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Phencyclidine The Dawn Of A New Age

Phencyclidine: The Dawn Of A New Age Essay, Research Paper


Phencyclidine: The Dawn of a New Age


April, 1956 : The pharmaceutical company Parke & Davis first synthesize what


they believe to be the perfect anesthetic (Souza, 1995). When administered to


patients, it causes a completely dissociative state, with no significant


respiratory or cardiovascular depression. Patients appear to be awake, eyes


open, breathing normally.but are unaware of their surroundings or the procedures


being performed upon them (Souza, 1995). Indeed, this is the perfect drug.


Unfortunately, like all good things, this one has a darker side. 15% of


patients awake from their slumber with what appeared to be an acute case of


paranoid schizophrenia (Peterson; Stillman, 1978). The drug is PCP, and to this


day it is the scourge of the underground drug community, and the focal point of


intense scientific research. Parke Davis and Company did not know how terrible,


and wonderful, a discovery they made that day; but our world has been changed


forever because of it.quite possibly for the better.


The Dust of Angels


Phencyclidine, more commonly known as PCP, is a polycyclic compound belonging to


the arylcyclohexylamine class of chemicals [figure 1.0] (Souza 1993). In pure


form, it is a white powder which readily dissolves in water. The cyclohexamines


are known for their the potent neurological effects, with PCP being the most


potent. Almost every variation has been administered to, or abused by, humans at


some time (Nintey Fifth Congress, 1978). All these compounds have similar


pharmacological effects, which vary considerably according to the amount


administered. Small doses produce a `drunken’ state, in which subjects report a


numbness in the extremities, while some species (like dogs and cats) become


quite excited (Halberstadt, 1995). Intermediate doses have anesthetic and


analgesic effects , with the psychic state resembling sensory isolation with one


important exception: the sensory impulses (when tested electrophysiologically)


reach the neocortex but “the neuronal signals are grossly distorted”


(Halberstadt, 1995). Large doses, especially of PCP, may produce convulsions.


Any dose produces cataleptoid muscle effects (Halberstadt, 1995). All the


chemicals in this class produce a range a physiological effects, including


tachydardia and hypertension (Halberstadt, 1995). Unlike the other


cyclohexamines, however, PCP causes severe “emergence delirium” when taken in


moderate to anesthetic quantities (Halberstadt, 1995). On the other hand,


ketamine, a close cousin of PCP, produces depressant effects which are more


amplified than PCP without the psychotic aftereffects (although hallucinations


are reported by patients during sedation, (Halberstadt, 1995)). In special cases,


ketamine is still used as an anesthetic. (C.H. Badenhorst M.D, personal


communication).


Ten years after its initial discovery, phencyclidine found a new


audience in the scientific and underground drug culture communities (Nintey


Fifth Congress, 1978). At this time, a few Freudian psychologists carried out


unauthorized experiments in which perfectly healthy patients were given PCP and


observed (Nintey Fifth Congress, 1978). Although their research did not provide


much useful data, it did begin a revolution in our knowledge of the chemical


basis for schizophrenia (Nintey Fifth Congress, 1978). In 1987, the FDA removed


Sernyl (phencyclidine’s market name) from the human market and reserved it for


use only as an animal tranquilizer, for which it is still used today (Peterson,


1978). Unfortunately, some individuals were still able to obtain the drug,


either through theft or home synthesis in a garage laboratory (Nintey Fifth


Congress, 1978). It was distributed under a number of slang terms, including


PeaCe Pill, THC, and Love Boat; and rapidly spread throughout the country as a


result of its low price and availability (Peterson, 1978). There were many


casualties.not because of the drug, but because of its effects. Hospitals also


noticed a sudden increase in paranoid schizophrenic admissions (Peterson, 1978),


which naturally sparked more interest in this enigma of a drug, and raised many


questions: Why were people addicted to a drug which seldom generated “good


trips”? Why (and more importantly, how) was this drug causing episodes of


paranoid schizophrenia? A new era in drug research for schizophrenia had been


opened.


