Ketamine for PTSD

TL;DR: Ketamine is a dissociative anesthetic with psychedelic properties that has been used in medical settings since the 1970s as an analgesic and anesthetic. In recent years, ketamine has gained popularity for its off-label uses in treating various health conditions, including chronic pain, anxiety, depression, suicidal thoughts, addiction, obsessive-compulsive disorder, and PTSD. A recent study suggests that ketamine may be effective in treating chronic PTSD. The study demonstrated that repeated intravenous ketamine infusions significantly reduced the severity of symptoms in patients who had suffered from severe chronic PTSD for an average of 15 years, with improvements lasting for several weeks afterward. Further research is needed to fully understand the implications and potential applications of the findings.

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What is Ketamine?

Ketamine is a dissociative anesthetic with psychedelic-like properties that can bring about a temporary change in conscious state similar to those achieved by classic psychedelics such as LSD and psilocybin.

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Synthesized in 1962 by chemist Calvin Lee Stevens, ketamine was administered to humans for the first time two years later by researchers Ed Domino and Dr. Guenter Corssen. Ketamine was integrated into clinical practice in 1970 where it functions safely and effectively as an analgesic and anesthetic (depending on the dose).

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Ketamine was classified as a Schedule III substance under the Controlled Substances Act in 1999 because of increased recreational use. Despite this, it has been on the World Health Organization's List of Essential Medicines since 1985. Because it is safe and effective for use in anesthesia, ketamine was never made completely illegal.

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Ketamine is a multifunctional drug that interacts with multiple brain receptors, including N-methyl-D-aspartate (NMDA) receptors, opioid receptors, and monoaminergic receptors. Ketamine has additional activity at several serotonin and norepinephrine transporters, which are proteins that are involved in the reuptake of the neurotransmitters serotonin and norepinephrine from the synapse (the space between two neurons). 

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The subjective effects of ketamine can vary depending on the dose and route of administration. At low doses, it can induce a sense of relaxation, euphoria, and mild dissociation. At higher doses, it can cause a more intense trance-like dissociation that may be experienced as meaningful or transformative. Some individuals may also experience transient side effects such as dizziness or nausea.

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Ketamine Therapy 

In recent years, ketamine therapy has emerged as a treatment option for a variety of psychiatric illnesses, most notably depression. In 2019, the US Food and Drug Administration (FDA) approved the ketamine derivative 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.

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

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Some recent studies have shown that ketamine can provide fast-acting and significant relief for patients suffering from symptoms of post-traumatic stress disorder (PTSD.

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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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Individuals with PTSD are thought to experience changes in their bodies that contribute to their symptoms. These changes include alterations in brain regions responsible for regulating emotions and stress responses, as well as changes in hormone levels and the immune system.

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They may also experience a "freeze" response, where they become stuck in a state of hyperarousal or dissociation. This can lead to symptoms such as flashbacks, nightmares, and avoidance of triggers associated with the traumatic event.

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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 clinical efficacy for the treatment of PTSD in conjunction with supportive psychotherapy. MDMA-assisted psychotherapy looks set to become FDA-approved for the treatment for PTSD by mid-2024, with ketamine showing some evidence of potential efficacy for the same complex illness.  

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Ketamine for Chronic PTSD: A Potential Alternative to Conventional Treatments

In 2021, researchers from the Icahn School of Medicine at Mount Sinai, led by two-time Brain & Behavior Research Foundation grantee Adriana Feder, M.D., published a study that demonstrates the effective use of ketamine in treating PTSD. The study showed that repeated intravenous (IV) ketamine infusions quickly reduced the severity of symptoms in patients who had suffered from severe chronic PTSD for an average of 15 years, with improvements lasting for several weeks afterward.

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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 20% of 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 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. While this study represents a significant step forward in understanding the potential of ketamine for treating chronic PTSD, more research is needed to fully evaluate its efficacy and safety.

