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Q&A Session with Dr. John Krystal: The Latest Insights on Ketamine Therapy for Mental Health

This week I had the privilege of participating in an enlightening Q&A session with Dr. John Krystal hosted by Big Tent Ketamine (BTK). It was Dr. Krystal's lab at Yale in the 1990s that pioneered the discovery of ketamine's rapid-acting antidepressant effects on patients, a contribution for which the world remains deeply grateful. Former National Institute of Health Director, Thomas Insel, lauded ketamine, especially when given intravenously, as potentially “the most important breakthrough in antidepressant treatment in decades.” Dr. Krystal stands at the forefront of research in areas such as alcoholism, post-traumatic stress disorder, schizophrenia, and depression. His innovative work seamlessly combines psychopharmacology, neuroimaging, molecular genetics, and computational neuroscience to delve deeper into the neurobiology and treatment of these disorders.

The BTK community, a collaborative group of practitioners (MD, PMHNP, PsyD, LCSW, etc.), researchers, and enthusiasts, is dedicated to advancing knowledge on administering ketamine therapy safely and effectively. Among the attendees were BTK founder Carl Spitzer, MD and Dr. Steven L. Mandel, Founder & President of the Ketamine Clinic Los Angeles, arguably the nation's most esteemed ketamine clinic. Today, we invite you to join us as we engage with these experts, offering the latest insights into the practice of ketamine therapy.

Dosage, Length of Administration, and Standard of Practice

Dr. Krystal consistently uses an initial dose of 0.5mg/kg administered over 40 minutes and avoids increasing this dose during the course of treatment. This specific dose has been observed to induce notable clinical improvement in depression. Presently, there is no evidence indicating that doses above 0.5mg/kg amplify the antidepressant effects or improve clinical outcomes. Dr. Krystal underscores that ketamine operates within a narrow therapeutic window. He has found that when the dosage is increased to 2mg/kg, patients often show anesthetic effects, negating the antidepressant benefits of ketamine. Yet, there's an exception to this general rule: when the goal is to counteract maladaptive behaviors with ketamine. Studies suggest that a dose of 0.8mg/kg can be effective in treating alcohol use disorder (AUD), resulting in reduced alcohol cravings and intake. Furthermore, Dr. Krystal advises against using dissociation as an indicator of therapeutic effectiveness. While some might experience dissociation at the initial dose, others could require more, but increased doses don’t necessarily translate to better efficacy.

Should one stop at six infusions or proceed with more? By the sixth infusion, 80% of individuals who respond to ketamine can be identified. For many, a longer course of treatment is required.

Oral, Sublingual, and Intranasal Ketamine.

The challenge with non-intravenous forms of ketamine, such as oral or intranasal ketamine, is the uncertainty of the actual blood levels achieved and whether they reach the threshold of 0.5mg/kg. In reality, many individuals taking oral and nasal ketamine do achieve an anxiolytic effect while the drug is in their system for a few hours, similar to the effect someone would experience using a benzodiazepine such as Xanax. However, the antidepressant effects of ketamine often emerge several hours after administration and continue to intensify over days and weeks. One primary concern with oral and nasal ketamine is ensuring the appropriate dose reaches both the blood and the brain to produce antidepressant effects. Simply put, it's difficult to be certain. Dr. Krystal notes that providing transient relief with a subtherapeutic dose of ketamine may offer an anxiolytic effect without addressing the underlying depression. As a result, a patient might feel better momentarily, but once the ketamine dissipates from their system, their distress returns. This can lead to a dangerous cycle: the depression remains untreated, yet the short-lived relief prompts individuals to consume increasing amounts of ketamine. Ultimately, this pattern might predispose individuals to addiction.

Pilot study: Synaptic Deficits, Disassociation, and Mechanism of Action

In patients with severe depression, the brain often exhibits a loss of connections (synapses) between nerve cells. Depression that is associated with such synaptic deficits tends to be more severe, rendering many patients "treatment-resistant" to conventional methods, such as antidepressants.

Research has demonstrated that ketamine can restore these lost connections within 24 hours of its administration. This reversal is evident through increased synaptic density in nerve cells, as observed in imaging studies.

His pilot study encompassed two groups of depressed patients: one group displayed synaptic deficits on PET CT scans, while the other did not. Both groups exhibited improvement following the administration of ketamine. Notably, in the group with synaptic deficits, clinical betterment was linked to dissociative symptoms. However, in the group without synaptic deficits, clinical improvement was not associated with such symptoms. To determine if a patient has the more severe form of depression characterized by synaptic deficits, certain indicators might be considered as markers of severity: cognitive impairment, functional disability, persistent symptoms, and treatment resistance (evidenced by failure to respond to multiple treatments).