The Excitory Amino Acid Link


If one takes a moment to consider what a amazing drug PCP is, then it is easy to


see just why scientists were so excited. Here was a single chemical which could


induce schizophrenia (Restak, 1994), a bright arrow pointing to a possible cause


of this terrible disorder. Scientists hypothesized that perhaps there were


naturally occurring phencyclidine-like substances within the brain which


malfunction and caused psychotic states (Restak 1994). This “magic” compound was


jokingly referred to as “Angle Dustin” (Restak, 1994). In truth, these


scientists were much closer to the truth than they thought.but there is an


interesting twist.


In the brain, there are three prevalent amino acid neurotransmitters:


glycine, glutamate, and aspartate; collectively these are referred to as the


excitory amino acids (Restak, 1994). They are secreted at nerve terminals, and


interact with receptors on the neuron at the post synaptic membrane (Haberstadt,


1995). Without these neurotransmitters, the brain would simply cease to work.


Too much of them, however, and the brain also tends to stop working. These


neurotransmitters function by opening ion channels within a neuron, effectively


depolarizing it; through “coupling via the glutamate receptor with other


chemicals that initiate a chain reaction of interlinked chemical processes


within the neuron” (Haberstadt, 1995). In other words, they excite the neuron by


allowing charged ions to enter it. As said before, however, too much of these


neurotransmitters would kill the neuron by exciting it to death. As a matter of


fact, this is the principle damaging factor in stroke patients (Restak, 1994).


When a neuron dies, it releases copious amounts of amino acid neurotransmitters


which then kill other brain cells through the excitotoxic effect (Souza, 1993).


In order to study this effect more fully, scientists used a glutamate analog


known as NMDA (N-methyl-D-Aspartate) which was considerably more potent than


glutamate by itself (Souza, 1993). Quite accidentally, the scientists also


discovered an NMDA antagonist, which turned out to be phencyclidine. Now here is


an interesting situation: PCP is known to be a “bad” drug, causing many unwanted


effects and hardly any beneficial ones. NMDA (or more appropriately, the


excitatory amino acids), on the other hand is a good drug; being necessary for


normal brain functioning. Ironically, PCP is a N-methyl-D-Aspartate antagonist


and counteracts any damage done by excitotoxic levels of NMDA in laboratory


animals (Restak, 1994). This is where a very important question is raised: What


role do excitory amino acids play in schizophrenia? There are, of course, two


possible directions to this question. Either schizophrenic patients have too


much glutamate, or too little (Haberstadt, 1995). Unfortunately, the answer is


never quite so simple; but some important pieces in the schizophrenia puzzle had


been found (Haberstadt, 1995).


Biochemistry of an Angel


For the last decade, scientists have been hard at work trying to


decipher the complex biochemistry of PCP. The results have been extraordinary,


with the effects of phencyclidine depending on a magnificent symphony of


receptor sites and chemical concentrations on the neuron. As was stated before,


the effects of the excitory amino acids are mediated by the NMDA receptor


subtype (in addition to 4 others) (Restak, 1995). It is known that one of PCP’s


major preferences lies with the NMDA receptor complex (Souza, 1993). The NMDA


receptor “mediates ion flux through a channel permeable to Na+, K+, and Ca2+”


(Souza, 1993). The ion flux is voltage dependent, which is in turn controlled by


Mg2+ and phencyclidine (Souza, 1993). On the other hand, the extent of channel


activation is controlled by glycine through the use of NMDA agonists (Souza,


1993). Some polyamines have also recently been shown to use some sites to


control glycine binding (Haberstadt, 1995). In addition, the NMDA and glycine


receptors have been shown to exist in both antagonist and agonist conformations,


depending on the relative concentrations of glutamate, glycine, and polyamine


compounds (Haberstadt, 1995). It is through this rather complex series of checks


and balances that the effects of PCP are mediated. In short, the effects depend


on the extent of channel activation; which is dependent on at least five


different receptor/binding sites.


