Discovery of PCP:
PCP was first synthesized at Parke Davis in 1956. Its synthesis was serendipitous, in that it was an entirely unexpected product from a reaction intended to produce another compound (ref. 1). Because it had such a unique structure, PCP was submitted for evaluation by general pharmacodynamic screening. This involves the administration of a test compound to an animal and observing its behavior. Although this may seem to be a low tech approach to the discovery of new drugs, a trained pharmacologist can often identify potentially interesting physiological effects of an unexplored compound in this manner. During these tests, PCP was found to have a few rather unique properties. It acted mainly on the central nervous system, producing a variety of effects that differed depending on the species and dosage. The responses ranged from ataxia (loss of coordination) and excitation to a condition of surgical anesthesia. Most species in which PCP was evaluated displayed a tameing and quieting effect at low doses. Because of these desirable anesthetic effects and the lack of respiratory depression, a medicinal chemistry program was initiated to evaluate the effect of structural modification on activity. Part of this work was eventually published in a paper that presented the synthesis and structure-activity relationship of sixty analogs (ref. 2).
Clinical studies on PCP:
Because of the promising nature of PCP as an anesthetic, toxicological, neuropharmacological, and metabolism trials were undertaken (reviewed in ref. 3). By 1957, only 3 years after the compound had been synthesized, human clinical trials were underway. By 1963, it had been administered to over 3,000 patients (ref. 5). The first trials ran smoothly, but limitations regarding its use as a surgical anesthetic in man soon became apparent. There was a prolonged postoperative psychosis ("emergence phenomina") produced in 15-30% of the patients (ref. 4). The emergence phenomina appeared as bizarre thought patterns, hallucinations, or delerium as the patient was recovering from anesthesia. Ironically these same therapeutically undesirable phenomina are the properties that make PCP and ketamine so much in demand as recreational or entheogenic drugs. A concensus of the early experiments was that the psychotomimetic effects result from PCP's ability to produce sensory deprivation. Despite its promising profile in low doses as an anesthetic agent (20 mg IV), the exited state often produced at the higher doses necessary for surgical anesthesia (4x this amount) lead to withdrawl of PCP from clinical use in 1965.
Additional effects were frequently noted during clinical tests, such as feelings of estrangement, lonliness, negativism, and hostility. These effects are much less common during non-clinical (recreational) administration, and are partially due to the stressful environment of the clinical tests and the test subject's expectations of the drug's effects. Such negative experiences are not surprising, and can be expected in subjects administered powerful mind-altering drugs while having their behavior closely monitored by experimenters. In contrast, when the drug is self administered by an idividual that is aware of the effects and is seeking an entheogenic/recreational experience, the mental set is entirely different and negative experiences much more infrequent.
PCP and its structural derivatives mimic the primary attention and cognition deficits of schizopherenia in normal individuals more closely than any other drug (ref. 6, 7). Administration of 0.1 mg/kg IV of PCP produces a predictable series of mental alterations that can be difficult to differentiate from true schizophrenia. These effects may include defective perceptual discrimination, concrete thinking, psychomotor retardation, distractibility, alteration of body image, loss of body boundaries, and a profound sense of unreality. LSD, on the other hand, more closely simulates the secondary symptoms of schizophrenia, such as hallucinations.
In the late 1950's, experiments were conducted on administration of PCP to schizophrenic patients. The results were striking. PCP was found to greatly intensify the thought disorders already present, and this effect could last from four to six weeks. This brings up a point that has become ingrained in the street lore surrounding PCP: that it can cause permanent insanity. Actually, PCP has been known to precipitate severe psychoses in individuals not previously diagnosed as schizophrenic. This situation has also been seen with amphetamine and LSD administration, where it is equally rare but still well documented. In these cases, it is likely that the drug unmasks a previously present but latent mental abnormality. In any event, the effects are definately unpleasant for some people, and PCP should never be dispensed in a casual manner.
