Experimental Schizophrenia-Like Symptoms

The nature and cause of the major psychoses are still unknown. Repeated attempts have been made to reproduce experimentally psychotic symptoms in the hope to uncover their psycho-physiological relationship. In 1886, Schmiedeberg succeeded in producing cataleptic phenomena in rabbits by the use of ethyl-urethan. In 1904, Peters(11) discovered the cataleptic action of bulbocapnine; Baruk and de Jong(1t, 9, 10) investigated this, as well as many related chemicals, more extensively and demonstrated the catatonic effect upon man and animals. With the discovery of new chemicals and chemical compounds, new tools are made available to the psychiatrist to investigate psychoses experimentally, and a new branch, experimental psychiatry, is emerging. The experimental psychiatrist has the advantage of knowing the one factor, in the causation of psychotic symptoms, the chemical that was administered to the patient and started the chain of reactions. The psychopathological genesis, however, of the psychotic phenomena will best be investigated by methods of the inter-

1 Read at the 107th annual meeting of The American Psychiatric Association, Cincinnati, Ohio, May 7-11, 1981.

From the Department of Psychiatry, Harvard Medical School, and the Boston Psychopathic Hospital; Dr. Harry C. Solomon, Director.

Aided by a grant from the McCurdy Company, Rochester, New York.

COOH

CH,

sycl latry Of xperimentally at present alkaloid known in its crude form as peyote for hun-

dreds of years, though only in the past few

are outstanding: mescaline, an

years chemically synthetized, and d-lysergic tartrate (L.S.D.), a member of the ergot group. Although these chemdifferent in

acid diethylamide

their chemical structure, in their effect upon normal subjects and psychotic patients they show i

cais are quite

great similarities with reg

chotic symptoms. The schizogenic effect of mescaline has been reported in a number of recently

articies, most

mental and Paul H. Hoch(8). Our

essentially with the description of the

ot d-lysergic acid diethylamide _ tartrate (L.S.D.) upe individuals

who, subsequent to the administration of this

effect and temale

cnemical, respont

led with the production of psychotic-schizophrenic-like phenomena.

Chemistry and Pharmacology,

, which stands for the German LyDidthylamid, is the abbreviation

used for the diethylamid tartrate of lysergic according to A. Stoll, A. Hofmann, and F. Troxler(17), is diastereomer }

acid which,

ut not structurally isomeric with isolysergic

acid as seen in the accompanying formula.

Hooc H

: \ \ | paper is ncerned H \ \ C—E ( CH; HC N—CH H¢ N—CH C——-CH CH Cc CH, ( CH, HC H¢ ( CH CH NH S72

It is water soluble and administered orally. Pharmacologically L.S.D. belongs in the group of the ergonovine substances. It has a definite effect upon the in situ uterus of the rabbit, and causes peculiar states of motor rigidity similar to the catatonic phenomena in the dog and cat as seen with bulbocapnine (19). In our own experiments we noted an especially strong physiological reaction in a 29-year-old very sensitive white girl who was menstruating at the time. She complained of most violent abdominal constrictions, which may have been caused by vehement uterine contractions. The peculiar psychological effect, seen as excitation in experimental animals, was first observed and described by the chemist, A. Hofmann. In his laboratory notes of April 4, 1943, he remarked that, while working with L.S.D., he noticed in himself a peculiar restlessness associated with slight dizziness. He had to interrupt his work and went home to rest. While at home, he felt as if intoxicated, a condition characterized by an extremely stimulated phantasy. After darkening his room, for the daylight bothered him very much, he had a most wonderful experience. Phantastic images of most extraordinary plasticity and intensive kaleidoscopic coloring passed before him. This state of intoxication lasted about 2 hours.