After considerable experimentation, the actual site of the PCP receptor


was pinpointed as being within the actual channel gated by the NMDA excitory


amino acid receptor (see figure 2.0). There are several important points which


support this conclusion. Most obvious is that the “PCP and NMDA receptors are


co-localized in the central nervous system” (Souza, 1995). Second, the “PCP


receptor ligands have been shown to inhibit NMDA-receptor-mediated conductance


non-competitively in a voltage and use dependent fashion” (Souza, 1995). Lastly,


the effectiveness of the PCP receptors is decreased by competitive NMDA receptor


agonists but increased by competitive NMDA receptor antagonists (Souza, 1993),


an exciting lead when it comes to determining the chemical mechanisms of


schizophrenia, as related to a malfunction in the NMDA receptor function. Since


PCP inhibits the NMDA receptor, the schizophrenic brain’s NMDA receptors may be


below normal functional parameters (Haberstadt, 1995).


The Crazy Angel is Blamed


There is no doubt that PCP induces a state very similar to positive


symptom schizophrenia. There is some doubt, however, if PCP’s tendency to block


the NMDA channel is to blame for the relevant clinical symptoms (Halberstadt,


1995). The ability for the PCP molecule to bond with such effectiveness to the


PCP receptor within the channel is certainly strong evidence, but some doubt the


degree of blame. Fingers have also been pointed at the “haloperidol-sensitive


sigma” receptor sites, and at monoamine reuptake sites (the core of the dopamine


hypothesis for schizophrenia) (Halberstadt, 1995). These alternative sites are


also receptive to a PCP molecule, and undoubtedly play a role in schizophrenia,


but several lines of evidence support the PCP receptor as the major force behind


the “psychotomimetic effects of PCP” (Svennson, 1995).


First, “PCP receptors have been shown to mediate the discriminative


stimulus effects of PCP in rodents” (Svennson, 1995). PCP researchers have


trained animals to discriminate between PCP and saline solutions. When these


animals are give one of a wide range of chemical substances (each from a


distinctive chemical class), the animal’s response is directly proportional to


the rank order of the drug’s binding power to the PCP receptor. Hence, a


stronger PCP receptor bond leads to a better NMDA channel blockade, and

a


stronger drug response. On the other hand, there is no PCP-like result when the


test animals are given drugs which selectively bind to sigma and/or dopamine


reuptake sites (Svennson, 1995).


Second, “psychotomimetic effects similar to those induced by PCP can be


induced by ketamine, a related arylcyclohexamine derivative” (Sevvenson, 1995).


This is a particulary strong point of evidence, especially when coupled with the


following point: A dosage of ketamine ten times that of PCP is required in order


to induce the same effect (Halberstadt, 1995). This fits perfectly with


ketamine’s reduced effectiveness in binding to PCP receptors, which is


approximately ten times less than that of PCP. Ketamine is also “essentially


inactive” (Halberstadt, 1995) at both sigma receptor and dopamine reuptake sites.


At this time it is important to note that PCP does indeed also bind to sigma


receptors and dopamine reuptake sites, albeit with a lower affinity (Okuyama,


1994). This may be an important functional link between schizophrenia and PCP;


since ketamine binds only to PCP receptors and does not induce paranoid


schizophrenia. PCP, on the other hand, has a broader receptor range and does


induce schizophrenia (Halberstadt, 1995).


Finally, there is consistent evidence that PCP psychosis can be induced


by serum concentrations of 20 nM (Souza, 1993). Any PCP levels which are higher


than 400 nM are associated with anesthetic effects. It has been shown that PCP


receptors bind to PCP at concentrations of 30-50 nM, “suggesting a highly


significant degree of receptor occupancy by levels of PCP present during low


dose PCP psychosis” (Souza, 1993). This point is hammered home, considering that


sigma binding and dopamine reuptake sites only bind to PCP along the order of


600 nM and 700 nM, respectivly (Souza, 1993). It is easy to see that the


affinity these sites have for PCP is significantly lower than that of the PCP


receptor. Hence, it is not very likely that the small amount of PCP needed for


psychosis would be acting on anything except the PCP receptors. Once again,


however, it is important to remember that PCP does not bind solely to PCP


receptors.


Opposites Attract


One of the prevailing theories of schizophrenia is the dopamine


hypothesis, in which abnormal dopamine levels are implicated as its cause. This


theory seems to conflict with the theory presented in this paper, in which


abnormal functioning of the NMDA ion channel is seen as the cause. There is,


however, another important aspect of PCP induced psychosis which has not yet


been discussed: the link to the A10 dopamine releasing neurons (Restak, 1994).


