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Ketamine or “K” is a dissociative anesthetic drug used in a variety of clinical settings, from veterinary clinics to the battlefield and hospital emergency rooms. It is on the World Health Organization’s Essential drug list and highly safe for clinical use because it anesthetizes patients without threatening their airways and other vital nervous system functions, and it is even used regularly on children2.

K is also widely used recreationally for its psychedelic effects at sub-anaesthetic or even fully anesthetic doses. The latter is often called a “K-hole”, the peak psychedelic experience of a ketamine trip. There are many interesting concepts surrounding the experiential topography of K, which I will not be discussing here. There is also an addictive potential for ketamine in its recreational use, but less than other substances such as nicotine, cocaine, opiates, and alcohol.

K has found other uses over the last fifty years, such as a potential treatment of chronic pain disorders5 and what this article intends to demystify, is its use as a fast acting antidepressant.

Ketamine For Depression

The potential of these anti-depressant effects are remarkable; a single session with K can help reduce symptoms of treatment-resistant depression, bipolar disorder, and acute suicidality for up to a week1,4. It has also been shown to offer noticeable reduction in symptoms of both obsessive-compulsive disorder and post-traumatic stress disorder4. What is most interesting is that these effects come on within about two hours of onset and depending on dose and duration of administration, can last for up to a week, long after the drug has be metabolized and removed from the system3. Whereas our other medications for treating depression—assuming it can be chemically treated at all—take several weeks of regular use to take effect, such is the case with Selective Serotonin Reuptake Inhibitors or SSRIs1.

Source: Wikipedia
Source: Wikipedia

The basic action of ketamine’s immediate effect is on the glutamate neurotransmitter system, wherein it binds to a very specific dock on the NMDA receptors (this dock also binds PCP), blocking the uptake of glutamate3. In that way, its actions are similar to Magnesium, leading to insight about magnesium deficiency and supplementation in the management of depression10. Glutamate is the major excitatory transmitter in the brain and thus effectively cuts off “go” signals between the brain and the body (anaesthetic). Yet it also has both positive and negative effects on other neurotransmitter systems such as dopamine, acetylcholine, and the opioid system, contributing to its psychoactive effect beyond sedation3.

K’s delayed effects are what seem to be playing a role in its anti-depressive actions. Ketamine seems to increase production of Brain Derived Neurotropic Factor (BDNF)1,2,3,4, and the mammalian target of rapamycin (mTOR) in the hippocampus and the medial prefrontal cortex (mPFC)2,3,4.

BDNF is a brain protein that helps with the production of new and protection of old neurons and synapses as well as adaptability to mood and emotions1,4,9. mTOR is also a protein responsible for various functions relating to cell growth and survival8. The hippocampus is a part in the brain involved in learning and memory7. The mPFC is thought to be an area responsible for planning complex cognitive behaviors, such as working towards goals and determining ‘good and bad’6. What is interesting here is that long-term depression actually reduces BDNF and mTOR in the hippocampus and mPFC1,4. It also causes changes to those areas in the brain, specifically decreased neural connectivity1,4,16.

A long-term effect of taking SSRIs is an increase in BDNF1. This observation along with the neurophysiological pathology of depression and the effects of ketamine lead to conjecture that drugs like SSRIs actually work to improve depressive symptoms via their direct effect on serotonin, by their ability to mitigate stress while the brain increases BDNF and mTOR again, or by directly increasing BDNF themselves1.


Ketamine Vs. Psilocybin

There is some interesting overlap in the potential use of psilocybin to treat depression. In humans, psilocybin has been shown to increase functional connectivity15 and reduce blood flow to the mPFC11 (giving it a break from rumination, in my opinion), as well as encourage neurogenesis in the hippocampus of mice13. Yet the positive effects psilocybin has on a person seem to be long lasting18. Lifetime psilocybin use has even been associated to a significantly lower rate of mental health illness compared to the general population17.

