2026 ECNP Congress

PS02-2130

Inhaled mebufotenin (GH001) is associated with rapid improvement in symptoms of anhedonia in treatment-resistant depression

Wiesław J. Cubała — B.T. Baune, N.P. Burns, K. Doolin, L. Harding, R.S. McIntyre, V. Valcheva, M.E. Thase · Medical University of Gdańsk, Department of Psychiatry, Gdańsk, Poland

2026 ECNP Congress

Background

Anhedonia, characterised by diminished interest or capacity to experience pleasure, is linked to increased suicide risk, impaired functioning, and treatment resistance in major depressive disorder (MDD). A domain-specific antianhedonic effect has been hypothesised for rapid-acting antidepressants such as ketamine and esketamine [1]. GH001, an inhaled formulation of mebufotenin, was evaluated in a Phase 2b trial (NCT05800860) in patients with treatment-resistant depression (TRD) [2, 3]. The trial comprised a 7-day, randomised, double-blind, placebo-controlled part and a 6-month open-label extension (OLE). GH001 demonstrated rapid reductions in Montgomery–Åsberg Depression Rating Scale (MADRS) total scores versus placebo at Day 8 (least-squares mean difference, −15.5; Cohen’s d=−2.0; P<0.0001) [2]. The median duration of psychoactive effects was 11 minutes, and at 99.0% (285/288) of treatment visits, patients were considered to be discharge ready at 1-hour post-dose on the dosing day.

Aims

This post hoc analysis investigates the effect of GH001 on symptoms of MADRS anhedonia factor in patients with TRD.

Methods

In the double-blind part, patients were randomised 1:1 to receive a single-day individualised dosing regimen (IDR) of GH001 (6, 12, and 18 mg) or placebo. In the 6-month OLE, up to five GH001 IDR treatments were administered, based on 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 standard of 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 and Day 8 after each treatment, and all scheduled OLE visits (Day 15 and monthly up to 6 months/end of treatment). Anhedonia was assessed using the MADRS 5-item anhedonia factor (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 MADRS anhedonia factor). 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 summarises MADRS anhedonia factor scores descriptively (mean [SD] changes from baseline).

Results

Eighty-one patients were randomised 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 MADRS anhedonia factor 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 timepoints (2 hours, Day 2, and Day 8), indicating clinically meaningful improvements. In contrast, placebo changes did not exceed the MCIC at any timepoint. These significant improvements were maintained at Month 6 after infrequent treatment in patients who completed the OLE (n=63; −12.2 (4.9); P<0.0001).

Conclusions

GH001 was associated with rapid reductions in MADRS anhedonia factor scores with sustained improvements observed in patients who completed the 6-month OLE after infrequent treatment. These findings suggest that GH001 may improve patients’ ability to experience pleasure and enhance overall functioning in TRD.

References

  1. Kwaśny A, Kwaśna J, Wilkowska A, et al. Ketamine treatment for anhedonia in unipolar and bipolar depression: a systematic review. Eur Neuropsychopharmacol. 2024;86:20-34. doi:10.1016/j.euroneuro.2024.04.014
  2. Cubała WJ, Bajbouj M, Bauer M, et al. GH001 vs Placebo in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA Psychiatry. Published online March 25, 2026. doi:10.1001/jamapsychiatry.2026.0096
  3. Gaynes BN, Lux L, Gartlehner G, et al. Defining treatment-resistant depression. Depress Anxiety. 2020 Feb;37(2):134-145. doi: 10.1002/da.22968.