Ketamine Augmentation of Exposure Response Prevention Therapy for Obsessive-compulsive Disorder

| October 1, 2021

by Hugo Bottemanne, MD, and Alice Arnould, MSc

Dr. Bottemanne and Ms. Arnould are with Sorbonne University, Paris Brain Institute–Institut du Cerveau (ICM), and Department of Psychiatry (Pitié-Salpêtrière Hospital, APHP) in Paris, France.

FUNDING: No funding was provided for this study. 

DISCLOSURES: The author has no conflicts of interest relevant to the content of this article. 

Innov Clin Neurosci. 2021;18(10–12):9–11.


Obsessive-compulsive disorder (OCD) is a disabling disease characterized by intrusive thoughts, with compulsions performed to lessen distress. Many patients with OCD do not respond to first-line intervention, such as serotonin reuptake inhibitors (SRIs) and exposure and response prevention (ERP) therapy. Previous studies have focused on the use of ketamine, a nonselective N-methyl D-aspartate receptor (NMDAR) antagonist, for treatment-resistant OCD. Research has shown that ketamine modulates NMDARs and gamma-aminobutyric acid receptors (GAMBAR), which are major pathways for contingency-learning, belief updating, and extinction learning. Here, we propose an augmented psychotherapy (AP) protocol combining ERP intervention with administration of ketamine. We describe the theory that NMDAR modulation might directly promote the therapeutic mechanisms involved in exposure and discuss the possibility that ketamine plasticity enhancement might potentiate extinction-based psychotherapy in the treatment of OCD.

Keywords: Ketamine, obsessive-compulsive disorder (OCD), exposure and response prevention (ERP), nonselective N-methyl D-aspartate receptor (NMDAR), belief

Obsessive-compulsive disorder (OCD) is a disabling disease characterized by repeated intrusive thoughts, with compulsions performed to lessen distress associated with obsessions.1 These cognitive and behavioral symptoms are associated with a range of affective experiences, including enhanced negative feelings, anxiety, and sadness.2 In this disorder, repeated compulsions against stressful obsessions paradoxically induce a reinforcement loop of obsessions. These symptoms are very difficult to treat, and few medical treatments have been approved for OCD by the United States Food and Drug Administration (FDA). Serotonin reuptake inhibitors (SRIs), drugs that increase serotonergic signaling, and exposure and response prevention therapy (ERP), a subtype of cognitive behavioral therapy (CBT), are considered first-line interventions for OCD.1–4 During ERP, patients are exposed to obsessive stressors and invited to inhibit the compulsive responses in an effort to break the reinforcement loop. The emotional response progressively declines through repeated exposure when anxiety is not otherwise assuaged by compulsive behavior. In randomized, controlled trials, ERP therapy has been shown to be as effective as medication alone and to potentiate the effect of SRIs.2,5 Many patients with OCD, however, respond partially or not at all to these pharmacological and cognitive behavioral approaches, leading to the diagnosis of treatment-refractory obsessive-compulsive disorder (TROCD).6

New Prospects for Treatment of TROCD with Ketamine

There has been renewed interest in ketamine, a nonselective N-methyl D-aspartate receptor (NMDAR) modeling glutamatergic signaling, for the treatment of TROCD.7 At subanesthetic doses (0.5mg/kg, intravenous), ketamine increases glutamatergic activity in the prefrontal cortex and induces a complex synaptogenesis cascade in the brain via mammalian target of rapamycin (mTOR), inhibition of eukaryotic elongation factor (eEF2) kinase, and brain-derived neurotrophic factor (BDNF) synthesis.8 These neurotrophic effects have been associated with a rapid and robust antidepressant effect in major depressive disorder (MDD) and treatment-resistant depression (TRD).9,10 Based on these successes in mood disorders and on prior reports suggesting reduction of symptoms in OCD, ketamine has emerged in OCD treatment strategies.11,12 

