Ketamine. A Review of its Current Uses and Future Possibilities


Academic Paper, 2020

8 Pages


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Abstract

Over the years our expectations of ketamine and its therapeutic effects has grown to encompass fields of use including depression therapy, analgesic effects, and hallucinatory models for schizophrenic pathology. Currently, the majority of studies aimed at understanding the psychopathology of ketamine and its unique composition and breakdown in the human blood stream have focused on the potential of this chemical to lead to hypo realistic drowsiness and a dreamlike state. The dreamlike state is characterized by mild hallucinatory images similar to the mild schizophrenic symptoms characteristic of phencyclidine (PCP) and their combination in the more historically fused optically developed regions of the brain. We seek to lay out a foundational summary of the available body of study on ketamine and its physiology as well as its potential to add to the medical discourse.

Introduction

Ketamine hydrochloride is in a class of drugs known as dissociatives, not far from the realm of the classic hallucinogens including LSD and psilocybin that are tryptaminergic hallucinogens. Reactions in humans to small doses received i.c.v., i.v., orally or intranasally can result in minor hallucinatory effects, drowsiness, and an overall inebriated feeling. Ketamine slightly impairs driving and has been known to cause delusions of sight including abnormal perception of size and distance while blurring object boundaries and the distinctions between such objects.

Ketamine has been studied as an effective instrument in producing analgesia, most commonly in conjunction with opiates so as to reduce the delirium caused by ketamine while maximizing the analgesic effects the solution may provide. (1) Ketamine has been abused for these effects for nearly 30 years, and animal models have shown potential for dependence. (2) Ketamine has shown promise in models for schizophrenia in rats and has shown promise in children with minimal side-effects, consistent with the schizophrenia model—that is to say it produces schizophrenic-like effects in adult humans and rats, but, similar to schizophrenia, these symptoms seem to not be present when the chemical is administered to a child. Most of the supply of ketamine used for recreational purposes is redirected from that intended for clinical use, contrary to the stated purpose of this regulated substance. The World Health Organization (WHO) has declared that ketamine has definite use as an analgesic and therefore cannot be suggested for international illegality. Despite this, it remains a Schedule I drug in the United States, the most highly illegal verdict to be given. (2) Street availability of ketamine for illicit use in the United States stems mostly from that diverted from veterinary uses, or that trafficked from Mexican enterprises.

A major drawback to ketamine use in the clinical sphere is emergent phenomena in patients awakening from ketamine narcosis including hallucinations, vivid dreams, floating sensations and delirium. (2) Ways to reduce these symptoms have included concurrent use of benzodiazepines, preoperatively providing patients with possible information on the physiological mechanisms of emergent reactions, and keeping the patient in a low-stimulus environment. These phenomena appear more frequently in adults than in children. (3) Though it is not immediately clear why these schizoid symptoms of ketamine administration are much rarer in children than adults this fact would seem to further the body of evidence showing how rare it is for children to experience schizophrenic symptoms. The prevalence of early onset psychosis is almost 50 times as rare as the adult-onset counterpart. (20)

Clinical Use

Outside of developed countries, ketamine holds a much higher esteem as a general anesthetic for humans due to a lack of competition and ketamine’s ease of clinical use. For clinical use there is available a racemic mixture and a formulation containing only the S-(+)-enantiomer which is shown to be slightly more effective as an analgesic. Furthermore, in patients with high tolerance to opioids or alcohol it can be used as a secondary analgesic and for psychotherapeutic purposes along with classical psychotherapy. (2)

It has been established that dissociative anesthetics such as ketamine are noncompetitive inhibitors of N-methyl-D-aspartate (NMDA) excitatory ligand-gated ion channels which are important modifiers of synaptic plasticity and memory. (4) However the sites by which ketamine produces a higher CNS depression than PCP when administered in high doses remains an enigma. Ketamine has been proven to produce the desired effect of analgesia when administered through drug-specific modes and can be effective even in treating chronic pain with its psychotropic effects being outweighed by concomitant application of benzodiazepine.

