Time Magazine brought ketamine into the mainstream in 2017. The FDA approved esketamine two years later.
Oral, intranasal, intravenous, and subcutaneous routes compared
STUDY: Słupska A et al, Frontiers in Psychiatry 2026
STUDY TYPE: Narrative review with expert-consensus practice recommendations
FUNDING: Medical University of Gdańsk, Poland; Several co-authors report financial ties to ketamine and esketamine makers, including Janssen
Background
Ketamine and its S-enantiomer, esketamine, produce rapid antidepressant effects in treatment-resistant depression, but only intranasal esketamine carries an FDA-approved label. Every other route, intravenous, subcutaneous, oral, or compounded nasal racemic ketamine, is off-label, and psychiatrists have had little formulation-specific guidance on dosing or when to stop.
The Study
- A narrative clinical review, not a systematic review, drawing on randomized trials, systematic reviews, and product labeling.
Five Forms
- Intranasal esketamine (Spravato) and IV racemic ketamine (0.5 mg/kg over 40 minutes, once or twice weekly) have the strongest evidence in depression. Both require direct supervision.
- Outside of those, subcutaneous ketamine has the best evidence. It outperformed an active comparator in a 4-week trial using flexible dosing from 0.5 to 0.9 mg/kg twice weekly, titrated by response.
- Oral ketamine is low-cost but not well studied, and its low bioavailability and risk of diversion makes it questionable.
- Compounded intranasal racemic ketamine, a different product from esketamine, has the weakest evidence.
How Long to Treat?
- For all routes, discontinue after 4 to 6 sessions without a 20% to 30% drop in depression scores and move responders to a continuation plan rather than treating indefinitely.
Practice Implications
- Use a written treatment contract outlining expectations, including events that would lead to stopping the medication.
- Safeguard against misuse with limited dispensing, no early refills, and monitoring for drug-liking behavior. Also rate depression and suicidality at each visit.
- If intravenous access isn’t feasible, supervised subcutaneous dosing, starting at 0.5 mg/kg twice weekly and titrating toward 0.9 mg/kg, is the best-supported off-label option.
- If a patient shows no improvement after 4 to 6 sessions, stop and reassess rather than raising the dose.
- IV ketamine is moving toward FDA approval; learn more in the Carlat Podcast.
—Chris Aiken, MD
Director, Psych Partners
Editor in Chief, Carlat Psychiatry Report
