Edward F. Domino, MD, and Shannon C. Miller, MD, FASAM, DFAPA
15
DEFINITION (DRUGS IN THIS CLASS)
Dissociatives should be distinguished pharmacologically and clinically from true hallucinogens. A simplified view suggests that dissociatives and hallucinogens share common features. However, hallucinogens affect primarily 5-HT2A receptors and dissociatives affect glutamic acid N-methyl-d-aspartate (NMDA) receptors. Intoxication (whereby dissociation or impaired reality testing) is typically involved. Dissociatives include various arylcyclohexylamines (of which phencyclidine and ketamine are best known), dizocilpine (MK-80l), dextromethorphan, and the gaseous anesthetic, nitrous oxide. Nitrous oxide or “laughing gas” is not typically classified as a dissociative (more commonly considered an inhalant); however, given its NMDA antagonist and dissociative-like clinical effect, it merits inclusion in this chapter. Dissociatives share the clinical effect of causing a dissociative state of intoxication, which is desired by the user.
SUBSTANCES INCLUDED IN THIS CLASS
Phencyclidine (PCP) and ketamine are the principal abused illicit compounds. DXM is the principal abused over-the-counter compound. Ketamine is a racemic mixture of d– and l-isomers. The (S)-isomer is more potent and is claimed to have less dysphoric effects. Other members of this class that are less commonly abused include cyclohexamine (N-ethyl- 1-phenylcyclohexylamine, CI, 400), 1-(1-(2- thienylcyclohexyl) piperidine, 1-(1-phenylcyclohexyl) pyrrolidine, and 4-methyl pip PCP (1-(phenylcyclohexyl)-4-methylpiperidine). Dextromethorphan (DM, DXM, D-3-methoxy- N-methylmorphinan) is the d-isomer of a codeine analogue, methorphan. In contrast to the l-isomer, which is an opioid analgesic, dextromethorphan is not. The PCP-derived designer drug N-(1-phenylcyclohexyl)-3-methoxypropanamine and the ketamine analog methoxetamine should also be included in this class.
U.S. FOOD AND DRUG ADMINISTRATION–APPROVED FORMULATIONS
Ketamine (Ketalar) is available as a sterile solution for use in general anesthesia in both animals and humans. It has also been used for prehospital analgesia, anesthesia, and conscious sedation and more recently as a rapid-acting antidepressant (non-FDA approved, research only).
PCP is no longer available as a medical commercial preparation approved by the U.S. FDA. It is available in many illicit preparations and has many of the pharmacologic effects of ketamine, but is more potent, longer acting, and more likely to produce seizures. Doses of only 120 mg of PCP may cause death.
Legal DXM preparations are administered orally. Capsules, tablets, lozenges, or solutions of dextromethorphan are available alone or in combination with many other substances as cough, cold, and flu relief preparations. Larger doses of DXM are abused for their mental effects. When taken as directed, dextromethorphan has a low toxicity and high therapeutic index.
HISTORICAL FEATURES
PCP was developed as an intravenous anesthetic. The unique anesthesia it produced was complicated by a prolonged emergence delirium, which led to its demise as a clinically useful agent. PCP is associated with symptoms that model both the positive (delusions, hallucinations) and negative (blunted affect, autistic-like effects) symptoms of schizophrenia. Years later, PCP was rediscovered by the drug abuse community and has also been known as “angel dust,” “hog,” and “crystal.”
The desirable anesthetic properties of PCP were retained in the short-acting arylcyclohexylamine derivative ketamine, which produced a more brief emergence delirium. The term dissociative anesthetic was coined to emphasize that the anesthetized patient was psychologically “disconnected” from his or her environment. Ketamine subsequently was discovered by the drug abuse community, where it is known as “K,” “super K,” “special K,” and “cat Valium,” among others. Ketamine has the reputation among users as being medically safe to use because it is made by pharmaceutical companies, most often for veterinary use.
