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What’s the deal with ketamine? Q&A on Special K

What’s the deal with ketamine? Q&A on Special K

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Previously thought of as either a horse tranquilizer or a dissociative recreational party drug, ketamine has re-emerged as a promising therapeutic agent to treat pain, PTSD, depression, anxiety and more. Named because it is the result of the joining two different chemical types – a ketone and an amine, ketamine was developed in 1962 as an alternative dissociative anesthetic drug to the potently hallucinogenic phencyclidine, known more commonly as PCP. 1

While trying to figure out how to describe this altered state without affecting the potential marketability of the drug, one of the lead researcher’s wives suggested the term “dissociative anesthetic” – and it stuck. Ketamine was approved by the FDA in 1970 and was immediately put to use as an important tool for war medics in the Vietnam War. It was also after the Vietnam War that widespread ketamine abuse would begin to show up as a party drug. 2 3

As clinical trials around the world proceeded in the late 1960s and 1970s, patients began reporting difficulty tolerating ketamine’s unpleasant hallucinogenic and dissociative properties. Additionally, ketamine, along with many of the anesthetics before it, produces excitement in some people. This can lead to panic attacks or rage fits on the operating table, which is of course less than ideal. It was becoming clear that another class of anesthetics was needed. 4

This led to the development of other drugs, including opioids, to help patients get through surgery without hallucinations or uncomfortable psychological “trips.” As these other drugs came onto the market, ketamine’s use among clinicians waned until eventually it was primarily relegated to veterinary medicine – because for some reason no one was very concerned about horses, cows, and dogs hallucinating.

When did ketamine become illegal?

As alternatives to ketamine emerged and ketamine abuse continued to rise, the United States government designated ketamine as a schedule III controlled substance. According to the DEA, “substances in this schedule have a potential for abuse less than substances in Schedules I or II and abuse may lead to moderate or low physical dependence or high psychological dependence.” Drugs in this class can still be prescribed, but there are restrictions on how long the prescription is good for, how many refills, and where you can have it filled.

The future looked bleak for ketamine, until some exciting research emerged in the 1980s that changed how researchers thought about the brain. In 1980, it was discovered that the stimulation of a calcium ion channel called the NMDA receptor (N-methyl-D-aspartate) was responsible for controlling the plasticity of the brain. Brain plasticity is basically the brain’s ability to adapt to stress, trauma, and injury. 5

Several years later in 1986, it was shown that blocking the NMDA receptor disrupted memory functioning in rodents. These findings are critical to our story because it was also around this time in the late 1980s and early 1990s that researchers ran into a problem with opioid based anesthetics – they made pain worse overall! This effect of opioids increasing the perception of pain is called opioid-induced hyperalgesia. What were clinicians to do? 6 7

Opioids produce this pain-promoting effect by opening up NMDA receptors too much. It turns out that ketamine is an NMDA receptor inhibitor, which means it could be used in patients with pain who are not responding to the typical opioid treatment. And just like that, all of a sudden ketamine had found a new role in modern medicine – an anti-hyperalgesic. As time marched on into the late 1990s and early 2000s, clinicians began exploring the role of low-dose ketamine for the treatment of things like chronic pain, depression, anxiety and other central nervous system disorders. 8

The resurgence of interest in ketamine has also led to the development of ketamine isomers and analogues that promise to provide some of the same antidepressant or pain-relieving properties of ketamine, without the dissociation or “K-hole” experience. The most popular of these is S-ketamine (usually referred to as simply “esketamine” and available under the names Ketanest® and Spravato®) and is commonly administered as a nasal spray. Today there are a number of ketamine clinics located across the United States where people struggling with chronic pain or depression can try ketamine or esketamine in controlled, safe conditions under the eye of medical professionals, as well as online and app-guided treatment programs. 9

How is ketamine commonly used?

Ketamine is most commonly administered through intravenous infusion, nasal spray, or sublingual lozenge. The effects can vary slightly depending on how the drug is administered. IV ketamine produces the most rapid and potent effects. It begins working rapidly and the effects start to dissipate very quickly after the infusion has stopped. 