A randomized, controlled trial with inactive placebo (saline infusion) demonstrated rapid anti-OCD effects in patients with persistent intrusive thoughts; a single intravenous dose of ketamine without SRI resulted in rapid clinical improvement, occurring within hours to days after treatment. For these patients, ketamine administration specifically resulted in a decrease in obsessions, leading to a secondary improvement in compulsions, with persistent effects at one week after administration.13 Another open-label study indicated that ketamine might temporarily improve symptoms of TROCD, but the effect appeared to wear off rapidly after the first administration. In this trial, the 10 patients enrolled received a single IV infusion of ketamine (0.5 mg/kg) over a 40 minute period. A significant and acute response was seen in OCD symptoms 1 to 3 hours following the administration of ketamine and persisted for 1 to 3 days according to the Yale-Brown Obsessive Compulsive Scale (YBOCS), but results did not appear to persist after the acute effects of ketamine.14 These reports suggest potential rapid antiobsessional effects of ketamine in OCD, but also a lack of extended therapeutic response when used alone. 

From pharmacotherapy to augmented psychotherapy with ketamine. Augmented psychotherapy (AP), an emerging and promising field in neuroscience, could extend and prolong the effects of ketamine.15 These translational techniques propose the use of pharmacotherapy to enhance the effects of psychotherapy, or psychotherapy to enhance the effects of pharmacotherapy.16–20 AP mainly focuses on synergic mechanic pathways between chemically induced brain plasticity and cognitive behavioral modulation by combining CBT techniques, such as metacognition, thought distancing, or positive-appraisal reinforcement, with molecules, such as ketamine, D-cycloserine, or even neurosteroid.16–20An open-label trial in which participants with OCD received a single ketamine infusion followed by 10 one-hour ERP sessions delivered over two weeks reported additional benefits from adding ketamine to ERP therapy.21 Other reports suggest that repeated intranasal ketamine combined with ERP promotes therapeutic effect.12 Interestingly, improvements in OCD symptoms were seen prior to ketamine administration after two weeks of CBT, but ketamine significantly reinforced these prior improvements and patient adherence with ERP techniques.12 However, these studies focused on the effect of ERP after ketamine treatment, not during acute administration of ketamine. Both approaches were used together but were not combined synergistically and did not measure the specific effects of ketamine during the infusion.12,21

Enhancing the effect of ERP psychotherapies with ketamine. Ketamine induces neurocognitive effects that might potentiate ERP.22 Subanesthetic intravenous and intranasal forms of ketamine can produce an altered state of consciousness (ASC), such as derealization and depersonalization and the feeling of world- and self-unreality.23 These symptoms dissipated within a few minutes after infusion and from 60 to 120 minutes following intranasal administration. These sensory and cognitive experiences have been associated with feelings of thought dissolution, as if judgments and mental frame were suppressed.24 Previous reports on OCD observed a rapid obsessional thought-dissolving effect of ketamine during infusion, persisting from 1 to 7 days post-administration.11 These thought-dissolving effects could potentially be used during ERP, particularly for the response prevention phase after the exposure. Moreover, classic ERP has been shown to be less effective for certain obsessive themes, such as moral or taboo thoughts, than for other obsessions, such as contamination, doubts, symmetry, or ordering. The intolerability of moral or taboo thoughts might make the confrontation by the patient more difficult.25 For these obsessive themes, the reinforcement loop mainly involves negative emotions and relatively few compulsions. The thought-dissolving effect of ketamine might assist the patient in breaking the reinforcement loop between obsession and emotion.

Promoting extinction learning process during ERP protocols with ketamine. The use of ketamine has been associated with positive effects on learning and belief updating.26 Studies have shown that ketamine modulates NMDARs and gamma-aminobutyric acid receptors (GABARs) in the amygdala and prefrontal cortex, two major mediators of glutamate signaling underlying fear extinction processes and memory reconsolidation.27,28 These results suggest that ketamine facilitated the fear memory extinction via glutamatergic presynaptic-mediated plasticity, which may provide new perspectives for treatment of OCD. Fear conditioning is an active learning process during which a neutral stimulus is paired with an aversive, distressing, unconditioned stimulus. During this process, neutral stimulus becomes itself stressful by association. In turn, the brain assumes an adaptive learning process leading to fear extinction through repeated exposure to the stressful stimulus. Research has shown that fear extinction is impaired in patients with OCD and substituted with compensatory compulsive behavior to mitigate distress. For these patients, the compulsion reduces fear, and the physiological mechanism of fear extinction is no longer used.29 

