Hallucinogens, PCP, and Ketamine

 

Hallucinogenic Drugs

Mescaline

Psilocybin

Dimethyltryptamine and Related Tryptamines

LSD

NBOMes

Salvinorin A

Pharmacology of Hallucinogenic Drugs

• Hallucinogens are substances that cause perceptual and cognitive distortions in the absence of delirium. Many hallucinogens, such as mescaline, psilocybin, DMT, 5-MeO-DMT, and salvinorin A, are plant compounds that were used for hundreds or thousands of years in spiritual or religious ceremonies before their discovery by Western culture. In contrast, LSD is a synthetic drug, although it is based on a series of alkaloids found in ergot fungus. NBOMes constitute an additional class of synthetic hallucinogens that have appeared on the street more recently.
• Recognition of the powerful mind-altering properties of hallucinogenic drugs led to both clinical and recreational use beginning in the late 1950s. Some psychiatrists gave patients LSD in the course of psycholytic or psychedelic therapy. At the same time, secret government programs were testing the feasibility of using LSD or other potent hallucinogens as weapons. LSD became readily available on the street despite a federal ban on recreational use in 1967.
• Many hallucinogenic drugs are orally active, with a slow onset of action and a long time course of action. Two exceptions are DMT and Salvia, which are usually smoked, thereby leading to rapid drug effects and a much shorter duration of action. NBOMes can be taken orally but are more typically administered by the sublingual or buccal routes. Of the commonly used hallucinogens, LSD is the most potent and mescaline is the least potent, based on the range of doses taken by users.
• An LSD “trip” can be divided into four phases: onset, plateau, peak, and comedown. During the trip, the user experiences vivid visual hallucinations, a slowing of the subjective sense of time, feelings of depersonalization, strong emotional reactions, and a disruption of logical thought. Research on hallucinogens has made use of the altered states of consciousness rating scale, which consists of the following five primary dimensions: oceanic boundlessness, ego-disintegration anxiety, visionary restructuralization, reduced vigilance, and auditory alterations. These primary dimensions can be divided into subdimensions to provide more detailed information on drug-induced reactions.
• Most hallucinogenic drugs are classified chemically as either indoleamines or phenethylamines. The indoleamines are related structurally to 5-HT, whereas the phenethylamines instead share a common structure with NE. Of the hallucinogens discussed in this chapter, only mescaline and the NBOMes belong to the phenethylamine class. Both the indoleamine and phenethylamine hallucinogens are 5-HT_2A receptor agonists. Of particular interest is a recent discovery that the binding of LSD to the receptor protein causes the drug to be trapped temporarily within the binding pocket by a lid-like structure. This accounts for the extended length of an LSD trip.
• Salvinorin A, the active compound in Salvia divinorum, does not interact with the 5-HT_2A receptor but instead is a κ-opioid receptor agonist. This difference accounts for why the subjective effects produced by salvinorin A are somewhat different from the effects associated with the other compounds that act through the serotonergic system.
• The specific brain areas and mechanisms responsible for the production of hallucinogenic drug effects are not yet fully understood. However, EEG studies have shown that hallucinogens disrupt the normal electrical oscillations measured in the cerebral cortex. This effect is thought to be mediated by activation of 5-HT_2A receptors on glutamatergic pyramidal neurons in layer 5 of the PFC and other cortical areas.
• Hallucinogens are not dependence forming or addictive for most users; however, a small percentage of users meet the DSM-5 diagnostic criteria for other hallucinogen use disorder. Most hallucinogenic drugs, except possibly DMT and salvinorin A, produce rapid tolerance with repeated use. This phenomenon has been linked primarily to 5-HT_2A receptor down-regulation.
• Use of hallucinogens can also lead to other adverse effects such as “bad trips” and flashbacks. People who suffer from severe, recurring flashbacks long after discontinuing hallucinogenic drug use are diagnosed as having hallucinogen persisting perception disorder. At the present time, little is known about the causes or treatment of HPPD, except for a possible involvement of the serotonergic system. Most seriously, dangerous toxic reactions involving psychiatric and/ or somatic symptoms have been known to occur following ingestion of a hallucinogenic agent. Psychiatric symptoms resemble those seen in acutely psychotic patients and are most likely to occur in users who either are suffering from a current psychiatric disorder or possess a preexisting vulnerability for developing psychosis. The most severe reactions, which consist of both behavioral and dangerous somatic symptoms, are produced by NBOMe use. Users may experience delusions, severe agitation and aggressive behavior, and numerous physiological reactions that can, in extreme cases, be fatal.
• In recent years there has been renewed interest in the potential use of hallucinogenic drugs as adjuncts to psychotherapy. Contemporary research of this kind is much more carefully and safely conducted than in the early days of LSD-based therapy. Psychedelic drug therapy is theoretically based on the ability of the drug to produce a peak experience in the patient, followed over succeeding days or weeks by an afterglow period characterized by elevated mood, reduced guilt and anxiety, and an enhanced ability to form close social relationships. Current studies involving hallucinogenic drug therapy are focused on the treatment of drug addiction, major depression, and obsessive-compulsive disorder and on helping terminally ill patients cope with their fear of dying.

PCP and Ketamine

Background and History

Pharmacology of PCP and Ketamine

• PCP and ketamine belong to the class of drugs known as dissociative anesthetics.
• PCP was withdrawn from clinical use because of its prominent adverse side effects, but ketamine, which is less potent than PCP, has significant applications in both human and veterinary medicine.
• The acute effects of PCP and ketamine include sensory distortions and altered body image, cognitive disorganization, and various affective changes. High doses of ketamine give rise to a state called the “K-hole,” in which the user feels separated from his body, perhaps in the manner of a near-death experience.
• PCP and ketamine bind to a site within the NMDA receptor channel, thereby acting as noncompetitive receptor antagonists. A secondary consequence of NMDA receptor blockade is increased presynaptic glutamate release, which may contribute to the behavioral and subjective effects of PCP and ketamine.
• Models of schizophrenia in both humans and experimental animals have been developed based on the hallucinogenic and cognition-impairing effects of PCP and ketamine.
• Both PCP and ketamine are reinforcing to animals, as indicated by drug self-administration. These reinforcing effects may be mediated by both dopaminergic and nondopaminergic mechanisms. Ketamine also produces pleasurable effects in humans.
• Although illicit use of ketamine has occurred for many years, the popularity of this compound is on the rise. Heavy ketamine users show dose escalation and compulsive use, which indicate the development of tolerance and dependence on the drug.
• Abuse potential has been shown for a few other noncompetitive NMDA receptor antagonists. These include dextromethorphan, an opioid-like compound found in cough medications, and the potent ketamine analog methoxetamine. These compounds produce dissociative subjective effects and, in the case of dextromethorphan, other effects like those of the classical hallucinogens.
• Chronic ketamine or PCP exposure leads to a variety of adverse effects including urological symptoms, cognitive deficits, gray and white matter abnormalities, altered dopaminergic function, and a reduced number of asymmetrical spine synapses in the prefrontal cortex. Repeated high ketamine doses also cause apoptotic cell death in the developing brains of laboratory animals, which raises concern for the use of this compound as a pediatric anesthetic agent. The acute toxic effects of methoxetamine are even more severe than those observed with ketamine or PCP. These effects have, in some cases, led to death of the user.
• Despite its potential for abuse, ketamine may have novel therapeutic applications in the treatment of major depression and for pain relief. Caution must be observed, however, because of the drug’s narrow therapeutic window.