# Serotonin: what the new evidence changes

*Hibbert Medical · Week of 7 September 2026 · Evidence briefing*

> **At a glance**
> **What we know** — A single-day inhaled 5-HT₂A agonist (GH001) produced a 15.5-point greater reduction in depression scores than placebo at day 8 in treatment-resistant depression, with 57.5% remission versus 0% for placebo and no severe adverse events [1]. Two phase 3 trials of synthetic psilocybin (COMP360) met primary endpoints in treatment-resistant depression, with response rates of 40–45% maintained through 26–52 weeks [2,3]. Memantine augmentation shows promise in treatment-resistant obsessive-compulsive disorder [4].
> **What we don't know yet** — Peer-reviewed publication of the COMP360 phase 3 trials is pending, confidence intervals for long-term outcomes are not available, and the optimal role of 5-HT₂A agonists relative to established treatments is undefined [2,3,5].
> **What changes Monday** — Nothing yet. GH001 and COMP360 are investigational with no regulatory approvals. Continue evidence-based treatment-resistant depression management with existing options while monitoring regulatory developments.

## What happened

 The same supplement includes abstract 268 summarising glutamatergic augmentation—particularly memantine at 5–20 mg/day—in severe treatment-resistant obsessive-compulsive disorder [4].

Also on 9 September 2026, Compass Pathways reported 52-week topline results from Part C of its phase 3 COMP005 trial of COMP360 synthetic psilocybin in United States participants with treatment-resistant depression, showing an average 13-point reduction from baseline on the Montgomery–Åsberg Depression Rating Scale by week 52, with response rates of 40–45% and remission rates around 30% [2].

On 25 March 2026, GH Research announced peer-reviewed publication of its phase 2b trial of inhaled GH001 in *JAMA Psychiatry* (DOI 10.1001/jamapsychiatry.2026.0096, PMID 41879760), reporting results from 81 adults randomised to receive individualised dosing or placebo [1,6].

## What the evidence actually shows

**GH001 (inhaled mebufotenin) in treatment-resistant depression: phase 2b randomised controlled trial.** The *JAMA Psychiatry* trial randomised 81 adults with treatment-resistant depression (defined as nonresponse to 2–5 oral antidepressants) to receive an individualised dosing regimen of inhaled GH001 (up to three escalating doses of 6, 12, and 18 mg on day 1) or matched placebo [1]. The primary endpoint, change in Montgomery–Åsberg Depression Rating Scale score from baseline to day 8, showed a least-squares mean difference of −15.5 points (SE 1.7; *P* <.001) favouring GH001, corresponding to a Cohen's *d* of −2.0 [1]. Day 8 remission rates were 57.5% (23/40) with GH001 and 0% (0/41) with placebo, with no severe or serious adverse events reported [1]. A post hoc analysis found no meaningful correlation between prior lifetime treatment failures and Montgomery–Åsberg Depression Rating Scale improvement at day 8 (*r* = −0.13; *P* = 0.44) [7]. This is **practice-informing**: the effect size is large and the remission rate is clinically meaningful, but the sample is small (n = 81), follow-up is short, and regulatory approval is absent.

**COMP360 (synthetic psilocybin) in treatment-resistant depression: phase 3 trials.** The COMP005 trial randomised 258 participants 2:1 to receive a single 25 mg dose or placebo [8]. In the 52-week topline report for Part C, participants originally assigned to the 25 mg group who received an additional dose exhibited an average 13-point reduction from baseline on the Montgomery–Åsberg Depression Rating Scale by week 52 [2]. Response rates ranged from 40% to 45% between day 1 and week 6, with remission rates around 30%, and no new safety signals [2]. The COMP006 trial enrolled 581 participants who received two fixed doses of 1, 10, or 25 mg COMP360 three weeks apart; 39% of participants receiving 25 mg achieved a clinically meaningful Montgomery–Åsberg Depression Rating Scale reduction of at least 25% at week 6 and maintained that benefit through at least week 26 [3]. Serious adverse events were reported in 6.3% of the 1 mg group and 5.7% of the 25 mg group over 26 weeks [3]. This is **practice-informing**: the trials are large, blinded, and demonstrate durable response, but peer-reviewed publication is pending and no regulatory approval exists.

