PCP Toxicity 

Phenylcyclohexyl piperidine (PCP), also known as phencyclidine, was originally discovered in 1926; however, PCP was not introduced as a dissociative general anesthetic until the 1950s. Because of severe adverse effects, such as postoperative psychoses and dysphoria, its clinical use in humans was discontinued in 1965, although it remained widely used in veterinary medicine. Ketamine, a dissociative anesthetic commonly used in pediatrics, and MK-801/Dizocilpine, a potent N-methyl-D-aspartate (NMDA) receptor antagonist commonly used for research purposes, are structural analogues of PCP that possess varying degrees of adverse clinical effects.

PCP was first introduced as a street drug in the late 1960s; despite gaining a reputation as a drug that could cause unpleasant side effects, its use grew to epidemic proportions during the 1970s for its mind-altering effects. Many PCP users state that they have feelings of strength, power, and invulnerability while intoxicated with PCP. Some also report a numbing effect that may lead to anger, rage, selective amnesia of unpleasant memories, and acute psychoses. In 1978, PCP was transferred from Schedule III to Schedule II under the Federal Controlled Substance Act.

2-(2-chlorophenyl)-2-(methylamino)-cyclohexanone (Ketamine) is a tranquilizer, analgesic, and dissociative anesthetic commonly used in pediatrics and surgery for procedural sedations, as well as in veterinary medicine. It was developed by Parke-Davis in 1962 to replace PCP. The drug was initially introduced as a battlefield anesthetic for American soldiers during the Vietnam War and is still widely used in humans. Its beneficial effect is the “dissociation” of brain stem functions from higher brain areas, which alters the sensation of pain and other stimuli during medical procedures, and produces amnesia to the event. In addition, patients receiving ketamine maintain spontaneous breathing and relatively stable cardiovascular functions.

Since 1965, the recreational use of ketamine has increased and it became very popular during the 1990s among young adults at dance clubs and raves in combination with other so-called “club drugs” (eg, gamma-hydroxybutyric acid, lysergic acid diethylamide [LSD], ecstasy). Because of its increased illicit use in the United States, ketamine was placed in Schedule III as a non-narcotic controlled substance in 1999.^{[1, 2]}

Drug forms

Because PCP is inexpensive and relatively easy to manufacture, it is often misrepresented as other hallucinogenic substances, such as LSD, tetrahydrocannabinol (THC), mescaline, psilocybin, cocaine, and amphetamine. PCP is distributed in widely varying purities and forms (eg, powder, liquid, tablets, leaf mixtures, rock crystal) (see image below).

Many drug users are unknowingly exposed to PCP because it is often used as an adulterant in marijuana, LSD, and methamphetamine to save on production costs of those other drugs. PCP can be taken in pill form, snorted as a powder, smoked, or injected intravenously or subcutaneously. In certain forms, PCP can inadvertently be absorbed by means of contact with the skin.

PCP that is sold on the street is known by names such as angel dust, ozone, wack, rocket fuel, dust, elephant tranquilizer, hog, ethyl-phenylcyclohexylamine (PCE), thienyl-cyclohexylpiperidine (TCP), porker, zoot, embalming fluid, love boat, crystal, horse tranquilizer, tic-tac, peace pill, sherms, purple rain, zombie, worm, live ones, little ones, and boat. When PCP is added to marijuana, the combination is sometimes sold as crystal super grass, killer joints, super weed, killer weed, krystal joint (KJ), and green leaves. When PCP is dusted on marijuana or mint leaves and soaked in embalming fluid, the combination is known as illy, wet, hydro, or fry. The various street names for PCP reflect its unpredictable and volatile effects.

Ketamine sold on the street is known by terms such as super acid, “K”, “special k,” vitamin K, cat Valium, cat tranquilizer, horse tranquilizer, ket, kit-kat, vetamine, K wire, KFC, keezy, kenny, ketanest, kenfitamine, ketaset, ketalar, kez, kitty, kustard, regretamine, wibble, forgetamine, triple K, and wonky. Ketamine is odorless and tasteless and is available as a clear liquid, or a white/near-white crystalline powder. The liquid form is injected, mixed into drinks, or added to materials that can be smoked as with PCP. The powdered form is mostly snorted, compressed into pills, or used for intravenous or intramuscular injection when dissolved. Because of the induction of amnesia the drug has reportedly been used in sexual assaults referred to as “drug rape” or “date rape."^[1]

Manufacture

Because PCP is relatively inexpensive to synthesize, it is an attractive drug for dealers. Its recipe can be found easily on the Internet, and it can be manufactured illegally in crude, underground laboratories. Most nonpharmaceutical PCP in the United States is manufactured in the Southern California area. Because of its continued use in veterinary medicine, pharmaceutical-grade formulations can be obtained through diversion.

Ketamine, unlike PCP, is relatively difficult to manufacture. For this reason, most illicit ketamine comes from diversion of pharmaceutical products destined for human or veterinary applications. According to reports from the US Drug Enforcement Administration (DEA), the major source of illegal ketamine in the United States is diverted from pharmacies in Mexico.

PCP is a 3-ringed molecule that is structurally similar to ketamine. However, PCP differs from ketamine in that it is longer acting, is more likely to cause seizures, and tends to cause more emergent confusion and delirium.

