What You Need To Know About Ketamine For PTSD

Post Traumatic Stress Disorder (PTSD) affects the lives of many people worldwide.  Shockingly, more military personnel die by suicide than in combat. Many treatments have been subpar in the past, however, ketamine may be an alternative treatment option for those who are still struggling.  But there are some caveats and considerations that need to be taken before jumping on the ketamine bandwagon.

Clinical Background & Mainstream Treatment of PTSD

PTSD is a difficult-to-treat disorder. An estimated 3.6% of U.S. adults have had PTSD, and it not only veterans. The rate of PTSD is actually higher in females (about 5.2%) versus males (1.8%), and typically stems from interpersonal violence. The overall lifetime prevalence of PTSD is at 6.8%. PTSD is often characterized by having disturbing feelings and thoughts related to a past event that was directly or indirectly experienced. As a result the individual experiences symptoms which fall into the four below categories

  1. Intrusive Thoughts: unpleasant dreams, flashbacks (so vivid the individual feels like they are reliving the event), and repetitive involuntary memories. 

  2. Avoiding Reminders Of The Traumatic Event: avoiding people, places, activities, and situations which bring on distressing memories. Resistance of talking about the event as to avoid remembering or thinking about it.

  3. Negative Thoughts & Feelings:  regarding oneself or others. Distrust of others and harboring feelings of detachment and estrangement from others. Continue fear, anger, or shame. 

  4. Arousal & Reactive Symptoms: anger outbursts, reckless self-destructive behavior, irritability and easily startled. Increased difficulty with sleeping or concentration

Currently, the only medications approved by the FDA for treatment of PTSD, are sertraline and paroxetine - both of which are SSRIs (selective serotonin reuptake inhibitors).  Full remission of PTSD with these medications alone doesn’t happen often. Often other medications such as anxiolytics (benzodiazepines), mood stabilizers, and atypical antipsychotics are prescribed “off-label.”  Off-label means that it is FDA approved for one indication, but physicians can still use a drug for a different purpose than intended. But there are limited studies supporting these drugs, and even when combined with SSRIs, it does not necessarily result in remission. 

Besides not providing lasting PTSD remission for some patients, these “off-label” medications, especially benzodiazepines, can be addictive in themselves. Living with PTSD is difficult, and individuals will often try self-medicating, especially with alcohol and other drugs. Therefore, PTSD can often be associated with drug addiction or alcoholism which needs attention as well. 

Ways Ketamine Helps In PTSD: From Biological Changes to Spiritual Healing and Creating A New Meaning

Ketamine is not just another selective serotonin reuptake inhibitor (SSRI). It is in a totally different class of medicine that works on the glutamatergic system via blockade of N-Methyl-D-Aspartate (NMDA) receptor. In addition to its dissociative properties, ketamine may have multiple ways of bringing about improvement of PTSD symptoms and potentially even providing deep healing. 

Understanding the difference between remission and healing requires a step out of the classic current model of western medical mental health care. Going to the root of the problem rather than masking the symptoms is key here. Besides addressing chemical imbalances and decreasing anxiety, the use of ketamine in an intentional, transformative way can allow a change of perspective to the traumatic event and help reconnect to those around them. So let’s look at each way ketamine can help in PTSD. 

Biochemical Model: From Decreasing Symptoms To Preventing Death By Suicide

Besides treating the associated depression with PTSD, the thought of using ketamine to treat PTSD is by leveraging it’s N-Methyl-D-Aspartate-type (NMDA) receptor antagonism. Ketamine is the most potent clinically available NMDA receptor blocker. Activation of this receptor has correlated with increased formation of intrusive memories (both depression and anxious). The hypothesis  is that high activity of the NMDA receptor may be a risk factor for developing PTSD. Since ketamine acts against this receptor, researchers began to think perhaps this could help patients. 

The first randomized clinical trial looking at ketamine as a treatment for PTSD demonstrated that ketamine not only significantly but rapidly reduced the severity of PTSD symptoms.

From 2009 to 2012, 41 participants, were either given intravenous ketamine or an active placebo drug, midazolam (a benzodiazepine).  All participants were determined to have moderate to severe PTSD, based on their interview and scoring on the Clinician-Administered PTSD Scale (CAPS). All received either a single dose of ketamine or midazolam. Twenty-four hours after the dose, they were rated on their PTSD symptoms.

