Clinical Psychopharmacology Seminar 1996-1997
Paul J. Perry, Ph.D., Bruce Alexander, Pharm.D., Vicki L.
Ellingrod, Pharm.D.
Peer Review Status: None
INTRODUCTION
Hallucinogenic drugs are primarily classified according to the physiologic changes they produce and upon demonstrations of cross-tolerance between drugs. Lysergic acid diethylamide (LSD), mescaline, psilocybin, dimethyltryptamine (DMT), diethyltryptamine (DET), and 2,5-dimethoxy-4-methyltryptamine (DOM) are classified as adrenergic hallucinogens despite dissimilar structures. They all produce varying degrees of autonomic stimulation resulting in mydriasis, increases in blood pressure, pulse, respiration, hyperglycemia, hyperthermia, hyperreflexia, nausea, salivation, vomiting and piloerection. Although cannabis preparations produce psychological disturbances similar to the adrenergic hallucinations, their changes are not as marked. Cannabis causes only a slight increase in blood pressure and pupillary size, a sedative effect, and often a craving for sweets rather than anorexia. No LSD cross-tolerance has been noted between amphetamines (Hoffman 1983, Jaffe 1985).
MECHANISM OF ACTION
The biochemical mechanism of hallucinogenic drugs is unknown, but probably involves a complex stimulation of serotonin, dopamine and tryptamine receptors, from the cortex to the spinal cord. Some of the best studies involve agonistic actions at presynaptic receptors for 5-HT (serotonin) in the mid-brain. An earlier view that the subjective effects of LSD were due to blockade of 5-HT, now seems unlikely, since these neurons continued to fire even after being bathed in LSD (Jaffe 1985).
There are at least two distinct receptors for 5-HT in the CNS, i.e., 5-HT1 and 5-HT2. Heym et al (1984) have demonstrated that the behavioral and possibly the psychoactive effects of the hallucinogens appear to be attributable to an action at 5-HT2 receptors presumably located postsynaptically. Haloperidol, which can block the hallucinogenic actions of LSD and mescaline, has a 400-fold greater affinity for the 5-HT2 receptor than the 5-HT1 receptor (Peroutka and Snyder 1983).
PHARMACODYNAMICS
LSD is rapidly absorbed from the gastrointestinal tract, is highly plasma protein bound and is distributed to body tissues, with the highest levels appearing in the brain. LSD has an onset of action within 30 to 40 minutes and lasts around 12 hours. The elimination half-life of LSD is estimated to be approximately 175 minutes. LSD is metabolized by the liver to 2-oxy-lysergic acid diethylamide, which is inactive. There is no evidence that physical dependence can develop to LSD. Thus physiologic withdrawal reactions do not occur. Tolerance can occur within five days, but disappears after three days of abstinence. Since relatively few users utilize the drug on a daily basis tolerance is rarely a problem of clinical importance (Mannaioni 1984).
In the normal adult, doses range from 50 to 100 mcg produces the
"psychedelic experience" (clinical grades 1 to 3), while doses
between 100 mcg and 1500 mcg produces the LSD psychosis (clinical
grade 4), which may last a short time followed by a full recovery,
or, as in chronic abuse, may produce a recurrent or prolonged
psychosis. The following table illustrates the clinical changes
observed with each "grade" of LSD reaction (Mannaioni 1984).
