Ketamine For Depression: A Mental Health Breakthrough

This article was originally published on Reality Sandwich, and appears here with permission.

Depression can be an almost intolerable burden to live with. While antidepressants help many to soothe their symptoms, many others find no relief in these substances. A decades-old drug, ketamine, is now offering hope to many of these people. Ketamine was first discovered in 1962. It was found to be a dissociative anesthetic and was used on the battlefields of the Vietnam war.  Today, health experts within the psychedelic industry are administering this substance, otherwise known as ketamine treatment.

While it can be used to dull pain at lower ketamine doses, at higher doses it can be profoundly hallucinogenic. With the emergence of ketamine as a promising new treatment for depression in recent years, it is now leading the way when it comes to legally available psychedelic therapy. The scientific and health communities are recognizing the tremendous potential for ketamine for depression.


While research shows what depression looks like, there is no currently accepted textbook understanding of what depression really is. Clinically, it is characterized by low mood, a loss of the ability to take pleasure in things, changes in weight and energy levels, negative thoughts about oneself, impairment in thinking, and suicidal thoughts. In essence, the psychology of a person with depression is characterized by emotional pain and hopelessness. It is a state of deep immobilization from which there seems no escape. It can feel like being alone at the bottom of the ocean with no way out.

Treatment-Resistant Depression

In the 20th century, several treatments for depression were developed, relieving suffering for countless people. For many, however, none of these interventions help.  These cases are classified clinically as treatment-resistant depression, and they typically represent the most severe and unrelenting instances of depression. Finding a way to help the group of people in the treatment-resistant classification is the holy grail for new antidepressant therapies.

How Was Ketamine Treatment Discovered?

At the beginning of the 21st century, exciting new therapies emerged that showed promise for helping those with severe, previously untreatable depression. One such therapy is a low-dose intravenous infusion type of ketamine. Scientists had previously observed a link between the brain receptor that ketamine targets and schizophrenia, alcoholism and depression. 

The possibility that this receptor plays a causal role in the origin of multiple mental health issues led scientists to consider whether ketamine might potentially treat such issues [1]. Researchers found that the antidepressant effects of ketamine kicked in quickly, within a matter of hours compared to weeks for traditional antidepressant medication. They also found that the effects could last for multiple weeks.  Scientists had discovered a promising new antidepressant therapy.

How Effective Is Ketamine for Depression?

When it comes to suicidality, the rapid onset of ketamine’s effects results in saving lives. The anti-depressant effects are powerful, even helping those with previously untreatable depression. Current evidence suggests that the effects appear to be limited to the short term, however, typically lasting on the order of weeks [2]. Individuals must return for repeated ketamine infusions to maintain the positive effect on their depressive symptoms.


To understand how ketamine works, it’s helpful to be familiar with some basics of neurobiology.  The brain is made of brain cells called neurons which signal to each other via chemicals called neurotransmitters. The cell sending the signal squirts out a chemical substance, and the chemical lands on the surface of the cell receiving the signal. This receiving cell has specialized receptors on its surface, which the chemicals fit into. When this happens, the signal has been received, and it sets in motion the appropriate event in the receiving cell. 

The main neurotransmitters in the brain used to transmit and process information are called glutamate and GABA. Glutamate increases activity in the brain while GABA decreases activity.  When activation is transmitted through networks of neurons via glutamate, the receiving cells register the presence of this neurotransmitter via multiple types of receptor.  One type is the AMPA receptor, which produces activity in the receiving cell. The other major type is the NMDA receptor. When activated, these receptors cause a strengthening of the connection between the two neurons, allowing learning to occur. It is the NMDA receptor that ketamine targets.

Ketamine in the Brain

When ketamine gets into our bloodstream, it crosses into the brain and can drift into these NMDA receptors. By imitating glutamate, it can cause activation of neurons and strengthening of connections in the brain. These processes have the potential to affect mood, perception and patterns of thinking. What’s more, this boost of activity may be only the first step in ketamine’s effect. By adding signals of this kind into the brain, the activated neurons may release other neurotransmitters, producing complex cascading effects. What’s more, ketamine’s effects are not just limited to NMDA receptors. It also activates opioid receptors.


