A pattern I’ve been tracking across my patient panel over the past several months: people who responded beautifully to ketamine, genuine, rapid antidepressant response within 24 to 72 hours, and then plateaued. They’re not non-responders. They’re something more complicated: initial responders who have exhausted the durability of the mechanism, often after six to twelve infusions, sometimes after a maintenance regimen that stretched across two years. They come back to my clinic not in crisis, but frustrated. The floor held, but the ceiling didn’t lift. They’re asking me what’s next, and until recently I didn’t have a strong answer beyond esketamine or a protocol enrollment conversation.

The JAMA Psychiatry randomized clinical trial of GH001, a synthetic inhaled formulation of mebufotenin, the compound also known as 5-MeO-DMT, is the most clinically relevant data I’ve read this quarter for exactly that population. The trial evaluated single-day treatment with GH001 versus placebo in patients with treatment-resistant depression. Forty patients received mebufotenin, forty-one received placebo. The signal was meaningful. For a field that has been watching esketamine, approved by the FDA on March 5, 2019, as the de facto rapid-acting benchmark for TRD, this is a mechanistic departure worth taking seriously.

Why the Mechanism Matters Here

Mebufotenin operates through a different receptor profile than ketamine. Where ketamine’s antidepressant effects are primarily attributed to NMDA receptor antagonism and downstream AMPA potentiation, mebufotenin is a serotonergic psychedelic, a 5-HT2A agonist, with a shorter experiential duration than psilocybin or classic LSD-like compounds. That brevity matters clinically and operationally. A single-session intervention measured in minutes rather than hours changes what supervised administration looks like, what the staff burden is, and critically, what the therapeutic model assumes about mechanism.

Having treated more than 30,000 patients through guided ketamine therapy, I can tell you that the durability question is the question nobody has fully solved. Single IV ketamine infusions produce 24-hour response rates around 64% against active placebo, the acute signal is strong. What erodes is the sustained benefit. The mebufotenin trial forces the same reckoning: a single-day administration paradigm looks elegant in a protocol, but the durability curve is where the clinical reality lives. A prior Phase 2 signal from individualized-dose mebufotenin was encouraging, and this JAMA Psychiatry publication adds controlled-trial rigor. What it doesn’t yet answer, and what the field desperately needs, is how long the response holds in patients who have already metabolized the optimism of earlier interventions.

The competitive context sharpens the stakes. The global psychedelic drugs market was valued at $3.63 billion in 2024, with ketamine holding a 42% share. COMPASS Pathways reported positive Phase 2b results for COMP360 psilocybin in TRD in August 2024. The pipeline is real and accelerating, which means trial designs filed today will be competing for the same TRD patient population, a population that, by consensus definition published in March 2022, requires at least two failed adequate treatments to qualify. That’s not a large or simple population to enroll.

The Design Question Nobody Is Asking Loudly Enough

The FDA’s June 2023 draft guidance on psychedelic drug clinical investigations raises important questions about endpoints and blinding in psychedelic trials, but the guidance stops short of resolving the core tension in single-dose paradigms: response at what timepoint, and sustained by what mechanism? In my practice, the patients who benefit most from rapid-acting interventions are often those with the highest baseline severity and the most robust acute CNS reactivity, but those same patients tend to show the steepest post-treatment return curves. Protocol designers who benchmark success at four weeks are measuring a different phenomenon than the one their drug is actually producing.

The population enrolled in the GH001 trial: TRD patients with adequate prior treatment failures, overlaps substantially with the ketamine plateau patients I described at the outset. That overlap is an opportunity the field keeps treating as a nuisance. Ketamine responders who have lost durability are arguably the most informative population for any rapid-acting serotonergic candidate: they have demonstrated CNS responsiveness to rapid-acting mechanisms, they’re treatment-literate enough to report symptom changes precisely, and their prior ketamine experience gives investigators a within-subject baseline that no depression rating scale alone can provide. Almost nobody is designing for them specifically.

Enrollment protocols that exclude patients with prior ketamine exposure, written to avoid confounding, are discarding exactly the subjects who could tell us whether mebufotenin’s serotonergic pathway produces additive, synergistic, or independent antidepressant effects relative to the glutamatergic cascade. That’s not a minor methodological footnote. That’s the mechanistic question the entire next decade of TRD pharmacology depends on answering.

I’ll be watching the durability data from the GH001 program closely, specifically whether Green Health Sciences reports any extended follow-up beyond the primary trial window, and whether the FDA’s advisory process for this compound class opens the blinding and endpoint questions the 2023 draft guidance left unresolved.

References

  1. JAMA Psychiatry: “GH001 vs Placebo in Treatment-Resistant Depression”
  2. American Health & Drug Benefits: “Spravato (Esketamine): First NMDA Receptor Antagonist Approved by the FDA for Adults with Treatment-Resistant Depression” (2019)
  3. ResearchGate: “Response Rates Over Time in Patients With Treatment-Resistant Major Depression Given a Single IV Ketamine Infusion”
  4. Precision for Medicine: “Unpacking FDA’s Draft Guidance on Psychedelic Research for Clinical Success” (June 2023)
  5. Science Media Centre: “Inhaled Mebufotenine Improves Symptoms of Depression: Phase 2 Trial”
  6. Neuroscience News: “Psilocybin Depression Remission” (Karolinska Institutet single-dose psilocybin study)
  7. Clinical Research News Online: “Consensus Definition of Treatment-Resistant Depression for Regulatory Trials” (March 23, 2022)
  8. SNS Insider: “Psychedelic Drugs Market Report 2024”
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Dr. Leonardo Vando, MD is Principal Investigator of Psychiatry at Vando Medical Services.