Ketamine

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Summary sheet: Ketamine
Ketamine
Ketamine.svg
Chemical Nomenclature
Common names Ketamine, K, Ket, Kitty, "Special K", "Cat Tranquilizer", Ketaset, Ketalar, Ketanest
Substitutive name Ketamine
Systematic name (RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone
Class Membership
Psychoactive class Dissociative
Chemical class Arylcyclohexylamine
Routes of Administration

WARNING: Always start with lower doses due to differences between individual body weight, tolerance, metabolism, and personal sensitivity. See responsible use section.



Oral
Dosage
Bioavailability 17%[2]
Threshold 50 mg
Light 50 - 100 mg
Common 100 - 300 mg
Strong 300 - 450 mg
Heavy 450 mg+
Duration
Onset 10 - 30 minutes
Come up 5 - 20 minutes
Peak 45 - 90 minutes
Offset 3 - 6 hours
After effects 4 - 8 hours


Sublingual
Dosage
Bioavailability 20%[3] - 29%[4]
Duration
Insufflated
Dosage
Bioavailability 45%[3]
Threshold 5 mg
Light 10 - 30 mg
Common 30 - 75 mg
Strong 75 - 150 mg
Heavy 150 mg +
Duration
Total 1 - 1.5 hours
Onset 2 - 5 minutes
Come up 5 - 10 minutes
Peak 30 - 60 minutes[1]
Offset 3 - 6 hours
After effects 2 - 12 hours






DISCLAIMER: PW's dosage information is gathered from users and resources for educational purposes only. It is not a recommendation and should be verified with other sources for accuracy.

Interactions
Amphetamines
Cocaine
Benzodiazepines
MAOIs
Grapefruit
Alcohol
GHB
Opioids
Trazodone
GBL
Tramadol

Ketamine (also known as Ket, K, Special K, Kitty, and others) is a classical dissociative substance of the arylcyclohexylamine class. It is perhaps the best-known and archetypal dissociative substance. The mechanism of action is not fully known, although NMDA receptor blocking is thought to be involved.

Developed in 1963 by Parke-Davis Laboratories, it was originally intended as a replacement for the surgical anesthetic phencyclidine (PCP).[5] Ketamine is widely used in human and veterinary medicine, typically in surgical and intensive care settings. Recently, it has generated significant clinical research following the discovery that it can rapidly relieve treatment-resistant depression and suicidal ideation.[6]

Recreational use was first reported amongst medicinal chemists in the United States in 1967,[7] and became more widespread in Europe in the 1990s, where it gained popularity as an adulterant in ecstasy tablets.[8][9] Today, it is associated in popular culture with the nightclub and rave scenes.[10]

Subjective effects include motor control loss, pain relief, internal hallucinations, memory suppression, conceptual thinking, euphoria, and depersonalization / dissociation. The effects are similar to PCP and DXM but with a shorter duration and a rapid onset. It is known for producing relatively "clean" dissociation, without as much mania and stimulation as PCP or MXE.

Additionally, the effects are highly dose-dependent. At lower doses, users report alcohol-like disinhibition and relaxation effects. At higher doses, however, it reportedly produces a hallucinogenic trance-like state (called a "k-hole") that is often described as an out-of-body or near-death experience.

It has moderate to high abuse potential. Chronic use (i.e. high dose, repeat administration) is associated with compulsive redosing and psychological dependence. Additionally, the health risks of chronic or heavy use are not well-known: there is growing evidence that it can cause bladder dysfunction[11] and it has also been linked with cognitive and memory issues (see this section for more information).[12][13]

It is highly advised to use harm reduction practices if using this substance.

History and culture

Ketamine was first synthesized at Parke Davis Laboratories by the American scientist Calvin Stevens. Stevens was searching for a new anesthetic to replace PCP, which was deemed not suitable for use in humans because of the severe hallucinogenic effects it produced upon recovery of consciousness.[citation needed]

Upon being patented in Belgium in 1963, ketamine was initially used as a veterinary anesthetic. After being patented by Parke-Davis for human and animal use in 1966, it became available by prescription in 1969 in the form of ketamine hydrochloride, under the name of Ketalar.