Particularly for the pain experienced during cancer and cancer treatment, ketamine in combination with an opioid that by itself can cause disorienting side effects at higher doses has been shown to be effective as a pain modifier. (5) Ketamine can produce rapid and sustained antidepressant-like effects in humans and rodents. It has been shown that long lasting effect of ketamine on forced swim test requires ventral hippocampal activity, damage to which can cause anterograde amnesia or acute dissociation with spatial orientation particularly of the head. (6)

Furthermore, its role as an NMDA receptor antagonist lends itself to applications in the prevention of morphine tolerance while inhibiting development of physical dependence to this opiate in mice. (2) The nucleus accumbens has been suggested as the active site by which ketamine has the possibility of suppressing morphine withdrawal syndrome. (2) Ketamine’s effects on the uptake and efflux of dopamine has been shown by mobilization of the dopamine storage pool to releasable sites. These dopaminergic affects in the reward pathway may be important areas of study for their euphoric and dependence-producing psychotomimetic properties.

Ketamine appears to stimulate the cardiovascular system, most likely caused by reuptake inhibition of circulating catecholamines. The cardiovascular effects of ketamine usually do not pose a serious risk, but its use in patients with a history of high blood pressure or cerebrovascular accidents should be avoided as it has been shown that from an emergency department tachycardia (high heart rate) in recreational users was the most common finding upon physical examination. (7)

The subanaesthetic effects of ketamine which produce psychedelic responses have shown useful in mitigating the effects of alcoholism through ketamine assisted psychedelic therapy (KPT). (11) Total abstinence from alcohol for more than one year was observed in 73 out of 111 (65.8%) of alcoholic patients in the KPT group, compared to 24% (24 out of 100 patients) of the conventional treatment control group (p<0.01). (11) Psychological changes including positive changes in life values and purposes, and an increase in the level of spiritual development were shown to favor a sober lifestyle. Data from biochemical research showed that KPT affects both monoaminergic and opioidergic neurotransmitter metabolism, which are both involved in the pathogenesis of alcohol dependence. (11)

Ketamine is a mild respiratory depressant. (2) Its affects on the CO2 dose-response curve shifts the curve to the right without having an effect on the slope of the curve. This effect is similar to that of opioids, suggesting that opioid receptors may play a role in the respiratory depressant effect.

Biotransformation of ketamine takes place in the liver, most importantly through N-demethylation to norketamine. The predominant route of elimination is by metabolism in the liver. It has been shown that ketamine induces the expression of multiple forms of P-450 in rat liver microsomes and increases CCI4-induced liver toxicity and cocaine mediated acute toxicity—a connection that should be further studied to reflect the use of cocaine and ketamine concomitantly in recreational users. (8)

There is a balance to be struck between prescribing ketamine “off-label” to patients exhibiting signs of depression and making all patients wait until ketamine or a licensed derivative for depression is a key dilemma facing physicians. Unfortunately, the emergent reactions ketamine produces, such as hallucinations, dream-like states, and out of body experiences, provide information on the facts about ketamine pathology that are least understood and in need of dire research. (17)

The main adverse effects of ketamine use can be noticed in the bladder and are prevalent in recreational users but are largely dependent on dose and frequency of use, seeing almost no effects in therapeutic users with physician assistance. For patients being treated for treatment resistant depression, ketamine can provide a much needed solace that sometimes cannot be found anywhere else. (17)

Of the two stereoisomers available, R-ketamine, compared to S-ketamine, has shown promise in eliciting a sustained antidepressant effect and appears to be a potent, long lasting and safe antidepressant. (18) Further, R-ketamine seems to be mostly free of psychotomimetic side effects and abuse potential. (18)

The Chinese government has played a pivotal role in the control and illegality of ketamine. (19) It has been pushed to be labeled as a Schedule I drug, with no therapeutic value and high potential for abuse by this government as a reaction to their high rate of use in the rave and party scene. (19) Furthermore, it has some potential and has been known to be used as a drug that is coincidental with rape and sexual assault cases, mostly in China as well. (19) However, ketamine has shown powerful clinical effect for patients who chronically use opioids and is useful when used in combination with these opioids for treatment. This concomitant use can help reduce side effects from opioids and reduce the need for high doses of these drugs. (19) Further, this conjoined use has shown promise in patients with chronic pain or cancer, sometimes offering relief or an increase in duration of life, predicted to be through its suppression of natural killer cell function. (19) However, ketamine is not a cost effective treatment for chronic pain as its effects are not long lasting. (19) In the United States, ketamine’s current status as a Schedule III drug and subsequent ban elsewhere makes it difficult to assess the long term effects of its use as license and use is rare. (19)

Ketamine has shown promise in helping to decrease agitation, manage pain, facilitate opioid and benzodiazepine withdrawal, prevent respiratory depression and potentially manage anxiety and depression in chronically ill patients. (21)