Ketamine in psychotherapy:
Recently Ketamine has been used in psychotherapy for the treatment of fear of dying (ref. 34). Ketamine has the ability, shared with PCP, to produce model Near Death Experiences (NDE's) (ref. 33). NDE's are of considerable interest in the study of medicine, neuroscience, psychiatry, philosophy, and religon, although they have not been adequately researched. They classically involve an experience of dying that is percieved as "real", with sensations of timelessness, clarity of thought and feelings, calmness and peacefulness, and the sense that the experience cannot be adequately described with language. NDE's can be experienced during surgical crises in which a patient has apparently died, with loss of vital signs. Such a NDE often results loss of the fear of death and a renewed interest in life. Production of artificial NDE's by ketamine has similarly been found effective to decrease an unatural fear of death. An outstanding article is available online concerning the use of ketamine to produce NDE's, and their therapeutic potential. Another excellent online article discusses the central role of the NMDA receptor in mediation of ketamine induced NDE's .
Ketamine has also been used in psychotherapy for alcoholism with a fair amount of success (Ketamine Psychedelic Therapy (KPT)). In one study, total abstinence for more than one year was observed in 65.8% of patients recieving ketamine, compared to 24% of the conventional treatment control group. Additional positive results were apparent, as assayed by Minnesota Multiphasic Personality Inventory (MMPI) profiles. The results included positive transformation of nonverbalized (mostly unconscious) self-concept and emotional attitudes. There were also significant positive changes in life values and purposes, important insights into the meaning of life and an increase in the level of spiritual development (ref. 35). Similar studuies have been undertaken on the use of ketamine in the treatment of heroin addiction (ref 36).
One very interesting focus of another study on KPT in alcoholism was the interactions of ketamine and nimodipine (ref 37). Nimodipine is a calcium channel blocker that is used to treat migraine headaches and complications arising from stroke. The underlying mechanism of ketamine is the blockade of another class of calcium channels. These calcium channels are known to be involved in the processes of thought, memory, emotions, seizures, and the development of alcohol withdrawal syndrome and alcohol dependence. Nimodipine has been previously shown to reverse memory disturbances induced by ketamine, and in this study nimodipine significantly improved the patient's memory of the content of the ketamine psychotherapy session.
PCP first appeared as an illicit drug in San Fransisco in 1967, and has remained available on the black market ever since. However, it is becoming a less commonly used drug, with only 3.9% of highschool seniors in 1997 having ever experienced it, compared to 12.8% in 1979. It has been sold under its true name and a variety of street names, as has been commonly misrepresented as any number of other drugs. Currently, the majority of the clandestine PCP synthesis occurs in the Los Angeles area, with distribution being controlled by street gangs such as the Crips. Its use today is mostly restricted to lower socioeconomic classes in large urban areas, such as L.A. and Washington, D.C.
Dangers associated with PCP use:
PCP has a remarkably negative popular image. This is partly due to the bizarre and violent actions that users may display, although PCP is probably just as likely to precipitate violence as society's favorite dissociative drug, alcohol. However, there is the definate potential to produce a mental state in which rational thought is entirely absent, resulting in strange and uncharacteristic behavior.
Although there is the possibility of vioent and bizarre behavior associated with PCP use, this potential has been greatly exagerated. Even in professional medical and law enforcement texts this is often apparent, as in this passage taken from a textbook on clinical toxicology (ref 66):
"Perhaps the hallmark of PCP intoxication is the recurring delusion of superhuman strength and invulnerability resulting from the analgesic and dissociative properties of the drug. Intoxicated patients have been known to snap hancuffs and, unarmed, attack, large groups of people or police officers. This loss of fear has led patients to try to stop a train by standing in front of it, to grossly mutilate thems elves and others, to climb into a polar bear's cave to take a picture, and to jump from windows or cliffs. The bizarre behavior is often violent, sometimes with gruesome mutilation of both the patient and his or her victim. One intoxicated abuser pulled out his front teeth with a pair of pliers. Another woman fried her baby in cooking oil."
Most casual users of the drug do not experience such effects, but this potential should be realized. Because bodily sensation is dissociated and pain perception can be lost, users may lose track of their bodies and seriously injurie themselves. Therefore, it is wise to only consume PCP in the presence of another individual that is not intoxicated and can act as a "babysitter", preventing the user from inadvertently harming himself. Even with this precaution, it may be difficult to prvent a user from trying to walk into traffic, drive, or engage in other potentially harmful activity.