This was the first study to indicate that ketamine, opposed to the placebo, reduced the severity of PTSD symptoms within 24 hours. Frequently the benefits of the ketamine lasted longer than 24 hours for participants. The study also found ketamine was low risk and had minimal side effects, while also reducing the depressive symptoms associated with PTSD. Although this study was limited to one infusion and did not have long-term followup, it still gives hope to scientific researchers and more importantly, to trauma survivors. 

Another way in which ketamine can play a role in PTSD in addressing suicidal ideation. Dr. DiazGranados and colleagues found thoughts of suicide significantly decreased within 40 minutes of an IV ketamine infusion. These thoughts significantly remained decreased for 4 hours after the infusion in the context of major depressive disorder (MDD). This study shows that ketamine can give mental health care providers a window of opportunity to counsel and create a plan to support the patient's recovery. Another study by Dr. Ionescu and colleagues showed repeated infusions extended the decrease in thoughts of suicide up to 3 months in some patients with treatment-resistant depression (TRD). 

Functional Model

Ketamine blocks activity of the Default Mode Network (DMN). The DMN is a portion of the brain which can become overactive with negative thoughts and beliefs.  Some believe it may be where the ego actually resides. 

Increased DMN activity and functional connectivity is found in depression as well as in pain disorders. In these disorders, there is much rumination (i.e. having repetitive, circular thoughts).  Those who deal with depression may replay depressing or sad memories over and over in their mind, somewhat similar to intrusive thoughts in PTSD. This prevents individuals from healing and creating room for more positive emotions and memories.  

When ketamine is given, the DMN becomes less active.  This can give the individual a chance to take a break from these unsupportive thoughts and detach from the ego which may aid in healing.

Check out 3 Reasons Why You Should Know About The Default Mode Network Of Your Brain to learn more!

Psychological Model 

In this model, each individual has a conscious (what they are aware of) and unconscious (what they are unaware of) part of the mind.  Ketamine may allow the individual to take a peek or even experience entering into the unconscious mind via its dissociative property.

Accessing the unconscious allows for exploration of memories, emotions, and stories which may contain unprocessed and/or repressed feelings of pain and sadness. Exploring the unconscious mind allows one to clean, clear, and integrate the event(s) which lead to PTSD, in turn allowing healing and improvement of symptoms.

The experience the individual has during the ketamine infusion could also give an opportunity to gain a new perspective on the event. Under the dissociative effect of ketamine, a patient may enter a space where they see the situation from an entirely different and possibly healing perspective. With the new perspective they can potentially move on. 

Prefer video format? Check out The Psychological Mechanism of Ketamine video with Dr. Ko

Spiritual Model

This model requires a couple things: belief in the soul and being comfortable with the absence of a hardcore scientific explanation.

Although not scientifically testable, we believe that ketamine infusions can potentially heal the soul and establish a reconnection to the universal. When the traumatic event occurred, the spiritual model believes that what the individual experienced resulted in a disconnection and spiritual trauma as well (insert belief beyond science here).

During the ketamine infusion, some patients have experienced feelings of connection to God, the Universe, or something beyond their physical self.  Some have seen people from their past or met spiritual beings. One of our patients experienced seeing their guardian angel and felt safe and calm. Because of this experience, the patient reported feeling a sense of relief they had not felt for many years.

There is a growing body of work and research behind the use of psychedelic medicines such as psilocybin to treat PTSD (this is currently under research trials). One thought behind this is that a negative profound event/experience happened causing disconnection and resultant PTSD, but what if a person was to have an equally profound and positive experience to counter and potentially reverse the effects? This is a very new area which future research will better answer!

While some are on-board with this model and others are very much not, this mechanism potentially explains why many individuals who have sought out traditional Western medical treatments for their PTSD symptoms are not find relief and healing.

More of a visual audio learner? Check out Dr. Ko’s Spiritual Mechanism of Ketamine video to learn more.

Ketamine Allows Patients To Create New Meanings

Humans are storytelling animals.  Tens of thousands of years ago, we would sit around the fire and share stories of what happened in the most recent hunt.  There were certainly traumatic events that occurred to humans back then too.  