Most of the brain’s dopamine is thought to be released from the A10-


mesolimbic-mesocortical system within the ventral tegmental region of the brain


(Halberstad, 1995). This area is thought to play an important role in addiction


to PCP since PCP seems to stimulate the release of dopamine, a behavior


enforcing mechanism (Halberstad, 1995). How phencyclidine was is able to do this


has remained a mystery until only recently. It was previously unknown as to


which receptor was more important in stimulating dopamine release, the PCP


receptor or the sigma receptor (Halberstad, 1995). To find out, scientists gave


test animals one of five PCP-receptor specific drugs; MK-801, PCP, (+)SKF, or


ketamine (Restak, 1994). The degree of A10 excitation was then measured. With


MK-801 being the most powerful PCP ligand, a 40% increase in A10 neuronal firing


rate is detected. Following closely behind are PCP, (+)SKF and ketamine,


respectively (Restak, 1994). This order correlates perfectly with the respective


order of PCP receptor binding, strong evidence in supporting the role of the


NMDA ion channel in A10 dopamine release (Restak, 1994). On the other end of the


spectrum, giving test animals the potent sigma ligand (+)pentazocine resulted in


only a 14% increase in A10 neuron firing rate (Halberstad, 1995), with DTG


having no measurable effect (Halberstad, 1995). Moreover, A10 activation by PCP


is not attenuated by haloperidol; which has the highest known sigma receptor


affinity (Halberstad, 1995). In other words, “The potency of PCP-like drugs to


alter A10 activity was found to correlate positively with their affinity for the


PCP receptor and consequently with their potency as NMDA agonists”. (Halberstad,


1995)


The obvious conclusion to draw from the above research is to say that


stimulation of the A10 neurons is the result of NMDA channel blockage. In a


strange twist however, this does not appear to be the case. The chemicals NPC


12626 and (?)CPP are among the most potent NMDA channel blockers known (Souza,


1995). When animals are given NPC 12626 or (?)CPP there is no change in A10


firing rate, even after 45 minutes of infusion (Souza, 1995). If this treatment


is then followed up by infusion with PCP, then the normal 40% increase in


dopamine firing is noted.not a higher rate as would be predicted by the current


model (Souza, 1995). Obviously, NMDA channel blockage is not behind the


increased A10 neuronal firing (Souza, 1995). The mechanisim by which PCP does


induce this effect is still subject to research (Halberstad, 1995). Regardless,


phencyclidine does have an effect on dopaminerginc activity and dopamine does


play an important role in schizophrenia (Souza, 1995). From this, one can see


that PCP agonists or antagonists may well be useful in treating schizophrenia.


The Crazy Crazy Man


When applying PCP psychosis to schizophrenia, a rather intriguing question


arises: What effect would PCP have on schizophrenics. The answer, of course,


raises more questions than it answers.


According to Crow, there are two types of schizophrenics, Type I and


Type II (Halberstad, 1995). Surprisingly, this model fits quite nicely when


these patients are treated with PCP. Type I schizophrenics have a “super


sensitive response to the normal amounts of endogenous PCP ligand” (Halberstad,


1995). Type II schizophrenics, on the other hand, show “Dysfunction of the


feedback look regulating PCP ligand activity, resulting in excess PCP ligand


levels” (Halberstad, 1995). Type I’s response is the result of excess A10


dopaminergic activity which makes the PCP receptor considerably more sensitive


(Halberstad, 1995). Type II’s response, the dysfunction of the feedback loop,


“is analogous to hypthalmic-pituitary-adrenal (HPA) axis dysfunction in


endogenous dysfunction (Halberstad, 1995). In general terms, a small dose


worsens Type I but leaves Type II untouched (Halberstad, 1995). A larger dose of


PCP worsens Type I to an even greater extent, while Type II shows moderate


improvement (showing the amphetamine-like activity induced by PCP) (Halberstad,


1995). From this data, it can be concluded that people who have a psychotic


response to PCP have a “biologic diathesis” (Restak, 1994) sensitivity to PCP


resembling that which Type I patients exhibit; except with a diminished


genotypic expression (Halberstad, 1995).


