Early reports on the side effects of the hallucinogenic drugs emphasized their short-term effects and their relative safety. In a review of the literature and poll of experimenters in 1960, Cohen(2) reported: "This inquiry into the adverse effects of the hallucinogenic drugs indicates that, with proper precautions, they are safe when given to a selected healthy group." Although the possibility of prolonged adverse effects has been acknowledged, the danger of these reactions has not been sufficiently recognized. This paper describes a type of prolonged adverse reaction, a persistent hallucinosis, seen after prolonged use of hallucinogenic drugs.

Elkes, et al.(2), in 1955 were among the first to suggest the possibility of prolonged adverse effects, but, subsequently, there was little emphasis on the prolonged effects. Eisner and Coben(3) commented: "We have also observed the appearance of LSD-like phenomena spontaneously in patients at varying intervals following treatment. These spontaneous occurrences were welcomed by our patients as relaxing and beneficial."

The assertion has been made frequently that dysphoric side effects are mainly the results of poor technique on the part of the person administering the drug and largely dependent on the setting. This assertion fails to take into account the inherent toxicity of the drug.

The acute dysphoric experiences are largely those of panic, depersonalization, somatization of pain, explosive anger and psychotic experience including hallucinations, illusions and delusions( 1 ). Acute paranoid reactions are occasionally seen. These experiences usually last only while the patient is under the influence of the drug, a period of some 8-12 hours, although they occasionally last some 24-28 hours. In addition, there are numerous reports of the transient return of hallucinatory experiences for days or weeks after single doses (l, 3).

Although there are reports of prolonged psychotic states resulting from ingestion of hallucinogens, there has been no clear-cut differentiation between the effects of single and multiple exposures. Cooper (4), in 1955, reported a series of 8 patients who had had effects lasting 24 hours or more, consisting of mood swings, hallucinations, illusions, and time and space distortions. In some cases they lasted several weeks or more. He commented that the mood swings may occur at any point but that hallucinations and related experiences were noted only after repeated heavy doses.

Cohen and Ditrnan (5, 6 ) have recently reported a series of 9 cases of prolonged adverse reactions to LSD, with effects lasting for a few months up to 2 years. They divide their cases into prolonged psychotic decompensations, depressive reactions, paranoid reactions, and the release of pre-existing psychopathic or asocial trends.

PROLONGED ADVERSE REACTIONS

With the relatively recent advocacy multiple exposures to hallucinogenic drugs by the "consciousness expanders" and the current fad of their use by college students "bohemians" and artists, there has been an accumulation of clinical experience with subjects who have had multiple exposures to these drugs (often without supervision), and more cases of prolonged sequelae are becoming evident. We wish to report on the cases in the literature, and a case of our own, of a type of prolonged psychotic decompensation which appears to be related specifically to multiple exposures to the hallucinogenic drugs.

Prolonged adverse reactions for the purposes of this presentation are divided into the following groups :

1. Prolonged Anxiety and Depressive Reactions. Agitated depressions with anxiety, guilt, hypochondriasis and shame, lasting months, have been reported after only one dose of LSD, especially "in rigid or overconscientious indiviauals" (5). In addition, panic, anxiety, and depression features in the other prolonged reactions noted below, whether following single or multiple exposures to the drugs. Anxiety and panic were already noted to be among the prominent acute and subacute adverse reactions.
   
   
2. Precipitation of Schizophrenic Reactions or Schizophreniform Reactions. Schizophrenic or schizophreniform reactions have been reported in a number of cases. They occur presumably by releasing overwhelming previously unconscious material in possibly "pre-schizophrenic" subjects and are often accompanied by anxiety or panic. They may take the form of acute paranoid reactions with delusions of persecution or grandeur. The transcendental experience with the drug may "confirm" previous suspicions of grandiosity(5). Other cases have shown acute indifferentiated schizophrenic reactions. These are phenomenologically schizophreniform with autism, loosening of associations and preoccupation with concepts such as truth, beauty and death. They may lead to prolonged periods of withdrawal and rumination, and chronic schizophrenic reactions. As with the anxiety and depressive schizophrenic or schizophreniform reactions may also have their one exposure to the hallucinogenic drugs and they do not have the shape and color distorting hallucinatory effects described in hallucinosis below.
   
