Psilocybin vs ketamine therapy in Canada: legal status and evidence side by side

Ketamine and psilocybin are often grouped together as “new” depression treatments, but in Canada they sit in very different places. One form of ketamine is a Health Canada-approved prescription drug for treatment-resistant depression. Psilocybin is a controlled substance with no approved product anywhere (Health Canada, psilocybin).

This page puts the two side by side for a Canadian reader: legal status, how each is delivered, what the main randomized trials found, how long the effects lasted, and what the known risks are. It does not give doses, and it does not suggest which, if either, anyone should try. Those are decisions for a patient and their own clinician.

What is the legal status of ketamine and psilocybin in Canada?

Both are controlled under the federal Controlled Drugs and Substances Act. Ketamine is listed in Schedule I, under the phencyclidine entry, and psilocybin is listed in Schedule III (Justice Laws, CDSA). The difference is what Health Canada has authorized for sale.

Esketamine (Spravato): approved for treatment-resistant depression

Esketamine is one of the two mirror-image forms that make up ordinary (racemic) ketamine. Health Canada’s Regulatory Decision Summary says Spravato nasal spray was approved on 20 May 2020, by prescription only, in combination with an SSRI or SNRI antidepressant, for adults with major depressive disorder who have not responded adequately to at least two different antidepressants in the current moderate to severe episode (Health Canada, decision summary). The Drug Product Database lists it as marketed since 11 June 2020 and scheduled as a narcotic under the CDSA (Drug Product Database).

The current product monograph, authorized 23 May 2025, adds a second indication: short-term use with an oral antidepressant for the rapid reduction of depressive symptoms in adults whose episode, in clinical judgement, needs urgent psychiatric care (Spravato product monograph). Health Canada noted that efficacy was not shown in a study of people aged 65 and over (Health Canada, decision summary).

Racemic ketamine: an anesthetic used off-label

Ketamine itself has been sold in Canada for decades as an injectable general anesthetic. Its Canadian product monograph lists anesthesia uses only: as the sole anesthetic for some procedures, to induce anesthesia, and to supplement other agents (Ketalar product monograph). Depression is not on that list, so when clinicians give ketamine for depression it is off-label use. A 2026 review notes that most racemic ketamine formulations remain off-label for psychiatric use, unlike esketamine nasal spray, which has its own regulatory framework (Słupska et al., 2026).

Psilocybin: not approved, with three narrow legal routes

Health Canada’s page says the production, sale and possession of magic mushrooms are illegal, and that there are no approved therapeutic products containing psilocybin in Canada or elsewhere. It names three legal routes to a regulated source: clinical trials (which it calls the first route to pursue), the Special Access Program, and individual exemptions under subsection 56(1) of the CDSA, which it says should generally come only after the other two (Health Canada, psilocybin). We explain each in our guides to the Special Access Program and section 56 exemptions.

How is each one delivered in Canada?

Esketamine has the most defined rules. The monograph says Spravato is available only through a controlled distribution program run by the manufacturer. Prescribers and pharmacists must enrol, the drug is shipped to the site of care, and patients use the spray themselves under the direct supervision of a health care professional. Blood pressure must be checked before and after each dose, and patients must be monitored for at least 2 hours, until clinically stable (Spravato product monograph).

For off-label racemic ketamine we found no single federal rulebook for clinics comparable to the Spravato program, and we did not survey clinics or their fees. Canada’s main depression guideline, from the Canadian Network for Mood and Anxiety Treatments (CANMAT), says monitoring of blood pressure and dissociative side effects is required and recommends periodic urine tests to check for cystitis in people on longer-term ketamine or esketamine (Lam et al., CANMAT 2023).

“Ketamine-assisted therapy” can mean different things. A 2026 scoping review led by Canadian researchers separated ketamine-assisted psychotherapy, where the altered state is central to the therapy, from ketamine combined with psychotherapy, where it is not. Of 47 studies it found, only 4 were randomized trials; the authors say higher-quality data so far support the combined model, with three studies suggesting benefit from adding cognitive behavioural therapy (Swainson et al., 2026).

Psilocybin in trials is given as a capsule in one or two long supervised sessions with psychological preparation and support. What a session involves is covered in what happens in a psilocybin therapy session, and the Canadian legal picture in psilocybin-assisted therapy in Canada.

Psilocybin vs ketamine: the comparison at a glance

The table summarizes what the sources below say. It is a description of status and evidence, not a ranking. Rows about effects describe trial populations, which were screened and supervised.

What do the ketamine and esketamine trials show?

The modern interest started with a small crossover trial at the US National Institute of Mental Health. 18 people with treatment-resistant depression received a single ketamine infusion and a placebo infusion a week apart. Depression scores improved significantly within 110 minutes and stayed better through the week. The day after the infusion, 71% met response criteria and 29% remission; 35% kept their response for at least a week (Zarate et al., 2006).

Because ketamine’s effects are obvious, a later two-site trial compared it with midazolam, a sedative chosen as an active placebo. Among 73 people, response at 24 hours was 64% with ketamine and 28% with midazolam (Murrough et al., 2013). In 2023 a trial of 403 patients referred for electroconvulsive therapy (ECT) found ketamine noninferior to ECT: 55.4% versus 41.2% responded. That trial was open-label, and ketamine was associated with dissociation (Anand et al., 2023).

For esketamine, a phase 3 trial randomized 227 people to esketamine spray or placebo spray, each with a newly started antidepressant. At day 28 depression scores fell 4.0 points more with esketamine on the 60-point MADRS scale; 7% of the esketamine group stopped because of side effects, against 0.9% on placebo (Popova et al., 2019). In a relapse-prevention study, among people in stable remission, 26.7% who continued esketamine relapsed versus 45.3% who were switched to placebo spray (Daly et al., 2019). An open-label trial with blinded raters found more remission at week 8 with esketamine than with quetiapine added to an antidepressant, 27.1% versus 17.6% (Reif et al., 2023).