Literature

Following this discovery a number of authors investigated the effect of L.S.D. in self-experiments, on normal subjects, and on psychotics. W. A. Stoll(18), who first systematically investigated the psychological phenomena of L.S.D., confirmed Hofmann's experiences and reported as the most striking psychological findings disturbances in perception that led to hallucinations, acceleration of thinking, slight dimming of consciousness, but maintenance of judgment. He regarded the psychotic condition as an acute exogenous reaction type and pathologically as diencephalosis. Condreau(4) confirmed most of

Stoll's findings, but reported that in his experiments the subjects' consciousness was not disturbed aside from the feeling of intoxication. He added that the subjects maintained their capacity of self-criticism, but showed increased distractibility and were less able

to concentrate. The basic theme of thought remained unchanged, and the changes in feeling tone he felt to be merely an intensification of the previous underlying mood. He added as a new observation forced laughing and one instance of athetoid movements as suggestive of involvement of the diencephalon, thus contributing to W. A. Stoll's original conception. A. M. Becker(2) essentially confirmed the observations of Stoll and Hofmann and emphasized the astounding production of psychosis-like syndromes following the administration of mere "traces" of a chemical substance. He believes the psychological manifestations are the result of two different basic disturbances: affectivity and impulsivity on the one hand, and intentionality on the other. The most striking contrasts among his observations were manic-hyperkinetic and inhibited. depersonalized manifestations. In contrast to Stoll, who termed L.S.D. a "Phantasticum," Becker suggested the designation of "Psychoticum" for L.S.D. Umberto de Giacomo(6, 7), of Italy, in his experiments with rather large amounts of L.S.D. (300 to 500 gamma) observed in his patients catatonic-like phenomena, which were similar to those produced by bulbocapnine. M. Rinkel(12) and Victor H. Vogel(18) reported their experiences with diethylamide of lysergic acid, adding as new observations paranoic trends and, in contrast to previous publications, slowing of thinking and poverty of thought. Bush and Johnson(3) used L.S.D. as an aid in psychotherapy, and reported that their psychotic patients responded with an increase in activity and greater verbalization of psychopathology. They noted occasional short periods of confusion and disorientation, and occasional transitory visual hallucinations. Most of their patients showed some degree of euphoria.

Method and Procedure

In our own experiments, L.S.D. was given 17 times to 15 normal adult volunteers, students, nurses, and doctors, in the 19-48 age range, and, as freshly prepared solution, to some psychotics: dementia praecox and manic-depressive, depressive type. The observations on the psychotic patients are still in progress and will be published later. The

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574 EXPERIMENTAL SCHIZOPHRENIA-LIKE SYMPTOMS [Feb

normal subjects, who were kept without breakfast, received L.S.D. in doses ranging irom 20 to go gamma p. ©0., in most cases one gamma per kilogram body weight, while the psychotics were given 3 gamma per kilogram body weight. This increased dosage for psychotics was chosen on the basis of the unanimous reports in the literature that psychotic patients were particularly resistant to the effect of L.S.D. The subjects were kept under continuous observation by at least one of the authors for the first 5 hours and, on occasions, tape recordings of the subject's productions were made. The subjects remained under observation the same day at the hospital, and were seen again the following day. The main emphasis in our observations was on the clinical psychiatric picture. Routine neurological and circulatory system examinations were not done, but signs occurring in these areas were noted, if observed, In g of the experiments, electroencephalograms at or near 2 hours after L.S.D. were taken, and Rorschach tests were given to 5 normal subjects and concrete-abstract thinking tests to 2 subjects during the height of the L.S.D. reaction. Controls of EEGs and psychological tests were done while the subjects were in their normal mental state.

Results

1. Disturbances of Thought and Speech. The most prominent psychological changes observed were those in thinking and speech. They were present in all our experiments. There was no cloudiness of consciousness, no intellectual weakness, but most frequently we observed difficulty in the power of expression. The subjects became more and more slowed down, poverty of thought became apparent, and the flow of speech became increasingly diminished and blocked. (me subject, a middle-aged depressed patient, went into a complete stupor. In another instance occurred unwillingness to speak, a symptom similar to the negativism of the schizophrenic. Hesitancy, indecision, and impairment of abstract thinking were frequently present; also looseness of thought and actual disconnection with increased distractibility were common observations. As in schizophrenic patients, some of the sub-

spontaneity, irrelevance, pedantic imitation, and subjectively aut tic speech. In one in stance, we had the impression of the forma tio neologism .cceleration of thought with fligl t of idea ciated with rhyming and punning; garrulity and loquacity of the hypomat type were seen in a cyclothymik

medical student within 45 minutes after the

administration of L.S.D. In general, the ef-

fects appeared within 30-45 minutes after the oral administration of L.S.D., and disappeared gradually after 3-4 hours,

