Ketamine can be given as an intravenous (IV) infusion, an injection into muscle or under the skin, or by mouth. These routes differ in how much medicine reaches the bloodstream, how predictable that amount is, how much research supports them and how closely you are monitored. IV ketamine has the largest body of depression research. None of these routes is FDA-approved for depression.
Part of our guide: A Patient’s Guide to Ketamine and Spravato
Research does not name one best route for everyone. A 2026 expert panel convened by the American Society of Clinical Psychopharmacology said uncertainties persist about novel formulations such as oral and intramuscular ketamine. The right question is which option fits your health, your history and the safety setup available to you.
If you are thinking about suicide or are in danger, call or text 988 (988 Suicide & Crisis Lifeline), call 911 or go to the nearest ER.
The off-label starting point
The FDA states that ketamine is not FDA-approved for the treatment of any psychiatric disorder. The approved product, Ketalar, is a general anesthetic given by IV or intramuscular injection. So every ketamine route below is off-label when used for depression, and oral, lozenge and compounded nasal forms have no FDA-approved version at all. Compounded drugs have no FDA-approved uses or routes, and the FDA has not evaluated their safety, effectiveness or quality before marketing.
The only FDA-approved option in this family for depression is Spravato (esketamine) nasal spray, a related but separate medicine. It has its own rules, covered in this overview of Spravato.
The routes at a glance
| Route | Share reaching the bloodstream | Evidence for depression | FDA status for depression |
|---|---|---|---|
| IV infusion | Complete, since it enters the blood directly | The most studied ketamine route, including a large trial against ECT | Off-label |
| Intramuscular injection | About 93% in one small study | Less studied; experts note open questions | Off-label |
| Subcutaneous injection | Not established in the sources reviewed here | One phase 3 trial with mixed results by dosing approach | Off-label |
| Oral or lozenge | About 17% by mouth in one small study; lower and more variable than injected routes. No lozenge figure in the sources reviewed here | Early, few randomized trials | Off-label, compounded products are unapproved |
| Spravato nasal spray (esketamine) | About 48% | Phase 3 trials | FDA-approved for specific uses |
The absorption figures for injected and oral ketamine come from a 1982 study in healthy volunteers using pain-relief doses, so treat them as rough guides. The Spravato figure comes from its FDA label. A 2026 review describes oral ketamine as having lower and more variable absorption than injected routes.
Why absorption matters, and where it has limits
More medicine reaching the blood does not automatically mean a better result for a given person. What low and variable absorption does mean is that the same dose can act differently from one person to another, and that it may be harder to predict how a dose will feel. Ask your clinician how they account for this.
IV infusion
Most ketamine depression research uses this route. A 2021 Cochrane review notes that most ketamine studies used IV administration. It found ketamine may be more effective than placebo at 24 hours, though much of that evidence was rated low or very low certainty.
The largest head-to-head study is ELEKT-D, which compared IV ketamine with ECT in 403 people with treatment-resistant depression without psychosis. In that study, 55.4% of the ketamine group and 41.2% of the ECT group met the response goal, and ketamine was noninferior to ECT. That design tests whether a treatment is not meaningfully worse, over a 3-week treatment phase. Other head-to-head evidence points the other way. In the 2022 KetECT trial of 186 hospitalized patients, 63% remitted with ECT and 46% with ketamine. A 2024 meta-analysis of six trials could not show ketamine was noninferior overall and favored ECT for inpatients, while a 2026 meta-analysis found no significant difference. The comparison is unsettled.
In that trial, each infusion ran over 40 minutes, twice a week for 3 weeks, and the main side effect linked to ketamine was dissociation. Even the approved anesthetic label calls for monitoring vital signs and heart function during Ketalar administration, because blood pressure and heart rate often rise for a short time.
Injection into muscle or under the skin
The evidence for injections is smaller than for infusions. A 2022 review of maintenance treatment found support for several routes but described intramuscular and subcutaneous use with the word "possibly." One controlled subcutaneous study is the KADS trial, a phase 3 study in Australia and New Zealand. In the group whose doses were adjusted by response, remission was 19.6% with ketamine and 2.0% with the comparison drug. In the fixed-dose group, there was no difference. The trial's authors concluded that adequately dosed subcutaneous ketamine was effective over 4 weeks, that the route is practical and feasible, and that short-term side effects resolved within 2 hours.
Oral and lozenge forms
Oral forms are easier to give and do not need a needle. A 2023 systematic review found 22 studies and only four randomized trials. It called the evidence preliminary and said those trials had a high risk of bias, largely because of how results and side effects were analyzed and monitored. Further study is needed, especially for treatment-resistant depression.
One newer development is an investigational extended-release tablet. In a phase 2 trial, people who first responded to the tablet then did better on the highest dose than on placebo over 13 weeks. Because only early responders moved into that phase, the result does not show how well the tablet works for everyone who starts it. It also does not apply to compounded lozenges or liquids.
Oral forms have become linked with home use, which raises separate safety issues. This article on the FDA's concerns explains them. Whether a route is safe depends partly on who is watching, and a 2026 review of ketamine practice recommends observation when oral doses are first given or increased.
Risks that apply across routes
The route changes how fast and how strongly effects come on, but the general risk list stays similar. The FDA's 2023 alert on compounded ketamine lists concerns that include:
- abuse and misuse
- psychiatric events
- increases in blood pressure
- slowed breathing
- lower urinary tract and bladder symptoms
- sedation and dissociation
Ketamine is a Schedule III controlled substance. Heart and blood pressure conditions, past psychosis, pregnancy and a history of substance use all deserve a direct conversation before any route. Long-term safety is also unsettled across routes. A Cochrane review called for rigorous real-world monitoring to build better safety data.
Spravato, the related FDA-approved spray, carries boxed warnings for sedation, dissociation, respiratory depression, abuse and misuse, and suicidal thoughts and behaviors in young people. Although those warnings are written for Spravato, the shared chemistry is a good reason to ask about each of them with ketamine.
Questions to ask about any route
- Which route and exact product is recommended, and why this one in particular?
- Is it FDA-approved for anything, or is it compounded?
- How strong is the evidence for this route in people with a similar history?
- Who stays present, and for how long after a dose?
- Are blood pressure and breathing checked, and when?
- Where does each dose happen, and who holds the medicine?
- What is the plan for anxiety or heavy sedation during a dose?
- How is benefit measured, and what happens if it fades?
Where to learn more
Routes available vary by clinician and setting. For how Mind Body Seven approaches this treatment, see its ketamine therapy page, and bring your questions about routes to a consultation, along with a list of your medicines and health conditions. This article on ketamine psychotherapy offers more background.
FAQs
Does a stronger feeling mean ketamine is working better?
Not necessarily. How intense a session feels and how much depression improves are separate questions. Track your mood over days and weeks with your clinician, and do not judge by a single session.
Is it possible to switch routes if one is a poor fit?
That is a clinical decision. Tell your clinician about side effects and how much benefit you noticed. Never adjust a dose or combine products yourself.
Is a compounded ketamine nasal spray the same as Spravato?
No. Spravato is an FDA-approved esketamine product with a required safety program. Compounded nasal sprays are not FDA-approved, and FDA has raised specific concerns about them.