One way that users reduce this possibility is by mentally "programming" themselves prior to ingestion not to move from the safe location chosen for the experience, even if it may seem like a good idea. Also, the use of tiny doses, by vaporization and inhalation until the desired effects are apparent, allows the production of a more managable, shorter lasting intoxication than other ingestion methods.
At low to moderate doses, the physiological effects of PCP may include a slight increase in breathing rate and a more pronounced rise in blood pressure and pulse rate. Respiration becomes shallow, and flushing and profuse sweating may occur. Generalized numbness of the extremities and muscular incoordination are common. The pupils are neither constricted nor dilated. Nystagmus (involuntary movement of the eyes) is a characteristic effect, and may be vertical, rotary, or horizontal. Motor symptoms are common and may include ataxia (impaired coordination of movement), athetosis (slow writhing movements), myoclonic jerks, and bizarre posture.
At higher doses, there is a drop in blood pressure, pulse rate, and respiration. This may be accompanied by nausea, vomiting, blurred vision, extreme nystagmus, drooling, loss of balance, and dizziness. High doses of PCP can cause seizures, coma, and death (though death more often results from accidental injury or suicide during PCP intoxication).
Treatment of PCP overdose is largely symptomatic and centers around increasing elimination. PCP is eliminated in the GI tract and then quickly reabsorbed, resulting in very long lasting effects. Oral administration of activated charcoal can therefore be helpful to bind it after elimination and remove it from circulation. Increasing the urine acidity by administration of ammonium chloride (or by drinking cranberry juice) also speeds elimination. If vital signs are stable and the primary symptom is confusion or agitation, it is best to reduce all sensory stimulation (such as touching and sound) as such stimulation may lead to an increase in disorientation. Agitation may be treated with valium. Phenothiazines such as haloperidol have been shown to decrease recovery time, but they may carry the increased risk of siezures (ref. 18).
The subjective effects of PCP can range from ecstatic bliss to psychotic episodes, depending on the particular user, their mental set, and the setting in which the drug is consumed. Recreational users frequently report euphoria, loss of ego boundries e.g. out of body experiences or "astral projection", reduced ability to distinguish fantasy from reality, blurring of the distinction between inner and exterior stimulus, feelings of omnipotence, contact with supernatural entities, alteration of time perception and reality, etc. A representative user report is "Life is dramatized onto a fantasy where you don't have to dream. Your wishes are fullfilled. What you want to happen comes true".
When taken in relatively small doses of 5-10 mg by smoking, it produces prompt alterations in perception. Moderate (10-25 mg) or high doses (greater than 20 mg), result in loss of consciousness. PCP can cause effects that mimic the full range of symptoms of schizophrenia, such as delusions, paranoia, disordered thinking, sensation of distance from one's environment, and catatonia. Speech is often sparse and garbled.
Interesting effects on spacial visualization may occur, particularly alterations of body image. Examples of this are the production of "microscopia" and/or "macroscopia", symptoms sometimes seen in schitzophrenic psychosis. These are conditions in which the concept of size becomes scrambled. Small objects can take on the impression of being enormous and large objects can be experienced as being infinitely small, even with the eyes closed. One experienced user has described this effect as rotating throughout the body, one leg seeming to be 10 miles long, or even boundless in space, while another portion of the body, such as the head may take on the impression of being microscopically small. This effect is not necessarily a visual phenominon, as may be more common under the influence of LSD or psilocybin, but rather a feeling more closely related to propioception itself.
Another effect can be the production of temporary anterograde amnesia, in which the interpretation of time flow becomes altered. In this case, it may not be possible to distinguish whether an event has already happened, is currently happening, or is about to happen.
Numbness, depersonalization, feelings of "sheer nothingness" and "endless isolation" are also possible. The most commonly seen effects include a feeling of inebriation and disorientation. Sometimes there is amnesia for the entire experience, although this is generally only at higher doses. Though visual, auditory, and tactile illusions and delusions (such as being God, the devil, or an animal) are common, actual hallucinations are relatively uncommon when compared with those produced by LSD.
