A transdiagnostic systematic review and meta-analysis of ketamine's anxiolytic effects

Anxiety disorders are highly prevalent and cause substantial impairment; significant anxiety symptoms also occur across other clinical settings such as major depressive disorder, chronic pain, advanced cancer and palliative care. Existing pharmacotherapies have limitations: selective serotonin reuptake inhibitors (SSRIs) act slowly and can initially worsen anxiety, while benzodiazepines act rapidly but carry risks of tolerance and dependence. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has established rapid antidepressant effects and growing evidence suggests it may also reduce anxiety symptoms across diagnostic categories, but the time course of any anxiolytic effect is uncertain and previous reviews have included lower-quality designs and non-blinded studies. Hartland and colleagues set out to quantify ketamine's anxiolytic effects using a transdiagnostic approach limited to blinded, randomised, placebo-controlled trials. The principal aim was to synthesise RCT evidence at prespecified time windows — acute (<12 hours), subacute (24 hours) and sustained (7–14 days) after a single ketamine dose — and to explore correlations between anxiety improvements and both depressive symptom change and peak dissociative effects.

This is a systematic review and meta-analysis conducted according to PRISMA guidance and registered on PROSPERO (CRD42022303070). The review restricted inclusion to single- or double-blind randomised controlled trials (including crossover designs) published in English and enrolling adult patients with clinically significant anxiety symptoms; in practice the review included trials conducted in anxiety disorders, mood disorders, PTSD, chronic pain and palliative settings where anxiety outcomes were measured. Three independent reviewers extracted descriptive and numerical data into a pre-specified table. Extracted study features included design, sample size, diagnosis, medication status, ketamine dose/route/frequency, control condition (inactive or active placebo) and anxiety outcome measures and time points. Numerical values were taken from publications, direct author contact, or digitised from graphs when necessary. The investigators pooled data using Review Manager (RevMan v5.4) to calculate standardised mean differences (SMDs) between ketamine and placebo, and generated forest plots. Analyses focused on three time windows: <12 hours (acute), 24 hours (subacute) and 7–14 days (sustained); time points beyond 14 days were summarised qualitatively. When studies reported multiple assessments within a time window, the modal time point across studies was used for comparability; in crossover trials, if a carryover effect was identified the first-period data only were used. In addition to the meta-analyses, the study team extracted depression and Clinician-Administered Dissociative States Scale (CADSS) data when available and conducted exploratory linear regressions in R (v3.5.3) to test (1) the correlation between percentage improvements in anxiety and depression, and (2) the correlation between peak dissociation and anxiety improvement. Risk of bias was assessed using the Cochrane tool.

The search returned 4,647 records (4,515 after duplicate removal); 309 full texts were assessed and 14 randomised controlled trials met inclusion criteria for the qualitative review. Due to missing or inaccessible numerical data, 11 trials were included in the quantitative meta-analyses. The 14 included RCTs primarily sampled patients with PTSD (k = 7), mood disorders (k = 5), anxiety disorders (k = 2) and chronic or cancer-related pain (k = 2). Cochrane risk-of-bias assessment indicated that all but two studies had some concerns or high risk of bias; among the 11 trials entering meta-analyses nine were rated as high risk by the authors, commonly due to unblinding, selective reporting and carryover effects in crossover designs. Acute (<12 hours): Seven studies measured anxiety within 12 hours, but two did not report usable data; five studies provided group-level data at ~3–4 hours post-administration, comprising 69 participants who received ketamine and 63 who received placebo. Meta-analysis produced a significant effect favouring ketamine (SMD = -1.07, 95% CI [-1.68, -0.46], p < 0.01). Moderate heterogeneity was observed (I2 = 51%, p = 0.08). Subacute (24 hours): Ten studies reported 24-hour outcomes and ten contributed data to the meta-analysis (ketamine n = 179, placebo n = 178). The pooled effect at 24 hours was significant in favour of ketamine (SMD = -0.43, 95% CI [-0.65, -0.22], p < 0.001) with no notable heterogeneity (I2 = 0%, p = 0.76). Several individual trials (including comparisons versus active midazolam in chronic PTSD) reported significant group differences on measures such as the HAM-A or IES-R at this time point. Sustained (7–14 days): Nine studies reported 7–14 day outcomes and nine were pooled (ketamine n = 157, placebo n = 150). The meta-analysis showed a significant advantage for ketamine (SMD = -0.43, 95% CI [-0.65, -0.20], p < 0.01). Reported heterogeneity was low (I2 = 0%). Four of the nine studies reported statistically significant drug–placebo differences at this sustained interval. Beyond 14 days: Four trials included assessments beyond two weeks; two of these reported significant treatment effects, and one trial reported anxiolytic benefit up to one month after a single dose. Data were insufficient for a pooled quantitative estimate at time points beyond 14 days. Correlation analyses: At the subacute time point, seven studies (n = 182) yielded a significant correlation between percentage improvement in anxiety and percentage improvement in depression (R2 = 0.621, p = 0.035). At the sustained time point, six studies (n = 175) also showed a significant correlation (R2 = 0.773, p = 0.021). In contrast, pooled analyses found no significant relationship between peak dissociative symptoms (CADSS) and anxiety improvement: at 24 hours (n = 222) R2 = 0.011, p = 0.808; at 7–14 days (n = 237) R2 = 0.171, p = 0.268.

Hartland and colleagues interpret their findings as evidence that single, subanaesthetic ketamine infusions produce rapid anxiolytic effects that emerge within three to four hours and remain significantly superior to placebo at 24 hours and at 7–14 days. The review is presented as the first transdiagnostic synthesis restricted to blinded RCTs that examines multiple post-dose time windows, and the authors note that the temporal profile for anxiety closely mirrors that observed for ketamine's antidepressant effects. The authors highlight the significant correlations between improvements in anxiety and depression at the subacute and sustained time points, suggesting overlapping or related mechanisms may contribute to symptom change; they propose future neuroimaging work to disentangle whether shared or distinct neural circuits underlie ketamine's effects on anxiety versus mood. By contrast, no significant relationship was observed between peak dissociation and anxiolytic outcome, and the authors note that the literature remains equivocal on whether dissociation mediates therapeutic benefit. Key limitations acknowledged by the investigators include the generally high risk of bias across included trials — primarily from unblinding and selective reporting — and the paucity of active-placebo controls (only five studies used an active comparator). Moderate heterogeneity in the acute meta-analysis (I2 ≈ 50%) was attributed to small sample sizes, protocol and timing differences, and clinical heterogeneity inherent to the transdiagnostic approach. The mixture of parallel-arm and crossover designs, with variable handling of carryover effects, is recognised as a potential source of bias. Finally, the authors emphasise the limited evidence base for settings such as chronic pain and palliative care, given only one eligible trial in those contexts. For future research the authors recommend larger, well-blinded RCTs using active placebos, sensitivity analyses to probe heterogeneity, exploration of longer-term efficacy beyond two weeks and mechanistic studies to clarify relationships between antidepressant and anxiolytic effects. Overall, the authors conclude that their meta-analysis supports both rapid and sustained anxiolytic effects of single-dose ketamine across a range of clinical settings, while underscoring the need for higher-quality trials to confirm and extend these findings.

The meta-analysis indicates that ketamine's anxiolytic effects appear rapidly (approximately three to four hours after a single dose) and persist for up to two weeks. This study is reported as the first transdiagnostic RCT-only review to assess ketamine's efficacy across multiple post-administration time points, and the authors frame the findings as supportive of ketamine's potential to deliver both fast and sustained reduction in anxiety symptoms while calling for further high-quality research.