Delivery methodOnset timeDurationOther Info
Nasal spray5 minutes1 hourFDA approved as esketamine
Oral15-30 minutes2-6+ hoursSlowest and least consistent absorption of listed methods
Intravenous (IV)30 seconds5-10 minutes (after end of infusion)May be administered as a one-time, rapid dose or as a slow continuous dose over a set amount of time.
Insufflation (powder)5-10 minutes40-75 minutesMost commonly abused form
Intramuscular (IM)3-5 minutes15-30 minutesA less common administration method
Sublingual (SL)5-15 minutes45-60 minutesThis route of administration – under the tongue – is more bioavailable than oral, with faster onset and short duration
10 11 12 13 14 15

Sublingual lozenges are often prescribed to patients after a series of IV infusions to help manage the recurrence of symptoms. The lozenge is held in the mouth and takes approximately 10 minutes to dissolve. As the lozenge dissolves, the mouth generally becomes numb before the effects are felt around the rest of the body. Holding the lozenge in the mouth produces more saliva, which can make it difficult to swallow with a  numb mouth. Expect the effects of a lozenge usually come on within 20 minutes and last for approximately 30 minutes. All in all, the ketamine experience from a lozenge can run its course in 1-2 hours.

Nasal sprays can take a few minutes to take effect and are generally less potent than other forms of administration. It should be noted that recreational ketamine use is often administered through snorting, which is generally done at higher doses with pure powdered ketamine compared to the dosages and formulations found in regulated, pharmaceutical-grade ketamine nasal sprays. In this context, nasal administration can be very potent as the dose delivered via these powders can be quite large, which also means that side effects are more common.

How does ketamine work on the brain?

Ketamine is very fast acting, and generally the effects only last for a couple hours after oral administration, and even shorter if given via intravenous or intramuscular injection. Once ketamine is ingested or injected, it very quickly travels to the brain where, as mentioned previously, it blocks NMDA receptors, which are responsible in part for regulating pain signals and mood. This NMDA blockade helps eliminate the sensation of pain, at least temporarily, and changes how the brain processes emotions, producing feelings of euphoria, happiness, contentment at the best of times, and feelings of confusion, panic and fear at the worst of times.

One of the most interesting aspects of ketamine’s pharmacology is its ability to produce altered states of consciousness that resemble classical psychedelic experiences. These effects are thought to be due to the way ketamine interacts with other receptor systems in the brain, such as the adrenaline, dopamine, and opioid systems.

Ketamine is also known to activate certain opioid receptors, which may explain its acute pain relieving effects. This less-discussed aspect of ketmaine’s pharmacology appears to be important, as blocking the opioid activity will also block ketamine’s antidepressant effects. 16

Additionally, ketamine administration is associated with the release of other excitatory neurotransmitters like dopamine, norepinephrine and epinephrine (adrenaline). This leads to an increase in heart rate and cardiac excitability, which explains some of ketmaine’s most common side effects – high blood pressure and rapid heart rate. 17

How does ketamine feel?

The effects of ketamine can vary person-to-person, but the experience usually begins with a tingling sensation in the hands and feet. As ketamine reaches the brain and begins to block the NMDA receptors, the body becomes more and more numb while the mind dissociates from the body. Some users have reported out-of-body experiences in which they see themselves or the world from a third-person perspective.

A common phenomenon associated with ketamine use that is reported especially by users of higher doses of the compound is the “K-Hole” effect. This is a feeling of nothingness that can either be comforting or distressing, depending on your mental state. The “K-Hole” is also referred to as “The Void” in many experience reports on Erowid.org, and is thought to be the experience of complete dissociation between the mind and body. While the mind is still active and capable of experience, it has no stimuli from the body. This can lead to hallucinogenic experiences and profound changes to consciousness. 

As the effects of ketamine wear off, the user can usually start to feel the reconnection between the mind and brain, slowly regaining the ability to move extremities and talk. Motor coordination is very difficult at this time, and patients often find themselves stumbling to grab a wall or chair to ground themselves to avoid falling. This sensation fades quickly, within 30 minutes for injection and within an hour or two the patient is generally back to baseline, relatively speaking.

How long does ketamine stay in your system?

The acute effects of ketamine can be felt shortly after taking the drug, depending on how you take it (similar to edibles vs inhalation for cannabis). The duration of effect is short, too, stopping soon after an IV dose and only 30 minutes after an injectable dose. Again, similar to edibles, the duration of effect with oral ketamine is longer and more variable, with noticeable effects that can last more than six hours in some people.

Overall ketamine does not stay in the body very long at all, and unless use is happening regularly the drug would clear from the body within a day or two. Ketamine is not on the standard 5 or 10 drug screen panel, meaning that employers and the government is not testing for it standardly. Ketamine can be screen for in blood and urine, but it is not part of a standard drug screening. 18

While ketamine’s effects on the brain are relatively short-lived, the changes it causes to the brain and central nervous system can be long-lasting, especially when used in the context of psychotherapy or other forms of treatment for mental health conditions. 

Is ketamine safe?

