This literature review (1984) examines the basic pharmacology and potential adverse effects of synthetic psychedelics, primarily LSD. It concludes that while acute adverse reactions occur, there is little evidence for organic brain damage or permanent negative changes in personality among users.
The use of naturally occurring and synthetically derived compounds for their psychedelic effects has been a part of human culture for thousands of years. The basic pharmacology of the major synthetic psychedelic compounds primarily lysergic acid diethylamide [LSD] is described and reference is made to their potentially beneficial psychological effects. Adverse reactions, defined as dysphoric and/or maladaptive/dysfunctional responses to the use of these drugs, sometimes require careful clinical judgment in order to diagnose. These reactions can be effectively classified along a temporal continuum, Acute, short-lived reactions are often fairly benign, whereas chronic, unremitting courses carry a poor prognosis. Delayed, intermittent phenomena flashbacks and LSD-precipitated functional disorders that usually respond treatment appropriate for the non-psychedelic-precipitated illnesses they resemble, round out this temporal means of classification, The question of organic brain damage as well as permanent changes in personality, attitudes, and creativity in patients and normals who have repeatedly ingested psychedelic drugs is controversial, but tends to point to subtle or nonsignificant changes. Future areas for study of the psychedelics’ pharmacological, psychological, and. therapeutic effects are suggested.
Abraham frames psychedelic use as a long-standing human practice and reviews the pharmacology and reported psychological effects of major synthetic psychedelics, with LSD-25 treated as the prototypical compound. Earlier therapeutic enthusiasm in the 1950s–60s is noted alongside growing public and legislative concern about adverse acute and chronic effects; the paper focuses on adverse reactions—defined as dysphoric and/or maladaptive responses—that sometimes require clinical judgement to diagnose. The review sets out to classify and summarise the literature on adverse reactions to psychedelics, to identify methodological problems in existing reports, and to suggest priorities for future research. Abraham seeks to place adverse events on a temporal continuum (acute, delayed/intermittent, chronic) and to examine evidence about etiologies, incidence, clinical management, and long-term sequelae, emphasising the limitations of the available data.
Papers cited by this study that are also in Blossom
Grof, S., Goodman, L. E., Richards, W. A. · Pharmacopsychiatry (1973)
Papers in Blossom that reference this study
Sulstarova, A., Scheuerlein, L., Monari, S. et al. · Asian Journal of Psychiatry (2025)
Hinkle, J. T., Graziosi, M., Nayak, S. et al. · JAMA Psychiatry (2024)
Sabé, M., Sulstarova, A., Glangetas, A. et al. · Molecular Psychiatry (2024)
This paper is a narrative review of the literature rather than a systematic meta-analysis. Abraham excluded case reports with fewer than 10 subjects and grouped the remaining studies into four categories: (a) studies of patients presenting acutely to treatment settings (emergency rooms, inpatient units) with symptoms attributed to LSD; (b) clinician- or researcher‑survey studies using mailed questionnaires about clinical experience; (c) follow-up studies of subjects who had taken LSD in experimental, therapeutic, or uncontrolled contexts; and (d) controlled administration studies where responses were evaluated immediately after dosing. Because many original reports lacked pre‑LSD baseline data, Abraham highlights that causal attribution is problematic for most outcomes. To aid appraisal, a set of methodological features for an “ideal” study is proposed: adequate sample size with sex ratio, clear case‑finding methods, age reporting, an operational definition of adverse reaction with inter‑rater reliability testing, documentation of drug source and cumulative exposure, interval since last exposure, detailed study methods (clinical interview, psychometrics, neurophysiology), description of set and setting, premorbid characteristics (including family psychiatric history and other drug use), motivation for use, use of placebo/active control and matched controls, presence of pre‑exposure data, and duration and completeness of follow‑up. Abraham reviews prospective and retrospective designs, and notes important confounders encountered across studies: polydrug use, heterogeneous definitions of adverse reactions, selection bias (volunteers versus clinical samples), lack of premorbid testing, variable drug purity in street samples, and differences in setting (supervised versus unsupervised).
Abraham organises adverse reactions along a temporal continuum. Acute reactions—commonly the “bad trip”—are typically transient (<24 hours) and characterised by panic, terrifying visual or auditory illusions/hallucinations, overwhelming anxiety, possible aggression, depressed mood with suicidal ideation, confusion and paranoid fear. More prolonged reactions (days to months) that sometimes require hospitalisation are often labelled “LSD psychoses” and present heterogeneously with thought disorder, hallucinations, delusions, affective disturbances, regression and behaviour disturbance. Between acute and chronic endpoints lie delayed or intermittent phenomena, notably flashbacks, and cases described as LSD‑precipitated major functional disorders (affective or schizophrenia‑like illnesses). Reported risk factors for more severe or prolonged adverse outcomes include younger age, poorer premorbid adjustment, prior psychiatric history (personal or familial), greater number of psychedelic exposures and higher cumulative dose, unsupervised settings, polydrug abuse, and self‑therapeutic or peer‑pressure motives for use. However, Abraham emphasises that individual prediction is difficult and that severe reactions have occasionally occurred in previously well‑adjusted people. Prospective administration studies that obtained pre‑drug data (Klee and Weintraub; Pauk and Shagass; Langs and Barr) identified psychological and personality predictors of short‑lived paranoid or disorganised reactions: high anxiety, projection as a defence, hostility, identity confusion, and impaired performance on tests such as the Bender‑Gestalt. Anastasopoulos and Photiades reported prolonged reactions in asymptomatic relatives of schizophrenics, although their methods were not fully elaborated. Follow‑up and longitudinal investigations produced mixed findings. McGlothlin and colleagues report a 10‑year follow‑up of 247 subjects who had received LSD in experimental or psychotherapeutic settings: patients given LSD in supervised therapeutic contexts showed no greater change on measured variables than matched controls, whereas those who continued nonmedical LSD use (the “continuers”) differed on a range of personality, values and substance‑use measures. Other cohort and cross‑sectional studies of heavy users produced inconsistent neuropsychological and electrophysiological findings. Several studies with methodological limitations reported isolated abnormalities (for example, increased EEG energy in some bands over left occipital cortex in the Blacker study; mixed deficits on Trail‑Making and Halstead tests in some samples), while better‑controlled investigations generally failed to find convincing evidence of gross, persistent brain damage attributable to LSD. Flashbacks are reported with widely varying incidence across studies—15% to 77% in samples of people with at least one psychedelic experience; Abraham notes an approximate figure of 50% reported in the literature, while stressing heterogeneity in populations and definitions. Phenomenology of flashbacks has been categorised into perceptual, somatic, and emotional types. Proposed explanations include a role‑playing/learned response under high arousal, situational exacerbation of underlying personality traits, psychodynamic conversion models, and neurophysiological hypotheses involving visual pathways; data do not clearly favour a single model. Extreme outcomes reported in case series—homicides, suicides, severe self‑injury—are described but Abraham cautions that these reports are usually confounded by polydrug use, alcohol intake, preexisting severe psychopathology, sleep deprivation or other precipitants, so a specific causal role for LSD is not clearly established. Treatment‑related findings summarised in the papers reviewed indicate that uncomplicated acute panic reactions usually resolve and can be managed with a calm supportive setting, orientation and reassurance. Short‑acting benzodiazepines and chlordiazepoxide were recommended for agitation; major tranquillisers are reserved for severe agitation or psychosis, with caveats about paradoxical reactions and anticholinergic or hypotensive risks. Extracted dosing details in some passages are unclear in the text. For flashbacks, education, reassurance and, if necessary, short‑term pharmacotherapy (benzodiazepines, occasionally antipsychotics) or behavioural approaches were reported; prognosis for flashbacks is generally favourable if further drug use is avoided.
