Ketamine and phencyclidine are chemically related to each other and have psychotropic effects similar to those of other prototypical hallucinogens such as lysergic acid diethylamide. Phencyclidine was developed first as a dissociative anesthetic for animals and humans, but seizures, recreational abuse, and unpredictable effects have prevented its therapeutic use. Ketamine was developed after phencyclidine and has similar properties, although it is still used therapeutically as an anesthetic and analgesic in humans and animals and is currently being studied as a treatment for depression and suicidal ideation. Most ketamine used illicitly is diverted from veterinary supplies but is also relatively easy to synthesize. Both drugs have been abused since the 1970s and became popular again in the 2000s, especially among young adults who are active in the club scene.
Mechanism of Action
Ketamine and phencyclidine are arylcyclohexylamines, which are dissociative anesthetics that produce perceptual distortions similar to those of hallucinogens, as well as other effects, so they are often classified as hallucinogens. Ketamine is a derivative of phencyclidine that is less potent and shorter-acting and is still used therapeutically in medical settings as an anesthetic and analgesic in humans, especially in countries where opioids are not available. Ketamine and phencyclidine selectively reduce the excitatory actions of glutamate on central nervous system neurons mediated by the N -methyl- d -aspartate (NMDA) receptor complex. These receptors mediate ion flux through channels permeable to sodium, potassium, and calcium, and are involved in synaptic transmission, long-term potentiation, and neuron plasticity. Pharmaco–magnetic resonance imaging (MRI) has confirmed that the subjective effects of ketamine are mediated by enhanced glutamate release. In addition, phencyclidine affects mu opioid receptors, blocks dopamine uptake, and inhibits serotonin uptake. Phencyclidine binds to specific receptors in the liver, kidney, lung, heart, and brain. However, the exact mechanism of the effects of ketamine and phencyclidine has not been determined. Metabolism of ketamine and phencyclidine occurs in the liver by oxidation, hydroxylation, and then conjugation with glucuronic acid.
Routes of Administration
Ketamine and phencyclidine can be taken orally, inhaled intranasally, smoked, or injected intramuscularly, subcutaneously, or intravenously. Ketamine is obtained primarily in powder form and taken by intranasal insufflation (“snorting”) of lines, which has a more rapid onset but a shorter duration of effects than when taken orally. Ketamine injection involves particular paraphernalia and high-risk practices. Intramuscular injection is perceived as easier and less threatening than intravenous injection.
Phencyclidine is taken as a tablet (“PeaCe Pill,” or “PCP”), powder (“angel dust”), or liquid (“whack”). It is smoked alone or when added to tobacco cigarettes or marijuana joints, a combination known as “fry.” The onset of effects when smoked is almost immediate, similar to intravenous administration, and is much more rapid than when taken orally (onset takes more than an hour).
Ketamine was developed in the 1960s as a surgical anesthetic. Recreational use began in the 1970s on the West Coast of the United States, but it was not registered as a scheduled drug in the United States until 1997 or until 2006 in the United Kingdom. The prevalence of ketamine use appears to be stabilizing in the United States but is rising in Europe and Asia. There are many different street names for ketamine ( Table 32.1 ). Nearly all ketamine users are polysubstance users, with 98% using drugs from three or more drug classes, such as inhalants and heroin.
|Cat valium||Angel dust|
|Vitamin K||PeaCe PillPurple HazeWhack|
The National Institute on Drug Abuse (NIDA) has identified six drugs as club drugs, including ketamine. Club drugs are licit and illicit drugs from different classes that are used primarily by young adults in bars, clubs, concerts, and dance parties (or “raves”). These substances are used illicitly in those settings due to the perception that they enhance the sensory experience at dance parties where strobe lights, glow sticks, and techno music (wordless music with a driving beat) are part of the overall event. More than 40% of individuals who use club drugs have tried ketamine. Regular ketamine users are older (in their 20s as opposed to teens), employed, and better educated compared with most other club drug users. Although ketamine use is very common among club goers—up to 66%—there is a very low prevalence of ketamine use among young people in the general population.
