Chemistry:Phencyclidine

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Short description: Dissociative hallucinogenic drug, mostly used recreationally
Phencyclidine
Phencyclidine.svg
Phencyclidine-from-xtal-3D-balls.png
Clinical data
Trade namesSernyl, Sernylan (both discontinued)
Other namesCI-395; Phenylcyclohexylpiperidine; "Angel dust"[1]
AHFS/Drugs.comphencyclidine
Addiction
liability		Variable, reported from low to high[2][3][4]
Routes of
administration		Smoking, injection, snorted, by mouth[5][6]
Drug classNMDA receptor antagonists; General anesthetics; Dissociative hallucinogens[5]
ATC code
  • None
Legal status
Legal status
Pharmacokinetic data
MetabolismOxidative hydroxylation in liver by CYP450 enzymes, glucuronidation
MetabolitesPCHP, PPC, PCAA
Onset of action2–60 min[7]
Elimination half-life7–46 hours
Duration of action6–48 hours[7]
ExcretionUrine
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H25N
Molar mass243.394 g·mol−1
3D model (JSmol)
Melting point46.5 °C (115.7 °F)
Boiling point136 °C (277 °F)
 ☒N☑Y (what is this?)  (verify)

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.[1][5] PCP may cause hallucinations, distorted perceptions of sounds, and violent behavior.[5][8][9] As a recreational drug, it is typically smoked, but may be taken by mouth, snorted, or injected.[5][6][8] It may also be mixed with cannabis or tobacco.[1][5]

Adverse effects may include seizures, coma, addiction, and an increased risk of suicide.[8] Flashbacks may occur despite stopping usage.[9] Chemically, PCP is a member of the arylcyclohexylamine class, and pharmacologically, it is a dissociative anesthetic.[5][10][11] PCP works primarily as an NMDA receptor antagonist.[10]

PCP is most commonly used in the United States.[12] While usage peaked in the US in the 1970s,[13] between 2005 and 2011 an increase in visits to emergency departments as a result of the drug occurred.[8] 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.[14]


Recreational uses

Illicit PCP in several forms seized by the DEA.

Phencyclidine is used for its ability to induce a dissociative state.[15]

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 analgesia and anesthesia. High doses may lead to convulsions.[16] The drug is often illegally produced under poorly controlled conditions; this means that users may be unaware of the actual dose they are taking.[17]

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.[18][19]:48–49[16] 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.[6]

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.[19]:48 Although uncommon, events of PCP-intoxicated individuals acting in an unpredictable fashion, possibly driven by their delusions or hallucinations, have been publicized.[20] Other commonly cited types of incidents include inflicting property damage and self-mutilation of various types, such as pulling one's own teeth.[19]:48[20] 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.[21][22]

Recreational doses of the drug also occasionally appear to induce a psychotic state, with emotional and cognitive impairment that resembles a schizophrenic episode.[23][24] Users generally report feeling detached from reality.[25]

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.[26]

Addiction

PCP is self-administered and induces ΔFosB expression in the D1-type medium spiny neurons of the nucleus accumbens,[2][27] and accordingly, excessive PCP use is known to cause addiction.[2] 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.[2] PCP has been shown to produce conditioned place aversion and conditioned place preference in animal studies.[28]

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%.[29]

Methods of administration

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.[30]

  • 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.[31]
  • PCP hydrochloride can be insufflated (snorted), depending upon the purity. This is most often referred to as "angel dust".[30]
  • An oral pill can also be compressed from the co-compounded powder form of the drug. This is usually referred to as "peace pill".[30]
  • The free base is quite hydrophobic and may be absorbed through skin and mucus membranes (often inadvertently). This form of the drug is commonly called "wack".[30]

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.[32][33][34] 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.[32][33] If an antipsychotic is given, intramuscular haloperidol has been recommended.[34][35][36]

Forced acid diuresis (with ammonium chloride or, more safely, ascorbic acid) may increase clearance of PCP from the body, and was somewhat controversially recommended in the past as a decontamination measure.[32][33][34] 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.[32][33]

