Phencyclidine

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| _other_data=1-(1-Phenylcyclohexyl)piperidine

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Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a street drug as angel dust among other names, is a dissociative anesthetic mainly used recreationally for its significant mind-altering effects.<ref name=Jus2003>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="Giannini 1998"/> PCP may cause hallucinations, distorted perceptions of sounds, and psychotic behavior.<ref name= "Giannini 1998"/><ref name=Bush2013>Template:Cite book</ref><ref name=NIH2016Hal/> As a recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected.<ref name="Giannini 1998"/><ref name=NIH2018Fact>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name= Bush2013/> It may also be mixed with cannabis or tobacco.<ref name=Jus2003/><ref name="Giannini 1998"/>

Adverse effects may include paranoia, addiction, and an increased risk of suicide, as well as seizures and coma in cases of overdose.<ref name=Bush2013/> Flashbacks may occur despite stopping usage.<ref name=NIH2016Hal>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Chemically, PCP is a member of the arylcyclohexylamine class.<ref name="Giannini 1998"/><ref name=Mar2014/><ref name=Zed2007>Template:Cite book</ref> PCP works primarily as an NMDA receptor antagonist.<ref name=Mar2014>Template:Cite book</ref>

PCP is most commonly used in the US.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> While usage peaked in the US in the 1970s,<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> between 2005 and 2011, an increase in visits to emergency departments as a result of the drug occurred.<ref name=Bush2013/> As of 2022, in the US, about 0.7% of 12th-grade students reported using PCP in the prior year, while 1.7% of people in the US over age 25 reported using it at some point in their lives.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Recreational uses

File:Phencyclidine (PCP).jpg

Illicit PCP in several forms seized by the DEA.

Phencyclidine is used for its ability to induce a dissociative state.<ref>Template:Cite journal</ref>

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.<ref name="Diaz">Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.</ref> The drug is often illegally produced under poorly controlled conditions; this means that users may be unaware of the actual dose they are taking.<ref name="Neuroscience for Kids">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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.<ref name="beyT"/><ref name=Inciardi/>Template:Rp<ref name="Diaz"/> 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.<ref name=NIH2018Fact/>

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.<ref name=Inciardi/>Template:Rp Although uncommon, events of PCP-intoxicated individuals acting in an unpredictable fashion, possibly driven by their delusions or hallucinations, have been publicized.<ref name="Morgan">Template:Cite journal</ref> Other commonly cited types of incidents include inflicting property damage and self-mutilation of various types, such as pulling out one's teeth.<ref name=Inciardi/>Template:Rp<ref name="Morgan"/> 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.<ref name=brecher>Template:Cite journal</ref><ref name=wish>Template:Cite journal</ref>

Recreational doses of the drug also occasionally appear to induce a psychotic state, with emotional and cognitive impairment that resembles a schizophrenic episode.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> Users generally report feeling detached from reality.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite book</ref>

Addiction

PCP is self-administered and induces ΔFosB expression in the D1-type medium spiny neurons of the nucleus accumbens,<ref name="NHM-PCP and ketamine">Template:Cite book</ref><ref name="PCP ΔFosB">Template:Cite journalTemplate:Cite journal</ref> and accordingly, excessive PCP use is known to cause addiction.<ref name="NHM-PCP and ketamine"/> 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.<ref name="NHM-PCP and ketamine"/> PCP has been shown to produce conditioned place aversion and conditioned place preference in animal studies.<ref>Template:Cite journal</ref>

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-induced (9%) psychoses. In comparison, the transition rate to schizophrenia for "brief, atypical and not otherwise specified" psychosis was found to be 36%.<ref>Template:Cite journal</ref>

Methods of administration

Template:Redirect 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.<ref name="Bertron_2018">Template:Cite journal</ref>

• 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.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

• PCP hydrochloride can be insufflated (snorted), depending upon the purity. This is most often referred to as "angel dust".<ref name="Bertron_2018" />
• An oral pill can also be compressed from the co-compounded powder form of the drug. This is usually referred to as "peace pill".<ref name="Bertron_2018" />
• 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".<ref name="Bertron_2018" />

Management of intoxication

Management of PCP intoxication mostly consists of supportive care – controlling breathing, circulation, and body temperature – and, in the early stages, treating psychiatric symptoms.<ref name=eMedicine>Template:Cite journal Retrieved on November 3, 2008.</ref><ref name=Goldfrank>Template:Cite book</ref><ref name=Milhorn>Template:Cite journal</ref> Benzodiazepines, such as lorazepam, are the drugs of choice to control agitation and seizures (when present). Typical antipsychotics such as phenothiazines and haloperidol have been used to control psychotic symptoms, but may produce many undesirable side effects – such as dystonia – and their use is therefore no longer preferred; phenothiazines are particularly risky, as they may lower the seizure threshold, worsen hyperthermia, and boost the anticholinergic effects of PCP.<ref name=eMedicine /><ref name=Goldfrank /> If an antipsychotic is given, intramuscular haloperidol has been recommended.<ref name=Milhorn /><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