Habitual use of PCP or its derivatives should be strongly discouraged. Subtle residual mental effects can be apparent for weeks after one use, although this may be a positive effect to some users. This effect is shared with ketamine, where prolonged use can result in alterations of thought process not recognized by the users themselves (ref 17). Additionally, repeated use of PCP is well known to hamper short and long term memory. Because of the strong decrease in motor coordination and judgement, PCP should never be used when driving. Also, it should be noted that most fatalities associated with PCP are drownings, often when an individual enters the water prior to the full onset of effects.
One aspect of PCP that has been enshrined in urban legend is the supposed ability of a user to have superhuman strength and be impervious to pain. There is some amount of truth to these claims. In several instances PCP users have actually been able to break handcuffs that were not defective, a force requiring 1800 pounds per square inch if pulled straight or 450 psi if pulled at a 90 degree angle. Generally this resulted in fractured wrists or forearms.
Additionally, it should be noted that PCP is well known to have psychologically addictive properties. In one study designed to assay the abuse potential of PCP derivatives, it was found that ketamine, PCE, and NPPCA (N-propyl-phenylcyclohexylamine) share this property. Since most people that experiment with PCP do not report adverse effects, and there is a large amount of data from clinical studies that demonstrate its safety, occasional use of the drug is classified as low risk. However, there is serious potential for negative consequences associated with chronic use. The consequences of psychological addiction can include profound shifts in personality and values, with realignment of philosophical/spiritual/moral outlooks to mesh with the percieved delerient effects. It has been noted that habitual users may develop strongly egocentric perspectives with a belief that previously hidden patterns in nature and reality are becoming apparent, i.e. the production of a God-like outlook. Also, the positive transformations in personality noted in Ketamine Psychedelic Therapy studies, such as increased spirituality and decreased fear of dying may be further enhanced to the point of becoming pathological. Other negative consequences that have been associated with chronic PCP abuse are memory loss, difficulties with speech and thinking, and depression, all of which can persist over a year after cessation of PCP use.
PCP has sedative effects, and interactions with other central nervous system depressants such as alcohol and benzodiazepines can lead to coma or accidental overdose. There is also a profoundly synergystic interaction with THC. It has been noted among recreational users that smoking marijuana while under the influence of PCP can cause an extreme intensification and modification of the experience. Smoking more than a small amount of marijuana however, may lead to production of strong hangover-like symptoms.
Recreational Dosage range:
In individuals without built-up tolerence, the minimal dose capable of producing subjective effects is around 1 mg. 5-10 mg is capable of producing the full spectrum of effects. 20 mg may put an individual into a comatose state, and 70 mg may induce seizures. Tolerence to effects is quickly produced by repeated use, and chronic users may ingest hundreds of milligrams a day for months at a time.
PCP can be administered by any route, such as orally, injection, intranasally, and by smoking. The subjective effects produced are closely correlated with the speed at which the concentration increases in the bloodstream. This is analogous to the production of the euphoric rush from IV or inhaled opiates and stimulants, where this desired effect is more related to speed of increase in plasma levels, rather than the total plasma concentration.
Thus, the route by which PCP is administered may have a profound effect on the experience. Oral administration is less common today than when PCP first appeared on the underground market in the 1960's. This method can lead to a much longer experience than other routes. Intensity of the experience by oral administration can also be very inconsistent, making it difficult to gauge dosage and resulting in increased possibility of overdosage. Snorting the drug results in increased speed of onset and better ability to achieve the desired effects without producing a cataleptic state. PCP may also be inhaled by smoking on parsely or other inert carrier. This results in very quick onset, and the effects may be continuously altered by additional inhalations. This is probably the safest method of administration.
If PCP is administered intranasally, the particular salt form employed may have an effect on the rate at which it is absorbed, and consequently on the quality and length of the experience. Thus, snorting15 mg of PCP hydrobromide produces an onset of effects at 40 min. and a duration of action of ~3 hours, while snorting 15 mg of PCP hydrochloride gives an onset at about 5 min., with a similar duration of action. There does seem to be a steep dose-response curve, as snorting 5 mg. of PCP HCl has an onset of about 30 min., and duration of about 1 hr.
For smoking, PCP is best used as the freebase, in contrast to other routes, where it should be administered as the hydrochloride or other salt. Analogs of PCP which contain a secondary, rather than a tertiary amine, such as ketamine or PCE are best administered as the HCl salts even by smoking, because the vapors of the freebases are too caustic.
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