Despite its potential benefits, ketamine is not without risks. The most common side effects reported by patients after consuming ketamine include “dissociation, nausea, headache, elevated heart rate, and blood pressure [changes].” Additionally, ketamine users sometimes experience problems processing and controlling the body’s urge to urinate. 19

Clinical trials of ketamine so far have not indicated any issues related to cognitive abilities and ketamine use – as long as it is used within accepted low-dose and infrequent administration protocols. However in recreational settings, urinary tract disorders, renal complications, memory defects and cognitive decline have been associated with repeated ketamine abuse. 20

Administered infrequently, ketamine does not appear to be acutely dangerous and can be very therapeutic for people with treatment resistant depression, PTSD, anxiety and chronic pain. However, there is a notable lack of research around the potential risks associated with repeated or chronic dosing of ketamine – so the jury is still out on that one. 21

Is ketamine addictive? 

While cases of ketamine addiction are reported far less than many other drugs of abuse like cocaine, heroin or alcohol, as the popularity of ketamine grows, there are growing concerns around ketamine’s addictive potential. Ketamine affects several different systems in the body that influence feelings of euphoria, drug seeking behavior, and addiction. Studies have shown that ketamine affects the brain’s reward system, especially in areas linked to addiction. It increases the release of dopamine, a chemical associated with pleasure, which encourages repeated use. 2223242526

At low doses, ketamine not only causes a release of dopamine, but it also can block the reuptake of dopamine in the brain, meaning that it allows more dopamine to linger in the brain for longer, contributing to its mood-enhancing effects as well as its addictive potential. On top of that, ketamine also tends to increase levels of serotonin in the brain – further leading to feelings of euphoria or happiness, and also one reason it can cause psychedelic-like effects. 27

There is no doubt that ketamine often makes people feel good, and the pharmacology behind those effects can lead to substance abuse and addiction problems. Anyone using ketamine should be aware of these risks and take caution, as they should with any prescription medication. Prolonged use of ketamine is discouraged, even at low doses, to minimize the disruptions to the brain’s pleasure-seeking and reward pathways.

Hope for ketamine as a treatment for addiction

Despite the concerns for ketamine misuse, there is emerging evidence pointing to the contrary – that could be helpful in treating addiction related disease.  Through the underlying mechanisms that are still being explored, it appears that ketamine could be helpful at reducing drinking in those battling alcoholism.  Studies have also shown that ketamine may be a useful therapeutic for treating cocaine addiction by reducing cravings, reducing relapse rates and improving the likelihood of quitting. 28

Ketamine continues to show promise as a treatment option for conditions we had not yet considered. Its unique and complex pharmacology is what makes it such a useful agent, but it is also what makes it a challenging agent to use and dose. We highly encourage anyone looking to use ketamine to seek the advice and support of a medical expert.


