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All About Ketamine: Medical Uses, Mechanisms, Side-Effects, And Other Risks

Written by Puya Yazdi, MD | Last updated:
Jonathan Ritter
Matt Carland
Medically reviewed by
Jonathan Ritter, PharmD, PhD (Pharmacology), Matt Carland, PhD (Neuroscience) | Written by Puya Yazdi, MD | Last updated:

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Ketamine

Ketamine is a medication used primarily as an anesthetic. Some early evidence also suggests that it may have the potential for treating a variety of other health conditions, although these uses have not been fully approved yet. Unfortunately, ketamine is also commonly abused for recreational purposes, in spite of the many risks and dangers that this poses. Read on to learn more about the medical uses, mechanisms, side-effects and other potential dangers of this drug.

Disclaimer: This post is not an endorsement or recommendation for the use of ketamine under any circumstances, except when prescribed and used under supervision by a qualified medical professional. We have written this post for informational purposes only, and our goal is solely to educate people about the potential medical uses of ketamine, as well as the science behind its effects and mechanisms.

What is Ketamine?

Ketamine – sometimes also known as Ketalar or Ketaject – is a drug that initiates and maintains anesthesia [1].

The original compound was first discovered in the early 1960s and was approved for use in the United States in 1970. Now it is considered by the World Health Organization (WHO) as one of the safest and most essential drugs in the healthcare system [2].

Ketamine is considered a Schedule III controlled substance by the FDA, which means that it requires a written, oral, or electronic prescription to legally buy or possess the drug [3].

Ketamine is also classified as a “dissociative” drug, which means that it alters the senses, leading to hallucinations and feelings of detachment from the environment and oneself [1].

Unfortunately, these dissociative effects are why some people abuse ketamine for recreational purposes – even in spite of the many risks and dangers that are associated with ketamine abuse. For this reason, ketamine has a significant and well-documented potential for abuse and addiction [4, 5].

Ketamine has many different “street names,” including K, special K, kit-kat, keets, super acid, super K, and jet [5].

It is often reported to induce a trance-like state. It also supposedly reduces pain, promotes sleep, and causes memory loss, while maintaining normal heart and lung function [6].

Ketamine is structurally similar to other anesthetic drugs like phencyclidine (also known as “PCP” or “angel dust” – the drug that ketamine is derived from) and cyclohexylamine [1, 7].

Ketamine generally only has short-lived psychoactive effects, which can last as little as 10 minutes. However, the drug remains in the body at detectable levels for 3 hours or more after initial consumption [8, 9].

Ketamine acts by selectively blocking the N-methyl-d-aspartate (NMDA) receptor, which is most likely responsible for its reported memory-reducing (amnestic) and mood-related (euphoric) effects [10, 11].

Mechanisms of Action

Ketamine blocks NMDA receptors, which in turn blocks out many important types of signaling by different neurotransmitter systems throughout the brain. This wide-ranging mechanism probably accounts for several of ketamine’s primary effects, including general anesthesia, hallucinations, dissociation (at lower doses), and memory loss (at higher doses) [12, 13].

Although the precise mechanisms of ketamine are not completely understood, there are a number of other mechanisms that have been suggested to underlie some of ketamine’s diverse range of effects:

  • Increasing AMPA receptor levels. This may cause an increase in BDNF levels, which may account for some of ketamine’s purported “antidepressant-like” effects [14].
  • Increasing glutamate levels. This is probably the mechanism that causes psychosis-like symptoms, such as “dissociation” (loss of contact with reality) [12]. The altered glutamate levels may also contribute to some of the “mood-related” effects, again possibly by increasing BDNF levels [14].
  • Blocking HCN1 channels. This mechanism is believed to produce the hypnotic, “trance-like” states caused by ketamine abuse [15].
  • Increasing dopamine and reducing nicotinic acetylcholine levels. These may be responsible for the feelings of “delirium” associated with recreational ketamine abuse [12].
  • Reducing opioid receptor activity. This mechanism may be especially relevant to medical users of ketamine, such as chronic pain patients, for whom controlled doses of ketamine are sometimes used to alleviate pain and reduce built-up tolerance to opioids [16].
  • Increasing serotonin and noradrenaline levels. Similar to the opioid-related mechanisms, these effects may also underlie some of the reported pain-relieving (analgesic) effects of ketamine [17].
  • Increasing amine levels. This leads to a generally increased state of overall brain stimulation [12], and may also play a part in reducing sensitivity to pain [17].
  • Inhibiting the production of nitric oxide, which may further alleviate sensations of pain [18].
  • Inhibiting calcium channel activity, which has muscle-relaxing effects [19].
  • Binding to acetylcholine sites on NMDA receptors. This reduces acetylcholine levels, leading to slower breathing and disrupted sleep [20].
  • Blocking sodium channels, which results in local anesthesia [21].