Ketamine has been used in conjunction with propofol, a strong, short-acting anesthetic, to induce anesthesia in children between the ages of 3 and 9 to facilitate circumcision with positive effects. (26) Ketamine with propofol provided better sedation and hemodynamy than ketamine therapy alone. (26)

Psychomimetic Effects

The main neurobehavioral effects of ketamine are anxiety, agitation, perceptual distortion disorientation and impairment of motor function, such as ataxia. (2) It appears that ketamine’s neurophysiological and behavioral pathology are highly similar to that of schizophrenic psychosis, and is therefore a useful model for schizophrenia in animals and humans. Ketamine profoundly affects perceptions of body, time, surroundings and reality similar to schizophrenic symptoms and can be useful for further study in this area.

According to Hansen, et al. all subjects exposed to ketamine reported feelings of: a sensation of light throughout the body, novel experiences of body consistency, grotesquely distorted shape or unreal size of body parts, a sensation of floating in a weightless condition in space, radiantly colorful visions, absence of sense of time, emotional consanguinity, and out of body experience. Furthermore, in every instance the subjects retained a sense of a witnessing “I” that could observe and remember the effects. (9) Long-term heavy use of ketamine may be associated with persisting deficits in attention and recall.

Ketamine has potential as a glutamate receptor modulator acting as an antidepressant in its effect on humans and rodents. This role gives it the ability to act as relief for patients with unipolar major depressive disorder and has shown efficacy in their treatment relative to other pharmacologically active agents and electroconvulsive therapy. (12) Though the psychomimetic effects felt at all doses discourage widespread analgesic use as a therapeutic, ketamine has enormous potential in these areas for producing a desirable effect with only minor psychological changes. It is a rapidly acting dissociative anesthetic which, when introduced intramuscularly or intravenously produces the desired effect. (13)

Unfortunately, ketamine use and self administration has proven to have largely disastrous effects, often leading to dependence as increased tolerance leads to increasingly uncontrollable addictive behavior. (14) Though ketamine treatment has shown usefulness, its destructive potential must not be overlooked and is a primary reason for its ban of sale and use in humans in many developed countries.

Ketamine and phencyclidine (PCP) use shows evidence for a glutaminergic response as a schizophrenic model as these drugs have shown pathologies similar to schizophrenia and its expression. (15) Phencyclidine and ketamine to a lesser extent binds to a group of receptors, primarily the NMDAR, leading to NMDAR hypofunction that results in the schizophrenic model. (15)

Intranasal drug delivery systems offer an alternative to i.c.v and i.v. delivery while providing a significant increase in efficacy over oral use. (22) This intranasal delivery can bypass problems related to gastrointestinal problems, first pass metabolism and the blood brain barrier while delivering fast onset of action and quick removal of the chemical from the body. Absorption happens at the olfactory epithelium, and can pass directly through the cribriform plate to the brain. (22) Intranasal use is common in recreational users and often as the drug metabolizes through the olfactory epithelium, users experience a “drip” of the drug downwards resulting in further oral delivery. This can create an enjoyably timed delayed effect in ketamine’s psychotomimetic advances. (22) Intranasal treatment as 50-80mg once each period of 2-3 days has shown promise in treatment resistant depressive patients. (22) While intranasal use is common in recreational use, its nature brings a level of noise regarding the amount of the chemical actually present in the user due to variations in the mechanisms of administration and the user’s own body. Unfortunately, bioavailability through oral use is limited to 16%, almost one fifth that of intravenous administration, making intravenous use the most effective use. (24)

In rats, ketamine has shown promise in reducing the effects of withdrawal from acute amphetamine use. Injection of ketamine provided reduced DA activity in the VTA and other brain regions after acute amphetamine use. (23) Reduced withdrawal symptoms have been linked with increasing ability to tolerate dependence reactions to drug intake and could lead to a solution for managing withdrawals in humans. Treatment resistant depression in animals and humans has been elusive in its development, but alternative treatments such as ketamine therapy have shown some efficacy. (24) These models target reducing changes from stress in the brain and have an all-around effect on physiological tolerance to pain and depression. (24)

