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Ketamine: A new frontier for depression treatment?

An insight into the use of Ketamine to treat depression.


Ketamine and depression

There’s a moment in that film Training Day with Denzel Washington where Ethan Hawke’s character smokes PCP out of a pipe. What has this got to do with anything? Watch on… the film tries to show his consequent, trippy experience as a frightening river of green-tinged hallucinations. PCP, which is an acronym for “phencyclidine”, was first synthesized in 1956 by chemists at the Parke Davis Company. PCP was used as an anaesthetic. The problem? Gradually, it was noted that humans experienced “emergence delirium”: when they awoke, patients would become “agitated, delusional, and irrational”. Ethan Hawke does in the film.

A History of Ketamine

Efforts were made to adapt the drug. In 1962, chemist Calvin Stevens developed ketamine, a cousin of PCP which had “one-tenth the potency” Ketamine had minimal side effects compared to those of PCP and could rapidly induce analgesia. The use of ketamine grew, as it was used to heal soldiers on the battlefields of the Vietnam War in the late 60s. In this article, we discuss “sub-anaesthetic ketamine”- levels of ketamine which are not high enough to induce anaesthesia. Ketamine is currently used as an anaesthetic in veterinary medicine. This is why many refer to ketamine as a “horse tranquiliser”, even though the drug has an accepted place in human medicine (Jansen, 2000).

Today, ketamine has a reputation for crazy use as a party drug. Karl Jansen (2000) completed a great review of the nonmedical use of ketamine. He reports illicit, recreational use of the drug as early as 1967. Young (1977) claims this use was the consequence of experiences in Vietnam. The drug is connected to those who seek dissociative, hallucinatory experiences. (A friend of Timothy Leary, John C. Lilly, spent decades exploring the mental frontiers of ketamine use floating in isolation tanks with dolphins.) West Australian law enforcement have made multiple seizures of ketamine in recent decades. Known as “Special K”, for decades ketamine has been associated with club and rave culture. What’s the subjective experience of ketamine? Users experience “ataxia (inability to coordinate muscular movement), slurring of speech, dizziness, mental confusion, blurred vision, anxiety, hyperexciteability and insomnia.” What is remarkable is that feature of rave culture has shown an excellent capacity to treat depression.

There are frequent comments on the epidemic of depression in modern society. The introduction to many papers will note the associated cost to the economy and healthcare system. Furthermore, treatment resistance “occurs commonly in up to 30%” of cases. Scientists argue that the current treatment system does not cut the mustard. There is this concept that recovery from depression requires a long and arduous timeline. This concept is associated with the dominant school of treatments for depression. Zoloft and Lexapro, common SSRIs, can take months to exhibit effects. The novelist William Stryon famously wrote that “the black and howling tempest” of depression was slow to abate.

What does Ketamine do differently?

We will not go too much into the neurochemistry of how ketamine works. Essentially, “most current antidepressants act on the monoamine systems of the brain and, crucially, are slow to elicit antidepressant effects”. “Ketamine exerts its antidepressive effect through a new mechanism.” The target of ketamine is the NMDA receptor, which is blocks. What is the consequence? The thumbnail explanation of depression, a “chemical imbalance” and “serotonin deficit” in the mind, is insufficient. In this model, SSRIs are the answer. Chronic stress and depression can flood the mind with hormones such as cortisol. This “depletes synapses in certain brain regions”. Ketamine “triggers reactions in your cortex”, enabling brain connections to regrow. As written by Dr Steven Levine, “ketamine can repair damage to the brain that are the result of long-term stress hormones.”

How does Ketamine help to treat depression?

The use of ketamine to treat depression, and quickly, is now affirmed by a body of scientific literature. Ketamine can “produce rapid and profound reductions in depressive symptoms following a single subanaesthetic infusion in individuals with major depressive disorder”. Ketamine acts quickly, with effects discussed at four hours after administration. There have been many meta-analyses; in 2015, Coyle and Laws completed a comprehensive effort which concluded that ketamine was an “effective and rapid treatment for depression in the short term”.

What does Ketamine treatment look like?

Ketamine “is water and lipid soluble, allowing it to be administered conveniently via various routes that emphasize its adaptability to many clinical scenarios”. It’s worth noting that “the optimal route of administration is intravenous”, that is, through injection. A cool Vox article details the author’s experience with ketamine treatment for depression. The author had a series of intravenous administrations on a hospital bed, each lasting around 45 minutes, and discusses the benefits.

The future of Ketamine treatment

It is certainly a robust area of study. Multiple questions remain. For example, use of ketamine to treat additional conditions such as bipolar (which is commonly comorbid with depression) and OCD has been explored. What is found is that the primary diagnosis affects the antidepressant outcome of ketamine infusion. More clarification on the effectiveness of ketamine is needed for patients struggling with comorbid diagnoses. Authors call for more placebo-controlled studies, with the use of the benzodiazepine Midazolam is a control in the experiments. Furthermore, the addictive potential of repeated ketamine exposure must be addressed. Those who self-administer the drug report elevated depression scores over a 12-month period. We have discussed the crazy history of ketamine, and its street reputation is not easy to forget. More trials are also needed to determine the average response to ketamine at the various timestamps post-infusion, as there are currently multiple disagreements. More experiments must be run. What’s certain? The transplantation of this drug from the clubs of Hong Kong to the clinical world is as refreshing and unexpected a connection as those it forges in our brains.


Anodyne is a multidisciplinary medical centre in Perth Western Australia. With a focus on patient centred approaches for pain and mental health recovery.

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