Disorders Relating to the Use of Phencylidine and Hallucinogens

Disorders relating to the use of phencylidine and hallucinogens.

Topics covered: 

  • Phencyclidine
    • Introduction
    • Epidemiology
    • Acute physiological effects
    • Adverse effects
    • Phencyclidine delirium
    • Phencyclidine-induced psychotic disorder
    • Phencyclidine abuse, dependence, and organic mental disorder
  • Hallucinogens
    • Introduction
    • Drug preparations
    • Epidemiology
    • Acute effects
    • Adverse effects
    • Panic reaction
    • Hallucinogen persisting perception disorder
    • Psychosis
  • Further reading 
  • References

Phencyclidine

Introduction

Phencyclidine (‘angel dust') is one of a class of arylcyclohexylamine dissociative anesthetics, along with ketamine. It was first abused in the United States in New York and San Francisco in the 1960s, but abuse declined when a broad range of unpredictable and adverse complications was noted. (1)

Epidemiology

While use of the unadulterated drug occurs, phencyclidine is more frequently mixed with LSD or cannabis. The drug may be ingested or injected, but more commonly it is smoked or snorted. Data suggest greater use in the United States than in Europe. (2) It traffics under a long and colourful list of street names, possibly reflecting the heterogeneity of its psychobiological effects. It has been suggested that any illicit smoked drug with an unrecognized street name (dust, mist, THC, embalming fluid, inter alia) should be considered phencyclidine until proven otherwise.

Acute physiological effects

The drug has a delayed onset of activity when taken orally. Unlike the major hallucinogens, phencyclidine requires doses in milligrams to be effective, a factor facilitating toxicological identification. When smoked, the onset of its main effects occurs immediately. The drug operates directly and indirectly at a number of receptor sites. The drug has particular affinity for the sigma opioid receptor, and non-competitively blocks the N-methyl-D-aspartate-type excitatory amino acid receptor. Other effects appear to be mediated indirectly by catecholamine release, cholinergic stimulation, and serotonergic receptors.

DSM-IV lists as criteria for acute phencyclidine intoxication the following: acute onset of agitation, belligerence, impaired judgement, nystagmus, hyperacusis, hypertension, tachycardia, numbness, ataxia, dysarthria, rigidity, salivation, seizures, and coma. It is clear from this daunting inventory that impaired judgement is likely to be present beforehand in any person intentionally choosing to abuse this drug.

Adverse effects

Phencyclidine affects not only adults, but fetuses transplacentally and infants by transmission in breast milk. Undisclosed use by pregnant women is detectable in meconium. (3) Exposure to phencyclidine in utero is associated with reduced fetal growth, precipitous labours, and longer hospital stays. (4) Neurological consequences include poor attention, hypertonia, and depressed neonatal reflexes. (5) In vitro studies show that phencyclidine causes inhibited axon outgrowth, degeneration, and death in human fetal cerebral cortical neurones. (6)

Pathophysiological effects of phencyclidine toxicity in adults include hypertension, hyperthermia, opisthotonus, cardiac arrhythmia, seizure, and stroke. Phencyclidine is capable of provoking extreme muscular agitation. This condition of heightened muscular activity has been found to cause rhabdomyolysis and secondary renal failure in 2.5 per cent of users. (7) DSM-IV lists psychiatric effects of phencyclidine including intoxication, delirium, phencyclidine-induced psychotic, mood, and anxiety disorders, and phencyclidine abuse and dependence. A criterion for diagnosis is the emergence of the disorder within a month of drug use. While these disorders have been reported in anecdotes, a substantial clinical characterization exists for phencyclidine delirium and psychosis.