Forced acid diuresis (with ammonium chloride or, more safely, ascorbic acid) may increase the clearance of PCP from the body, and was somewhat controversially recommended in the past as a decontamination measure.<ref name=eMedicine /><ref name=Goldfrank /><ref name=Milhorn /> However, it is now known that only around 10% of a dose of PCP is removed by the kidneys, which would make increased urinary clearance of little consequence; furthermore, urinary acidification is dangerous, as it may induce acidosis and worsen rhabdomyolysis (muscle breakdown), a not-unusual manifestation of PCP toxicity.<ref name=eMedicine /><ref name=Goldfrank />

Pharmacology

Pharmacodynamics

citation

CitationClass=web }}</ref><ref name="pmid29953199">Template:Cite journal</ref>
Site	Ki (nM)	Action	Species	Ref
Template:Abbrlink	59	Antagonist	Human	<ref name="pmid23527166">Template:Cite journal</ref><ref name="pmid7968938" />
Template:Abbrlink	>10,000	Template:Abbr	Human	<ref name="pmid23527166" />
Template:Abbrlink	>10,000	Template:Abbr	Human	<ref name="pmid23527166" />
Template:Abbrlink	>10,000	Template:Abbr	Human	<ref name="pmid23527166" />
Template:Abbrlink	>10,000	Template:Abbr	Human	<ref name="pmid23527166" />
σ1	>10,000	Agonist	Guinea pig	<ref name="pmid23527166" /><ref name="pmid24257811">Template:Cite journal</ref>
σ2	136	Agonist	Rat	<ref name="pmid23527166" />
D2	>10,000	Template:Abbr	Human	<ref name="pmid23527166" />
D2High	2.7–4.3 144 (EC50)	Partial Agonist	Rat/human Human	<ref name="pmid18720422">Template:Cite journal</ref><ref name="pmid12232776">Template:Cite journal</ref> <ref name="pmid19391150">Template:Cite journal</ref>
5-HT2A	>10,000	Template:Abbr	Human	<ref name="pmid23527166" />
5-HT2AHigh	≥5,000	Partial Agonist	Rat	<ref name="pmid12232776" /><ref name="pmid11343613">Template:Cite journal</ref>
Template:Abbrlink	2,234	Inhibitor	Human	<ref name="pmid23527166" />
Template:Abbrlink	>10,000	Inhibitor	Human	<ref name="pmid23527166" />
Template:Abbrlink	>10,000	Inhibitor	Human	<ref name="pmid23527166" />
[[Phencyclidine site 2|Template:Abbr2]]	154	agonist	Human	<ref name="pmid7968938">Template:Cite journal</ref>
[[Serotonin reuptake inhibitor|[3H]Template:Abbr uptake]]	1,424 (IC50)	Inhibitor	Rat	<ref name="pmid8134901">Template:Cite journal</ref>
[[Norepinephrine reuptake inhibitor|[3H]Template:Abbr binding]]	16,628 (IC50)	Inhibitor	Rat	<ref name="pmid8134901" />
[[Dopamine reuptake inhibitor|[3H]Template:Abbr uptake]]	347 (IC50)	Inhibitor	Rat	<ref name="pmid8134901" />
[[Dopamine reuptake inhibitor|[3H]Template:Abbr binding]]	1,547 (IC50)	Inhibitor	Rat	<ref name="pmid8134901" />
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

PCP is well known for its primary action on the NMDA receptor, an ionotropic glutamate receptor.<ref>Template:Cite journal</ref><ref name="pmid19391150" /> 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<ref>Template:Cite journal</ref> and colleagues.<ref name="Morris2014">Template:Cite journal</ref> Other NMDA receptor antagonists include ketamine,<ref name=Caddy2010>Template:Cite journal</ref> tiletamine,<ref>Template:Cite journal</ref> dextromethorphan,<ref name=Burns>Template:Cite journal</ref> 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<ref>Template:Cite journal</ref> and NMDA receptors.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> These effects can lead to inhibition of excitatory glutamate activity in certain brain regions such as the hippocampus<ref>Template:Cite journal</ref> and cerebellum<ref>Template:Cite journal</ref> 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.<ref name=NIH2016Hal/>

PCP, like ketamine, also acts as a potent dopamine D₂^High receptor partial agonist in rat brain homogenate<ref name="pmid19391150" /> and has affinity for the human cloned D₂^High receptor.<ref name="D2 in ketamine and pcp">Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref> However, PCP has little affinity for the human monoamine transporters, including the dopamine transporter (DAT).<ref name="pmid23527166" /> Instead, its inhibition of monoamine reuptake may be mediated by interactions with allosteric sites on the monoamine transporters.<ref name="pmid23527166" /> 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.<ref name="pmid7968938" />

Studies on rats indicate that PCP interacts indirectly with opioid receptors (endorphin and enkephalin) to produce analgesia.<ref>Template:Cite journal</ref>

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).<ref name="pmid23527166" /> 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.<ref name="pmid23527166" /> These results suggest that PCP is a highly selective ligand of the NMDAR and σ₂ receptor.<ref name="pmid23527166" /> However, PCP may also interact with allosteric sites on the monoamine transporters to produce inhibition of monoamine reuptake.<ref name="pmid23527166" />

