Psilocybin Therapy for Treatment-Resistant Depression

Psilocybin-assisted therapy is one of the most-studied investigational treatments for treatment-resistant depression (TRD). In Canada, legal patient access to psilocybin is available only through Health Canada authorization, granted on a case-by-case basis and initiated by a physician. This page explains what the published evidence shows, how the therapy works, who may qualify, and how that access pathway works in Canada.

Medically reviewed by Jacque Lovely, RN, MN, MBA, PMP, Reg #74334 on 2026-05-27.

Key takeaways

• Treatment-resistant depression usually means major depressive disorder that has not responded to at least two adequate antidepressant trials. TRD is one of the indications for which physicians most often seek Health Canada authorization to use psilocybin.
• The strongest single trial is Goodwin 2022 (COMP360 Phase 2b, 233 adults with TRD). A single 25 mg dose lowered depression scores more than a 1 mg comparator at three weeks (a 6.6-point difference on the MADRS scale).
• In Carhart-Harris 2021, psilocybin and the antidepressant escitalopram did not differ on the trial's main measure. Some secondary measures favoured psilocybin, but those results were not adjusted for multiple comparisons, so they should be read with caution.
• Psilocybin has no approved depression indication in Canada. Legal access requires Health Canada authorization, obtained on a case-by-case basis, and is not guaranteed.
• ATMA CENA supports patients generally through preparation and integration, and through CoCare can partner with a patient's existing trained therapist; any request for Health Canada authorization is initiated by the patient's prescribing physician, not by ATMA CENA.

If you have documented treatment-resistant depression and want to understand whether this access pathway may apply to your situation, you can book a free information call to talk it through with ATMA CENA's clinical team.

What is treatment-resistant depression?

Treatment-resistant depression refers to major depressive disorder that has not improved after at least two adequate antidepressant trials in the current episode. "Adequate" means a therapeutic dose taken for long enough to judge the response, usually six weeks or more. The published psilocybin and ketamine depression trials enrolled people who met criteria close to this definition. TRD is common: a meaningful share of adults with major depression do not respond fully to their first two medications.

Before any third-line treatment, careful reassessment matters. Some depression labelled "treatment-resistant" reflects an inadequate dose, too short a trial, difficulty taking medication consistently, or a diagnosis that was not quite right, including undetected bipolar disorder. A thorough psychiatric review is part of responsible care and part of what a prescribing physician documents when considering options like psilocybin.

Is psilocybin therapy approved for depression in Canada?

No. Psilocybin has no Health Canada-approved indication for depression or any other condition. It is a restricted drug under Canada's Controlled Drugs and Substances Act. For patients, clinical access is available only through Health Canada authorization, which a physician applies for on a case-by-case basis. Treatment-resistant major depressive disorder is one of the indications for which physicians most often seek this authorization, alongside distress related to a life-threatening illness. Eligibility is not the same as access: a request must be initiated and justified by a prescribing physician, and approval is never guaranteed. The full compliance language appears later on this page.

What the psilocybin evidence shows for depression

The evidence base for psilocybin in depression is real and has grown over the past decade, though the trials are still relatively small compared with long-established treatments. The clearest signal comes from a handful of well-designed studies. Read together, they suggest psilocybin given with structured psychological support can reduce depression symptoms for some adults, with effects that last weeks to months in many trial participants. None of these trials promised a cure, and response varied between people. The summary below describes each trial honestly, including its size and design limits.

Carhart-Harris 2016: the first modern TRD signal

The Imperial College London open-label study gave two psilocybin doses (10 mg, then 25 mg) with psychological support to 12 adults with treatment-resistant depression [Carhart-Harris 2016]. Depression scores dropped at one week and remained lower at three months in most participants, and the treatment was well tolerated. Because it was open-label with no control group, it could only show feasibility and an early signal, not prove effectiveness. It was the first contemporary study to suggest high-dose psilocybin might produce lasting antidepressant effects in TRD specifically. (This study was published in Lancet Psychiatry.)