The United States Food and Drug Administration approved it for human consumption in 1970. Due to its favorable sympathomimetic properties and its wide margin of safety, it was administered as a field anaesthetic to soldiers during the Vietnam War.[14]

Ketamine is on the World Health Organization’s “Essential Drugs List”, a list of the safest and most effective drugs needed in a modern health system.[15]

Common names

Street names include "Special K", "K", "Kit Kat", "kitty", and "horse/dog/cat tranquilizer" (which refers to its use in veterinary medicine), "Cat Valium", and "Jet".[16]

Chemistry

Ketamine, or (RS)-2-(2-Chlorophenyl)-2-(methylamino)cyclohexanone, belongs to a class of synthetic organic compounds called arylcyclohexylamines. Arylcyclohexylamines are named for their chemical structures, which include a cyclohexane ring bound to an aromatic ring along with an amine group.

Ketamine's chemical structure contains a phenyl ring with a chlorine substituent at R2 bonded to a cyclohexane ring substituted with an -Oxo group (cyclohexanone). An amino methyl chain (-N-CH3) is bound to the same location (R1) of the cyclohexanone ring.

Enantiomers

Ketamine is a mixture of equal amounts of two enantiomers: esketamine and arketamine. Esketamine is a more potent NMDA receptor antagonist and dissociative hallucinogen than arketamine.[17] Because of the hypothesis that NMDA receptor antagonism underlies the antidepressant effects of ketamine, esketamine was developed as an antidepressant.

However, multiple other NMDA receptor antagonists, including memantine, lanicemine, rislenemdaz, rapastinel, and 4-chlorokynurenine, have thus far failed to demonstrate sufficient effectiveness for depression.[18]

Furthermore, animal research indicates that arketamine, the enantiomer with a weaker NMDA receptor antagonism, as well as (2R,6R)-hydroxynorketamine, the metabolite with negligible affinity for the NMDA receptor but a potent alpha-7 nicotinic receptor antagonist may have antidepressive action.[18]

Pharmacology

Further information: NMDA receptor antagonist

Ketamine is classified as a non-competitive NMDA receptor antagonist.

The NMDA receptor, an ionotropic glutamate receptor, allows for electrical signals to pass between neurons in the brain and spinal column; for the signals to pass, the receptor must be open. Dissociatives close the NMDA receptors by blocking them. This disconnection of neurons leads to loss of feeling, difficulty moving, and eventually, the state known as the “K-hole”.

It is one of the most recognizable dissociatives, a diverse group that includes phencyclidine (PCP), methoxetamine (MXE), dextromethorphan (DXM), and nitrous oxide.

At high, fully-anesthetic level doses, ketamine has also been found to bind to μ-opioid receptors type 2 in cultured human neuroblastoma cells without agonist activity[19] and to sigma receptors in rats.[20] Also, ketamine interacts with muscarinic receptors, descending monoaminergic pain pathways and voltage-gated calcium channels.[21]

At subanesthetic and fully anesthetic doses, ketamine has been found to block serotonin depletion in the brain by inhibiting 5-HT receptors rather than through monoamine oxidase inhibition.[22]

The estimated bioavailabilities are as follows: nasal (45%), oral (17%), rectal (25%).[23]

Subjective effects

At higher doses, ketamine is reported to produce significant cognitive impairment and alteration, often resulting in the complete loss of symbolic reasoning, communication, and fine motor abilities. These changes appear to coincide with its transpersonal and therapeutic effects.

Some users also report an antidepressive afterglow, which may last days or weeks.

Disclaimer: The effects listed below cite the Subjective Effect Index (SEI), an open research literature based on anecdotal user reports and the personal analyses of PsychonautWiki contributors. As a result, they should be viewed with a healthy degree of skepticism.

It is also worth noting that these effects will not necessarily occur in a predictable or reliable manner, although higher doses are more liable to induce the full spectrum of effects. Likewise, adverse effects become increasingly likely with higher doses and may include addiction, severe injury, or death ☠.