Abraham interprets the reviewed literature as showing that adverse reactions to psychedelics form a spectrum from brief, self‑limited panic states to prolonged, treatment‑resistant psychotic presentations. He emphasises that methodological shortcomings in the available studies—retrospective designs, lack of premorbid data, selection bias toward clinically ascertained “LSD casualties,” polydrug confounding, variable drug purity and inconsistent definitions—severely limit causal inferences about long‑term harm, brain damage, or personality change. The investigators position their findings within multifactorial etiological frameworks. Biological (serotonergic and possibly dopaminergic) mechanisms are discussed alongside psychological and systems models; Abraham favours an interactional perspective in which constitutional vulnerability (personal or family history of major mental illness, characterological pathology), motivation for use, inadequate preparation/support and unsupervised settings combine with drug effects to produce adverse outcomes. Prospective studies with pre‑exposure testing suggest that specific personality and defence‑style features predict acute adverse responses, supporting the importance of screening. In terms of clinical implications, supervised administration with careful screening, preparation and follow‑up appears associated with a low incidence of severe adverse events, whereas many severe cases in the literature derive from unsupervised recreational use of street drugs of uncertain purity. Abraham notes uncertainty about whether characteristic personality profiles among frequent users are preexisting selection effects or consequences of repeated use, and he reports that the best‑designed follow‑ups (therapeutic settings) did not show greater deterioration in supervised patients versus controls; continuers of nonmedical use did show measurable differences in values and behaviours. Key limitations acknowledged by the author include the predominance of retrospective and uncontrolled data, inadequate accounting for other substance use, and sparse premorbid and family history information in many reports. These gaps constrain conclusions about LSD’s role in precipitating major functional disorders or producing permanent organic deficits. Abraham therefore argues for more rigorous, prospective research with standardised definitions, premorbid assessment, control groups and careful monitoring.
Abraham concludes that, on the basis of the available literature, the incidence of severe adverse reactions to psychedelics is low when compounds of pharmaceutical quality are administered to carefully screened, prepared and supervised subjects. Conversely, unsupervised use of street drugs of uncertain purity is associated with a higher frequency of reported adverse events. The author recommends restricting participation in future human research to individuals without a personal or strong family history of severe mental illness, or to those who can be closely supervised and followed for at least 1–2 weeks after exposure. He also calls for renewed, cautiously regulated research into psychedelic neurobiology, phenomenology and therapeutic potential, using contemporary methods (PET imaging, refined EEG/evoked‑potential analysis, standardised psychometrics) and rigorous study designs to address the methodological shortcomings identified in the existing literature.
The use of naturally occurring, exogenously admin istered substances for inducing altered states of con sciousness extends back to ancient times. Cannabis products and certain species of mushrooms were used as long ago as the time of the Vedas, in India, nearly 5000 B.C. In the New World, mushrooms and certain cacti, barks, and vines were employed for similar pur poses by indigenous cultures 147. Abuse apparently was fairly rare, perhaps because careful cultural, reli gious, and social proscriptions determined a uniform manner in which these substances were used and the experiences one was expected to have as a result of their use 167. The "modern era of speciflcallv mind-altering drugs is often said to have begim with Albert Hof mann's accidental ingestion of LSD-25 in 1943 77. However, interest in mescaline/neyote was briefly pursued at the turn of the century 48 and in the 19305A great flurry of scientific activity with LSD and Similarly acting drugs occurred in the 1950s and 1960s, 'Department of Psychiatry, University of California, Davis, Medical Center, 2315 Stockton Boulevard, Sacramento, California 958j7, but was just as quickly aborted in the late 1960s as fears of adverse acute and chronic effects of wide spread use and abuse began to come to the attention of media and legislators. Therapeutic and "growth-enhancing" aspects of these substances were widely pursued early on, spurred by such "auto-experimenters'? 9 as Aldous, Timothy, and Carlos Casts neda 32, A discussion of these aspects of "psyched elic" drug use is beyond the scope of this paper, but interested readers are referred to
The confusion regarding the tenninology of this class of drugs, of which LSD-25 is considered the prototype. is reflective of the various orientations respective investigators have taken in approaching them. For those who have been struck by the primarily perceptual effects of these drugs, the terms halluci nogenic or illusogenic are used. The similarity between the effects of LSD-like substances and certain psy chotic phenomena a feature that caused them to be employed as potentially producing a "model' of schiz 577 ophrenia has induced others to label them as psycho toinimetics or psychotogens 39. Psychedelic, a term attributed to Osmond 64, p. 8 and defined as "mindmanifesting," although somewhat vague, also carries a less restrictive connotation, and for that reason is the preferred term in this paper. Other words that have been used to describe this class of drugs include psychodysleptics 29, p. 4 mind distortive or mind disruptive, deliriants, and mind-exnandinR drugs, Definition Psychedelic drugs can be distinguished from other centrally active drugs that can also under certain conditions induce perceptual distortions e.g., anti cholinergics, paranoid and other delusions e.g., am phetamineS, and other alterations of cognition, be havior, and affect e.g., opiates, bromides. They are capable of, when pathological effects are absent or minimal, "reliably inducing or compelling states of altered perception, thought, and feeling that are not or cannot be experienced otherwise except in dreams or at times of religious exaltation" 84, pp. 563-564. Lysergic acid diethylamide-25 is the prototypical psychedelic compound, and was often the active ingre dient in most street "psychedelics," during the period in which most of the reference studies were performed. even those labeled "mescaline" or "psiiocybin" Unless otherwise mentioned, LSD-25 will be used inter changeably with "psychedelic" in this paper. It is, as are psilocybin, psilocin, diethyltryptamine, and dime thyltryptamine, a member of the indolealkylamine class 'fdr:;s. Mescaline one of the most active ingredients in peyote cactus is a phenylisopropylam me 84. Phencychcline PeP, "hog," "angel's dust," etc., an arylcyclohexylainine, has attained great cur rency in the last 10 years, as a common street "psy chedelic" in its own right, as well as a substitute/ adulterant for other psychedelics. Many current satpies of thugs sold as psychedelic, are often found to contain variable amounts of PCP. However, PCP did not become a popularly abused street psychedelic until the mid-1970s, a time by which almost all of the major reports of adverse reactions to LSD had been pub lished. The effects of PCP can be differentiated both pharmacologically and clinically from true psyche delics 84. The interested reader is referred to Lis ansky et al. 101 for a fuller discussion of these important distinctions. On the basis of a subjective effects and neurophys iological actions, b cross-tolerance between com pounds, and c response to selective antagonists, Mar tin and Sloan 105 have classified LSD, mescaline, psilocybin, and psilocin as "LSD-like" Differences among the various LSD-like drugs referred to here as the psychedelics are primarily a matter of rate or onset, peripheral side effects, duration of action, and intensity of experience. For example, LSD is longer acting 8 to 12 hours and more potent average dose of 100 to 500 pg than mescaline average dose of 209 to 500 nig arid average duration of 6 to 8 hours and psilocybin or psilocin average duration of 4 to .12 hours and a dose range of it to 50 mg.
Serotonergic 5-HT systems especially in the mid brain raphe nuclei, or neurons projecting from those nuclei have classically been implicated as the primary source of psychedelics' effects 11, 17, 69, 102. They seem to preferentially inhibit serotonergic cell firing via binding to cell-body or dendritic 5-HT receptors and seem to spare postsynaptic receptors, although this is controversial 83. As serotonin is primarily an inhibitory neurotransmitter, inhibition of these cells by LSD would allow the next neuron in the chain to be freed from inhibition 166. Dopaminergic systems may also be involved in the central effects of psychedelics. There are preliminary data 41 indicting an agonistic and antagonistic effect of LSD on postsynaptic dopamine receptors. Carbon-14-labeled LSD given to animals has been found to be maximally concentrated in liver and kid ney. Brain concentrations are maximal in hippocam pus, basal ganglia, thalamic nuclei, and cerebral cor tex. Most of LSD's etabc.lites are exacted in the feces 127. Implanted cortical electrodes in humans have shown LSD-associated paroxysmal electrical activity in hippocampal gyri, amygdaloid nuclei, and septum during perceptual changes which are reversed by chlorpromazine 117.
