Ketamine Therapy for Anxiety

Ketamine for anxiety disorders is emerging-evidence, off-label medicine. There is encouraging peer-reviewed data — particularly for treatment-refractory generalized anxiety disorder (GAD) and social anxiety disorder (SAD) — but the evidence base is much smaller and earlier-stage than for treatment-resistant depression. Spravato (esketamine) is approved only for treatment-resistant depression in Canada and the United States; it is not approved for any anxiety indication. Any use of ketamine for primary anxiety in Canada is off-label and should be framed honestly. This article walks through the actual evidence (Glue 2017/2018/2020, Taylor 2018 SAD RCT, Whittaker 2021 meta-analysis, Tully 2022 systematic review, Drozdz 2022 KAP review, Masdrakis 2025 latest review), CANMAT's positioning, how anxiety-primary versus anxious-depression presentations are typically framed at intake, and what the realistic decision is for patients who have not responded to first-line treatments.

Key takeaways

• Ketamine for anxiety is off-label and emerging-evidence — encouraging signal in treatment-refractory GAD and SAD, but a much smaller evidence base than for treatment-resistant depression (TRD).
• Spravato (esketamine) is NOT approved for any anxiety indication in Canada or the United States. Any anxiety use is off-label and uses racemic ketamine.
• The strongest anxiety-specific data is from the Glue group's RCTs in treatment-refractory GAD/SAD (2017, 2018, 2020) and the Whittaker 2021 meta-analysis showing a large effect for SAD.
• CANMAT's 2021 racemic ketamine task force notes "preliminary" evidence in social anxiety disorder, OCD, and PTSD — not a formal recommendation.
• At ATMA CENA, anxiety-primary patients are typically evaluated as anxious-depression / TRD with anxious features, since ketamine's strongest evidence base sits there. The information call screens for fit before any commitment.

What is ketamine-assisted therapy?

Ketamine therapy uses sub-anaesthetic doses of ketamine — a Health Canada-approved anaesthetic — delivered alongside structured psychotherapy. Health Canada has approved ketamine as an anaesthetic; psychiatric use is off-label, a legal and common practice in Canadian medicine. Spravato (intranasal esketamine) is Health Canada-approved for treatment-resistant MDD as of May 2020. Spravato is not approved for any anxiety indication. All ketamine-for-anxiety in Canada uses racemic ketamine off-label.

When ketamine is paired with structured psychotherapy before, during, and after dosing, the treatment is called ketamine-assisted psychotherapy (KAP) or ketamine-assisted therapy (KAT). For the full mechanism breakdown, see What Is Ketamine Therapy?.

How ketamine could affect anxiety circuits

The mechanistic story behind ketamine's antidepressant effect translates plausibly — but not certainly — to anxiety circuits. NMDA receptor antagonism on cortical GABAergic interneurons disinhibits glutamatergic projections. The resulting glutamate surge activates AMPA receptors and triggers BDNF release, mTOR-pathway signalling, and synaptogenesis in prefrontal cortex (PFC), hippocampus, and amygdala within 24 to 72 hours of a dose (Aleksandrova et al., 2017; Lullau et al., 2023).

For anxiety specifically, the mechanistically relevant outcome is restored PFC inhibitory tone over the amygdala. Anxiety disorders are characterized by amygdala hyperactivity and weakened top-down PFC regulation; ketamine's synaptogenic effect appears to strengthen this top-down circuit, which would predict reductions in fear/threat salience and rumination. This is a plausible mechanism for the clinical effects observed in the Glue trials and Whittaker meta-analysis described below — but mechanism-to-clinic translation in psychiatry is rarely linear, and the role of NMDA antagonism specifically in anxiety reduction remains an open research question (Tully et al., 2022).

What the evidence actually shows

The peer-reviewed data on ketamine for anxiety disorders is real but small. Here's what's been published.

Treatment-refractory GAD and SAD: the Glue trials

Glue et al. 2017 — Journal of Psychopharmacology — was the first dose-finding RCT of ketamine in treatment-refractory GAD/SAD. Twelve patients received ascending subcutaneous doses (0.25, 0.5, 1.0 mg/kg). HAM-A and Fear Questionnaire scores fell substantially within 1 hour of dosing and persisted at 7 days; 10 of 12 (83%) responded at 0.5–1 mg/kg with a clear dose-response signal (PubMed).

