Phencyclidine

Phencyclidineorphenylcyclohexyl piperidine(PCP), also known in its use as astreet drugasangel dustamong other names, is adissociativeanestheticmainlyused recreationallyfor its significant mind-altering effects.PCP may causehallucinations, distorted perceptions of sounds, andpsychotic behavior.As arecreational drug, it is typicallysmoked, but may be takenby mouth,snorted, orinjected.It may also be mixed withcannabisortobacco.
Adverse effectsmay includeparanoia,addiction, and an increased risk ofsuicide, alsoseizuresandcomain case ofoverdose.Flashbacksmay occur despite stopping usage.Chemically, PCP is a member of thearylcyclohexylamineclass.PCP works primarily as anNMDA receptor antagonist.
PCP is most commonly used in the US.While usage peaked in the US in the 1970s,between 2005 and 2011, an increase in visits to emergency departments as a result of the drug occurred.As of 2022, in the US, about 0.7% of12th gradestudents 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.
Phencyclidine is used for its ability to induce a dissociative state.
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 produceanalgesiaand anesthesia. High doses may lead toconvulsions.The drug is often illegally produced under poorly controlled conditions; this means that users may be unaware of the actual dose they are taking.
Psychological effects include severe changes inbody image,loss of ego boundaries,paranoia, anddepersonalization. Psychosis, agitation and dysphoria, hallucinations, blurred vision,euphoria, andsuicidal impulsesare also reported, as well as occasional aggressive behavior.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.
Studies by theDrug Abuse Warning Networkin 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.Although uncommon, events of PCP-intoxicated individuals acting in an unpredictable fashion, possibly driven by their delusions or hallucinations, have been publicized.Other commonly cited types of incidents include inflicting property damage and self-mutilation of various types, such as pulling out one's teeth.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.
Recreational doses of the drug also occasionally appear toinduce a psychotic state, with emotional and cognitive impairment that resembles aschizophrenicepisode.Users generally report feeling detached from reality.
Symptoms are summarized by themnemonicdevice RED DANES: rage,erythema(redness of skin), dilated pupils, delusions,amnesia,nystagmus(oscillation of the eyeball when moving laterally), excitation, and skin dryness.
PCP is self-administered and inducesΔFosBexpression in theD1-typemedium spiny neuronsof thenucleus accumbens,and accordingly, excessive PCP use is known to causeaddiction.PCP'srewardingandreinforcingeffects are at least partly mediated by blocking theNMDA receptorsin the glutamatergic inputs to D1-type medium spiny neurons in the nucleus accumbens.PCP has been shown to produceconditioned place aversionandconditioned place preferencein animal studies.
A 2019 review found that the transition rate from a diagnosis ofhallucinogen-induced psychosis(which included PCP) to that of schizophrenia was 26%. This was lower thancannabis-induced psychosis (34%) but higher thanamphetamine(22%),opioid(12%),alcohol(10%), andsedative(9%) induced psychoses. In comparison, the transition rate to schizophrenia for "brief, atypical and not otherwise specified" psychosis was found to be 36%.
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.
Management of PCP intoxication mostly consists of supportive care – controlling breathing, circulation, and body temperature – and, in the early stages, treating psychiatric symptoms.Benzodiazepines, such aslorazepam, are thedrugs of choiceto control agitation and seizures (when present).Typical antipsychoticssuch asphenothiazinesandhaloperidolhave been used to control psychotic symptoms, but may produce many undesirable side effects – such asdystonia– and their use is therefore no longer preferred; phenothiazines are particularly risky, as they may lower theseizure threshold, worsenhyperthermia, and boost theanticholinergiceffects of PCP.If an antipsychotic is given,intramuscularhaloperidol has been recommended.
Forced acid diuresis(withammonium chlorideor, more safely,ascorbic acid) may increase the clearance of PCP from the body, and was somewhat controversially recommended in the past as adecontaminationmeasure.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, urinaryacidificationis dangerous, as it may induceacidosisand worsenrhabdomyolysis(muscle breakdown), a not-unusual manifestation of PCP toxicity.
PCP is well known for its primary action on theNMDA receptor, anionotropic glutamate receptor.As such, PCP is a non-competitiveNMDA receptor antagonist. The role of NMDAR antagonism in the effect of PCP,ketamine, and related dissociative agents was first published in the early 1980s byDavid Lodgeand colleagues.Other NMDA receptor antagonists includeketamine,tiletamine,dextromethorphan,nitrous oxide, anddizocilpine(MK-801).
Research also indicates that PCP inhibitsnicotinic acetylcholine receptors(nAChRs) among other mechanisms. Analogues of PCP exhibit varying potency at nACh receptorsand NMDA receptors.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.These effects can lead to inhibition of excitatory glutamate activity in certain brain regions such as thehippocampusandcerebellumthus potentially leading to memory loss as one of the effects of prolonged use. Acute effects on thecerebellummanifest as changes in blood pressure, breathing rate, pulse rate, and loss of muscular coordination during intoxication.
PCP, like ketamine, also acts as a potentdopamineD2receptorpartial agonistin rat brain homogenateand has affinity for the human cloned D2receptor.This activity may be associated with some of the other more psychotic features of PCP intoxication, which is evidenced by the successful use of D2receptor antagonists (such ashaloperidol) in the treatment of PCP psychosis.