The effects of an oral dose of LSD as low as 20 to 25 gig can be perceived within a few minutes, aJthougb with psilocybin and mescaline, onset of initial symp toms is somewhat later 15 to 30 minutes. Initial physical symptoms are sympathomimetic in nature. These include dilation of the pupils which retain their reactivity, nausea, flushing, chilliness, increased blood pressure and heart rate, tremor, hy perreflexia, piloerection, weakness, elevated blood temperature, and dizziness 84, 102. Psychological effects soon follow, and, within 30t0 90 minutes, include feelings of inner tension, affective lability, visual illusions and hallucinations followed in decreasing frequency of occurrence by auditory and other sense-modalities, blending of sensory modah ties e.g., 'seeing sound"-synesthesia, a slowing of subjective time, a sense of ego dissolution/detach ment/fragmentation, recollection of long-forgotten memories, and increased sense of meaningfulness of what is being experienced. Religious and mystical insights occasionally occur. As the drug effect wears off, and if the xperience has been regarded as gener ally positive, there is a calm, yet energetic sense of detachment and control. In comparison with the aforementioned positive-valued effects, adverse reac tions can occur at any stage of the acute experience and may end up being fairly prolonged. Between doses of 1 and 16 ag/kg, the intensity of effect is proportionate to the dose 84. The half-life of LSD is about 8 hours in humans 8. Tolerance rapidly develops for psychedelic drugs, and at least 3 to 4 days are necessary for recovery of preexisting sensitivity to a drug of this type. A withdrawal syndrome does not occur with abupt cessation of LSD-iike drugs, and a syndrome of phys ical dependence is not known. LSD use has been reported to be associated with the occurence of rand mal seizures 52. "Overdoses" of LSD are not directly fatal; however, one suspected case of LSD as a cause of death, in a man whose body was found in a ware house 1 month after death, has been published 63. An LD50 for the human is not known. although an elephant has been killed by a 300-mg intramuscular injection 169. Death occurred in this instance by asphyxiation secondary to laryngospasm. There are several theoretical frameworks available for understanding the role of LSD in producing psy chological effects. None of them are necessarily pro posed as absolute, and a perspective that takes into account as many viewpoints as possible will undoubt edly prove most useful. From a neurobiological point of view, the exact effects of LSD are controversial, but appear to impli cate serotonergic function. In the most general sense, inhibited serotonergic function, especially in cortex, raphe, and limbic system, csn be presumed to decrease the "filtering" of cognition, perception, and feeling in which serotonergic systems are probably involved. Therefore, mental and physical events are experienced in a novei, less processe& manner.has described the effect of LSD on ego functioning i.e., thought, motility and perception. Body image is disorganized, time sense is profoundly altered, and perceptions of others are distorted, re sulting in the sense of "self"-perception being, by and large, lost. Therefore, distinctions between reality and fantasy suffer. Thought processes become dreamlike and concentration becomes difficult. Primary process thinking comes to the fore, and previously neutral Words and ideas are responded to as though they were traumatic. The distinction between autonomous and conflictual areas of the ego becomes blurred. From an ego-defense perspective, repression and reaction for mation appear most sensitive to the disruptive effects of LSD; projection, denial, introjection, and regression may continue to function effectively. Motorically, some individuals experience impairment in the ability to tolerate tension and delay discharge. Linton and Langs 99 validated and quantified many similar findings described by Klee. They con cluded that "the drug produces an accentuation of thinking by means of images, alterations of self-ex perience, including feelings of detached self-observa tion and estrangement, confusion of personal identity, the experiencing of events in terms of implied mean ings, loss of boundaries between the self and the environment, drive-dominated thinking, alterations in the distribution of attention cathexis, somatization, and an increase in feelings of passivity, expressed as a subjective loss of control" 99, p. 366. Tart, in his systems approach to states of conscious ness, describes a discrete state of consciousness as a "unique dynamic pattern or configuration of psycho. logical structures, an active system of psychological subsystems" 152, p. 5. This pattern is stabilized by several processes he has described. A change in state of consciousness occurs through the effect of disrupt ing forces and subsequent action of patterning forces-and then is stabilized by the same processes. Psychedelic drugs are thought to provide disrupting and patterning forces, the effects of which operate in combination with other psychological factors me diated by the operative state of consciousness. Tart feels that LSD causes a highly unstable pattern of psychological structures, characterized by transient formations of patterns that constitute discrete states of consciousness.
It is important to use caution in discussing the concept of adverse reactions to psychedelic drugs. At one extreme are those who believe that the druginduced state itself is either primarily a pathological one i.e.. a "model psychosis" or that the desire to induca such a state is a fnction ofpreexistinnersc.n aiity dysfunction. At the other extreme is the view that even the most disorganized, frightened, dysfunc tional, and regressed reactions to psychedelic drugs are necessary/healthy reactions seen in throwing off "straight" society's "shackles" and in reaching a "higher" level of consciousness. The description and/ or reporting of adverse reactions to psychedelics is, therefore, subject to some degree of investigators' per spective on the use of these drugs. It is clearly an adverse reaction when one presents himself or herself to a mental health practitioner with complaints referrable to symptoms induced or exacerbated by psychedelic drugs. It is less clear when changes in behavior, values, or life-style that are brought on, solidified, or symbolized by psychedelic drug use are brought to the attention of care-givers by a concerned other-e.g., friends, co-workers, or rela tives. These are cases where sensitive :i. udg ment plays as ntuch a role in determining pathological diagnoses as do the salient presenting features of the syndrome. A large number of methodological issues need to be addressed before beginning an analysis of available reports of adverse reactions. I will attempt to address certain of the most salient features before discussing these studies. I have excluded from analysis reports that include less than 10 subjects. Many of these are case reports of a few individuals, Some are in-depth analyses of these subjects, often from a psychodynamic and ge netic perspective. Although heuristically of value, they are difficult to evaluate from the viewpoint of devel oping testable hypotheses. The remaining studies, I believe, can be divided into four general categories: a Studies with patients seen in an acute treatment facility emergency room or inpatient unit because of symptoms thought to be related to LSD. b Studies where questionnaires were mailed to cli nicians and/or researchers, polling their experi ences with subjects in therapeutic, experimental, and uncontrolled settings. c Follow-up studies of subjects who took LSD in experimental, therapeutic, or uncontrolled set tings. d Studies where subjects were given LSD in a con trolled environment and then responses evaluated immediately thereafter. Tableis organized around this categorization of relevant studies. One of the most confounding aspects of almost all studies of either acute or chronic effects of LSD is their lack of pre.LSD data. The role of LSD in pro ducing "LSD psychoses," brain damage, long-lasting personality change, and flashbacks is difficult, if not impossible to discern without pre-LSD values for the dependent variables. Tablelists the features I believe to be important to address in studies of adverse reactions to psyched elics. They would be included in what might be called the "ideal" study on adverse reactions to psychedelics. Sample size: Should include ratio of male to female subjects. Case-finding methods: This will obviously have an effect on the population studies. For example, subjects volunteering to be studied will often have different character traits, and possibly pathology, from those refusing to do so. Age range and average age should be specified, a reports often emphasize the increased susceptibiljj of younger subjects to adverse reactions e.g.,. The definition of an adverse reaction needs to be specified. as more or less liberal definitions will have related effects on the frequency of their occurrence. It would be ideal to test inter-rater reliability and valid ity of the definitions, as well. Source of the drug is self-evident, as adulterants of "psychedelics" can be quite psychotoxic. The number of drug exposures and, if available, the dosage taken can indicate total cumulative exposure to psychedelics, a factor that appears to be quite important in several regards e.g., frequency of adverse reactions, long term psychological effects, flashbacks, etc.. The time elapsed between the last trip and the date of being interviewed or tested is important, both in terms of retrospective alteration of the subject's mem ory of the experience 100, as well as the presence or absence of acute drug effects. Study methods can vary widely and range from simple direct clinical observations, to detailed neuro chemical studies. Other methods have included indepth clinical interviews, questionnaires, paper and pencil psychological testing, and interviewing subjects' therapists and families. The setthg i.e., i3OC and people present needs to be specified. Early reports of adverse reactions occur ring in controlled supervised settings were marked by a very low frequency of occurrence k34, and whether or not the setting was unsupervised could have a powerful effect on the frequency and nature of adverse reactions. Premorbid population characteristics include a lEgal history as an indicator of sociopathy, drug abuse, and object relations in general; b previous psychiatric his tory, either in the subject or in the family of origin. This is particularly germane to addressing the ques tions of preingestion psychopathology and whether or not a genetic/biological "diathesis" exists in selected individuals to develop adverse reactions e.g., 61; c other drug use is obviously relevant, particularly if one is to assign an etiological role to LSD is causiflf aberrant behavior, brain damage, or personal distress' Motloation for psychedelic drug use has been showfl by many groups to be related to outcome of the drug experience and relates both to premorbid character istics of the subject, as well as to the setting in which he/she would most likely be taking the drug e.g., Sb. The presence of placebo, whether preferably active one e.g., stimulant drug or an inactive Ofl e.g., saline in controlled experiments would add to the validity of a psrticular study. The presence of appropriately matched controls would also provide helpful comparison data. The presence or absence of pre-LSD data as previ ously discussed, helps differentiate the etiological vs. associative relationship between LSD use and relevant findings. Presence or absence of follow-up and its duration need to be specified, especially in terms of studying long term effects of these drugs. The re-emergence, disappearance, or prolongation of symptoms will de termine, to a large extent, the degree of disability incurred by the use of the psychedelics. The incidence of adverse reactions obviously is de termined by the definition of these reactions, and the poulation being studied. It is clear that, among inpa dents admitted because of LSD reactions, 100 per cent of these individuals have had an "adverse reaction." Likewise, the incidence of transient painful, anxious, and depressed experiences at some time during most LSD experiences appears to be quite common. Most studies have defined adverse reactions operationally, i.e., those reactions that have come to the attention of individuals in the mental health field. Keeping these points in mind, one can begin sorting through the voluminous and variegated literature on adverse reactions to psychedelic drugs 33, 25-37, 137. Tableis meant to aid in analyzing various reports, particularly in terms of the absence or pres ence of these parameters being specified.