Curing the Ill


A number of novel drug treatment ideas have arisen from all the PCP


research, the most obvious of which is a attempted treatment of schizophrenia by


drugs which keep the NMDA channel open. This is, however, more difficult than


one would first expect. Direct stimulation on the channel is not possible, since


neurotoxicity would result from excessive calcium ion levels within the neuron


(Peterson, 1978). Instead, many of the current drugs call on glycine to


stimulate the channel indirectly. Recall that glutamate is responsible for


keeping the channel open, with help from certain reinforcing molecules like


glycine and polyamines (PCP closes the channel, and causes psychosis).


In one experiment, 11 schizophrenic patients were given 5-25mg of


glycine per day as “a concomitant drug to the neuroleptic treatment” (Souza,


1993). Four of the initial eleven patients responded favorably to this, as would


be expected. In a related open study, glycine was given to six chronic


schizophrenic patients. Two of the subjects benefited, one of which deteriorated


when denied the drug (Souza, 1993). Two other patients actually worsened as a


result of the treatment, while the remaining four showed no change (Souza, 1993).


In another study, five male schizophrenic patients were given the pro-


drug known as Milacemide (Souza, 1993), which is an acetylated version of


glycine. Milacemide is better able to cross the blood brain barrier, as compared


to pure glycine (Souza,1993). Milacemide was given to five male schizophrenic


patients after a three day medication free period (Souza, 1993). All of the


subjects worsened, three of which could not complete the study due to increases


suspiciousness, hostility, or agitation. The negative results, however, could


have been the result of the 3 day drug free period preceding the test period


(Souza, 1993).


Although no real benefit has been shown by the preceding treatments, the


principle behind their action is still strong. It has been suggested that tests


be run on other glutaminergic drugs, like polyamines (Souza, 1993). The NMDA


complex will probably be better stimulated by “direct glutamate agonists”


(Halberstad, 1995), which we may be able to synthesize in the future without


their neuron damaging effects. Regardless, we must not be dissuaded by these


disappointing results. PCP does induce schizophrenia, and there must be a


preventive or curative measure.


Conclusion It is ironic to think that a drug as terrible as phencyclidine could


hold such incredible promise in cracking the mystery of schizophrenia. Although


that day may be far in the future, PCP research has already opened many new


doors in other areas of neurologic dysfunction; such as in the treatment of


epilepsy and stroke damage. PCP has already been shown to have a number of good


uses,If not anything else, this amazing substance has given us a fascinating


look into the elegantly complex world of neurochemistry.


Bibliography – dont forget this!


Carroll, Marilyn. (1992). Encyclopedia of Psychoactive Drugs. New York, N.Y:


Chelsea House Publishers.


Halberstadt, A.L. (1995). The phencyclidine-glutamate model of schizophrenia.


Clinical Neuropharmacology. (Vol. 18) 237-249.


Nintey Fifth Congress. (1978). Abuse of dangerous and illicit drugs -


psychotropics, phencyclidine (PCP), and talwin; Hearings before the select


committee on narcotics abuse and control house of representatives. Washington,


DC: US Government Printing Office.


Okuyama, Shigeru. (1994). NE-100, a novel sigma receptor ligand: Effect on


phencyclidine-induced behaviors in rats, dogs, and monkeys. Life Sciences. (Vol.


55) PL133-138


Peterson, R.C, & Stillman, R.C. (1978). PCP-Phencylidine Abuse: An appraisal.


New York, NY: National Institute on Drug Abuse.


Restak, R.M. (1994). Receptors. New York, N.Y: Bantam Books.


Souza, Errol B., & Clouet, D., & London, E.D. (1993). Sigma, PCP, and NMDA


Receptors. New York, NY: National Institute on Drug Abuse.


Svensson, T.H. (1995). Mode of action of atypical neuroleptics in relation to


the phencyclidine model of schizophrenia. Journal of Clinical Psychopharmacology.


(Vol. 15) 11S-18S

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