Like most chemical treatments for mental health disorders, the therapeutic effects of ketamine were first stumbled on before we had a good understanding of why it works. Why ketamine produces antidepressant effects is actively being researched. Science may not have the definitive answer, but there are promising leads.

A Shock to the System

One way of thinking about the possible mechanism behind the anti-depressant effects is that it may operate something like shock therapy. In the 20th century, passing an electrical current through the brain was found to have antidepressant effects. Ketamine may also produce additional activation of networks in the brain, albeit via a more targeted chemical route.  Since depression is characterized by being stuck in a specific psychological mode, shocks to the system of different kinds may be what the system needs to escape its rut temporarily, find relief and hopefully a better equilibrium after. This finding of a new balance is one reason that altered states, in general, have therapeutic potential.  

Brain Plasticity

Since ketamine acts on pathways involved in learning, the activation of NMDA receptors that promote brain plasticity may be particularly important, allowing the brain to adapt and flexibly change its perspective. Taken in combination with the change in the biochemical state produced by ketamine, the result may be the recruitment of the brain’s natural healing intelligence.  Biological systems have a remarkable tendency to move towards health if allowed to.  Simulating the system using ketamine combined with the effects of potentially increasing brain plasticity may give the brain a chance to move into a healthier state.

Opioid Receptors

As well as activating NMDA receptors, ketamine also activates opioid receptors. This is thought to account for its pain-relieving properties. One study found that chemically blocking opioid receptors so that ketamine couldn’t act on them dulled its antidepressant effects [3]. This research provides evidence that opioid receptors at least contribute to the overall therapeutic effects of ketamine. There is currently no explanation for this, but it may help to soothe the emotional pain that is a core part of the depressed state. What’s most likely is that a range of mechanisms is involved in the therapeutic effects of ketamine, from soothing psychological pain to providing a shock to the system to increasing brain plasticity.


Traditional antidepressant medications act on the serotonin system and slowly build up their effects over weeks. Researchers still do not know why they can help to soothe the symptoms of depression in some patients. Ketamine is more effective for patients who receive no benefit from these serotonergic antidepressants. Arguably the most important difference is the time course of the effects. The rapid onset of ketamine’s antidepressant effect makes it a potentially life-saving option for those who are suicidal.  However, in both cases, long-term treatment is typically required, as the symptoms often return without repeated doses.


Ketamine therapy is the first legal psychedelic therapy to date. This is thanks largely to ketamine being placed on the World Health Organization’s “List of Essential Medicines” for its use as an anesthetic. As a result, ketamine hasn’t been prohibited as fully as psilocybin, creating fewer legal barriers for doctors to provide this medicine.  The antidepressant effects can last for several weeks, but further treatments are typically necessary to maintain the effect.

Psilocybin therapy, on the other hand, has been found to reduce depressive symptoms for six months following a single session. A common method of administering small doses of the psilocybin treatment is with psilocybin nasal spray. The key difference may be that psilocybin experiences in therapy settings often goes to the emotional root of the depression, while ketamine may act at the level of the symptoms. Without addressing the root cause, the symptoms will gradually return over time.


Legal ketamine clinics now exist throughout the United States, a list can be found here. A ketamine nasal spray is also available for depression. Access to this treatment is likely to only increase over time as many more people continue to find relief from their depression through the use of ketamine.


Dr. James Cooke is a neuroscientist, writer, and speaker, whose work focuses on consciousness, with a particular interest in meditative and psychedelic states.  He studied Experimental Psychology and Neuroscience at Oxford University and is passionate about exploring the relationship between science and spirituality, which he does via his writing and his YouTube channel,  He splits his time between London and the mountains of Portugal where he is building a retreat centre, The Surrender Homestead.

Disclaimer: LSD is potentially categorized as an illegal drug. Reality Sandwich is not encouraging the use of these drugs where prohibited. However, we believe that providing information is imperative for the safety of those who choose to explore these substances. This guide is intended to give educational content and should in no way be viewed as medical recommendations.

Read the original Article on Reality Sandwich.

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