Physical effects
Child.svg

Visual effects
Eye.svg

Cognitive effects
User.svg

Disconnective effects
Chain-broken.svg

Multi-sensory effects
Gears.svg

Transpersonal effects
Infinity4.svg

Experience reports

Anecdotal reports which describe the effects of this compound within our experience index include:

Additional experience reports can be found here:

Research

Novel antidepressant

Ketamine has been shown to be effective for patients suffering from chronic depression and bipolar disorder. Studies have shown[25][26] that the effect of the drug is immediate or within 2 hours and consistent in relieving a patient’s depressive and/or suicidal symptoms, lasting up to 3 days after a single dose. In comparison, common antidepressants such as fluoxetine (Prozac) can take weeks to show therapeutic effects.

Ketamine is a racemate composed of the R-(−)-ketamine enantiomer (arketamine) and the S-(+)-ketamine enantiomer (esketamine). Esketamine inhibits the reuptake of the dopamine transporter about 8-fold more potently than does arketamine, and so is about 8 times more potent as a dopamine reuptake inhibitor.[27] Arketamine appears to be more effective as a rapid-acting antidepressant than esketamine.[28]

A study conducted in mice found that ketamine's antidepressant activity is not caused by ketamine inhibiting NMDAR, but rather by sustained activation of a different glutamate receptor, the AMPA receptor, by a metabolite, (2R,6R)-hydroxynorketamine; as of 2017 it was unknown if this was happening in humans.[29][30] Arketamine is a AMPA receptor agonist.[31]

Anesthetic doses may not produce an antidepressant effect. While the research is limited, between .5 and 1mg/kg IV given over about 40 mins seems to be the optimal dose. [32] A typical anesthetic dose is 1-2 mg/kg given over 2 minutes, followed by .5-1.8mg/kg/hr. Benzodiazepines and GABA agonist (both of which are often used alongside ketamine in anesthesia) may mitigate the antidepressant effect of ketamine.

Reagent results

Exposing compounds to the reagents gives a colour change which is indicative of the compound under test.

Marquis Mecke Mandelin Liebermann Froehde Gallic Robadope
No reaction No reaction Deep brownish orange/red Light yellow No reaction No reaction No reaction
Ehrlich Hofmann Simon’s Zimmermann Scott Folin
No reaction No reaction Orange - Pink - Yellow Slow pink No reaction No reaction

Toxicity and harm potential

Ambulance2.png

This toxicity and harm potential section is a stub.

As a result, it may contain incomplete or even dangerously wrong information! You can help by expanding upon or correcting it.
Note: Always conduct independent research and use harm reduction practices if using this substance.

This radar plot shows relative physical harm, social harm, and dependence of ketamine.[33]

There is some evidence that ketamine may have antibiotic properties at higher doses.[34] It is unclear how this affects normal human use.

It is strongly advised to use harm reduction practices if using this substance.

Cognition and well-being

The first large-scale, longitudinal study of ketamine users found that frequent ketamine users (at least 4 days/week, averaging 20 days/month) had increased depression and impaired memory by several measures, including verbal, short-term memory and visual memory. However, infrequent (1–4 days/month, averaging 3.25 days/month) ketamine users and former ketamine users were not found to differ from controls in memory, attention and psychological well-being tests.

This suggests the infrequent use of ketamine does not cause cognitive deficits and that any deficits that might occur may be reversible when ketamine use is discontinued. However, abstinent, frequent, and infrequent users all scored higher than controls on a test of delusional symptoms.[35]

Urinary tract effects

According to a 2010 systematic review, 110 documented reports of irritative urinary tract symptoms from ketamine dependence exist.[36] Urinary tract symptoms have been collectively referred to as "ketamine-induced ulcerative cystitis" or "ketamine-induced vesicopathy" and they include urge incontinence, decreased bladder compliance, decreased bladder volume, and painful haematuria (blood in urine).

The time of onset of lower urinary tract symptoms varies depending, in part, on the severity and chronicity of ketamine use; however, it is unclear whether the severity and chronicity of ketamine use correspond linearly to the presentation of these symptoms. All reported cases where the user consumed greater than 5 grams per day reported symptoms of the lower urinary tract.[37]

A study conducted in 2015 demonstrated that co-administration of EGCG (10mM/kg) in rats receiving a daily dose of ketamine (25 mg/kg/d), significantly reduced ketamine-induced bladder damage to almost control levels, showing potential benefits of EGCG consumption to prevent or reverse ketamine-induced cystitis (KIC) and ovariectomy-induced overactive bladder (OAB).[38] However, the application to human use is not clear.