Davis 2021: a Johns Hopkins randomized trial

This randomized trial at Johns Hopkins enrolled 24 adults with major depressive disorder, many meeting TRD criteria, and used a waiting-list control [Davis 2021]. Participants received two psilocybin sessions with supportive psychotherapy. At four weeks after treatment, 71% showed a clinically meaningful improvement and 54% met remission criteria, with a large measured effect size. The trial was small, and a waiting-list control cannot fully account for expectation effects, but it strengthened the earlier open-label work with a more rigorous design.

Carhart-Harris 2021: psilocybin compared with an antidepressant

This trial compared psilocybin with the SSRI escitalopram in 59 adults with depression [Carhart-Harris 2021]. On the trial's main measure (change in a depression rating scale over six weeks), the two treatments did not differ significantly (a MADRS change of −8.0 with psilocybin versus −6.0 with escitalopram, P = 0.17). Several secondary measures, including response and remission rates, favoured psilocybin, but the study authors noted these comparisons were not corrected for multiple testing. The honest reading is that this trial did not show psilocybin was superior to a standard antidepressant on its primary outcome; the secondary results are encouraging but not definitive.

Goodwin 2022: the largest TRD trial

The COMP360 Phase 2b dose-finding trial is the largest published psilocybin study in treatment-resistant depression, with 233 adults [Goodwin 2022]. It compared three single doses: 25 mg, 10 mg, and 1 mg (the 1 mg dose acting as a comparator). The 25 mg dose is the high-dose arm in this trial and corresponds to the high-dose range used in earlier landmark studies; it is not a universal standard dose. At three weeks, depression scores fell most in the 25 mg group (a MADRS reduction of 12.0 points, versus 5.4 in the 1 mg group), a difference of 6.6 points that was statistically significant. About 29% of the 25 mg group were in remission at three weeks. The 10 mg dose did not clearly outperform the 1 mg comparator. Adverse events, including headache and short-term worsening of mood in some participants, were reported and are part of the safety picture.

Where the research is heading

A later-stage COMP360 Phase 3 program in treatment-resistant depression has reportedly met its primary endpoint, according to published reporting on the trial. Longer-term and confirmatory data continue to be evaluated, and no Canadian regulatory approval should be assumed from this. We describe this as a developing area rather than a settled one.

How psilocybin therapy is thought to work

Psilocybin is a serotonergic compound: the body converts it to psilocin, which acts mainly on the 5-HT2A serotonin receptor in the brain. Research points to several overlapping mechanisms rather than one. Brain-imaging work shows psilocybin temporarily reduces activity and rigidity in networks tied to repetitive, self-focused thinking, which is a feature of depression [Carhart-Harris 2017]. Laboratory studies suggest serotonergic psychedelics can promote neuroplasticity, the brain's ability to form new connections. The subjective experience also appears to matter: in the TRD research cohort, the quality and depth of the acute psilocybin experience predicted how much depression improved afterward [Roseman 2018]. This is one reason the therapy pairs the dosing session with structured psychological preparation and integration rather than offering the drug on its own. For the foundational explanation, see What Is Psilocybin Therapy?.

What to expect from psilocybin therapy for depression

Psilocybin-assisted therapy is a structured process, not a single appointment. Across the published depression trials, the shape is consistent: preparation, a supervised dosing session, then integration.

• Preparation. Several sessions build rapport, set intentions, explain what the experience may involve, and confirm medical readiness. Antidepressant medication is reviewed here, because some serotonergic antidepressants are tapered before dosing under medical supervision (see the FAQ below).
• Dosing session. A single high-dose session typically lasts six to eight hours in a calm, prepared setting, with trained clinicians present throughout and the patient usually wearing eyeshades and listening to music. Most depression trials used one or two dosing sessions in total.
• Integration. Follow-up sessions help translate the experience into durable change, usually beginning within a day or two of dosing and continuing over the following weeks.

Watch out: A psilocybin session can bring up difficult emotions and intense, sometimes distressing, experiences during the dosing hours. This is why supervised, prepared settings and integration support matter, and why self-directed or unsupervised use carries added risk.

How psilocybin compares with ketamine for depression

Both psilocybin and ketamine have evidence in treatment-resistant depression, and both are accessed in Canada through different regulatory routes. The table below summarizes the practical differences. It is a starting point, not a recommendation; the right option depends on your clinical situation, access, and coverage, and is a decision for you and your prescribing physician.

