Psychedelic Therapy for Treatment-Resistant Depression in Canada

Medically reviewed by Jacque Lovely, RN, MN, MBA, PMP (Reg. #74334) — Head of Western Operations, ATMA CENA.

Treatment-resistant depression (TRD) is the one mental-health condition where all three Canadian regulatory tiers meet in the same place. Esketamine (Spravato) is Health Canada-approved for it. Ketamine is used off-label for it. Psilocybin is being investigated for it through Health Canada's Special Access Program. This guide explains what each option is, what the evidence shows, and where the honest limits are.

Key takeaways

• TRD means a major depressive episode that has not responded to at least two adequate antidepressant trials from different drug classes. Roughly one in three people with major depression meet this description after standard trials [Rush 2006].
• Spravato (esketamine) is the only Health Canada-approved psychedelic-type therapy for TRD, for adults aged 18 to 64. It is approved for TRD only, not for other depression types and not for suicidal-ideation indications in Canada [Health Canada 2020].
• Ketamine is used off-label. Health Canada approves it as an anaesthetic, not for depression. In the ELEKT-D trial, IV ketamine was non-inferior to electroconvulsive therapy for non-psychotic TRD [Anand 2023].
• Psilocybin is investigational. In Canada it is available only through the Special Access Program, case by case, and is not guaranteed [Health Canada 2022].
• No option is a cure, and none works for everyone. Response rates in trials are meaningful but partial. Decisions are individual and belong with a prescribing physician.

If you are weighing your options for treatment-resistant depression, you can book a free information call to talk through the evidence with our clinical team.

What is treatment-resistant depression?

Treatment-resistant depression is a clinical situation, not a separate diagnosis. The most common research definition has four parts: a current major depressive episode meeting DSM-5 criteria; failure of at least two prior antidepressant trials; from different pharmacological classes; each given at an adequate dose for an adequate duration, usually six to eight weeks [Sackeim 2001]. About 30 percent of people with major depressive disorder still have not responded after first- and second-line trials [Rush 2006].

TRD is more than a label. It is linked to greater day-to-day impairment, more healthcare use, more overlapping anxiety, substance-use, and chronic-pain conditions, and higher suicide risk. That burden is why several newer treatments have been studied specifically in TRD populations, and why TRD is the condition where psychedelic-type and dissociative therapies have their strongest Canadian footing.

The three Canadian options for TRD, side by side

TRD is unusual because three different regulatory pathways apply to it at once. One drug is approved. One is used off-label. One is investigational. The table below lays out the trichotomy so you can see where each option actually stands in Canada.

Factor	Spravato (esketamine)	Off-label ketamine	Psilocybin (SAP)
Health Canada status	Approved for TRD, adults 18–64	Approved as an anaesthetic only; psychiatric use off-label	Not approved; investigational, SAP only
How it is given	Nasal spray, in-clinic	IV, IM, or sublingual, in-clinic	Oral dose, in-clinic with psychological support
Strongest evidence	SUSTAIN-1 and SUSTAIN-2 [Daly 2019; Wajs 2020]	ELEKT-D vs ECT [Anand 2023]; pooled safety [Wan 2015]	COMP360 phase 2b [Goodwin 2022]
Monitoring	About 2 hours post-dose	In-clinic supervision per provincial rules	Full-day supervised session
Insurance	Prior-authorization pathways exist	Generally not covered; some exceptions	Not covered
Psychotherapy	Optional per label	Often paired, not required	Built into the protocol

The sections below explain each column in plain terms.

Spravato (esketamine): the approved option

Esketamine, sold as Spravato, is an intranasal medication that Health Canada approved in May 2020 for treatment-resistant depression in adults, taken together with an oral antidepressant [Health Canada 2020]. It is the only psychedelic-type therapy with a Health Canada label for TRD. Two points matter for eligibility. First, the Canadian approval is for TRD only, in adults aged 18 to 64. Second, the US Food and Drug Administration also approved esketamine for major depression with acute suicidal ideation or behaviour, but Health Canada has not approved that second indication [Health Canada 2020]. If you read about Spravato for suicidality, that is a US label, not a Canadian one.