|
Table 1. Clinical grades for LSD reaction (Strassman 1984) | |
|
Grade 1 |
Anxiety and nervousness without perceptual distortion or hallucinations. |
|
Grade 2 |
Anxiety, nervousness and visual perceptual distortions without true hallucinations. |
|
Grade 3 |
Anxiety, nervousness, perceptual distortions, and true hallucinations, but with insight maintained. |
|
Grade 4 |
Same as grade 3 except that insight (realization that the effects are due to the drug) is lost. |
PHARMACOLOGIC EFFECTS OF LSD
In 1938 Stoll and Hoffman (1943), of Sandoz Pharmaceuticals succeeded in synthesizing LSD along with a number of other alkaloid congeners of the ergonovine type. However, it was not until 1943 that Hoffman serendipitously discovered the hallucinogenic properties of the drug. A series of experiments by Stoll showed that oral doses of 30 mcg administered to nonpsychotic individuals produced marked sympathomimetic changes that induced nausea, salivation, lacrimation, tremor, muscle weakness, mydriasis, hypertension, tachycardia, hyperreflexia, hyperthermia, slight ataxia, and facial flushing (Stoll 1943). The most important effects, however, were the psychic effects that appeared with low to medium oral doses of 0.5-2.0 mcg/kg. These include dizziness, weakness, drowsiness, nausea, and paresthesias. They may be followed by a feeling of inner tension relieved by laughing and crying. Several moods may seem to coexist at the same time, although euphoria tends to predominate. In the second to third hour, visual illusions, wavelike recurrences of perceptual changes (micropsia, macropsia, etc.), and affective symptoms may occur. There may be difficulty in locating the source of a sound, the user may be hypervigilant or withdrawn, or may alternate between these two states. Many subjects have a fear of fragmentation or disintegration of the self. Auditory hallucinations are rare. Synethesias, the overflow from one sensory modality to another may occur such that colors are heard and sounds are seen. Clock time seems to slow significantly. During the trip, thoughts and memories can vividly emerge under self-guidance or unexpectedly to the user's distress. Mood may be labile, shifting from depression to euphoria or elation to fear and panic. After 4 to 5 hours if a panic attack does not occur, a feeling of detachment and conviction that one is magically in control may ensue. Other potential symptoms include acusis, synesthesia, tactile paresthesias, illusions, distortions of body image, derealization, depersonalizations, and mood disturbances. These occurred in the presence of unaltered orientation, and critical self-judgment. Subjects retained their ability to respond to interrogation by an observer (Jaffe 1985).
PATTERN OF USE (Hoffman 1983, Mannaioni 1984)
Doses of LSD greater than 30 mcg are considered hallucinogenic with "street doses" usually ranging from 50-300 mcg. The drug is sold as a powder, liquid, capsule, or tablet. The tablets often have distinctive shapes and colors. Additionally, drops of LSD are placed on sugar cubes, animal crackers, or blotting paper and sold in these unique dosage formulations. The drug is most commonly taken by mouth, and only rarely injected, but occasionally tobacco is saturated with LSD and then smoked. However, it is notable that this last "high" is regarded as unacceptable quality. Daily use of LSD is quite rare, with most use being "weekend" or recreational. "Acid heads" or frequent users rarely use the drug more than biweekly.
PRESENTATION
Frosh et al. described twelve LSD-intoxicated patients who were admitted to New York's Bellevue Psychiatric Hospital. Three overlapping types of presenting syndromes were described:
One patient experienced a panic attack and a month later experienced a recurrence of symptoms despite no additional LSD doses. The seven patients who experienced panic attacks had some personality characteristics in common. They were overly ideational, obsessive, constricted, and stereotyped in their responses to people and new situations. Recovery was rapid with all being discharged within one to three days. Two of the three patients suffered recurrences one to two months later, manifested as depersonalization and perceptual distortions. Both patients had taken the drug over a limited period of time and had relatively few exposures (9 to 15). The third patient however had taken the drug over many years with greater than 200 exposures. His last exposure prior to the recurrence was over a year prior to admission, during which time he had experienced multiple episodes of catatonia and visual hallucinations. Two of the three were diagnosed as chronic schizophrenics while the third was classified as borderline. Stress or anxiety were subjectively correlated with the return of symptoms. Finally, the three patients who experienced the prolonged psychoses following a single dose of LSD had previously been diagnosed as chronic schizophrenics. At the time of admission two patients were catatonic while the third had catatonic features and was also markedly paranoid. Two patients were discharged after a month of hospitalization while the third was transferred to a long-term care facility. None showed any significant improvement of their schizophrenic illness after one month in the hospital.