In a patient with phantom leg pains ketamine has shown promise in reducing the effects of this phantom limb syndrome and have provided some relief on a multitude of occasions for the patient when used in combination with traditional opioids, providing relief for sensations of “burning” and “cramping.” (25) Ketamine has been known to, in addition to acting as a NMDA receptor agonist, act on the nicotinic, muscarinic, and opioid receptors. (25) This characterization of ketamine as a widely acting anesthetic with dissociative properties is the pathology that we must keep in mind when considering its use both in off-label and in novel treatments of pain, depression, or chronic fatigue. (25)

Mechanism of Action

Positron emission tomography studies have shown ketamine use leads to an increase in dopamine in the ventral tegmental area (VTA) correlating with elevated mood, and increases in dopamine in the nucleus accumbens. Ketamine in animals produces patterns of self-administration and repeated use causes behavioral tolerance in animals and humans. Ketamine mainly acts in the prefrontal cortex and limbic system, with the highest density of NMDA receptors being in the prefrontal cortex (PFC) and hippocampus. (10)

Changes in midbrain dopamine as well as PFC dopamine and glutamate function have correlates to addiction. Damage to the dopamine system diminishes the ability of dopamine to signal novel salient events, leading to under-excitability to biologically relevant stimuli. As addiction progresses, the behavioral system changes from a dopamine-oriented one in the nucleus accumbens to a glutamate-based system in the PFC. Specifically, the system becomes highly excitable to drug-conditioned cues and under-excitable to biologically relevant cues. (10)

As a non-competetive NMDA receptor antagonist, ketamine acts as an open channel pore blocker at the PCP binding site. Its attachment prevents the flow of cations (mainly calcium) into the cell, preventing depolarization and therefore neuronal excitation. (16) By preventing neuronal excitation in these glutamic receptors, ketamine has an overall depressive effect on the nervous system that slowly dissociates the capacity of its user to differentiate between reality and imagined concepts, creating a dream-like state. This unique capacity of ketamine to act in a hallucinogenic sense with the unpredictability and excitement of phencyclidine without the vigor of damage to the nervous and somatic systems that gives it its unique profile in the underground world of the rave scene. However powerfully ketamine acts on the brain, its effects are relatively short lived, with recreational users often redosing within the hour and depression treatments often requiring the same. Therefore, its clinical advancement in treating major depressive disorders may be limited, but its vigor in acting as a quick all around anesthetic to treat suicidality has shown some strength. (16)

References:

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2. World Health Organization. (2014). Ketamine update review report. In Expert Committee on Drug Dependence Thirty-sixth Meeting Geneva (pp. 16-20).

3. White, J. M., & Ryan, C. F. (1996). Pharmacological properties of ketamine. Drug and alcohol review, 15 (2), 145-155.

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6. Jett, J. D., Boley, A. M., Girotti, M., Shah, A., Lodge, D. J., & Morilak, D. A. (2015). Antidepressant-like cognitive and behavioral effects of acute ketamine administration associated with plasticity in the ventral hippocampus to medial prefrontal cortex pathway. Psychopharmacology, 232 (17), 3123-3133.

7. Weiner, A. L., Vieira, L., McKay Jr, C. A., & Bayer, M. J. (2000). Ketamine abusers presenting to the emergency department: a case series. The Journal of emergency medicine, 18 (4), 447-451.

8. Chan, W. H., Sun, W. Z., & Ueng, T. H. (2005). Induction of rat hepatic cytochrome P-450 by ketamine and its toxicological implications. Journal of Toxicology and Environmental Health, Part A, 68 (17-18), 1581-1597.

9. Hansen G, Jensen SB, Chandresh L, Hilden T. The psychotropic effect of ketamine. J Psychoactive Drugs 1988;20:419-425

10. De Sousa, A., & Macheswalla, Y. (2010). Ketamine dependence: case report and review. J Pak Psychiatr Soc, 7 (2), 1.

11. Krupitsky, E. M., & Grinenko, A. Y. (1997). Ketamine psychedelic therapy (KPT): a review of the results of ten years of research. Journal of psychoactive drugs, 29 (2), 165–183. https://doi.org/10.1080/02791072.1997.10400185

12. Bobo, W. V., Vande Voort, J. L., Croarkin, P. E., Leung, J. G., Tye, S. J., & Frye, M. A. (2016). KETAMINE FOR TREATMENT-RESISTANT UNIPOLAR AND BIPOLAR MAJOR DEPRESSION: CRITICAL REVIEW AND IMPLICATIONS FOR CLINICAL PRACTICE. Depression and anxiety, 33 (8), 698–710. https://doi.org/10.1002/da.22505

