CNSPulse
W41

RAPID AND SUSTAINED IMPROVEMENT IN ANHEDONIA FOLLOWING INHALED MEBUFOTENIN (GH001) TREATMENT IN PATIENTS WITH TREATMENT-RESISTANT DEPRESSION

Roger McIntyre — Nathan P. Burns2, Wiesław J. Cubała3, Kelly Doolin2, Lisa Harding4, Velichka Valcheva2, Michael E. Thase5 1University of Toronto, 2GH Research, 3Medical University of Gdańsk, 4Mood Institute, Yale School of Medicine, 5Perelman School of Medicine, University of Pennsylvania, and Corporal Michael J. Crescenz VAMC

2026 ASCP Annual Meeting

Background

Anhedonia, a lack of interest or ability to feel pleasure in activities and experiences, is associated with suicide risk, functional impairment, and treatment resistance in patients with major depressive disorder (MDD). Improvement in anhedonia symptoms in patients with MDD has been associated with improvements in quality of life and physical, psychological and social functioning. GH001, a synthetic formulation of mebufotenin (5-MeO-DMT) administered via pulmonary inhalation, was evaluated for efficacy and safety in a Phase 2b clinical trial (NCT05800860) in patients with treatment-resistant depression (TRD). The trial consisted of a 7-day, randomized, double-blind, placebo-controlled part (Part 1) and a 6-month open-label extension (OLE, Part 2). GH001 showed rapid reductions in Montgomery-Åsberg Depression Rating Scale (MADRS) total scores, with a least squares mean difference of −15.5 points vs placebo at Day 8 (P < 0.001). GH001 was well tolerated. This post hoc analysis investigates GH001’s impact on anhedonia in patients with TRD.

Methods

In Part 1, patients were randomized 1:1 to receive a single-day individualized dosing regimen (IDR) of GH001 (6, 12, and 18 mg) or placebo via pulmonary inhalation. In the OLE (Part 2), up to five GH001 IDR treatments were administered, based on the patients’ MADRS score, and safety and tolerability of previous dose(s). This trial was conducted under the supervision of qualified healthcare professionals, providing psychological support per standardof-care, but without any planned psychotherapeutic intervention before, during, or after dosing. MADRS assessments were performed at Day 1 (baseline and 2 hours post-dose), Day 2, Day 8, and all scheduled OLE visits (Day 15 and monthly up to Month 6/end of treatment). Anhedonia was assessed using the MADRS 5-item anhedonia subscale (items 1: apparent sadness; 2: reported sadness; 6: concentration difficulties; 7: lassitude; 8: inability to feel; score range: 0-30, with lower scores indicating less severe anhedonia). Clinically meaningful improvement was defined using a published minimal clinically important change (MCIC) threshold of -4.6 to -5.5 points for patients with MDD. This post hoc analysis summarizes anhedonia subscale scores descriptively (mean [SD] changes from baseline).

Results

Eighty-one patients were randomized in the double-blind part (GH001: n=40; placebo: n=41). Mean (SD) total MADRS scores at baseline were 29.0 (5.4) for GH001 and 28.2 (4.6) for placebo. Baseline anhedonia subscale scores were 17.6 (3.2) for GH001 and 17.4 (2.6) for placebo, and changes from baseline at Day 8 were −9.9 (6.6) and 0.0 (2.3), respectively. For GH001, mean changes exceeded the MCIC threshold at all post-dose time points (2 hours, Day 2, and Day 8), indicating clinically meaningful improvements. In contrast, placebo changes did not exceed the MCIC at any time point. For the OLE completers (n=63), change from baseline in MADRS anhedonia subscale score was −12.2 (4.9) at Month 6 (P < 0.001) suggesting a clinically meaningful improvement in MADRS anhedonia score was maintained at 6 months.

Conclusion

Patients with TRD receiving GH001 in Part 1 achieved rapid reductions in MADRS anhedonia subscale scores that exceeded the MCIC at all assessed time points, with sustained improvements observed in the OLE at 6 months. These findings suggest GH001 enhance patients’ ability to experience pleasure and improve overall functioning.