Studies with Lysergic Acid Diethylamide in Regressed Schizophrenics

CHAPTER 15 _

By FREDERICK B. CHARAT AN, M.D.

OF THE MANY studies carried out with lysergic acid diethylamide in the last 15 years, relatively few have dealt with regressed schizophrenics. Most workers have used comparatively small doses of LSD. Some gave up to 600 gamma orally. Others reported the effects of up to 500 gamma intramuscularly, 180 gamma intravenously and 60 gamma intrathecally in small series of cases. Several investigators agreed that in chronic schizophrenics higher doses of LSD than those administered to undeteriorated schizophrenics and nonpsychotics have been required to produce psychic effects. Apart from the slight response of chronic schizophrenics to doses of LSD which lead to marked and characteristic effects in other subjects, tolerance to the drug seems to develop in as brief a period as three days. These differences in response to LSD pose some interesting problems. Is the lack of response in chronic schizophrenics merely an apparent one caused by their inability to communicate their inner experiences? Is it due to the development of some immune state connected with biochemical alterations produced during the psychosis? Is it the reflection of a metabolic difference between schizophrenics and non-schizophrenics? May it be a general manifestation of schizophrenic underresponsiveness to virtually any stress, once the chronic stagnant phase of the psychosis has been reached? Clear answers to all these questions cannot yet be given. The present investigation was undertaken to examine further the responses of chronic schizophrenics to large doses of LSD and also to observe the effect of other drugs upon this response.

MATERIALS AND METHODS Eight female patients were selected by the following criteria: they had all been ill for many years; they all showed well marked signs of schizophrenic deterioration; they had been under observation for at least six months in the same ward, and cared for by the same nursing staff. There are some advantages in selecting such patients. Thus, their behavior, speech and mannerisms are well known to the staff.

From the Research Division, Manhattan State Hospital, Ward's Island, New York, N. Y. 195 196 BIOLOGICAL PSYCHIATRY

They are very limited in their activities, which makes any departure from the usual pattern readily observed. Over a period of time ranging from several months to several years, the illness had reached a stagnant phase, and change has become a rarity. All these patients had had various treatments, including long courses of thorazine or similar drugs without improvement. One had had a topectomy. On 47 separate occasions the patients were given increasing doses of LSD by mouth and also intravenously, following which they were observed closely for six hours. Administrations were separated by at least five days to prevent the development of tolerance. The nurse also reported on the patients on the day of administration and subsequently.

RESULTS

Oral administration. In every case, the autonomic effects were far more pronounced than the psychological, and set in 20 to 45 minutes after ingestion. Tachycardia and pupillary dilatation were seen in all patients. With the highest doses, patients became very restless, but did not speak more freely or communicate fresh material. The commonest affective changes were in the direction of an increase in hostility or depression. In five patients an unstable affective state which included weeping and sobbing was produced. The LSD state showed a definite waxing and waning. By six hours, the reaction usually subsided, patients being restored to their former state on the next day. Patients were questioned directly regarding hallucinations, alterations in body image, sensory disturbances, orientation and the total experience. As these patients at their best were poorly accessible, it is not surprising that equivocal responses or no answers were given to these questions. A good example of such a response was that of a patient who was clearly restless, confused, perspiring and showed marked tachycardia after LSD. When asked how she felt, she said, "I feel fine". Intravenous administration. Patients were given LSD intravenously in doses up to 400 gamma. Reactions commenced within five minutes of administration and were more intense than with the same dose by mouth. Autonomic features-tachycardia, tachypnea, mydriasis, salivation-and nausea were prominent. Two patients showed pyrexia, the temperature rising 1 to 2° F. Restlessness was more marked than with oral administration. Ataxia, pseudochoreic movements and coarse tremors occurred in some patients. The same fluctuations of mood were seen. Clouding of conscious- ness and reduced accessibility were more evident.

