In PTSD, Evidence That a Single Ketamine Infusion May Enhance Extinction of Recalled Traumatic Memories

Posted: October 24, 2023
In PTSD, Evidence That a Single Ketamine Infusion May Enhance Extinction of Recalled Traumatic Memories

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A pilot study generated evidence that a single ketamine infusion may have enhanced extinction of traumatic memories, following their initial retrieval, in PTSD patients. Ketamine combined with talk therapy is a potential novel future intervention for PTSD and anxiety disorders, the researchers concluded.


Intrusive memories of trauma are among the classic symptoms of PTSD that can haunt and impair sufferers. The traumatized individual re-experiences the traumatic event via a memory which carries the event’s original emotional intensity and vividness. These intrusions can be spurred by stimuli or cues in the environment which are, in themselves, innocuous. An example often given is the sound of a car backfiring that triggers memories of combat in a PTSD-affected war veteran.

But what if traumatic memories could be rewritten—overwritten and replaced with other memories, or in some other way modified so that the memory-induced fear response to the original trauma is, in the language of neuroscience, “extinguished”?

A first-line treatment for PTSD aims at fear extinction (or reduction) via exposure therapy. It works very well in some patients, although its benefits are often not enduring. In exposure therapy, the therapist provides a safe environment in which to expose the traumatized individual, often gradually, to the original traumatic memory and things they fear or avoid. This process helps the patient to master their response to fear triggers or cues and to better tolerate the original traumatic memory. When successful, the involuntary connection between environmental triggers and memory of the original trauma is at least for the time being interrupted.

This way of taming fear is thought to take advantage of a phenomenon called memory reconsolidation. In reconsolidation, recall of a memory opens a window in time—in humans it lasts from about 10 minutes following recall to as long as 10 hours—during which the memory exists in what researchers call a “labile” state. It can potentially be modified, before it is once again “reconsolidated” in the brain areas in which memory traces are stored (the hippocampus and amygdala).

Researchers at Yale University led by 2015 BBRF Independent Investigator Ilan Harpaz-Rotem, Ph.D., have recently reported on their efforts to study what happens in the brain when the drug ketamine is administered to PTSD patients, followed by an intensive exposure treatment. They and others have been exploring whether ketamine treatments, alone or in combination with psychotherapy (including exposure therapy), might improve outcomes in PTSD, perhaps by enhancing mechanisms involved in fear extinction.

There have been indications of ketamine’s potential utility in PTSD and anxiety in various studies, but it is still not understood how changes in the brain induced by the drug might enhance the therapeutic process in fear and anxiety patients. Developed as an anesthetic, ketamine has been shown to rapidly reduce symptoms of severe, treatment-resistant depression when delivered at doses far below those used in anesthesia. A co-author of the new study, John H. Krystal, M.D., was among the first to test and demonstrate the benefits of ketamine in severely depressed patients. Dr. Krystal is a member of the BBRF Scientific Council, winner of the BBRF Colvin Prize for his work on ketamine, and a 2006 and 2000 BBRF Distinguished Investigator and 1997 Independent Investigator. Ben Kelmendi, M.D., also of Yale and a 2016 BBRF Young Investigator, was also a co-author on the new paper, which appeared in Neuropsychopharmacology. Co-first authors were Drs. Or Duek and Nachshon Korem of Yale.

Team leader Dr. Harpaz-Rotem devoted his 2015 BBRF grant to testing whether a single dose of ketamine, followed by intensive prolonged exposure therapy, enhances therapy’s effectiveness. Exploring in the newly published study why this might be so, the team hypothesized that ketamine temporarily increases the brain's capacity to rewire its connections, possibly affording a window of opportunity to enhance the effects of trauma memory extinction during therapy. Past research indicates ketamine promotes neurogenesis (birth of new neurons), cell proliferation, and the creation of new synapses, which all occur in parts of the brain involved in memory reconsolidation.

Twenty-seven patients with moderate to severe PTSD persisting for a year or longer, and in most cases based on trauma that occurred over 10 years prior, were randomly assigned to receive either a single sub-anesthetic dose of ketamine or the anti-anxiety drug midazolam following retrieval of each participant’s traumatic memory. Then, 24 hours following the infusion of either drug, all participants received 4-day trauma-focused psychotherapy. Symptoms were clinically assessed prior to treatment, at the end of treatment, and 30 days post-treatment. Brain activity and structural features were also assessed at these points, using MRI brain scanning. A large fraction of participants had current episodes of major depressive disorder in addition to PTSD, and most had histories of substance dependency. Most were between 35 and 45 years old and over one-third were female. Sources of trauma varied and had combat, sexual, and violent precipitants, among others.

PTSD symptoms improved about equally in the two groups. But there was evidence that the single ketamine infusion might have enhanced extinction of traumatic memories, following their initial retrieval. The evidence for ketamine’s utility was in differences noted between participants in the ketamine and midazolam groups. In patients who received ketamine, the team noted diminished reactivity of the amygdala to the recall of traumatic events and a weakening of connectivity between the amygdala and hippocampus. There was evidence, too, that ketamine promoted therapeutic changes to key bundles of white matter (composed mainly of axons that connect brain regions) in a part of the brain called the uncinate fasciculus (which connects limbic areas with the amygdala and other areas involved in memory retrieval).

The researchers said it was possible that the interaction of psychotherapy and ketamine yields an advantage in the therapeutic reorganization of synapses, but the current pilot study was not able to prove this. “Further exploration of dosage, frequency, and timing of ketamine when combined with psychotherapy is needed” in future studies, they said. Their results were consistent, they said, with a recent study in participants with harmful drinking patterns. “While ketamine [alone] was ineffective in reducing drinking, when administered in conjunction with alcohol cues, ketamine interfered with the reconsolidation of alcohol-reward memories and significantly reduced drinking.”

In the current study, however, all participants received psychotherapy and thus it was impossible to determine the specific effect of ketamine alone and the effect of the combined therapy. Nevertheless, the researchers concluded, since “the enhancement of post-retrieval [fear] extinction presented in our study was demonstrated using real-life traumatic events, the [clinical] applicability of this procedure is high and it might serve as a potential novel future intervention for PTSD and anxiety disorders.” Based on the results of this BBRF-funded study, Dr. Harpaz-Rotem has received funding from the NIMH to further investigate the potential of ketamine to enhance the effect of exposure therapy in a larger sample of patients.