In my opinion, these positive effects K has on the hippocampus and mPFC allow for thought patterns and behaviors that transcend the previously ingrained detrimental behaviors of depression. The temporary release from depressive symptoms and behaviors, in addition to an increase in the aforementioned brain proteins, as well as the modulation of dopamine, acetylcholine, and norepinephrine associated with the drug’s effect, creates a cascade of positive feeling and self-image alterations in the individual, and perhaps a celebratory sense of being free of their depression. This same cascade begins to reverse when the depressive feelings return as a result of the continuation of the same stresses having produced the depression in the first place.

Psilocybin Mushrooms
Source: Wikipedia

I believe this happens because the temporary relief comes so fast and without any actual awareness or connection to the emotional source of the depression, that the Ketamine acts like a quick fix, rather than a rebuild. In comparison, psilocybin produces an extended positive effect on personality14 because the very nature of psilocybin is to face the emotional source of detrimental behavior and properly integrate into our sense of self, which includes a sense of openness, possibility, and positive mystery. In my opinion, when the root of depression is not addressed, it will eventually return when the chemical crutches are removed.

That being said, ketamine’s potential for operating as an acute antidepressant is groundbreaking and exciting. Where it fails and will continue to fail is due to an exclusively neurochemical-centric model for treating depression, rather than a psychoneuroimmunological model.

Ketamine Risks & Gains

Of course, Ketamine is also dangerous. If you are reading this as part of an intention to help yourself or someone else out of depression, there are damaging consequences to be considered. For example, regular, long-term ketamine use is associated with severe damage to the bladder2,5, which can include the need for it to be surgical removed. It has also been shown to produce “persistent or recurrent schizotypical behaviour and memory defects”5. It also has potential for addiction.

Source: Wikipedia
Source: Wikipedia

Even with K’s positive effects on things like BDNF, it also creates oxidative stress on the brain by decreasing levels of Superoxide Dismutase4, an essential antioxidant. So the more you take ketamine, the more the collateral oxidation will further stress your brain and your depressive symptoms. This is where I believe the neurological side of Ketamine dependence emerges. Psychologically, you take it, you feel good and free, for a while. Then, things turn back and you reach to the Ketamine again. Physically, each time you take it, you need an increased dose due to tolerance, which creates ever-stronger recoil of oxidation, thus a stronger desire to redose.

So self-treatment with ketamine is NOT to be considered a safe alternative for those of us who have been conditioned to distrust SSRIs due to the distasteful ethics of the pharmaceutical industry.

In summary, Ketamine presents a vital opportunity to emergency medicine for the acute treatment of depression and suicidality. But in the author’s opinion, as an essential means for treating depression over the long term or accomplishing complete remission, it falls short due to its inability to physically or psychologically (or spiritually) address the root cause of depression.

[UPDATE July 2016

Although I am not intending to keep this essay perfectly up to date due to constant progression of the research, a very important discovery was recently made that I feel essential to be retrofitted.

In May of 2016 a team at the National Institute of Mental Health (NIMH) discovered that the antidepressant effects of ketamine seem to be caused by the metabolite hydroxynorketamineThis metabolite does not cause the the anesthetic or euphoric effects related to K, not does it block NMDA receptors. It does however, have the effect of activating another aspect of the glutamate receptors, which is AMPA.

Check out this article to read more about this discovery]

You can help James Jesso continue writing via his Patreon Page


{Please note, the author is not a doctor or a certified scientist, just a well-read guy with a deep fascination for psychopharmacology. Statements directly cited are the information of others; anything else is the personal opinion of the author. Citations are presented accurately, but casually, for reference to the sources of facts presented in this article, but are not to be considered a complete or exhausted list of relevant information}

1 – ‘New Mechanisms Elicited with Ketamine in Treatment-Resistant Depression’ Ronald S. Duman, PhD, 2012, (Lecture), YalePsychiatry/YouTube

2 – ‘Ketamine: clinical significance & recreational harm reduction’ Ian Mitchell, 2015, (Podcast Interview), ATTMind Radio

3 – ‘Ketamine – more mechanisms of action than just nmda blockade’ Jamie Sleigh et al., 2014, (Article In Digital Journal), Trends In Anaesthesia & Critical Care

