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Ketamine, also known as “Special K” among recreational users or as the marketed medication Ketelar (Vetalar), Ketaset or Ketanest, is an often overlooked compound when thinking of substances that may be abused but also possess medicinal applications. It is most often associated with veterinarians as it has been utilized for many years as an “animal tranquilizer” or anesthetic, although it was originally developed for use in humans (Beck, 1976; Mozayani, 2002). Ketamine in humans has found use as a powerful anesthetic and analgesic (Oduntan & Gool, 1970; Schmid, Sandler & Katz, 1999) and a compound for neuronal preservation after ischemic attacks (Hoffman, Pelligrino, Werner, Kochs, Albrecht & Esch, 1992). It is also a compound which can cause neuronal damage in animals but apparently not in humans (Green & Cote, in press) and be used as a recreational drug (Jansen, 2000). The literature is replete with the songs of praise and tales of woe in ketamine’s role as a dissociative anesthetic and analgesic. However, less attention has been given to some of the more interesting information found in the use of ketamine such as its use to induce near-death-like experiences and its use as a fast-acting antidepressant medication and pharmacological agent for treatment of addiction.

Ketamine was developed in 1962 by pharmacist Calvin Stevens at the pharmaceutical company Parke-Davis, now a subsidiary of the Pfizer firm (Pfizer, 2009) and patented in 1966. It became available for use in animals and humans marketed as Ketalar (Mozayani, 2002). It was developed as a safer replacement for PCP (phencyclidine) as an anesthetic and was found in early clinical trials to be useful in that respect (Oduntan & Gool, 1970). It has found use in humans as a very useful anesthetic and analgesic especially for children (Cotsen, Donaldson, Uejima & Morello, 1997; Haley-Andrews, 2006). It has also found use as a recreational drug and has been found to have some consequences of repeated use such as persisting perceptual distortions, schizotypal symptomology, as well as negative effects on episodic memory and attentional functioning (Morgan, Monaghan & Curran, 2004). Ketamine has a wealth of literature upon its applications in these areas and is the focus of much continuing research. However, there are other areas of research and interest which are not all well understood or investigated in relation to ketamine, such as its role in the investigation of NDEs (near-death experiences) and its use in treatment of medication resistant depression as well as heroin addiction.

Chemically, ketamine is derivative of phencyclidine (PCP), another dissociative drug. The compound has a biological half life of approximately two hours and is broken down into two metabolites norketamine and dehydronorketamine (Hijazi, Bodonian, Bolon, Salord & Boulieu, 2003) by the cytochrome P450 enzyme CYP3A4 (Hijazi & Boulieu, 2002). Ketamine is a non-competitive NMDA type glutamate receptor antagonist which functions by either attaching to the PCP binding site or a second attachment site on the outer surface of the receptor protein (Julien, 2008). It also interacts with opioid receptors of the mu and kappa types but with far less affinity than for NMDA receptors (Pai & Heining, 2007). It is the effects ketamine produces upon these NMDA receptors which may account for the implication of the drug in production of states which can closely resemble NDE experiences (Jansen, 1997).

Near-death experiences are odd and enigmatic phenomena which have fascinated people since ancient times. People report visions of “tunnels of light”, meeting dead relatives and religious content as well as a sense of well-being and “calmness” and a feeling of being detached from their bodies (Woerlee, 2003). Many believe it is evidence of an after-life or some other spiritual realm, however, many researchers disagree and are quick to point to research which shows a naturalistic explanation for these experiences. One often cited point is that of the ketamine mergence phenomenon. In clinical use of ketamine as an anesthetic, it has been found to sometimes produce a particular phenomenon in which the person may hallucinate and even slip into delirium – emergence phenomenon, which is very similar to reports from those having experienced NDEs (Jansen, 1997). This phenomenon with occurs in approximately 5-30% of cases in which ketamine is utilized and may be more likely to be seen in women, older individuals, and those who normally dream. It is often controlled for by the use of benzodiazepines (Pai & Heining, 2007). The use of music was found to increase the incidence of emergence, however, the patients reported a more pleasant awakening (Ambesh, Kumar, Sarkar & Bajaj, 1991). It is thought that this effect along with other aspects such hypoxia and endorphin release plays a part in the production of near-death experiences (Jansen, 1997).

Ketamine has also found itself associated with another clinical use outside of being an anesthetic and analgesic – the treatment depression. In 2006, a study by Carlos Zarate and colleagues investigated the use of intravenous injections of ketamine as a treatment for those with treatment-resistant depression. The study examined 18 patients over the course of 11 months. The study was a randomized, placebo controlled, double-blind crossover design. The study found improvement in those patients receiving ketamine injections as opposed to the controls within 110 minutes with these results persisting for up to one week. These results are not unique as others have previously found similar results (Berman, Cappiello, Anand, Oren, Heninger, Charney et al., 2000; Kudoh, Takahira, Katagai & Takawaza, 2002).