Arylcyclohexylamine abuse occurs primarily in large metropolitan areas. Because the drugs are easy to synthesize, they are relatively inexpensive substitutes for many street drugs. The user may not realize that he or she has used an arylcyclohexylamine because the drugs frequently are misrepresented as LSD-25, amphetamine, or synthetic marijuana. Moreover, they may be added to marijuana by the user to enhance marijuana’s desired effects.
In contrast to the arylcyclohexylamines, MK-801 (dizocilpine) was developed as an anticonvulsant and subsequently was used as a brain-protective agent; however, it was discarded because of its PCP-like effects. Clinical trials of MK-801 have been extremely limited, and the results are not publicly available. Very little is known of its properties in humans.
The history of DXM begins with the synthesis of racemethorphan (deoxydihydrothebaiodine) or methorphan (Dromoran). After the d– and l-isomers were isolated, it was discovered that the d-isomer was antitussive and had less analgesic- and narcotic-like properties. DXM is nearly equal to codeine as an antitussive. However, unlike codeine, DXM is fairly devoid of other opioid effects such as analgesia, central nervous system depression, and respiratory suppression. DXM is metabolized to dextrorphan (DXO), an NMDA receptor antagonist, which is the more psychoactive form. DXO binding sites in the brain include more than the NMDA receptor. DXM’s mechanism in low doses as an antitussive is unknown. In doses of 300 to 1,800 mg (20 to 120 times the recommended dose), DXM produces PCP-like mental effects. However, larger doses (237 times the recommended dose) are regularly abused. DXM abuse has been a concern since at least the 1960s.
Nitrous oxide has been known for more than 225 years. It is widely used today in anesthesia. In addition, its recreational use as “laughing gas” has been well described since it was first discovered. Ketamine and nitrous oxide still are medically used in humans as anesthetic agents. Ketamine is used in circumstances in which other anesthetic agents are relatively contraindicated. In contrast, nitrous oxide is widely used today as part of the mixture of anesthetics used to achieve “balanced anesthesia.” The S-isomer of ketamine has been developed as a rapid-acting antidepressant. Its effects last for only about 1 to 2 weeks per single dose.
EPIDEMIOLOGY
PCP abuse is more of a problem in large cities like Washington, DC, Philadelphia, Miami, and Los Angeles than in the rest of the United States. Ketamine is often used with other drugs; however, sole use of ketamine has been reported and is increasing. Although ketamine has often been self-administered, there is an emerging problem in youth. Such youth are more likely to engage in multiple injections, shared bottles of ketamine, and use of syringes obtained from secondary sources—practices that increase risk for transmission of infectious diseases.
DXM is considered one of the most commonly abused over-the-counter medications in the United States. Poison Control Center data support increasing DXM abuse, particularly among adolescents.
PHARMACOKINETICS
The pharmacokinetics of PCP in humans have never been well studied with psychoactive doses using modern methods. Blood PCP concentrations from 7 to 240 ng/mL (mean, 75) were found in arrested persons intoxicated in public or driving under its influence. The blood/plasma concentration ratio is 1. The plasma half-life (t½) of PCP has been reported to vary from 7 to 46 hours, suggesting the influence of dose and/or multiphase elimination processes. PCP is biotransformed in the liver to several metabolites and excreted in the urine as both free and glucuronide conjugates. Acidification of the urine increases its renal clearance because PCP is a base. However, this maneuver is no longer recommended clinically because of the risk of increasing urinary myoglobin precipitation.
Ketamine’s greater lipophilicity than phencyclidine accounts for its rapid onset, short anesthetic duration of action, and shorter period of emergence delirium. Plasma concentrations of ketamine vary widely depending on the dose, route, and time elapsed since administration. Anesthetic doses produce plasma or serum concentrations of 1.0 to 6.3 μg/mL, and nonanesthetic psychoactive blood concentrations of ketamine are in the low ng per mL range (100 to 400). Ketamine follows a three-phase plasma pharmacokinetic model when given intravenously. There is a brief initial (alpha) phase with t½ of about 7 minutes because of rapid redistribution, followed by a longer elimination (beta) phase with t½ of 3 to 4 hours. As used in general anesthesia, an intravenous dose of 2.0 mg/kg produces rapid induction. This dose produces an onset in 30 seconds, with the coma lasting for 8 to 10 minutes. The intramuscular injection of ketamine has a latency of 3 to 5 minutes and a duration of 10 to 20 minutes or more, depending on the dose administered.