Glue et al. 2018 — Journal of Psychopharmacology — extended the work to maintenance dosing in 20 patients (75% GAD, 90% SAD) with weekly to twice-weekly subcutaneous 1 mg/kg ketamine over 3 months. Anxiety scores remained reduced ~50% from baseline; 18 of 20 (90%) reported improved social/work functioning. Dissociative effects diminished with repeated dosing (PubMed).

Glue et al. 2020 — Journal of Psychopharmacology — was an exploratory double-blind psychoactive-controlled (midazolam) replication study (N=28). Single-dose 0.5 mg/kg ketamine outperformed midazolam on Fear Questionnaire and HAM-A; the effect was sustained at 7 days. Adding the active control adds rigour to the earlier signal (PubMed).

Social anxiety disorder: the Yale RCT

Taylor et al. 2018 — Neuropsychopharmacology — was a randomized placebo-controlled crossover trial in 18 SAD patients. Single IV ketamine 0.5 mg/kg significantly reduced Liebowitz Social Anxiety Scale scores at 2 weeks; 33% of the ketamine arm versus 0% of the placebo arm achieved ≥30% improvement. A clean proof-of-concept for SAD efficacy (PubMed).

Pooled and synthesis evidence

Whittaker et al. 2021 — Therapeutic Advances in Psychopharmacology — pooled 6 acute ketamine RCTs across SAD (n=2 trials), PTSD (n=3), and OCD (n=1). For SAD, the pooled odds ratio was 28.94 (95% CI 3.45–242.57; p=0.002) — a very large effect. PTSD findings were mixed (OR 2.03, not statistically significant). The authors concluded that ketamine is "broadly effective across treatment-resistant anxiety spectrum disorders" but cautioned about study heterogeneity (PubMed).

Tully et al. 2022 — British Journal of Clinical Pharmacology — a systematic review of 18 studies (513 participants) covering single-dose ketamine across refractory anxiety disorders. Conclusion: single-dose ketamine produces fast-acting anxiolytic effects sustained up to a week; calls for standardized RCTs to clarify durability and optimal protocols (PubMed).

Drozdz et al. 2022 — Journal of Pain Research — a systematic narrative review of 17 KAP studies (603 participants) covering anxiety, depression, PTSD, and pain. Conclusion: combining psychotherapy with ketamine "can initiate and prolong clinically significant reductions in pain, anxiety, and depressive symptoms," with a need for more RCT-grade evidence on optimization (PubMed).

Masdrakis et al. 2025 — Journal of Psychopharmacology — the most recent systematic review covering both racemic ketamine and esketamine across primary anxiety disorders and anxiety symptoms in depression. Off-label racemic ketamine shows efficacy across GAD, SAD, OCD, and PTSD; esketamine's anxiety improvements are secondary benefits within depression treatment, since esketamine is not approved for primary anxiety. The review highlights the need for long-term durability data and standardized dosing.

How big is the effect, and how durable?

Across the Glue/Taylor/Whittaker trials, single-dose subcutaneous or IV ketamine at 0.5–1 mg/kg produced anxiety symptom reductions within 1–24 hours with effects sustained up to ~7 days. Maintenance dosing (weekly to twice-weekly) extended the effect through the active treatment period. Compared to ketamine for TRD — where antidepressant effects are similarly rapid but typically last days to a couple of weeks per dose with maintenance protocols — the anxiety durability data is comparable but with much smaller sample sizes and shorter follow-up. The honest summary: encouraging but preliminary.

CANMAT's positioning

The Canadian Network for Mood and Anxiety Treatments (CANMAT) issued formal recommendations on racemic ketamine for adults with major depressive disorder in 2021 (Swainson et al., 2021) — placing IV racemic ketamine as a third-line treatment for adults with TRD. CANMAT's 2023 MDD guideline update reinforces this positioning. CANMAT has not issued standalone anxiety-disorder guidelines that include ketamine as a recommended therapy.

The 2021 task force does specifically note: "Some controlled data suggest that (R,S)-ketamine may have therapeutic benefits in other disorders and symptom domains — including bipolar depression, post-traumatic stress disorder (PTSD), obsessive–compulsive disorder, social anxiety disorder, substance dependence, and suicidal ideation — although this evidence is preliminary and needs to be replicated in larger controlled studies."

The practical takeaway: Canadian clinical guidelines treat ketamine for primary anxiety disorders as preliminary, not recommended at a treatment-pathway level. This is honest framing for patients deciding whether to pursue it.