The temporal relationship between the ingestion of a psychedelic drug and subsequent dysphoric or ma ladaptive symptoms is probably the most helpful means of beginning a classification of adverse reac tions, i.e., on a continuum from acute to chronic. Between these two ends of the spectrum would be the phenomena of delayed reactions e.g., a panic reaction or psychosis occurring after an asymptomatic interval 70, intermittent reactions such as "flashbacks", and the "LSD psychoses" including the psychedelic-pre civitated major functional disorders. The most common adverse reaction is a temporary less than 24 hours episode of panic-the bad trip 159-462. Symptoms include frightening illusions/ hallucinations usually visual and/or auditory; over whelming anxiety to the point of panic aggression with possible violent acting-out behavior; depression with suicidal ideations, gestures, or attempts; confu sion; and fearfulness to the point of paranoid delu Sions. Reactions that are prolonged days to months and/ or require hospitalization, are often referred to as "LSD psychoses," and include a heterogenous popu lation and group of symptoms. Although there are no hard and fast rules, some trends have been noted in retro spective analyses of these patients. There is a tend ency for people with poorer premorbid adjustment, a history of psychiatric illness and/or treatment, a greater number of exposures to psychedelic drugs and correlatively, a greater average total cumulative dos age taken over time, drug-taking in an unsupervised setting, a history of polydrug abuse, and self-therapeu tic and/or peer-pressure-submission motive 122 for drug use, to suffer these complications. In spite of the impressive degree of prior problems noted in many of these patients, there are occasional reports of severe and prolonged reactions occurring in basically well adjusted individuals 70. in the same vein, there are many instances of fairly poorly adapted individuals who suffer no ill effects from repeated psychedelic drug use. In fact, it has been hypothesized that some schizophrenics do not suffer adverse reac tions because of their familiarity with such acute alt.ered states, sr1d their ability to let the run thair course 59. Another possibility is that these individ uals may be "protected" by possible "down-regulation" of the receptors for LSD, by the overproduction of some endogenous compound. Individual prediction of adverse reactions, therefore, is quite diffleult. How ever, some well designed prospective studies have shown that particular individuals are especially prone to adverse acute reactions see below. Symptomatically, these patients present with a wide variety of symptoms, belying the great variety of their premorbid features 120. Formal thought disorder, hallucinations, illusions, violence, paranoid and other delusions, depression, regression, emotional lability, bizarre behavior, insomnia, hypomania, depersonali zation, dissociative states 43, confusion, and apathy can be seen. Bowers et al. analyzed some neurohumoral features of LSD-induced vs. non-LSD-induced psychoses, and found that the CSF of the former group gave evidence of decreased central 5-hyd.roxyindoleacetic acid a me tabolite of serotonin formation, a finding that per sisted during phenothiazine treatment. Homovaniffic acid a dopamnne metaboiite in the OSE did not show a difference in levels between these two groups 24. Infrequently reported, but receiving great publicity, were the articles on homicides that occurred in asso ciation with L8D use. Knudsen 93 described a young woman with a long history of polydrug and alcohol abuse, sexual masochism, sociopathy, and a major depression treated with electroconvulsive therapy ECT, who murdered her sexual partner 3 days after the fifth of a series of LSD psychotherapy sessions. Barter and Reite 16 described the case of a young chronic paranoid schizophrenic male who killed his mother-in-law. He had taken small quantities of LSD in the past, his last experience having been a month before the murder. In the interim, he had been drink ing large quantities of alcohol and abusing barbitu rates. The same authors described another young man with no previous drug abuse or psychiatric history who murdered a "comparative stranger during an argu ment" 16. n. 33: the details of both :tis ;eiationsnip to the stranger and the nature of the argument are not included in the report. He had also been drinking that night and remembered nothing of the incident. Klepfisz and Racy 92 described a young man with a 3-year history of polydrug abuse, including amphet amines and cocaine, who killed a girlfriend 2 days after an LSD experienceS Reich and Hepps 126 described a young man with paranoid and borderline character pathology who killed a stranger after 8 days of sleep deprivation, round-the-world travel, and psychosis, following an LSD experience. He had a history of depression and polydrug abuse. These cases, except perhaps for the Reich and Hepps example, do not clearly implicate LSD in the murders described. The role of other drugs and alco hol, as well as chronic psychosis, seem at least equally relevant, in the Reich and Hepps case, a temporal relationship between LSD use and psychosis was ap parent, but as will be discussed later, the specific nature of LSD as having precipitated the psychosis, as opposed to other drugs, jet travel, or the cumulative effscts or transient, unsatistactory relationships in a previously marginally adapted individual, is difficult to determine. Reports of suicide have been occasionally described in the literature 86, and are most often included in large case analyses. Data regarding the role of LSD in these individuals' self-destructive behavior is difficult to glean from these reports, but McGlothlin et at. 115, for example, described a weak temporal rela tionship between LSD Use and suicidal actions. What is missing in these reports, but most germane to them, is information regarding premorbid symptomatology and suicide attempts, other drug alcohol abuse, and the nature of the situation in which LSD was taken. Self-inflicted ocular injuries, including seif-enucle ation 130, 155 or retinal burns from staring at the sun 58, have been reported infrequently. These in juries were described in individuals for whom little or no premorbid and/or psychiatric follow-up data are available, and what was described demonstrated poor adjustment in the years before the self-inflicted inju ries. Major "functional" psychoses vs. "LSD psychoses. A diagnostic issue dealt with explicitly in only a few papers is that of LSD-precipitated major functionaj illnesses, e.g., affective disorders or schizophrenia. j other words, many of these so-called LSD psychose3 could be other illnesses that were triggered by the stress of a traumatic psychedelic drug experience. Some of the same methodological issues descrThe earlier affect these studies, but they are, on the aver age, better controlie-± with more family and past psy chiatric history available for compariscn. Hensala et at. 74 compared LSD-using and non LSD-using psychiatric inpatients. They found that this group of patients was generally of a younger age and contained more characterologically disordered in dividuals than the non-LSD-üsing group. Patients with specific diagnoses with or without LSD histories were not compared. Based on their observations, they concluded that LSD was basically just another drug of abuse in a population of frequently hospitalized individuals in the San Francisco area, and that it was unlikely that psychedelic use could be deemed etiolog ical in the development of their psychiatric disorders. Roy 133, Breakey at al. 28, and Yardy and Kay 165 have attempted to relate LSD use to the onset and development of a schizophrenia-like syndrome. A few comments regarding this conceptual framework seem in order, before their findings are discussed. The major factor here is that of choosing schizophrenia, or in the Vardy and Kay study, schizophreniform disor ders, as the comparison group. There is an implication here that LSD psychoses are comparable, phenorne nologicaily, to schizophrenia-like disorders, and that LSD can "cause" the development of such disorders. The multiplicity of symptoms and syndromes de scribed in the "adverse reaction" literature should make it clear that LSD can cause a number of reac tions that can last for any amount of time-from minutes to, possibly, years. 