Pharmacology

Pharmacodynamics

Site Ki (nM) Action Species Ref
MOR >10,000 ND Human [37]
DOR >10,000 ND Human [37]
KOR >10,000 ND Human [37]
NOP >10,000 ND Human [37]
σ1 >10,000 Agonist Guinea pig [37][38]
σ2 136 Agonist Rat [37]
D2 >10,000 ND Human [37]
  D2High 2.7–4.3
144 (EC50)		 Partial Agonist Rat/human
Human		 [39][40]
[41]
5-HT2A >10,000 ND Human [37]
  5-HT2AHigh ≥5,000 Agonist? Rat [40][42]
SERT 2,234 Inhibitor Human [37]
NET >10,000 Inhibitor Human [37]
DAT >10,000 Inhibitor Human [37]
PCP2 154 ND Human [43]
[3H]5-HT uptake 1,424 (IC50) Inhibitor Rat [44]
[3H]NIS binding 16,628 (IC50) Inhibitor Rat [44]
[3H]DA uptake 347 (IC50) Inhibitor Rat [44]
[3H]CFT binding 1,547 (IC50) Inhibitor Rat [44]
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.[45][41] As such, PCP is a noncompetitive 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[46] and colleagues.[47] Other NMDA receptor antagonists include ketamine,[48] tiletamine,[49] dextromethorphan,[50] 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[51] and NMDA receptors.[52] 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.[53] These effects can lead to inhibition of excitatory glutamate activity in certain brain regions such as the hippocampus[54] and cerebellum[55] 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.[9]

PCP, like ketamine, also acts as a potent dopamine D2High receptor partial agonist in rat brain homogenate[41] and has affinity for the human cloned D2High receptor.[56] 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.[57]

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.[58] However, PCP has little affinity for the human monoamine transporters, including the dopamine transporter (DAT).[37] Instead, its inhibition of monoamine reuptake may be mediated by interactions with allosteric sites on the monoamine transporters.[37] 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.[43]

Studies on rats indicate that PCP interacts indirectly with opioid receptors (endorphin and enkephalin) to produce analgesia.[59]

A binding study assessed PCP at 56 sites including neurotransmitter receptors and transporters and found that PCP had Ki values of >10,000 nM at all sites except the dizocilpine (MK-801) site of the NMDA receptor (Ki = 59 nM), the σ2 receptor (PC12) (Ki = 136 nM), and the serotonin transporter (Ki = 2,234 nM).[37] The study notably found Ki values of >10,000 nM for the D2 receptor, the opioid receptors, the σ1 receptor, and the dopamine and norepinephrine transporters.[37] These results suggest that PCP is a highly selective ligand of the NMDAR and σ2 receptor.[37] However, PCP may also interact with allosteric sites on the monoamine transporters to produce inhibition of monoamine reuptake.[37]

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.[60][18] 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.[61] The PCP binding site is within close proximity to the magnesium blocking site, which may explain the similar inhibitory effects.[62] Binding at the PCP site is mediated by two non-covalent interactions within the receptor: hydrogen bonding and hydrophobic interaction.[63] 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.[64]

Neurotoxicity

Some studies found that, like other NMDA receptor antagonists, PCP can cause a kind of brain damage called Olney's lesions in rats.[65][66] 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,[67] 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.[68] It also induces symptoms in humans that mimic schizophrenia.[69] 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.[70] PCP-induced augmentation of dopamine release may link the NMDA and dopamine hypotheses of schizophrenia.[71]

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.[62] 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.[18]

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.[18]

Chemistry

PCP is an arylcyclohexylamine.

Analogues

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.[47] Only of a few of these compounds were widely used including rolicyclidine (PCPy), eticyclidine (PCE), and tenocyclidine (TCP).[47] 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.[72][73]

History

PCP was initially made in 1956 and brought to market as an anesthetic medication.[74][11][75][76][77] 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][11][78] Moreover, ketamine was discovered and was better tolerated as an anesthetic.[78]

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.[47]

Society and culture

Regulation

PCP is a Schedule II substance in the United States and its ACSCN is 7471.[79] Its manufacturing quota for 2014 was 19 grams.[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 United Kingdom.[81]

Frequency of use

PCP began to emerge as a recreational drug in major cities in the United States in the 1960s.[8] In 1978, 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.[19]:46–49