DXM is readily absorbed from the gut. Peak serum levels are reached at 2 to 3 hours for immediate release and 6 hours for sustained release preparations. DXO levels peak at 1.6 to 7 hours. Humans have a genetic polymorphism for the biotransformation of DXM. Rapid metabolizers have a plasma elimination t½ of about 3.4 hours, and slow metabolizers may have t½’s exceeding 24 hours. Slow metabolizers of DXM represent about 10% to 15% of the population. Phenotypic “slow” metabolizers of DXM report fewer intoxication effects than normal subjects. Thus, clinically slow metabolizers might be at higher risk for developing DXM dependence/addiction.
PHARMACODYNAMICS
Depending on the dose and specific arylcyclohexylamine ingested, patients who have taken PCP or ketamine present with widely different neurologic and psychiatric signs and symptoms. These signs and symptoms can be generally subdivided into three major clinical pictures: (1) confusion, delirium, and psychosis; (2) semicoma and coma; and (3) coma with seizures. Patients may become progressively more obtunded and eventually comatose, or the reverse, with the patient emerging from coma and showing emergence delirium. Most PCP abusers do not grossly overdose themselves to the point of semicoma and coma. Hence, most patients intoxicated with PCP show a clinical picture of confusion, delirium, and psychosis. Tolerance occurs with PCP, and to a greater degree with continuous dosing. Human evidence remains limited regarding dissociative withdrawal.
About a third of patients in the early clinical trials of ketamine as a general anesthetic experienced an obvious emergence delirium. Why two thirds did not remain unexplained, but this suggests the importance of preoperative and postoperative medications, dosage, environmental, psychological, or genetic factors. People with schizophrenia are much more susceptible to a prolonged psychotic episode related to PCP than are other individuals. In addition, environmental and genetic factors influence PCP biotransformation in animals and humans.
The clinical effects of ketamine are akin to PCP and include analgesia, dissociation, hallucinations, and anesthesia. Agitation and cardiovascular and respiratory stimulation tend to be less than with PCP. Violence and unintended trauma may also result. Long-term chronic effects include dysphoria, impaired memory and cognition, apathy, and irritability, as well as distortion in the subjective experience of time. Chronic ketamine use has been associated with increased serum levels of brain-derived neurotrophic factor. Some anecdotal evidence supports the potential for tolerance and physical dependence with ketamine, but this needs further study.
Many years ago, it was reported that subanesthetic doses of ketamine produced antidepressant effects in depressed patients. This surprising finding was ignored by most researchers. There were subsequent isolated case reports that ketamine was antidepressant. It was a controlled clinical trial of ketamine for treatment-resistant major depression that first convincingly documented its therapeutic effectiveness. In the past 7 years, its effectiveness has been reproduced in controlled clinical trials. The most common side effects were dissociative symptoms at the end of the 40 minutes of ketamine infusion.
DXM has significant serotonergic properties, including increasing the synthesis and release of serotonin, as well as inhibiting the reuptake of serotonin from the synaptic cleft. DXM in clinical therapeutic doses produces relatively few side effects. These include body rash, itching, nausea, and vomiting and are most likely when DXM is combined with the other ingredients in cough preparations. Depending on dose, the drug can cause drowsiness, dizziness, altered vision, cardiovascular, and significant central nervous system effects that may resemble PCP intoxication. Euphoria and hallucinosis can occur within 15 to 30 minutes of ingestion of intoxicating doses, with peak effects experienced after roughly 2.5 hours. An intoxication state can persist in varying degrees for about 3 to 6 hours (called a “plateau”). DXO is a stronger NMDA receptor antagonist than DXM. DXO is relatively inactive at μ, κ, and δ opioid receptor sites; thus, it is essentially devoid of the more conventional opiate properties, although respiratory depression has been reported with massive ingestion.