1 believe that what is being studied here is the question of the potential role of LSD in accelerating or precipitating the onset of an illness that was "programmed" to develop ultimately in a particular individual-in a manner comparable to the major physical or emotional Stress that often precipitates a bona fide myocardial infarction in an individual with advanced coronary atherosclerosIs-The stress did not cause the heart disease; it was only the stimulus that accelerated the inexorable process to manifest illness. In looking at the relevant studies, Breakey at ci-28 found that schizophrenics who "used drugs" had a earlier onset of symptoms and hospitalization than non-drug-using schizophrenics, and had possibly bet ter premorbid personalities than non-drug-using pa tients although Vardy and Kay have challenged thts analysis of Breakey's data. Bowers 23 compared 12 first-admission patients with psychoses related to LSD use, requiring hospi talization and phenothiazines, to 26 patients hospital ized and treated with phenothiazines with no history of drug use. Six of these controls had been previously hospitalized. Drug-induced psychotic patients were found to have better premorbid histories and prognos tic indicators than the nondrug groups. There was no difference in rates of family history of psychiatric illness, However, several issues flaw this study. One is the polydrug-abusing nature of the "LSD-induced" psychotic patients, compared to the controls. The role of LSD, therefore, in causing or precipitating these symptomatic disorders, is open to dispute. The other is the lack of an adequate comparison control group, i.e., the controls were specified only as "psychotic," and did not necessarilymatch the LSD group in either symptoms or diagnostic classification. A follow-up study of the LSD patients occurred between 2 and 6 years later 25. One half did well and one half did poorly, although the lack of control group for a followup in a similarly symptomatic control group makes interpretation of the data difficult. Roy ,i33y, in a somewhat different design, compared chronic schizophrenic patients diagnosed according to DSM-III criteria who had used LSD within the week preceding hospitalization, and found no differ ences in age of symptom onset or hospitalization compared to patients without a history of illicit drug use. Vardy and Kay, in an elegant study with a 3-to 5year follow-up period, demonstrated that patients hos pitalized for a schizophrenic picture that developed within 2 weeks of LSD use patients with other diag noses were explicitly excluded from comparisons with non-drug-using schizophrenics were "fundamentally similar to schizophrenics in geneology, phenomenol ogy, and course of illness" 165, p. 877. Premorbid adjustment, age of onset of symptoms and hospitali zation, family history of psychosis or suicide, and most cognitive features were also equal between groups. Family histories of alcohol abuse were markedly greater in the LSD group. I believe that these data, taken as a whole, limited as they are in terms of comparing subgroups i.e., LSD-using vs. non-LSD-using of "schizophrenia like" disorders. point toward, at the most, a possible precipitatory role in the development of these disor ders, in a nonspecific and not etiologically related manner. Most reports have stressed the similarities between LSD-induced psychotic states and schizophrenia, and therefore compare "functional" schizophrenia to LSD induced states that resemble schizophrenia. However, tive iliness and LSD-induced psychoses. Lake et at. 95 described a case of mania precipitated by LSD; Muller 119 and Dewhurst and Hatrick 44 described the efficacy of ECT in LSD psychoses; cases have also been treated with lithium 80., in his discussion of the role of serotonin in psychosis, em phasizes the fact that "good prognosis" schizophrenics and LSD-induced psychoses have similar CSF levels of the serotonin metabolite 5 -hydroxyindole-acetic acid. The fact that many of the so-called "good prog nosis" schizophrenics are either often rediagnosed as affectively ill, and/or will often have family histories of affective illness, lends support to the contention that the relationship between relatively long-lasting psychedelic drug-induced psychoses and affective dis orders deserves further study 85. Prospective studies of acute adverse reactions, A unique group of studies deserves mention: those of Klee and Weintraub 90, Pauk and Shagass 125, Anastasopoulos and Photiades 10, Fink at at, 50, and Langs and Barr 96. These are representative of the small number of studies that have looked at indi viduals before administration of LSD, in order more confidently to state relationships between adverse drug reactions and preexisting characteristics. Three studies of somewhat similar design are those of Klee and Weintraub, Pauk and Shagass, and Langs and Barr. Here, individuals were pretested with various instruments before being given LSD. Klee and Wein traub found that individuals with a fear of cioseness of same-sex others and a strong tendency to use pro jection as a major defense mechanism were regularly those who developed a paranoid reaction during the LSD state, lasting, at themost, 24 hours. Pauk and Shagass found that individuals who re sponded to low doses of LSD with disorganization of their Bender-Gestalt tests were most likely to develop "psychotic" states after higher dose LSD ingestion. They thought that this test was helpful in indicating "ego-function" impairment by LSD. Langs and Barr applied multiple psychological tests, interviews, and questionnaires to a group of "nor mals." Those who had short-lived less than 24 hours paranoid reactions were found to be "more anxious, manipulative, hostile with conflicts about aggression, depressed and self-punitive: to feel physically im paired, prone to a thought-disorder and confused in their identities; and likely to use projection as a de fense" 96, p. 168. These three studies all point to ward the possible development of more effective per sonality screening tools for individuals being consid ered for LSD experiments. Anastasopoulos and Photiades administered LSD to previously "asymptomatic" relatives of schizo phrenics, although more sophisticated studies were there are data to support a relationship between affec not performed. A very high percentage of these indi viduals had adverse reactions lasting up to 6 weeks. Siblings of schizophrenics showed adverse reactions to LSD only in cases where one or both parents showed decompensation. The significance of these findings is clear, and may relate to the often found relatively high rate of familial mental illness in the so-called LSD psychoses. Fink et at, gave LSD to 65 psychotic subiects and noted a 2 per cent incidence of nroionged adverse reactions, which were described as basically exacer bations of preexisting psychopathology with accom panying signs of a confusional delirium. Chlorproma zine, later introduced as a prophylactic agent at the end of subsequent LSD studies, was successful in preventing ny further prolonged adverse reactions from occurring-These data are particularly interesting from the perspective of the high incidence of premor bid psychopathology of many of the "LSD casualties" reported in the literature on unsupervised use of the drug.
