Ketamine and the suicidal crisis. What we know, what we don't — and a white paper that says which is which.

Ketamine can lift suicidal thinking within hours. Whether it prevents suicide, nobody yet knows. Those two sentences are both true, they are routinely confused, and the gap between them is where patients, families and clinicians are making decisions right now. So I wrote the long version.

Why a white paper, and why now

In Keeping people safe I gave ketamine one section and a chart. It deserved more, for a reason that has nothing to do with my own history with the drug and everything to do with timing: more clinicians every month are reaching for ketamine or esketamine when a patient is in acute suicidal danger, and the evidence they are reaching with has changed a lot in the last eighteen months — a 26-trial meta-analysis in JAMA Psychiatry¹, a secondary analysis of the French KETIS trial showing psychological pain falling within 40 minutes², a preprint pooling 73 trials for attempts and deaths³, and a large claims cohort published three weeks ago⁴.

Those studies do not all point the same way, and that is the point. A blog post can carry a conclusion. A white paper can carry the disagreement. So this is the first in what I intend to be an occasional series: one clinical question, the whole evidence base, every claim numbered, in a PDF you can hand to a colleague or a family member — and a version number so you know when it's been updated.

The five things the paper says

1. IV ketamine reduces suicidal thinking, fast. Twenty-six randomized trials now say so, with a standardized effect around 0.7 at 24 hours¹. This is no longer a promising signal; it is one of the better-replicated findings in acute psychiatry.
2. It is not just "depression getting better." In the best single trial, mood improvement explained only about a third of the effect on suicidal thoughts⁵. The likeliest explanation runs through Shneidman's old idea of psychache — unbearable psychological pain — which the KETIS data show dropping within the hour^2,7.
3. Esketamine is a different evidence base. The nasal spray beat placebo on depression at 24 hours in patients hospitalized for suicidal intent — but not on the suicide-specific scale, because hospitalization improved that for everyone^8,9. The FDA label says prevention of suicide has not been demonstrated¹⁰. That is honest reporting, not failure, and the paper explains why the two drugs' trials are so hard to compare.
4. Nobody knows whether it prevents attempts or deaths. The pooled trials contain 83 attempts and 8 deaths across 5,671 people — far too few to tell³. The largest real-world cohort found a hazard ratio of 1.02 with an interval wide enough to hold benefit or harm⁴. Anyone who tells you otherwise, in either direction, is ahead of the data.
5. So use it as a bridge. A suicidal crisis is fast — half of survivors say the decision-to-action interval was ten minutes or less¹¹ — and ketamine is the only medicine that works on that timescale. Its value is the window it opens. What you put in the window — a safety plan, which halves suicidal behavior on its own¹², means safety, a follow-up within days, people — is what saves the life.

What's in it that isn't in the blog post

• A key-numbers table with every headline figure and its source on one page.
• A timeline figure of what changes when: psychological pain first, then ideation, and the evidence thinning the further out you look.
• The rescue–repair model of how ketamine might act — NMDA, glutamate, AMPA, BDNF, and the stubborn opioid-system question — drawn as one picture and labeled as the hypothesis it is.
• A side-by-side ketamine vs esketamine table: molecule, dose, regulatory status, what each trial compared against, and what each showed.
• "How to read a ketamine-and-suicide study" — five questions that will let you evaluate the next headline yourself.
• A safety section and a plain-language page for patients and families.
• My disclosures, up front. I founded Utah's first esketamine clinic and ran ketamine programs for years. You should know that before you weigh my summary — which is exactly why I let the trials do the talking.

Ketamine has changed the way psychiatry thinks about time. It has not yet answered the question that matters most. The paper is my attempt to hold both of those facts in the same hand.

Read it, argue with it, and send me what I missed. Version 1.1 will carry the corrections.

— Reid