Ketamine and Esketamine for Suicidal Ideation: A Stratified Evidence Synthesis Across Intravenous, Intranasal, and Injection Routes (2016–2026)

A synthesis of 31 studies from 2016 to 2026 finds that intravenous ketamine rapidly reduces suicidal ideation, with 63% of patients achieving full remission by Day 3 compared to 32% on placebo, effects appearing within 40 minutes. Intranasal esketamine shows inconsistent results across studies, but when confounding factors such as hospitalization floor effects, insensitive measurement, and treatment resistance are accounted for, its anti-suicidal effect becomes clear and lasts up to 18 weeks. Injection routes show promise but lack randomized trial evidence. The analysis is based on a publicly available dataset.

Study at a glance

Abstract

This white paper reports a stratified evidence synthesis of 31 peer-reviewed studies (2016–2026) examining ketamine and esketamine as rapid-acting treatments for suicidal ideation. Studies were classified by administration route — intravenous racemic ketamine (14 primary studies, N=1,258), intranasal esketamine/Spravato (6 primary studies, N=844), and injection routes combining intramuscular and subcutaneous delivery (4 studies, N=118) — and analyzed using a random-effects model with pre-specified heterogeneity thresholds. The intravenous track yielded moderate heterogeneity (I²=58%) and a high-certainty pooled verdict: IV ketamine produces rapid, independent anti-suicidal effects within 40 minutes, with 63% full ideation remission by Day 3 versus 32% for placebo, extendable through buprenorphine follow-on or maintenance infusion. The intranasal track yielded massive heterogeneity (I²=84%), triggering meta-regression that identified three load-bearing confounders: a hospitalization floor effect masking drug-specific signal in registration trials, single-item measurement insensitivity, and baseline treatment refractoriness. When these confounders are removed — in outpatient settings and CBT-augmented protocols — esketamine's anti-suicidal signal emerges clearly and extends to 18 weeks. The injection track shows promising acute results but lacks randomized controlled trial evidence. The underlying dataset is publicly available on Zenodo (DOI: 10.5281/zenodo.20802538).