Meta-Analyses of Low-Dose Ketamine

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Treatment-resistant depression (TRD), major depressive disorder that has not responded to two or more adequate antidepressant trials, affects an estimated 30 percent of patients with major depressive disorder (MDD). Over the past two decades, low-dose ketamine, typically an intravenous infusion of 0.5 mg/kg given over 40 minutes, has become one of the most heavily studied rapid-acting antidepressants for this population. As randomized controlled trials (RCTs) have accumulated, researchers have pooled that data into a growing series of meta-analyses of low-dose ketamine for treatment-resistant depression. This article summarizes what those pooled analyses show about effect size, response and remission rates, durability, and where racemic ketamine and intranasal esketamine diverge, along with the methodological limits readers should weigh before treating any single meta-analysis as definitive.

Quick Answer

Meta-analyses of low-dose ketamine for treatment-resistant depression consistently report large effect sizes at 24 hours, generally a Cohen's d or standardized mean difference of about 0.8 to 1.2 compared with placebo, along with response rates near 50 percent after a single infusion. A 2023 meta-analysis in eClinicalMedicine pooling 49 randomized trials and 3,299 participants found that racemic ketamine's benefit remained statistically significant at 28 days or later, while intranasal esketamine's did not. A single infusion's antidepressant effect typically fades within one to two weeks, which is why most protocols use repeated dosing to sustain response.

Early evidence: Zarate et al. and the Cochrane review

The foundational trial came from Zarate et al. at the National Institute of Mental Health, a 2006 crossover study in Biological Psychiatry that showed antidepressant effects within hours of a single ketamine infusion. It was not itself a meta-analysis, but it set off the wave of RCTs that later reviews would pool. In 2015, Caddy et al. published a systematic review in the Cochrane Database of Systematic Reviews, a widely cited repository of independent evidence reviews in medicine, covering ketamine and other glutamate receptor modulators for depression. That early review found a consistent, though modest, signal favoring ketamine over placebo at 24 hours and up to 7 days, limited mainly by small trial sizes and short follow-up.

Pooled effect sizes: Kishimoto, Fond, and Coyle and Laws

Kishimoto et al. (2016), publishing in Psychological Medicine, pooled nine RCTs and reported a large effect size, Cohen's d near 0.9, a standardized measure of how big the average difference between two groups is in standard deviation units, for ketamine over placebo at 24 hours. The number needed to treat (NNT), the number of patients who would need to be treated for one additional patient to respond, was roughly 3 to 5. Fond et al. (2014) in the Journal of Psychiatric Research and Coyle and Laws (2015) in Human Psychopharmacology reached similar conclusions independently, with effects holding at 24 hours, 72 hours, and 7 days versus saline or midazolam controls. Coyle and Laws specifically flagged the value of active placebo controls like midazolam, since ketamine's dissociative effects can unblind patients and raters.

Repeated dosing: Zheng et al. (2018)

As clinics moved toward serial infusion protocols, Zheng et al. pooled data in the Journal of Affective Disorders on repeated ketamine dosing, typically two to three infusions weekly for two to three weeks. Repeated dosing produced more durable improvement than single infusions in pooled estimates, with response rates reaching roughly 70 percent and remission rates of 30 to 40 percent. For more on how infusion schedules affect outcomes, see how many ketamine treatments are typically needed.

Racemic ketamine versus esketamine: the 2023 eClinicalMedicine meta-analysis

The most comprehensive recent analysis is a 2023 meta-analysis published in eClinicalMedicine, a Lancet-affiliated journal, which screened 687 articles and pooled 49 RCTs covering 3,299 participants. According to the study, racemic IV ketamine produced significantly larger immediate effects than intranasal esketamine, the FDA-approved S-enantiomer of ketamine marketed as Spravato, at comparable time points (standardized mean difference around -0.73 for high-dose racemic ketamine versus -0.48 for high-dose esketamine). The gap widened at follow-up: racemic ketamine's benefit remained statistically significant at 28 days or later (SMD about -0.65), while esketamine's did not (SMD about -0.33, not statistically significant). Dropout rates were similar between ketamine and control arms (odds ratio 1.18), suggesting the added benefit did not come with a meaningfully higher discontinuation rate. This was the first meta-analysis to incorporate a large phase 3 RCT of repeated racemic ketamine dosing, closing a gap earlier reviews could not address.

Real-world data points the same direction, though it is not meta-analytic evidence. A 2025 naturalistic comparison from Mass General Brigham and McLean Hospitalreported by Harvard Medical School, found IV ketamine produced a larger average reduction in depression scores than intranasal esketamine in a retrospective cohort of 153 patients (49.22 percent versus 39.55 percent), with IV ketamine also producing a faster initial response. This is a single retrospective study, not a meta-analysis, but it is consistent with the pooled RCT findings above.

Key Takeaway

Across independent meta-analyses, low-dose ketamine's antidepressant effect at 24 hours is large and consistent, roughly a Cohen's d of 0.8 to 1.2, but the benefit of a single infusion typically fades within one to two weeks. Repeated infusion protocols, and racemic ketamine specifically, show more durable effects in pooled data than single dosing or intranasal esketamine.