Neurotoxicity

Short-term exposure of cultures of GABAergic neurons to ketamine at high concentrations led to a significant loss of differentiated cells in one study, and non-cell death-inducing concentrations of ketamine (10 μg/ml) may still initiate long-term alterations of the dendritic arbor in differentiated neurons.[39][40]

More recent studies of ketamine-induced neurotoxicity have focused on primates in an attempt to use a more accurate model than rodents. One such study administered daily ketamine doses consistent with typical recreational doses (1 mg/kg IV) to adolescent cynomolgus monkeys for varying periods of time.

Decreased locomotor activity and indicators of increased cell death in the prefrontal cortex were detected in monkeys given daily injections for six months, but not those given daily injections for one month.[41]

Dependence and abuse potential

Ketamine has moderate to high abuse potential and produces psychological dependence with chronic use. When dependence has developed, cravings and withdrawal effects may occur if a person suddenly stops their usage.

Tolerance to the main effects of ketamine develops with prolonged and repeated use. This results in users having to administer increasingly large doses to achieve the same effects. After that, it takes about 3 - 7 days for the tolerance to be reduced to half and 1 - 2 weeks to be back at baseline (in the absence of further consumption).

Ketamine presents cross-tolerance with all dissociatives, meaning that after the consumption of ketamine all dissociatives will have a reduced effect.

Permatolerance

Dissociatives are reported to be unique from other substances because they are capable of producing a long-term or permanent form of tolerance ("permatolerance") that accumulates slowly and independently from normal tolerance.

Many chronic ketamine users report that they need to consume substantially more to achieve dissociation or k-hole compared to their first use, even after taking extended breaks. The cause is unknown, although it has been suggested to be a potential indicator of some form of neurotoxicity.

Dissociative permatolerance poses an additional problem considering ketamine's negative effects on the urinary tract. As a result, heavy or chronic use of all dissociatives is strongly discouraged.

Overdose

Fatal ketamine overdoses are rare. However, there is evidence that suggests extremely high doses may result in damage to the brain and other organs.[citation needed]

Dangerous interactions

Warning: Many psychoactive substances that are reasonably safe to use on their own can suddenly become dangerous or even life-threatening when combined with certain other substances. The following lists some known dangerous interactions (although it is not guaranteed to include all of them).

Always conduct independent research (e.g. Google, DuckDuckGo, PubMed) to ensure that a combination of two or more substances is safe to consume. Some of the listed interactions have been sourced from TripSit.

  • Amphetamines - No unexpected interactions, though likely to increase blood pressure (likely not an issue with sensible doses). Moving around on high doses of this combination may be ill-advised due to risk of physical injury.
  • Cocaine - No unexpected interactions, though likely to increase blood pressure (likely not an issue with sensible doses). Moving around on high doses of this combination may be ill-advised due to risk of physical injury.
  • Benzodiazepines - Both substances potentiate the ataxia and sedation caused by the other and can lead to unexpected loss of consciousness at high doses. While unconscious, vomit aspiration is a risk if the user is not placed in the recovery position.
  • MAOIs - MAO-B inhibitors appear to increase the potency of ketamine. MAO-A inhibitors have some negative reports associated with the combination but there isn't much information available
  • Alcohol - Both substances cause ataxia and bring a very high risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
  • GHB / GBL - Both substances cause ataxia and bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
  • Opioids - Both substances bring a risk of vomiting and unconsciousness. If the user falls unconscious while under the influence there is a severe risk of vomit aspiration if they are not placed in the recovery position.
  • Trazodone - When used as a sleep aid and taken close to that of a dose of ketamine, there is a risk of respiratory depression when high amounts of either are consumed.
  • Tramadol - Tramadol lowers the seizure threshold. Both substances increase the risk of vomiting and unconsciousness.
  • Grapefruit - Grapefruit juice significantly increases oral absorption of ketamine. This may result in the user having double the concentration of ketamine in their system compared to normal. The ketamine may also have a longer duration of effect.[42] This likely applies to oral, sublingual, and intranasal administration.