	Psilocybin	Ketamine / esketamine
Canadian access	Health Canada authorization only; case-by-case; not guaranteed	Ketamine off-label (provincially regulated); esketamine (Spravato) Health Canada-approved for TRD
Typical acute course	1–2 dosing sessions	Multiple sessions over weeks
Largest depression trial cited here	Goodwin 2022, 233 adults	Larger and more numerous trials overall
Maintenance dosing	Not established	Used in some protocols
Insurance coverage	Generally none outside limited precedents	More established pathways for esketamine and some ketamine forms

Who may qualify, and who may not

Eligibility for psilocybin is decided by a prescribing physician, who documents the clinical case to Health Canada. The published trials and pathway practice point to a consistent picture of who is and is not a candidate. The list below reflects common screening criteria from trial protocols; it is general information, not a substitute for clinical assessment.

Commonly required:

• Documented treatment-resistant depression, typically at least two adequate antidepressant trials in the current episode.
• A clear record of prior medications, doses, durations, and responses, often including augmentation strategies that have been tried.
• A prescribing physician willing to initiate and justify the request.

Common reasons psilocybin may not be appropriate:

• A personal history of a psychotic disorder, or in some protocols a close family history.
• Active mania or recent hypomania.
• Uncontrolled cardiovascular disease.
• Pregnancy.
• Certain concurrent medications that a physician will review individually.

Note on safety and honesty: Psilocybin is investigational for depression. It is not first-line care, it does not work for everyone, and the published trials are smaller and shorter than those for long-established treatments. Anyone considering it should do so with a prescribing physician, alongside, not instead of, appropriate psychiatric care.

How legal access works for treatment-resistant depression

For a patient with treatment-resistant depression, legal access runs through a prescribing physician. The physician submits a request to Health Canada that documents the diagnosis, the failed treatments, and why psilocybin is being considered, and that confirms standard safety screening. Because approval is case-by-case and not guaranteed, patients pursuing this pathway should expect real effort: finding a willing physician, assembling treatment history, and allowing time for review.

Access has also become harder recently. According to PsyCan's September 2025 analysis of Health Canada data, Health Canada approved roughly half as many psilocybin requests in 2025 as in 2024, with approximately 301 cumulative approvals from January 2022 through mid-2025 [PsyCan 2025]. These figures are best read as an indication of a tightening trend rather than a precise forecast for any individual request.

How ATMA CENA supports patients pursuing psilocybin therapy for TRD

ATMA CENA's role in psilocybin work is to support the patient's journey, not to provide psilocybin directly or to initiate the request for Health Canada authorization. That request is made by the patient's prescribing physician. Around it, ATMA CENA supports the preparation and integration phases through its psychedelic-assisted therapy model, coordinating with the patient's treating physician where appropriate (for example, on the timing of any antidepressant taper). Through the CoCare program, ATMA CENA can partner with a patient's existing therapist, where that therapist has the appropriate training and a service agreement is in place. ATMA CENA's intake also supports careful screening for fit, including reassessment for undetected bipolarity, contraindications, and realistic planning.

If you want to understand whether this pathway fits your situation, you can book a free information call with ATMA CENA's clinical team.

Frequently asked questions

Is psilocybin therapy approved for treatment-resistant depression in Canada?

No. Psilocybin has no Health Canada-approved indication. For patients, access for treatment-resistant depression requires Health Canada authorization, which a prescribing physician applies for on a case-by-case basis. Approval is not guaranteed.

What is the strongest evidence for psilocybin in depression?

The largest published trial is Goodwin 2022 (COMP360 Phase 2b, 233 adults with TRD), in which a single 25 mg dose lowered depression scores more than a 1 mg comparator at three weeks. Davis 2021 (a smaller Johns Hopkins randomized trial) reported a 71% rate of clinically meaningful improvement at four weeks. Carhart-Harris 2021 compared psilocybin with the antidepressant escitalopram and found no significant difference on the trial's main measure.

Is psilocybin better than antidepressants?

The evidence does not support that claim. In Carhart-Harris 2021, psilocybin and escitalopram did not differ significantly on the trial's primary outcome. Some secondary measures favoured psilocybin, but those were not adjusted for multiple comparisons and cannot be treated as proof of superiority. Psilocybin is investigational and is considered after standard treatments, not instead of them.

