Phencyclidine (PCP)-Related Psychiatric Disorders

Phencyclidine (PCP) was originally developed as an anesthetic agent and marketed for a time as Sernylan; however, the agitation that some people developed following phencyclidine-induced anesthesia quickly led to its abandonment for this indication. Unfortunately, it then became a drug of abuse for a small but significant population, mostly younger in age and of minority ethnicity. Other chemical names for phencyclidine are: 1-(phenylcyclidine) piperidine or phenyl cyclohexyl piperidine, either of which may have given rise to the "PCP" acronym. Phencyclidine was used for a time as an animal anesthetic, but even this use has ceased in the United States. It is no longer manufactured in the United States for any clinical use, although it continues to be investigated for possible beneficial effects.

PCP has been studied in animal models of schizophrenia. More recently, PCP-like compounds have been investigated for use in treating brain ischemia. PCP is known to produce a syndrome that mimics schizophrenia in humans with no prior psychiatric illness. PCP may also exacerbate psychotic symptoms in individuals who have schizophrenia or other psychotic illnesses. PCP is an N-methyl-D-aspartate (NMDA) antagonist; thus, it blocks the action of glutamate and aspartate, excitatory amino acid CNS neurotransmitters. PCP is also highly anticholinergic in nature.

PCP can be smoked, ingested orally, snorted intranasally, or injected intravenously. Today, the usual route of administration is smoking, often as an additive to marijuana cigarettes. Because it is inexpensive to produce, PCP is sometimes palmed off on unsuspecting street drug buyers as "THC" (delta-9-tetrahydrocannabinol, the active ingredient in marijuana); lysergic acid diethylamide (LSD); or as some other, more exotic "designer" hallucinogen.

PCP first came to the attention of ED physicians and psychiatric ED physicians in California and New York during the 1960s. At that time, it was ingested in pill form (the "PeaCePill"). During the early 1970s, PCP became available as a white powder, which could also be put into a solution and then insufflated, ingested by mouth, or smoked on tobacco or marijuana or even on mint leaves, parsley, or other leafy materials, usually to cool the otherwise hot and orally irritating smoke.

The creation of this powdered form may have led to its increased use from the early to late 1970s. The percentage for high school seniors who had "ever used" PCP was found to be 12.8% in 1979. Its use has waxed and waned since but has never again attained double digit popularity. A slight increase in use was noted during the early 1980s, followed by another decline, with another small increase in use among high-school seniors seen from 1996–2002.

The ED visits associated with PCP use have been tracked through the Drug Abuse Warning Network (DAWN), a public health surveillance system that monitors drug-related ED visits in the United States. In the 2013 DAWN report, the number of PCP-related ED visits increased more than 400% between 2005 and 2011 (from 14,825 to 75,538 visits), but the number of visits doubled between 2009 and 2011 (from 36,719 to 75,538). ^[1] The largest increase in PCP-related ED visits was among patients aged 25 to 34 years, with an increase of more than 500% from 2005 to 2011 (from 5,556 to 34,329 visits). ^[1] In 2011, 69% of PCP-related ED visits were made by males, and in 48% of PCP-related ED visits, other illicit drugs, such as marijuana, cocaine, and heroin, were involved. ^[1]

Historically, PCP has gone by many street names, including angel dust, crystal, hog, embalming fluid, ozone, and rocket fuel. In combination with marijuana, street names such as krystal joint (KJ), mintweed, supergrass, and killer weed have been used. When PCP is combined with cocaine, the resultant concoction is sometimes called space base or tragic magic.

In recent times, PCP analog drugs such as methoxetamine have come to the attention of clinicians. Methoxetamine is a synthetic analog of PCP and acts in a similar manner through the NMDA receptor. ^[2]

Case Vignette

Jay, a 20-year-old man, is brought to the emergency department of an inner-city general hospital by the police after he is taken into custody for fighting and then resisting arrest. The arresting officer says that he believes Jay may be hurt, perhaps with a fracture of his right arm, but he has never before seen anyone so violent. The patient is extraordinarily agitated and has to be placed in leather restraints immediately upon being brought to the ED. He does not complain of pain and seems to deny having any when asked. With considerable difficulty, the triage nurse is able to take some of his vital signs. His pulse is elevated at 128 beats per minute, and his blood pressure is also high at 150/98.