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It is important to conduct larger, well-controlled studies to confirm these findings and better understand the long-term effects of repeated ketamine administration. Additionally, different patient populations may respond differently to ketamine treatment, and further research is necessary to identify which patients may benefit most from this treatment.

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Low-dose Ketamine During Surgery Could Reduce PTSD Risk

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

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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 suggested some potential explanations for this finding, including the protection of neurons and better pain management, which could help to reduce the psychological trauma associated with surgery. 

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However, since the no-ketamine group had a very small number of subjects and a high rate of positive PTSD screenings, a retrospective study was carried out. This study compared the incidence of PTSD in two groups: 189 patients who received intraoperative ketamine and 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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Additional studies on the effects of ketamine could provide valuable insights into practical ways to reduce the occurrence of PTSD in both military personnel and civilians who are at risk.

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How Ketamine Impacts the Brain in PTSD Patients: Insights from Imaging Studies

A recent study conducted by Mount Sinai researchers analyzed detailed brain imaging data of 21 individuals with chronic PTSD who participated in the clinical trial discussed above conducted by researchers from the Icahn School of Medicine at Mount Sinai

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By comparing brain imaging data collected before and after ketamine infusions, the team was able to identify changes in brain activity associated with the responses to ketamine in trial participants. The study suggests that improvements in PTSD symptoms observed in the trial were linked to changes caused by ketamine in the way different parts of the brain communicate with each other.

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These changes were seen in brain regions that are known to have abnormal activity in people with PTSD. Specifically, the brain regions affected by ketamine were the ventromedial prefrontal cortex (vmPFC), the dorsal/rostral anterior cingulate cortex (d/rACC), and the anterior insula, and the amygdala — a small almond-shaped structure in the brain that plays a key role in processing emotions, particularly fear.

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The researchers noticed changes in connectivity between different brain regions while participants viewed images of faces that were either neutral or showed negative emotions like fear.

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A Closer Look at The Role of Ketamine in Treating PTSD Symptoms

In particular, the researchers suggest that ketamine may improve PTSD symptoms by increasing the control that the vmPFC has over the amygdala. In the study, this control helped prevent the amygdala from becoming too active when viewing faces that displayed negative emotions. 

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According to lead researcher Agnes Norbury, Ph.D., and her colleagues, ketamine might be useful in treating PTSD by reducing the intensity of the threat response and/or by improving the ability to overcome fear responses based on memories.

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Reduction in symptom severity, the authors suggest, may also be a result of ketamine’s capacity to promote neural plasticity in parts of the brain associated with the persistence of symptoms. This refers to changes in the structure and function of brain cells, particularly in the connections between neurons, that occur as a result of exposure to ketamine. The exact mechanisms by which ketamine induces neural plasticity are not yet fully understood, but research in this area is ongoing

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Understanding ketamine-induced changes in brain connectivity could help researchers to develop more effective treatments for the condition. For example, ketamine could be administered in conjunction with types of psychotherapy that also focus on fear-extinction learning, which refers to the process by which a person learns to reduce or eliminate a fear response to a specific trigger. 

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Key Takeaways: Ketamine and PTSD

Ketamine has shown potential as a treatment for PTSD in recent studies. One 2021 study found that repeated ketamine infusions rapidly reduced the severity of symptoms in patients who had severe chronic PTSD, with improvements maintained for several weeks thereafter. 

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Previous 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), which can take weeks to months to work and are considered ineffective in approximately one-third of cases, have not been successful. 

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Additional research is necessary to determine the full extent of ketamine's effectiveness in treating PTSD, however, the current studies indicate encouraging possibilities for future treatment options. As researchers continue to investigate its therapeutic potential, ketamine may prove to be a valuable tool in treating various mood disorders beyond depression, such as PTSD. Nonetheless, at this stage, further research is required to confirm its effectiveness.

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Also, 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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Without proper support, patients may not receive the full benefits of the therapy, or may even be at risk of negative side effects.