A tand A 1.—Clear-cut blunting ot aftect nd Spi ness, as often seen in schizophrenic patients, were outstanding These symptoms frequently led to feelings

of indifference and unreality with disturb-

ances in body image Che subjects experienced hostilit nd resentment, and on rare occasions ambivalence. The phenomena occurred about 15 minutes after the adminis-

tration of L.S.D.; feelings of indifference and blunting tended to be protracted; suspiciousness, hostility, and resentment were always more transient. Changes in mood were twofold: euphoria and depression, which occurred in about equal number. Euphoria was either of the shallow elation type with silliness, as seen in the hebephrenic, or, in a cyclothymic subject, of the jovial and infectious type, as found in hypomanic and manic states. Depression was combined with dependency, indecision, insecurity, passivity, and feelings of being "lost.'"' In no instance did we observe the happy and dreamy feeling of ecstasy as it has been described by other 10 experimented with L.S.D., mescaline, and other similar chemicals Usually within 40 minutes after the intake of L.S.D. disturbI

ANCES ¢ f percepti n were observed. hose of

visual perception were most common and ] isional type. The subjects would see rippling or wavy lines on the wall that might evolve into geometrical pattern, or be associated with color such as yellow, orange, or pink. In some instances, subjects aw a thermostat on the wall as a crucifix

but fully realized that the experience was an

illusion. None of the subjects, however, had the feeling of seeing si inething of extraor-

jects exhibited such phenomena as lack of : | Ne

| _ dinary beauty, as it was stated in early re- S

1952] M. RINKEL, H. J. DESHON, R.

W. HYDE AND H. C. SOLOMON

ports on L.S.D., or as it may occur under the influence of mescaline.

frequently ; the subjects experiencing a metallic or "funny" taste or heavy tongue.

Gustatory disturbances occurred

Auditory perception was changed only in a few instances. The subject would hear a sound that was either near or distant, and in

one instance of a depressed patient, the noise of a typewriter in an adjoining room was perceived as music, seemingly beautiful music.

The sense of time was disturbed in 11 out of 17 experiments. It was characterized by the feeling of time accelerated or retarded.

IV. Hallucinations and Delusions.—Disturbarices in perception, in a complex way, often lead to hallucinations and delusions. A vivid phantasy, a pseudohallucination or illusion, in the process of mental dissociation, may ultimately appear as a real object outside the subject and thus constitute a real hallucination. By a similar process, changes in auditory perception, combined with existing suspiciousness, may lead to ideas of reference and delusions of persecution. It may be stated that hallucinations, predominant under the influence of most phantastica, subsequent to the injection o1 L.S.D. were rather meager and never showed the quality of an extraordinarily beautiful or threatening experience. The occasional visual hallucinations consisted mainly of formed images, which occasionally were preceded by crude flashes of light. Perhaps the above-mentioned disturbances of taste perception should be mentioned here as gustatory hallucinations. In only one instance we noticed an auditory hallucination, which consisted in hearing bells, although there were none anywhere around. Haptic hallucinations were experienced by two subjects. One male subject had the rather vivid feeling of his trousers being wet from urine, and one female schizoid patient was convinced that she lost urine and wet her slacks and the bed. She actually, later on, did wet the bed, and it may be possible that her hallucination was stimulated by autonomic excitation of the bladder mechanism. Morbid ideas were common; they included ideas of reference and ideas of influence. One female volunteer became quite paranoic and was still disturbed the following day. Major delusions, ideas of gran-

deur or persecution, as seen in the delusional states of the paranoic or paraphrenic, were not observed. That may be due, perhaps, to the fact that in our experiments on normal volunteers we used only relatively small amounts of L.S.D.

V. Depersonalization.—Alteration of personality occurred rather frequently. Those changes consisted mainly in the subject's feeling that his legs were either extraordinarily long or heavy; in one psychotic patient the feeling was that the leg between ankle and hip had disappeared entirely. Most common was the feeling of unreality as regard to the subject, himself, and the outer world. Though these phenomena were of minor magnitude, they, too, indicate symptoms particularly observed in the schizophrenic patient. In no instance were we able to elicit experiences of synesthesias, as frequently seen in mescaline intoxications.