Phencyclidine delirium

Unlike acute intoxication with other hallucinogens, phencyclidine delirium is commonly associated with neurological disturbances. A continuum of effects is noted depending on dose. (8) Psychiatric symptoms occur early in drug use, with stupor and coma occurring later. Shortly after drug use, patients appear confused and ataxic. Analgesia in fingers and toes may be described. Phencyclidine can produce complex hallucinations resembling LSD intoxication. Differentiating the two drugs in emergencies is important, since high-potency neuroleptics, which are useful in phencyclidine toxicity, may exacerbate LSD, while the use of benzodiazepines, helpful in acute LSD toxicity, may disinhibit an assaultive phencyclidine patient. Unlike LSD, phencyclidine is readily identified in routine toxicological screening of blood and urine, but such data may not be readily available. One rapid bedside technique to differentiate the two drugs is the palm sign. The examiner asks the patient to describe the names of all the colours seen in the examiner's outstretch palm. A typical LSD patient reports with misplaced awe a vision of multiple colours and images. A phencyclidine patient simply attacks the hand. Dexterity on the part of the examiner is suggested. Unfocused aggression makes phencyclidine delirium a particularly dangerous disorder. The spectrum of violence includes both suicide and homicide. (9) The technique of ‘talking down' acutely toxic patients is contraindicated. Environmental stimuli should be minimized, and the patient provided with protective supervision. The use of physical restraints is relatively contraindicated because of the potential for rhabdomyolysis.

Specific treatments involve intravenous naloxone to rule out narcotics overdose, activated charcoal to retard any further gastrointestinal absorption, and acidification of the patient's urine with vitamin C, ammonium chloride, cranberry juice, or all three in combination. Once the urine has been acidified, diuresis can be induced with frusemide (furosemide, Lasix). Antihypertensives may be indicated for uncontrolled blood pressure. For agitation high-potency neuroleptics or barbiturates are indicated. Phencyclidine has mixed agonist and antagonist effects at cholinergic receptors. Anticholinergic drugs may precipitate a synergistic reaction with phencyclidine, worsening delirium. Thus, low-potency neuroleptics, tricyclic antidepressants, and the anticholinergic antiparkinsonian drugs should be avoided.

Phencyclidine-induced psychotic disorder

Phencyclidine delirium may evolve into a chronic phencyclidine psychosis that is differentiated from schizophrenia only with difficulty. Alternatively, a phencyclidine delirium may clear, only to be replaced by the insidious onset of a post-phencyclidine psychotic disorder. Because phencyclidine-induced psychosis incorporates both positive (e.g. hallucinations and paranoia) and negative (e.g. emotional withdrawal and motor retardation) schizophrenic symptoms, the drug has been considered a molecular model of the latter illness. (10)

Certain features of phencyclidine psychosis, namely neurological abnormalities, dose-related severity of symptoms, and regularity of the length of illness, are not noted with other psychedelic drugs, leading to the suggestion that phencyclidine psychosis is a toxic drug effect rather than a functional illness. Four classes of agents are reported to help phencyclidine psychosis. They are benzodiazepines, neuroleptics, acetylcholinesterase inhibitors, such as physostigmine, and catecholamine depleters, such as reserpine. Otherwise, treatment considerations are those for phencyclidine delirium. The long-term prognosis for this disorder appears to be poor, according to data from a 10-year follow-up of such patients. (11)

Phencyclidine abuse, dependence, and organic mental disorder

Rhesus monkeys will self-administer phencyclidine in a dose-dependent way, (12) suggesting that repeated abuse in humans may be associated with psychophysiological dependence. This in turn is likely to be associated with a decline in social and occupational function characteristic of other forms of addiction. Because of its widespread neuropsychological effects, any intentional, informed use of phencyclidine should be considered maladaptive. For the habituated patient, long-term treatment is indicated. Issues that should be addressed in the process are emotional lability, cognitive defects, depression, and possible phencyclidine withdrawal effects.

Many of the treatments applicable to patients addicted to the opiates, alcohol, and cocaine apply to this population. Several aspects of treating the phencyclidine patient depart from the more conventional addiction treatments. A triad of confusion, decreased cognitive function, and assaultiveness mark an organic mental disorder associated with phencyclidine use. Reduced cognition is a barrier to recovery that must be recognized and addressed in any prospective treatment plan. Neuropsychological assessment is helpful in this regard. Secondly, there is good evidence that phencyclidine is sequestered in fat for extended periods of time. (13) Conditions associated with weight loss are likely to release long-held phencyclidine into the blood and brain.