Anxiety-primary versus anxious-depression: how ATMA CENA frames it

In the real Canadian clinic population, fully anxiety-primary patients (no depressive features) are uncommon among ketamine candidates. The most common presentation is anxious depression — major depression with prominent anxious features, or comorbid GAD/SAD/panic with depression. Ketamine has Level 1 evidence in TRD; in anxious-depression, the standard framing is to treat the depression component with ketamine and observe whether the anxiety dimension co-improves (which the broader evidence base, including Whittaker 2021, suggests is common).

For patients who present anxiety-primary without depressive features and who have failed first- and second-line anxiety treatments (SSRIs, SNRIs, CBT, exposure therapy, possibly augmentation strategies), ketamine remains an off-label option with the evidence base described above. ATMA CENA's intake call works through:

• Diagnostic clarification (primary anxiety disorder, anxious depression, or another presentation)
• Treatment history (which first-line and second-line treatments have been tried, at adequate dose and duration)
• Comorbidity (substance use, bipolarity, psychosis, cardiovascular risk)
• Psychosocial readiness for the KAP model (preparation, dosing, integration)

The honest principle: ketamine for primary anxiety is reasonable to consider after evidence-based first-line treatments have been adequately tried, with informed consent that the evidence base is preliminary.

Who is a candidate?

Most ketamine programs use the following inclusion criteria for anxiety-related referrals:

• Adults 18 or older
• Diagnosis of treatment-refractory GAD, SAD, panic disorder, or anxious depression with documented adequate trials of first-line treatments (SSRIs/SNRIs at therapeutic dose for 6+ weeks; CBT or exposure therapy)
• Medically stable; able to provide informed consent
• Realistic expectations grounded in the evidence

Absolute contraindications: active psychosis, uncontrolled severe hypertension, severe cardiovascular disease, current pregnancy, anaphylactic reaction to ketamine, active manic episode. Relative contraindications: history of substance use disorder, severe personality disorder with marked instability, recent stroke, untreated severe sleep apnea, concurrent MAOIs or high-dose benzodiazepines (note that benzodiazepines may blunt ketamine's effect — this is a meaningful pharmacodynamic consideration for many anxiety patients on ongoing benzodiazepine treatment).

For full eligibility detail, see How to Qualify for Ketamine Therapy in Canada.

What does ketamine therapy cost?

ATMA CENA's published KAT pricing applies across the network: KAT Psychedelic Pathway from CAD $1,585 + $795 per additional session; KAT Psycholytic Pathway from CAD $1,530 + $740 per additional session; customized programs CAD $2,325–$6,930. A non-refundable deposit of CAD $300 applies. For the full Canadian pricing context, see Ketamine Therapy Cost in Canada.

Important: most provincial drug plans do not cover off-label ketamine for psychiatric use. Spravato has prior-authorization pathways through some private insurers for documented TRD — but Spravato is not approved for any anxiety indication, so a TRD diagnosis is what enables the Spravato pathway. For full insurance navigation, see Insurance Coverage for Ketamine Therapy.

Frequently asked questions

Is ketamine approved for anxiety in Canada? No. Ketamine is approved by Health Canada as an anaesthetic. Any psychiatric use is off-label. Spravato (esketamine) is approved only for treatment-resistant depression — it is not approved for any anxiety indication. All ketamine-for-anxiety in Canada uses racemic ketamine off-label.

What's the strongest evidence for ketamine in anxiety disorders? The Glue group's RCTs in treatment-refractory GAD and SAD (2017, 2018, 2020) and the Yale Taylor SAD RCT (2018), with pooled SAD effects in the Whittaker 2021 meta-analysis (OR 28.94, 95% CI 3.45–242.57). Beyond SAD, the evidence is preliminary.

Does CANMAT recommend ketamine for anxiety? Not at a treatment-pathway level. CANMAT's 2021 racemic ketamine task force notes preliminary evidence in social anxiety disorder, OCD, and PTSD, but does not formally recommend ketamine for primary anxiety disorders. CANMAT's MDD guideline places IV ketamine as a third-line treatment for treatment-resistant depression.

What if my anxiety is part of treatment-resistant depression? This is the most common ATMA CENA referral. In anxious-depression, ketamine is treating documented TRD; the anxiety dimension often co-improves. The evidence base for TRD is much stronger than for primary anxiety, and Spravato pathways through private insurance generally apply when TRD is the diagnosis.

How fast does ketamine work for anxiety, and how long does it last? Across the Glue/Taylor trials, anxiety reductions occurred within 1–24 hours and were sustained up to ~7 days from a single dose. Maintenance dosing (weekly to twice-weekly) extended effects through the active treatment period. Long-term durability data is limited.