In 1967, Smart and Bateman (1967) reviewed 21 reports of a total of 225 adverse reactions to LSD. They were able to divide the case reports into four groups: 1) intoxications; 2) prolonged psychotic reactions; 3) spontaneous recurrences; and 4) prolonged non-psychotic reactions.
In man, fatal intoxications directly attributable to LSD's physiological effects are unknown, although fatal accidents and suicides during the intoxicated state have occurred. In this series there were: 19 attempted suicides, 11 successful suicides, 4 attempted homicides of which 1 was successful. Convulsions were also reported in 5 of 150 (3.3%) patients (Smart and Bateman 1967).
Of the 225 adverse reactions, 142 (63%) cases of prolonged psychotic reactions to LSD occurred. The most common symptoms reported were paranoid delusions, hallucinations, and overwhelming fear (Smart and Bateman 1967). In another series of 52 patients, 30 (58%) cleared within 48 hours, and 11 (21%) cleared in 2 to 7 days (Medical Society of the County of New York 1966). It should be noted that 12 (23%) of the 52 patients were described as psychotic or schizoid personalities.
Spontaneous recurrences, i.e. flash-backs, manifested as frightening delusions or hallucinations reappearing months to years after the last ingestion and after an interval of normality occurred in 11 (5%) of the patients (Smart and Bateman 1967). It has been hypothesized that recurrences are correlated to stress and the frequency of LSD ingestion. Six of the eleven patients and ingested LSD on 9, 10-12, 15, 25, 200-300 and greater than 200 occasions. On the other hand, about half of the 142 patients with prolonged psychoses had ingested the drug only once.
Sixty-three cases of prolonged nonpsychotic reactions were described. Of these 39 (17%) were panic attacks or confusion reactions, 17 (8%) were depression, 5 (2%) were antisocial or psychopathic personalities, 1 (0.5%) was "motor excitatory state", and 1 (0.5%) was chronic anxiety (Smart and Bateman 1967).
DIFFERENTIAL DIAGNOSIS
Some observers regard the LSD psychosis as an entity which is separate from schizophrenia; others speculate that the drug unmasks latent schizophrenia, while others believe that ingestion is coincidental to the development of the disease. Hays and Tulley (1973) compared 15 patients who developed an LSD psychosis within a year of ingestion to 114 consecutively admitted schizophrenic (SP) patients diagnosed according to Blueler. Of the 114 controls, 38 (33%) had a positive family history of SP while none of the LSD group had a positive family history (p < 0.05). The patients with LSD psychosis had significantly fewer auditory hallucinations, more visual illusions, fewer secondary delusions, and more auditory misinterpretations than the control group of schizophrenics.
Vardy and Kay (1983) attempted to determine whether patients hospitalized for LSD psychosis were separable from acute schizophrenics. They analyzed the family history, presentation (admission, 3 and 5 years later), premorbid adjustment, initial hospitalization, and number of hospitalizations for 52 LSD psychotics and 29 matched schizophrenics. LSD psychotics fundamentally did not differ from schizophrenics except for the amount of parental alcoholism.
Young (1974) compared the results of an interview of 20 LSD, 20 schizophrenic, and 20 control subjects. Visual hallucinations were reported by 60% of the LSD group and 45% of the schizophrenic group. Auditory hallucinations were very surprising reported by 30% of LSD patients and only 5% of the schizophrenic patients. There were not differences in the amount of thought disorder present between the LSD group and the schizophrenic group. The schizophrenics were significantly more delusional. Additionally, no differences were noted between these two groups with respect to motor function, memory changes, or sensitivity. Affective changes seemed to be the predominant difference between the two groups. Seventy percent of the LSD groups reported happiness or elation while 30% reported sadness or depression. On the other hand, in the schizophrenic group 25% reported being sad or depressed, 25% reported anxiousness, 30% reported happiness or elation while 30% reported sadness or depression. On the other hand, in the schizophrenic group 25% reported being sad or depressed, 25% reported anxiousness, 30% reported happiness, and 20% reported indifference or flatness as their predominant moods. Thus the significant differences between LSD and schizophrenic psychoses appear to be in the affective nature of LSD psychosis and the greater incidence of delusions and auditory hallucinations in schizophrenics.