PCP is a noncompetitive antagonist at the glutamate NMDA receptor and binds to sites located in the cortex and limbic structures of the brain. This mechanism is believed to be responsible for most of the dissociative effects of PCP. PCP has been shown to effect biogenic amine (eg, dopamine, norepinephrine, serotonin) release and reuptake in a dose-dependent manner. These actions may account for the sympathomimetic effects after PCP ingestion. In addition, PCP may indirectly modulate cholinergic and GABAergic outflow in the CNS.

Ketamine’s molecular structure and mechanism of action are similar to those of PCP. It acts as a noncompetitive antagonist on the NMDA receptor. The drug's secondary interactions with muscarinic, nicotinic, and cholinergic receptors inhibit the neuronal uptake of norepinephrine, dopamine, and serotonin. At high doses, ketamine binds to mu and sigma opioid receptors, which are thought to be responsible for the loss of consciousness under controlled anesthesia.^[2]

Pharmacokinetics

PCP is a weak base with a pKa of 8.6-9.4. In its nonionized or free base form, PCP is lipid soluble and easily diffuses across membranes. However, in an acidic environment, such as the stomach, PCP forms an ionized salt and becomes functionally trapped, preventing it from freely diffusing across the gastric mucosa. PCP that is absorbed from the alkaline duodenum can be secreted into the acidic stomach, creating a gastroenteric circulation. This phenomenon may explain the prolonged and wavering course of PCP intoxication.

PCP has a large volume of distribution (6.2 L/kg). Although the initial dose is distributed quickly in the brain, it is redistributed to other lipid-containing organs and can remobilize for hours, days, or possibly even weeks.^[3] After entering the brain and reaching the acidic environment of the CSF, PCP becomes ionized. This ion trapping can produce levels of PCP in the CSF that are 6-9 times higher than those in plasma. PCP is predominantly metabolized in the liver to form glucuronide metabolites that are then excreted in the urine. A small amount of PCP is excreted unchanged in the urine.

Ketamine acts similarly to, but is less potent than PCP. The drug is highly bioavailable after intravenous or intramuscular injection with a volume of distribution of about 3-5 L/kg. Oral doses are less well absorbed and undergo extensive first-pass metabolism in the liver. The elimination phase lasts 45-60 minutes but can be as long as 4-6 hours in combination with other cerebral depressants. The half-life of ketamine is 10-15 minutes; however, 24-48 hours may be required before the user returns completely to baseline. Similar to PCP, ketamine is redistributed from the CNS and undergoes hepatic transformation by the cytochrome P450 system into its active metabolite norketamine. Norketamine has about one third of the anesthetic potency of ketamine with a half-life of 2.5 hours. Ketamine metabolites are mainly excreted in the urine.^[2]

Frequency

United States

Epidemiologic data indicate that PCP abuse is not widespread and that its abuse is not prevalent in adolescents. The National Institute on Drug Abuse (NIDA) Monitoring the Future Study revealed that the overall use of PCP by high-school seniors has decreased since 1979, when 7% of seniors used PCP.^[4] In 2006, 0.7% of high-school seniors used PCP at least once during the year before the study, with little change thereafter. Recently, PCP has retained the lowest lifetime prevalence and highest noncontinuation rates among high-school seniors compared with other hallucinogenic drugs (eg, LSD, ecstasy).

The Drug Abuse Warning Network (DAWN) estimates that 7,535 emergency department (ED) visits were related to PCP in 2005, representing approximately 2.5 ED visits per 100,000 population.^[5] PCP use was found to be highest in black adults aged 21-24 years.

The use of ketamine among high-school seniors has declined in recent years, and the 2006 prevalence in this group was 1.4%. Ketamine use tends to be more frequent among high-school seniors of lower socioeconomic status. According to the 2002 estimates from DAWN, “club drugs” including ketamine were involved in about 8,100 ED visits. From 1994-1999, ketamine-associated ED visits increased from 19 per year to 400 per year but have remained relatively unchanged since that point. Approximately 80% of ketamine-related ED visits involved consumption of multiple drugs in addition to ketamine, mostly other “club drugs,” or in combination with alcohol, marijuana, cocaine, and heroine. Ketamine use was found to be highest among males younger than 26 years.^{[4, 6]}

Mortality/Morbidity

Doses of PCP exceeding 200 mg have resulted in death. The 2002 Mortality Data report published by DAWN listed Washington, DC, Philadelphia, and Baltimore among those US cities with highest PCP-related mortality rates (27 PCP related deaths were reported in Washington, DC, in 2002).^[7] A survey from 1981-1986 in metropolitan Saint Louis, Missouri, reported that 81 homicides, 13 suicides, 6 unintentional deaths, and 4 deaths of unknown causes were related to PCP intoxication.^[8]

The major cause of death with PCP intoxication is behavioral disturbances that lead to self-destructive behaviors and impaired judgment, including self-inflicted injuries, injuries resulting from exceptional physical exertion, or injuries sustained from resisting physical restraints. Deaths from the direct effects of PCP intoxication are related to hyperthermia, renal failure, disseminated intravascular coagulation (DIC), and rhabdomyolysis. In a study of 1000 patients with phencyclidine intoxication, rhabdomyolysis occurred in 25 patients and 10 patients developed acute renal failure.^{[9, 10]}

Despite reports of increased recreational use, only a few fatalities are attributed to ketamine poisoning alone or in combination with other drugs. Deaths related to ketamine abuse are mainly caused indirectly and related to falls, traffic injuries, drowning, and burns due to impaired perception, muscle weakness and ataxia. However, death through choking on vomit has been reported.^[11]