Ketamine for PTSD

Increased recreational use led to ketamine’s classification as a Schedule III substance under the Controlled Substances Act in 1999. However, ketamine has been on the World Health Organization’s List of Essential Medicines since 1985, and, due to its remarkably safe and effective use in the induction and maintenance of anesthesia, was never made fully illegal. 

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In recent years, ketamine therapy has emerged as a promising treatment option for a variety of psychiatric illnesses, most notably depression, but also post-traumatic stress disorder (PTSD) — a devastating mental health condition triggered by either witnessing or experiencing a traumatic event.

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Currently, PTSD affects approximately 11-20% of veterans. A 2010 study found that 20% of returning injured service members who served in Iraq and Afghanistan reported symptoms consistent with PTSD

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Several studies have shown that ketamine can provide fast-acting and significant relief for patients suffering from PTSD symptoms. This is particularly true for patients who have not responded to traditional treatments, such as talk therapy and traditional antidepressant medications which can take weeks to even months to work and are considered ineffective in at least one-third of cases.

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Furthermore, studies have demonstrated its effectiveness in reducing suicidal thoughts — the risk for which is considerably higher in PTSD patients — especially where traditional treatments like selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy (CBT) have not been successful. SSRIs and CBT can be effective for some patients, but alternative treatments like ketamine may offer hope for those who have not been as lucky. 

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What is Ketamine?

Ketamine, also referred to as ketamine hydrochloride, is a powerful dissociative anesthetic with psychedelic-like properties that can bring about significant temporary change in one’s consciousness. Ketamine is a multifunctional drug that interacts with multiple receptors, including N-methyl-D-aspartate (NMDA) receptors, opioid receptors, and monoaminergic receptors.

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Synthesized in 1962 by chemist Calvin Lee Stevens, ketamine was administered to humans for the first time two years later when researchers Ed Domino and Dr. Guenter Corssen administered it to volunteer Jackson State Prison inmates. Ketamine was integrated into clinical practice in 1970 where, to this day, it functions to tremendous effect as both an analgesic, and an anesthetic, depending on plasma concentration.  

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The therapeutic versatility of ketamine has led to an increase in its usage in the medical environment. Beyond its FDA-approved use as an anesthetic for surgical and diagnostic procedures, ketamine has been utilized off-label to, in many cases, successfully treat various health conditions, including chronic pain, anxiety, depression, suicidal thoughts, PTSD, addiction, and obsessive-compulsive disorder.

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In more recent years, the ketamine derivative, esketamine, has made headlines for its medicinal applications. In 2019, the FDA approved esketamine in the form of a nasal spray called Spravato, which can be prescribed in combination with an oral antidepressant for treating adults with treatment-resistant depression. This introduction marks a significant milestone in the medical field as it is one of the first instances of a psychedelic substance receiving regulatory approval for therapeutic use.

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What is PTSD?

PTSD is a psychiatric disorder that can occur in people who have experienced or witnessed a traumatic event. Examples include natural disasters, serious accidents, terrorist acts, war and combat, rape and sexual assault, historical trauma, intimate partner violence, and bullying.

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PTSD affects approximately 3.5% of U.S. adults every year. An estimated one in 11 people will be diagnosed with PTSD in their lifetime. PTSD symptoms include:

• Intrusive thoughts
• Social withdrawal 
• Forgetfulness 
• Nightmares
• Flashbacks
• Alterations in cognition, mood, arousal, and reactivity

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In the last decade, another psychedelic compound, MDMA, has demonstrated powerful clinical efficacy for the treatment of PTSD, prompting the US Food and Drug Administration (FDA) to grant breakthrough therapy status to MDMA-assisted psychotherapy. That treatment looks set to become FDA-approved for PTSD by the end of 2023, with ketamine showing some evidence of potential efficacy for the same complex illness.  

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Ketamine and Chronic PTSD

An example of ketamine's effective application can be seen in a 2021 study published by researchers from the Icahn School of Medicine at Mount Sinai led by two-time Brain & Behavior Research Foundation grantee Adriana Feder, M.D. Feder and colleagues found that repeated intravenous (IV) ketamine infusions rapidly reduced the severity of symptoms in patients who had severe chronic PTSD for a median duration of 15 years, with improvements maintained for several weeks thereafter. 

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Specifically, the researchers reported that significantly more participants in the ketamine group (67%) attained at least a 30% or more reduction in symptoms from baseline at week two compared to just 20% of study participants that received the benzodiazepine medication, midazolam. Ketamine infusions were associated with marked improvements across three of the four symptom clusters of PTSD.

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Also noteworthy, participants in the ketamine group experienced a greater reduction in comorbid depressive symptoms. Considering the high comorbidity of depression among individuals with PTSD, this is a very promising finding. 