Ketamine actually exists as two slightly different molecules, also known as the ‘R’ and ‘S’ enantiomers. Although they are chemically and structurally identical, the two forms are “mirror images” of each other. Although this might sound like a minor difference, this can actually have a major effect on exactly how each molecule interacts with the body. For example, the ‘S’ isomer is 3 times more potent than the R isomer and results in faster recovery of brain and motor (movement) function post-anesthesia. However, the “racemic” form of ketamine (which is just a mixture of the two molecular forms) is currently the most commonly used form in medical applications, as its interaction with the body is roughly similar to that of the S isomer alone [22, 23].

Official Medical Uses of Ketamine

Ketamine has a number of accepted medical uses for treating certain specific medical conditions and situations. Although this means that the evidence for its efficacy in these conditions is relatively solid, always keep in mind that this is a federally-controlled prescription medication that must only be used under the direction and supervision of a qualified medical professional.

Additionally, none of these medical uses should be interpreted as general “benefits” for health! For all of the cases described below, any reported medical benefits only apply to contexts in which ketamine is being administered by qualified medical professionals in a controlled setting. There is no reason to expect any beneficial or therapeutic effects if ketamine is abused recreationally or taken outside of a conventional medical setting.

In medical settings, ketamine is most commonly used as an anesthetic (i.e. to make people unconscious during medical procedures). It is officially approved for this purpose by the FDA and is widely used both by itself and in combination with other anesthetic drugs [3].

Ketamine is also sometimes used – usually at lower doses – as a fast-acting sedative [3].

For example, when ketamine was administered intravenously in 30 children, all patients experienced sedation within 2 minutes [24].

In another study of 431 children, ketamine was administered through the muscles. In this study, 98% of patients experienced rapid sedation [25].

Off-Label Medical Uses of Ketamine

Occasionally, doctors will prescribe medications to help treat conditions that fall outside of the official uses approved by the FDA – also known as “off-label” drug use [26]. Usually, this is done because there is actually decent evidence that the drug may help, although this evidence might not be quite strong enough to get full FDA approval (which generally has very strict requirements).

As always, however, always remember that the decision to use medications in this way can only be made by a licensed medical professional.

Ketamine and Pain Relief

In addition to its official use as an anesthetic, ketamine also has a number of effects that can significantly reduce the perception of pain (i.e. an analgesic effect). Because of this, it is frequently used by doctors – albeit “unofficially” – to help control and manage pain. In this context, ketamine can be used either by itself or in combination with other pain-killing drugs [3].

For example, when administered by doctors, ketamine may potentially aid in reducing chronic pain. In a study of 12 male volunteers, low doses of ketamine were reported to activate portions of the brain that are believed to be involved in the inhibition of pain (such as the prefrontal cortex and certain areas of the brainstem) [27].

In one 11-week double-blind randomized controlled trial of 60 female patients with complex regional pain syndrome (CRPS), a steady 100-hour intravenous infusion of ketamine was reported to significantly relieve pain. This effect was even reported to last up to 3 months following treatment [28].

Additionally, a study of 12 cancer patients with severe cancer pain reported that patients required 50% less morphine to reduce their pain after prolonged use of ketamine [29].

Ketamine also reportedly enhanced the effectiveness of spinal cord (“intrathecal”) injections of morphine treatment in a double-blind randomized control trial in 20 cancer pain patients [30].