How many psilocybin sessions are typical for depression?

Most published depression trials used one or two dosing sessions in total. Carhart-Harris 2016 used two; Goodwin 2022 used a single dosing session. Each session is paired with preparation beforehand and integration afterward.

Can I keep taking my antidepressant during psilocybin therapy?

This is a decision for your prescribing physician. Many psilocybin trials tapered certain serotonergic antidepressants before dosing under medical supervision, both for safety reasons and because some antidepressants may blunt the psilocybin experience. Any taper should be planned and supervised, never done abruptly on your own.

How long do the effects last?

It varies. In Davis 2021, follow-up reporting found meaningful effects persisting for many participants at one year, while in other trials effects waned over months for some people. The honest framing is that some patients have a prolonged response from a short course and others do not, which is one reason ongoing psychiatric care continues alongside the therapy.

Is psilocybin therapy safe?

In the published trials, psilocybin given in a supervised clinical setting was generally well tolerated, with adverse events such as headache, nausea, and short-term mood worsening reported. The experience itself can be intense and at times distressing during the dosing hours. Safety depends heavily on careful screening, a prepared setting, trained supervision, and integration support, which is why unsupervised use carries added risk.

Where can I learn how to access psilocybin therapy in Canada?

The application process is initiated and justified by a prescribing physician on a case-by-case basis.

Compliance disclaimer

Psilocybin and MDMA are restricted drugs under Canada's Controlled Drugs and Substances Act. Patient access to psilocybin- or MDMA-assisted therapy is available only through Health Canada authorization, granted on a case-by-case basis and initiated by a physician. Approval is not guaranteed. Authorization for psilocybin is primarily granted for adults with treatment-resistant major depressive disorder or distress associated with a life-threatening illness. Authorization for MDMA is primarily granted for adults with PTSD.

This article is educational and is not medical advice or a clinical recommendation for any individual. Psilocybin is investigational for depression and has no Health Canada-approved indication. Clinical decisions belong with a qualified prescribing physician.

About the author

Reverdi Darda, RN, BScN, Reg #61707 | CEO & Founder, ATMA CENA

Reverdi Darda, RN is CEO & Founder of ATMA CENA and a Registered Nurse with over three decades of experience in healthcare operations, community engagement, policy development, and strategic planning. A recognized leader in mental health access, Reverdi has dedicated her career to advancing evidence-based treatment models and advocating for policy change that prioritizes effective care. She founded ATMA CENA to expand practitioner and public access to psychedelic-assisted therapy across Canada.

Sources

1. Carhart-Harris RL, et al. (2016). Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. https://pubmed.ncbi.nlm.nih.gov/27210031/
2. 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/
3. Carhart-Harris RL, et al. (2021). Trial of psilocybin versus escitalopram for depression. New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/33852780/
4. Goodwin GM, et al. (2022). Single-dose psilocybin for a treatment-resistant episode of major depression. New England Journal of Medicine. https://pubmed.ncbi.nlm.nih.gov/36322843/
5. Carhart-Harris RL, et al. (2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific Reports. https://pubmed.ncbi.nlm.nih.gov/29032520/
6. Roseman L, Nutt DJ, Carhart-Harris RL (2018). Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Frontiers in Pharmacology. https://pubmed.ncbi.nlm.nih.gov/29387009/
7. PsyCan (2025). PsyCan discovers sharp decline in Health Canada approvals for doctors seeking legal psychedelic therapy for patients. https://psychedelicscanada.org/media/2025/09/psycan-discovers-sharp-decline-in-health-canada-approvals-for-doctors-seeking-legal-psychedelic-therapy-for-patients
8. Health Canada (2022). Notice: Requests involving 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
9. ATMA CENA. Information Call. https://atmacena.com/information-call/
10. ATMA CENA. CoCare. https://atmacena.com/cocare/
11. ATMA CENA. How to Access Psilocybin Therapy in Canada.

Related articles in this cluster

• What Is Psilocybin Therapy?

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Last updated: 2026-05-27. This article is reviewed every 3 months.