DARK Classics in Chemical Neuroscience: Phencyclidine (PCP).

Phencyclidine (PCP, "angel dust", an arylcyclohexylamine) was the first non-natural, man-made illicit drug of abuse, and was coined 'the most dangerous drug in America" in the late 1970s (amidst sensational horror stories of the drug's effects); however, few other illicit drugs have had such a significant and broad impact on society-both good and bad. Originally developed as a new class of anesthetic, PCP-derived psychosis gave way to the PCP hypothesis of schizophrenia (later coined the NMDA receptor hypofunction hypothesis or the glutamate hypothesis of schizophrenia), which continues to drive therapeutic discovery for schizophrenia today. PCP also led to the discovery of ketamine (and a new paradigm for the treatment of major depression), as well as other illicit, designer drugs, such as methoxetamine (MXE) and a new wave of Internet commerce for illicit drugs (sold as research chemicals, or RCs). Furthermore, PCP is a significant contaminant/additive of many illegal drugs sold today, due to its ease of preparation by clandestine chemists. Here, we will review the history, importance, synthesis (both legal and clandestine), pharmacology, drug metabolism, and folklore of PCP, a true DARK classic in chemical neuroscience.

Twenty-five years of glutamate in schizophrenia: are we there yet?

At present, all medications for schizophrenia function primarily by blocking dopamine D2 receptors. Over 50 years ago, the first observations were made that subsequently led to development of alternative, glutamatergic conceptualizations. This special issue traces the historic development of the phencyclidine (PCP) model of schizophrenia from the initial description of the psychotomimetic effects of PCP in the early 1960s, through discovery of the link to N-methyl-D-aspartate-type glutamate receptors (NMDAR) in the 1980s, and finally to the development of NMDA-based treatment strategies starting in the 1990s. NMDAR antagonists uniquely reproduce both positive and negative symptoms of schizophrenia, and induce schizophrenia-like cognitive deficits and neurophysiological dysfunction. At present, there remain several hypotheses concerning mechanisms by which NMDAR dysfunction leads to symptoms/deficits, and several theories regarding ideal NMDAR-based treatment approaches as outlined in the issue. Several classes of agent, including metabotropic glutamate agonists, glycine transport inhibitors, and D-serine-based compounds are currently in late-stage clinical development and may provide long-sought treatments for persistent positive and negative symptoms and cognitive dysfunction in schizophrenia.

Phencyclidine/schizophrenia: one view toward the past, the other to the future.

The history of the chemical synthesis and animal/human pharmacology of phencyclidine is documented. From its early use as a general anesthetic, chemical model of schizophrenia, and drug of abuse, phencyclidine has had a checkered history. Research with this agent and its chemical derivatives like ketamine have provided a solid foundation for just a beginning to understanding the neuropathology of schizophrenia.

Taming the ketamine tiger. 1965.

Pharmacologic actions of CI-581, a chemical derivative of phencyclidine, were determined in 20 volunteers from a prison population. The results indicate that this drug is an effective analgesic and anesthetic agent in doses of 1.0 to 2.0 mg per kilogram. With intravenous administration the onset of action is within 1 min and the effects last for about 5 to 10 min, depending on dosage level and individual variation. No tachyphylaxis was evident on repeat doses. Respiratory depression was slight and transient. Hypertension, tachycardia, and psychic changes are undesirable characteristics of the drug. Whether these can be modified by preanesthetic medication was not determined in this study. Recovery from analgesia and coma usually took place within 10 min, although from electroencephalographic evidence it may be assumed that subjects were not completely normal until after 1 to 2 h. No evidence of liver or kidney toxicity was obtained. CI-581 produces pharmacologic effects similar to those reported for phencyclidine, but of shorter duration. The drug deserves further pharmacologic and clinical trials. It is proposed that the words "dissociative anesthetic" be used to describe the mental state produced by this drug.

Phencyclidine use among youth: history, epidemiology, and acute and chronic intoxication.

Phencyclidine use appears to be in a growth phase nationally. Factors contributing to the increasing popularity include the user's ability to control the dosage, an understanding of the immediate effects, and its availability. Those most at risk appear to be young Caucasian males. Phencyclidine-related problems are often like tips of icebergs, the underlying causes of which are hidden from public view. The problems often surface in the form of speech difficulties, memory loss, thinking disorders, personality changes, paranoia, severe depression, violence, accidents, suicides and homicides. Of particular concern to law enforcement personnel is the upsurge in phencyclidine-related violent crimes and carrying of weapons by users to protect themselves from their imagined persecutors. The evidence currently available supports the assumption that if there is a solution to the problem of phencyclidine abuse, that solution is prevention. Therefore, medical personnel and others within the helping professions must be alerted to the fact that phencyclidine is not just another drug problem. The findings from users we have already studied strongly suggest that phencyclidine is not an "upper" or a "downer," but perhaps an "insideouter", with longer term implications.