Separate from clubs and raves, ketamine is also frequently used in other settings, such as at home or at a friend’s house. In addition to club goers, it is used by young injection drug users, health care workers, and men who have sex with men.
Phencyclidine was first synthesized in the 1950s as a dissociative anesthetic for therapeutic use and originally described as a drug of abuse in the 1960s. Phencyclidine at various times has achieved popularity as a street drug with many different street names (see Table 32.1 ), and is frequently sold in mixtures with other drugs. Its use waxes and wanes because of its unpredictable effects. Its use increased in the 1970s and peaked in the 1980s but has experienced a resurgence in popularity since the late 1990s. Although not classified as a club drug by NIDA, phencyclidine is used by young adults in settings similar to those of other club drugs.
Trends in the popularity of specific drugs of abuse tend to be cyclic. Relatively large numbers of new users will experiment with a given drug or develop a pattern of recurrent use, often in combination with other substances. With more users, information about undesirable effects spreads among users, or public health concern prompts a response with dissemination of information about abuse and problems. Then the prevalence of abuse may subside for a while. Phencyclidine has gone through previous cycles of popularity because it is relatively easy to manufacture in clandestine laboratories. However, unpleasant effects of repeated use (including propensity to violence and psychotic symptoms, as well as a high frequency of “bad trips”) result in a drop in popularity. Phencyclidine use is on the rise again, along with the use of ketamine as part of the club drug scene.
Phencyclidine is often used in combination with other substances, primarily alcohol. It may be added to tobacco cigarettes or marijuana joints, a combination known as “fry.” When added to tobacco, it is also called “Shermans” because it was first added to Sherman cigarettes, which are a private brand.
Diagnostic and Statistical Manual of Mental Disorders Criteria
The criteria in the Diagnostic and Statistical Manual of Mental Disorders , Fifth Edition (DSM-5) 3 for use disorders for ketamine and phencyclidine do not differ significantly from the general criteria for substance use disorder ( Table 32.2 ). Ketamine use disorder falls under the heading of phencyclidine-like substances in the DSM-5 and does not have a separate diagnosis or criteria set. A specific withdrawal syndrome has not been identified for these drugs, which is also the case for other hallucinogens. Therefore, criteria specific to withdrawal are not utilized to determine a diagnosis of use disorder for either ketamine or phencyclidine. There are no other unique criteria for ketamine or phencyclidine in the DSM-5.
|A pattern of use leading to clinically significant impairment or distress, manifested by at least 2 of the following, occurring within a 12-month period:||Specify current severity:|
Tolerance and Withdrawal
Tolerance develops rapidly to the desired effects, resulting in reduced length of the subjective experience and requiring an increase in dose to maintain the expected effects. Users escalate the amount used to achieve the full hallucinogenic experience, up to seven times the original amount. Use of higher recreational doses can result in more adverse effects, especially physiological side effects. Use of very high doses can result in onset of full anesthetic effects, which may result in an overdose situation for a recreational user. Continued use of ketamine or phencyclidine, despite experiencing these consequences, constitutes addiction.
A definitive physiological withdrawal syndrome does not appear to develop after stopping use of ketamine or phencyclidine. Phencyclidine users who smoked at least weekly and acknowledge psychological dependence reported no withdrawal symptoms upon stopping.
Initial use of ketamine is based primarily on a desire for experimentation and openness to new experiences, and secondarily for pleasure. Appealing effects described by users include visual hallucinations and out-of-body experiences; undesirable effects include memory loss and decreased sociability. General central nervous system depressant effects include poor concentration and poor recollection similar to that associated with alcohol intoxication, which is not unexpected for an anesthetic drug.
Ketamine effects include profound changes in consciousness and psychotomimetic effects such as changes in body image (feeling that the body is made of wood, plastic, or rubber) and possible feelings of spiritual separation from the body, including out-of-body experiences. At low doses, users describe mild dissociative effects, distortion of time and space, and hallucinations. At large doses, users experience severe dissociation with intense detachment such that their perceptions seem to be located deep within their consciousness and reality is far off in the distance; this is called the “K-hole.”
