Psilocybin Therapy for Treatment-Resistant Depression

Psilocybin-assisted therapy for treatment-resistant depression (TRD) is the second-most-common indication Health Canada has authorized through the Special Access Program (SAP) since the January 5, 2022 amendment, after end-of-life distress. The peer-reviewed evidence base is real, growing, and honestly smaller in scale than the ketamine TRD literature: Carhart-Harris 2016 open-label proof-of-concept (Imperial College, N=12), Davis 2021 randomized trial (Johns Hopkins, N=24), Carhart-Harris 2021 NEJM head-to-head against escitalopram in MDD, and Goodwin 2022 NEJM COMP001 Phase 2b (N=233) anchor the published evidence. CANMAT does not yet include psilocybin in its TRD treatment recommendations — psilocybin remains off-label and SAP-pathway-only in Canada. This article walks through what the evidence actually shows, where psilocybin sits relative to ketamine and ECT in the third-line TRD landscape, how the Canadian SAP pathway works for TRD specifically, and how ATMA CENA supports SAP-pathway TRD patients.

Key takeaways

• Psilocybin therapy for TRD is off-label, SAP-pathway-only in Canada. CANMAT 2023 MDD guidelines do not yet include psilocybin among TRD recommendations.
• Strongest evidence: Goodwin 2022 NEJM COMP001 Phase 2b (N=233) showed single 25 mg COMP360 psilocybin produced significantly greater MADRS reduction than 1 mg comparator at 3 weeks. Davis 2021 JAMA Psychiatry (N=24) showed ~71% response at 4 weeks. Carhart-Harris 2021 NEJM compared psilocybin to escitalopram in MDD with mixed primary/secondary outcomes.
• The evidence base is smaller in scale than ketamine TRD evidence — both substances have third-line-equivalent positioning in current clinical landscape, but ketamine has CANMAT 2021 task force recommendations and the ELEKT-D 2023 head-to-head against ECT; psilocybin does not.
• For documented TRD patients, psilocybin SAP applications are a real clinical pathway when the prescribing physician documents failed antidepressant trials. Approval rates declined through 2025 per PsyCan.
• ATMA CENA supports preparation and integration for SAP-pathway TRD patients via the coordinated care model, in coordination with the patient's treating psychiatrist.

What is treatment-resistant depression?

Treatment-resistant depression typically refers to failure of at least two adequate antidepressant trials at therapeutic dose for ≥6 weeks each in the current depressive episode. CANMAT 2023's MDD treatment hierarchy reflects this threshold; the FDA Spravato approval used the same operationalization; published TRD ketamine and psilocybin trials enrolled patients meeting these criteria.

The "pseudoresistance" question matters: many patients labelled TRD have actually had inadequate dose, inadequate duration, poor adherence, or wrong diagnosis (often missed bipolarity). For the screening framework, see Ketamine Therapy for Treatment-Resistant Depression (deep dive).

What the psilocybin TRD evidence actually shows

Carhart-Harris 2016 — open-label proof of concept

Carhart-Harris et al. 2016, Lancet Psychiatry — Imperial College open-label feasibility trial in 12 patients with TRD. Two psilocybin sessions (10 mg followed by 25 mg) with psychological support. Findings: significant reduction in depressive symptoms at 1 week sustained at 3 months in most participants. As an open-label trial without controls, it was proof-of-concept rather than efficacy demonstration, but it was the first contemporary signal that high-dose psilocybin could produce durable antidepressant effects in TRD specifically.

Carhart-Harris 2018 — long-term follow-up

Carhart-Harris et al. 2018, Psychopharmacology followed up the 2016 cohort for 6 months. Results showed that significant reductions in depressive symptoms were maintained at 3 and 6 months, though with attrition of effect over time in some participants. This established that single-course psilocybin could produce effects extending months without maintenance dosing.

Davis 2021 — Johns Hopkins randomized trial

Davis et al. 2021, JAMA Psychiatry — randomized waiting-list controlled trial in 24 patients with MDD (mostly meeting TRD criteria). Two psilocybin sessions with structured supportive psychotherapy produced approximately 71% response and 54% remission at 4 weeks post-treatment, with effects sustained at 1-year follow-up in subsequent reporting. The Johns Hopkins trial extended Carhart-Harris's open-label work with a more rigorous design.