In Dr. Viktor Frankl’s book, Man’s Search for Meaning, he writes, “Those who have a 'why' to live, can bear with almost any 'how'.  In some ways suffering ceases to be suffering at the moment it finds a meaning, such as the meaning of a sacrifice.”

Although the past cannot be changed, we may be able to create a new empowering meaning behind it.  Ketamine can be the transformational tool to create a meaning behind the story that is held in the mind by seeing things in a new way.  This results in a paradigm mental shift and accordingly new beliefs and actions surrounding the trauma.  

Some people may actually re-experience the traumatic event during a ketamine infusions, but since they are dissociated the remembered trauma may be significantly diminished.  One patient described recalling the event, but from a third person perspective, giving them the space to create new meanings and obtain insights that otherwise would not be possible.  

Other ways Ketamine Could Help In PTSD: Looking At Animal Research

Much scientific research, which eventually translates to medical treatment, starts from animal studies and PTSD is no different.  Dr. Neil Fournier at Yale University School of Medicine wondered if ketamine may aid in treating PTSD since glutamate, a mediator of excitatory signals in the brain, contributes significantly to memory and is influenced by ketamine. He theorized, since glutamate is important in forming memories and that 30-40% of PTSD patients also have depression, ketamine may be an important treatment.

To test his theory, Fournier and colleagues studied rats using classic fear conditioning (pain with an auditory cue, then just the auditory cue resulting in a fear response, i.e. freezing in place). Rats who had been treated with ketamine within 24 hours had lower freezing behaviors compared to the placebo treated rats. This suggests that the ketamine helped extinguish the traumatic memory.

 In a different study by Dr. Brachman et al, mice were put into stress inducing situations such as exposure to social defeat, learned helplessness, or chronic corticosterone exposure. Two groups of mice were given saline or ketamine. The mice who did not receive the prophylactic ketamine, demonstrated depressive-like behaviors, while the mice given ketamine appeared to be protected against depressive-like behaviors. This early study suggests treatment with ketamine may provide resilience to future traumatic events. Both studies support a role for ketamine in the trauma setting, however, further human research is always necessary. 

Can Ketamine Make PTSD Worse?: Research Support The Answer No

Some individuals have raised concerns that ketamine could potentially worsen PTSD. There is concern that the NMDA receptor blocking property of ketamine could theoretically worsen PTSD symptoms, which would offset any helping by the medicine.  Let’s dive into some of the studies out there to find out more. 

So “yes” there are studies which suggest worsening of PTSD with the use of Ketamine. One study looked at if ketamine would affect PTSD symptoms in accident victims. This study asked them to rate their PTSD symptoms. 56 individuals included in this retrospective study, were given a single dose of racemic ketamine (which has both R and S ketamine), S-ketamine, or an opioid during the ambulance transportation. The study found that patients who received S-ketamine had significantly elevated symptoms of PTSD, compared to those who received racemic ketamine and opioids (in which there was no difference between). whereas there was no difference in patients who received racemic ketamine and opioids. The outcomes of this lead the researchers to conclude that ketamine, in particular S-ketamine could worsening the traumatic experience in the acute early stage. 

There are several things to consider regarding the above study.  First, the ketamine given during ketamine infusions are racemic. Meaning they contain both the R and S enantiomers. You are getting both forms of the ketamine during a clinical infusion. Also you are being given it for the purpose of treating PTSD or another related mood disorder like depression.  The retrospective studies involving PTSD and ketamine, one needs to remember, were given ketamine for the purpose of anesthesia or acute pain relief which is a different purpose and intent.

Ketamine’s dissociative psychomimetic effects by some have been thought to make PTSD worse or even cause trauma or exacerbating the traumatic event. Because of this concern further studies were made to explore the development or worsening of PTSD with the use of ketamine.  

In a study looking at prevalence of PTSD in burn patients who received ketamine compared to those who did not. This military study involved patients who were service members in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF). The study included 147 soldiers who underwent surgery, of which 119 had received ketamine (for the purpose of anesthesia) and 28 who did not (meaning a different anesthetic was used). The prevalence of PTSD was 27% (32 of 119) in the ketamine group versus 46% (13 of 28) in those who did not receive ketamine.