Spravato is given as a two-phase course: twice-weekly dosing during an induction period, then less frequent maintenance dosing based on response. Each session includes about two hours of in-clinic monitoring because of possible sedation, dissociation, and short-term blood-pressure increases. The maintenance evidence is solid: in the SUSTAIN-1 randomized-withdrawal trial, continuing esketamine plus an antidepressant delayed relapse compared with placebo plus an antidepressant, with relapse in 26.7 percent of stable remitters on esketamine versus 45.3 percent on placebo [Daly 2019]. The one-year SUSTAIN-2 safety study followed 802 patients and reported no cases of interstitial cystitis [Wajs 2020].

For a deeper look at how this medication works, see intranasal ketamine and Spravato.

Off-label ketamine: the established off-label option

Ketamine is approved by Health Canada as an anaesthetic. Its use for depression and other mental-health conditions is off-label, regulated by provincial medical regulators such as the CPSA in Alberta, CPSO in Ontario, and CPSM in Manitoba. Off-label does not mean unapproved or experimental in the regulatory sense; it means a Health Canada-approved drug is being prescribed for a use outside its official label, which is a normal and lawful part of medical practice.

The evidence base is substantial. A pooled safety analysis of 205 IV ketamine infusions in 97 patients with TRD reported a 67 percent response rate and good tolerability, with no persistent psychotomimetic effects [Wan 2015]. The strongest recent trial is ELEKT-D, a five-site randomized study of 403 patients with non-psychotic TRD. IV ketamine was non-inferior to electroconvulsive therapy, with a 55.4 percent response rate versus 41.2 percent for ECT, and fewer memory side effects [Anand 2023]. A large Canadian real-world study found large effects at three months (Cohen's d 0.75 to 0.86) that were sustained at six months (d 0.61 to 0.73), though attrition over time was high [Yermus 2024].

For the full picture, see ketamine therapy for treatment-resistant depression.

Psilocybin: the investigational option

Psilocybin is a restricted drug under Canada's Controlled Drugs and Substances Act. It is not approved for any condition. In Canada, patients can access it only through Health Canada's Special Access Program, on a case-by-case basis, and approval is not guaranteed [Health Canada 2022].

The pivotal TRD evidence is COMP360, a phase 2b trial of single-dose psilocybin with psychological support [Goodwin 2022]. It tested three doses (25 mg, 10 mg, and 1 mg) and measured depression change at week three. The 25 mg arm showed the largest improvement, a 6.6-point greater drop on the MADRS depression scale than the 1 mg arm, with 29 percent of the 25 mg group in remission at week three [Goodwin 2022]. A separate Johns Hopkins trial in major depression (not specifically TRD) found 71 percent of participants showed clinically meaningful improvement and 54 percent were in remission at week four [Davis 2021]. Larger phase 3 trials in TRD are underway, so the durability picture is still developing.

For more, see psilocybin therapy for treatment-resistant depression.

Watch out: Be cautious of any provider who frames psilocybin as a routine or guaranteed TRD treatment, or who suggests SAP approval is a formality. It is investigational, access is limited, and approval depends on Health Canada's case-by-case review.

What the evidence does not say

Honest framing matters more here than in almost any other area, because TRD is a high-stakes condition and the marketing around psychedelics often outruns the science.

• None of these options is a cure. For Spravato and off-label ketamine, ongoing maintenance is the realistic pattern for many people. For psilocybin, durability of effect is still being studied.
• Response is partial, not universal. The COMP360 25 mg arm reached 29 percent remission at week three [Goodwin 2022]. ELEKT-D ketamine matched but did not exceed ECT [Anand 2023]. These are meaningful results, not finish lines.
• Suicidality is a separate, urgent situation. Ketamine can rapidly reduce suicidal thoughts in studied populations, but it does not replace acute psychiatric care. If you are in crisis, contact 9-8-8 (Suicide Crisis Helpline) or your local emergency department. See suicidality and psychedelic therapy.
• There are real contraindications. All three options require careful screening. A personal history of psychosis is a near-absolute exclusion in psilocybin trials, and a history of mania (bipolar I) is a strong caution across the board, including an explicit bipolar exclusion in the Spravato label [Health Canada 2020]. People with a history of mania need especially careful assessment; see bipolar disorder and psychedelic therapy.