The ED physician tries to examine Jay, but Jay is yelling and threatening so continuously that chest and abdominal exams are impossible to perform. The doctor does note pronounced nystagmus when Jay looks up at him and also notes that deep tendon reflexes are quite brisk in those locations that can be checked.

Because of the agitation and screaming, the psychiatric resident on call is asked to see the patient as quickly as possible. She arrives in the ED some 20 minutes later. At that point, the patient is sobbing uncontrollably and babbling about of his fear of suicide. Trying without success to perform at least a partial cognitive examination, the resident asks her faculty attending to come to the ED to see Jay. By the time the attending arrives, the patient is talking calmly and, when asked about drug use, admits to smoking some “really great pot” earlier that day. Blood and urine samples are quickly ordered, but by the time the phlebotomy team arrives, the patient is trying to remove all of his clothing even while in restraints and is once again cursing and threatening loudly whether anyone is in the room with him or not.

Is this a case of someone with schizophrenia, a person with an exceptionally rapid cycling bipolar disorder, a picture of hyperthyroidism presenting as thyroid storm, or just a very bad reaction to marijuana?

When a urine drug screen is finally obtained on the inpatient unit in a moment of relative calm, cannabis is present, but so is PCP. Later that evening, radiography also confirms a right wrist fracture about which the patient has yet to complain. Unbeknownst to Jay, his marijuana had been laced with PCP by his drug dealer to "give it a bigger kick."

"Jay" is a fictional name, but this case vignette is a compilation of dozens of ED encounters by the lead author with young men and women having a psychotic reaction to PCP.

PCP is a sympathomimetic dissociative anesthetic. The term "dissociative" is used to describe a state wherein a person feels that his or her mind is separated or "dissociated" from the body. PCP is often classified with the hallucinogens; however, because it can also act a stimulant or even a CNS depressant, it is usually classified separately from all other street drugs. Chemically, it is an arylcycloalkylamine. To this point at least 20 analogues and metabolites of PCP have been identified within this chemical family.

The current understanding is that PCP acts as a noncompetitive antagonist at the NMDA excitatory amino acid receptor channel complex. The molecule binds to a site within this channel system, thereby physically preventing sodium, calcium, and potassium ions from moving across the cell membrane. This prevention of ion movement results in decreased neuronal firing; however, PCP cannot bind within an ion channel unless it is initially opened by glutamate, NMDA, or an NMDA agonist. PCP is absorbed rapidly whether it is smoked, ingested orally, inhaled intranasally, or injected into the veins. PCP-hydroxylated metabolites are excreted mainly in the urine.

PCP may cause neurotoxicity in humans; however, the majority of scientific evidence for CNS damage to date has been found in animal model and preclinical studies. Neurotoxicity may be due to dioxin contaminants rather than to the phencyclidine molecule directly.

Olney et al found vacuoles in areas comprised largely of glutaminergic pyramidal neurons in the posterior cingulate and retrosplenial cortex in rats after PCP ingestion. Reports have also described immunotoxicity in mice (reduced humoral immunity and impaired T-cell cytolytic activity), cattle (thymic hypoplasia), and young pigs (decreased total leucocyte counts, reduced gamma globulins, and suppressed IgG). Pregnant mice show increased embryonic mortality when exposed to PCP, but no increase in birth defects; thus, PCP can be said to be "fetotoxic" but not "teratogenic" in mice. The doses of PCP investigated were often quite high; how this evidence might relate to people using lower doses is not known. Interestingly, Olney's results were found using relatively low doses.

Evidence for behavioral toxicity in the human population is better documented, and numerous deaths from suicide, homicide, and accidents related to bizarre behavior have been reported in those intoxicated with PCP. ^[3] Primary intoxication lasts from 4-6 hours, but behavioral abnormalities may last for as long as several weeks. This lingering presence of behavioral effects is thought to be due to storage of PCP within fatty tissues of the body resulting from PCP's lipophilic chemical nature.