ERP is an extinction-based psychotherapy. The objective of ERP is the restoration of extinction learning through repeated exposure without engagement in compensatory behaviors (e.g., avoidance or compulsion) and the absence of a stressful outcome. Clinical and biochemical insights suggest that ketamine’s modulation of NMDAR and GABAR signaling might directly enhance fear extinction and promote ERP therapeutic mechanisms. The ketamine-induced fear extinction process could potentially be used during the response prevention phase, defusing the reinforcement loop between stressful obsessions and compensatory compulsions. These ketamine extinction learning effects have been recognized as a promising strategy toward desensitization in patients suffering from addiction and posttraumatic stress disorder (PTSD).27,30 In PTSD, ketamine could help repair poor fear extinction mechanisms (associated with traumatic memory), and might enhance the efficacy of psychotherapeutic interventions harnessing ketamine-induced neuroplasticity.31 In addiction, these synaptic plasticity modulation mechanisms could be used to modify the self-reinforcing cortical loops of addictive behaviors, by promoting the learning of new behavioral alternatives.32

AP with ERP and ketamine in OCD. Based on the preliminary data, we propose an AP protocol synergistically combining acute ketamine administration with ERP in the treatment of OCD. Specifically, we propose to combine the plasticity-enhancing and fear-extinguishing effects of ketamine administration with ERP. During this protocol, clinicians would administer intravenous ketamine at a subanesthetic dosage (0.5mg/kg) over 40 minutes, or intranasal esketamine (28–86mg) according to current clinical recommendations in MDD and TRD.9 At ketamine administration onset, the clinician would induce physical or virtual exposure to stimuli associated with obsessional thoughts and engage the patient with ERP protocol with response prevention.5 Repeated exposure and response prevention should be continued until the patient feels the psychodysleptic effects of ketamine (ACS, derealization, and depersonalization). The peak of these effects occurs 30 to 40 minutes after intravenous administration and at variable times following intranasal administration. After the peak, exposure can be decreased and then stopped when the patient no longer feels psychodysleptic effects. OCD symptomatology should be assessed using YBOCS before and after ketamine administration.33 In addition to the benefits of combining ERP and classic CBT, a conventional approach such as metacognitive therapy (MCT) could be implemented over the following days to improve clinical outcomes.34 

Limitations. Little data are available regarding the tolerance of ketamine in the treatment of OCD. Previous studies have suggested that ketamine’s effects on memory reconsolidation and information processing result in long-lasting impairment of belief updating, favoring delusional processes.35 The disruption of belief update mechanisms by ketamine could result in the emergence of aberrant, distorted beliefs.56 This effect has been used to provide pharmacological models of psychotic disorder.35 Differentiating between obsessions and delusions can be difficult; thus, ketamine protocols should be used with caution in cases of OCD with psychotic features. Moreover, derealization and depersonalization during ketamine administration might increase anxiety in some patients.24 This paradoxical effect, in which patients exhibit exceptionally high sensitivity to anxiety and fail to acclimate to their anxiety, could worsen the response to ERP therapies.36 This possible effect should be considered during ketamine-augmented ERP and carefully monitored to prevent worsening the patient’s clinical condition.


We propose that the thought-dissolution and extinction-learning effects observed during acute ketamine administration could potentially promote response to ERP therapy in the treatment of OCD. Moreover, ketamine enhanced-neuroplasticity (via mTOR, eEF2 kinase inhibition, and BDNF synthesis) might potentiate cognitive and behavioral relearning, improving long-term clinical outcomes in OCD.21 This ketamine-assisted psychotherapy may be a useful tool to identify OCD pathophysiological impairment and develop more effective treatment strategies with faster onset of action. Additional research in larger groups of patients is needed to evaluate the efficacy, safety, and computational mechanisms for these novel translational treatment approaches using ketamine.

Author Contributions

HB wrote the first draft. All authors contributed to and approved the manuscript.


