Ketamine dosing

The short version: ketamine dosing for depression is a real intervention with real effects, but the evidence base is thin, short-term, and funded by interests that profit from its use.

You asked about dosing. The most studied regimen is a single intravenous infusion of 0.5 mg/kg given over 40 minutes [1, 2]. That dose produces a rapid antidepressant effect in about 40-50% of people with treatment-resistant depression, lasting roughly one to three weeks [2, 4]. A 2018 dose-ranging trial found that 0.5 mg/kg and 1.0 mg/kg both outperformed an active placebo (midazolam) within 72 hours, while lower doses (0.1 and 0.2 mg/kg) did not [1]. The 0.5 mg/kg dose is the sweet spot: effective enough, with fewer dissociative side effects than 1.0 mg/kg.

For repeated dosing, the standard induction schedule is two to three infusions per week for two to three weeks, then maintenance every three weeks or at relapse [2, 3]. A 2020 trial found that six infusions did not significantly outperform a single infusion at 24 hours, but the repeated group had earlier remission and longer relapse-free periods (median 6 weeks vs 2 weeks) [8]. That is a meaningful difference, but the trial was small (54 people total) and the primary endpoint was not met.

Oral ketamine is a different story. Bioavailability is only about 8% because the liver breaks it down on first pass [6]. One trial gave 0.5 mg/kg orally daily for 28 days and saw some improvement in hospice patients, but only 14 people were studied [2]. A 2018 Iranian trial added oral ketamine (50 mg daily) to sertraline and found faster improvement and higher response rates (85% vs 58%) over six weeks [7]. That is promising but small (90 people, single site, no long-term follow-up).

The safety data is where the picture gets murkier. A review of 60 studies found that 72% reported psychotomimetic side effects (dissociation, perceptual disturbances) and 38% reported cardiovascular effects (blood pressure spikes) [5]. Five participants withdrew due to suicidal ideation [5]. The dissociative effects are dose-dependent and usually resolve within hours, but they are real and can be frightening. The blood pressure increase is also real: systolic rises about 25 mmHg during infusion [8]. For someone with untreated hypertension or a history of psychosis, these are not trivial.

What is missing from this evidence is long-term safety data. The studies follow people for weeks, not years. There is no large, independently funded trial comparing ketamine to a true placebo (not midazolam, which has its own effects) over months or years. The manufacturer of esketamine (Spravato) funded much of the research, and the liability shield for that product means the market pressure to find rare harms is weak. Bladder toxicity, a known risk of chronic ketamine use, has not been studied in these depression protocols because the doses are lower and intermittent, but no one has run the study that would rule it out.

My call: for a person with treatment-resistant depression who has failed multiple standard treatments, a short course of IV ketamine at 0.5 mg/kg is a reasonable option with a moderate evidence base for short-term benefit. The risks are real but mostly acute and manageable in a monitored setting. Oral ketamine is less well studied and should be approached with caution. The evidence does not support long-term use, and the absence of long-term safety data is a genuine gap, not a reassurance. Confidence: moderate for short-term efficacy, low for long-term safety.