Safety and eligibility, briefly

Every TRD pathway begins with screening, not dosing. A thorough intake reviews your diagnosis and prior treatments, your cardiovascular and blood-pressure history, any history of psychosis or mania, current medications including benzodiazepines, and substance-use history. Significant cardiovascular disease, uncontrolled hypertension, active psychosis, active mania, and pregnancy or breastfeeding are standard exclusions across these therapies, reflected in the published trial protocols and the Spravato label [Goodwin 2022; Health Canada 2020]. None of this is a checklist you pass or fail on your own; it is a conversation with a prescribing physician who can weigh your specific situation.

How to decide

There is no single best option for TRD. The right path depends on factors only you and a prescriber can weigh together: which treatments you have already tried, your cardiac and blood-pressure history, whether coverage is available, how quickly you can access a clinic, and your own comfort with each approach. Spravato has the clearest regulatory and insurance footing. Off-label ketamine has the broadest off-label evidence and route flexibility. Psilocybin remains investigational and access-limited.

If you want help thinking it through, you can book a free information call. Our clinical team can walk through what the evidence does and does not say for your situation, with no obligation to proceed.

Frequently asked questions

What counts as treatment-resistant depression?

TRD describes a current major depressive episode that has not responded to at least two adequate antidepressant trials from different drug classes, each at a proper dose for six to eight weeks [Sackeim 2001]. About 30 percent of people with major depression meet this description after standard trials [Rush 2006]. It is a clinical situation rather than a separate diagnosis.

What is actually approved for TRD in Canada?

Spravato (esketamine) is the only psychedelic-type therapy Health Canada has approved for TRD, for adults aged 18 to 64, taken with an oral antidepressant [Health Canada 2020]. It is approved for TRD specifically, not for other depression types, and not for the acute-suicidality indication that exists under the US FDA label.

Is off-label ketamine legal and safe?

Yes, off-label ketamine prescribing is legal in Canada. Ketamine is Health Canada-approved as an anaesthetic, and prescribing it off-label for TRD is within normal medical practice, regulated by provincial colleges. In the ELEKT-D trial it was non-inferior to ECT for non-psychotic TRD [Anand 2023]. Like any treatment it carries risks and requires in-clinic monitoring.

How strong is the psilocybin evidence for TRD?

The main trial, COMP360, found that a single 25 mg dose with psychological support produced a 6.6-point greater drop in depression scores than a 1 mg dose at week three, with 29 percent remission in the 25 mg group [Goodwin 2022]. This is promising phase 2 evidence. Larger phase 3 trials are ongoing, and psilocybin remains investigational in Canada.

Why is Spravato covered by insurance but ketamine usually is not?

Insurers generally reimburse medications for their Health Canada-approved indications. Spravato is labelled for TRD, so prior-authorization pathways exist. Ketamine is labelled as an anaesthetic, so its use for depression is off-label and usually not covered, though some workers' compensation and veterans' pathways are exceptions.

Can I get psilocybin therapy for depression in Canada?

Only through Health Canada's Special Access Program, which a prescribing physician applies to on your behalf. Approval is case by case and is not guaranteed [Health Canada 2022]. Psilocybin is not an approved or routinely available TRD treatment in Canada.

What if my depression is severe or I am having suicidal thoughts?

Severe or suicidal depression needs a full psychiatric assessment and may call for hospital-level care, ECT, or close outpatient monitoring. Ketamine can rapidly reduce suicidal thoughts in studied groups, but it does not replace crisis care. If you are in crisis, call or text 9-8-8 in Canada, or go to your nearest emergency department.

Does psychotherapy have to be part of it?

It depends on the option. For Spravato, psychotherapy is optional under the label. For off-label ketamine, it is often paired but not required. For psilocybin under SAP, psychological preparation and integration are built into the protocol [Goodwin 2022].

