Phencyclidine

Effects

Behavioral effects can vary by dosage. Low doses produce numbness in the extremities and intoxication, characterized by staggering, unsteady gait, slurred speech, bloodshot eyes, and loss of balance. Moderate doses (5–10 mg intranasal, or 0.01–0.02 mg/kg intramuscular or intravenous) will produce analgesia and anesthesia. High doses may lead to convulsions.^[15] The drug is often illegally produced under poorly controlled conditions; this means that users may be unaware of the actual dose they are taking.^[16]

Psychological effects include severe changes in body image, loss of ego boundaries, paranoia, and depersonalization. Psychosis, agitation and dysphoria, hallucinations, blurred vision, euphoria, and suicidal impulses are also reported, as well as occasional aggressive behavior.^{[17][18]: 48–49 [15]} Like many other drugs, PCP has been known to alter mood states unpredictably, causing some individuals to become detached, and others to become animated. PCP may induce feelings of strength, power, and invulnerability as well as a numbing effect on the mind.^[8]

Studies by the Drug Abuse Warning Network in the 1970s show that media reports of PCP-induced violence are greatly exaggerated and that incidents of violence are unusual and often limited to individuals with reputations for aggression regardless of drug use.^[18]: 48 Although uncommon, events of PCP-intoxicated individuals acting in an unpredictable fashion, possibly driven by their delusions or hallucinations, have been publicized.^[19] Other commonly cited types of incidents include inflicting property damage and self-mutilation of various types, such as pulling out one's teeth.^{[18]: 48 [19]} These effects were not noted in its medicinal use in the 1950s and 1960s, however, reports of physical violence on PCP have often been shown to be unfounded.^[20][21]

Recreational doses of the drug also occasionally appear to induce a psychotic state, with emotional and cognitive impairment that resembles a schizophrenic episode.^[22][23] Users generally report feeling detached from reality.^[24]

Symptoms are summarized by the mnemonic device RED DANES: rage, erythema (redness of skin), dilated pupils, delusions, amnesia, nystagmus (oscillation of the eyeball when moving laterally), excitation, and skin dryness.^[25]

Addiction

PCP is self-administered and induces ΔFosB expression in the D1-type medium spiny neurons of the nucleus accumbens,^[3][26] and accordingly, excessive PCP use is known to cause addiction.^[3] PCP's rewarding and reinforcing effects are at least partly mediated by blocking the NMDA receptors in the glutamatergic inputs to D1-type medium spiny neurons in the nucleus accumbens.^[3] PCP has been shown to produce conditioned place aversion and conditioned place preference in animal studies.^[27]

Schizophrenia

A 2019 review found that the transition rate from a diagnosis of hallucinogen-induced psychosis (which included PCP) to that of schizophrenia was 26%. This was lower than cannabis-induced psychosis (34%) but higher than amphetamine (22%), opioid (12%), alcohol (10%), and sedative (9%) induced psychoses. In comparison, the transition rate to schizophrenia for "brief, atypical and not otherwise specified" psychosis was found to be 36%.^[28]

Methods of administration

PCP has multiple routes of administration. Most commonly, the powder form of the drug is snorted. PCP can also be orally ingested, injected subcutaneously or intravenously, or smoked laced with marijuana or cigarettes.^[29]

• PCP can be ingested through smoking. "Fry" and "sherm" are street terms for marijuana or tobacco cigarettes that are dipped in PCP and then dried.^[30]
• PCP hydrochloride can be insufflated (snorted), depending upon the purity. This is most often referred to as "angel dust".^[29]
• An oral pill can also be compressed from the co-compounded powder form of the drug. This is usually referred to as "peace pill".^[29]
• The free base is hydrophobic and may be absorbed through skin and mucous membranes (often inadvertently). This form of the drug is commonly called "wack".^[29]

Pharmacodynamics

PCP is well known for its primary action on the NMDA receptor, an ionotropic glutamate receptor.^[46][43] As such, PCP is a non-competitive NMDA receptor antagonist. The role of NMDAR antagonism in the effect of PCP, ketamine, and related dissociative agents was first published in the early 1980s by David Lodge^[47] and colleagues.^[48] Other NMDA receptor antagonists include ketamine,^[49] tiletamine,^[50] dextromethorphan,^[51] nitrous oxide, and dizocilpine (MK-801).

Research also indicates that PCP inhibits nicotinic acetylcholine receptors (nAChRs) among other mechanisms. Analogues of PCP exhibit varying potency at nACh receptors^[52] and NMDA receptors.^[53] Findings demonstrate that presynaptic nAChRs and NMDA receptor interactions influence the postsynaptic maturation of glutamatergic synapses and consequently impact synaptic development and plasticity in the brain.^[54] These effects can lead to inhibition of excitatory glutamate activity in certain brain regions such as the hippocampus^[55] and cerebellum^[56] thus potentially leading to memory loss as one of the effects of prolonged use. Acute effects on the cerebellum manifest as changes in blood pressure, breathing rate, pulse rate, and loss of muscular coordination during intoxication.^[7]

PCP, like ketamine, also acts as a potent dopamine D₂^High receptor partial agonist in rat brain homogenate^[43] and has affinity for the human cloned D₂^High receptor.^[57] This activity may be associated with some of the other more psychotic features of PCP intoxication, which is evidenced by the successful use of D₂ receptor antagonists (such as haloperidol) in the treatment of PCP psychosis.^[58]