Cultural depictions

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

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "PCP Fast Facts". National Drug Intelligence Center. 2003. https://www.justice.gov/archive/ndic/pubs4/4440/. 
  2. ↑ 2.0 2.1 2.2 2.3 "Chapter 15: Reinforcement and Addictive Disorders". Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. 2009. pp. 374–375. ISBN 9780071481274. 
  3. ↑ (in en) The Principles and Practice of Medicine. McGraw Hill Professional. 1996. p. 933. ISBN 9780071383653. https://books.google.com/books?id=aA9mMB3lDh4C. "high abuse liability" 
  4. ↑ (in en) Perspectives on Substance Use, Disorders, and Addiction: With Clinical Cases. SAGE Publications. 2015. p. 145. ISBN 9781483377773. https://books.google.com/books?id=7qxiCgAAQBAJ&pg=PT145. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 "Chapter 35: Phencyclidine". Handbook of Substance Abuse: Neurobehavioral Pharmacology. New York City: Plenum Publishing Corporation. 1998. pp. 579–587. ISBN 978-1-4757-2913-9. https://books.google.com/books?id=-0r0BwAAQBAJ&pg=PA579. 
  6. ↑ 6.0 6.1 6.2 "NIDA InfoFacts: Hallucinogens – LSD, Peyote, Psilocybin, and PCP". National Institute on Drug Abuse. http://drugabuse.gov/infofacts/hallucinogens.html. 
  7. ↑ 7.0 7.1 Manual of forensic emergency medicine : a guide for clinicians. Sudbury, Mass.: Jones and Bartlett Publishers. 2010. pp. 41–42. ISBN 9780763744625. https://books.google.com/books?id=keng9ELAE2IC&pg=PA41. 
  8. ↑ 8.0 8.1 8.2 8.3 8.4 "Emergency Department Visits Involving Phencyclidine (PCP)". The CBHSQ Report. Rockville (MD): Substance Abuse and Mental Health Services Administration (US). 2013. "PCP can lead to hostile behavior that may result in episodes of extreme violence" 
  9. ↑ 9.0 9.1 9.2 "Hallucinogens" (in en). National Institute on Drug Abuse. January 2016. https://www.drugabuse.gov/publications/drugfacts/hallucinogens. 
  10. ↑ 10.0 10.1 (in en) Drugs in American Society: An Encyclopedia of History, Politics, Culture, and the Law [3 volumes]. ABC-CLIO. 2014. p. 732. ISBN 9781610695961. https://books.google.com/books?id=c5PgBQAAQBAJ&pg=PA732. 
  11. ↑ 11.0 11.1 11.2 (in en) Forensic Pharmacology. Infobase Publishing. 2007. p. 97. ISBN 9781438103822. https://books.google.com/books?id=tyBE3F5ACK4C&pg=PA97. 
  12. ↑ "GINAD" (in en). http://www.ginad.org/en/drugs/drugs/306/pcp-. 
  13. ↑ "PCP" (in en). http://www.cesar.umd.edu/cesar/drugs/pcp.asp. 
  14. ↑ "Hallucinogens". https://www.drugabuse.gov/drugs-abuse/hallucinogens. 
  15. ↑ "Contrasting mechanisms of action and sensitivity to antipsychotics of phencyclidine versus amphetamine: importance of nucleus accumbens 5-HT2A sites for PCP-induced locomotion in the rat". The European Journal of Neuroscience 11 (12): 4419–32. December 1999. doi:10.1046/j.1460-9568.1999.00858.x. PMID 10594669. 
  16. ↑ 16.0 16.1 Diaz, Jaime. How Drugs Influence Behavior. Englewood Cliffs: Prentice Hall, 1996.
  17. ↑ "Neuroscience for Kids – PCP". Neuroscience for Kids. http://faculty.washington.edu/chudler/pcp.html. 
  18. ↑ 18.0 18.1 18.2 18.3 "Phencyclidine intoxication and adverse effects: a clinical and pharmacological review of an illicit drug". The California Journal of Emergency Medicine 8 (1): 9–14. February 2007. PMID 20440387. 
  19. ↑ 19.0 19.1 19.2 19.3 The War on Drugs II. Mayfield Publishing Company. 1992. ISBN 978-1-55934-016-8. 