   
3. Hallucinosis. Hallucinosis as a prolonged adverse reaction to the hallucinogenic drugs is proposed as a specific reaction seen in subjects who have had multiple administrations. Its onset may be heralded by a change in the experienced obtained by use of the drugs. Where the effect had been euphoric, it becomes dysphoric, sometimes causing the subject to discontinue the use of the drug voluntarily. There then follows a prolonged period of intermittent recurrence of spontaneous visual hallucinations, lasting as long as 6 months or more after the last drug experience. The hallucinations are marked by their similarity to those experienced while under the influence of the drug itself. Both pleasant and frightening effects are seen. The fright ening hallucinations are involuntary. Cats, crabs, insects, corpses and the skulls of familiar people are among the things that have been reported. The pleasant sensations are semivoluntary in the sense that the subject can make them more or less intense to the extent that be concentrates on them. They consist characteristically of the breakup of light into droplets of color, shimmering panels of color before the patient's eyes and brightly colored shape distortions. Hallucinosis may also be accompanied by fear and panic.
   
   

It is also to be noted that the hallucinations are visual and of a type characteristic of the acute experience with the hallucinogenic. drugs, but not characteristic of schizophrenia. The patients ordinarily are not psychodynamically schizophrenic and may hallucinate while having no other thought disorder. They recognize the unreality of their visual hallucinations although they may be frightened by them, and they recognize the etiological relationship of the hallucinations to the drug experience. It should also be noted that these hallucinations are similar to, and may be related to, the transient returns of hallucinatory and illusory experiences sometimes seen after single doses for a much shorter period of time. These may be a specific toxicity of the hallucinogenic drugs on the retina, optic pathways or visual cortex. (See below.)

Previous Case Reports. Previous cases of this proposed syndrome have been reported. Cohen and Ditman (5) describe a 32-year-old secretary of a psychotherapist who had taken LSD (in doses of 25-400 micrograms) 200 to 300 times over a 3-year period. The experiences were initially pleasant but finally became dysphoric and she then experienced a panic-like state with loose verbal associations and fear of being alone. "Frightening spontaneous recurrences of the hallucinatory phenomena which had been seen under LSD were almost daily events. These consisted of skulls of familiar faces moving on the wall and feelings of accompanying horror." The same authors report a white married male who took LSD about 25 times for psychotherapeutic purposes. He complained of periodic visual distortions and emotional upsets with anxiety, a variety of pains and depression. These continued to occur at times of stress over a period of 7 months. During these episodes, in addition to visual distortions, he hallucinated animals and faces moving on the wall.

Cooper (4) reported adverse reactions lasting more than 24 hours in 8 patients. He noted that mood swings might occur at any point but that hallucinations, illusions and space and time distortions were seen only after repeated heavy doses. He reported visual hallucinations including crabs, cats, insects and suicidal implements, and space distortions which were under limited voluntary control although their appearance was predominantly spontaneous.

Cohen and Ditrnan(5) also report a case of a 10-year-old boy who ingested 100 micrograms of LSD accidentally. He had colored visual distortions and hallucinations with anxiety. These became less distressing after 3 days but did not subside. After a week he continued to experience pages wavering before his eyes and to see movements on the TV screen, without the set being on, on some days but not others. One month, after the incident he continued to see light halos with his eyes closed.

This last case was atypical because only one exposure was involved, but it is included because of the clarity of the resemblance of the prolonged reaction to an acute toxic state.

Case Presentation. An additional case report of hallucinosis is presented:

The patient is a 23-year-old white married female artist who was admitted to the hospital because of a reoccupation with death, a feeling that she might jump in front of a car, and the presence of visual hallucinations. Two days prior to admission she had discovered that she was definitely pregnant. She desired to terminate her pregnancy because she felt that a baby would make it impossible for her to be artistically creative.

Five years previously, at age 18, the patient had had a brief, 1½-month hospitalization in another city for a series of 4 dissociative states or "spells" in which she lost her identity for a period of hours or days. These were first thought to be atypical epilepsy but finally diagnosed as hysterical dissociative personality. After her discharge she ceased living with her family where she had been in conflict with her mother and she had no further dissociative episodes. She finished art school, became a registered art teacher and after several years of a "bohemian" type existence she married a graduate student 1½ years ago. She remained preoccupied with her art and her need to be creative.

Six months prior to admission here she sought out an LSD therapist because of a preoccupation with death and the desire for a mystical experience. Her initial drug experience was one of profound terror (which she describes as "the fear of losing my ego") and somatization of pain throughout her body. She later became euphoric and had a mystical experience. Subsequently, she procured mescaline, psilocybin and LSD for 10-12 self-administered unsupervised experiences. During period she journeyed to Mexico in search of further drug experience with a group which was establishing a setting for this, but on her arrival she found that they had already been ejected. The drug experiences were pleasant but later became dysphoric and caused her to discontinue taking the drugs. She began feeling increasing anxiety. She lost interest in life, in her marriage, and in her work in which she "could not hope to approach" the experiences which she had under the influence of the drugs. She began to have spontaneous hallucinatory experiences. These included pleasant shifting panels of light visualized 3 or 4 feet in front of eyes, and the breaking of light into droplets of color. She had limited control over these effects and could intensify them by concentration. She also had terrifying involuntary illusions of people decomposing in the street in front of her, and had nightmares in vivid color. She continued to have these symptoms 5 months after her last drug experience. On the ward the patient presented as an attractive, slim girl of medium height with long hair, wearing a loose sweater, dungarees, and sneakers. She was quiet and cooperative, making herself busy with painting and rug making and she showed obvious artistic talent. Her verbal associations were good and she had no delusions, ideas of reference or psychotic thinking. She talked expressively, often in superlatives. Her mood was more frightened than depressed, although she did cry briefly when talking about her fear of having a baby. In the hospital her generalized fear dissipated but her spontaneous visual hallucinatory experiences remained. She did not object to having "visions," as she called them, but only wished to have voluntary control over them. Although she was aware that her taking the drugs was followed by her present anxiety, by an intensification of her preoccupation with death, and by her hallucinations and her decreased artistic effectiveness, she still contemplated further use of these drugs.