The analgesic and dissociative effects may result in injury or even death in users. The number of ketamine-related emergency department visits increased more than 500 percent between 2005 and 2011 (from 303 to 1550 visits). Because of its lower potency and shorter duration of action, ketamine has less severe psychiatric issues than phencyclidine, which may be why there are far fewer emergency department visits for ketamine than for phencyclidine. Cognitive impairments can occur even when a user is drug-free, and frequent users have greater impairment than infrequent users when drug-free.
Several clinical trials have evaluated ketamine as a treatment for major depression that has been resistant to other medications and electroconvulsive therapy, and for depression associated with bipolar disorder. Ketamine has been administered as an intravenous infusion in a medical setting with monitoring for 24 hours after. Response is rapid, with improvement rates of 25%–85% at 24 hours and 14%–70% at 72 hours, and side effects have been mild. Intranasal esketamine was recently approved for treatment-resistant depression. Phencyclidine has not shown such robust antidepressant effects.
At low doses, ketamine causes stimulant effects with a temporary increase in blood pressure and heart rate, as well as diplopia and nystagmus. Tachycardia and hypertension are the most common physical findings after illicit use. Other findings of intoxication include pupil dilation and muscle rigidity. Rhabdomyolysis may result from muscle rigidity combined with exertion in severe agitation. Very large doses result in deep anesthesia with coma and respiratory depression. Other physiologic effects of ketamine include severe epigastric pain known as “K-cramps,” which may be due to smooth muscle relaxation in the biliary tract.
Management of ketamine intoxication is primarily supportive, and adverse effects typically resolve over several hours for mild to moderate intoxication. A thorough history and physical examination, along with toxicological screening for the presence of ketamine, establish the diagnosis. A quiet environment without bright light can help reduce the agitation and psychotic behaviors that are due to overstimulation.
Additional supportive care may be required for severe intoxication or overdose. Benzodiazepines such as lorazepam are helpful for more severe agitation, anxiety, and/or muscle rigidity.
A reason for initial use of phencyclidine has been described as a desire for enhancement of the user’s everyday life. Reasons for continuation of use include feelings of strength, power, and invulnerability, as well as psychic numbing to self-medicate anger and dysphoric symptoms. The phencyclidine experience is regarded as pleasant only half the time and aversive the other half, but some users report that this unpredictability of effects is an attractive feature.
Phencyclidine produces brief dissociative psychotic reactions, similar to schizophrenic psychoses. These reactions are characterized by changes in body image similar to those of ketamine as described in the preceding text. Moderate phencyclidine intake may lead to a catatonic-like presentation with the individual staring blankly and not responding to stimuli; the eyes remain open, even when the individual is in a comatose state. At higher doses, users have great difficulty differentiating between themselves and their surroundings. Some users have religious experiences while intoxicated, such as feelings of meeting God or knowledge of their own impending death.
A dissociative phenomenon occurs occasionally, with phencyclidine abusers exhibiting dangerous or violent behaviors. The individual also may appear psychotic. Previous psychiatric history is associated with a higher likelihood for assaultive behavior from phencyclidine use. Levels of consciousness may fluctuate rapidly while the individual is recovering from the intoxication. The effects of phencyclidine can last for several days, since it is one of the longest-acting drugs of abuse.
The number of phencyclidine-related emergency department visits increased by more than 400% between 2005 and 2011 (from 14,825 to 75,538 visits), especially among young adults 25 to 34 years of age, and 69% of visits were by males; nearly half of visits were for phencyclidine in combination with other illicit drugs. There is significant geographical variation among emergency department visits for phencyclidine use, with visits increasing in cities such as New York and Chicago, but remaining stable in other major metropolitan areas of the United States.
In low-dose intoxication, the individual presents with nystagmus, confusion, ataxia, and sensory impairment. This is the only drug of abuse that causes a characteristic vertical nystagmus (it can also cause horizontal or rotatory nystagmus), which helps to identify it as the cause when an individual presents with intoxication by an unknown drug. The DSM-5 provides a specific criteria set for phencyclidine intoxication based primarily on physiological signs and behavioral changes ( Table 32.3 ). Three stages of phencyclidine intoxication have been described, and individuals may fluctuate between the first two stages for several hours; the third stage occurs when individuals take high doses ( Table 32.4 ).