Phencyclidine

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Phencyclidine
Clinical data
Trade namesSernyl, Sernylan (both discontinued)
Other namesCI-395; Phenylcyclohexylpiperidine; "Angel dust"[1]
AHFS/Drugs.comphencyclidine
Dependence
liability		Physical: Low[2]
Dissociative hallucinogens[7]
ATC code
  • None
Legal status
Legal status
Oxidative hydroxylation in liver by CYP450 enzymes, glucuronidation
MetabolitesPCHP, PPC, PCAA
Onset of action2–60 min[9]
Elimination half-life7–46 hours
Duration of action6–48 hours[9]
ExcretionUrine
Identifiers
  • 1-(1-Phenylcyclohexyl)piperidine
JSmol)
Melting point46.5 °C (115.7 °F)
Boiling point136 °C (277 °F)
  • c1ccccc1C2(CCCCC2)N3CCCCC3
  • InChI=1S/C17H25N/c1-4-10-16(11-5-1)17(12-6-2-7-13-17)18-14-8-3-9-15-18/h1,4-5,10-11H,2-3,6-9,12-15H2 checkY
  • Key:JTJMJGYZQZDUJJ-UHFFFAOYSA-N checkY
Data page
Phencyclidine (data page)
 ☒NcheckY (what is this?)  (verify)

Phencyclidine or phenylcyclohexyl piperidine (PCP), also known in its use as a

recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected.[7][8][10] It may also be mixed with cannabis or tobacco.[1][7]

class, and pharmacologically, it is a dissociative anesthetic.[7][12][13] PCP works primarily as an NMDA receptor antagonist.[12]

PCP is most commonly used in the United States.[14] While usage peaked in the US in the 1970s,[15] between 2005 and 2011 an increase in visits to emergency departments as a result of the drug occurred.[10] As of 2017 in the United States, about 1% of people in 12th grade reported using PCP in the prior year while 2.9% of those over the age of 25 reported using it at some point in their lives.[16]

Recreational uses

DEA
.

Phencyclidine is used for its ability to induce a dissociative state.[17]

Effects

Behavioral effects can vary by dosage. Low doses produce a 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

convulsions.[18] The drug is often illegally produced under poorly controlled conditions; this means that users may be unaware of the actual dose they are taking.[19]

Psychological effects include severe changes in

suicidal impulses are also reported, as well as occasional aggressive behavior.[20][21]: 48–49 [18] Like many other drugs, PCP has been known to alter mood states in an unpredictable fashion, 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.[21]: 48  Although uncommon, events of PCP-intoxicated individuals acting in an unpredictable fashion, possibly driven by their delusions or hallucinations, have been publicized.[22] Other commonly cited types of incidents include inflicting property damage and self-mutilation of various types, such as pulling one's own teeth.[21]: 48 [22] These effects were not noted in its medicinal use in the 1950s and 1960s, however, and reports of physical violence on PCP have often been shown to be unfounded.[23][24]

Recreational doses of the drug also occasionally appear to induce a psychotic state, with emotional and cognitive impairment that resembles a schizophrenic episode.[25][26] Users generally report feeling detached from reality.[27]

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.[28]

Addiction

PCP is self-administered and induces

conditioned place aversion and conditioned place preference in animal studies.[30]

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%.[31]

Methods of administration

"Sherm stick" redirects here. For the song by Jayo Felony, see Take a Ride.

PCP is easily accessible because of the various routes of administration available. 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.[32]

  • 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.[33]
  • PCP hydrochloride can be insufflated (snorted), depending upon the purity. This is most often referred to as "angel dust".[32]
  • An oral pill can also be compressed from the co-compounded powder form of the drug. This is usually referred to as "peace pill".[32]
  • The free base is hydrophobic and may be absorbed through skin and mucus membranes (often inadvertently). This form of the drug is commonly called "wack".[32]

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.

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.[34][35] If an antipsychotic is given, intramuscular haloperidol has been recommended.[36][37][38]

ascorbic acid) may increase clearance of PCP from the body, and was somewhat controversially recommended in the past as a decontamination measure.[34][35][36] 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.[34][35]

Pharmacology

Pharmacodynamics

Phencyclidine[39][40]
Site Ki (
nM
)		 Action Species Ref
NMDA
Tooltip N-Methyl-D-aspartate receptor		 44–59 Antagonist Human [41][42]
MOR
Tooltip μ-Opioid receptor		 >10,000 ND Human [41]
DOR
Tooltip δ-Opioid receptor		 >10,000 ND Human [41]
KOR
Tooltip κ-Opioid receptor		 >10,000 ND Human [41]
NOPTooltip Nociceptin receptor >10,000 ND Human [41]
σ1 >10,000 Agonist Guinea pig [41][43]
σ2 136 Agonist Rat [41]
D2
 >10,000 ND Human [41]
  