What about ketamine for panic disorder or OCD specifically? There are smaller signals for panic and OCD in the literature, including case reports and small trials. The evidence is weaker than for SAD and GAD. ATMA CENA evaluates these on a case-by-case basis.

Can I combine ketamine with my current SSRI or SNRI? Generally yes. Most ketamine protocols are compatible with ongoing SSRI/SNRI treatment. MAOIs and high-dose benzodiazepines are the main concerns; benzodiazepines may blunt ketamine's effect. ATMA CENA's clinical screening reviews concurrent medications.

Will I need to come off my benzodiazepines? Not necessarily, but expectation-setting matters: ongoing benzodiazepine use may reduce ketamine's antidepressant and anxiolytic effect. ATMA CENA's clinical team will discuss whether dose timing or tapering is appropriate for your situation.

Is ketamine addictive? I'm nervous about adding another dependence on top of anxiety medication. Ketamine has misuse potential when used recreationally and unsupervised. In supervised clinical KAP protocols at typical sub-anaesthetic doses, dependence has not emerged as a clinical issue. The Glue maintenance studies (3 months of weekly–twice-weekly dosing) did not report dependence outcomes; clinical screening for substance use history is part of intake.

What are the main side effects? Acute: transient dissociation (typically 30–60 minutes), elevated blood pressure, mild nausea. Less common: dizziness, headache, anxiety surge during dosing (counterintuitively — this is part of why preparation work matters for anxiety patients). Most acute effects resolve within 1–2 hours. Some patients find the dissociative experience itself anxiety-provoking; honest preparation helps.

Where can I get ketamine therapy in Canada? See the city- and province-specific articles in this cluster: Calgary, Edmonton, Winnipeg, Toronto/GTA, Vancouver, Saskatoon, Mississauga, Hamilton, Ottawa, Montreal, Halifax, Victoria BC, Kelowna, London ON.

Sources

1. ATMA CENA — Psychedelic-Assisted Therapy (pricing): https://psychedelic.healthcare/
2. Glue P, et al. (2017). Ketamine's dose-related effects on anxiety symptoms in treatment-refractory anxiety disorders. J Psychopharmacol. https://pubmed.ncbi.nlm.nih.gov/28441895/
3. Glue P, et al. (2018). Maintenance ketamine in treatment-refractory GAD and SAD. J Psychopharmacol. https://pubmed.ncbi.nlm.nih.gov/29561204/
4. Glue P, et al. (2020). Double-blind psychoactive-controlled replication. J Psychopharmacol. https://pubmed.ncbi.nlm.nih.gov/31838954/
5. Taylor JH, et al. (2018). Ketamine for Social Anxiety Disorder RCT. Neuropsychopharmacology. https://pubmed.ncbi.nlm.nih.gov/28849779/
6. Whittaker E, et al. (2021). Meta-analysis of ketamine in refractory anxiety spectrum disorders. Ther Adv Psychopharmacol. https://pubmed.ncbi.nlm.nih.gov/34925757/
7. Tully JL, et al. (2022). Ketamine for refractory anxiety: a systematic review. Br J Clin Pharmacol. https://pubmed.ncbi.nlm.nih.gov/35510346/
8. Drozdz SJ, et al. (2022). Ketamine-Assisted Psychotherapy: a systematic narrative review. J Pain Res. https://pubmed.ncbi.nlm.nih.gov/35734507/
9. Masdrakis VG, et al. (2025). Ketamine/esketamine for anxiety disorders and anxiety symptoms in depression: systematic review. J Psychopharmacol. https://journals.sagepub.com/doi/10.1177/02698811251389583
10. Aleksandrova LR, et al. (2017). Antidepressant mechanisms of ketamine — AMPA, mTOR, BDNF. Can J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/28234212/
11. Lullau APM, et al. (2023). Antidepressant mechanisms of ketamine. Front Neurosci. https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1223145/full
12. Swainson J, et al. (2021). CANMAT racemic ketamine task force recommendations. Can J Psychiatry. https://pubmed.ncbi.nlm.nih.gov/33174760/
13. Health Canada DPD — Spravato: https://health-products.canada.ca/dpd-bdpp/info?lang=eng&code=98903

Related articles in this cluster

• Ketamine Therapy in Canada
• What Is Ketamine Therapy?
• Ketamine Therapy Cost in Canada
• How to Qualify for Ketamine Therapy in Canada
• Ketamine Therapy for Depression
• Ketamine Therapy FAQs
• Insurance Coverage for Ketamine Therapy
• Ketamine vs Psilocybin Therapy

Last updated: 2026-05-05