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.<ref name=drugbank>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=beyT>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref> The PCP binding site is within close proximity to the magnesium blocking site, which may explain the similar inhibitory effects.<ref name="Kohrs_1998">Template:Cite journal</ref> Binding at the PCP site is mediated by two non-covalent interactions within the receptor: hydrogen bonding and hydrophobic interaction.<ref>Template:Cite journal</ref> 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.<ref>Template:Cite journal</ref>

Neurotoxicity

Some studies found that, like other NMDA receptor antagonists, PCP can cause a kind of brain damage called Olney's lesions in rats.<ref>Template:Cite journal</ref><ref>Template:Cite book</ref> Studies conducted on rats showed that high doses of the NMDA receptor antagonist dizocilpine caused reversible vacuoles to form in certain regions of the rats' brains. All studies of Olney's lesions have only been performed on non-human animals and may not apply to humans. One unpublished study by Frank Sharp reportedly showed no damage by the NMDA antagonist ketamine, a structurally similar drug, far beyond recreational doses,<ref>Jansen, Karl. Ketamine: Dreams and Realities. MAPS, 2004. Template:ISBN</ref> but due to the study never having been published, its validity is controversial.

PCP has also been shown to cause schizophrenia-like changes in N-acetylaspartate and N-acetylaspartylglutamate levels in the rat brain, which are detectable both in living rats and upon necropsy examination of brain tissue.<ref name=psychotic_PCP_rats>Template:Cite journal</ref> It also induces symptoms in humans that mimic schizophrenia.<ref>Template:Cite journal</ref> PCP not only produced symptoms similar to schizophrenia, it also yielded electroencephalogram changes in the thalamocortical pathway (increased delta decreased alpha) and in the hippocampus (increase theta bursts) that were similar to those in schizophrenia.<ref name="Lodge_2015">Template:Cite journal</ref> PCP-induced augmentation of dopamine release may link the NMDA and dopamine hypotheses of schizophrenia.<ref>Template:Cite journal</ref>

Pharmacokinetics

File:PCP2PCandPOPERIDINE.png

Conversion of PCP into PC and piperidine by heat.

PCP is both water- and lipid-soluble and is therefore distributed throughout the body quickly.<ref name="Kohrs_1998" /> 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.<ref name=beyT />

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.<ref name=beyT />

Chemistry

PCP is an arylcyclohexylamine.

Analogues

File:ACHA SAR.png

Possible analogues of PCP

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.<ref name="Morris2014" /> Only a few of these compounds were widely used, including rolicyclidine (PCPy), eticyclidine (PCE), and tenocyclidine (TCP).<ref name="Morris2014" /> 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.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

History

Phencyclidine was initially discovered in 1926 by Template:Ill and his student Paul Merkel as a product of a Grignard reaction of 1-piperidinocyclohexancarbonitrile.<ref name="Kötz_1926">Template:Cite journal</ref>

It was again synthesized in 1956 by chemist H Victor Maddox and brought to market as an anesthetic medication by pharmaceutical company Parke-Davis, now a subsidiary of Pfizer.<ref name="Lodge_2015" /><ref name="Zed2007" /><ref>Template:Cite book</ref><ref name="Kötz_1926" /><ref name="Lindgren 1983 61–73">Template:Cite book</ref> Its use in humans was disallowed in the US in 1965 due to the high rates of side effects, while its use in animals was disallowed in 1978.<ref name="Jus2003" /><ref name= "Zed2007" /><ref name="Tas2015">Template:Cite book</ref> Moreover, ketamine was discovered and was better tolerated as an anesthetic.<ref name="Tas2015" />

PCP is classified as a schedule II drug in the US.<ref name= "Jus2003" /> Derivatives of PCP have been sold for recreational and non-medical use.<ref name= "Morris2014" />

Society and culture

Regulation

PCP is a Schedule II substance in the US. The Administrative Controlled Substances Code Number (ACSCN) for PCP is 7471.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Its manufacturing quota for 2014 was Template:Convert.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Frequency of use

PCP began to emerge as a recreational drug in major cities in the US in the 1960s.<ref name=Bush2013/> 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.<ref name=Inciardi>Template:Cite book</ref>Template:Rp

Cultural depictions

Jean-Michel Basquiat depicted two angel dust users in his 1982 painting Dustheads.<ref>Template:Cite news</ref>

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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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,<ref>Template:Cite press release</ref> who in Hell took on the name "Angel Dust" as his chosen all-encompassing persona name, and one he uses exclusively in place of his actual name. It is intended as multipurpose for both his drag queen persona and his sex-work persona.<ref>HAZBIN HOTEL Animation Cleanup Pt. 7 Ft. Michael Kovach and Vivziepop (2:31:28) – via YouTube.</ref>

External links

• Erowid.org – PCP Information
• National Institute of Drug Abuse InfoFacts: PCP (Phencyclidine) Template:Webarchive
• Drugs and Human Performance Fact Sheets on Phencyclidine
• Phencyclidine and Ketamine: A View From the Street-1981 article on the use and effects of PCP Template:Webarchive
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