**Psilocybin-assisted therapy in treatment-resistant depression: 12-month naturalistic follow-up.** A naturalistic follow-up of a phase 2b trial examined antidepressant effects of one or two doses of psilocybin (5 mg, 25 mg, or active placebo) with adjunct psychotherapy until 12 months [9]. Among 126 of 144 randomised participants who completed at least one follow-up visit, estimated average changes from baseline in Hamilton Rating Scale for Depression scores were −7.93 (95% CI −9.17 to −6.70, adjusted *P* <.0001) at six months and −7.74 (95% CI −9.04 to −6.43, adjusted *P* <.0001) at 12 months, without significant group differences [9]. This is **practice-informing**: the follow-up demonstrates stable long-term benefit, but the naturalistic design permits confounding by subsequent treatment choices.

**Psilocybin-assisted therapy in treatment-resistant depression: National Health Service feasibility trial.** A double-blind, randomised, placebo-controlled feasibility trial conducted at one National Health Service site in England enrolled 60 participants who met DSM-5 criteria for major depressive disorder with inadequate response to ≥2 antidepressant treatments [10]. Participants received 25 mg psilocybin or placebo with preparation, dosing support, and integration [10]. The adjusted between-group difference at week 3 on the Montgomery–Åsberg Depression Rating Scale was −10.41 (95% CI −14.86 to −5.95; Cohen's *d* = −1.70), favouring psilocybin, which was sustained at week 6 [10]. This is **practice-informing**: the trial demonstrates feasibility in a public healthcare setting and a large effect size, but the sample is small (n = 60) and follow-up is short.

**Memantine augmentation in treatment-resistant obsessive-compulsive disorder.** Abstract 268 in the September 2026 *International Journal of Neuropsychopharmacology* supplement summarises open-label and controlled data on memantine augmentation in severe treatment-resistant obsessive-compulsive disorder, noting that memantine at 5–20 mg/day has shown promising results with clinically meaningful reductions in Yale–Brown Obsessive Compulsive Scale scores and favourable tolerability [4]. The 2025 Canadian Network for Mood and Anxiety Treatments/International College of Obsessive-Compulsive Spectrum Disorders guidelines reaffirm SSRIs and clomipramine as first-line pharmacotherapies and review augmentation strategies with antipsychotics, glutamatergic agents, and neuromodulation [11]. This is **practice-informing**: memantine augmentation is plausible for treatment-resistant cases, but evidence is limited to open-label and small controlled studies.

## How clinicians are reacting

- **The Psychedelic Podcast, 31 August 2026** — Dr Josef Witt-Doerring highlighted the profound evidence gap supporting chronic antidepressant use, noting that pivotal trials for the most commonly prescribed agents rarely exceed 12 weeks, with none extending beyond 52 weeks [12].
- **Dr Matt and Dr Mike's Medical Podcast, 12 September 2026** — Dr Kieran Kennedy emphasised that ADHD involves attention dysregulation, not deficit, and that patients can hyperfocus when appropriately stimulated [13].
- **High Yield Family Medicine, 8 September 2026** — The episode provided a comprehensive review of high-yield adverse drug reactions and interactions, emphasising the dangerous respiratory depression from opioid-benzodiazepine combinations [14].
- **Ancient Health Podcast, 7 September 2026** — Dr Chris Motley examined neuroborreliosis as an underrecognised cause of sudden paediatric behavioural and cognitive decline that can clinically mimic ADHD [15].