What are the etiologies of the above described ad verse reactions to psychedelic drugs? I believe that this question should be addressed from several per spectives, with multiple levels of interaction. The het erogeneity of responses to LSD make generalizations about responsiveness to the drug impossible. Theoret ical frameworks explaining their effects have been proposed in terms of biological, psychological, and systems aunroaches. The interulav of these factors, combined wrth the effect of' the drug and particular setting, result in one particular individual's "LSD experience." Constitutional predispositions have been described, wherein family histories of major functional illnesses are often associated with poor outcome in uncon trolled settings. A past personal history of previous psychiatric treatment and/or the presence of particu lar characterological pathology have also been shown to be associated with adverse reactions. My feeling is that, in a particularly predisposed individual be it genetic, motivational, or character ological, the flood of images, drives, feelings, and perceptions, occurring in a setting where the person has not been either adequately prepared and/or sup ported, a breakdown in the normal means of process ing internally and externally derived information oc curs, with associated reactions, depending on one's ability to tolerate such experiences. I will not address the issue of mystical experiences obtained during the breakdown of normal mental processes occurring dur ing LSD intoxication, except to say that they do occur e.g., 106] and appear to be most likely subject to the same formal rules of operation and development as adverse reactions [i.e., constitutional, genetic, char. acterological, preparation, motivation, etc.]. Now, the duration of such an experience may last from minutes to hours to weeks or longer. The dura tion appears to be dependent on several variables, including, most likely, a familial or personal predis. position to the major functional psychoses 158. TouJ cumuiative ernosure may also have direct bearing especially as described by Abraham 3 and Glass and Bowers 60. Chronic effects. The chronic adverse reactions to psychedelic drugs described in the literature are also composed of a fairly heterogenous population and group of symptoms 37, 51, 87. Studies of chronic effects of. LSD can be divided into two categories: 1 those involving long-lasting psychological and person ality effects of LSD use in patients and nonpatients including experimental subjects; and 2 those involv ing measures of organicity in individuals with repeated use. The study of Blacker at at. 20 focused on 21 chronic LSD-using volunteer nonpatients, a group they referred to as "acidheads." Predrug measures of personality or other variables were not available. These individuals were described as "having profound non-aggressive attitudes, magic-mystical beliefs, rela tively intact interpersonal relationships, and cognitive abilities that are more similar to individuals usually termed eccentric than to individuals diagnosed as schizophrenic" 20, p. 349. However whether these beliefs predated the LSD use could not be determined. IvlcGlothhn et at. 115 studied changes in person ality, attitude, values, aesthetic interest, and perform ance resulting from LSD administration in normals who had participated in a series of three well con trolled LSD sessions. Follow-up on this group was at 2 weeks and 6 months. Galvanic skin response dropped in three individuals at 6-month follow-up, idjcating an elevated ability to manage stressful situations. In spite of subjective feelings that subjects had become more creative, aesthetically appreciative, and less de fensive, objective data did not particularly support these perceptions. Axelrod and Kessel 12 administered the Ror schach to three groups of 10 individuals described as having taken LSD more than 30 times in a 3-year period, one to five times in that same period, or never. Significantly more "ego disturbance" was found in the LSD-using groups compared to nonusers. However, this study suffers from lack of premorbicl testing, and control issues regarding use of other drugs. Salzman at at. 135 compared individuals who had discontinued taking psychedelic drugs 6 months before being studied with those still taking psychedelics-In-dividuals were studied by a variety of paper and pencil psychological tests. Except for elevated risk-taking behavior among continuers, the two populations could ot be differentiated. McGlothlin and Arnold 113 performed a 10-year follow-up on 247 individuals who had received LSD in an experimental N = 123 or psychotherapeutic set ting N = 124 with careful medical supervision. The groups were controlled by comparing patients who took LSD on their therapists' initiative, with patients of the same therapists who did not use LSD in therapy. The sample was further distinguished by a group who continued using psychedelics after the experiments or therapy were over. Patients who had LSD in a thera peutic setting initiated by their therapists, showed no greater changes on individual variables than the nondrug-experienced control group over a comparable time period. The LSD continuers did show appreciable differences in a number of areas relating to measures of personality, values, beliefs, and attitudes. The nonmedical continuers of LSD also used more drugs and alcohol in general than the two other groups. Thsy also engaged in and v-crc interested in nonphar macological ways of altering consciousness. The au thors thought that perhaps a particular type of indi vidual was drawn to LSD, which then acted in a catalytic manner to reinforce the individuals' interest in altered. states of consciousness. Interestingly, LSD use, by the "continuing" sample, declined with time. The question of organic deficits in users of LSD has been addressed by several investigators. Blacker at at. 20 used cognitive, perceptual, and EEG tests in their population of "acidheads." The incidence of abnormal baseline KEGs was thought to be no greater than might have been expected in a non-drug-using group of young adults. Computer analyses of EEG data showed increased energy in four specific frequency bands in the LSD group over the left occipital area as compared to LSD nonusers. The significance was unknown. Visual evoked potential studies showed in creased sensitivity in a few instances in the LSD group. Auditory evoked potential responses were sim ilar to normals, and cognitive studies revealed some slower response times as compared to normals. The authors could not conciude that LSD produced any form of CNS damage. As in the description of the characterological analysis part of this study previously described, these findings are limited by a lack of premorbid studies and control for other drug use. Accord 5 studied 40 white males, with an average age of 20 and a mean educational level of 12 years. Intelligence tests were thought to be an average. Neu ropsychological testing was performed using the In diana Neuropsychological Battery. Thirty-two sub jects performed in the "brain-damaged range" on at least one test, 18 on at least two, and five on all three. No gross cerebral pathology was noted. This study, however, is flawed by lack of controls, premorbid testing, and consideration of other drug use. In a later publication, Accord and Barker 7 studied in the same manner, 15 patients with a history of psychedelic use. In this study an age-matched popu lation of non-psychedelic-using patients was obtained.. Psychedelic-using patients scored lower than nondrug-using patients. In one of the three tests, the results of psychedelic Users fell below cutoff scores for non-brain-damaged individuals. However, these norms were established for individuals nearly twice as old as the subjects of the study. This study is also flawed by lack of predrug use measures and poor control for other drugs. Culver and King 40 performed a retrospective study of 42 college seniors, divided into three equal groups of 1 controls, 2 marijuana/hashish users, and 3 LED users all of whom also used cannabis prod ucts. Other drug use was carefully controlled for, except alcohol. Groups were matched by verbal and math Scholastic Achievement Test SAT scores freshman MMPI profiles. Grade point averages among groups showed no differences. A neuropsychological test battery was administered, including the Haistead Battery, Wechsler Adult Intelligence Scale, Reitan's Trail-Making Test, and several others. The Only ab normality found in the LSD group was a poorer per formance on the Trail-Making Tests although scores were well within the normal range. The degree of LED use did not correlate with subjects' performance. Alcohol use was greater in both LED and cannabis users, but the abnormal results of the Trail-Making Test persisted after a statistical adjustment for alcohol consumption was made. The authors were unclear as to the significance of the relatively low Trail-Making Test performance and thought that lack of pre-drug use testing could not rule out the existence of this finding as a "premorbid" characteristic. Cohen and Edwards 38 compared 30 LED-using nonpatient volunteers equal numbers of men and women to 30 age-. sex-, education-, IQ-, and socio economic status-matched controls. Members of the LSD group had taken illicit LED in uncontrolled settings at least 50 times, and had used very large quantities of other illicit drugs as well. Glue-sniffers were excluded, and individuals were asked to refrain from taking drugs for 48 hours before testing. The drug-taking group was found to perform significantly worse on Trail-Making Test A and the visual spatial orientation test of the Haistead-Reitan Battery. Both groups performed equally well on all other subtests, and on the Raven Progressive Matrices. There was no pre-drug use data, nor could the effect of LED per se be specified, particularly with the quantities of other drugs abused. McGlothin et al. 114 studied i43 individuals with an average age of 40. All were white, two thirds were male, and all but one had a college education. Ten had received LED as psychotherapy subjects ar1d six as experimental subjects. Average number of doses was 20, and 13 had used LED outside of a medical setting. Combined number of exDosures in medical and nonneical settings was 5. Most had not taken LED for i year before testing. A control group, matched for age, sex, education, psychotherapy, occupation, and use of marijuana, was also studied. A large number of tests were administered, including the Trail-Making A Test and the Spatial-Orientation Test, these two tests having demonstrated performance abnormalities by LED uses in Cohen and Edwards' study. This group found only one subtest to be performed in a statistically significant poorer manner by the LED group, and this test Haistead's Category Test was still performed within the normal range. No correla tion was shown between degree of LED use and scores on this subtest. In spite of this being a generally muchbetter-designed protocol, it still lacks the crucial factor of pre-drug use testing. Wright and Hogan 170 studied a group of 20 frequent LED users five women and 15 men with a mean age of 20 and a mean duration of LSD use of 12 months. The average number of LED experiences was 30. Approximately 1 month was the average time from last using LSD. Twenty age-, sex-, education-, and intelligence-matched non-drug users were used as con trols. The Halstead-Reitan Neuropsychological Test Battery and the Halstead-Wepman Aphasia Test were administered to both groups. No