LSD Psychosis

Original Author: Paul Perry, Ph.D, BCPP
Latest Reviser: Michael Trnka, Pharm D Candidate, Paul Perry, Ph.D, BCPP, FCCP
Creation Date: 1996
Last Revision Date: June 2005

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. (Is this still a legitimate statement according to the Inaba UDAARs book?)  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

It is generally believed that the mechanism of action of hallucinogenic drugs is mediated by central serotonin (5-HT) receptors.   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 the postsynaptic 5-HT2 receptors. 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).  In animal models 5-HT2 antagonists (ketanserin and spiperone) were shown to block the psychotomimetic effects of both LSD and DOM.  Antagonists of muscarinic, alpha-1 adrenergic or histamineric receptors failed to demonstrate similar effects (Sanders-Bush 1988).  Thus it appears that LSD pharmacologic activity is likely a function of 5-HT2 stimulation (Stahl 2000).    

PHARMACOKINETICS AND 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 15 minutes to 1 hour with the effects persisting 8 or more hours.   “Being stuck” refers to individuals who experience longer lasting effects after a single LSD ingestion (Lerner 2002c).   These episodes are characterizedby anxiety and/or visual disturbances such as halos.  The cause of this effect is unknownbut it is believed that LSD may be neurotoxic to 5-HT receptors.  The elimination half-life of LSD is estimated to be approximately 175 minutes.LSD or its cross-reactive metabolites were detectable for periods of 34-120 hours at concentrations of 2-28mcg/L in the urine of 7 subjects who received a 300mcgoral dose (Peel and Boynton 1980).  LSD is metabolized by the liver to 2-oxy-lysergic acid diethylamide, which is inactive.Urine from suspected drug abusers contained 2-oxo-3-OH-LSD as the major metabolite (Eades et al 1998)species. There is no evidence that physical dependence can develop to LSD since physiologic withdrawal reactions do not occur. Tolerance usually develops within can occur within five days, but can occur after a single use.  However, but it disappears quickly-, usually after three days of abstinence. Since relatively few users utilize the drug on a daily basis tolerance is rarely a problem of clinical importance (DEA 2003).

In the normal adult, doses range from 150 to 300 mcg produces the "psychedelic experience" (clinical grades 1 to 3), while doses up to 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 as in flashbacks or Hallucinogen Persisting Perception Disorder (HPPD).  Flashbacks are generally short-term, non-distressing, recurrent, spontaneous, reversible and benign conditions.  HPPDis described in DSM-IV-TR as the reexperienceing of one or more of the perceptual symptoms that were experienced while intoxicated.   In both flashbacks and HPPD one must first rule out psychological illness or the effects of other drugs.  Flashbacks differ from HPPD in that they are non-distressing and short, usually lasting only seconds to minutes.  While HPPD causes significant distress and may occur for prolonged periods of time or in clusters usually resolving in a few months but sometimes continuing for years.The following table illustrates the clinical changes observed with each "grade" of LSD reaction (Mannaioni 1984).

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 less common than visual hallucinations. 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).

Estimates of average lethal doses in humans range from 0.2 to 1 milligram/kilogram.  (Leiken 1998, Hoffer 1989).  Overdose deaths occur by respiratory arrest but are rare.  It is more likely that a person intoxicated with LSD will die accidentally due to poor decision as a result of their intoxicated state.  In one case 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).

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.

INTOXICATION PRESENTATION

Frosh et al (1965) described twelve LSD-intoxicated patients who were admitted to New York's Bellevue Psychiatric Hospital. Three overlapping types of presenting syndromes were described:

1. acute panic reactions (7 patients);
2. recurrence of symptoms in a period of abstinence after multiple ingestions (3 patients); and
3. prolonged psychosis (3 patients)

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 wereanxiety was 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.   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.

In the great majority of circumstances LSD intoxication is acute and reversible.  However, some subjects may experience prolonged or even permanent effects from the drug.  Individuals have reported effects lasting up to 24 hours or reoccurring 5 years after discontinuation of use (Cooper1955, Abraham 1983).  Long-term symptoms are believed to occur secondary to neurotoxic effects of LSD to the 5HT2 receptors and/or EEG changes (Lerner 2002c).

Spontaneous recurrences, i.e. flashbacks or in the more severe case HPPD, 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.  It has been hypothesized that recurrences are correlated to stress and the frequency of LSD ingestion. Six of the eleven patients hadand 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 (Smart and Bateman 1967).

Flashbacks and HPPD are now recognized as distinct disorders.  Flashbacks are characterized by short-term, spontaneous, reversible and benign reoccurrences of hallucinogenic symptoms.  HPPD is generally long-term, distressing, recurrent, spontaneous, pervasive, either slowly reversible or irreversible and non-benign.  HPPD can occur as prolonged psychosis or as more frequent and shorter episodes.  The onset of HPPD can be months to several years after the last ingestion of LSD.  If HPPD does not resolve in a few weeks to months after episodes start, it is likely that the patient will suffer from this condition for an extended periodof time. The prevalence of HPPD ranges from 0.08-4.6% (mean of 2.7%).  Theprevalence data has been derived retrospectively from small studies and case reports most published before the DSM-IV criteria for HPPD was established(Halpern 2003, Abraham 1993).