Berman, Cappiello, Anand, Oren, Heninger, Charney et al. (2000) looked at the results of intravenous ketamine injections in depressed patients in a similarly designed study. They found that their patients who received ketamine showed marked improvement within 72 hours.

Similar results were found in a case study in 2007 reported by Liebrenz, Borgeat, Leisinger and Stohler. The team examined the effects of intravenous ketamine injections upon a 55 year old man who suffered from treatment-resistant depression. Alleviation of symptoms were reported in as little as 25 minutes and the results persisted for up to one week. Liebrenz et al remain skeptical of the role of NMDA receptors in the pathology of depression and call for further research, while Berman et al (2000) conclude such that results show unequivocally the role of the glutamate receptors and mu opioid receptors. A study conducted by Maeng, Zarate, Du, Schloesser, McCammon, Chen et al (2008) found a evidence for the role of AMPA receptors in the observed ketamine results. The team found that by utilizing an AMPA antagonist, NBQX, they were able to “dull” the results of ketamine whereas without the antagonists the rapid and robust antidepressant effects of ketamine were seen. They conclude that antagonists, “exert their antidepressant effects by regulating the functional interplay between AMPA and NMDA throughput” (pp. 352) – further solidifying the importance of glutaminergic receptors in depression.

Ketamine research has found some evidence for its usefulness in the treatment of addiction as well. One study looked at the use of ketamine as an pharmacological intervention for use with heroin addicts. Krupitsky, Burakov, Romanova, Dunaevsky, Strassman & Grinenko (2002) found that an intravenous dose of 2.0 mg/kg of ketamine elicited a greater period of abstinence from heroin within two years of a follow up (patients were followed up monthly for 24 months) compared to a lower dose of 0.2 mg/kg. The higher dose also produced a marked decrease in anxiety and anhedonia and modifications to several subscales of the MMPI such as depression, paranoia, conversion hysteria and schizophrenia. Interestingly it also showed an increase in the “internal” locus of control as well as a higher level of spiritual development in the patients. The authors mention that their high dose induces a state that may be close to that needed to produce a NDE-similar experience. They also note that similar changes are found in those who experience NDEs and those who received the higher doses of ketamine treatment. Such results have spurned research into the use of NMDA antagonists as treatment for addictions ranging from nicotine to opiates (Bisaga & Popik, 2000).

Ketamine was once simply viewed as a dissociative anesthetic and recreational drug found in the “club scene”. However, over the past decade research on the usefulness of this PCP derivative has been expanded greatly. Results may not only offer insight into treatment for depression and addiction, but may also offer insight into the neurobiology of one of the most enigmatic experiences people have reported – NDEs. While, as Liebrenz and colleagues have stated, more research is needed, there is definitely a need to explore the use of this chemical compound further.

References

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Beck, C. (1976). Vetalar (Ketamine Hydrochloride) a Unique Cataleptoid Anesthetic Agent for Multispecies Usage. The Journal of Zoo Animal Medicine, 7, 11-38.

Berman, R., Cappiello, A., Anand, A., Oren, D., Heninger, G., Charney, D. (2000). Antidepressant effects of ketamine in depressed patients. Biological Psychiatry, 47, 351-354.

Bisaga, A. & Popik, P. (2000). In search of a new pharmacological treatment for drug and alcohol addiction: N-methyl-D-aspartate (NMDA) antagonists. Drug and Alcohol Dependece, 59, 1-15.

Cotsen, M., Donaldson, J., Uejima, T. & Morello, F. (1997). Efficacy of Ketamine hydrocholoride sedation in children for interventional radiologic procedures. American Journal of Roentgenology, 169, 1019-1022.

Green, S & Cote, C. (in press). Ketamine and neurotoxicity: Clinical perspectives and implications for emergency medicine. Annals of Emergency Medicine.

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Hoffman, W., Pelligrino, D., Werner, C., Kochs, E., Albrecht, R. & am Esch, J. (1992). Ketamine decreases plasma catecholamines and improves outcome from incomplete cerebral ischemia in rats. Anesthesiology, 76, 755-792.

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Maeng, S., Zarate, C., Du, J., Schloesser, R., McCammon, J., Chen, G. et al. (2008). Cellular mechanisms underlying the antidepressant effects of ketamine: Role of α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors. Biological Psychiatry, 63, 349-352.

Mozayani, A. (2002). Ketamine – Effects on human performance and behavior. Forensic Science Review, 14, 123-131.

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Schmid, R., Sandler, A. & Katz, J. (1999). Use and efficacy of low-dose Ketamine in the management of acute postoperative pain: A review of current techniques and outcomes. Pain, 82, 111-125.

Woerlee, G. (2003). Mortal Minds: The Biology of Near-Death Experiences. Amherst: Prometheus Books.

Zarate, C., Singh, J., Carlson, P., Brutsche, N., Ameli, R., Luckenbaugh, D. et al. (2006). A randomized trial of N-methyl-D-aspartate antagonist in treatment-resistant major depression. Archives of General Psychiatry, 63, 856-864.