This patient's experience with more than one of the hallucinogenic drugs is typical of the pattern of those who obtain the drugs through unorthodox channels. It has been called "multihabituation" by Cohen and Ditman.

Possible Mechanism of Hallucinosis. There are as yet few cases of hallucinosis following the ingestion of the hallucinogenic drugs and these few cases may be coincidental in both the peculiar phenomenology of the condition and in the fact that they are seen after repeated closes. The incidence of this condition is apparently low as many workers have given repeated dosages of hallucinogenic drugs to patients in therapy, with few reports of this specific condition. Other workers have given LSD in increasing doses to produce tolerance without reporting prolonged aftereffects (8, 9).

Cases of prolonged adverse reactions to drugs are not reported routinely. Cohen ( 1 ), in 1960, polled 62 investigators and received responses 44, yielding data on almost 5,000 patients who had received either LSD or mescaline a total of more than 25,000 times. The author mentioned that adverse responses tend to occur at the higher dosage levels, but he did not relate them to the number of doses received. A number of cases of prolonged psychotic reactions, mostly schizophreniform, were noted which were not previously reported. The exact number of these reactions is not mentioned. Perhaps with the formulation of the syndrome of hallucinosis proposed in this paper, more cases will be reported.

Hallucinosis following repeated administration of psychotomimetic drugs is apparently uncommon and may be coincidental or related to defects in the premorbid personality of the subject. An alternate mechanism, however, is the following: that hallucinosis may be related to a specific toxic effect of the drug on the visual system. The effects of LSD on the various parts of the visual system have been studied by a number of workers in pharmacology, physiology and ophthalmology in an attempt to elucidate the etiology of LSD hallucinations. A large part of the work has been done on animals.

Purpura(10-12) studied the effects of LSD on the response of the visual cortex in unanesthetized, paralyzed cats. He discovered that in doses less than 60 microgm./kg., LSD caused facilitation of visual cortical response to photic stimulation of the retina, while at higher doses, between 70 and 100 microgm./kg. LSD caused inhibition. He also showed that LSD facilitated the response of the visual cortex to lateral geniculate body stimulation.

Evarts, et al.(13-15), studied the effect of LSD on synaptic transmission in the visual pathways. Working with cats, under LSD they showed a decreased amplitude in the response of the post-synaptic ganglion on cells in the lateral geniculate body with stimulation of the optic nerve. There was little depression, however, of either the response of the optic tract to photic stimulation of the retina or of the response of the visual cortex to stimulation of optic radiation fibers.

Curtis and Davis(16) observed:

The psychotomimetic action of lysergic acid diethylamide and of related compounds, in the human subject, is produced by doses which are much lower than those necessary to depress lateral geniculate responses in the cat. However, the depression of potentials generated by many cells, or even the prevention of firing of one cell are relatively crude methods of assessing alterations in neuronal function. With smaller doses of these compounds, subtle alterations in the responses of certain neurones, produced by the same mechanisms by which larger doses block these responses, may be sufficient to cause psychic manifestations.

The visual threshold has been studied in both animals and man, and LSD has been shown to elevate it in both. Blough(17) studied the absolute visual threshold in the pigeon and found a considerable elevation. Carlson(18) showed that in man the threshold for the entire adaptation curve was raised a small but significant amount.

The electro-retinogram (ERG) has been evaluated in animals (cats, opossums and monkeys) in a number of studies(19-23). LSD caused the evocation of spontaneous retinal potentials and simultaneous spontaneous potentials from the optic nerve and visual cortex. The same ERG findings were seen after the administration of mescaline, strychnine and atropine in cats. After severing the optic nerve, the potentials in the distal end and retina remained while those in the proximal end and in the visual cortex disappeared, implying that the latter were dependent on the retinal potentials.