  20. ↑ 20.0 20.1 "The Dusting of America: The Image of Phencyclidine (PCP) in the Popular Media". Journal of Psychedelic Drugs 12 (3–4): 195–204. July 1980. doi:10.1080/02791072.1980.10471426. PMID 7431414. 
  21. ↑ "Phencyclidine and violence: clinical and legal issues". Journal of Clinical Psychopharmacology 8 (6): 397–401. December 1988. doi:10.1097/00004714-198812000-00003. PMID 3069880. 
  22. ↑ "PCP and crime: just another illicit drug?". NIDA Research Monograph 64: 174–89. 1986. PMID 3086733. 
  23. ↑ "Functional roles of the glial glutamate transporter (GLAST) in emotional and cognitive abnormalities of mice after repeated phencyclidine administration". Eur Neuropsychopharmacol 29 (8): 918–24. August 2019. doi:10.1016/j.euroneuro.2019.06.005. PMID 31303267. 
  24. ↑ "The phencyclidine psychosis: phenomenology and treatment". NIDA Research Monograph (National Institute on Drug Abuse) (21): 241–253. August 1978. PMID 101872. https://archives.drugabuse.gov/sites/default/files/monograph21.pdf. 
  25. ↑ "Dissociative anesthesia". California Medicine 117 (4): 46–47. October 1972. PMID 18730832. 
  26. ↑ Drugs of Abuse (Second ed.). Los Angeles: Practice Management Information Corp. 1997. p. 126. ISBN 978-1-57066-053-5. 
  27. ↑ "Review. Transcriptional mechanisms of addiction: role of DeltaFosB". Philos. Trans. R. Soc. Lond. B Biol. Sci. 363 (1507): 3245–3255. October 12, 2008. doi:10.1098/rstb.2008.0067. PMID 18640924. "Table 1: Drugs of abuse known to induce ΔFosB in nucleus accumbens after chronic administration". Philos. Trans. R. Soc. Lond. B Biol. Sci. 363 (1507): 3245–55. October 2008. doi:10.1098/rstb.2008.0067. PMID 18640924. 
  28. ↑ "Neuronal mechanisms of phencyclidine-induced place aversion and preference in the conditioned place preference task". Methods and Findings in Experimental and Clinical Pharmacology 20 (7): 607–11. September 1998. doi:10.1358/mf.1998.20.7.485726. PMID 9819806. 
  29. ↑ "Transition of Substance-Induced, Brief, and Atypical Psychoses to Schizophrenia: A Systematic Review and Meta-analysis". Schizophrenia Bulletin 46 (3): 505–516. April 2020. doi:10.1093/schbul/sbz102. PMID 31618428. 
  30. ↑ 30.0 30.1 30.2 30.3 "DARK Classics in Chemical Neuroscience: Phencyclidine (PCP)". ACS Chemical Neuroscience 9 (10): 2459–2474. October 2018. doi:10.1021/acschemneuro.8b00266. PMID 29953199. 
  31. ↑ "Fry Fast Facts". National Drug Intelligence Center. https://www.justice.gov/archive/ndic/pubs11/12208/. 
  32. ↑ 32.0 32.1 32.2 32.3 "Phencyclidine Toxicity". eMedicine. October 6, 2008. http://www.emedicine.com/med/TOPIC1813.HTM.  Retrieved on November 3, 2008.
  33. ↑ 33.0 33.1 33.2 33.3 "Chapter 69: Phencyclidine and ketamine". Goldfrank's Toxicologic Emergencies. New York: McGraw-Hill. 2002. pp. 1034–1041. ISBN 978-0-07-136001-2. https://books.google.com/books?id=HVYyRsuUEc0C&pg=PA1041. 
  34. ↑ 34.0 34.1 34.2 "Diagnosis and management of phencyclidine intoxication". American Family Physician 43 (4): 1293–302. Apr 1991. PMID 2008817. 
  35. ↑ "PCP: Management of acute intoxication". Medical Times 113 (9): 43–49. 1985. 
  36. ↑ "Comparison of haloperidol and chlorpromazine in the treatment of phencyclidine psychosis". Journal of Clinical Pharmacology 24 (4): 202–4. Apr 1984. doi:10.1002/j.1552-4604.1984.tb01831.x. PMID 6725621. 
  37. ↑ 37.00 37.01 37.02 37.03 37.04 37.05 37.06 37.07 37.08 37.09 37.10 37.11 37.12 37.13 37.14 37.15 37.16 Cite error: Invalid <ref> tag; no text was provided for refs named pmid23527166