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As the first randomized controlled trial of repeated ketamine administration for chronic PTSD, this study is significant in the area of research. 

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Ketamine and PTSD: A Protective Effect?

A 2008 study found that perioperative (the time period of a patient's surgical procedure) low-dose ketamine use in burned soldiers undergoing surgery may have a protective effect against the development of PTSD. The study, which was conducted at the U.S. Army Institute of Surgical Research (USAISR), found that burn victims who received ketamine during surgery had a lower prevalence of PTSD compared to those who did not receive the drug.

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Executive Officer at the United States Army Research Institute of Environmental Medicine, Laura L. McGhee, Ph.D., and colleagues discovered that the prevalence of PTSD among those who received ketamine was 26.9% (32 of 119) compared to 46.4% in those who did not receive ketamine (13 of 28). The authors of this study did suggest some potential explanations for this finding, including neuronal protection and better pain management, which could help to reduce the psychological trauma associated with surgery. 

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However, as there were a very small number of subjects, particularly in the no-ketamine group, and a high prevalence of positive screens for PTSD in the no-ketamine group, a retrospective study was conducted comparing the incidence of PTSD in 189 patients who received intraoperative ketamine versus 100 patients who did not.

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This time, the researchers reported no difference between the groups in the incidence or severity of PTSD symptoms. However, patients that received intraoperative ketamine had more severe injuries, higher percent total body surface area burned, underwent more surgeries, and spent more time in the Intensive Care Unit and in the hospital. 

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Further research into the role of ketamine and other anesthetic agents and anesthetic techniques may help elucidate practical perioperative approaches in decreasing the prevalence of PTSD in the combat wounded as well as the civilian population who are at risk for this devastating disorder. 

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How Does Ketamine Treat Chronic PTSD Symptoms?

A new study by researchers at Mount Sinai has analyzed detailed brain imaging data of 21 individuals with chronic PTSD treated in the aforementioned 2021 clinical trial. Assessing brain imaging data collected before the trial began and again after ketamine infusions had been administered enabled the team to identify changes in brain activity associated with the responses to ketamine in participants.

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The study's results suggest that improvements in PTSD symptoms were related to specific ketamine-induced changes in connectivity between several brain regions that show abnormal activity in PTSD, including the ventromedial prefrontal cortex (vmPFC), the dorsal/rostral anterior cingulate cortex (d/rACC), the amygdala, and the anterior portion of the insula.

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Connectivity changes were observed mainly when participants were asked to respond to "emotional faces" while their brain was being scanned. Specifically, faces that were ambiguous or neutral and those that displayed negative emotions such as fear.

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The authors hypothesize that ketamine may improve PTSD symptoms by inducing changes in connectivity between the vmPFC and amygdala following treatment. In particular, the researchers reported increased "top-down" inhibition of the amygdala, mediated by the vmPFC, in participants whose PTSD symptoms were decreased by ketamine during the viewing of emotional faces. 

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Lead researcher, Agnes Norbury, Ph.D., and colleagues, suggest that ketamine may help to treat PTSD by decreasing the intensity of the threat response and/or enhancing one’s ability to extinguish memory-based fear responses. Reduction in symptom severity, the authors hypothesize, may also be a result of ketamine’s fascinating capacity to promote neural plasticity in parts of the brain associated with the persistence of symptoms.

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Understanding ketamine-induced changes in brain connectivity could help researchers to develop more effective, synergistic treatments for the condition, for example, by administering ketamine in conjunction with types of psychotherapy that also focus, to some extent, on fear-extinction learning.

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That all said, there is a need for considerably more brain imaging data before any reliable biological mechanism behind ketamine's apparent efficacy for PTSD can be determined.

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Ketamine for PTSD: A Promising Treatment Option

Research has shown that ketamine, a dissociative anesthetic with analgesic and psychedelic properties at subanesthetic doses, can effectively reduce symptoms of PTSD in patients. Ketamine therapy has been shown to have a significant impact on treatment-resistant PTSD patients, offering new hope for those who have previously struggled to find effective treatment options.

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However, it is crucial to remember that ketamine’s psychoactive effects require that it be used in conjunction with supportive medical and therapeutic care. This includes appropriate preparation, monitoring, and follow-up care, to ensure that the drug is administered in a safe and effective manner.

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The importance of providing comprehensive care throughout the ketamine treatment process cannot be overstated. Without proper support, patients may not receive the full benefits of the therapy, or may even be at risk of negative side effects. 

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As for research on ketamine, it is exciting to think about the potential for new and effective treatment options for those struggling with mental health concerns. With research on ketamine expanding, it may be a valuable addition to the mental health treatment toolkit. 

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As we continue to dive deeper into its therapeutic effects, research suggests that this powerful compound could play a powerful role in treating a diverse range of mood disorders in addition to depression, including PTSD. But, as of now, further research is warranted. 

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