The Science behind Ketamine
Over 50 years of research has confirmed that ketamine is more than an anesthetic as originally discovered, but a highly effective means of treating a variety of mental health conditions—particularly depression, anxiety, bipolar post-traumatic stress disorder, PTSD, and more. In the last two decades, over 4,000 patients have been enrolled in clinical trials to determine the effectiveness of ketamine therapy. The American Psychiatric Association and the National Institute of Mental Health have reviewed the literature and confirmed that ketamine is one of the fastest-acting antidepressant medications available today. And fortunately, it works in populations of people who fail multiple traditional antidepressant therapies.
Background and History of Ketamine: Where it’s been and where it is now
Ketamine was first synthesized in the 1960s and gained FDA approval in 1970 for its potent effects on consciousness. Even at significant doses ketamine had an excellent safety profile for anesthesia. It is often preferred over other anesthetics due to its unique ability to maintain stable blood pressure and respiration. This property is one of the reasons it has been considered an essential medication by the World Health Organization since 1985. The most unique effect of ketamine had nothing to do with anesthesia, however, but rather its powerful ability to reshape neural networks and create profound antidepressant effects.
The first documented antidepressant effects of ketamine were in a psychiatric unit of a university hospital in 1973. This trial showed an improved ability to discover insights in psychotherapy and provided symptom relief from mental health conditions. It’s superior safety profile on vital organ systems and ease of administration made it a life-saving medication for the U.S. military in the field since the Vietnam conflict. A serendipitous discovery of administering ketamine in these traumatic settings revealed ketamine’s ability to prevent the development of post-traumatic stress disorder, PTSD, as well as provide significant pain management for soldiers dealing with amputations and burn injuries.
What Conditions can Ketamine Treat?
Thousands of patients across dozens of high-quality clinical trials make it clear that ketamine has positive treatment outcomes across multiple mental health conditions. Ketamine can treat major depression, bipolar depression, PTSD, anxiety, OCD, eating disorders, addiction, and the possibilities continue to expand. Many mental health disorders share some common mechanisms and so ketamine’s medicinal properties likely produce a central role in the healing process that gives rise to depression, anxiety and trauma. One such mechanism is the role of stress in the development of these conditions. Chronic stress is known to produce toxic effects on synapses within the brain. Synapses are the physical connections between neurons. So in effect, chronic stress creates a synaptic disconnection syndrome. Ketamine works directly to restore these synapses.
The Mechanics behind the Treatment
At a neurobiological level, our brain is not functioning optimally when we’re depressed or anxious. Stress disrupts normal brain patterns and disrupts synaptic connections (the physical connections between neurons). Ketamine works directly to restore these synapses by targeting the NMDA receptor and releasing a surge of glutamate. This release in turn activates pathways that release growth factors like BDNF that help grow new synapses and create healthier stronger connections between neurons. Ketamine also has properties at other receptors including the mu-opioid receptor that in part can lead to pain-relieving properties.
It’s then unsurprising that ketamine can produce powerful antidepressant effects when traditional antidepressants have failed because it works on a completely different mechanism. Traditional antidepressants work on the serotonin, dopamine, and norepinephrine systems. Ketamine works by blocking the NMDA receptor and multiple other targets that lead to neuroplasticity and an altered state of consciousness that opens doors to new insights, meaning, and the processing of trauma. Trauma can leave the body in a dysregulated state. Altered states of consciousness can accelerate the healing process by helping regulate the nervous system.
Ketamine and Neuroplasticity
Neuroplasticity refers to our brain’s ability to adapt and learn to new inputs and circumstances. Certain things can limit our neuroplasticity like depression, stress, addictive or compulsive behaviors, dull environments, and traumas. At times, it may feel like we need a mental reset. Ketamine creates a dramatic surge of the excitatory neurotransmitter glutamate to certain brain regions that in turn release growth factors; including brain-derived neurotrophic factor, or BDNF. BDNF helps in the growth and maintenance of healthy neurons. This directly primes the brain for new learning and provides an interruption of negative thought patterns to help reset the neural networks. New information, patterns of behavior, and new insights are more easily learned with the brain primed for learning at a neurobiological level. This may be the reason why ketamine helps accelerate the process of psychotherapy and create lasting meaningful changes during ketamine enhanced sessions.
Oral Vs IV Ketamine Therapy
Ketamine has commonly been administered intravenously only because it was typically used for anesthesia in the past. Ever since its role in mental health conditions was discovered, there have been more trials with ketamine in a variety of formulations to make it more accessible and easy to administer in outpatient settings. Oral ketamine has been confirmed in multiple randomized clinical trials to be a safe and highly effective method of administering ketamine at home. Rates of absorption and bioavailability vary so ketamine dosing must be done carefully and ideally in a stepwise fashion to determine the most accurate and effective dose for an individual. Fortunately, wide dose ranges have been tested to be safe for at-home use with minimal adverse events reported.
While IV ketamine therapy has been considered the gold standard since 2000, and the data supporting its use has been confirmed in dozens of studies, there is no reason in principle why oral ketamine cannot be as effective. It is true that IV ketamine is by definition 100% bioavailable while oral ketamine ranges from 15-30% bioavailability. This means that a fraction of the oral dose will be absorbed and make it into the bloodstream. This difference in bioavailability can be corrected by increasing the total dose - which is often done to 4-8 times higher than the IV equivalent dose to achieve similar effects. Patients have had significant success from oral ketamine therapy but there have not yet been any high-quality clinical trials to prove that it is equally effective to IV therapy. However, oral ketamine is certainly much more affordable and can safely be done at home with proper screening and education.
Written by Kazi Hassan, MD
Dedicated to sustainable mental wellness, Dr Hassan has worked with clients and My Ketamine Home over the years to support individuals looking for an effective treatment for mental relief and reset. He has spent a career focusing on pain management, rehabilitation, and physical medicine after training at Jackson Health Systems, University of Miami, and Miami VA.
References
Andrade, C. Oral Ketamine for Depression, 1. The Journal of Clinical Psychiatry 80, (2019)
Arabzadeh S, Hakkikazazi E, Shahmansouri N, et al. Does oral administration of ketamine accelerate response to treatment in major depressive disorder? results of a double-blind controlled trial. J Affect Disord. 2018;235:236–241.PubMed
Domany Y, Bleich-Cohen M, Tarrasch R, et al. Repeated oral ketamine for out-patient treatment of resistant depression: randomised, double-blind, placebo- controlled, proof-of-concept study. Br J Psychiatry. 2019;214(1):20–26.PubMed
Jafarinia M, Afarideh M, Tafakhori A, et al. Efficacy and safety of oral ketamine versus diclofenac to alleviate mild to moderate depression in chronic pain patients: a double-blind, randomized, controlled trial. J Affect Disord. 2016;204:1–8.
NewportDJ,CarpenterLL,McDonaldWM, Potash JB, Tohen M, Nemeroff CB; APA Council of Research Task Force on Novel Biomarkers and Treatments. Ketamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression. Am J Psychiatry. 2015; 172(10):950-966.
Salloum, N. C. et al. Time to relapse after a single administration of intravenous ketamine augmentation in unipolar treatment-resistant depression. Journal of Affective Disorders 260, 131–139 (2020).
Sanacora, G. et al. A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders. JAMA Psychiatry 74, 399 (2017).
Schenberg, E. E. Psychedelic-Assisted Psychotherapy: A Paradigm Shift in Psychiatric Research and Development. Frontiers in Pharmacology 9, (2018).
