GH001 vs Placebo in Patients With Treatment-Resistant Depression A Randomized Clinical Trial

Eighty-one patients were randomised and all completed the placebo-controlled part of the trial: 40 received GH001 and 41 received placebo. Baseline characteristics were similar between groups. In the GH001 arm, 9 patients received only the 6 mg dose, 21 received 6 mg and 12 mg, and 10 received all three doses. The median duration of psychoactive effect was brief, ranging from 9.0 to 14.0 minutes across GH001 doses. Placebo recipients received three placebo doses, and although none had a peak experience, all had some measurable psychoactive-effect score above zero. The primary outcome favoured GH001. Change in MADRS from baseline to day 8 was significantly greater with GH001 than placebo, with a least squares mean difference of -15.5 points (SE 1.7; P < .001; effect size -2.0). Remission at day 8 occurred in 23 of 40 patients (57.5%) in the GH001 group and 0 of 41 patients in the placebo group. The paper also reports improvements in anxiety, global severity, and quality of life, although the extracted text does not provide the full numerical results for all secondary outcomes in the main body here. The authors describe these secondary findings as large. Safety during the placebo-controlled period was broadly acceptable but not free of adverse events. Treatment-emergent adverse events occurred in 29 of 40 GH001-treated patients (72.5%) and 3 of 41 placebo-treated patients (7.3%). The extracted text does not clearly list the full set of most common adverse events, although nausea is mentioned as one of them. There were no severe or serious adverse events in the placebo-controlled period, no suicidality signal judged to be treatment-emergent in the GH001 group, and no suicide behaviours were reported in either group. Most patients were rapidly discharge-ready after dosing, with only one GH001-treated patient not meeting discharge readiness at 1 hour post-dose. In the 6-month open-label extension, all 23 patients who entered remission on day 8 had originally received active GH001 in part 1. Three of these 23 patients (13%) remained in remission without additional treatment across the follow-up. Among the 20 who met retreatment criteria, the median time to first retreatment was 6 weeks, and most required 3 to 4 retreatments. At the final assessment, the mean MADRS score among the 23 day-8 remitters was 7.2. Overall, 20 of 23 patients (87.0%) who remitted in part 1 were in remission at the end of 6 months. No serious treatment-related adverse events were reported during the extension, and the extracted text states there was no evidence of tolerance, although the sentence is truncated.

The authors interpret the placebo-controlled findings as showing that a single-day individualised dosing regimen of inhaled GH001 produced rapid and clinically meaningful improvement in depressive symptoms in TRD. They emphasise the size of the day-8 MADRS advantage over placebo and note that GH001 also improved anxiety, global illness severity, and patient-reported quality of life. They present the magnitude of symptom reduction as comparing favourably with results reported in earlier TRD studies of other interventions, including esketamine, olanzapine/fluoxetine, electroconvulsive therapy, and repetitive transcranial magnetic stimulation, while acknowledging that direct comparisons are difficult because trials differ in design, duration, and patient characteristics. The authors argue that the short psychoactive effect, rapid discharge readiness, and lack of serious adverse events in part 1 support GH001’s tolerability and possible clinical usefulness. They also interpret the open-label extension as suggesting that remission may be sustained over 6 months with relatively infrequent retreatment, although they describe this as an initial finding. They note that the absence of planned psychotherapy may have reduced expectancy and performance bias, and they view the use of the MGH-SAFER interview and the relatively low prior psychedelic exposure in the sample as strengths. Several limitations are highlighted. The psychoactive effects of GH001 would be difficult to mask fully, so functional unblinding may have influenced perceived benefit or response. Although remote MADRS ratings were performed by blinded independent raters who were separated from treatment administration and safety monitoring, the authors say future studies should formally assess blinding integrity. They also note that the sample included relatively few patients with very extensive treatment resistance or long-standing chronic illness, that the Phase IIb sample size was insufficient for robust subgroup analyses, and that the short double-blind period limits comparison with longer TRD trials. The authors conclude that future research should include patients with more advanced illness and should further evaluate durability and safety.