VI. Behavior—The most and _ striking change consisted in underactivity, associated with lack of spontaneity and initiative. One schizoid-depressed patient went into a state of catatonia; another one became stuporous. A female schizophrenic patient, who had received 3 gamma/kg. body weight of L.S.D., became agitated ; after an initial state of inertia, she suddenly stood up and went through many and various motions. She knelt down, kissing the wall, the floor, the examining table, and progressively became more and more excited. She tore off her clothes and became noisy to such an extent that the experiment had to be terminated by the intravenous injection of 0.5 g. of sodium amytal. In our normal subjects, overactivity or inappropriate behavior was rarely noted, but psychomotor manifestations, such as smiling, giggling, and laughing, more often appropriate than inappropriate, were frequently observed. This was particularly so in a student of cyclothymic personality make-up.

VIL. Jntellect—In our normal subjects, intellectual functions were never disturbed. The subjects were aware of what they were doing at every moment of the experiment. Their memory also never became disturbed ; each one was able to give, in a written report, a description of all the experiences he went through. Also, the psychotic patients did not show any particular memory defect.

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• Hing a

79 EXPERIMENTAL SCHIZO!

Patients whose verbal expression becany slowed down and finally completely cease as in the case of stupor or catatonia, were able the following morning, under sodium amytal or d-desoxy-ephedrine, to recall their thoughts or personal experiences of the day before under the influence of L.S.D.

VILL. Autonomic Nervous System—All normal subjects and also the psychotic patients had numerous subjective complaints and symptoms. Since they mostly belong in the group of disturbances of the autonomic nervous system, they are best described here. The most common symptom was change in appetite, which more often was decreased, and associated with nausea, than increased. Complaints of headiness, giddiness, faintness, tremulousness, and shaking were frequently expressed. The subjects complained of chilliness and coolness of whole or part of the body, lump and "funny" feelings in abdomen, constriction with oppression in chest and precordial discomfort, violent cramps and constriction in the abdomen in a patient who just happened to menstruate. Objectively observed were flushing, sweating, shivering, and shivering with goosepimples. Tachypnoea, salivation, pallor, sighing, and urgency of micturation were scattered observations. Changes in pulse rate and blood pressure were of minor magnitude and observed only occasionally. Involuntary smiling, giggling, or laughing were considered in the nature of "risus sardonicus'" where the subject described these phenomena as occurring without or against his will. One subject stated that in a smile he felt as if his facial muscles were like plastic wax being moved by some inexorable force. Pupils were often maximally dilated.

Gross disturbances of the cerebrospinal nervous system were not observed, except in some instances "dysarthria," which consisted of a transient stumbling over words and was never marked.

IX. were taken in 9 experiments at about the height of L.S.D. reaction, and compared with the I.EG of the same subject in his normal state. In general, the EEG changes were only

slight. Principal changes occurred in the alpha rhythm, which was characteristically increased in rate from 1-3 cycles per second.

HRENIA-LIKE SYMPTOMS [Feb

n one case, an individual who was very r laxed, a slowing of about 2 cycles per second was observed. Hyperventilation showed a diminished responsiveness and may be due to the subject's reduced cooperation.

Psychological Tests.

A. Rorschach.—Controlled Rorschach tests were given to 5 subjects at the height of L..5.D. reaction. All tests given during L..5.D. reaction showed abnormalities prin-

cipally of the schizophrenic or paranoic

type. There was noticed autistic thinking with decreased organization, contamination responses, and lack of logical thinking, also

negativism and diminished emotional inhibition indicating anxiety, depression, and aggression. One Rorschach test revealed a moderately schizophrenic picture with autistic thinking and withdrawal.

B. Concrete-Abstract Thinking.—The tests consisted in employing proverbs and aphorisms and recording the subject's reaction. On the wh le, the results, especially the wide range of responses in abstraction and overgeneralized and tangential thinking, were similar to those obtained in schizophrenic patients.