He suggests two primary mechanisms behind ketamine's antidepressant effect:

  1. An increase in synapses, leading to enhanced communication between different brain regions.
  2. A modification in how individuals process certain memories. Ketamine not only affects learning during its administration but also broadens the capacity for learning (neuroplasticity) in the subsequent days to weeks.


An increasing number of studies suggest that patients who undergo psychotherapy in the days following a ketamine treatment tend to benefit synergistically from the combination. The magnitude and duration of ketamine's antidepressant effect are more pronounced in those who engage in psychotherapy afterward. This is likely due to enhanced brain function and increased neuroplasticity. However, he notes that some individuals achieve a complete remission of their depression without supplementing with psychotherapy.

For those grappling with maladaptive behaviors driving addiction cravings, or with PTSD, ketamine might work through a different mechanism. By activating trauma memories and then administering ketamine, the intensity of those memories diminishes. This means the capacity of these memories to spark arousal, activate the amygdala, and exacerbate PTSD symptoms is reduced. The resulting relief often proves to be long-lasting.

Without a comprehensive approach that provides a broader context of support, patients might be underserved. By not preparing them or their families for the upcoming journey, and by not aiding their return to health, we fall short of optimal care. He cautions against clinics that lack mental health expertise, ones that are ill-equipped to guide individuals through these transitions and that treat patients without considering the broader context of their care.

"Someone needs to be looking out for the best interest of the patient throughout this process"

Ketamine for Other Mental Disorders: Bipolar Disorder, Anxiety, OCD, etc.

Much remains unknown in this area, but it's a vibrant field of research. One observation is that patients with bipolar depression tend to respond to ketamine more quickly than those with unipolar depression. There are promising results from ongoing research into ketamine's use for anxiety disorders. However, given the high comorbidity rates between anxiety and depression - many people with anxiety also suffer from depression, and vice versa - it's frequently observed that when depression symptoms improve with ketamine, the symptoms of anxiety often do as well.

Ketamine for Adolescents

Adolescents have brains that are still developing and are experiencing neuroplasticity. He argues that ketamine should not be the first-line therapy for this age group. Instead, the decision to treat adolescents should involve a thorough discussion of the risks and benefits. He emphasizes that the notion of someone taking their own life due to treatment-resistant depression concerns him more than the potential risks of ketamine on the developing brain. To date, there have been two placebo-controlled studies; one suggests that ketamine can be effective for treating resistant depression in adolescents. However, more long-term data on the subject is needed.

Abuse and Addiction

"Benzodiazepines are drugs of abuse, opioids are drugs of abuse, ketamine is a drug of abuse. We have to treat ketamine with the respect that it deserves"

This underscores the importance of regulation and the implementation of best practices for safe use. In China and Taiwan, ketamine ranks as the third most abused drug. Individuals abusing ketamine in these countries consume up to 5 grams daily. (For context, the therapeutic dose for a 70kg person is 0.035 grams or 35mg.) Some of these individuals develop depressive states, while others experience persistent psychotic symptoms even after the drug has left their system. As a somewhat ironic consequence of the increased media coverage on ketamine, abuse rates are rising in the US. He mentions that every patient he encountered who suffered from ketamine abuse had self-administered the drug at home. They were typically prescribed a bottle of ketamine tablets or a nasal spray. Initially, they would use ketamine only in extreme situations. Over time, they began using it in anticipation of stress, and eventually, they started taking it recreationally.

"It’s something we need to take very seriously, the most powerful way we have of containing it is to restrict it to the clinic"
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Big Tent Ketamine


Key points from the discussion include Dr. Krystal's standard initial dose recommendation of 0.5mg/kg of ketamine administered over 40 minutes, emphasizing its effectiveness and cautioning against higher doses that might nullify its benefits. He also discussed the challenges of non-intravenous ketamine forms and the potential for misuse, especially when the substance is taken outside a clinical setting. Dr. Krystal highlighted ketamine's ability to restore lost neural connections in depressed patients, potentially alleviating symptoms of severe, treatment-resistant depression. He stressed the synergy of combining ketamine treatment with psychotherapy and highlighted the need for holistic patient care and proper regulation, particularly given the rise in ketamine abuse in certain parts of the world.

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