  1. Hirota K, Lambert DG. Ketamine; history and role in anesthetic pharmacology. Neuropharmacology. 216: 109171. https://doi.org/10.1016/j.neuropharm.2022.109171
  2. Mion G. History of anaesthesia. The ketamine story – past, present and future. Eur J Aneasthesiol. 2017. 34:571-575. https://doi.org/10.1097/EJA.0000000000000638
  3. Jansen KL. A review of the nonmedical use of ketamine: use, users and consequences. J Psychoactive Drugs 2000; 32:419–433.
  4. Hirota K, Lambert DG. Ketamine; history and role in anesthetic pharmacology. Neuropharmacology. 216: 109171. https://doi.org/10.1016/j.neuropharm.2022.109171
  5. Collingridge G. Synaptic plasticity. The role of NMDA receptors in learning and memory. Nature 1987; 330:604–605
  6. Davies SN, Alford ST, Coan EJ, et al. Ketamine blocks an NMDA receptor mediated component of synaptic transmission in rat hippocampus in a voltage-dependent manner. Neurosci Lett 1988; 92:213–217.
  7. Mion G. History of anaesthesia. The ketamine story – past, present and future. Eur J Aneasthesiol. 2017. 34:571-575. https://doi.org/10.1097/EJA.0000000000000638
  8. Ilkjaer S, Petersen KL, Brennum J, et al. Effect of systemic N-methyl-D-aspartate receptor antagonist (ketamine) on primary and secondary hyperalgesia in humans. Br J Anaesth 1996; 76:829–834.
  9. Harvey M, Sleigh J, Voss L, et al. Development of rapidly metabolized and ultra-short-acting ketamine analogs. Anesth Analg 2015; 121: 925–933
  10. Poonai, N., Canton, K., Ali, S., Hendrikx, S., Shah, A., Miller, M., Joubert, G., Rieder, M., & Hartling, L. (2017). Intranasal ketamine for procedural sedation and analgesia in children: A systematic review. PloS one, 12(3), e0173253. https://doi.org/10.1371/journal.pone.0173253
  11. Mion, G., & Villevieille, T. (2013). Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS neuroscience & therapeutics, 19(6), 370–380. https://doi.org/10.1111/cns.12099
  12. Majidi, S., Parna, A., Zamani, M., & Akhbari, K. (2018). Onset and Effect Duration of Intrabuccal Space and Intramuscular Ketamine in Pediatrics. Advanced biomedical research, 7, 91. https://doi.org/10.4103/abr.abr_114_17
  13. Zanos, P., Moaddel, R., Morris, P. J., Riggs, L. M., Highland, J. N., Georgiou, P., Pereira, E. F. R., Albuquerque, E. X., Thomas, C. J., Zarate, C. A., Jr, & Gould, T. D. (2018). Ketamine and Ketamine Metabolite Pharmacology: Insights into Therapeutic Mechanisms. Pharmacological reviews, 70(3), 621–660. https://doi.org/10.1124/pr.117.015198
  14. Rolan, P., Lim, S., Sunderland, V., Liu, Y., & Molnar, V. (2014). The absolute bioavailability of racemic ketamine from a novel sublingual formulation. British journal of clinical pharmacology, 77(6), 1011–1016. https://doi.org/10.1111/bcp.12264
  15. Andrade C. Oral ketamine for depression, 1: pharmacologic considerations and clinical evidence. J Clin Psychiatry. 2019;80(2):19f12820.
  16. Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., & Schatzberg, A. F. (2018). Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. The American journal of psychiatry, 175(12), 1205–1215. https://doi.org/10.1176/appi.ajp.2018.18020138
  17. Mion, G., & Villevieille, T. (2013). Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS neuroscience & therapeutics, 19(6), 370–380. https://doi.org/10.1111/cns.12099
  18. Verstraete AG, Mukhdomi T. Clinical Drug Testing. [Updated 2022 Aug 8]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK557523/
  19. Nikayin S, Murphy E, Krystal JH, Wilkinson ST. Long-term safety of ketamine and esketamine in treatment of depression. Expert Opin Drug Saf. 2022 Jun;21(6):777-787. doi: 10.1080/14740338.2022.2066651. Epub 2022 Apr 19. PMID: 35416105.
  20. Niesters, M., Martini, C. and Dahan, A. (2014), Ketamine risks and benefits. Br J Clin Pharmacol, 77: 357-367. https://doi.org/10.1111/bcp.12094
  21. Short B, Fong J, Galvez V, Shelker W, Loo CK. Side-effects associated with ketamine use in depression: a systematic review. Lancet Psychiatry. 2018 Jan;5(1):65-78. doi: 10.1016/S2215-0366(17)30272-9. Epub 2017 Jul 27. PMID: 28757132.
  22. Orhurhu, V. J., Vashisht, R., Claus, L. E., & Cohen, S. P. (2022). Ketamine toxicity. In StatPearls. StatPearls Publishing, Treasure Island (FL).
  23. Li, J. H., Vicknasingam, B., Cheung, Y. W., Zhou, W., Nurhidayat, A. W., Jarlais, D. C., & Schottenfeld, R. (2011). To use or not to use: an update on licit and illicit ketamine use. Substance Abuse and Rehabilitation, 2, 11-20.
  24. Morgan, C. J., & Curran, H. V. (2012). Ketamine use: a review. Addiction, 107(1), 27-38.
  25. Dillon, P., Copeland, J., & Jansen, K. (2003). Patterns of use and harms associated with non-medical ketamine use. Drug and Alcohol Dependence, 69(1), 23-28.
  26. Krystal, J. H., Abdallah, C. G., Sanacora, G., Charney, D. S., & Duman, R. S. (2019). Ketamine: A Paradigm Shift for Depression Research and Treatment. Neuron, 101(5), 774-778.
  27. Can, A., Zanos, P., Moaddel, R., Kang, H. J., Dossou, K. S. S., Wainer, I. W., Cheer, J. F., Frost, D. O., & Gould, T. D. (2016). Effects of ketamine and ketamine metabolites on evoked striatal dopamine release, dopamine receptors, and monoamine transporters. Journal of Pharmacology and Experimental Therapeutics, 359(1), 159-170.
  28. Sepulveda Ramos, C., Thornburg, M., Long, K., Sharma, K., Roth, J., Lacatusu, D., Whitaker, R., Pacciulli, D., Moredo Loo, S., Manzoor, M., Tsang, Y. Y., Molenaar, S., Sundar, K., & Jacobs, R. J. (2022). The Therapeutic Effects of Ketamine in Mental Health Disorders: A Narrative Review. Cureus, 14(3), e23647. https://doi.org/10.7759/cureus.23647
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