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Randomized Controlled Trial
. 2025 Jan;39(1):23-28.
doi: 10.1177/02698811241301215. Epub 2024 Nov 28.

Ketamine for treatment-resistant obsessive-compulsive disorder: Double-blind active-controlled crossover study

Ben Beaglehole  1 , Paul Glue  2 , Shona Neehoff  2 , Shabah Shadli  3   4 , Neil McNaughton  3 , Bridget Kimber  1 , Chrissie Muirhead  1 , Aroha de Bie  1 , Rachel Day-Brown  1 , Natalie J Hughes-Medlicott  5
Affiliations
Randomized Controlled Trial

Ketamine for treatment-resistant obsessive-compulsive disorder: Double-blind active-controlled crossover study

Ben Beaglehole et al. J Psychopharmacol. 2025 Jan.

Abstract

Background: Obsessive-Compulsive Disorder (OCD) may respond to ketamine treatment.

Aim: To examine the responsiveness and tolerability of treatment-refractory OCD to intramuscular (IM) ketamine compared to IM fentanyl.

Methods: This was a randomised double-blind psychoactive-controlled study with single doses of racemic ketamine 0.5 mg/kg, 1.0 mg/kg or fentanyl 50 µg (psychoactive control). Pre-dosing with 4 mg oral ondansetron provided nausea prophylaxis. Eligible participants were aged between 18 and 50 years with severe treatment-resistant OCD. The primary efficacy measure was the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Tolerability was measured with the Clinician-Administered Dissociative States Scale (CADSS). Repeated measures analysis of variance with orthogonal polynomial trends was used to assess the effect of drug treatment on Y-BOCS and CADSS scores.

Results: Twelve participants were randomised and 10 completed the study (7 females, 3 males, mean age 33 years). Two participants dropped out due to not tolerating dissociative effects associated with the study medication. The reductions in Y-BOCS scores were greater and statistically dose-related for both ketamine doses than fentanyl (dose [linear], F(1, 9) = 6.5, p = 0.031). Score changes for all treatments were maximal at 1-2 h with a steady separation of scores out to 168 h. Ketamine was associated with short-term dissociative and cardiovascular effects.

Conclusions: We provide further preliminary evidence for the efficacy and tolerability of IM ketamine in an outpatient cohort of OCD. Additional work is required to establish the optimal dosing regimen and longer-term role of ketamine for OCD. These findings are encouraging given the well-known limitations that exist for treatments in this area.

Keywords: Ketamine; obsessive-compulsive disorder.

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Conflict of interest statement

Data accessThe data underlying this study can be accessed from the authors on reasonable request. Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Drs. Glue and Hughes-Medlicott have a contract with Douglas Pharmaceuticals to develop novel ketamine formulations. No other authors have disclosures.

Figures

Figure 1.
Figure 1.
Consort diagram of participation flow.
Figure 2.
Figure 2.
Mean change in Y-BOCS scores over time. The data shown are after subtraction of the pre-drug score to make the trends clearer but standard errors are shown from the raw data. Fent: fentanyl; K0.5: ketamine 0.5 mg/kg; K1.0: ketamine 1.0 mg/kg; Y-BOCS: Yale-Brown Obsessive-Compulsive Scale.
Figure 3.
Figure 3.
CADSS scores over time by treatment group. Bars are two standard errors. CADSS: Clinician-Administered Dissociative States Scale; Fent: fentanyl; K0.5: ketamine 0.5 mg/kg; K1.0: ketamine 1.0 mg/kg.
See this image and copyright information in PMC

References

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    1. Beaglehole B, Glue P, Neehoff S, et al. (2024) Ketamine for treatment-resistant post-traumatic stress disorder: Double-blind active-controlled randomised crossover study. [Manuscript submitted for publication].
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