Combining findings across these analyses, several patterns hold:

Acute efficacy (24 hours): large effect sizes, Hedges' g or Cohen's d generally 0.8 to 1.2, favoring ketamine over placebo.
Short-term efficacy (3 to 7 days): moderate to large effects that persist through the first week.
Durability beyond 7 days: effects attenuate, and most patients see symptoms recur within 1 to 2 weeks after a single infusion.
Repeated infusions: better durability than single dosing, though controlled data beyond 4 to 6 weeks remains limited.

Three methodological issues limit how far these numbers should be extrapolated. First, blinding is imperfect: ketamine's dissociative effects can signal to patients and raters which arm they are in, though subgroup analyses using active placebos like midazolam still show a ketamine advantage, just a smaller one. Second, funnel plot and Egger's test results for publication bias are mixed across analyses, and the still-modest number of pooled trials limits statistical power to detect it. Third, heterogeneity in infusion protocols, outcome measures, such as the Montgomery-Asberg Depression Rating Scale (MADRS), the Hamilton Depression Rating Scale (HDRS), and the Beck Depression Inventory (BDI), three standardized scales used to quantify depression severity, and assessment timing adds statistical noise. Sensitivity analyses that remove outlier trials have generally not changed the direction of the pooled effect. For a broader look at how this evidence is evaluated, see our research and evidence overview.

Strengths of the Evidence

Multiple independent research teams, including Kishimoto, Fond, Coyle and Laws, Zheng, and the 2023 eClinicalMedicine authors, converge on the same direction of effect.
Effect sizes at 24 hours are large and consistent across analyses, roughly 0.8 to 1.2.
Dropout rates in pooled RCTs are similar between ketamine and control arms, per the 2023 eClinicalMedicine analysis (odds ratio 1.18).
Repeated infusion protocols show meaningfully better durability than single infusions in pooled data.

Limitations to Weigh

Blinding is difficult to fully achieve because ketamine's dissociative effects are perceptible to patients and raters.
Most trials measure outcomes only through 7 days; controlled follow-up data beyond 4 to 6 weeks is still limited.
Studies vary in infusion protocol, dose, and outcome scale, adding heterogeneity to pooled estimates.
RCT samples generally exclude patients with active substance use disorders, so meta-analytic findings may not generalize to every real-world TRD patient.

Important

Most of the evidence above comes from ketamine delivered in monitored clinical or research settings. According to Cleveland Clinic researchers, ketamine prescriptions have increased roughly 5.5-fold since 2017, including growth in telehealth and at-home routes that fall outside the RCT protocols these meta-analyses studied. Ask a provider how closely their dosing and monitoring match the in-clinic protocols used in the trials summarized here. See our guide to telehealth ketamine protocols for what oversight typically looks like in that setting.

Future meta-analyses of low-dose ketamine for treatment-resistant depression will likely lean on individual patient data (IPD) rather than pooled summary statistics, since IPD analyses can identify which patients respond best rather than only the average effect. Other open questions include head-to-head trials of racemic ketamine against esketamine at matched doses, more data on oral and sublingual ketamine formulations, and longer controlled follow-up beyond the current 4 to 6 week window. Understanding which patient characteristics predict response is a related priority. See our overview of biomarkers and ketamine response for what early research suggests.

How to Read a Ketamine Meta-Analysis

Check the dose and route (IV, intranasal, or sublingual) used in the pooled trials, since racemic ketamine and esketamine have not performed identically.

Look at the follow-up window. A large effect at 24 hours does not guarantee benefit at 4 weeks.

Check whether trials used an active placebo like midazolam, which better controls for ketamine's dissociative effects.

Note the number of pooled trials and participants. Wider confidence intervals mean less certainty.

See whether response and remission rates are reported separately, since they measure different outcomes.

Helpful next step

See how long a single ketamine infusion's antidepressant effect typically lasts and what determines relapse timing.

Read the guide

Learn More

Talk with a clinician about whether low-dose ketamine fits your treatment-resistant depression history.

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Frequently Asked Questions

Most meta-analyses report a large effect size at 24 hours post-infusion, generally a Cohen's d or standardized mean difference between 0.8 and 1.2 compared with placebo. Effects are smaller, though still significant in several analyses, when measured against an active placebo like midazolam.

A 2023 meta-analysis in eClinicalMedicine pooling 49 RCTs found racemic IV ketamine produced larger immediate effects than intranasal esketamine and remained statistically significant at 28 days or later, while esketamine's benefit did not. This is pooled trial data, not a guarantee of outcome for any individual patient.

Across the meta-analyses summarized here, a single infusion's benefit generally fades within 1 to 2 weeks. Repeated infusion protocols, typically two to three sessions weekly for two to three weeks, produce more durable response in pooled data.

The number varies by analysis. Kishimoto et al. (2016) pooled 9 RCTs, while the 2023 eClinicalMedicine meta-analysis pooled 49 RCTs covering 3,299 participants, the largest pooled sample to date for ketamine and esketamine in depression.