessment, revealed a strong reduction of overall psychiatric symptoms after administration of GH001 throughout the treatment week. The assessments of the C-SSRS and the CADSS, which were also included as safety endpoints, did not show any clinically significant change at any post-dose assessment as compared to their values at baseline. PVT and DSST were included in order to capture potential negative effects on cognition and did not show any impairment of cognitive function. Further, no clinically significant changes in vital parameters, ECG and safety laboratory analyses were observed. A summary of these measures is provided in. Supplementary material

A summary of adverse drug reactions (ADRs) is listed in Table 2, all of them being mild or moderate and resolving spontaneously. No Serious Adverse Events (SAEs) were reported. In their assessment of the overall safety data in the context of the safety endpoints, the SSG concluded that administration of GH001 via inhalation was safe and well tolerated for the investigated single dose levels of the Phase 1 part and for the IDR of the Phase 2 part of the study and considered the endpoints met. A summary of mean (SE) systolic and diastolic blood pressure and heart rate is given in Supplementary material.

The twofold aim of this study was to assess safety and efficacy of single-day dosing of a GH001 formulation for inhaled delivery of 5-MeO-DMT in patients with TRD. In the Phase 1 part of the trial, patients with TRD received a single dose of GH001 (either 12 or 18 mg) whereas in the Phase 2 part, a flexible IDR was applied to control the inter-personal dose variability commonly observed with administration of serotonergic agents, thereby aiming to optimize the therapeutic benefit, while at the same time avoiding unnecessarily high doses. Applying the IDR, 7 out of 8 patients (87.5%) achieved remission (MADRS ≤ 10) at day 7 after GH001 dosing with a mean MADRS reduction vs. baseline of −24.4 (p < 0.0001). This was superior to the outcome achieved with single 12 mg and 18 mg doses of GH001 in the Phase 1 part of the GH001-TRD-102 trial, where 2 out of 4 patients (50%) and 1 out of 4 patients (25%) achieved a remission (MADRS ≤ 10) at day 7 after dosing, with mean MADRS reductions vs. baseline of −21.0 and −12.5, respectively.

The antidepressant effect of GH001 occurred rapidly after administration and all remissions were observed from day 1, with 6 of 10 remissions already observed from 2 h. Even with the small sample size, these findings suggest that GH001 can exert a fast and significant reduction in depressive symptoms that can culminate in a full remission throughout 1 week after dosing. According to FDA draft guidance for industry “Major Depressive Disorder: Developing Drugs for Treatment,” a 1 week endpoint is an appropriate primary efficacy endpoint for rapid-acting antidepressants (37).

Peak experiences (i.e., PES ≥ 75) were recorded in 7 out of 8 patients in the IDR group and in 2 out of 8 patients in the single dose group. This indicates that peak psychoactive experiences are more likely to be achieved after the IDR regimen as compared to single dose administration of GH001. This finding is in line with a previous study in healthy volunteers that also reported more peak experiences in the IDR group as compared to the single dose groups (7). Importantly, the proportion of patients in remission that achieved a PE was 8 out of 10 and the proportion of patients with a PE that achieved a remission was 8 out of 9, while the proportion of patients without a PE that achieved a remission was only 2 out of 7. This supports that the magnitude of a psychedelic experience is a strong predictor of a positive therapeutic response in patients suffering from depression (10, 26, 38). No patient with a PE and less than 3 doses failed to achieve a remission, validating the IDR from a clinical dosing targeting perspective.

In this trial, no safety signals were observed in terms of any severe adverse effects, and in terms of any of the safety laboratory analyses, vital signs, psychiatric safety assessments or measures of cognitive function. In fact, assessment of the BPRS, while formally a safety assessment, revealed a strong reduction of overall psychiatric symptoms after administration of GH001 throughout the treatment week. These results are in line with safety data from a previous trial with GH001 in healthy volunteers (7), and further attest to the safety profile of the GH001 dosing approach, which is delivered in an outpatient setting with standard supportive care, but without extensive requirements for the therapeutic environment and without specific psychotherapeutic interventions before, during and after dosing, as done in other psychedelic development programs. In conclusion, administration of the inhaled GH001 formulation of 5-MeO-DMT in an outpatient setting 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 on a single day was superior to single dose administration. The finding of an antidepressant effect of GH001 in this open-label study warrants further clinical research to confirm efficacy and safety in a larger patient population as part of a randomized, controlled clinical trial.

The datasets presented in this article are not readily available because data are proprietary to GH Research. The datasets presented in this article are not readily available to protect proprietary information. Requests to access the datasets should be directed to. clinicaltrials@ghres.com

The studies involving human participants were reviewed and approved by Medical Ethics Review Committee azM/UM. The patients/participants provided their written informed consent to participate in this study.

TT and JRa were involved in designing the study. JRe, JRa, NM, TA, CH, RP, and CL were involved in data collection and study logistics. JRe, JRa, and TT were involved with data analysis, interpretation, and visualization. All authors contributed to the article and approved the submitted version.

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.

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