Some preliminary evidence suggests that ketamine may also be especially effective at reducing pain when combined with certain other medications. For example, a combination of ketamine and a local anesthetic (bupivacaine) reduced post-operative pain in a double-blind randomized placebo-controlled trial of 53 amputee patients [31].

When used as a local anesthetic with diazepam (a benzodiazepine), meperidine (also known as Demerol – a narcotic pain-killer medication), and nitrous oxide, ketamine was reported to reduce pain, discomfort, and anxiety in a study of 40 healthy adults undergoing oral surgery [32].

Potential New Medical Uses of Ketamine

In addition to some of the relatively well-accepted (but still technically unofficial) “off-label” uses, ketamine has also been studied for its potential to treat a variety of other health conditions.

However, keep in mind that the evidence supporting these potential applications is still very preliminary, and a lot more additional research would still be needed before any of these applications are ever officially approved for medical use. Therefore, it is important to take all of the information below with a healthy grain of salt!

1) Ketamine and Depression

One of the most promising potential medical applications of ketamine is for treating depression – especially forms of depression that have not responded to many of the more common, “conventional” forms of treatment, such as SSRIs [3].

For example, in a double-blind randomized controlled trial of 7 patients with major depression, ketamine was reported to reduce depression symptoms after just 72 hours [11].

Some early evidence also suggests that ketamine may also be effective in alleviating symptoms in patients with treatment-resistant depression (TRD). For example, in one review, it was reported that a single dose of ketamine (administered intravenously) produced a strong and rapid antidepressant effect, and which lasted up to 1 week in patients with TRD [33].

Additionally, it was reported that depressive symptoms improved just 40 minutes after ketamine use in one 14-day double-blind randomized controlled trial of 18 treatment-resistant bipolar depression patients [34].

In a randomized control study of 73 patients over 24 hours, patients who used ketamine were reported to show a greater improvement in their scores on the Montgomery-Åsberg Depression Rating Scale (MADRS), one of the tests that psychiatrists use to measure the relative severity of individual cases of depression. According to the authors of this study, ketamine’s effects on depression symptoms were significantly stronger than midazolam (a benzodiazepine) [35].

However, while some of these early results might seem promising, there is one major catch: we really don’t know much about the long-term effects of ketamine, or how safe it would be to use on a regular basis.

Furthermore, the little data that currently exists on using ketamine more than just once paints a very complex and inconclusive picture.

For example, one study of 24 TRD patients over 83 days reported that many patients experienced over 2 weeks of sustained improvement of their symptoms after 6 repeated doses of ketamine [36].

Another study reported that ketamine, when used in combination with the electroconvulsive therapy (commonly used to treat depression), was more effective in improving depression symptoms than another anesthetic, propofol, in a year-long study of 31 inpatients [37].

In a 4-week double-blind randomized controlled trial, 42 depression patients were given an initial dose of ketamine followed by a dose of riluzole (a drug that increases glutamate). About a fourth of the patients did not experience a depression relapse by the end of the trial. However, riluzole did not potentiate the antidepressant effects of ketamine [38].

Similar to ketamine, esketamine (the name given to just the “S(+) enantiomer” form of ketamine) has been reported to be a rapid-acting antidepressant. However, in a review comparing the individual effects of ketamine isomers, it was found that arketamine (the R(-) enantiomer form) was a safer and more effective antidepressant than esketamine [39, 40, 41].

While these early studies might seem encouraging, other, larger-scale studies have come to opposing conclusions.

For example, according to a larger-scale review, the authors concluded that ketamine probably only has relatively short-term effects on alleviating depression symptoms [42].

Similarly, another large-scale review concluded that while ketamine may act as an effective antidepressant (likely by blocking NMDA receptors), it may have significant dissociative side-effects (disconnecting from one’s sense of identity) if used long-term [43].

All in all, a lot more research will be needed before we can know just how safe or effective ketamine might be when it comes to treating depression.

Also, its high potential for abuse – combined with the potentially serious side-effects associated with it – also makes it quite unlikely that the FDA will ever approve ketamine for widespread use.