In a follow up study with a larger sample size by the same lead author, again looking at service members given ketamine vs not during surgery for their burns. This study had 189 who received ketamine and 100 who did not.  This time the study showed no statistically significant difference in the incidence of PTSD in those who received ketamine (28%) vs. those who did not (26.15%, p = 0.843). While this study didn’t show a lower prevalence of PTSD like the earlier study, it did demonstrate ketamine does not increase rates of PTSD in burn patients. 

Special Considerations In Using Ketamine for PTSD

If someone has an active substance abuse disorder, then it will be better to get treatment for this prior to undergoing ketamine infusions. Although there is some research for ketamine in actually treating substance use disorders, it can complicate the infusion treatment.  If an individual continues to abuse a substance, this can impair the effectiveness of the ketamine infusions to treat PTSD. 

Often patients with PTSD are treated with benzodiazepines to address their anxiety. This class of medications could actually decrease the effectiveness of the ketamine infusion.  That being said however, there are many clinics which may provide these medications during the infusion to minimize the dissociative effects which they view as side effects.  We believe the dissociative non-ordinary states of consciousness (which some ketamine doctors believe to be unnecessary or problematic) to be essential and transformative for the healing process. 

If an individual with PTSD has active delusions and hallucinations, ketamine should be avoided. The ketamine induced non-ordinary states of consciousness could potentially enhance or worsen delusions and active hallucinations. 

Learn something new? Have any questions? Please share and leave any comments or questions below!

References:

Brachman, Rebecca A et al. “Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior.” Biological psychiatry vol. 79,9 (2016): 776-786. doi:10.1016/j.biopsych.2015.04.022

DiazGranados, Nancy et al. “Rapid Resolution of Suicidal Ideation after a Single Infusion of an NMDA Antagonist in Patients with Treatment-Resistant Major Depressive Disorder.” The Journal of clinical psychiatry 71.12 (2010): 1605–1611. PMC. Web. 9 June 2018.

Feder, Adriana, et al. “Efficacy of Intravenous Ketamine for Treatment of Chronic Posttraumatic Stress Disorder.” JAMA Psychiatry, vol. 71, no. 6, 2014, p. 681., doi:10.1001/jamapsychiatry.2014.62.

Hamilton, J Paul et al. “Default-mode and task-positive network activity in major depressive disorder: implications for adaptive and maladaptive rumination.” Biological psychiatry vol. 70,4 (2011): 327-33. doi:10.1016/j.biopsych.2011.02.003

Ionescu, Dawn F., et al. “Rapid and Sustained Reductions in Current Suicidal Ideation Following Repeated Doses of Intravenous Ketamine.” The Journal of Clinical Psychiatry, Oct. 2016, doi:10.4088/jcp.15m10056.

Kucyi, Aaron, et al. Enhanced Medial Prefrontal-Default Mode Network Functional Connectivity in Chronic Pain and Its Association with Pain Rumination. Journal of Neuroscience 12 March 2014, 34 (11) 3969-3975; DOI:10.1523/JNEUROSCI.5055-13.2014

Liriano, Felix et al. “Ketamine as treatment for post-traumatic stress disorder: a review.” Drugs in context vol. 8 212305. 8 Apr. 2019, doi:10.7573/dic.212305

Mcghee, Laura L., et al. “The Correlation Between Ketamine and Posttraumatic Stress Disorder in Burned Service Members.” The Journal of Trauma: Injury, Infection, and Critical Care, vol. 64, no. Supplement, 2008, doi:10.1097/ta.0b013e318160ba1d.

Mcghee, Laura L., et al. “The Intraoperative Administration of Ketamine to Burned U.S. Service Members Does Not Increase the Incidence of Post-Traumatic Stress Disorder.” Military Medicine, vol. 179, no. 8S, 2014, pp. 41–46., doi:10.7205/milmed-d-13-00481.

Schönenberg, Michael, et al. “Effects of Peritraumatic Ketamine Medication on Early and Sustained Posttraumatic Stress Symptoms in Moderately Injured Accident Victims.” Psychopharmacology, vol. 182, no. 3, 2005, pp. 420–425., doi:10.1007/s00213-005-0094-4.

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