Breakey et al (1974) has suggested that the use of LSD can accelerate the onset of schizophrenia. He found that 26 hallucinogenic drug users experienced the onset of schizophrenic symptoms and were hospitalized significantly earlier than non-drug users, i.e. 19 ± 2.5 years versus 23 ± 4.6 years. Roy (1981) however was unable to replicate this finding. In a study matched according to sex, marital status, number of admissions, and follow-up, 37 chronic schizophrenics (DSM- III criteria) who had taken LSD preceding the onset of their illness were compared with 37 schizophrenics who had not ingested LSD. There were no significant differences between the two groups as to age of onset (19 ± 2.3 years, users, versus 20.8 ± 3.8 years, non-users) or for age of first admission 20.3 ± 2.6 years, users, versus 21.8 ± 4.3 years, non-users. Thus Roy concluded that the use of LSD does not hasten the onset of chronic undifferentiated schizophrenia of at least three years duration.
LSD reactions are difficult to distinguish from reactions to other hallucinogenic drugs such as mescaline, psilocybin, or DMT and the treatment is similar. However, LSD reactions can be differentiated from those of amphetamines and belladonna derivatives and schizophrenic reactions.
Amphetamine produces sympathomimetic effects such as mydriasis, tachycardia, and sweating that are usually less prominent than those of LSD. Amphetamine users may have needle marks, appear thin and malnourished, and suffer from anorexia and insomnia. The clinical picture includes acute paranoid delusions, loose associations, inability to concentrate, and inappropriate affect. The amphetamine user may be very agitated or even abusive. As in acute schizophrenia there are vivid hallucinations that are predominately auditory in contrast to the much more frequent visual illusions and pseudo-hallucinations produced by LSD. Furthermore, patients with amphetamine psychosis will often fail to differentiate hallucinations from reality. On the other hand, LSD patients have a relatively intact sensorium. A urine sample will remain positive up to 72 hours after use of amphetamine but only 8 to 10 hours after LSD use (Mannaioni 1984). Patients with adverse reactions from ingestion of anticholinergic preparations will show severe confusion, disorientation, and inability to concentrate or to express a complete thought. In contrast to amphetamine or LSD, anticholinergics cause mydriasis and cycloplegia; the patient's skin will be warm, dry, and flushed, the mouth dry, and temperature elevated (Wardy and Kay 1983). "Red as a beet, dry as a bone, and mad as a hatter" is a colloquialism used to describe anticholinergic intoxications.
TREATMENT
Acute Panic Reactions. Treatment of acute panic reactions should be directed toward relieving the patient's overwhelming anxiety. He or she should be kept in a quiet, comfortable room free from disturbing stimuli and anxious friends. Reassurance should be given by physician, nurse, or nurse's aid that nothing wrong or damaging has happened to the patient's mind or brain and that the effects of the drug will gradually disappear. The patient should not be left alone; a calm, supportive friend or relative should stay with the patient (Strassman 1984).
If the patient is severely agitated and if the drug or drug combination taken by the patient cannot be definitely identified, medication may be necessary. Diazepam (Valium), 15 to 30 mg orally or slow IV push may be given and repeated as necessary until the patient is calm. The use of chlorpromazine (Thorazine) is best avoided here since other hallucinogenic drugs such as DMT (dimethyltryptamine), may be involved, which can result in an increase in the potential for adverse reactions such as hypertension and seizures (Strassman 1984).
Restraints should not be used, since it may accentuate the patient's anxiety and paranoia. However, measures should be taken to prevent the patient from hurting himself or others. Hospitalization is not always indicated, but is appropriate in the suicidal patient and/or the psychotic patient. After the reaction is over, the patient should be examined psychiatrically and only discharged when his mental status has returned to normal (Strassman 1984).