Legal status

  • Australia: Ketamine is a Schedule 8 drug in Australia, meaning that possession, manufacture or supply without authority is illegal.[43]
  • Austria: Ketamine is legal for medical and veterinary use and illegal when sold or possessed without a prescription under the NPSG (Neue-Psychoaktive-Substanzen-Gesetz Österreich).[citation needed]
  • Belgium: Ketamine is legal for medical and veterinary use and illegal when sold or possessed without a prescription.[citation needed]
  • Brazil: Ketamine is legal for veterinary use and illegal when sold or possessed for human use.[citation needed]
  • Canada: Ketamine is controlled under Schedule I of the Controlled Drugs and Substances Act[44]. Activities such as sale, possession or production of ketamine are illegal unless authorized for medical, scientific or industrial purposes. In Canada, ketamine has legitimate uses in medicine.[45]
  • China: Ketamine is a Schedule II drug.[citation needed]
  • Czech Republic: Ketamine is legal for medical and veterinary use and illegal when sold or possessed without a prescription.[citation needed]
  • Denmark: Ketamine is legal for medical and veterinary use and illegal when sold or possessed without a prescription.[citation needed]
  • France: Ketamine is a Schedule IV drug in France.[citation needed]
  • Germany: Ketamine is a prescription medicine, according to Anlage 1 AMVV.[46]
  • Hong Kong: Ketamine is a Schedule I drug in Hong Kong.[citation needed]
  • Luxembourg: Ketamine is a prohibited substance for recreational use.[47]
  • Malaysia: Ketamine is illegal to sell and possess in Malaysia.[citation needed]
  • Mexico: Ketamine is a Category 3 drug in Mexico.[citation needed]
  • New Zealand: Ketamine is a Class C drug in New Zealand.[citation needed]
  • Norway: Ketamine is a Class A drug in Norway.[citation needed]
  • Singapore: Ketamine is a Class A drug in Singapore.[citation needed]
  • Slovakia: Ketamine is a Schedule II drug in Slovakia.[citation needed]
  • South Korea: Ketamine is illegal to possess and sell in South Korea.[citation needed]
  • Spain: Ketamine is a Schedule IV drug in Spain.[48]
  • Sweden: Ketamine is a Schedule IV drug in Sweden.[citation needed]
  • Switzerland: Ketamine is a controlled substance specifically named under Verzeichnis B, when possessed or handled without a license. Medicinal use is permitted.[49]
  • Taiwan: Ketamine is a Schedule III drug in Taiwan.[citation needed]
  • Turkey: Ketamine is a 'green prescription' only substance[50] and illegal when sold or possessed without a prescription.[citation needed]
  • United Kingdom: Ketamine is a Class B drug in the United Kingdom.[51]
  • United States: Ketamine is a Schedule III drug in the United States.[citation needed]
  • Poland: Ketamine is illegal to possess, manufacture and sell except for medical purposes. [52]

See also

External links

Media

Literature

  • Durieux, M., & Kohrs, R.T. (1998). Ketamine: teaching an old drug new tricks. Anesthesia and A nalgesia, 87 5, 1186-93. PMID: 9806706
  • Mion, G. (2017). History of anaesthesia: The ketamine story–past, present and future. European Journal of Anaesthesiology (EJA), 34(9), 571-575. https://doi.org/10.1097/EJA.0000000000000638
  • Krystal, J. H., Karper, L. P., Seibyl, J. P., Freeman, G. K., Delaney, R., Bremner, J. D., . . . Charney, D. S. (1994). Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans: Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. Archives of General Psychiatry, 51(3), 199-214. http://dx.doi.org/10.1001/archpsyc.1994.03950030035004
  • Morris, H., & Wallach, J. (2014). From PCP to MXE: A comprehensive review of the non-medical use of dissociative drugs. Drug Testing and Analysis, 6(7–8), 614–632. https://doi.org/10.1002/dta.1620

References

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  44. Controlled Drugs and Substances Act
  45. Heatlh Canada
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