Coming out of a horse sized K-hole: Ketamine's antagonist action at NMDA receptors and impacts of D1 upregulation in dlPFC

One class of addictive drugs called dissociatives include such drugs as dextromethorphan (DXM), phencyclidine (PCP), and ketamine (K). Ketamine, commonly used in both veterinary and human medicine (high dose) as an anesthetic, is also used recreationally (typically in lower, subanesthetic doses), bringing on feelings of derealization, euphoria, dissociation, depersonalization, hallucinations, spiritual mind trips, etc., and is often used at dance events and parties. More specifically, “[k]etamine is a noncompetitive antagonist at the glutamatergic N-methyl-D-aspartate (NMDA) receptor” usually administered by intramuscular injection (IM) (Narendran, R., Frankle, W., Keefe, R., Gil, R., et al., 2005, p. 2352; action at the NMDA receptor as an indirect antagonist - Carlson, 2010, p. 615). Loose translation of the previous is that ketamine interferes with glutamate transmission at the NMDA receptor (not unlike alcohol, that also acts on GABA(A) receptors – Carlson, 2010, p. 631).

Perhaps not surprisingly, ketamine is linked to memory impairments, as the NMDA receptors are involved in long-term potentiation, implicit in learning (Carlson, 2010, p. 447). However, the long term effects of chronic ketamine use remain largely unknown (Narendran, 2005, p. 2352), while commonly thought to include K-pains – due to deterioration of the bladder, cognitive impairments – including memory, and neural network dysfunctions of various sorts (dearborization, etc. – see also common encyclopedic entries, ketamine was first synthesized in 1962 and is easily researched; see also RxList.com or Wikipedia.com).

Interestingly, the study I reviewed attempted to substantiate effects of chronic NMDA antagonist users (of ketamine) on the dorsolateral prefrontal cortex (dlPFC) because of earlier findings from “animal data indicated that the dorsolateral prefrontal cortex dopamine projections were especially vulnerable to repeated NMDA antagonist administration” (Narendran, et al., 2005, p. 2357). The study found that “D1 (dopaminergic) receptor availability was significantly up-regulated [“a compensatory increase in the sensitivity of receptors” (Carlson, 2010, p. 631); here, in correlation with the number of vials used per week] in chronic ketamine users… relative to comparison subjects … [and that] [n]o significant differences were noted in other cortical, limbic, or striatal regions” (Narendran, et al., 2005, p. 2357). While the authors did not, much to their surprise, find any cognitive deficits in users, it was made explicit that the typical user (who was not admitted to the study due to various psychiatric comorbidities, including polysubstance abuse), “even in the absence of cognitive deficits… repeated ketamine exposure… [is] associated with signs of disruptions of a critical component of cognition, the prefrontal dopamine system” (p. 2357).

In sum, the authors found that more research was needed, despite the evidence of neurotoxicity in animal models, as to the toxicity in humans (2005). They clearly stated, however that “the repeated use of ketamine for recreational purposes affects prefrontal dopaminergic transmission, a system critically involved in working memory and executive function [and might damage brain neurotransmission generally]” (p. 2358).

This study is a good one because of the link between exogenous substances, the dlPFC and receptor sites, with such illnesses as schizophrenia. Schizophrenia is characterized by an imbalance in dopamine transmission, especially at the D1 receptors (DA deficit; cognitive impairment) and the D2 receptors (DA excess; psychosis) (p. 2358). The authors provided the following link: “[t]he fact that chronic ketamine users and patients with schizophrenia exhibit the same endophenotypic trait (up-regulated D1 receptor expression in the dorsolateral prefrontal cortex) supports the hypothesis that in schizophrenia, this alteration might be secondary to NMDA dysfunction” (p. 2358). In fact, many researchers have long since established the link between DA agonists like cocaine and amphetamine, that also cause positive symptoms of schizophrenia (hallucinations, delusions, etc.), as well as PCP (angel dust) and ketamine (Special K or Vitamin K), as capable of causing positive, negative (poverty of speech, anhedonia, etc.), and cognitive symptoms (attentional problems, deficits in learning and memory, poor problem solving, etc.) of schizophrenia and therefore study the effects of these drugs with the hope of curing schizophrenia (Carlson, 2010, pp. 557, 567)

While not formally addressed in the article reviewed, is withdrawal from ketamine. I looked up information from a drug treatment center that described both the physiological and psychological processes involved. Since ketamine involves both psychological and physical effects, withdrawal is both a physical and mental process. The person undergoing the process should be kept under close supervision, due to the strength of the psychological addiction. While displacement away from the sources of drugs are a good tactic for the person in withdrawal, along with psychotherapy and behavior modification, another aspect of ketamine withdrawal, which is best addressed in a professional setting, is the physical side of ketamine withdrawal. The user more often than not has neglected their own physical well-being and often needs the help of nutritionists and physicians. (see also http://www.ketamine-effects.com/ketamine-withdrawal.htm)

Prolonged use has been associated with physical and psychological addiction. In the majority of individuals who frequently use ketamine, tolerance does develop to these effects, thus requiring the addicts to consume higher doses.

Although ketamine does not give rise to physical dependence like that seen with morphine, heroin or alcohol, it is associated with a powerful psychological addiction - like that seen with cocaine. Because of its ability to produce intense, vivid psychedelic effects it is frequently abused. The psychedelic effects and out of body experiences have been primary reasons why the drug is abused.

In conclusion, ketamine addiction, like all addiction begins with the acceptance of a problem by the individual. Many drug rehabilitation and treatment facilities are available for ketamine treatment. There are no antidotes to ketamine and the majority of therapy is psychotherapeutic. (see also http://www.addictionsearch.com/treatment_articles/article/ketamine-addiction-abuse-and-withdrawal_23.html)

References

Carlson, N. (2010). Physiology of behavior, (10th ed.). Boston: Allyn & Bacon.

Narendran, R., Frankle, W., Keefe, R., Gil, R., et al. (2005). Altered Prefrontal Dopaminergic Function in Chronic Recreational Ketamine Users. The American Journal of Psychiatry, 162(12), 2352-9. doi: 942933491.