Ultimately, even if ketamine does turn out to be effective for depression, the most realistic scenario is that it will be reserved only for a minority of the most severe cases of depression, and would only be used once all other treatment options have already been tried. In other words, it’s not likely that we’ll see widespread use of ketamine anytime soon!

2) Ketamine and Seizure Control

Some preliminary evidence suggests that ketamine may be useful in reducing the duration or severity of seizures.

For example, ketamine was reported to decrease the duration of seizures in 10 patients undergoing electroconvulsive therapy [44].

While much more human studies will be needed to confirm this finding, there are a few animal studies that tentatively back this up.

For example, in rats, ketamine effectively controlled seizures in all animals 1 hour after seizure stimulation [45].

Another study in rats found that ketamine stopped seizure activity in 3 rats 30 minutes after administration [46].

Because of its potential to reduce the severity and length of seizures, some evidence suggests that ketamine may also be useful in partially protecting the brain from damage during seizures.

For example, ketamine was reported to reduce damage from increased intracranial pressure (pressure inside the skull) in traumatic brain injury patients during propofol sedation in a study of 8 male patients [47].

Similarly, ketamine was reported to significant protect 22 out of 24 regions of the rat brain after artificially-induced seizures [46].

Systematic dosing of ketamine also prevented the loss of neurons caused by persistent seizures in rats [48].

According to several cell studies, ketamine may help preserve the function and structure of brain cells during hypoxia (lack of oxygen) [49].

Nonetheless, given that most of these findings have only been reported in cell- or animal studies, a lot more research will be needed to know whether ketamine might be effective for controlling and managing seizures in actual human patients.

3) Ketamine and PTSD

Some early evidence suggests that ketamine might be potentially useful in treating PTSD – but the science behind this is still very young, and it’s still far too early to draw any solid conclusions yet.

According to one study, ketamine quickly and effectively reduced the symptoms of PTSD compared to midazolam (a benzodiazepine) 24 hours after administration in a double-blind randomized controlled trial of 41 patients with chronic PTSD [50].

In a study of 603 burn victims, patients who received ketamine after being operated on were reported to show lower rates of later developing PTSD, compared to burn patients who received other post-operative drugs [51]. Although this finding could be taken to suggest that ketamine had a “protective” effect, it’s more likely that PTSD rates were lower in the ketamine group simply because it was just more effective at controlling and reducing pain in general.

4) Ketamine and Asthma

According to one study, ketamine improved the breathing of 11 patients with severe asthma 2 hours after administration, when other therapies, as well as assisted breathing, failed [52].

While the authors of this study concluded that ketamine was potentially “a useful and safe drug” for treating certain cases of asthma, they also noted that it should only be considered when other, more conventional treatments have failed – in other words, it’s quite unlikely that ketamine will become a common treatment for asthma anytime soon!

5) Ketamine and Obsessive-Compulsive Disorder (OCD)

There’s some very early evidence suggesting that ketamine may target some of the symptoms associated with OCD – however, this evidence is still extremely preliminary, and should be taken with some skepticism.

According to a 1-week double-blind randomized controlled trial of 15 drug-free OCD adults, ketamine significantly improved obsessive symptoms in comparison to treatment with a placebo [53].

In another study of 10 treatment-resistant OCD patients, 35% of patients reported improvement in their symptoms after 3 days of ketamine treatment [54].

While these studies might sound promising, one major limitation is their relatively small sample sizes – just 15 and 10 patients each – which means that a lot more research would be needed to justify the use of ketamine in treating OCD.

Side-Effects of Ketamine

Like any drug, ketamine has a number of potential adverse side-effects that are important to be aware of.

If you have a condition that might require you to be treated with ketamine, the best way to minimize your risk of adverse side-effects is to make sure your doctors are fully informed about your medical history, any other medications you are currently taking, and other relevant factors.

Some of the reported side-effects of ketamine include [55]:

    • Hallucinations
    • Disorientation or confusion after anesthesia
    • Drowsiness
    • Nausea and/or vomiting
    • Increased heart rate
    • Elevated blood pressure (hypertension)
    • Increased salivation
    • Muscle spasms
    • Temporary rashes and other skin irritations

According to some early evidence from cell studies, ketamine may induce apoptosis, or programmed cell death, in the brain [56].