In addition to its well explored interactions with NMDA receptors, PCP has also been shown toinhibit dopamine reuptake, and thereby leads to increased extracellular levels of dopamine and hence increaseddopaminergicneurotransmission.However, PCP has littleaffinityfor the humanmonoamine transporters, including thedopamine transporter(DAT).Instead, itsinhibition of monoamine reuptakemay be mediated by interactions withallosteric siteson the monoamine transporters.PCP is notably a high-affinityligandof thePCP site 2(Ki= 154 nM), a not-well-characterized site associated with monoamine reuptake inhibition.
Studies on rats indicate that PCP interacts indirectly withopioid receptors(endorphinandenkephalin) to produce analgesia.
A binding study assessed PCP at 56 sites includingneurotransmitter receptorsandtransportersand found that PCP had Kivalues of >10,000 nM at all sites except thedizocilpine(MK-801) site of the NMDA receptor (Ki= 59 nM), theσ2receptor(PC12) (Ki= 136 nM), and theserotonin transporter(Ki= 2,234 nM).The study notably found Kivalues of >10,000 nM for theD2receptor, theopioid receptors, theσ1receptor, and thedopamineandnorepinephrine transporters.These results suggest that PCP is a highly selective ligand of the NMDAR and σ2receptor.However, PCP may also interact with allosteric sites on the monoamine transporters to produce inhibition of monoamine reuptake.
Phencyclidine is a noncompetitive NMDA receptor antagonist that blocks the activity of the NMDA receptor to cause anaesthesia and analgesia without causing cardiorespiratory depression.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.The PCP binding site is within close proximity to the magnesium blocking site, which may explain the similar inhibitory effects.Binding at the PCP site is mediated by two non-covalent interactions within the receptor: hydrogen bonding and hydrophobic interaction.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.
Some studies found that, like other NMDA receptor antagonists, PCP can cause a kind ofbrain damagecalledOlney's lesionsin rats.Studies conducted on rats showed that high doses of the NMDA receptor antagonistdizocilpinecaused reversiblevacuolesto 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,but due to the study never having been published, its validity is controversial.
PCP has also been shown to cause schizophrenia-like changes inN-acetylaspartate andN-acetylaspartylglutamate levels in the rat brain, which are detectable both in living rats and upon necropsy examination of brain tissue.It also induces symptoms in humans that mimic schizophrenia.PCP not only produced symptoms similar to schizophrenia, it also yieldedelectroencephalogramchanges in the thalamocortical pathway (increased delta decreased alpha) and in the hippocampus (increase theta bursts) that were similar to those in schizophrenia.PCP-induced augmentation of dopamine release may link the NMDA anddopaminehypotheses of schizophrenia.
PCP is both water and lipid-soluble and is therefore distributed throughout the body quickly.PCP is metabolized intoPCHP,PPCandPCAA. The drug is metabolized 90% byoxidativehydroxylationin theliverduring thefirst pass.Metabolitesareglucuronidatedandexcretedin theurine. Nine percent of ingested PCP is excreted in its unchanged form.
When smoked, some of the compound is broken down by heat into1-phenylcyclohexene(PC) andpiperidine.
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.
PCP is anarylcyclohexylamine.
Fewer than 30 differentanalogsof PCP were reported as being used as astreet drugduring the 1970s and 1980s, mainly in the United States.Only of a few of these compounds were widely used includingrolicyclidine(PCPy),eticyclidine(PCE), andtenocyclidine(TCP).Less common analogs include3-HO-PCP,3-MeO-PCMo, and3-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 theFederal Analog Actand are hence illegal drugs if sold for human consumption.
Phencyclidine was initially discovered in 1926 byArthur Kötz[de]and his student Paul Merkel as a product of aGrignard reactionof 1-piperidinocyclohexancarbonitrile.
It was again synthesized in 1956 by chemist H Victor Maddox and brought to market as ananestheticmedication by pharmaceutical company Parke-Davis, now a subsidiary ofPfizer.Its use in humans was disallowed in the US in 1965 due to the high rates ofside effects, while its use in animals was disallowed in 1978.Moreover,ketaminewas discovered and was better tolerated as an anesthetic.
PCP is classified as aschedule II drugin the US.Derivatives of PCP have been sold for recreational and non-medical use.
PCP is aSchedule IIsubstance in the US. TheAdministrative Controlled Substances Code Number(ACSCN) for PCP is 7471.Its manufacturing quota for 2014 was 19 grams (0.67 oz).It is a Schedule I drug by the Controlled Drugs and Substances act in Canada, a List I drug of theOpium Lawin theNetherlands, and aClass Asubstance in the UK.
PCP began to emerge as arecreational drugin major cities in the US in the 1960s.In 1978,Peoplemagazine andMike Wallaceof the TV news program60 Minutescalled 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 ofhigh schoolstudents admitting to trying PCP at least once fell from 13% in 1979 to less than 3% in 1990.
Jean-Michel Basquiatdepicted two angel dust users in his 1982 paintingDustheads.
Tsukasa Hojo's 1985mangaCity Hunterfeatures a drug, Angel Dust, presumably a reference to PCP'sstreet 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 fictionnanomachineserum developed by abiotechcompany to create super-soldiers with a tendency to drive them berserk, side-stepping the real-life PCP.
InVivienne Medrano's adult animated musical comedy television seriesHazbin Hotel, Angel Dust is an adult film star in Hell and one of the main protagonists,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.