DRUG–DRUG INTERACTIONS
Many centrally acting drugs can produce an additive pharmacodynamic interaction with all of the agents described herein. Therapeutic combinations of ketamine with benzodiazepines reduce its emergence delirium, depending on the pharmacokinetics of the drug involved. Clonidine and related alpha-adrenergic agonists such as dexmedetomidine have been given clinically with ketamine to reduce its dissociative effects.
DXM can induce a serotonin syndrome when taken with monoamine oxide inhibitors, selective serotonin reuptake inhibitors, or other serotonergically active substances. Genetic polymorphism in the biotransformation of DXM via CYP2D6 may enhance the toxicity of the former by inhibitors of the latter.
NEUROBIOLOGY
Recent imaging data show that ketamine-induced antagonism of the NMDA receptor is directly correlated with negative symptoms of schizophrenia, suggesting that dissociatives may induce negative symptoms via NMDA antagonism. It has also been hypothesized that dissociatives induce positive symptoms via enhancing glutamate release. NMDA antagonists block excitation of gamma-aminobutyric acid (GABA) interneurons, resulting in removal of GABAergic inhibition of cholinergic, serotonergic, and glutamatergic afferents to posterior retrosplenial cingulate cortex. This suggests a mechanism for triple excitotoxicity and the subsequent posterior cingulate pyramidal cell neurodegeneration.
Ketamine administration induces a rapid, focal decrease in ventromedial frontal cortex regional blood oxygenation level–dependent (BOLD) fMRI signals that strongly correlates with its dissociative effects. These results in significantly increased BOLD activity in midposterior cingulate, thalamus, and temporal cortical regions—increases correlated with Brief Psychiatric Rating Scale (BPRS) psychosis scores. Pretreatment with lamotrigine (a sodium channel blocker that decreases glutamate release) prevented many of the BOLD changes and increases in BPRS psychosis scores. Thus, dissociatives may induce positive symptoms via enhancing glutamate release. There may be other mechanisms at play that relate to the association of positive and negative symptomatology with dissociative exposure. While ketamine and dissociatives remain a promising area of research for depression, limitations remain (very few randomized controlled trials exist, an active placebo is typically lacking, long-term data are scant, and risks remain uncertain), and this approach remains experimental. Proposed mechanisms for the rapid antidepressant action of ketamine include ketamine-mediated blockade of NMDA receptors at rest, resulting in release of brain-derived neurotrophic factor (BDNF) via desuppression of its translation. Previous studies suggest increased BDNF function as one possible mechanism of action for traditional antidepressants.
The action of nitrous oxide as an NMDA antagonist is another major advance in our knowledge. Nitrous oxide is thought to stimulate the neuronal release of endogenous opioid peptide or dynorphins; the molecular aspects of this process are as yet unknown. Nitrous oxide may have an excitatory action on neurons via GABA-A receptor–mediated disinhibition.
Addiction Liability
Why these substances are reinforcing is difficult to understand, except in the context of individuals who wish to experience the feelings dissociation and sensory isolation that dissociatives provide. Dissociatives are self-administered by animals. Rhesus monkeys self-administer PCP, and social stimulation among monkeys in adjoining cages enhances reinforcing strength of PCP. Changes in dopaminergic or cAMP signal cascades induced by single or repeated PCP doses in mice likely play a role in the development of PCP-induced rewarding effects. Rodent and primate animal studies of DXM support reinforcement by DXO, akin to PCP. DXM is also strongly self-administered.