Some studies have reported that certain ketamine side-effects, such as hallucinations or delirium, may potentially be reduced by taking benzodiazepines along with lowering the dose of ketamine [57].

Users can also experience extreme dissociation from their environment (known as the “K-hole”) when taking high doses (over 150 mg) of ketamine [58].

Long-term use of ketamine may also cause brain damage. In young rhesus monkeys, a single 24-hour episode of ketamine-induced anesthesia triggered brain cell death [59].

Contraindications of Ketamine

Although ketamine has a number of relatively well-supported medical uses when administered by qualified medical professionals, there are a number of factors that doctors may look for that might disqualify someone from receiving ketamine treatment (due to elevated risk of negative side-effects or other adverse reactions).

Some of these contraindications include [3]:

  • A medical history of past adverse reactions to ketamine (such as hypersensitivities)
  • A prior history of alcoholism/alcohol abuse, or acute alcohol intoxication
  • Pre-existing cardiovascular conditions, such as elevated blood pressure/hypertension, aneurysms, or heart attacks
  • A previous diagnosis of schizophrenia

Ketamine During Pregnancy and Breastfeeding

Ketamine should not be used during pregnancy or while breastfeeding, as its effects in pregnancy have not been evaluated and it is unknown whether the drug is present in breast milk [3].

Drug Interactions With Ketamine

Medical Interactions

In medical settings, ketamine is often administered along with other drugs. According to the specific context, this might be done either to minimize the chances of side-effects associated with ketamine itself, or even to modify the way that another, different drug works.

For example, some early evidence suggests that some of the side-effects of ketamine (such as delirium and hallucinations) may be reduced when ketamine is administered in combination with benzodiazepines [57].

According to another study, vomiting caused by ketamine decreased in children when taken with midazolam, another anesthetic (a benzodiazepine). However, this combination reduced oxygen levels in the blood and had no effect on post-anesthesia anxiety, which raises some potential questions about just how useful this effect might really be [60, 61].

Sufficient anesthesia with a smooth, negative hallucination-free recovery may be induced and maintained by combining ketamine with methohexitone (a barbiturate derivative), diazepam (also commonly known as Valium – a benzodiazepine), and alcuronium (a muscle relaxant) [57].

When taken with halothane, another anesthetic, ketamine remained in the brain tissue of rats longer than when ketamine was taken alone [62].

Ketamine may also enhance the effects of other drugs, specifically opioids. For example, very small doses of ketamine (75-150mg/kg) has been reported to reduce some patients’ need for the opioid painkiller alfentanil after surgery [63].

Similarly, an animal study reported that when the painkilling opioid tramadol was taken with ketamine, the pain-reduction effects of both drugs in mice were relatively increased [64].

According to a study in 44 post-operative patients, ketamine enhanced the pain-relieving effects of morphine following surgery [65].

Additionally, it has also been reported that ketamine’s sedative effects may be more effective when administered with propofol (another anesthetic drug) [66].

Some doctors may also administer ketamine alongside anti-seizure medications. When combined with diazepam and the anti-seizure drugs carbamazepine (also known as Tegretol) and phenytoin (Dilantin), ketamine was reported to reduce brain damage caused by seizures in rats [67].

According to some studies, ketamine concentrations may also be affected by some antibiotics. For example, a study in 20 healthy male volunteers reported that ketamine concentrations were lower when it was taken with the antibiotic rifampicin [68].

Ketamine can sometimes increase the amount of fluid pressure in the brain and spine, which can damage these organs. However, administering diazepam along with ketamine has been reported to reduce these effects [69].

Interactions In Drug Abuse

Apart from some of the interactions that can occur when ketamine is administered properly in an official medical setting, there are also a number of other dangerous interactions that can occur when ketamine is taken along with other common drugs of abuse.

Ketamine should never be taken with alcohol. This combination has been reported to lead to severe liver and kidney damage in mice [70, 71].