Chronic LSD ingestion has also been associated with impairment of visual function.  Several studies demonstrated depressed critical flicker frequencies, reduced sensitivity to light during dark adaptation, shorter visualevoked response and isolated occipital disinhibition upon eye closure.  Clinicians should inquire about past LSD use in all patients who initiallyhave seemingly spontaneous palinopsia.  Recognition of this distinctive clinical syndrome associated withLSD use might avoid unnecessary anxiety and excessive diagnostic tests for patients with this disorder.  It is unclear if visual function changes are directly related to HPPD.  Two of the three studies looked specifically at patients that met the DSM-IV criteria for HPPD.  The other did not specifyif the subjects had HPPD because it was published before DSM-IV (Abraham 1988, 1996, 2001)

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).

A meta-analysis of nine studies from 1968 to 1996 revealed no long-term cognitive effect in LSD users.  The studies looked at changes in intelligence, psychomotor speed, executive functions, visuospatial ability, kinesthetic function and electrophysiological measures.  This study focused on long-term effects and did not examine the effects of LSD on these functions while under the influenceof the drug (Halpern 1999).

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 could be differentiated 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,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.

HPPD should be diagnosed by the DSM-IV criteria presented in Table 2.  Full insight, reality testing and judgment are retained by subjects.  Visual symptoms usually predominate but subjects often experience anxiety and depersonalization.  Flashbacks are shorter, less distressing and usually not reported.  Flashbacks are referred to by users as “free trips” and do not require treatment.  HPPD is commonly reported and does require treatment due to the long and distressing nature and the tendency of the symptoms to cause social and psychologicalimpairment.  Users with HPPD will often refer to themselves as “scratched” or “bruised.”  Physicians should beware of prolonged depersonalization sometimes called “the bubble” or “window syndrome” in reference for the tendency of these users to commit suicide (Lerner 2002c).

TREATMENT

Acute Panic Reactions. Treatment of acute panic reactions should be directed toward relieving the patient's overwhelming anxiety, to allow them to relax and to get them to a safe environment where they can not harm themselves or others. 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).  The Haight Ashbury Detox Clinic uses the five step process presented in Table 3 called by the acronymARRRT to deal with people experiencinghaving a bad trip.  LSD trips are often responsive to this technique,however if the care-giver is unaware of the drug or drug combination that the patient has ingested they should remain cautious.

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 are considereddangerous to the patient and should not be used.  Restraints may accentuate the patient's anxiety and paranoia. Two cases of acute renal failure have been reported secondary to straitjacket use in LSD intoxicated patients.  Rhabdomyolysis resulted from a combination of severe restraint and the violent movements of the patient induced by the drug (Brown 1984).  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.  Flashbackshave been variously reported in 23% to 64% 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). 

HPPD.  Those who do seek treatment for reoccurring or prolonged hallucinogenicepisodes are usually experiencing HPPD not flashbacks.  Treatment of HDDP is symptomatic and can often alleviate the condition to the point where the subject can function normally but is not curative.  Most patients require long term treatment.  This condition is slow to respond therefore, drugs should be given a 2 month trial before being consideredineffective.  Several treatment options have been explored in the literature however efficacy is controversial because there is a lack of double blind placebo controlled studies.  Low dose clonidine (0.05-0.075 mg/day)appears to have emerged as the treatmentof choice.  A small open label study has reported mild successwith the agent.  Eight patients were entered in a 2 month trial, there where 2 drop outs, the remaining 6 reported an averageof a 2.75 point improvement on the Clinical Global Impression Scale (CGI) and a 2 point improvement on a self reported scale (SRS) (Lerner 2000a). 

Dopamine receptor antagonists have also shownefficacy for the treatment of HPPD.  Perphenazine is preferredover haloperidol and triflouperaxzine, because it is associated with a lower incidence of discontinuation due to adverse effects (Lerner 2002c).

Benzodiazepines, most notablyclonazepam, have hadsuccessat targeting anxious mood, tension, insomnia and intellectual symptoms of HPPD.  A group of 16 subjects were treated with clonazepam for 2 months and then given a 6 month follow up.  There were two drop outs.  The remaining subjects reported improvements on the CGI, SRS and Hamilton Anxiety Scale (HAM-A).  The improvements were retained at follow-up (Lerner 2003).  However these agents have been reserved for third lineuse because of their potential for abuse in this population.  Other agents including opiates, phenytoin and SSRIs have been used with moderate success (Lerner 2002c).

Risperidone should not be used in the treatment of HPPD because it has been shown to exacerbate LSD-like panic and visual symptoms.  This has been attributed to the action of risperidone on the 5-HT2 receptor.  (Lerner 2002b, Abraham 1996)

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).

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