## What this changes in practice, and what it doesn't

**What to start doing.** Continue evidence-based management of treatment-resistant depression with existing options [1,10]. For obsessive-compulsive disorder, continue SSRIs or clomipramine as first-line pharmacotherapy, and consider memantine augmentation at 5–20 mg/day in severe treatment-resistant cases, recognising that evidence is limited [4,11]. Monitor for serotonin syndrome in patients on multiple serotonergic agents, using the Hunter Toxicity Criteria for diagnosis and discontinuing all serotonergic agents immediately if syndrome is suspected [16,17].

**What to stop doing.** Do not prescribe or recommend GH001 or COMP360 outside of clinical trials; both are investigational, and no regulatory approvals exist [1,2,3].

**What to wait for.** Await peer-reviewed publication of the COMP005 and COMP006 phase 3 trials, including detailed confidence intervals, subgroup analyses, and safety data [2,3].

## For learners

**Question 1.** A 42-year-old woman with treatment-resistant depression has failed trials of sertraline, venlafaxine, and bupropion, each at adequate doses for at least eight weeks. She is considering participation in a clinical trial of inhaled GH001. Which of the following best describes the evidence for GH001 in treatment-resistant depression?

A. GH001 is approved by the United States Food and Drug Administration for treatment-resistant depression
B. A phase 2b trial showed a 15.5-point greater reduction in Montgomery–Åsberg Depression Rating Scale scores at day 8 versus placebo, with 57.5% remission and no severe adverse events
C. GH001 is less effective in patients with more prior antidepressant failures
D. GH001 is contraindicated in patients taking SSRIs due to serotonin syndrome risk

**Answer: B.** A phase 2b trial (n = 81) showed a least-squares mean difference of −15.5 points on the Montgomery–Åsberg Depression Rating Scale at day 8, with 57.5% remission versus 0% for placebo and no severe adverse events; GH001 remains investigational and is not approved [1].

**Question 2.** A 35-year-old man with severe obsessive-compulsive disorder has not responded to fluoxetine 80 mg daily for 12 weeks or to subsequent augmentation with aripiprazole 10 mg daily. His Yale–Brown Obsessive Compulsive Scale score is 32. Which of the following augmentation strategies is supported by emerging evidence?

A. Memantine 5–20 mg/day
B. Lamotrigine 200 mg/day
C. Bupropion 300 mg/day
D. Buspirone 60 mg/day

**Answer: A.** Memantine at 5–20 mg/day has shown promising results with clinically meaningful reductions in Yale–Brown Obsessive Compulsive Scale scores and favourable tolerability in severe treatment-resistant obsessive-compulsive disorder, though evidence is limited to open-label and small controlled studies [4].

**Question 3.** A 28-year-old woman presents with agitation, diaphoresis, tremor, hyperreflexia, and clonus two days after her GP increased her sertraline dose from 100 mg to 150 mg daily. Her temperature is 38.2°C, heart rate 110 bpm, and blood pressure 145/95 mmHg. Which of the following is the most appropriate initial management?

A. Administer cyproheptadine 12 mg orally
B. Discontinue sertraline and provide supportive care with intravenous fluids and benzodiazepines
C. Reduce sertraline to 100 mg daily and observe
D. Administer haloperidol 5 mg intramuscularly

**Answer: B.** Serotonin syndrome is diagnosed clinically using the Hunter Toxicity Criteria; management involves immediate discontinuation of all serotonergic agents and supportive care with intravenous fluids, oxygen, cardiac monitoring, and benzodiazepines for agitation [16,17].