Some have believed that the behavioral problems associated with PCP ingestion that had been reported in the 1970s were exaggerated. However, violence and other problematic behaviors have been observed in multiple patients and in various EDs and psychiatric units across the country as a result of PCP intoxication both historically and in recent case studies. ^[3]

The behavioral and physiologic effects depend on dose, with lower blood levels in the range of 20-30 ng/mL usually causing sedation, irritability, hyperactivity, impaired attention, and mood elevation. As serum levels rise above 30 ng/mL, ataxia, psychosis, analgesia, paresthesia, and mood lability may occur. The range in which paranoia and aggressive behaviors are most likely to occur is 30-100 ng/mL. When serum levels are higher than 100 ng/mL, patients become stuporous, hyper-reflexive, and hypertensive, and, ultimately, may experience seizures, coma, and death. Note that serum levels with PCP are relatively unreliable, so treatment-related decisions always should be based on any given specific patient's clinical status. The clinical findings may vary greatly from patient to patient as a result of differences in dosing and metabolism. ^[4]

In terms of metabolism, PCP has a large volume of distribution due to its lipid solubility. This is the reason for the relative lack of correlation between serum or urine values and clinical manifestations. PCP is metabolized primarily in the liver, with renal elimination of the resulting hydroxylase metabolites. Consequently, acidification of the urine has little effect in facilitating detoxification. Indeed, alkalinization is the recommended treatment for the myoglobinuria that can accompany PCP intoxication.

Frequency

United States

Abuse of PCP began in the United States in the 1960s and peaked in the late 1970s. In 1978, the National Annual High School Senior and Young Adult Survey found that 12.8% of high school seniors had used PCP. Actually, more may have used PCP without realizing it because a 1975 survey showed that 91% of the street substances sold as "THC," "LSD," or some other hallucinogen such as mescaline actually contained PCP instead of, or in addition to, other ingredients. Overall, abuse of this substance has fluctuated in the United States, and a 2007 survey found that only 2.1% of high school seniors had ever knowingly used PCP. However, according to data from the 2005–2011 Drug Abuse Warning Network (DAWN), the number of PCP-related ED visits increased more than 400% between 2005 and 2011 (from 14,825 to 75,538 visits), in which the number of visits doubled between 2009 and 2011 (from 36,719 to 75,538 visits). ^[1]  A 2013 survey suggested that use of PCP has reemerged in recent years. ^[4]

In the United States, quite a lot of regional variability in the abuse of PCP exists, with some of the highest areas of use being Washington, D.C. Newark, New Jersey; Philadelphia, Pennsylvania; Baltimore, Maryland; and Dallas, Texas. The reasons for such regionalization remain unclear.

International

International use of this substance is also regional. The use of all drugs in Canada, including PCP, is similar to use in the United States, except that the relative percentages are usually smaller there. Mexico has an unusually large number of available indigenous hallucinogens, such as peyote cacti, Psilocybe mushrooms, and psychedelic morning glory seeds (ololiuqui); therefore, artificial hallucinogens are not as much in demand there. In the rest of the world, various preferred substances of abuse are regionally determined. PCP use has never been as much of a problem globally as it was in the United States in the 1960s and 1970s. In recent years, there have been reports of the usage of PCP analogs, such as 3-methoxy-phencyclidine. ^[5] Another case report in Scotland implicated the abuse of analogs such as 3-methoxy-phencyclidine as causational of extreme violence in patients with no prior violent history. ^[3]

Mortality/Morbidity

Death from PCP is usually caused by one of the following: overdose (serum levels >100 ng/mL), suicide while under the influence of the drug, or accidental death due to bizarre behavior during intoxication or withdrawal. Those intoxicated with PCP also have been reported to be more likely to be violent, up to and including the commission of homicides.

Nonlethal physical injuries are an additional possible complication because PCP has anesthetic properties and greatly decreases pain perception such that individuals under its influence may not realize how badly injured they are, and thus may greatly aggravate what were originally more minor physical injuries.

Race

PCP seems to have been abused more often by members of inner-city minority groups than by members of the middle class. The reasons for this are not clear.

Sex

In terms of sexual distribution, PCP is more likely to be knowingly abused by males, but this is true of many substances of abuse.

Age

PCP is a drug primarily abused by adolescents and young adults. Older users tend to have started using when they were young.

A clinical study of approximately 200 emergency room patients with apparent exposure to PCP suggested that an average length of stay in the emergency department for an acute PCP intoxication is a couple of hours. In this study, approximately 82% of patients were discharged home and about 8% required inpatient hospital admission. Althought visit lengths can be brief, evidence suggests that such visits can be very resource intensive. ^[4]

Because 62% of people abusing PCP are aged 20-29 years, most people clearly stop using PCP once they have passed young adulthood. Thus, for most people, the long-term prognosis probably is good.