Ketamine and Phencyclidine

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

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.

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

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.