Systematic review and meta-analysis of randomized controlled trials of ketamine in the treatment of refractory anxiety spectrum disorders

This meta-analysis (2021) assessed the literature regarding the possibilities of using ketamine to treat anxiety disorders. Six RCTs investigating various disorders were included. Ketamine was associated with treatment response for social anxiety disorder but not for PTSD. Doses of >0.5 mg/kg were associated with a greater reduction in scores of anxiety and these anxiolytic effects could be sustained.


Background: Anxiety disorders are common, associated with significant burden of disease, and have high levels of treatment resistance. Low-dose ketamine has been extensively studied in treatment-resistant depression, with fewer reports in treatment-resistant anxiety disorders.

Aims: This systematic review and meta-analysis collected efficacy, safety, and tolerability data for ketamine as a treatment for anxiety spectrum disorders.

Methods: We conducted a systematic search for randomized controlled trials (RCTs) of acute ketamine treatment for patients with anxiety disorders. Open-label trials of ketamine maintenance therapy were also considered. Qualitative and, where possible, quantitative syntheses of findings were performed using Review Manager software (RevMan). Acute dose-response and maintenance treatment data were also collected.

Results: There were six eligible acute RCTs – two in social anxiety disorder (SAD), three in post-traumatic stress disorder (PTSD), and one in obsessive-compulsive disorder (OCD). Four of the six showed significant improvement in anxiety rating scores in ketamine compared with control groups. Pooled analysis showed ketamine was associated with an increased likelihood of treatment response for SAD (odds ratio (OR): 28.94; 95% confidence interval [CI]: 3.45-242.57; p = 0.002) but not for PTSD (OR: 2.03; 95% CI: 0.67-6.15; p = 0.21). A dose-response profile was observed for ketamine and changes in SAD symptoms, with doses ⩾0.5 mg/kg associated with a greater reduction in anxiety rating scores than lower doses. Ketamine maintenance therapy was associated with sustained anxiolytic effects and improved social and/or work functioning.

Conclusion: These preliminary analyses suggest that acute ketamine may be broadly effective across treatment-resistant anxiety spectrum disorders. These effects can be prolonged with maintenance treatment. Future studies will be needed to provide critical knowledge gaps around off-label use, side effects, and potential risks for abuse in clinical settings.”

Authors: Elizabeth Whittaker, Alisher R. Dadabayev, Sonalee A. Joshi & Paul Glue


Anxiety disorders are among the most prevalent psychiatric conditions, and treatment resistance or relapse is a frequent problem.

Over 20 years ago, ketamine was reported to have rapid-onset antidepressant activity in treatment-resistant major depression and bipolar depression. Since then, it has been widely replicated.

Little clinical research has been published on the use of ketamine in treatment-resistant anxiety disorders. This may be due to the lack of consistency in defining treatment resistance for anxiety disorders.

Established pharmacotherapies for anxiety disorders include drugs that interact with monoamine and GABA-A systems. Glutamate may play an important role in fear extinction, the stress response, and synaptic and neural plasticity linked to anxiety disorders. Ketamine is a noncompetitive antagonist at NMDA glutamatergic receptors, but it also has a number of active metabolites with additional pharmacologies. This systematic review and meta-analysis assessed the current evidence base for ketamine efficacy, safety, and tolerability in a number of anxiety disorders.


This review included prospective acute treatment RCTs of ketamine therapy in adults with DSM-51-diagnosed anxiety spectrum disorders. The studies were assessed for eligibility using keywords and the reference lists of eligible papers were manually searched for additional papers.

This structured review and meta-analysis included studies that had previously received ethics committee approval. Efficacy and safety results were pooled using a random-effects meta-analysis, and statistical heterogeneity was assessed using chi-square and I-squared tests.


Eight studies were included in the review: six double-blind acute treatment RCTs, one acute dose-response analysis, and one open-label maintenance therapy trial.

Acute treatment

Six RCTs were identified that assessed ketamine as an acute treatment for anxiety disorders. The Cochrane risk-of-bias assessment tool categorized crossover designs as high risk, and parallel studies as low risk.

In crossover RCTs, glue et al.21 and Taylor et al.22 treated patients with SAD with ascending-dose ketamine administered subcutaneously (SC) at weekly intervals, or a single dose 0.5 mg/kg intravenous (IV) given over 40 minutes. Ketamine demonstrated anxiolytic effects within 1 hour of administration, lasting up to a week.