significant differ ences between groups could be found. Here again, pre drug use testing, and control for other drug and alcohol use were not performed. An unusual chronic adverse reaction was recently described by Abraham 1. Forty-six patients with a history of LED use average number of experiences was 88 with an average duration of 2 years since last use, were studied in an experiment of color discrimi nation. A control group of 31 patients, with unspeci fied criteria for matching, were also studied. The LED users were further divided into those with flashbacks see below 25 per cent and those without flashbacks. No difference was found between the two LSD groups, but the controls scored significantly better than the LED groups. Once more, however, these findings must be interpreted with some skepticism, as other drug use and pre-drug use testing were not included. There are surprisingly few case studies of the chronic, undifferentiated, ego-syntonic psychotic state, gradually resulting from hundreds of psychedelic drug experiences during difficult maturational periods in the patients' lives 59, 60. These individuals closely resemble chronic undifferentiated schizophrenics and are quite disabled and treatment resistant. They an often referred to as "burnt out." Very little is known about predisposing features. family history, motiva tions for use. etc., for these individuals. In summary, it appears that nonpsychotic individ uals who have taken LED a large number of times appear to nave particular personality characteristics that may or may not have predated their use of LED 116. They may be described in terms of being some. what odd, noncompetitive, and eccentric, but are not grossly impaired. The critical question that remains is whether these particular characteristics belong to a group of individuals who seek out, and are reaffirmed in their beliefs by, altered states of consciousness, including psychedelic-drug-induced ones, or if the ex periences themselves are etiological. Evidence appears to point toward the former explanation. The question of long term organic impairment has beem complicated by poorly controlled studies, How ever, the most carefully performed studies to date do not lend evidence to support the contention that fre quent LED use is associated with permanent brain damage. Flashbacks. These are intermittent phenomena which may last for some time after psychedelic drug use up to years and are one of the most intriguing forms of "chronic" psychedelic drug-induced altered states of consciousness. They may be defined as tran sient. spontaneous recurrences of the psychedelic drug effect appearing after a period of normalcy following a psychedelic drug experience 168. Schick and Smith 140 have divided these into a "perceptual," b "so matic," and c "emotional," depending upon the pre dominant aspects of the experience. The reported incidence of flashbacks varies from 15 to 77 per centin those subjects who have had at least one psychedelic expe rience. Subjects will often not report these phenom ena, however, either because of their acceptance of flashbacks as part and parcel of the psychedelic drug subculture's expectations, and/or because of the gen eral positive connotation these experiences have, i.e., they are sometimes referred to as a "free trip." As was described in the preface to Adverse Reactions, using the term "adverse" when discussing flashbacks can also be fraught with interpretive difficulties. The etiology of flashbacks is a topic of debate at the present time. Various theories have been proposed and may not necessarily be mutually exclusive, de pending on the subject population. Although predisposing factors in the development of flashbacks have not been as well documented as for the more severe psychopathological reactions de scribed above, it does appear that a greater number of psychedelic drug experiences in subjects may increase the likelihood of flashback development e.g., 124. There is some sense that perhaps those with adverse acute or chronic reactions may be more likely to develop and/or report such phenomena 79. Matefy and co-workers 108, 109, 111, 112 have shown that "flashbackers" show no significant psy chopathological differences as measured by the MMPI, or attentional processes as measured by the Embedded Figures Test, as compared to "non-flashbacking" drug users. Flashbackers have also been shown to score higher on a hypnotic suggestibility scale than nonflashbapking drug users. This research group flavors a "role-playing" model of flashbacks, whereby the phenomenon is described as a reaction learned during a state of high arousal resulting from drug use. Therefore, under other nonspecific high arousal states, a "psychedelic effect" is again experi enced by means of conscious or unconscious associa tion. Other groups 72, 73, 124 believe that flashbacks are a result of situationally induced exacerbations of pervasive personality characteristics. These charac teristics would lead toward the experiencing of flash backs in circumstances that tend to induce altered states of awareness, e.g., decreased sensory input, fa tigue, fever 142, extreme relaxation 110, stress, marijuana use 49, 149, and emergence into a dark environment 4. Psychodynamic formulations 81, 134 consider flashbacks to be comparable to conversion reactions/ traumatic neuroses where defensive functions of the ego are incapable of completely repressing memories/ conflicts that were stimulated/exacerbated by the in tense psychedelic drug-induced effects. Symptomatic expressions flashbacks are the result. Rosenthal 132, in one of the earliest reports of flashback phenomena, proposed a physiological, neu rochemical basis of flashbacks, which has been elab orated upon by, who hypothesizes that LSD's effect on visual pathways routed through the lateral geniculate nucleus could result in "visual sei SExes."
One of the major differential diagnostic questions confronting the clinician in the case of psychedelicrelated psychoses is that of schizophrenia. In the early years of psychedelic drug research, there was hope that a psychedelic drug-induced altered state of con sciousness could provide a "model psychosis," whereby theoretical and clinical tools could be brought to bear on an easily inducible, reproducible, and reversible state resembling schizophrenia 27. Several excellent reviews of this subject have appeared, beginning with Holliter's in 1962 78. Subsequent studies 71, 91, 96, 104, 171 using a variety of approaches have all confirmed that there are significant major differences between these two syndromes, especially in comparing psychedelic drug-induced states with the chronic form of schizophrenia. There appears to be a greater simi larity between LED-induced states and acute schizo phrenia, but careful observation can still usually dis tinguisb these two states. Affectively, LSD states show less flattening of mood than schizophrenia. Visual perceptual alteration.s hallucinations, illusions generally predominate in LED states compared to schizophrenia, where audi tory perceptual changes hold sway. LSD-induced states tend to show less well fixed delusional symp toms than schizophrenia, most likely due to the ac knowledgment of the drug-induced nature of their experience. Historically, the knowledge that a patient has taken a psychedelic drug is of obvious value in clinical di agrosis. Also, the absence or uresence of a family history of schizophrenia is helpful, as is premorbid history, in arriving at a quick working differential diagnosis, viz., the etiology of a particular psychotic episode.
Treatment of acute panic reactions should be di rected toward allaying the patient's overwhelming anxiety. A quiet, comfortable room with a minimum of distractions should be available, and the patient should not be left alone. Most of these individuals can be "talked down" by calmly discussing their fears and fantasies, orienting the patient as necessary, reinforc ing the concept that the experience is drug induced and time limited, and that no permanent brain damage has been suffered. For more severe agitation, minor tranquilizers such as diazepam should be used, in oral or parenteral form chlordiazepoxide is preferable for intramuscular use, as its absorotion by this route is more consistent than for diazepam. Usual doses range from 15 to 30 mg for diazepam 50 to 100mg for chiorthazeporide repeated every hour or two as necessary to calm or sedate the patient 154, 164. -Major tranquilizers should be reserved for only the most disturbed and agitated patients. Chlorpromazine was initially believed to be a specific LSD antagonist 5, but paradoxical reactions 138 and the problems of hypotensive and anticholinergic crises when used with 2,5-dimethoxy-4-methylamphetaniine "STP" and PC? 101, 143, 144 would point toward using mg by mouth, a high potency antipsychotic with minimal anticholinergic effects, every hour, as neces sary. Antiparkinsonian drugs e.g, benztropine or tn herphenidyl should be available for use in the case of acute extrapyramidal side effects from halopenidol. Restraint and/or gastric lavage are generally avoided in a frightened, hallucinating patient, al though where there is a concern that the patient may hurt himself or herself, or others, or where other more potertiaiy life-threatenrng druss have been ingested, these procedures might be necessary. Hospitali2ation is usually not necessary, but should be available. Once the acute reaction has subsided usually within 12 to 24 hours, the patient should be sent home with someone responsible for monitoring him or her for the next 12 to 24 hours. A follow-up appointment should be arranged in order to evaluate the need for further therapy 68. The prognosis is generally good for uncomplicated panic reactions, and many drug users will curtail the use of these drugs subsequently on their own. The treatment of the "LSD psychoses," as the pre vious discussion of these states would imply, will vary with the salient symptomatology 14. Tricychc antidepressants, monoamine oxidase MAO inhibitors, major tranquilizers, lithium carbonate 80, ECT 44, 53, 119, vitamin B5 75, and the serotonin precursor, L-5-hydroxytryptophan 2 have all been used, with varying rates of success. A period of drug.free obser vation for at least several days if possible, using only minor tranquilizers as necessary, and then treating the resulting clinical picture a it comes more clearly into focus, would seem the most prudent means of clinical management. Treatment of flashbacks should be tempered by the fact that they are usually self-limited and diminish in duration, intensity, and frequency with time. The individual often responds to assurance and education about the phenomena, but if extremely panicky, the treatnient should be similar to that of the acute panic reactions. Minor tranquilizers may be used acutely, and on a judicious, time-limited, "as needed" basis. Behavior modification 107, ECT 44, diphenylhy dantoin 156, psychotherapy 184, and other phar macotherapeutic strategies, including haloperidol which may transiently increase visual flashbacks [1l8J and benzodiazepines 4 have all been used, also with varying rates of success. Patients should be advised that their flashbacks will most likely increase if psychedelic drugs are used again, as may also be the case with stimulants and/or marijuana. Persistently troublesome or increasing flashbacks indicate the need for a more thorough psychiatric and/or neurologic work-up. The prognosis for flashbacks, if the patient refrains from further use of mind-altering drugs, is generally good.