We thank Anne Claret, Lucie Berkovitch, and Elodie Weyrich for their valuable work on this project.


  1. Hirschtritt ME, Bloch MH, Mathews CA. Obsessive-compulsive disorder: advances in diagnosis and treatment. JAMA. 2017;317(13):1358–1367. 
  2. Romanelli RJ, Wu FM, Gamba R, et al. Behavioral therapy and serotonin reuptake inhibitor pharmacotherapy in the treatment of obsessive-compulsive disorder: a systematic review and meta-analysis of head-to-head randomized controlled trials. Depress Anxiety. 2014;31(8):641–652. 
  3. Rosa-Alcázar AI, Sánchez-Meca J, Gómez-Conesa A, Marín-Martínez F. Psychological treatment of obsessive-compulsive disorder: a meta-analysis. Clin Psychol Rev. 2008;28(8):1310–1325. 
  4. Williams T, Stein DJ, Ipser J. A systematic review of network meta-analyses for pharmacological treatment of common mental disorders. Evid Based Ment Health. 2018;21(1):7–11. 
  5. Foa EB, Liebowitz MR, Kozak MJ, et al. Randomized, placebo-controlled trial of exposure and ritual prevention, clomipramine, and their combination in the treatment of obsessive-compulsive disorder. Am J Psychiatry. 2005;162(1):151–161. 
  6. Kühne F, Ay DS, Marschner L, Weck F. The heterogeneous course of OCD–a scoping review on the variety of definitions. Psychiatry Res. 2020;285:112821. 
  7. Thompson SL, Welch AC, Iourinets J, Dulawa SC. Ketamine induces immediate and delayed alterations of OCD-like behavior. Psychopharmacology (Berl). 2020;237(3): 627–638. 
  8. Abdallah CG, Averill LA, Collins KA, et al. Ketamine treatment and global brain connectivity in major depression. Neuropsychopharmacology. 2017;42(6): 1210–1219. 
  9. Fava M, Freeman MP, Flynn M, et al. Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD). Mol Psychiatry. 2020;25(7):1592–1603.
  10. Bottemanne H, Claret A, Fossati P. [Ketamine, psilocybin, and rapid acting antidepressant: new promise for psychiatry?]. Encephale. 2021;47(2):171–178. 
  11. Rodriguez CI, Kegeles LS, Flood P, Simpson HB. Rapid resolution of obsessions after an infusion of intravenous ketamine in a patient with treatment-resistant obsessive-compulsive disorder. J Clin Psychiatry. 2017;72(4):567–569. 
  12. Sharma LP, Thamby A, Balachander S, et al. Clinical utility of repeated intravenous ketamine treatment for resistant obsessive-compulsive disorder. Asian J Psychiatr. 2020;52:102183. 
  13. Rodriguez CI, Kegeles LS, Levinson A, et al. Randomized controlled crossover trial of ketamine in obsessive-compulsive disorder: proof-of-concept. Neuropsychopharmacology. 2013;38(12):2475–2483.
  14. Bloch MH, Wasylink S, Landeros-Weisenberger A, et al. Effects of ketamine in treatment-refractory obsessive-compulsive disorder. Biol Psychiatry. 2012;72(11):964–970. 
  15. Bottemanne H, Baldacci A, Muller C, et al. [Ketamine Augmented Psychotherapy (KAP) in mood disorder: User guide]. Encephale. 2021;S0013-7006(21)00224-4.
  16. Kayser RR, Raskin M, Snorrason I, et al. Cannabinoid augmentation of exposure-based psychotherapy for obsessive-compulsive disorder. J Clin Psychopharmacol. 2020;40(2):207–210. 
  17. Kellner M, Nowack S, Wortmann V, et al. Does pregnenolone enhance exposure therapy in obsessive-compulsive disorder? a pilot, interim report of a randomized, placebo-controlled, double-blind study. Pharmacopsychiatry. 2016;49(2):79–81. 
  18. Mataix-Cols D, Fernández de la Cruz L, Monzani B, et al. D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data. JAMA Psychiatry. 2017;74(5):501–510. 