Ketamine is often combined with other recreationally-abused drugs, such as MDMA (“ecstasy”), LSD (“acid”), GHB, and flunitrazepam (Rohypnol). These combinations can have negative effects. For example, one user reported that while he normally had no problems taking ketamine, the combination of ketamine and LSD made him feel “unpleasant” and “unsettled” [72, 73].

In mice, ketamine combined with MDMA (ecstasy) was reported to increase the number of toxic byproducts created as a result of dopamine metabolism in the brain. This leads to the inhibition of cellular respiration – the set of metabolic processes that create usable energy in the body [74, 75].

Cocaine increased ketamine-induced sleep and loss of movement control in mice [76].

When administered by medical professionals, Rohypnol and ketamine taken together may actually have some medically-useful interactions. For example, according to one study done on 140 women undergoing an abortion, a ketamine-rohypnol combination reduced restlessness and confusion after the surgery. Dreams were also less frequent [77]. However, keep in mind that these “benefits” only apply to post-surgical care, and don’t imply any benefits for these drugs when used illegally outside of a medical setting.

Other Interactions

Interestingly, according to a study in 12 healthy subjects, ketamine concentrations increased when ingested with grapefruit juice. For this reason, the study’s authors concluded that treatment dosages should be reduced when consumed with grapefruit juice [78].

Forms and Dosage of Ketamine

Note: The information in this section describes typical dose information for medical applications of ketamine: it is not a guide to recreational or other non-medical use.

When used for medical purposes, ketamine is usually kept in liquid form, which is then injected with a syringe (typically either into muscle tissue or directly into the bloodstream). Alternatively, ketamine can also take the form of a fine white power, although this is more typical of ketamine that is sold on the street for the purposes of recreational abuse, which is then typically snorted or consumed orally.

Generally, doses vary from person to person and are based on the method of ketamine administration. For example, a low dose of ketamine for an adult is 0.5 mg/kg when administered intravenously (i.e. injected into the bloodstream) or epidurally (injected into the spinal column), and less than 2 mg/kg when administered by injection into the muscles [79].

For children, the dosage is usually much smaller – between 3-10 mg/kg for oral administration, or 2-4 mg/kg when given through muscle injections. It is also effective when combined with local anesthesia in a dose of 0.5 to 1 mg/kg [80].

Ketamine Overdose

As with many drugs, ketamine abuse comes with a very real risk of overdose.

This is especially true for any recreational drug that is bought off the street, which can contain any number of impurities and other contaminants, and which can pose any number of additional health dangers.

The exact amount of ketamine needed to overdose varies considerably from person to person. Because overall body weight is one of the main factors, accidental ketamine overdoses pose and especially high risk for children [81].

When an overdose occurs, the user may experience severe sedation, nausea, vomiting, respiratory failure, coma, and even death [81, 82, 83, 84].

There is also a high possibility of permanent brain damage during overdose [85].

All in all, while ketamine has many medical uses, it is a volatile and unpredictable drug, which is a large part of the reason why it should never be taken without direct medical supervision.

About the Author

Puya Yazdi

Puya Yazdi

MD
Dr. Puya Yazdi is a physician-scientist with 14+ years of experience in clinical medicine, life sciences, biotechnology, and nutraceuticals.
As a physician-scientist with expertise in genomics, biotechnology, and nutraceuticals, he has made it his mission to bring precision medicine to the bedside and help transform healthcare in the 21st century.He received his undergraduate education at the University of California at Irvine, a Medical Doctorate from the University of Southern California, and was a Resident Physician at Stanford University. He then proceeded to serve as a Clinical Fellow of The California Institute of Regenerative Medicine at The University of California at Irvine, where he conducted research of stem cells, epigenetics, and genomics. He was also a Medical Director for Cyvex Nutrition before serving as president of Systomic Health, a biotechnology consulting agency, where he served as an expert on genomics and other high-throughput technologies. His previous clients include Allergan, Caladrius Biosciences, and Omega Protein. He has a history of peer-reviewed publications, intellectual property discoveries (patents, etc.), clinical trial design, and a thorough knowledge of the regulatory landscape in biotechnology.He is leading our entire scientific and medical team in order to ensure accuracy and scientific validity of our content and products.

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