Hallucinogens

Introduction

Agents that alter perception and mood without disorientation typify hallucinogenic drugs. They have been known and used for millennia for purposes ranging from magical to medical. Anthropologists trace back the earliest use of hallucinogens to palaeolithic Europe, although 80 per cent of extant hallucinogenic plants are to be found in the New World. Galen ( AD 130–200) wrote that it was customary to give dinner guests hemp seeds to promote the evening's proceedings. The ergot-bearing fungus Claviceps purpurea infected rye in tenth-century France and claimed 40 000 lives. Despite such calamities, ergot continued to be used by midwives in medieval Europe. In search of a benign ergot derivative for use in childbirth, Albert Hofmann synthesized lysergic acid diethylamide (LSD-25) in 1938.

Five years later he accidentally ingested a trace amount of the drug, and fell into an intoxicated, dream-like reverie in which an uninterrupted stream of imagery flowed before his closed eyes. Three days later he intentionally ingested 250 μg of LSD in an attempt to take notes of his experience. Forty minutes after ingestion he wrote in his laboratory journal, ‘Beginning dizziness, feeling of anxiety, visual distortions, symptoms of paralysis, desire to laugh...'. From that point Hofmann's journal is blank. Later he would recall visions and notions that he believed were heralding his insanity.

In 1947 Stoll in Switzerland published the first experimental use of LSD in psychiatry, soon to be followed by Sandison and Elkes in England, Cohen and Eisner in the United States, Leuner in Germany, and Grof in Czechoslovakia. Within a decade the drug moved from scientists to clinicians, clergy, curious professors, and a widening number of students on both sides of the Atlantic. Military investigators in the United States gave the drug surreptitiously to recruits. By the late 1960s LSD and cannabis led the way to a pandemic of drug abuse, particularly among the young.

For the majority of the 1960s, LSD earned a positive reputation as a tool for the study and treatment of psychiatric illnesses. From 1968 onward, adverse reports outnumbered positive ones, thus illustrating an axiom that is revisited multiple times throughout history, that new discoveries are often met with inflated enthusiasm, only to be tempered in time by sober reconsideration. The reconsideration of LSD was based on the fact that with the synthesis of high-potency hallucinogenic drugs such as the substituted indole and alkyl amines, a line was crossed separating botanical forms of hallucinogens from those derived solely in the laboratory. The former exist in nature in low concentrations amidst innumerable psychoactive congeners, while laboratory preparations are available in high concentrations and purity. This factor, along with their psychoactive potency in microgram quantities, coupled with the ease with which this class of drugs can be synthesized, transported, and sold, accounts for their enduring role as abusable substances. 

Drug preparations

While Hofmann describes 11 classes of hallucinogenic compounds which can be isolated from botanicals, by far the most common hallucinogen of abuse appears to be LSD. (14) Recently the serotonin-2A receptor has been shown to bind strongly to hallucinogenic drugs, and the drugs appear to act as partial agonists. (15) LSD is psychoactive in a single droplet of solvent. The drug is easily dissolved in an aqueous solution. Drops of the drug are placed on sugar cubes or blotting paper stamped with coloured cartoon figures to mark the drug's location. Sheets of the paper are then distributed, and the figures ingested. Injection is not necessary, and seldom used as a means of administration. Dosages commonly range from 25 to 100 μg. A hallucinogenic trip can occur after 75 μg. Other hallucinogens, such as dimethyltryptamine, must be injected. Common botanical hallucinogens include fungi and angiosperms (flower-bearing plants), of which approximately 100 are recognized to possess hallucinogenic properties. Ibogaine is derived from the root of the Tabernanthe iboga plant cultivated in Gabon and eaten as a rite of passage. Mescaline (trimethoxyphenylethylamine) is a predominant hallucinogen in the cactus Lophophora williamsii of the American Southwest. Strips of cactus are cut from the plant, dried, and eaten. Hallucinogenic mushrooms contain psilocybin and psilocin, which are phosphorylated hydroxylated congeners of dimethyltryptamine. Mushrooms are ingested for their effect, or brewed first and the broth consumed. Not all consumers respond identically. The American psychologist William James reported ingesting several dozen hallucinogenic mushrooms and only experiencing headache. Shulgin has synthesized and tested 179 phenylethylamines for hallucinogenic properties. Their effects on the human brain are complex and largely unknown.