Flashbacks. Recurrences of drug effects without the drug also known as "free trips" are a puzzling phenomena without any generally acceptable explanation. They have been variously reported in 15% to 77% of users (Strassman 1984). They are reportedly commonly precipitated by marijuana, anxiety, fatigue, or movement in a dark environment (Jaffe 1985). They may persist intermittently for several years following the last exposure to LSD. They are reportedly exacerbated by the administration of phenothiazines (Abraham 1983). Treatment is the same as acute panic reactions. The patient should be reassured that there has been no damage to mind or body. The patient should be cautioned against taking any hallucinogenic substance, including marijuana and antihistamines as well. If flashbacks persist or become more intense, psychiatric and neurologic examinations and psychotherapy are necessary. With time, restraint from intake of hallucinogens, use of mild antianxiety and sedative drugs, and if necessary, flashbacks generally disappear.
Psychosis. Phenothiazines are often useful for emergency treatment of agitated or uncontrolled patients before a diagnosis can be established. However, the phenothiazines, especially chlorpromazine (Thorazine) and thioridazine (Mellaril), can induce severe postural hypotension, lower the seizure threshold, and might increase the toxic effects of anticholinergic drugs if they have been ingested concomitantly with the LSD. Diazepam (Valium) for agitation followed by haloperidol (Haldol) for hallucinations and delusions are better choices for the treatment (Roy 1981).
REFERENCES
Abraham HD (1983). Visual phenomenology of the LSD flash. Arch Gen Psychiatry 40:884-9.
Breakey W, Goodell H, Lorenz P, et al (1974). Hallucinogenic drugs as precipitants of schizophrenia. Psychol Med 4:255-261.
Frosh W, Robbins E, Stern M. Untoward reactions to LSD resulting in hospitalization. N Engl J Med 273:1235-1239.
Hays P, Tilley JR (1973). The differences between LSD psychosis and schizophrenia. Can Psychiatry Assoc J 18:331-333.
Heym J, Rasmussen K, Jacobs BL (1984). Some behavioral effects of hallucinogens are mediated by a postsynaptic serotonergic action: evidence from single unit studies in freely moving cats. Europ J Pharmacol 101:57-68.
Hoffman FG (1983). A handbook on drug and alcohol abuse: the biomedical aspects. New York: Oxford University press.
Jaffe JH 91985). Drug addiction and drug abuse. In: Gilman AG, Goodman LS, Rall TW, Murad F: The pharmacological basis of therapeutics. Macmillan 562-581.
Mannaioni PF (1984). Clinical pharmacology of drug dependence. Piccin Nova Libraria, S.P.A.
Medical Society of the County of New York, Public Health Committee (1966). NY Med 22:241.
Peroutka SJ, Snyder SH (1983). Multiple serotonin receptors and their physiological significance. Fed Proc 42:213-7.
Roy A (1981). LSD and onset of schizophrenia. Can J Psychiatry 26:64-65.
Smart FR, Bateman R (1967). Unfavorable reactions to LSD: a review and analysis of the available case reports. Can Med Assoc J 97:1214-1221.
Stoll A, Hoffman A (1943). Partial synthese von alkaliolen vom typus des engobasins. Helvet Chim Acta 26:944-965.
Stoll W (1949). Eline neues in sehr kleiner mengen wirksames Phatastikum. Schweiz Arch Neurol U Psychiat 64:483.
Strassman RJ (1984). Adverse reactions to psychedelic drugs. A review of the literature. J Nerv Ment Dis 172:577-94.
Vardy MM, Kay SR (1983). LSD psychosis or LSD-induced schizophrenia? Arch Gen Psychiatry 40:877-883.
Young BG (1974). A phenomenological comparison of LSD and schizophrenic states. Br J Psychiatry 124:64-74.
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