Ketamine Research: What the Evidence Shows and Where It Is Thin

The core evidence comes from randomized controlled trials in treatment-resistant depression. In a trial run at the National Institute of Mental Health and published in 2006, 18 adults received a single intravenous dose of ketamine and of placebo, in random order. Improvement on ketamine appeared within about two hours and remained significant for a week.

A larger two-site trial published in 2013 randomized 73 participants to ketamine or midazolam, an anesthetic used as an active placebo because it also produces noticeable effects. Ketamine produced greater improvement at 24 hours. The authors added that more information on how long responses last, and on safety, was needed before routine clinical use.

Taken together, single-dose trials show that a short-term effect exists for some people. They do not show how to sustain it, and they do not predict who will respond.

Later studies tested courses of treatment rather than one dose. The KADS trial, published in 2023, randomized adults with treatment-resistant depression at seven mood disorder centers in Australia and New Zealand to twice-weekly injections under the skin of ketamine or midazolam for four weeks.

With flexible, response-guided dosing, more participants reached remission on ketamine than on midazolam; at a lower fixed dose there was no difference between the groups. Acute side effects, such as unusual perceptions and increases in blood pressure, resolved within two hours, and the authors judged the subcutaneous route practical and feasible.

The 2006 and 2013 trials used intravenous dosing, which our clinic does not offer; KADS used the subcutaneous route, which is the route we use. Even so, trial results describe groups, and they cannot tell any one person how they will respond.

For post-traumatic stress disorder, a 2014 proof-of-concept trial in JAMA Psychiatry gave 41 adults with chronic PTSD a single infusion of ketamine and of midazolam in a crossover design. Symptom severity dropped more quickly after ketamine, measured at 24 hours, and the treatment was generally well tolerated. The authors described the study as the first evidence of its kind and said the findings needed replication.

For other diagnoses, ask any provider which controlled trials support treatment for your specific condition, how many people they included, and how long participants were followed. If the answer is a handful of small or uncontrolled studies, the evidence is early, whatever the marketing says.

Study design matters as much as the headline. Randomized controlled trials assign treatment by chance and are the strongest test of whether an effect is real. Open-label studies, in which everyone knows what they received, can show feasibility but are prone to expectation effects. Case reports describe individual patients and can raise questions without answering them.

Ketamine is hard to study blind because its effects are noticeable, which is why careful trials compare it with an active placebo such as midazolam rather than an inert salt solution. When you read a study, look for these points:

A 2018 systematic review in The Lancet Psychiatry found that psychiatric, psychotomimetic, cardiovascular and neurological side effects were reported more often with ketamine than with placebo after single doses, and that long-term use and safety had received limited assessment. Its authors called for large trials with repeated dosing and long-term follow-up.

We describe ketamine therapy as an option that may help some people, never as a sure thing. Ketamine is not FDA-approved for depression or any psychiatric condition, and the ketamine we use comes from a licensed outsourcing facility that compounds it, so it is not FDA-approved either. Every dose is given at the clinic with a clinician monitoring, plans are individualized, and a typical plan is a series of sessions over several weeks followed by reassessment.