Epidemiology

Recent surveys in the United States and Europe indicate that hallucinogen use is increasing. Johnson et al., (2) for example, reported that the trend for the lifetime prevalence of LSD use among American high school seniors rose from 7.7 to 13.6 per cent from 1988 to 1997. Similarly, a German sample of 3021 adolescents found a twofold increase in LSD and substituted amphetamines from 1990 to 1995. (16) From 1990 to 1992 in East Germany there was a ninefold increase in LSD use, compared to a fivefold increase in all other illegal drugs. In the United Kingdom LSD use increased from 7 per cent in 1989 to 11 per cent in 1993. In Denmark 7.2 per cent of students surveyed reported using hallucinogenic mushrooms in 1993. In surveys of American undergraduates, an 18.4 per cent prevalence of mushroom experimentation was found in the years 1993 to 1994. LSD users tend to start in adolescence, and because this class of drugs lacks the addiction potential of alcohol, cocaine, or opiates, hallucinogen use typically declines in the mid-twenties.

Acute effects

Albert Hofmann, who drew international attention to an accidental ingestion of the drug, classically describes the effects of ingesting LSD. (17) The characteristic LSD trip comprises autonomic arousal, marked mydriasis, and progressive modulations of sensory, more often visual, imagery, which appear to be generated both from external objects and distortions of eidetic imagery. Ordinarily benign objects may take on new emotional meanings. Geometric imagery may rise and fall before one's eyes. A prevalent feeling one experiences is a sense of helplessness to control one's streaming images and emotions, hence the hippie advice of ‘going with the flow'. The loss of cognitive, perceptual, and affective control for some users leads to panic, which in turn results in the so-called ‘bad trip.' As these effects decline, they may be replaced with a sense of oceanic well being or residual paranoia.

Adverse effects

Adverse reactions to hallucinogens include panic reactions associated with a bad trip, hallucinogen persisting perception disorder, and prolonged psychoses.

Panic reaction

Panic may arise during the acute drug experience. It is characterized by a crescendo of rising anxiety accompanied by autonomic arousal in the context of streaming emotions and imagery. Mydriasis is greater than that seen in non-drug-induced panic. While lay interventionists have encouraged treatment of such panic by ‘talking the victim down', the use of an oral benzodiazepine such as diazepam 20 mg is utterly effective in stopping the panic, and bad trip, within an equal number of minutes. The utter efficacy of this class of drugs in aborting a hallucinogenic trip in minutes is strong evidence that the g-aminobutyric acid-A receptor plays a role in modulating the effects of hallucinogens.

Hallucinogen persisting perception disorder

It became apparent within the first few years of experimentation with LSD that this class of drugs was capable of inducing visual disturbances days to weeks following drug exposure. Subsequent research found that these disturbances, dubbed ‘flashbacks' because of their evanescent visual appearance, appeared to be an intermittent form of postdrug visual disorder that in its extreme form was experienced continually. Thus, hallucinogen persisting perception disorder patients are capable of describing a range of visual disturbances that fluctuate in intensity, but are observable from moment to moment. Such imagery includes geometric hallucinations, false perceptions of movement, usually in the peripheral visual field, afterimagery, and the perception of trails of images as an object moves across the visual field. Patients can also visualize myriad clear or coloured pinpoint dots in a bright sky, an experience that they describe as seeing the air (‘aeropsia'). These visual disturbances may be intensified by emergence into a dark environment, or by experiencing a variety of psychostimulants such as marijuana, amphetamines, cocaine, anxiety, and the stress of intercurrent illnesses. (18) While recovery may occur over months and years following last drug use, approximately half of the patients so afflicted appear to develop a permanent alteration of the visual apparatus. Neurophysiological studies confirm cerebral disinhibition involving those regions of the cortex processing visual information. (19)