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15. Haaf, M., Leicht, G., Curic, S., & Mulert, C. (2018). Glutamatergic Deficits in Schizophrenia - Biomarkers and Pharmacological Interventions within the Ketamine Model. Current pharmaceutical biotechnology, 19 (4), 293–307. https://doi.org/10.2174/1389201019666180620112528

16. Reinhart, K. M., & Shuttleworth, C. W. (2018). Ketamine reduces deleterious consequences of spreading depolarizations. Experimental neurology, 305, 121–128. https://doi.org/10.1016/j.expneurol.2018.04.007

17. Gutkin, E., Hussain, S. A., & Kim, S. H. (2012). Ketamine-induced biliary dilatation: from Hong Kong to New York. Journal of addiction medicine, 6 (1), 89-91.

18. Yang, C., Shirayama, Y., Zhang, J. C., Ren, Q., Yao, W., Ma, M., Dong, C., & Hashimoto, K. (2015). R-ketamine: a rapid-onset and sustained antidepressant without psychotomimetic side effects. Translational psychiatry, 5 (9), e632. https://doi.org/10.1038/tp.2015.136

19. Meng, L., Li, J., Lu, Y., Sun, D., Tao, Y. X., Liu, R., & Luo, J. J. (2015). Ketamine - A Multifaceted Drug. Translational perioperative and pain medicine, 1 (2), 20–26.

20. Eggers, C., & Bunk, D. (2009). Frühentwicklung kindlicher Schizophrenien [Early development of childhood-onset schizophrenia]. Fortschritte der Neurologie-Psychiatrie, 77 (10), 558–567. https://doi.org/10.1055/s-0028-1109737

21. Shah, P., McDowell, M., Ebisu, R., Hanif, T., & Toerne, T. (2018). Adjunctive Use of Ketamine for Benzodiazepine-Resistant Severe Alcohol Withdrawal: a Retrospective Evaluation. Journal of medical toxicology : official journal of the American College of Medical Toxicology, 14 (3), 229–236. https://doi.org/10.1007/s13181-018-0662-8

22. Andrade C. (2015). Intranasal drug delivery in neuropsychiatry: focus on intranasal ketamine for refractory depression. The Journal of clinical psychiatry, 76 (5), e628–e631. https://doi.org/10.4088/JCP.15f10026

23. Belujon, P., Jakobowski, N. L., Dollish, H. K., & Grace, A. A. (2016). Withdrawal from Acute Amphetamine Induces an Amygdala-Driven Attenuation of Dopamine Neuron Activity: Reversal by Ketamine. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41 (2), 619–627. https://doi.org/10.1038/npp.2015.191

24. Brachman, R. A., McGowan, J. C., Perusini, J. N., Lim, S. C., Pham, T. H., Faye, C., Gardier, A. M., Mendez-David, I., David, D. J., Hen, R., & Denny, C. A. (2016). Ketamine as a Prophylactic Against Stress-Induced Depressive-like Behavior. Biological psychiatry, 79 (9), 776–786. https://doi.org/10.1016/j.biopsych.2015.04.022

25. Stannard, C. F., & Porter, G. E. (1993). Ketamine hydrochloride in the treatment of phantom limb pain. Pain, 54 (2), 227–230. https://doi.org/10.1016/0304-3959(93)90214-a

26. Gulec, H., Sahin, S., Ozayar, E., Degerli, S., Bercin, F., & Ozdemir, O. (2015). Ketamine-propofol sedation in circumcision. Brazilian journal of anesthesiology (Elsevier), 65 (5), 367–370. https://doi.org/10.1016/j.bjane.2014.03.002

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Title
Ketamine. A Review of its Current Uses and Future Possibilities
College
University of California, Los Angeles
Authors
Year
2020
Pages
8
Catalog Number
V907758
ISBN (eBook)
9783346223531
Language
English
Tags
ketamine, alcohol withdrawal, benzodiazepines, agitation, children, early-onset, opiates, NMDA, ketalar, Ketamin, Ketamina, Ketaminol, Ketanest, Ketaset, Tekam, UCLA, pharmacology, research, paper
Quote paper
Joseph Parampathu (Author)Blake Nawrocki (Author), 2020, Ketamine. A Review of its Current Uses and Future Possibilities, Munich, GRIN Verlag, https://www.grin.com/document/907758

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