Canada’s Drug Agency, then called CADTH, read the same core trials more cautiously. In December 2020 its expert committee recommended that esketamine not be reimbursed. It said only one of the two four-week trials showed a statistically significant difference, there was no direct comparison with other effective treatments, unblinding was possible, and the trials were short (CDEC final recommendation, 2020; Canada’s Drug Agency project page). We did not check each provincial formulary. For how public coverage works in Ontario, see psychedelic therapy cost in Toronto and OHIP.

What do the psilocybin trials show?

Psilocybin has fewer and smaller randomized trials. In the largest phase 2 trial, 233 adults with treatment-resistant depression received one session at one of three dose levels with psychological support. The highest dose lowered MADRS scores 6.6 points more than the lowest dose at week 3, but sustained response at 12 weeks did not support the primary result (Goodwin et al., 2022). In 104 adults with major depression, a single session lowered scores 12.3 points more than an active niacin placebo at day 43 (Raison et al., 2023). A 59-person trial against the antidepressant escitalopram found no significant difference on its primary measure at week 6 (Carhart-Harris et al., 2021).

A 2025 meta-analysis raised a caution about these numbers. Control groups in psilocybin trials improved much less than control groups in esketamine or SSRI trials, while the active groups improved by similar amounts, which the authors say might mean psilocybin’s effect is overestimated compared with esketamine and SSRIs (Hieronymus et al., 2025). CANMAT likewise calls psilocybin-assisted psychotherapy investigational, citing lack of blinding, expectancy bias, varied psychological support and missing long-term safety data (Lam et al., CANMAT 2023). More trial detail is in our psilocybin depression trials article, and the status of the drug furthest along is in COMP360 and the FDA.

Has anyone compared psilocybin and ketamine directly?

Not in a completed, published trial that we could find. ClinicalTrials.gov lists a blinded phase 2 trial in Czechia comparing psilocybin, ketamine and midazolam in treatment-resistant depression, with 60 planned participants; its status is unknown and its record was last updated in May 2022 (NCT05383313). A Finnish trial that planned to use ketamine as an active placebo for psilocybin was listed as not yet recruiting when last updated in 2017 (NCT03380442). We found no published results from either.

Comparisons so far are indirect. A 2024 network meta-analysis of 28 randomized trials included nine of intravenous ketamine (226 participants) and three of psilocybin (231). Both beat placebo; only ketamine was significantly better than placebo at one week or less, and both were at four weeks or more. The authors rated confidence as very low to moderate and stressed the lack of direct comparison trials (Terao and Kodama, 2024). Indirect comparisons cannot account for differences between trial populations, so they cannot say which drug works better.

What are the known risks of each?

Esketamine’s monograph carries a boxed warning: a high risk of dissociation and sedation after each dose, and blood pressure rises that peak about 40 minutes after dosing. In the four-week fixed-dose trial, dissociation measured on a rating scale occurred in 61% and 69% of the two esketamine groups, against 5% on placebo. It is contraindicated where a rise in blood pressure or intracranial pressure poses a serious risk, such as aneurysms or a recent heart attack or stroke (Spravato product monograph). Health Canada listed suicide risk, respiratory depression, cognitive decline, interstitial cystitis and abuse as significant safety uncertainties (Health Canada, decision summary).

Bladder damage is the best-documented harm of heavy ketamine use. The Ketalar monograph warns of severe bladder and urinary tract inflammation, including cystitis, in people with chronic ketamine use or misuse, and says dependence and tolerance can develop (Ketalar product monograph). A meta-analysis of 45 studies covering 4,921 patients with ketamine-associated uropathy found frequency (77.1%), urgency (69.9%) and pain above the pubic bone (60.4%) were the most common symptoms, and that stopping ketamine was necessary for improvement. The review’s search was built around ketamine misuse, not medical treatment (Chan et al., 2022).

Psilocybin’s risks in trials were mostly short-lived but not trivial. In the large phase 2 trial, 77% of participants had adverse events, including headache, nausea and dizziness, and suicidal ideation, suicidal behaviour or self-injury occurred in all dose groups (Goodwin et al., 2022). Trials screened people out heavily: one excluded anyone with a history of psychosis or mania, an active substance use disorder, or active suicidal ideation with intent (Raison et al., 2023). Health Canada adds that people predisposed to or living with psychiatric conditions may face an elevated risk, and that raised blood pressure and heart rate could harm people with heart disease (Health Canada, psilocybin). Our safety page covers these risks outside trials.

What is still unknown?

• Which works better for whom. No completed randomized trial has compared psilocybin with ketamine or esketamine directly.
• How long benefits last. Single ketamine infusions fade within days to weeks, and maintenance data exist mainly for esketamine. Long-term psilocybin data are limited.
• Whether blinding is good enough. Both drugs have obvious effects, and reviewers have raised unblinding for esketamine (CADTH) and psilocybin (CANMAT, Hieronymus et al., 2025).
• The role of psychotherapy. Psilocybin is studied with structured support, and the evidence on ketamine with psychotherapy is still mostly observational.
• Long-term safety of repeated treatment for either drug outside screened trial populations.

Anyone weighing treatment options for depression in Canada can raise these questions with a family doctor or psychiatrist, who can explain what is approved, what is covered locally and what is available through research.

Shroomverse sells mushroom products. This article is general information about drug regulation and clinical research in Canada. It is not medical, legal or purchasing advice, and it does not recommend any product or treatment.