It has been hypothesized that this disorder occurs when a potent hallucinogen such as LSD excitotoxically stimulates and destroys serotonin-2A receptor bearing inhibitory neurones, leading to a chronic disinhibition of visual information processing. That such a response occurs in only a minority of users, while others may apparently use such drugs with impunity, suggests that the disorder may be mediated by a genetic vulnerability to the drug.

Because the disorder is exacerbated by psychological and physiological conditions of arousal, benzodiazepines have been used for management of visual symptoms. The results of these efforts are palliative at best, and complicated by the prospect of treating a drug abuser with an abusable substance. Recent case reports of treatment with sertraline, naltrexone, and clonidine are encouraging.

In addition to pharmacotherapy, hallucinogen persisting perception disorder patients often require supportive psychotherapy to deal with the issues of learning to cope with what may be a permanent alteration in perception. Therapy is also indicated to educate the patient, and prevent the development of common comorbid disorders in hallucinogen persisting perception disorder, namely, major depression, panic disorder, and alcohol dependence.

Psychosis

The suggestion that the use of potent hallucinogens can trigger prolonged psychotic episodes is controversial. Evidence supporting the existence of hallucinogen-induced psychotic disorders is found in a review of longitudinal, cross-sectional, and case studies. (20) Psychiatric patienthood appears to be a risk factor for the development of psychosis following LSD. The clinical picture of post-LSD psychosis resembles schizoaffective disorder more than it does schizophrenia, with the commonly added feature of chronic visual disturbances. Clinically such patients resemble those with good-prognosis schizophrenia, since they possess more affect than those with poor prognosis, have less thought disorder, are more socially related, and appear to have fewer signs of negative schizophrenia. Mystical preoccupations reminiscent of acute drug experiences can predominate. Visual hallucinations often are of the variety that are seen in hallucinogen persisting perception disorder, although in contradistinction to such patients, post-hallucinogen psychotic patients may describe delusions and auditory hallucinations as well.

Atypical pharmacotherapies appear to have an important role in treatment, and in selected cases are preferable to dopamine-blocking neuroleptics. Reports in the literature describe cases responding to electroconvulsive therapy, lithium, anticonvulsants, and the serotonin precursor, l-5-hydroxytryptophan. Long-term supportive psychotherapy is almost always indicated to help the patient and his or her family make painful adjustments to the patient's chronic disappointments in relationships and employment, frequently made all the more poignant by the illness's propensity to preserve the patient's insight as it progresses. This last factor may partially explain the high risk for suicide. (21) No definitive clinical characterization of the disorder exists as yet.

Further reading

Abraham, H.D. (1983). Visual phenomenology of the LSD flashback. Archives of General Psychiatry, 40, 884–9.

Abraham, H.D., Aldridge, A.M., and Gogia, P. (1996). The psychopharmacology of hallucinogens. Neuropsychopharmacology, 14, 285–98.

Hofmann, A. (1980). LSD: my problem child. McGraw-Hill, New York.

Johnson, L.D., O'sMalley, P.M., and Bachman, J.G. (1998). National survey results on drug use from the monitoring the future study, 1975–1997, Vol. 1. Publication No. 98–4345. National Institutes of Health, Rockville, MD.

McCarron, M.M., Schulze, B.W., Thompson, G.A., Conder, M.C., and Goetz, W.A. (1981). Acute phencyclidine intoxication: incidence of clinical findings in 1000 cases. Annals of Emergency Medicine, 10, 237–42. 

References

1. McCarron, M.M., Schulze, B.W., Thompson, G.A., Conder, M.C., and Goetz, W.A. (1981). Acute phencyclidine intoxication: incidence of clinical findings in 1000 cases. Annals of Emergency Medicine, 10, 237–42.