Carhart-Harris 2021 NEJM — psilocybin vs escitalopram

Carhart-Harris et al. 2021, New England Journal of Medicine — Phase 2 randomized double-blind active-comparator trial in MDD (N=59) comparing two psilocybin sessions (25 mg each) versus 6 weeks of escitalopram (10–20 mg/day). The primary outcome — change in QIDS-SR-16 from baseline to week 6 — did not show statistically significant superiority of psilocybin (the primary efficacy endpoint was not met for non-inferiority either, depending on framing). However, most secondary outcomes favoured psilocybin: response rates, remission rates, anhedonia, work/social functioning, anxiety, and several wellbeing measures. The trial established that psilocybin produced meaningful antidepressant effects comparable to or in some dimensions exceeding standard SSRI treatment in MDD.

Goodwin 2022 NEJM COMP001 — pivotal Phase 2b

Goodwin et al. 2022, New England Journal of Medicine — Compass Pathways' Phase 2b dose-finding RCT in 233 TRD patients. Three arms: 25 mg COMP360 psilocybin, 10 mg COMP360, or 1 mg active comparator. Primary outcome: change in MADRS at 3 weeks. The 25 mg arm showed significantly greater MADRS reduction than the 1 mg comparator (mean difference 6.6 points). Response rates: 25 mg arm ~37% at 3 weeks; 1 mg arm ~18%. The 10 mg arm did not significantly differ from 1 mg. This is the largest published psilocybin RCT in TRD and is the basis for Compass Pathways' ongoing Phase 3 program.

Mechanistic context

Mechanism evidence for psilocybin in TRD echoes the broader psilocybin literature: 5-HT2A serotonin receptor agonism, default mode network modulation (Carhart-Harris 2017, Sci Rep — fMRI in TRD specifically), neuroplasticity, and mystical experience as mediator (Roseman, Nutt, Carhart-Harris 2018, Front Pharmacol — the quality of the acute experience predicted antidepressant response in the TRD cohort).

For the foundational mechanism deep dive, see What Is Psilocybin Therapy?.

Evidence honesty — psilocybin vs ketamine for TRD

The psilocybin TRD evidence base is real but much smaller in scale than the ketamine TRD evidence:

Both work for TRD per published evidence. Both are accessed in Canada through different regulatory pathways (off-label / Spravato-approved for ketamine; SAP-only for psilocybin). For the cross-treatment decision framing, see Psilocybin vs Ketamine Therapy (Wave 2 sibling article).

Where psilocybin sits in the Canadian TRD landscape

CANMAT 2023 MDD treatment hierarchy does not include psilocybin among recommended treatments. CANMAT 2021's racemic ketamine task force recommends IV ketamine as third-line for TRD; CANMAT does not have an equivalent psilocybin task force. Psilocybin is off-label and SAP-pathway-only.

Realistic Canadian TRD treatment ladder (with prescribing physician):

1. First-line: SSRIs, SNRIs, bupropion, vortioxetine, agomelatine — typically with psychotherapy (CBT, IPT).
2. Inadequate response after one trial: switch within or across class, augment (aripiprazole, brexpiprazole, lithium, T3).
3. TRD (≥2 failed adequate trials): psychiatric reassessment for pseudoresistance and missed bipolarity. If genuine TRD, third-line options include:
   • IV ketamine (CANMAT 2021 third-line; off-label legal access)
   • Spravato (Health Canada-approved; with concurrent oral SSRI/SNRI)
   • ECT (gold-standard historically; ELEKT-D 2023 demonstrated IV ketamine non-inferior)
   • Psilocybin via SAP (peer-reviewed evidence; SAP-pathway access; CANMAT does not yet recommend)

The honest framing: psilocybin sits within the third-line landscape with meaningful but smaller evidence than ketamine and ECT. Patients pursuing psilocybin SAP for TRD are typically those who have engaged with the regulatory pathway through their prescribing psychiatrist and accept the access constraints.

For the Canadian TRD landscape detail, see Ketamine Therapy for Treatment-Resistant Depression (deep dive).

