What Is Ketamine?

Contrary to popular belief, ketamine isn’t just a “party drug.” In fact ketamine is a substance which has been in clinical practice since the 1960’s. So just exactly what is ketamine, anyways?

Examining Preconceptions and Negative Stereotypes

Sometimes referred to as “Special K” or simply as a “horse tranquilizer”, Ketamine is often thought of as a rave or clubbing drug. While ketamine is used this way this application of the compound deviates significantly from its original, intended use. 

Ketamine is a dissociative anaesthetic that was first developed in 1962 by organic chemist Calvin Stevens. The first pharmacological study examining ketamine use in humans was conducted by two University of Michigan professors: Dr. Edward Domino of Pharmacology and Dr. Guenter Corssen of Anesthesiology. Domino and Corssen found that ketamine was capable of inducing a potent anesthetic (painkilling) effect “with a unique state of altered consciousness.” The two researchers also noted ketamine had a short duration in terms of its effect as well as minimal side effects, which made it an excellent candidate for clinical anaesthetic use. 

In 1970 Ketalar became the first ketamine based drug approved by the FDA for human use. Ketamine also became known as a battlefield drug thanks to its fast-acting analgesic properties and ability to be administered by soldiers, earning it the moniker of “the buddy drug.”

The Controlled Substances Act, however, was also passed in 1970. The Act introduced a new classification system for categorizing drugs “with no accepted medical use.”

That didn’t stop ketamine from developing its reputation as a party drug in the 80’s and 90’s. Ketamine use became so widespread that the United States federal government categorized it as a Schedule III substance in 1999, effectively halting additional research into its potential therapeutic uses.

While ketamine’s recreational use was still being disputed by the government, determined researchers continued to explore the unique substance. 

Uncovering Therapeutic Use

The initial discovery which led scientists to discover ketamine could produce rapid antidepressant effects in patients with Major Depressive Disorder (MDD), “has been hailed as one of the most important discoveries in psychiatry in the last decades.” Effects for MDD and bipolar patients were described as “rapid, robust, and relatively sustained.”

First made in 2000, this remarkable discovery had since been confirmed by a number of randomized trials. Off-label ketamine use has since been used to help treat patients with suicidal thoughts. A 2017 meta-analysis published in The American Journal of Psychiatry found that ketamine exerted rapid antidepressant effects that were sustained for up to a week after treatment (compared with placebo).

The ketamine-based drug Spravato (Esketamine) received approval in 2019 by the FDA as a medication for treatment-resistant depression. Spravato is also currently undergoing additional Phase III clinical trials. One Phase II clinical trial found Spravato, “...demonstrated rapid and clinically relevant improvements in depressive symptoms compared to placebo.” Authors also discovered Spravato exerted “a rapid antisuicidal effect.”

Ketamine is currently being evaluated for its potential to treat a range of other disorders. These include Obsessive Compulsive Disorder (OCD), Post Traumatic Stress Disorder (PTSD) and bipolar depression.

Ketamine Assisted Therapy (KAP)

While Ketamine’s documented uses were valuable to anaesthesiologists, the substance had its own unique side effects. Of particular concern to medical professionals was ketamine’s psychedelic profile. Despite not being a member of the “traditional” hallucinogen family (LSD, DMT, Psilocybin), ketamine’s unique dissociative properties imbued it with psychedelic-like effects. Patients would appear to be awake but would be unresponsive to stimuli. They might hallucinate, experience out of body sensations or experience other cognitive distortions that could impact mood and perception of reality. 

Dubbed “psychomimetic effects”, these side effects were viewed as undesirable by many clinicians who believed ketamine's psychedelic effects “limit clinical use.”

A new school of thought, however, gradually emerged in contrast to this viewpoint. While some professionals argued ketamine’s psychomimetic properties limited its use, others put forth the idea that these psychedelic effects were responsible for ketamine’s therapeutic effects. In a 2019 research paper published in the Journal of Psychoactive Drugs, the authors of the paper opened with this assertion:

“...we believe ketamine can benefit patients with a wide variety of diagnoses when administered with psychotherapy and using its psychedelic properties without need for intravenous (IV) access.”

This belief has since been translated into a new practice known as Ketamine Assisted Psychotherapy (KAP). Researchers suggested that KAP is an effective method for treating patients suffering from depression, especially “those with severe symptom burden.” They lamented conventional attempts to create analogous drugs of ketamine that lacked its mind-altering effects, and showed evidence that psychedelic experiences created enhanced benefits for patients. Parallels between ketamine and psilocybin, the primary constituent of “magic mushrooms”, led researchers to conclude mystical experiences were correlated with positive treatment outcomes:

“This association suggests that profound psychedelic experiences, regardless of the medicine facilitating them, may improve mental health and overall well-being (Sullivan 2018).”

Rather than search for a way to eliminate psychedelic effects, KAP aims to utilize the psychedelic experience to help patients engage in introspective thought. This theory postulates that, under the influence of ketamine, patients may experience the absence of typical “emotional constraints of the ordinary mind.” The lack of these constraints helps patients achieve personal elucidation, or find deep meaning in their experiences. These revelations and other insights gained during the trip, called anchoring, can cause decreases in symptomatology for patients:

“This is about learning from the experience, bringing it as a method to everyday life. In essence, we use the experiential component of the medicine to bring new perspective and the direct experience of seeing ourselves in a new way—the missing link that gives hope to many sufferers of mental illness and others who cannot achieve this critical reframing by other means.”

This idea of anchoring also supports the theory that ketamine can help induce neuroplasticity. 

Proposed Mechanism of Action

Despite being in use for 50 years, the exact mechanism of action for ketamine is still unknown. 

Ketamine is water and lipid soluble. It can be administered in a number of different ways including orally, nasally, intravenously, intramuscularly, subcutaneously and through epidural. Bioavailability depends on the route of administration, with IV administration at 100% and oral as low as 20%.

There are two different types of ketamine: S and R ketamine. The use of intranasal S-ketamine for depression was granted fast track designation by the FDA in 2019. 

We do currently know that ketamine is an NMDA (N-Methyl-D-aspartate) antagonist. NMDA receptors modulate glutamate, an excitatory neurotransmitter. Recent studies have found NMDA receptors as well as serotonin receptors are involved in depression. 

Substances that antagonize channels prevent them from functioning as normal. Ketamine non-competitively antagonizes NMDA receptors in a couple of ways. The first is by acting as an open-channel blocker, binding to a site on the receptor and reducing the time the channel spends open. The second is as an allosteric modulator which decreases the frequency that the channel opens.

Ketamine has been shown to reduce neuronal excitation due to glutamate. This is thought to be one mechanism of action that produces its anxiolytic effects. Another theory suggests inhibition of serotonin reuptake may be behind ketamine’s analgesic properties. Ketamine’s interactions with GABA, a naturally occurring amino acid, have also been implicated in several pathologies including OCD and depression. 

A Bright Future

Ketamine is a dissociative anaesthetic drug with a high safety profile and relatively low side effects. It’s been in clinical use for over 50 years now and has been shown to exert rapid antidepressant and anxiolytic effects. Current research indicates promise for ketamine use in a number of pathologies including treatment resistant depression and OCD.