Evidence Based This post has 54 references
6

What is Ketamine? + Mechanism of Action & Side Effects

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:

SelfHacked has the strictest sourcing guidelines in the health industry and we almost exclusively link to medically peer-reviewed studies, usually on PubMed. We believe that the most accurate information is found directly in the scientific source.

We are dedicated to providing the most scientifically valid, unbiased, and comprehensive information on any given topic.

Our team comprises of trained MDs, PhDs, pharmacists, qualified scientists, and certified health and wellness specialists.

All of our content is written by scientists and people with a strong science background.

Our science team is put through the strictest vetting process in the health industry and we often reject applicants who have written articles for many of the largest health websites that are deemed trustworthy. Our science team must pass long technical science tests, difficult logical reasoning and reading comprehension tests. They are continually monitored by our internal peer-review process and if we see anyone making material science errors, we don't let them write for us again.

Our goal is to not have a single piece of inaccurate information on this website. If you feel that any of our content is inaccurate, out-of-date, or otherwise questionable, please leave a comment or contact us at [email protected]

Note that each number in parentheses [1, 2, 3, etc.] is a clickable link to peer-reviewed scientific studies. A plus sign next to the number “[1+, 2+, etc...]” means that the information is found within the full scientific study rather than the abstract.

Ketamine

Ketamine is a medication used primarily as an anesthetic. 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 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].

To learn about the medical and experimental (research-only) uses of ketamine, check out this post.

Ketamine is an anesthetic drug that was discovered in the 1960s. It is a schedule III controlled substance, meaning that it requires a doctor’s prescription to legally buy or possess it.

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].

Ketamine produces anesthesia by blocking NMDA receptors, which in turn blocks or modifies many other neurotransmitters.

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 [24]:

    • 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 [25].

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 [26].

Users can also experience extreme dissociation from their environment (known as the “K-hole”) when taking high doses (over 150 mg) of ketamine [27].

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 [28].

Ketamine is a potentially dangerous drug with many possible side effects, including hallucinations, disorientation, nausea and vomiting, increased heart rate, muscle spasms, and cell death in the brain.

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
Doctors will not prescribe ketamine to anyone with a medical history of poor response, alcohol abuse, heart conditions, or 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 [26].

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 [29, 30].

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) [26].

When taken with halothane, another anesthetic, ketamine remained in the brain tissue of rats longer than when ketamine was taken alone [31].

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 [32].

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 [33].

According to a study in 44 post-operative patients, ketamine enhanced the pain-relieving effects of morphine following surgery [34].

Additionally, it has also been reported that ketamine’s sedative effects may be more effective when administered with propofol (another anesthetic drug) [35].

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 [36].

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 [37].

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 [38].

Ketamine is often given alongside other drugs, but to avoid unwanted interactions, these combinations must be very carefully monitored and administered by a medical professional.

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 [39, 40].

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” [41, 42].

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 [43, 44].

Cocaine increased ketamine-induced sleep and loss of movement control in mice [45].

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 [46]. 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.

Ketamine interacts dangerously with many drugs of abuse, including alcohol, MDMA, LSD, GHB, rohypnol, and cocaine.

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 [47].

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 [48].

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 [49].

Ketamine should only be administered by a medical professional.

Medical ketamine is usually injected, and the dosage varies broadly depending on route of administration and the patient’s weight and age.

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 [50].

When an overdose occurs, the user may experience severe sedation, nausea, vomiting, respiratory failure, coma, and even death [50, 51, 52, 53].

There is also a high possibility of permanent brain damage during overdose [54].

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.

Ketamine overdose can cause severe sedation, nausea, vomiting, respiratory failure, coma, permanent brain damage, and death.

Further Reading

Takeaway

Ketamine is an anesthetic drug that was discovered in the 1960s. It is a schedule III controlled substance, meaning that it requires a doctor’s prescription to legally buy or possess it. It causes sedation by blocking NMDA receptors, which in turn block the action of many neurotransmitters.

Ketamine is a potentially dangerous drug that may cause hallucinations, disorientation, nausea and vomiting, increased heart rate, muscle spasms, and cell death in the brain. It also has the potential to interact with many other drugs and should never be administered without the direct supervision of a medical professional. People with a history of alcohol abuse, heart conditions, or schizophrenia should not be given ketamine.

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.

Click here to subscribe

RATE THIS ARTICLE

1 Star2 Stars3 Stars4 Stars5 Stars
(No Ratings Yet)
Loading...

FDA Compliance

The information on this website has not been evaluated by the Food & Drug Administration or any other medical body. We do not aim to diagnose, treat, cure or prevent any illness or disease. Information is shared for educational purposes only. You must consult your doctor before acting on any content on this website, especially if you are pregnant, nursing, taking medication, or have a medical condition.

Leave a Reply

Your email address will not be published. Required fields are marked *

This site uses Akismet to reduce spam. Learn how your comment data is processed.