Toxicity/Adverse Effects
NMDA antagonists have remarkable effects on brain neurons, including toxicity, which can be reduced or prevented. Not all species of animals evidence these changes. The relationship of such neurotoxicity to humans who use or abuse of NMDA antagonists remains unclear. Such neurotoxic changes are reduced by pretreatment with benzodiazepines, further supporting the mechanism of NMDA antagonists blocking GABA interneuron activity, resulting in disinhibition of cholinergic, serotonergic, and glutamatergic afferents—resulting in excitotoxicity. Repeated high-dose administration of DXM during adolescence in rats may induce permanent deficits in cognitive function; increased expression of NMDA receptor AR 1 subunits in the prefrontal cortex and hippocampus may play a role in these DXM-induced memory deficits. This has troublesome implications in the setting of the increasing prevalence of DXM abuse in adolescents coincident with a remarkable period of brain growth during this age period. Human studies show impairments in working and episodic memory, among other cognitive problems, correlating with ketamine exposure levels. Human chronic ketamine users, compared to controls, show less bilateral dorsal prefrontal grey matter, with duration of use negatively correlating with grey matter volume and estimated total lifetime consumption of ketamine negatively correlating with grey matter volume in the left superior frontal gyrus. White matter abnormalities in bilateral frontal and left temporoparietal cortices have been found with anisotropy values negatively correlating with the total lifetime ketamine consumption (indicating pathology of white matter/axons in these brain regions). Studies using dissociative drug intoxication as a model of cognitive dysfunction in schizophrenia to develop new pharmacotherapies may also reveal solutions for the cognitive consequences of chronic dissociative use.
Intoxication and Overdose
Although a preliminary diagnosis of arylcyclohexylamine intoxication can be made on the basis of history, clinical signs, and symptoms, only a drug-positive blood or urine specimen will unequivocally establish it. Most clinically used drug screening panels include PCP, but not the other agents discussed herein; thus, a request may be required for specialized testing.
Psychotic manifestations of arylcyclohexylamine poisoning can be confused with catatonic schizophrenia, an acute toxic psychosis induced by other hallucinogens, and various acute organic brain syndromes. Arylcyclohexylamine intoxication can induce an organic brain syndrome, as well as cardiovascular and renal complications that are seldom, if ever, seen with other psychiatric syndromes. Lower urinary tract symptoms are common. Body image loss (especially numbness of the entire body), feelings of being in outer space, and (less commonly) visual hallucinations suggest arylcyclohexylamine abuse, as opposed to classic hallucinogens such as LSD-25 or related agents. DXM is associated with psychosis at doses >300 to 600 mg or in fast metabolizers of DXO. Psychosis may occur at lower doses when DXM is combined with other drugs such as alcohol. Folate deficiency may also be associated with DXM abuse. DXM abuse may result in brain damage, seizure, loss of consciousness, irregular heartbeat, and death. Respiratory depression from DXM may be reversed with naloxone.
CONCLUSIONS AND FUTURE RESEARCH
The evaluation of this drug class for its neuroprotective qualities may prove increasingly fruitful as the world population increases in average life span and the need for such agents increases as well. The rapid antidepressant qualities of ketamine infusion is a recent discovery already resulting in increased research, with interest in extending this research to dextromethorphan. Possible future expanded clinical use of ketamine as an antidepressant raises concern for future ketamine/dissociative abuse from a novel group of users—depressed individuals. Finally, the increasing prevalence and significance of DXM abuse are alarming, particularly for the concentrated involvement of young people who appear unaware of its potential toxicities. Preliminary data suggest neuronal toxicity and resultant neuropsychologic impairment may result from DXM abuse, particularly in the adolescent, developing brain. Public policy may be increasingly directed toward controlled access to DXM versus its current over-the-counter (or behind the counter) availability.
KEY POINTS
1. Dissociatives are a unique pharmacologic class of drugs of abuse, with NMDA antagonism as their shared pharmacodynamics effect.
2. Phencyclidine, ketamine, and dextromethorphan are the drugs most commonly abused in this class; however, nitrous oxide also shares similar pharmacodynamics.
3. Only dextromethorphan is available over-the-counter and typically has to be abused at doses well outside those directed to achieve a dissociative state.
4. All dissociative drugs above have significant medical and psychiatric complications when abused.
5. Currently, there are no pharmacotherapies or psychotherapies FDA approved to treat substance use disorders relating to these drugs.
REVIEW QUESTIONS
1. Choose all that apply. The active isomer of ketamine now being proposed for the treatment of depression is:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