Compliance and safety information

Ketamine is approved by Health Canada as an anaesthetic. Its use for depression, anxiety, PTSD, and other mental-health indications is off-label, regulated by provincial medical regulators (for example, CPSA in Alberta, CPSM in Manitoba, CPSO in Ontario).

Psilocybin is a restricted drug under Canada's Controlled Drugs and Substances Act. Patient access to psilocybin-assisted therapy is available only through Health Canada's Special Access Program (SAP). SAP approval is granted on a case-by-case basis and is not guaranteed. Psilocybin SAP is primarily approved for adults with treatment-resistant major depressive disorder or distress associated with a life-threatening illness.

Esketamine (Spravato) is Health Canada-approved for treatment-resistant depression in adults aged 18 to 64 and is administered under medical supervision. Nothing in this article is medical advice or a recommendation for any specific person. Treatment decisions belong with a qualified prescribing physician who knows your history.

Sources

1. Rush AJ, Trivedi MH, Wisniewski SR, et al. (2006). Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. American Journal of Psychiatry, 163(11):1905–1917. https://pubmed.ncbi.nlm.nih.gov/17074942/
2. Sackeim HA. (2001). The definition and meaning of treatment-resistant depression. Journal of Clinical Psychiatry, 62 Suppl 16:10–17. https://pubmed.ncbi.nlm.nih.gov/11480879/
3. Daly EJ, Trivedi MH, Janik A, et al. (2019). Efficacy of esketamine nasal spray plus oral antidepressant treatment for relapse prevention in treatment-resistant depression (SUSTAIN-1). JAMA Psychiatry, 76(9):893–903. https://pubmed.ncbi.nlm.nih.gov/31166571/
4. Wajs E, Aluisio L, Holder R, et al. (2020). Esketamine nasal spray plus oral antidepressant in patients with treatment-resistant depression: long-term safety (SUSTAIN-2). Journal of Clinical Psychiatry, 81(3):19m12891. https://pubmed.ncbi.nlm.nih.gov/32316080/
5. Wan LB, Levitch CF, Perez AM, et al. (2015). Ketamine safety and tolerability in clinical trials for treatment-resistant depression. Journal of Clinical Psychiatry, 76(3):247–252. https://pubmed.ncbi.nlm.nih.gov/25271445/
6. Anand A, Mathew SJ, Sanacora G, et al. (2023). Ketamine versus ECT for nonpsychotic treatment-resistant major depression (ELEKT-D). New England Journal of Medicine, 388(25):2315–2325. https://pubmed.ncbi.nlm.nih.gov/37224232/
7. Goodwin GM, Aaronson ST, Alvarez O, et al. (2022). Single-dose psilocybin for a treatment-resistant episode of major depression (COMP360). New England Journal of Medicine, 387(18):1637–1648. https://pubmed.ncbi.nlm.nih.gov/36322843/
8. Davis AK, Barrett FS, May DG, et al. (2021). Effects of psilocybin-assisted therapy on major depressive disorder. JAMA Psychiatry, 78(5):481–489. https://pubmed.ncbi.nlm.nih.gov/33146667/
9. Yermus R, et al. (2024). Real-world effectiveness of ketamine-assisted therapy: a large multi-site analysis. Psychedelic Medicine, 2(2). https://pubmed.ncbi.nlm.nih.gov/40051583/
10. Health Canada (2020). Regulatory Decision Summary: Spravato (esketamine hydrochloride). https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=98903
11. Health Canada (2022). Notice to stakeholders: Requests to the Special Access Program (SAP) 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

Related articles

• Conditions Treated With Psychedelic Therapy (Hub) (parent hub)
• Ketamine Therapy for Treatment-Resistant Depression (off-label ketamine deep dive)
• Psilocybin Therapy for Treatment-Resistant Depression (SAP-investigational deep dive)
• Intranasal Ketamine and Spravato (the approved esketamine option)
• PTSD and Psychedelic Therapy (sister condition)
• Suicidality and Psychedelic Therapy (crisis-context companion)

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

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