Practice Essentials
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.
PCP was first introduced as a street drug in the late 1960s; despite gaining notoriety for unpleasant adverse effects, its use grew to epidemic proportions during the 1970s for its mind-altering properties. 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.
PCP is a potent N-methyl-D-aspartate (NMDA) receptor antagonist. Other NMDA receptor blockers that share similar chemical structures and possess varying degrees of adverse clinical effects are ketamine and MK-801 (dizocilpine), which is commonly used for research purposes. Ketamine is a tranquilizer, analgesic, and dissociative anesthetic commonly used for anesthesia induction (and off-label for procedural sedation/analgesia in children and for resistant depression), as well as in veterinary medicine.
Ketamine was developed by Parke-Davis in 1962 to replace PCP. It was initially introduced as a battlefield anesthetic for American soldiers during the Vietnam War and is still widely used in clinical practice. 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 regarding 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). [3]
Phenylcyclohexyl piperidine (PCP), also known as phencyclidine, in tablet form. Image courtesy of the US Drug Enforcement Administration.
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 through 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.
Pathophysiology
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. [4] 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]
Epidemiology
Epidemiologic data indicate that PCP abuse is not widespread and is not prevalent in adolescents. The National Institute on Drug Abuse (NIDA) Monitoring the Future Study, which included survey results from 1975-2006, revealed that the overall use of PCP by high-school seniors had decreased since 1979, when 7% of seniors used PCP. [5] PCP has retained the lowest lifetime prevalence and highest noncontinuation rates among high-school seniors compared with other hallucinogenic drugs (eg, LSD, ecstasy).
A study of the prevalence of hallucinogen use from 2002-2019 reported a decline in PCP use during this timespan, overall [prevalence difference (PD) = −0.06, P < 0.001] and for adolescents (PD = −0.24, P < 0.001) and young adults (PD = −0.32, P < 0.0001). [6]
The 2022 Annual Report of the American Association of Poison Control Centers' National Poison Data System reported 116 single exposures of PCP, with 26 major outcomes and no deaths. In addition, 160 single exposures to ketamine with 9 major outcomes and 1 death were also reported. Of note, children and adolescents age 19 and younger accounted for 22 cases of PCP exposure and 27 cases of ketamine exposure. [7]
The Drug Abuse Warning Network (DAWN) estimated that the number of PCP-related ED visits rose more than fivefold from 2005 to 2011, increasing from 14,825 to 75,538. During that time, the largest increase in PCP-related ED visits was seen in patients 25 to 34 years old (from 5,556 to 34,329 visits). In 2011, 69% of patients making PCP-related ED visits were males, and 45% were 25 to 34 years old. Other illicit drugs, such as marijuana, cocaine, and heroin, were involved in 48% of PCP-related ED visits in 2011. [8]
The 2022 National Survey on Drug Use and Health (NSDUH) reported that 15,000 individuals 12-17 years old used PCP in the past 12 months. An additional 13,000 18-25 year olds and 177,000 adults 26 years old or older reported usage during the past year. [9]
The use of ketamine among high-school seniors has declined in recent years. According to the NIDA, reported past-year use by 12th graders peaked in 2002, at 2.6%, then fell to 1.2% in 2022. [10] Ketamine use tends to be more frequent among high-school seniors of lower socioeconomic status.
From 1994-1999, ketamine-associated ED visits increased from 19 per year to 400 per year but have remained relatively unchanged since then. 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. [5]
The 2014 National Survey on Drug Use and Health comparison of 12-month ketamine use during 2006-2014 found that usage spiked in 2011 with 336,000 users then steadily declined, with 247,000 users in 2014. Male users outnumbered female users by approximately 2 to 1. [11]
Prognosis
The usual street dose of PCP is 1-6 mg and results in mild intoxication. Larger ingestions (6-10 mg) can cause toxic psychoses and signs of sympathetic hyperactivity, including hypertension, rigidity, hyperthermia, tachycardia, and seizure. Very large doses (≥ 200 mg) can result in death.
The major cause of death with PCP intoxication is behavioral disturbances that lead to self-destructive behaviors and impaired judgment. Injuries may be self-inflicted, result from exceptional physical exertion, or be sustained from resisting physical restraints. Deaths from the direct effects of PCP intoxication are related to hyperthermia, kidney failure, disseminated intravascular coagulation (DIC), and rhabdomyolysis. In a study of 1000 patients with PCP intoxication, rhabdomyolysis occurred in 25 patients and 10 patients developed acute kidney injury. [12, 13]
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. [14]
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Phenylcyclohexyl piperidine (PCP), also known as phencyclidine, in tablet form. Image courtesy of the US Drug Enforcement Administration.
