Ketamine itself is not FDA approved for treating depression or any psychiatric disorder. However, a closely related form called esketamine (brand name Spravato) is FDA approved as a nasal spray for specific types of depression. This distinction matters because it affects how each version is regulated, administered, and covered by insurance.
What the FDA Has Actually Approved
Ketamine received its original FDA approval in 1970, but only as an injectable anesthetic for surgical procedures. The FDA has never approved ketamine for depression, anxiety, PTSD, or any other psychiatric condition. As the FDA states plainly: “Ketamine is not FDA approved for the treatment of any psychiatric disorder,” and the agency has not established safe or effective dosing of ketamine for these uses.
What is approved is esketamine, a nasal spray that contains one half of the ketamine molecule (the “S” mirror image). The FDA approved Spravato in 2019 for two specific situations: treatment-resistant depression in adults, and depressive symptoms in adults with major depressive disorder who have acute suicidal ideation or behavior. For the suicidal ideation indication, it must be used alongside an oral antidepressant. For treatment-resistant depression, it can be used as a standalone treatment or combined with an oral antidepressant.
The Difference Between Ketamine and Esketamine
Ketamine is a mixture of two mirror-image molecules. Esketamine isolates just one of those molecules, which binds more potently to the brain receptors involved in its antidepressant effects. Both work by blocking a receptor called NMDA, which plays a role in how brain cells communicate using the chemical messenger glutamate. This is fundamentally different from traditional antidepressants, which target serotonin, norepinephrine, or dopamine. By acting on a completely different signaling system, ketamine and esketamine can produce rapid improvements in mood, sometimes within hours, compared to the weeks that conventional antidepressants typically require.
The practical difference for patients is significant. Esketamine went through the full FDA approval process with large clinical trials demonstrating safety and effectiveness. IV ketamine for depression, while widely used in private clinics, has not gone through that process. This means IV ketamine clinics are using the drug “off-label,” which is legal but means the FDA has not verified its safety or effectiveness for that purpose.
Who Qualifies for Esketamine
Treatment-resistant depression is diagnosed when at least two different first-line antidepressants, each taken at an adequate dose for six to eight weeks, have failed to adequately manage a depressive episode. This is a higher bar than simply not responding to one medication. Roughly 30% of people with major depression meet this threshold, which represents a large population with limited remaining options.
The second approved use covers adults experiencing active suicidal thoughts or behavior alongside major depression. This indication reflects esketamine’s unusually fast onset of action, which can be critical when someone is in immediate crisis and cannot wait weeks for a traditional antidepressant to take effect.
How Esketamine Treatment Works
Esketamine is not something you pick up at a pharmacy and use at home. Every dose must be administered in a certified healthcare setting under direct observation. You self-administer the nasal spray while a healthcare provider watches, then you’re monitored for at least two hours afterward. During that observation period, staff check for sedation, dissociation (a feeling of being detached from your body or surroundings), and changes in blood pressure.
The treatment schedule follows a structured timeline. During the first four weeks (the induction phase), you visit the clinic twice per week. Weeks five through eight shift to once weekly. From week nine onward, the frequency drops to once every one or two weeks depending on your response. This tapering schedule means the early weeks require a substantial time commitment, with each visit lasting at least two and a half hours including the monitoring period.
These strict requirements exist because of a mandatory safety program called REMS (Risk Evaluation and Mitigation Strategy). Only certified healthcare settings can dispense esketamine, and patients cannot take the medication home. This is one of the most tightly controlled distribution systems for any FDA-approved psychiatric medication.
Side Effects During Treatment
The most common side effects are dissociation, dizziness, nausea, sedation, and vertigo. These tend to be worst during the first week. In clinical trials, about 21% of patients experienced dizziness during week one, 17% experienced dissociation, 14% had nausea, and 12% reported vertigo. The good news is that these rates dropped noticeably after the first few sessions as the body adjusted.
Blood pressure increases are another concern, occurring in about 4% of patients during the first week. This is why blood pressure monitoring is part of the two-hour observation window after each dose. People with a history of bleeding in the brain, aneurysms, or abnormal blood vessel connections should not use esketamine. Severe liver disease is also a reason to avoid it, since the body may not clear the drug effectively.
Because of the sedation and dissociation effects, you cannot drive or operate heavy machinery for the rest of the day after a treatment session. Most clinics require you to arrange a ride home.
What About IV Ketamine Clinics?
Hundreds of private clinics across the United States offer IV ketamine infusions for depression, despite ketamine lacking FDA approval for this use. Physicians are legally permitted to prescribe FDA-approved drugs for off-label purposes, and ketamine’s approval as an anesthetic makes this possible. However, there are important differences from the approved esketamine pathway.
IV ketamine clinics are not subject to the same REMS safety monitoring requirements. Dosing varies from clinic to clinic because the FDA has never established safe or effective psychiatric dosing. Insurance rarely covers IV ketamine for depression, meaning patients typically pay out of pocket, often $400 to $800 per infusion. Compounded ketamine products, including lozenges, nasal sprays, and at-home formulations sold through telehealth companies, carry additional risks. The FDA has issued warnings that compounded ketamine products have not been evaluated for safety, effectiveness, or quality.
This does not mean IV ketamine is ineffective. A substantial body of research supports its rapid antidepressant effects. But the regulatory gap means patients navigating the IV ketamine landscape face less standardization and fewer safety guardrails than those receiving esketamine through the approved pathway.