Discussion

The common denominator in all our experiments with L.S.D. on normal subjects is a profound transformation and alteration of the psychic state of the individual, as it is 1 common factor in all psychotic states. The various mental phenomena that we have reported were brought about by mere traces (1:1,000,000g/kg. weight) of a chemical, d-lysergic acid diethylamide tartrate. The mental phenomena show similarities to symptoms that occur in actual psychoses. We noticed, predominantly, changes similar to those seen in schizophrenic patients. The subjects exhibited preeminently difficulties in thinking, which became retarded, blocked, autistic, and disconnected. The affect was shallow or there was clear-cut blunting. leelings of indifference and unreality with suspiciousness, hostility, and resentment also approximated schizophrenic phenomena. Hallucinations and delusional disturbances though present were much less prominent or striking, but together with the manifestation

. > o |

1952] M.

RINKEL, H. J.

DESHON, R. W. HYDE AND H. C.

of depersonalization were most reminiscent of schizophrenic dissociation.

To a much lesser degree were there similarities to the confusional states. Gross clouding of consciousness was absent in our experiments, but illusional misinterpretations were not infrequently observed.

A few cases showed similarities to the manic-depressive states, with changes in mood of euphoria or depression. However, only in one cyclothymic-pyknic subject the intensity was of a hypomanic or manic state.

Delusions of grandiose or persecutory nature, familiar in the paranoic psychoses, were not seen.

We mention the similarities of the experimental phenomena to actual psychotic states in order to caution against fallacies that may occur in the interpretation of experimental psychotic disturbances. The same caution that is warranted in the application of an animal experiment to a pathological condition in man is needed in the application of the psychiatric experiment to natural psychosis. Our experiments have brought to light the fact that, in a short space of time, under the influence of a mere trace of a chemical agent in normal subjects, a variety of mental symptoms occur that are similar to natural psychoses, and that in psychotic patients an accentuation of existing, or elicitation of latent, schizophrenic phenomena takes place. It may be possible to assume that fundamentally the mechanism of origin of natural and experimental psychotic phenomena is a similar one: a chemical agent that pathologically stimulates selectively various higher, especially perceptive, brain centers with the result of hallucinatory and delusional experiences. H. J. DeShon, M. Rinkel, and H. C. Solomon(5) have already pointed out that the clinical effects of L.S.D. imply such an involvement of the higher and highest centers of the central nervous system, and perhaps of lower levels of the nervous system as well,

Many authors assume that chemical endogenous substances are the cause of schizophrenic psychosis. We must bear in mind that, in addition to d-lysergic acid, a great variety of seemingly unrelated chemical substances are capable of producing transi-

tory psychotic-like symptoms. Although observations are still too few to allow the formulation of a well-founded scientific theory as to the chemical origination of psychotic symptoms, we strongly believe that this branch of experimental psychiatry is progressing in the right direction, and may some day provide an answer to the most perplexing problems in psychiatry.

Summary

1. The effects of minute amounts of dlysergic acid diethylamide tartrate (L.S.D.) on normal subjects, with an age range of 19-48 years, and some psychotic patients of the schizophrenic, depressive, and paranoic type are reported.

1. Psychotic phenomena and _ alterations of the autonomic nervous system were observed. The psychotic phenomena were predominantly schizophrenia-like symptoms that were manifested in disturbances of thought and speech; changes in affect and mood; perception ; production of hallucinations and delusions ; depersonalization and changes in behavior. The basic intelligence was not reduced.

1. Electroencephalographic examinations at the height of the L.S.D. reaction revealed only slight changes, principally increased alpha rhythm, except in one case where there occurred a slowing of about 2 cycles per second.

1. Rorschach tests showed abnormalities principally of the schizophrenic or paranoic type. Concrete-abstract thinking tests also, on the whole, showed responses similar to those obtained in schizophrenic patients.

1. No scientific theory for the origination of the natural psychotic phenomena or psychoses is being advanced, but the belief is expressed that experimental psychiatry progresses in the right direction.

Credits

Our preparation of L.S.D. was supplied, in ampules containing 1 mg. substance, by courtesy of Professor E. Rothlin, Director of the Pharmacological Laboratories of Sandoz Chemical Company, Inc., Basel, Switzerland.

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