  19. Farrell LJ, Waters AM, Boschen MJ, et al. Difficult-to-treat pediatric obsessive-compulsive disorder: feasibility and preliminary results of a randomized pilot trial of D-cycloserine-augmented behavior therapy. Depress Anxiety. 2013;30(8):723–731. 
  20. Rothbaum BO. Critical parameters for D-cycloserine enhancement of cognitive-behaviorial therapy for obsessive-compulsive disorder. Am J Psychiatry. 2008;165(3): 293–296. 
  21. Rodriguez CI, Wheaton M, Zwerling J, et al. Can exposure-based CBT extend IV ketamine’s effects in obsessive-compulsive disorder? An open-label trial. J Clin Psychiatry. 2016;77(3):408–409. 
  22. Wilkinson ST, Holtzheimer PE, Gao S, et al. Leveraging neuroplasticity to enhance adaptive learning: the potential for synergistic somatic-behavioral treatment combinations to improve clinical outcomes in depression. Biol Psychiatry. 2019;85(6):454–465. 
  23. Vlisides PE, Bel-Bahar T, Nelson A, et al. Subanaesthetic ketamine and altered states of consciousness in humans. Br J Anaesth. 2018;121(1):249–259. 
  24. Broström J. Ketamine for depression: the role of dissociative effects. 2020. Available from: Accessed 15 Nov 2020.
  25. Williams MT, Farris SG, Turkheimer EN, et al. The impact of symptom dimensions on outcome for exposure and ritual prevention therapy in obsessive-compulsive disorder. J Anxiety Disord. 2014;28(6):553–558. 
  26. Stuart SA, Butler P, Munafò MR, et al. Distinct neuropsychological mechanisms may explain delayed- versus rapid-onset antidepressant efficacy. Neuropsychopharmacology. 2015;40(9):2165–2174. 
  27. Girgenti MJ, Ghosal S, LoPresto D, et al. Ketamine accelerates fear extinction via mTORC1 signaling. Neurobiol Dis. 2017;100:1–8.
  28. Wei MD, Wang YH, Lu K, et al. Ketamine reverses the impaired fear memory extinction and accompanied depressive-like behaviors in adolescent mice. Behav Brain Res. 2020;379:112342.
  29. Milad MR, Furtak SC, Greenberg JL, et al. Deficits in conditioned fear extinction in obsessive-compulsive disorder and neurobiological changes in the fear circuit. JAMA Psychiatry. 2013;70(6):608–618;        quiz 554. 
  30. Das RK, Gale G, Walsh K, et al. Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories. Nature Communications. 2019;10(1):5187.
  31. Veen C, Jacobs G, Philippens I, Vermetten E. Subanesthetic dose ketamine in posttraumatic stress disorder: a role for reconsolidation during trauma-focused psychotherapy? Curr Top Behav Neurosci. 2018;38:137–162. 
  32. Worrell SD, Gould TJ. Therapeutic potential of ketamine for alcohol use disorder. Neurosci Biobehav Rev. 2021;126:573–589.
  33. Tolin DF, Abramowitz JS, Diefenbach GJ. Defining response in clinical trials for obsessive-compulsive disorder: a signal detection analysis of the Yale-Brown Obsessive Compulsive Scale. J Clin Psychiatry. 2005;66(12):1549–1557. 
  34. Rector NA, Richter MA, Katz D, Leybman M. Does the addition of cognitive therapy to exposure and response prevention for obsessive compulsive disorder enhance clinical efficacy? a randomized controlled trial in a community setting. Br J Clin Psychol. 2019;58(1):1–18. 
  35. Corlett PR, Cambridge V, Gardner JM, et al. Ketamine effects on memory reconsolidation favor a learning model of delusions. PLoS One. 2013;8(6):e65088. 
  36. Pence SL, Sulkowski ML, Jordan C, Storch EA. When exposures go wrong: troubleshooting guidelines for managing difficult scenarios that arise in exposure-based treatment for obsessive-compulsive disorder. Am J Psychother. 2010;64(1):39–53.

Tags: , , , ,

Category: Current Issue, Impulse Control Disorders, Original Research, Psychiatry

Comments are closed.