The mid-l950s to mid-1960s showed a great burst of enthusiasm for the therapeutic, growth-enhancing and heuristic value of LSD-25 and other psychede0 drugs. However, the increasingly reported and occa sionaily lethal adverse reactic-ns to these drugs in unsupervised settings made subsequent obtaining and using psychedelics in human subjects quite difficult. Their black market use, on the other hand, continued to flourish,, and it is unfortunate that the only current data on the use of psychedelics are being generated by street-drug-using "LSD casualties" outside of major psychiatric research centers. Adverse reactions to this class of psychoactive drugs can be conceptualized as occurring along a temporal continuum with acute panic reactions that often re solve spontaneously within a day, and chronic undif ferentiated psychotic, treatment-resistant cases, at the two ends of the spectrum. In between exist "LED psychoses," lasting longer than 1 to 2 days after the ingestion of a psychedelic compound, and "flash backs," transient recurrences of some aspects of the original LSD experience after an intervening period of normality. The research on adverse reactions to psychedelic drugs is fraught with methodological difficulties. Many of these have been addressed in this paper, and suggestions for data to be included in an "ideal" study have been given. With the available data, it appears that the inci dence of adverse reactions to psychedelic drugs is low, when individuals both normal volunteers and pa tients are carefully screened and prepared, super vised, and followed up, and given judicious doses of pharmaceutical quality drug. The few prospective studies noting adverse reactions have fairly consist ently described characteristics predicting poor re sponse to these drugs. The majority of studies of adverse reactions, retrospective in nature, have de scribed a constellation of premorbid characteristics in individuals seeking treatment for these reactions where thugs of unknown purity were taken in unsu pervised settings. The relationship between drug-induced mental ill ness and mental illness accompanied by psychedelic drug use has been discussed. The majority of studies have focused primarily on "schizophrenia-like" i-IF nesses and seem to indicate a fairly similar clinical picture and course for both schizophrenics who have or have not used psychedelic drugs. A possible rela tionship between affective disorders and LSD psy choses has been raised.. The "long term effects" of LED use have been studied in a variety of settings and populations. Ob jective data in normal volunteers do not appear to tap the subjective sense of subjects' changed internal worlds, although individuals who appear to use LSD regularly as a tool for consciousness alteration have been found to show a characteristic personality and coping style. Long term psychiatric sequelae in pa tients have been studied in surprisingly few large case load reports, with a very tentative conclusion being that chronic, heavy LSD use appears to produce an unusually ego-syntonic disorder, in fringe-element type individuals, which is quite resistant to treatment. Comprehensive and well controlled studies of neu ropsychological function have generally failed to dis cern significant differences between groups of LED users and controls. Studies of flashbacks have also focused on the de scription of subject characteristics who experience these usually short-lived, delayed, intermittent phe nomena, and have generally found an incidence of about 50 per cent. Populations experiencing these events have been found to be of varying degrees of psychopathology and associated drug use, thus engen dering quite different causal explanations for their occurrence. Etiologies of adverse reactions to psychedelic drugs have been proposed, from psychodynamic, behavioral, and biological perspectives. The systems approach to understanding these disorders has also been intro duced.
The human neurobiology of psychedelic drugs is still poorly understood. Several of the recently de scribed biological markers for the major functional disorders, e.g., platelet MAO activity in schizophrenia, and abnormal cortisol suppression in response to ex ogenous steroids in depression, might possibly be used to analyze more carefully the effect of psychedelic drugs on relevant biological parameters. Newly refined means of computer-assisted power band and spectral anaiyses of EBOs and evoked potentials, and the effects of psychedelics on these, may also provide additional insights into the mechanism of action and effect of these thugs. A particularly exciting develop ment in neurobiological research is that of positron emission tomography PET scanning, whereby radio actively labeled pharmaceutical agents can be shown to bond to specific brain sites in vivo. Labeling psy chedelic compounds in this manner could possibly help elucidate localization of their effects, as could studying the effect of LED on regional metabolism of other compounds e.g., dopamine or serotonin. From a clinical perspective, it appears that certain individuals should probably be excluded from psy chedelic drug research participation in the futurethese are those with either overt, or a history of, severe mental illness, unless they were institutionalized at the time of drug exposure and could be followed in a carefully supervised setting for at least 1 to 2 *eeks after the drug experience, or after any acute sequelae resolved. Individuals with poor object relations e.g., unemployment, uninvolved with a significant other, or showing "downward drift" or those with primary defensive mechanisms including projection, denial, and tendency toward psychotic thought disorders, should also be included in drug studies only with the utmost caution and close follow-up. Individuals who are currently well functioning but have a family his tory of mental illness, especially schizophrenia, should be enlisted with extra caution, and perhaps screened with some of.the more current biological markers to test for presence of "trait" abnormalities. There are several psychological areas that call for expanded investigation. One is a further elucidation of the phenomenology of the psychedelic state, partic ularly with regard to some other, recently well studied altered states of consciousness, e.g., the so-called near death experience, and states of religious exaltation. in my own observations of students of meditative disci plines in various settings, I have often struck upon a theme that runs through the motivation of many of these students; that is, psychedelic drugs led them to discover the existence of these "sublime" states, but were too unpredictable and toxic for regular use. Prep aration for the development of the gradual unfolding of various states of consciousness was a much appre ciated element of these individuals' involvement in meditative disciplines. Grof 65 has attempted to draw together these disparate phenomena in a cohe sive framework. Much more work is needed, and a topographical map of consciousness could begin to be drawn up. Buddhist psychological works have recently been published 30 and have been shown to have heuristic value in describing various levels of altered states of consciousness 62, 150. Their relevance to the studies of psychedelic states remains uninvesti gated, although Hofmann, the discoverer of LSD, has suggested that psychedelics' use be returned to that of a "sacred" drug, useful in supplementing meditational practices for the attainment of religious insights 77. Another clinical use for psychedelics is in terms of therapeutic values. Who can benefit from psychedelicassisted psychotherapy? How best to utilize these agents? What agents are most useful with what groups? For example, some early work seemed to indicate a particularly positive therapeutic response to LED in sociopaths 47, 136, a traditionally very treatment-resistant group. Intriguing are the reports of helping the dying with the aid of psychedelic drugs 66, 67. The development of agents with specific character istics, in terms of duration of action, side effects, with specific perceptual, cognitive, or emotional effects could be pursued, using carefully prepared and trained individtais i5:3 in order to match more carefully drue with specific therapeutic requirements. With the severe restrictions placed on research with psychedelics in the 1960s, investigative work with psychedelic drugs has ground to a halt. It appears that, with proper restrictions and safeguards, it might be time to carefully begin this work again. The question of reinstituting psychedelic research in humans is bound to arouse powerful arguments both for and against. My feeling is that a decade of inactivity in this area of research has given us the necessary time to reflect on what has been learned and what needs further investigation. The relative roles of set and setting, motivations for drug use, personal and family history of mental illness, defensive style, and level of object relatedness, should all be used in careful selec tion, screening, and preparation of subjects for psy chedelic research. It appears that, if these factors are carefully controlled, the incidence of acute and more long term problems associated with their use can be kept to a minimum. The benefits that can be obtained in terms of an increased knowledge of psychedelic drug-induced altered mental states, and their potential therapeutic roles, seems to justify these risks.
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