Phencyclidine (PCP), also known as angel dust among other names, is a drug used for

its mind-altering effects.[5] PCP may cause hallucinations, distorted perceptions

of sounds, and violent behavior.[7][8] As a recreational drug, it is typically
smoked, but may be taken by mouth, snorted, or injected.[7][4] It may also be mixed
with cannabis or tobacco.[5]

Adverse effects may include seizures, coma, addiction, and an increased risk of
suicide.[7] Flashbacks may occur despite stopping usage.[8] Chemically, PCP is a
member of the arylcyclohexylamine class, and pharmacologically, it is a
dissociative anesthetic.[9][10] PCP works primarily as an NMDA receptor antagonist.
[9]

PCP is most commonly used in the United States.[11] While usage peaked there in the
1970s,[12] between 2005 and 2011 an increase in visits to emergency departments as
a result of the drug occurred.[7] As of 2017 in the United States about 1% of
people in grade twelve 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 life.[13]

PCP was initially made in 1926 and brought to market as an anesthetic medication in
the 1950s.[10][14] Its use in humans was disallowed in the United States in 1965
due to the high rates of side effects while its use in other animals was disallowed
in 1978.[5][15][10] Moreover, ketamine was discovered and was better tolerated as
an anesthetic.[15] PCP is classified as a schedule II drug in the United States.[5]
A number of derivatives of PCP have been sold for recreational and non-medical use.
[16]

Contents
1 Recreational uses
1.1 Effects
1.2 Addiction
1.3 Methods of administration
2 Management of intoxication
3 Pharmacology
3.1 Pharmacodynamics
3.2 Mechanism of action
3.3 Pharmacokinetics
4 Chemistry
4.1 Analogues
5 Usage
6 History
7 Regulation
8 References
9 External links
Recreational uses

Illicit PCP in several forms seized by the DEA.

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

Effects
See also: Excited delirium
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.[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 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.[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.[4]

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.[citation needed] One example is the case of Big Lurch, a
former rapper with a history of violent crime, who was convicted of murdering and
cannibalizing his roommate while under the influence of PCP.[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
that resembles a schizophrenic episode.[25] Users generally report feeling detached
from reality.[26]

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.[27]

Addiction
PCP is self-administered and induces ?FosB expression in the D1-type medium spiny
neurons of the nucleus accumbens,[1][28] and accordingly, excessive PCP use is
known to cause addiction.[1] 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.[1] PCP has been shown to
produce conditioned place aversion and conditioned place preference in animal
studies.[29]

Methods of administration
PCP comes in both powder and liquid forms (PCP base is dissolved most often in
ether), but typically it is sprayed onto leafy material such as cannabis, mint,
oregano, tobacco, parsley, or ginger leaves, then smoked.[citation needed]

PCP can be ingested through smoking. "Fry" or "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.
The free base is quite hydrophobic and may be absorbed through skin and mucus
membranes (often inadvertently).
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.[31][32][33] 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.[31][32] If an antipsychotic is given, intramuscular
haloperidol has been recommended.[33][34][35]

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.[31][32][33] 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), which is not an unusual manifestation of PCP toxicity.[31][32]

Pharmacology
Pharmacodynamics
Phencyclidine[36][37]
Site Ki (nM) Action Species Ref
NMDA 44�59 Antagonist Human [38][39]
MOR >10,000 ND Human [38]
DOR >10,000 ND Human [38]
KOR >10,000 ND Human [38]
NOP >10,000 ND Human [38]
s1 >10,000 Agonist Guinea pig [38][40]
s2 136 Agonist Rat [38]
D2 >10,000 ND Human [38]
D2High 2.7�4.3
144 (EC50) Agonist Rat/human
Human [41][42]
[43]
5-HT2A >10,000 ND Human [38]
5-HT2AHigh =5,000 Agonist? Rat [42][44]
SERT 2,234 Inhibitor Human [38]
NET >10,000 Inhibitor Human [38]
DAT >10,000 Inhibitor Human [38]
PCP2 154 ND Human [39]
[3H]5-HT uptake 1,424 (IC50) Inhibitor Rat [45]
[3H]NIS binding 16,628 (IC50) Inhibitor Rat [45]
[3H]DA uptake 347 (IC50) Inhibitor Rat [45]
[3H]CFT binding 1,547 (IC50) Inhibitor Rat [45]
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, in rats and in rat brain homogenate.[46][43] As such, PCP is an
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.[16] 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.[8]