## References

1. Cubala WJ, Bajbouj M, Bauer M, et al. GH001 vs Placebo in Patients With Treatment-Resistant Depression: A Randomized Clinical Trial. JAMA psychiatry 2026. doi:10.1001/jamapsychiatry.2026.0096. PMID: 41879760. https://pubmed.ncbi.nlm.nih.gov/41879760/
2. Compass Pathways reports 52-week Phase 3 COMP005 results for COMP360. finance.yahoo.com. https://finance.yahoo.com/healthcare/articles/compass-pathways-reports-52-week-124831805.html
3. Psilocybin drug hits 39% response rate in phase 3. beckersbehavioralhealth.com. https://www.beckersbehavioralhealth.com/interventional-psychiatry/psilocybin-drug-hits-39-response-rate-in-phase-3-depression-trial-6-things-to-know/
4. https://academic.oup.com/ijnp/article/29/Supplement_1/i16/8789000.[5. academic.oup.com. https://academic.oup.com/ijnp/article/29/Supplement_1/i16/8789000.[5
5. Sabani A, Khatak A. Psilocybin-assisted therapy in treatment-resistant depression: rapid remission, uncertain durability, and the next phase of clinical evidence. Annals of medicine and surgery (2012) 2026. doi:10.1097/MS9.0000000000005244. PMID: 42433813. https://pubmed.ncbi.nlm.nih.gov/42433813/
6. https://doi.org/10.1001/jamapsychiatry.2026.0096. doi.org. https://doi.org/10.1001/jamapsychiatry.2026.0096
7. Thase ME, Brennan B, MacIsaac R, et al. GH001 Efficacy is Independent of Prior Antidepressant Treatment Failures in Treatment-Resistant Depression: A Post Hoc Analysis of a Phase 2b Randomized Controlled Trial. Psychopharmacology bulletin 2026. doi:10.64719/pb.18507. PMID: 42267234. https://pubmed.ncbi.nlm.nih.gov/42267234/
8. Company Announcements. markets.ft.com. https://markets.ft.com/data/announce/detail?dockey=600-202504220600BIZWIRE_USPRX____20250422_BW821349-1
9. Mertens LJ, Betzler F, Brand M, et al. Long-Term Efficacy of Psilocybin with Adjunct Psychotherapy in Treatment-Resistant Major Depression: 6- and 12-Month Naturalistic Follow-Up of a Phase 2b Trial. Psychotherapy and psychosomatics 2026. doi:10.1159/000552272. PMID: 42201843. https://pubmed.ncbi.nlm.nih.gov/42201843/
10. Rucker JJ, Mantingh T, Kerr-Gaffney J, et al. Psilocybin-assisted therapy for treatment-resistant major depressive disorder in a public healthcare setting: a randomized controlled trial. Nature medicine 2026. doi:10.1038/s41591-026-04541-0. PMID: 42562964. https://pubmed.ncbi.nlm.nih.gov/42562964/
11. https://pubmed.ncbi.nlm.nih.gov/42441734/.[15. pubmed.ncbi.nlm.nih.gov. https://pubmed.ncbi.nlm.nih.gov/42441734/.[15
12. The Psychedelic Podcast. SSRI Tapering and Psychedelic Readiness - Dr. Josef Witt-Doerring. podcast, 2026-08-31. https://thethirdwave.co/podcast/episode-371/?ref=278
13. Dr. Matt and Dr. Mike's Medical Podcast. ADHD Made Easy w/ Dr Kieran Kennedy. podcast, 2026-09-12. https://drmattdrmike.com.au/
14. High Yield Family Medicine. #60 - Adverse Effects and Interactions. podcast, 2026-09-08. https://podcasters.spotify.com/pod/show/christopher-anghel/episodes/60---Adverse-Effects-and-Interactions-e3ofa5j
15. Ancient Health Podcast. Could a Tick Bite Be Mistaken for ADHD? Lyme Rage in Kids: A Deep-Dive. podcast, 2026-09-07.
16. Serotonin Syndrome - StatPearls - NCBI Bookshelf. ncbi.nlm.nih.gov. https://www.ncbi.nlm.nih.gov/books/NBK482377/
17. https://iaem.ie/wp-content/uploads/2024/04/IAEM-Serotonin-Syndrome-V1.0.pdf.[19. iaem.ie. https://iaem.ie/wp-content/uploads/2024/04/IAEM-Serotonin-Syndrome-V1.0.pdf.[19