Glue et al.21 and Taylor et al.22 had study populations with high comorbidity of SAD and GAD, and ketamine showed a higher likelihood of treatment response in patients with GAD.

Three studies investigated the use of ketamine as a treatment for patients with PTSD. Ketamine was associated with significantly greater improvement in PTSD symptom severity at 24 h compared to midazolam.

Dadabayev et al.23 conducted a randomized parallel-arm trial of ketamine (0.5 mg/kg IV over 40 minutes) compared to ketorolac (15 mg IV over 40 minutes) in participants with chronic pain and PTSD.

In a modified crossover design, ketamine 0.5 mg/kg IV infusion was compared to normal saline infusion for the treatment of chronic PTSD in 10 patients. Ketamine showed a more sustained response to treatment compared to saline, although this was not statistically significant.

Results from all three studies were pooled for responder analysis, and there was no statistically significant difference in odds of treatment response between ketamine and control groups.

Rodriguez et al.26 found that acute ketamine treatment reduced OCD symptoms in 15 participants with near-constant obsessions compared to saline. A higher proportion of treatment response was also found in participants receiving ketamine compared to those receiving placebo.

We calculated a statistically nonsignificant greater reduction in Y-BOCS score and OCD-VAS after ketamine treatment compared with control treatment at 7 days post-infusion.

Safety and tolerability

Ketamine administration increased Clinician-Administered Dissociative States Scale (CADSS) scores compared with control, and returned to baseline by 120 minutes. Patients with comorbid PTSD and CP reported minimal dissociative effects after ketamine administration.

Ketamine has sympathomimetic effects and may increase heart rate and blood pressure. Patients given ketamine had statistically significantly greater odds of feeling spaced out, nauseated, dizzy/light-headed, and fatigued than those given a placebo.

Acute dose response in SAD/GAD

Two publications reported acute ketamine dose-responses in change in anxiety rating scores. Higher doses were associated with greater reduction in anxiety symptoms than the lowest dose used (0.25 mg/kg).

Maintenance treatment, SAD and GAD

There were two publications reporting on mood responses to ketamine maintenance therapy. The FQ, HAM-A, and SSAI scores improved over 14 weeks, and 50% reductions in anxiety scale scores occurred by 1 hour after dosing, which occurred consistently for 14 weeks.

This review includes data from controlled acute ketamine studies in anxiety spectrum disorders, and provides insight into the potential treatment efficacy, safety, and tolerability of ketamine for a range of anxiety spectrum diagnoses.

Four studies involving patients with SAD/GAD, PTSD, and OCD found evidence of significant benefit from ketamine compared to placebo. Two studies found no significant difference between ketamine and controls.

Based on pooled analysis, ketamine was associated with a statistically significant increased likelihood of acute treatment response for SAD and GAD, but not for PTSD. However, differences in study design could have influenced response rates in control arms.

Ketamine has an acute dose-response profile, and a similar dose-response profile for antidepressant effects. It has been shown to improve social and/or work functioning, and reduce PTSD symptoms in patients after repeated infusions.

Ketamine was reported to be generally safe and well tolerated, with the dissociative and sympathomimetic effects well recognized. Dizziness and nausea/vomiting are common side effects, but can be managed by resting comfortably.

This review has a number of limitations, including the small number of eligible studies, different study protocols, and small numbers of participants. No adjustments for multiple measures were made in this meta-analysis, and blinding could have been affected by the psychogenic nature of ketamine. This review includes patients with multiple psychiatric and physical diagnoses, which increases clinical heterogeneity but also reflects the real-world population. There are also no accepted operational definitions for TR anxiety disorders.

In conclusion, this review suggests that ketamine may be a safe and broadly effective anxiolytic for patients with anxiety spectrum disorders, including treatment refractory cases. However, further studies are needed to confirm these findings.

Conflict of interest statement

The authors have disclosed that Dr Glue has a contract with Douglas Pharmaceuticals to develop novel ketamine formulations.

Study details

Compounds studied

Topics studied
Anxiety PTSD Obsessive-Compulsive Disorder

Study characteristics
Meta-Analysis Literature Review

0 Humans

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