Ketamine History: Battlefield to Depression Battles

About the Author Dr. Steven P. Levine is a board-certified psychiatrist internationally recognized for his contributions to advancements in mental health care. Though he is a psychiatrist who places great emphasis on the importance of psychotherapy, medication is often a necessary component of treatment, and he was dissatisfied with the relatively ineffective available options with burdensome side effects. Dr. Levine pioneered a protocol for the clinical use of ketamine infusions, has directly supervised many thousands of infusions and has helped establish similar programs across the country and around the world.

Ketamine: A Medication We’ve Been Using for Over Fifty Years

Ketamine was developed as an anesthetic for surgery and trauma.  It was approved by the FDA in 1970 for human use, with indications as for the sole anesthetic agent for diagnostic and surgical procedures that do not require skeletal muscle relaxation.  Ketamine was then literally battle-tested during the Vietnam War, where it was vital in caring for wounded soldiers.

Ketamine Applications

It is also indicated for the induction of anesthesia prior to the administration of other general anesthetic agents and to supplement low-potency agents.  Ketamine has been used in the following surgical procedures1:

Ketamine is quick acting and then leaves the body quickly. When given intravenously (IV) the half-life of ketamine is 2.5 hours and offers 100% bioavailability.  Therefore, patients recover quickly after treatment with minimal lingering side effects.

Ketamine Research

Beginning in the mid-1990’s at Yale University, researchers began to explore other possible applications of ketamine, including its use in depression.  By this time, ketamine had lost its patent protection, making it unprofitable for pharmaceutical companies to apply for a new FDA indication. Therefore, these applications are considered off-label, a common practice in medicine, as up to 70% of medications are used in this manner.

The data from both research trials and real-world use of ketamine for psychiatric conditions is growing, with dozens of studies, review papers, and meta-analyses available on its use for major depressive disorder, bipolar depression, PTSD, OCD, and anxiety.  A recent trial measured response after only one treatment of ketamine versus an active control, midazolam.2 68% of patients responded after a single dose versus 28% for midazolam.  Additional trials have shown similar results that were maintained over time through a series of infusions given over a few weeks.  Major academic and teaching centers such as Yale University, Baylor University, the National Institute of Mental Health, Stanford University, The Mayo Clinic, The Cleveland Clinic, and Mt. Sinai Hospital have completed trials and are currently involved in more studies to review additional applications of ketamine therapy for mood and anxiety disorders.

The primary mechanism of action involves blockade of N-methyl-D-aspartate (NMDA receptors), a type of glutamate receptor, in the brain. Glutamate is the most common chemical messenger in the body. While ketamine also has many other activities in the brain, it is believed that this mechanism assists in repairing signaling neurons and synapses that are not optimally functioning in patients with mood and anxiety disorders. This is a very different mechanism than traditional antidepressants that focus on increasing brain chemicals such as serotonin, norepinephrine, and dopamine. Having a novel mechanism is exciting for the field, as large depression studies show us that up to 50% of patients may be considered “treatment resistant” with standard medications.  Treatment-resistant does not mean that someone is resisting getting well, it means that the medicine has not adequately helped to reduce that person’s symptoms. Even for those who have not responded to many medications or even electroconvulsive therapy (ECT), many may still be able to get relief with IV ketamine.

The Future of Ketamine

In this way, there is good reason to believe there is hope for those suffering from depression and related conditions.  Ketamine is serving as an effective tool in its own right, but also as an example of progress being made on behalf of those battling for their mental health…fitting then that ketamine got its start on the battlefield.

For more research on ketamine, please visit our Ketamine in the Media page.

  1. Graven-Nielsen T, Aspegren Kendall S, Henriksson KG, et al. Ketamine reduces muscle pain, temporal summation, and referred pain in fibromyalgia patients. Pain. 2000;85(3):483-491.
  2. Schwartz J, Murrough JW, Iosifescu DV. Ketamine for treatment-resistant depression: recent developments and clinical applications. Evid Based Ment Health. 2016;19(2):35- 38. doi:10.1136/eb-2016-102355.