D2High
 2.7–4.3
144 (EC50)		 Partial Agonist Rat/human
Human		 [44][45]
[46]
5-HT2A >10,000 ND Human [41]
  5-HT2AHigh ≥5,000 Agonist? Rat [45][47]
SERTTooltip Serotonin transporter 2,234 Inhibitor Human [41]
NETTooltip Norepinephrine transporter >10,000 Inhibitor Human [41]
DATTooltip Dopamine transporter >10,000 Inhibitor Human [41]
PCP2
 154 ND Human [42]
[3H]5-HT uptake 1,424 (IC50) Inhibitor Rat [48]
[3H]NIS binding 16,628 (IC50) Inhibitor Rat [48]
[3H]DA uptake 347 (IC50) Inhibitor Rat [48]
[3H]CFT binding 1,547 (IC50) Inhibitor Rat [48]
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

David Lodge[50] and colleagues.[51] Other NMDA receptor antagonists include ketamine,[52] tiletamine,[53] dextromethorphan,[54] 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[55] and NMDA receptors.[56] Findings demonstrate that presynaptic nAChRs and NMDA receptor interactions influence postsynaptic maturation of glutamatergic synapses and consequently impact synaptic development and plasticity in the brain.[57] These effects can lead to inhibition of excitatory glutamate activity in certain brain regions such as the hippocampus[58] and cerebellum[59] 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.[11]

PCP, like ketamine, also acts as a potent

D2High receptor partial agonist in rat brain homogenate[46] and has affinity for the human cloned D2High receptor.[60] 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.[61]

In addition to its well explored interactions with NMDA receptors, PCP has also been shown to

allosteric sites on the monoamine transporters.[41] PCP is notably a high-affinity ligand of the PCP site 2 (Ki = 154 nM), a not-well-characterized site associated with monoamine reuptake inhibition.[42]

Studies on rats indicate that PCP interacts indirectly with

endorphin and enkephalin) to produce analgesia.[63]

A binding study assessed PCP at 56 sites including

D2 receptor, the opioid receptors, the σ1 receptor, and the dopamine and norepinephrine transporters.[41] These results suggest that PCP is a highly selective ligand of the NMDAR and σ2 receptor.[41] However, PCP may also interact with allosteric sites on the monoamine transporters to produce inhibition of monoamine reuptake.[41]

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.[64][20] 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.[65] The PCP binding site is within close proximity to the magnesium blocking site, which may explain the similar inhibitory effects.[66] Binding at the PCP site is mediated by two non-covalent interactions within the receptor: hydrogen bonding and hydrophobic interaction.[67] 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 in order for PCP to enter, bind to the PCP site, and block the channel.[68]

Neurotoxicity

Some studies found that, like other NMDA receptor antagonists, PCP can cause a kind of

brain damage called Olney's lesions in rats.[69][70] 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 NDMA antagonist ketamine, a structurally similar drug, far beyond recreational doses,[71]
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.

electroencephalogram changes in the thalamocortical pathway (increased delta decreased alpha) and in the hippocampus (increase theta bursts) that were similar to those in schizophrenia.[74] PCP-induced augmentation of dopamine release may link the NMDA and dopamine hypotheses of schizophrenia.[75]

Pharmacokinetics

Conversion of PCP into PC and piperidine by heat.

PCP is both water and lipid soluble and is therefore distributed throughout the body quickly.

glucuronidated and excreted in the urine. Nine percent of ingested PCP is excreted in its unchanged form.[20]

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.[20]

Chemistry

PCP is an arylcyclohexylamine.

Analogues

Possible analogues of PCP

Fewer than 30 different

street drug during the 1970s and 1980s, mainly in the United States.[51] Only of a few of these compounds were widely used including rolicyclidine (PCPy), eticyclidine (PCE), and tenocyclidine (TCP).[51] 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 some countries such as the United States, Australia, and New Zealand, 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.[76][77]

History

Phencyclidine was initially discovered in 1926 by Arthur Kötz [de] and his student Paul Merkel as a product of a Grignard reaction of 1-piperidinocyclohexancarbonitrile.[78]

It was again made in 1956 and brought to market as an anesthetic medication.[74][13][79][78][80] Its use in humans was disallowed in the United States in 1965 due to the high rates of side effects, while its use in animals was disallowed in 1978.[1][13][81] Moreover, ketamine was discovered and was better tolerated as an anesthetic.[81]

PCP is classified as a

schedule II drug in the United States.[1] A number of derivatives of PCP have been sold for recreational and non-medical use.[51]

Society and culture

Regulation

PCP is a Schedule II substance in the United States and its ACSCN is 7471.[82] Its manufacturing quota for 2014 was 19 grams.[83]

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 United Kingdom.[84]

Frequency of use

PCP began to emerge as a

People magazine and Mike Wallace of 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.[21]
: 46–49 

Cultural depictions

Jean-Michel Basquiat depicted two angel dust users in his 1982 painting Dustheads.[85]

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.[86] He is known to struggle with addiction to phencyclidine, currently and during his time on earth. Additionally his canon cause of death is overdose by phencyclidine, naming himself after the drug.[87]

References

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External links

Scholia has a profile for phencyclidine (Q407324).
Wikimedia Commons has media related to Phencyclidine.