2. Johnson, L.D., O'sMalley, P.M., and Bachman, J.G. (1998). National survey results on drug use from the monitoring the future study, 1975–1997, Vol. 1. Publication No. 98–4345. National Institutes of Health, Rockville, MD.

3. Moore, C., Negrusz, A., and Lewis, D. (1998). Determination of drugs of abuse in meconium. Journal of Chromatography B: Biomedical and Science Applications, 713, 137–46.

4. Tabor, B.L., Smith-Wallace, T., and Yonekura, M.L. (1990). Perinatal outcome associated with PCP versus cocaine use. American Journal of Drug and Alcohol Abuse, 16, 337–48.

5. Golden, N.L., Kuhnert, B.R., Sokol, R.J., Martier, S., and Williams, T. (1987). Neonatal manifestations of maternal phencyclidine exposure. Journal of Perinatal Medicine, 15, 185–91.

6. Mattson, M.P., Rychlik, B., and Cheng, B. (1992). Degenerative and axon outgrowth-altering effects of phencyclidine in human fetal cerebral cortical cells. Neuropharmacology, 31, 279–91.

7. Akmal, M., Valdin, J.R., McCarron, M.M., and Massry, S.G. (1981). Rhabdomyolysis with and without acute renal failure in patients with phencyclidine intoxication. American Journal of Nephrology, 1, 91–6.

8. Milhorn, H.T.J. (1991). Diagnosis and management of phencyclidine intoxication. American Family Physician, 43, 1290–302.

9. Poklis, A., Graham, M., Maginn, D., Branch, C.A., and Gantner, G.E. (1990). Phencyclidine and violent deaths in St. Louis, Missouri: a survey of medical examiners's cases from 1977 through 1986. American Journal of Drug and Alcohol Abuse, 16, 265–74.

10. Javitt, D.C. and Zukin, S.R. (1991). Recent advances in the phencyclidine model of schizophrenia. American Journal of Psychiatry, 148, 1301–8.

11. Wright, H.H., Cole, E.A., Batey, S.R., and Hanna, K. (1988). Phencyclidine-induced psychosis: eight-year follow-up of ten cases. Southern Medical Journal, 81, 565–7.

12. Campbell, U.C., Thompson, S.S., and Carroll, M.E. (1998). Acquisition of oral phencyclidine (PCP) self-administration in rhesus monkeys: effects of dose and an alternative non-drug reinforcer. Psychopharmacology (Berlin), 137, 132–8.

13. Misra, A.L., Pontani, R.B., and Bartolomeo, J. (1979). Persistence of phencyclidine (PCP) and metabolites in brain and adipose tissue and implications for long-lasting behavioural effects. Research Communications in Chemistry, Pathology, and Pharmacology, 24, 431–45.

14. Schultes, R. and Hofmann, A. (1980). The botany and chemistry of hallucinogens. Thomas, Springfield, IL.

15. Glennon, R.A., Titeler, M., and McKenney, J.D. (1984). Evidence for 5-HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences, 35, 2505–11.

16. Schuster, P., Lieb, R., Lamertz, C., and Wittchen, H.U. (1998). Is the use of ecstasy and hallucinogens increasing? Results from a community study. European Addiction Research, 4, 75–82.

17. Hofmann, A. (1980). LSD: my problem child. McGraw-Hill, New York.

18. Abraham, H.D. (1983). Visual phenomenology of the LSD flashback. Archives of General Psychiatry, 40, 884–9.

19. Abraham, H.D. and Duffy, F.H. (1996). Stable quantitative EEG difference in post-LSD visual disorder by split-half analysis: evidence for disinhibition. Psychiatry Research and Neuroimaging, 67, 173–87.

20. Abraham, H.D., Aldridge, A.M., and Gogia, P. (1996). The psychopharmacology of hallucinogens. Neuropsychopharmacology, 14, 285–98.

21. Bowers, M.B., Jr (1977). Psychoses precipitated by psychotomimetic drugs: a follow up study. Archives of General Psychiatry, 34, 832–5.