Leading Ketamine Treatments for TRD in 2026

For people with treatment-resistant depression (TRD) — defined as depression that has not responded to at least two adequate antidepressant trials — the leading ketamine treatments in 2026 are FDA-approved esketamine (Spravato) nasal spray, intravenous (IV) racemic ketamine infusions, intramuscular (IM) injections, and physician-supervised at-home oral or sublingual programs. Each delivers ketamine differently, with different evidence, monitoring, and cost. This guide explains how they compare so you can have a more informed conversation with a qualified clinician.

The leading ketamine treatments for treatment-resistant depression in 2026

Ketamine works on a different brain pathway than traditional antidepressants — chiefly the glutamate and NMDA-receptor system — which may help explain why some people who have not improved on SSRIs or SNRIs respond to it. Studies suggest a meaningful share of people with TRD experience rapid reductions in depressive symptoms, sometimes within hours to days, though responses vary widely and are not guaranteed. The four delivery methods below are the most established options patients encounter today.

1. Esketamine (Spravato) nasal spray

Spravato is the only ketamine-based product FDA-approved specifically for treatment-resistant depression and for depressive symptoms in adults with major depressive disorder who have suicidal thoughts or behavior. It is given in a certified healthcare setting under a federal safety program (REMS), where you self-administer the spray and are monitored for at least two hours afterward. Because it is FDA-approved, it is the option most likely to be covered by insurance.

2. Intravenous (IV) racemic ketamine infusions

IV infusions deliver racemic ketamine directly into the bloodstream over roughly 40–60 minutes in a clinic, allowing precise, adjustable dosing. This is the most-studied route in depression research and is used off-label for TRD. An initial series of several infusions over a few weeks is common, sometimes followed by maintenance sessions. IV care is typically not covered by insurance and is paid out of pocket.

3. Intramuscular (IM) injections

IM injections offer many of the benefits of IV without an infusion line, using a single injection administered and monitored in-clinic. Dosing is less adjustable mid-session than IV, but the approach can be faster and lower-cost to deliver. Like IV, IM ketamine for depression is off-label.

4. At-home oral and sublingual ketamine programs

Telehealth-based programs prescribe low-dose oral or sublingual (under-the-tongue) ketamine for use at home after a clinical evaluation, often paired with virtual support. Convenience and lower cost are the main draws, but bioavailability is lower and supervision is remote. Quality and safety screening vary significantly between providers. Learn what to look for in our guide to at-home telehealth ketamine.

How the options compare

Treatment	Setting	Regulatory status	Typical insurance coverage
Spravato (esketamine)	Certified clinic, monitored	FDA-approved for TRD	Often covered
IV infusion	Clinic, monitored	Off-label	Usually out of pocket
IM injection	Clinic, monitored	Off-label	Usually out of pocket
At-home oral/sublingual	Home, remote support	Off-label	Usually out of pocket

For a deeper side-by-side look at routes, evidence, and trade-offs, see our treatment comparisons.

How to choose the right treatment for you

No single option is best for everyone. The right choice depends on your diagnosis and history, safety considerations, how much in-person monitoring you need, and your budget. Consider these factors with your clinician:

• Severity and urgency. People with acute suicidality may be steered toward closely supervised, FDA-approved care.
• Medical and psychiatric history. Conditions such as uncontrolled blood pressure, certain heart problems, psychosis, or substance use history affect eligibility.
• Monitoring needs. In-clinic routes provide immediate medical supervision; at-home routes rely on screening and remote support.
• Cost and coverage. Spravato is most often insurance-eligible; other routes are commonly self-pay.

Whatever route you consider, vetting the people delivering it matters. Our guides to choosing a qualified provider and ketamine safety cover the credentials, screening, and monitoring standards to expect from a reputable program.

What to ask before starting

1. What are your clinicians' credentials, and who monitors me during and after treatment?
2. How will you screen me for medical and psychiatric risks?
3. What does a full course cost, and is any part covered by insurance?
4. What is the plan if I respond — and if I don't?
5. How do you handle side effects and emergencies?

Ketamine is not a cure, and benefits often require maintenance and integration with other care. Discuss realistic expectations openly.

This article is patient education, not medical advice. Always consult a licensed healthcare professional about your individual situation before starting or changing any treatment.

Frequently Asked Questions

Which ketamine treatment for TRD is FDA-approved?

Esketamine (Spravato) nasal spray is the only ketamine-based product FDA-approved specifically for treatment-resistant depression. IV, IM, and at-home oral or sublingual ketamine are used off-label for depression.

Is ketamine a cure for treatment-resistant depression?

No. Ketamine is not a cure. Studies suggest it can rapidly reduce depressive symptoms in some people with TRD, but responses vary, and benefits often require maintenance sessions and integration with other mental health care.

Does insurance cover ketamine treatment in 2026?

Coverage varies. Because Spravato is FDA-approved, it is the option most likely to be covered, often with prior authorization. IV, IM, and at-home ketamine are typically paid out of pocket. Check directly with your insurer and provider.

Is at-home ketamine safe for depression?

At-home oral or sublingual programs can be convenient and lower-cost, but supervision is remote and screening quality varies. Safety depends heavily on thorough medical screening and a reputable provider. Discuss risks with a licensed clinician first.