  38. ↑ "Reviewing the ketamine model for schizophrenia". J. Psychopharmacol. (Oxford) 28 (4): 287–302. 2014. doi:10.1177/0269881113512909. PMID 24257811. 
  39. ↑ "Phencyclidine and glutamate agonist LY379268 stimulate dopamine D2High receptors: D2 basis for schizophrenia". Synapse 62 (11): 819–28. 2008. doi:10.1002/syn.20561. PMID 18720422. 
  40. ↑ 40.0 40.1 "NMDA receptor antagonists ketamine and PCP have direct effects on the dopamine D(2) and serotonin 5-HT(2)receptors-implications for models of schizophrenia". Mol. Psychiatry 7 (8): 837–44. 2002. doi:10.1038/sj.mp.4001093. PMID 12232776. 
  41. ↑ 41.0 41.1 41.2 "Dopamine D2High receptors stimulated by phencyclidines, lysergic acid diethylamide, salvinorin A, and modafinil". Synapse 63 (8): 698–704. 2009. doi:10.1002/syn.20647. PMID 19391150. 
  42. ↑ "Role of serotonergic 5-HT2A receptors in the psychotomimetic actions of phencyclidine". Int. J. Neuropsychopharmacol. 3 (4): 333–338. 2000. doi:10.1017/S1461145700002091. PMID 11343613. 
  43. ↑ 43.0 43.1 "PCP site 2: a high affinity MK-801-insensitive phencyclidine binding site". Neurotoxicol Teratol 16 (4): 343–53. 1994. doi:10.1016/0892-0362(94)90022-1. PMID 7968938. https://zenodo.org/record/1258623. 
  44. ↑ 44.0 44.1 44.2 44.3 "RTI-4793-14, a new ligand with high affinity and selectivity for the (+)-MK801-insensitive [3H1-]1-(2-thienyl)cyclohexyl]piperidine binding site (PCP site 2) of guinea pig brain"]. Synapse 16 (1): 59–65. 1994. doi:10.1002/syn.890160107. PMID 8134901. https://zenodo.org/record/1229378. 
  45. ↑ "The efficacy of sodium channel blockers to prevent phencyclidine-induced cognitive dysfunction in the rat: potential for novel treatments for schizophrenia". The Journal of Pharmacology and Experimental Therapeutics 338 (1): 100–13. Jul 2011. doi:10.1124/jpet.110.178475. PMID 21487071. 
  46. ↑ "The dissociative anaesthetics, ketamine and phencyclidine, selectively reduce excitation of central mammalian neurones by N-methyl-aspartate". British Journal of Pharmacology 79 (2): 565–575. 1983. doi:10.1111/j.1476-5381.1983.tb11031.x. PMID 6317114. 
  47. ↑ 47.0 47.1 47.2 47.3 "From PCP to MXE: a comprehensive review of the non-medical use of dissociative drugs". Drug Testing and Analysis 6 (7–8): 614–32. 2014. doi:10.1002/dta.1620. PMID 24678061. 
  48. ↑ "Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy". Therapeutic Advances in Psychopharmacology 4 (2): 75–99. Apr 2014. doi:10.1177/2045125313507739. PMID 24688759. 
  49. ↑ "Paradoxical convulsant action of a novel non-competitive N-methyl-D-aspartate (NMDA) antagonist, tiletamine". Brain Research 461 (2): 343–8. Oct 1988. doi:10.1016/0006-8993(88)90265-X. PMID 2846121. 
  50. ↑ "Antitussives and substance abuse". Substance Abuse and Rehabilitation 4: 75–82. 2013. doi:10.2147/SAR.S36761. PMID 24648790. 
  51. ↑ "Site of action of phencyclidine. IV. Interaction of phencyclidine and its analogues on ionic channels of the electrically excitable membrane and nicotinic receptor: implications for behavioral effects". Molecular Pharmacology 21 (3): 637–47. May 1982. PMID 6287200. 
  52. ↑ "Novel analogues of ketamine and phencyclidine as NMDA receptor antagonists". Bioorganic & Medicinal Chemistry Letters 21 (7): 2059–63. Apr 2011. doi:10.1016/j.bmcl.2011.02.009. PMID 21334205. 
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