In addition to its well explored interactions with NMDA receptors, PCP has also been shown to inhibit dopamine reuptake, and thereby leads to increased extracellular levels of dopamine and hence increased dopaminergic neurotransmission.^[59] However, PCP has little affinity for the human monoamine transporters, including the dopamine transporter (DAT).^[38] Instead, its inhibition of monoamine reuptake may be mediated by interactions with allosteric sites on the monoamine transporters.^[38] PCP is notably a high-affinity ligand of the PCP site 2 (K_i = 154 nM), a not-well-characterized site associated with monoamine reuptake inhibition.^[39]

Studies on rats indicate that PCP interacts indirectly with opioid receptors (endorphin and enkephalin) to produce analgesia.^[60]

A binding study assessed PCP at 56 sites including neurotransmitter receptors and transporters and found that PCP had K_i values of >10,000 nM at all sites except the dizocilpine (MK-801) site of the NMDA receptor (K_i = 59 nM), the σ₂ receptor (PC12) (K_i = 136 nM), and the serotonin transporter (K_i = 2,234 nM).^[38] The study notably found K_i values of >10,000 nM for the D₂ receptor, the opioid receptors, the σ₁ receptor, and the dopamine and norepinephrine transporters.^[38] These results suggest that PCP is a highly selective ligand of the NMDAR and σ₂ receptor.^[38] However, PCP may also interact with allosteric sites on the monoamine transporters to produce inhibition of monoamine reuptake.^[38]

Mechanism of action

Phencyclidine is a noncompetitive NMDA receptor antagonist that blocks the activity of the NMDA receptor to cause anaesthesia and analgesia without causing cardiorespiratory depression.^[61][17] NMDA is an excitatory receptor in the brain, when activated normally the receptor acts as an ion channel and there is an influx of positive ions through the channel to cause nerve cell depolarisation. Phencyclidine inhibits the NMDA receptor by binding to the specific PCP binding site located within the ion channel.^[62] The PCP binding site is within close proximity to the magnesium blocking site, which may explain the similar inhibitory effects.^[63] Binding at the PCP site is mediated by two non-covalent interactions within the receptor: hydrogen bonding and hydrophobic interaction.^[64] Binding is also controlled by the gating mechanism of the ion channel. Because the PCP site is located within the ion channel, a coagonist such as glycine must bind and open the channel for PCP to enter, bind to the PCP site, and block the channel.^[65]

Pharmacokinetics

PCP is both water and lipid-soluble and is therefore distributed throughout the body quickly.^[63] PCP is metabolized into PCHP, PPC and PCAA. The drug is metabolized 90% by oxidative hydroxylation in the liver during the first pass. Metabolites are glucuronidated and excreted in the urine. Nine percent of ingested PCP is excreted in its unchanged form.^[17]

When smoked, some of the compound is broken down by heat into 1-phenylcyclohexene (PC) and piperidine.

The time taken before the effects of PCP manifest is dependent on the route of administration. The onset of action for inhalation occurs in 2–5 minutes, whereas the effects may take 15 to 60 minutes when ingested orally.^[17]

Analogues

Fewer than 30 different analogs of PCP were reported as being used as a street drug during the 1970s and 1980s, mainly in the United States.^[48] Only of a few of these compounds were widely used including rolicyclidine (PCPy), eticyclidine (PCE), and tenocyclidine (TCP).^[48] Less common analogs include 3-HO-PCP, 3-MeO-PCMo, and 3-MeO-PCP.

The generalized structural motif required for PCP-like activity is derived from structure-activity relationship studies of PCP derivatives. All of these derivatives are likely to share some of their psychoactive effects with PCP itself, although a range of potencies and varying mixtures of anesthetic, dissociative, and stimulant effects are known, depending on the particular drug and its substituents. In the United States, all of these compounds would be considered controlled substance analogs of PCP under the Federal Analog Act and are hence illegal drugs if sold for human consumption.^[73][74]

Regulation

PCP is a Schedule II substance in the US. The Administrative Controlled Substances Code Number (ACSCN) for PCP is 7471.^[79] Its manufacturing quota for 2014 was 19 grams (0.67 oz).^[80] It is a Schedule I drug by the Controlled Drugs and Substances act in Canada, a List I drug of the Opium Law in the Netherlands, and a Class A substance in the UK.^[81]

Frequency of use

PCP began to emerge as a recreational drug in major cities in the US in the 1960s.^[6] In 1978, People magazine and Mike Wallace of the TV news program 60 Minutes called PCP the country's "number one drug problem". Although recreational use of the drug had always been relatively low, it began declining significantly in the 1980s. In surveys, the number of high school students admitting to trying PCP at least once fell from 13% in 1979 to less than 3% in 1990.^{[18]: 46–49}

Cultural depictions

Jean-Michel Basquiat depicted two angel dust users in his 1982 painting Dustheads.^[82]

Tsukasa Hojo's 1985 manga City Hunter features a drug, Angel Dust, presumably a reference to PCP's street name. The related 2023 animated film, City Hunter: Angel Dust, more directly moved the franchise's angel dust into the realm of fantasy, as it is portrayed as a science fiction nanomachine serum developed by a biotech company to create super-soldiers with a tendency to drive them berserk, side-stepping the real-life PCP.^[83]

In Vivienne Medrano's adult animated musical comedy television series Hazbin Hotel, Angel Dust is an adult film star in Hell and one of the main protagonists.^[84] He is known to struggle with addiction to phencyclidine, during his lifetime as well as the afterlife. His cause of death was an overdose of phencyclidine, so renamed himself in the afterlife after the drug.^[85]