Side effects of ketamine and esketamine for depression: a review of 47 studies

The question

How safe and tolerable are ketamine and esketamine when used to treat major depressive disorder, and does one appear easier to tolerate than the other?

What they did

Researchers searched four large research databases up to 1 May 2025 for studies in adults with major depressive disorder that compared ketamine or esketamine against a placebo, another psychiatric medication, or electroconvulsive therapy. They screened 5,473 articles and included 47. They pooled the results and calculated the “number needed to harm” (NNH) — how many people would need to be treated for one extra person to experience a given harm. A low NNH means the harm is common.

What they found

Compared with placebo, ketamine was linked to significantly more dropouts (NNH of 12) and more adverse events overall (NNH of 2, meaning roughly one extra person in every two reported a side effect). Esketamine showed a similar pattern but with higher NNH values, meaning side effects were less frequent. Serious adverse events were not significantly increased for either drug. Common side effects included dizziness, dissociation (feeling detached from oneself or one’s surroundings), nausea, vertigo and blurred vision, and these appeared to increase with higher doses. Both drugs were linked to short-lived psychiatric side effects, rises in blood pressure and sedation after dosing, while no significant problems were found in cognition, lab tests, bladder symptoms, nasal examinations or addiction-related measures.

The fine print

No trial directly compared ketamine with esketamine, so the comparison between them is indirect and should be treated as preliminary. The abstract does not report the total number of participants, the doses used, or how the drugs were given. The findings apply to short-term use only, so longer-term risks such as bladder problems or dependence are not well addressed. This summary is based on the abstract alone.

What it means

Both ketamine and esketamine cause frequent but mostly short-lived side effects in people treated for depression, with no clear rise in serious harms in these short-term studies; esketamine may be somewhat easier to tolerate, though direct comparison trials are still needed.

Evidence grade: Moderate. A systematic review and meta-analysis of comparative studies, but the two drugs were compared indirectly rather than head to head, and the abstract does not report the total number of participants.

This summary is based on the study’s published abstract.