How the SAP pathway works for TRD specifically

For TRD specifically, SAP applications typically require:

• Diagnosis confirmation: documented TRD (≥2 failed adequate antidepressant trials at therapeutic dose for ≥6 weeks each in the current episode).
• Prior treatment documentation: which medications, at what dose, for what duration, with what response. Augmentation strategies (lithium, atypical antipsychotic, T3) often included to demonstrate breadth of attempted optimization.
• Other third-line treatments considered: ECT consultation outcome, IV ketamine consideration, Spravato consideration. SAP applications often reflect that conventional and approved third-line options have been considered.
• Prescribing physician: psychiatrist or psychiatric NP willing to apply. TRD applications typically involve a psychiatrist familiar with interventional psychiatry.
• Standard SAP screening: no psychotic disorder history, no recent mania/hypomania, no uncontrolled cardiovascular disease, no pregnancy, no concurrent lithium.

For the full SAP-pathway detail, see How to Access Psilocybin Therapy in Canada.

The 2025 PsyCan-reported decline in SAP approvals applies to TRD applications as much as to other indications. Patients pursuing this pathway in 2026 should expect a meaningful prescriber search, documentation effort, and possible review-timeline extension.

How ATMA CENA supports SAP-pathway TRD patients

ATMA CENA's role in SAP-pathway psilocybin work for TRD:

• The medical SAP application is initiated by the patient's prescribing psychiatrist or psychiatric nurse practitioner — not ATMA CENA directly.
• ATMA CENA supports preparation and integration through the three-phase psychedelic-assisted therapy model. For TRD specifically, this often includes coordinated dose-stabilization or tapering planning with the prescribing psychiatrist (e.g., timing SSRI taper around psilocybin session, where clinically appropriate).
• The coordinated care model lets the patient's treating psychiatrist remain primary while ATMA CENA's clinical infrastructure supports the psychotherapy wraparound around dosing.
• ATMA CENA's intake call screens for fit — pseudoresistance, comorbid bipolarity, contraindications, realistic course planning.

For patients who have documented TRD and are evaluating whether psilocybin or ketamine is the right next step, ATMA CENA intake includes both pathways. The decision often comes down to access (psilocybin SAP timeline vs ketamine off-label availability), insurance (Spravato more often privately covered; psilocybin generally not covered outside Quebec RAMQ), and clinical fit.

Frequently asked questions

Is psilocybin therapy approved for TRD in Canada? No — psilocybin has no Health Canada-approved indication. Clinical access for TRD is via the Special Access Program (SAP) only, with prescribing physician initiation. Spravato (esketamine) is the only Health Canada-approved psychiatric ketamine-family product, approved May 2020 for TRD.

What's the strongest evidence for psilocybin in TRD? Goodwin 2022 NEJM COMP001 Phase 2b (N=233) is the largest published RCT — 25 mg COMP360 psilocybin produced significantly greater MADRS reduction than 1 mg comparator at 3 weeks. Davis 2021 JAMA Psychiatry (N=24) showed ~71% response at 4 weeks. Carhart-Harris 2021 NEJM compared psilocybin to escitalopram in MDD with most secondary outcomes favouring psilocybin.

Is psilocybin better than ketamine for TRD? Both have evidence in TRD; both are accessed through different Canadian regulatory pathways. Ketamine's RCT base is much larger and CANMAT 2021 has formal task-force recommendations; psilocybin's evidence is real but smaller in scale and CANMAT does not yet include psilocybin in TRD recommendations. The right pathway depends on access, coverage, and clinical fit. See Psilocybin vs Ketamine Therapy.

How many psilocybin sessions are typical for TRD? Most published TRD trials use one or two dosing sessions over the acute course (Carhart-Harris 2016: two sessions; Davis 2021: two sessions; Goodwin 2022: single 25 mg session). This contrasts with ketamine TRD protocols (4–8 IV sessions over 2–3 weeks per CANMAT; 12 Spravato sessions over 8 weeks).

Can I keep my SSRI while doing psilocybin therapy? This is a clinical decision with the prescribing psychiatrist. Many published psilocybin trials tapered SSRIs before dosing under medical supervision (theoretical serotonin syndrome concern at high doses; possible blunting of psychedelic experience). ATMA CENA's intake coordinates with the prescribing psychiatrist on timing.