PCP, like ketamine, also acts as a potent dopamine D2High receptor partial agonist
in rat brain homogenate[43] 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).[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
(Ki = 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.[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 s2 receptor (PC12)
(Ki = 136 nM), and the serotonin transporter (Ki = 2,234 nM).[38] The study notably
found Ki values of >10,000 nM for the D2 receptor, the opioid receptors, the s1
receptor, and the dopamine and norepinephrine transporters.[38] These results
suggest that PCP is a highly selective ligand of the NMDAR and s2 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 an NMDA receptor antagonist that blocks the activity of the NMDA
receptor to cause anaesthesia and analgesia without causing cardiorespiratory
depression.[60][61] 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 enters
the ion channel and binds, reversibly and non-competitively, inside the channel
pore to block the entry of positive ions to the cell therefore inhibiting cell
depolarisation.[60][62]

Neurotoxicity
Some studies found that, like other NMDA receptor antagonists, PCP can cause a kind
of brain damage called Olney's lesions in rats.[63][64] 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 similar drug, far beyond recreational doses,[65] 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.[66] It also induces
symptoms in humans that mimic schizophrenia.[67] 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.[68] PCP
induced augmentation of dopamine release may link the NMDA and DA hypothesis of
schizophrenia.[69]

Pharmacokinetics
PCP is metabolized into PCHP, PPC and PCAA. 90% of phencycledine is metabolised by
oxidative hydroxylation in the liver on first pass. Metabolites are glucroniated
and excreted in the urine. 9% of the drug is excreted in its unchanged form.[61]

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

Conversion of PCP into PC and piperidine by heat.

It takes 15 to 60 minutes for effects of phencyclidine to come into action.[61]

Chemistry
PCP is an arylcyclohexylamine.

Analogues

Possible analogues of PCP

Fewer than 30 different analogues of PCP were reported as being used on the street
during the 1970s and 1980s, mainly in the United States.[16] The best known of
these are rolicyclidine (PCPy or 1-(1-phenylcyclohexyl)pyrrolidine); eticyclidine
(PCE or N-ethyl-1-phenylcyclohexylamine); and tenocyclidine (TCP or 1-(1-(2-
thienyl)cyclohexyl)piperidine).[70] Only of a few of these compounds were widely
used.[16]

The generalized structural motif required for PCP-like activity is derived from
structure-activity relationship studies of PCP derivatives, and summarized in the
illustration (right). 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 analogues of PCP, and are hence illegal drugs if sold for
human consumption, even though many of them have never been made or tested.[71][72]
[clarification needed]

Other analogues of PCP include 3-HO-PCP, 3-MeO-PCMo, and 3-MeO-PCP.

Usage
PCP began to emerge as a recreational drug in major cities in the United States in
1960s.[7] 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.[21]:46�49

History
It is commonly mistakenly reported that PCP was first synthesized in 1926.[73] This
early synthesis, in fact, refers to the PCP intermediate PCC.[16] PCP was actually
discovered by Victor Maddox, a chemist at Parke-Davis in Michigan, while
investigating synthetic analgesic agents. Although unexpected, PCP was identified
as potentially interesting, and as such, was submitted for pharmacological testing.
The promising results of these pharmacological investigations led to the rapid
development of PCP. It was approved for use as an investigational drug under the
brand names Sernyl and Sernylan in the 1950s as an anesthetic, but because of its
long terminal half-life and adverse side effects, such as hallucinations, mania,
delirium, and disorientation, it was removed from the market in 1965 and limited to
veterinary use.[16][74][75]

Regulation
PCP is a Schedule II substance in the United States and its ACSCN is 7471.[76] Its
manufacturing quota for 2014 was 19 grams.[77]

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.[78