Krill, et al.(24), in 1960, examined ERG's in humans. They demonstrated that while visual hallucinations and illusions were being experienced, LSD induced measurable changes in retinal function. These changes were evident in both dark-adaptation and ERG studies. LSD delayed the rod-cone break and elevated the entire rod threshold in the dark adaptation curve. In the ERG, the scotopic b-wave amplitudes were increased as well. These changes were interpreted as mildly hypoxic or toxic retinal effects of LSD. No changes in retinal function occurred in patients receiving non-hallucinogenic analogues of LSD or doses of LSD low enough not to be hallucinogenic.

Because hallucinations and illusions were reported only when ERG and dark adaptation changes occurred, a possible primary retinal role has been considered in the etiology of LSD hallucinations. To test this, Krill, et al. (25), did a double-blind controlled test with 24 blind subjects. Thirteen of 24 subjects including some with bilateral enucleations reported visual hallucinations with LSD, making it evident that a normal retina is not needed for visual hallucinations to be produced by hallucinogenic drugs. The ERG in 2 blind subjects with total optic atrophy was similar to those seen in normals with LSD but these blind subjects did not have hallucinations. Hallucinations occurred in blind subjects reporting prior spontaneous visual activity. (Two previous uncontrolled studies(27,28) had reported visual hallucinations in blind subjects on hallucinogenic drugs while one study(29) reported no visual hallucinations produced in 2 subjects with bilateral optic atrophy.) It was concluded that LSD hallucinations can occur without a functioning retina and that LSD causes independent retinal and higher visual pathway effects. That the visual system must be at a minimum functioning level is evidenced by the fact that some spontaneous visual activity must be present for hallucinations to occur.

The site of origin cannot be determined by the type of visual hallucinations produced. Simple or complex visual hallucinations have been reported with stimulation of the optic radiation, optic tract, optic chiasm and optic nerve by tumors in man(30). Thus the precise site of the origin of LSD hallucinations is not yet pin-pointed, but it is clear that LSD has effects (some of which are presumed to be hypoxic or toxic) on many levels of optic pathways. It is the proposal of paper that, with continued and repeated use of LSD, some of these effects may come permanent or semipermanent and long outlast the effects of the individual dose. The resultant changes may be hypoxic or toxic effects on the retina, spontaneous potentials in the visual systems, disorders in synaptic transmission, or some yet undiscovered reaction. It is not determined why some patients seem to be more sensitive to these effects than others.

It should also be noted that the visual system is not the only one affected by LSD as auditory, tactile and olfactory hallucinations have also been reported in the acute state.

COMMENT

As more clinical experience is accumulating with subjects with multiple exposures to hallucinogenic drugs, a new clinical state is emerging. This is a persistent hallucinatory state or hallucinosis with spontaneous recurrence of brightly colored visual illusions and hallucinations similar to those experienced while under the acute influence of the drugs, and it is often accompanied by a state of anxiety or near panic. Due to its distinctive features, hallucinosis would only rarely be confused with a typical schizophrenic reaction. This paper cites several case reports which illustrate this condition and a new case is added here. Hallucinosis seems to be uncommon relative to the number of people who have been exposed, but it is likely that many adverse reactions are unreported.

There is some similarity between the condition reported here and alcoholic hallucinosis. In the latter the hallucinations are auditory and accusatory or threatening. They occur, however, as do the visual manifestations reported here, in an unclouded sensorium with a prevailing affect of intense fear. There may also be olfactory hallucinations or visual illusions in alcoholic hallucinosis. The patients remain well oriented and often continue to function at their jobs, but they tend to elaborate a delusional system to explain their experiences. Some come for help complaining of being disturbed by their auditory hallucinations. Acute alcoholic hallucinosis ,usually lasts 5-14 days. Cases lasting months or more are considered to be instances of chronic paranoid schizophrenia. While presumably a toxic state, the condition is said to be more common in specific personality types such as cychlothymic or extroverted personalities. It is seen after a period of heavy alcohol consumption in a chronic alcoholic.

Hallucinosis due to hallucinogenic drugs may also be of toxic origin. The various studies of the physiologic and pharmacological effects of LSD on the visual system have been reviewed above. Although the precise site of- the etiology of the hallucinations is not certain, it would seem that LSD acts on many parts of the visual sys- tem to cause transient electrophysiological changes. It is hypothesized here that some of these changes may be prolonged in patients who have taken the drug repeatedly.

It is likely that more cases of this condition will occur because of the current fad of unsupervised consumption of hallucinogenic drugs in repeated doses.

SUMMARY

The use of hallucinogenic drugs carries a danger which is not sufficiently recognized, namely that of prolonged adverse reactions. Among these reactions is a chronic hallucinatory state or hallucinosis which is occasionally seen after repeated drug administrations. Several characteristic cases have been reported in the literature and a further case is added here.

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