What's the SAP approval rate for TRD applications? Historical psilocybin SAP approval rates were ~78% per industry reporting through 2024. PsyCan reported a sharp decline through 2025. TRD applications specifically are typically approved when documented antidepressant failures and a willing prescribing psychiatrist are in place.

How does this fit with my existing antidepressant treatment? Psilocybin is generally framed as a third-line intervention after antidepressant trials and conventional augmentation strategies. Most patients pursuing psilocybin SAP for TRD continue some form of psychiatric care — psychotherapy, possibly maintenance antidepressant — alongside or after the psilocybin course.

What about Spravato — should I consider that first? For Canadian TRD patients with private insurance, Spravato (intranasal esketamine) is often the most affordable third-line option due to private prior-auth coverage. The clinical question of psilocybin vs Spravato is partly a coverage question and partly a fit question. See Ketamine vs Spravato.

How long does the psilocybin antidepressant effect last? Davis 2021 follow-up found significant effects at 1 year in many participants. Goodwin 2022 measured primary outcome at 3 weeks; longer-term data is part of ongoing Phase 3 programs. Carhart-Harris 2016/2018 follow-up showed response in some participants sustained at 6 months. The honest framing: durability varies; some patients have prolonged response from a single course, others see waning over months and may need additional sessions.

Where can I access psilocybin TRD therapy in Canada? SAP-authorized clinicians. TheraPsil-trained psychiatrists, Numinus-network providers, Quebec providers (Farzin / Stephan model), Roots to Thrive (Nanaimo BC, group format), and other clinicians with SAP-pathway experience. ATMA CENA supports preparation and integration via coordinated care. See How to Access Psilocybin Therapy in Canada.

Sources

1. ATMA CENA — find care near you: https://psychedelic.healthcare/find-care
2. Carhart-Harris RL, et al. (2016). Psilocybin with psychological support for treatment-resistant depression: open-label feasibility study. Lancet Psychiatry. https://pubmed.ncbi.nlm.nih.gov/27210031/
3. Carhart-Harris RL, et al. (2018). Psilocybin with psychological support for treatment-resistant depression: 6-month follow-up. Psychopharmacology. https://pubmed.ncbi.nlm.nih.gov/29119217/
4. Davis AK, et al. (2021). Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. https://pubmed.ncbi.nlm.nih.gov/33146667/
5. Carhart-Harris RL, et al. (2021). Trial of psilocybin versus escitalopram for depression. NEJM. https://pubmed.ncbi.nlm.nih.gov/33852780/
6. Goodwin GM, et al. (2022). Single-dose psilocybin for a treatment-resistant episode of major depression (COMP001 Phase 2b). NEJM. https://pubmed.ncbi.nlm.nih.gov/36322843/
7. Carhart-Harris RL, et al. (2017). Psilocybin for TRD: fMRI brain mechanisms. Sci Rep. https://pubmed.ncbi.nlm.nih.gov/29032520/
8. Roseman L, Nutt DJ, Carhart-Harris RL (2018). Quality of acute psychedelic experience predicts therapeutic efficacy. Front Pharmacol. https://pubmed.ncbi.nlm.nih.gov/29387009/
9. Swainson J, et al. (2021). CANMAT racemic ketamine task force recommendations (TRD comparison context). Can J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/33174760/
10. Anand A, et al. (2023). Ketamine versus ECT for nonpsychotic TRD: ELEKT-D (TRD comparison context). NEJM. https://pubmed.ncbi.nlm.nih.gov/37224135/
11. Health Canada — SAP psychedelic-assisted psychotherapy: https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/announcements/requests-special-access-program-psychedelic-assisted-psychotherapy.html

Related articles in this cluster

• Psilocybin Therapy in Canada
• What Is Psilocybin Therapy?
• How to Access Psilocybin Therapy in Canada (SAP)
• Psilocybin vs Ketamine Therapy
• Psilocybin Therapy for Anxiety
• Psilocybin Therapy for End-of-Life Distress
• Ketamine Therapy for Treatment-Resistant Depression (deep dive)
• Find care near you

Last updated: 2026-05-06