4 – ‘Antidepressant Mechanism Of Ketamine: Perspective From Preclinical Studies’ Lisa Scheuing et al., 2015, (Article In Digital Journal), Frontiers In Nueroscience

5 – ‘Ketamine for chronic pain: risks and benefits’ Marieke Niesters et al., 2014, (Article in Journal), British Journal of Clinical Pharmacology [Volume 77, Issue 2, pages 357–367]

6 – ‘Prefrontal cortex’, (Website), Wikipedia, accessed Dec. 28, 2015

7 – ‘Hippocampus’, (Website), Wikipedia, accessed Dec. 28, 2015

8 – ‘Mechanistic target of rapamycin’, (Website), Wikipedia, accessed Dec. 28, 2015

9 – ‘Brain-derived neurotrophic factor’ Wikipedia, (Website), accessed Dec. 28, 2015

10 – ‘Magnesium and the Ketamine Connection’ Emily Deans, (Website Article), Psychology Today, accessed Dec. 28, 2015

11 – ‘Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin’ Robin L. Carhart-Harris et al., (Article In Digital Journal), 2012, PNAS

12 – ‘Mystical Experiences Occasioned by the Hallucinogen Psilocybin Lead to Increases in the Personality Domain of Openness’ Katherine L. MacLean et al., (Article In Digital Journal), 2011, Journal Of Psychopharmacology

13 – ‘Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning’ Briony J Catlow et al., (Article In Journal), 2013, Experimental Brain Research [Volume 228, Issue 4, pp 481-491]

14 – ‘Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance’ Roland R. Griffiths et al., (Article in Journal), 2006, Psychopharmacology [Volume 187, Issue 3, pp 268-283]

15 – ‘Homological scaffolds of brain functional networks’ Giovanni Petri et al., (Article In Digital Journal), 2014, Journal of The Royal Society: Interface

16 – ‘Depression and Anxiety Disorders Damage Your Brain, Especially When Untreated’ David Hellerstein, (Website Article), Psychology Today, accessed Dec. 28, 2015

17 – ‘Psychedelics and Mental Health: A Population Study’ Teri S. Krebs, (Article In Digital Journal), 2013, PLOS One

18 – ‘Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later’ Roland Griffiths et al., (Article in Journal), 2008, Journal of Psychopharmacology [Volume xxx, Issue xx) (2008) pp 1–12]



***Featured Image Courtesy of Wikipedia

*** Copy Editing Credit To Lauren Cote


  1. I feel it’s important to note another risk that can come about – one that I guess technically isn’t about ketamine itself – that true ketamine can sometimes be extremely hard to find these days, and many people are finding (through the use of easily obtainable test kits, please go get yourselves one) that what they are coming across more often is actually quite concentrated with some form of 2c drugs – which will really exasperate any depression one might be trying to heal. Keep it safe 😉

    • Thank you for that important comment! Of course my article wasn’t discussing the acquisition of ketamine outside of the medical setting, however it’s pretty obvious that a lot of people who will read this are already exposed to ketamine in a recreational context. So your warning here is important. A couple friends of mine this summer faced that exact situation and the results could have been a lot worse than they thankfully were. I will be having a harm reduction specialist on ATTMindRadio in the coming weeks.

  2. Umm, i stopped reading when the false statement was made that ketamine was/is used feequently in the clinical setting. Have you ever read Davis’ Drug Handbook? You havent because ketamine is generally avoided for its dangerous disassociative affect, when, on very rare occasions it is used t get the patients are put in restraint s because of the dangerous psychosis it causes. You should be ashamed for liei g to people in your attempt to sell drugs!

    • Thanks for your comment. First and foremost, I am not in anyways trying to sell this drug with this article. If you had read beyond the first paragraph you would have seen I suggested against it. The intention was educational only.

      Also, not only did you not read the whole article, you didn’t even read the first paragraph properly. I said it was used in a variety of clinical settings, not that it is used frequently. Also, its clinical use was sourced from a medical doctor working in emergency medicine who is very well versed in the ketamine literature and uses it in clinical settings as well. I suggest you review my sources as he talks about the very phenomenon you are mentioning regarding episodes from patients.

      It seems like you came to this article with a negative bias.

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