Effects of other drugs upon the LSD response. Methyl Amphetamine. Patients were premedicated with methyl amphetamine, 30 mg. daily, for periods of 5 to 24 days, and given the same dose of LSD intravenously as they had received previously. The effect of the methyl amphetamine on these regressed patients before LSD was very con- LYSERGIC ACID DIETHYLAMIDE IN REGRESSED SCHIZOPHRENICS 197 sistent. The patients became worse within 48 hours. They became more restless, confused, incontinent and difficult to nurse. However, no change following LSD intravenously compared with the previous reaction was seen, nor was the reaction prolonged. Intramuscular Methedrine, 15 mg. in two patients at the height of the LSD reaction, was without noticeable effect. Iproniazid. All patients were premedicated with iproniazid, 150 mg. daily, for periods of 5 to 33 days. Like methyl amphetamine, iproniazid tended to increase restlessness and regressive phenomena in these chronic schizophrenics, although to a lesser extent. The schizophrenics premedicated with iproniazid were given LSD intravenously in the same doses they had previously received. No difference in either the intensity or the duration of the reaction to LSD was observed. Diethazine. Following intravenous LSD in doses of 200 to 400 gamma, 250 mg. diethazine was given intramuscularly at the height of the reaction. In every case, the LSD reaction was terminated within one hour after the injection. Sodium amy tal explorations in chronic schizophrenics. As an aid in deter- mining whether underlying trends might be present, each patient was given a sodium amy tal exploration; 5 per cent sodium amytal was injected slowly intravenously until slight slurring of speech was apparent. Only one patient showed an increase in spontaneity, becoming more euphoric and talkative in a disorganized way, the context being about dying and being killed. The other seven patients remained empty of content. No fresh material was obtained. Changes in affect did not occur, with the exception mentioned. When questioned about topics expected to elicit responses, e.g., about children, husbands, families, ambitions, reasons for admission to the hospital, they remained apathetic and replied briefly or not at all. When thought disorder was present in the conscious state, no changes were brought about under sodium amytal. Patients' replies were "beside the point" or completely irrelevant. When asked about their thoughts or feelings they made stereotyped responses: "I feel fine," "Nothing," or "O.K." When invited to discuss problems they remained silent. To summarize: sodium amytal gave rise to hardly any change in the psychological responses of these patients and merely highlighted the stunting and withering of their mental life.

DISCUSSION

Several workers have pointed out that chronic schizophrenics show reduced psychodynamic responses to LSD. Occasionally this phenomenon has been seen in normals who received up to 225 gamma. The present results are in conformity with earlier reports in which doses of LSD of up to 6 gamma per Kg. were required to produce undifferentiated emotional responses in 198 BIOLOGICAL PSYCHIATRY this schizophrenic group. It must be stressed, however, that chronic schizophrenics show well marked autonomic symptoms after quite small doses of LSD. Increasing the dose increases the predominantly sympathicomimetic features such as tachycardia, tachypnea, mydriasis, nausea and vomiting. With the highest doses affective instability, pseudochoreic movements and motor restlessness occur. Ideational content remains unaffected.DiMascio and co-workers have pointed out the early generalised sympathetic excitation occurring in the march of events after LSD in doses of 1 gamma per Kg. has been administered to healthy volunteers. The march of events in chronic schizophrenics halts short of discernible ideational features. One must conclude that LSD has a specific stimulating effect upon the hypothalamus-particularly those nuclei which integrate sympathetic activity. Kies and co-workers'" demonstrated an antidiuretic effect of 100 gamma of LSD in healthy subjects. Evidence for stimulation by LSD of the mesodiencephalic activating system has been provided by Himwich.F Instillation of LSD into the cerebral ventricles of cats produced minor diffuse autonomic symptoms in small doses and "sham rage" in larger doses, a sequence of events paralleling to some extent those observed in the administration of LSD to chronic schizophrenics.LSD is remarkable in causing gross changes in the affect of chronic schizophrenics who may have remained frozen for years. It is hardly necessary to recall that in- creased lability and incongruity of affect may be seen in localized sub- cortical lesions in basal ganglia, hypothalamus and brain stern."? The reversible toxic effect of LSD may set off unusually intense neuronal dis- charges from this region, in effect amounting to, if I may be allowed the term, status epilepticus hypothalamicus. This has been reported clinically as a fluctuation-a waxing and waning of the LSD effect. Murphy and 25 Gellhorn ,26 have provided evidence of a central direct effect upon cortical activity from hypothalamic stimulation. The changes induced were in the direction of greater cortical excitability and were associated with change to fast activity in the spontaneous rhythms.Moreover, the hypothalamic areas, whose stimulation produced this type of EEG change, were those areas, and only those areas, whose stimulation also resulted in sympathetic autonomic phenomena. A central effect of this kind originating from the hypothalamus might help to explain the other features of the LSD state reported in the liter- ature. For example, if we accept Adrian's view of the neurophysiologic basis of perception," then the effect of LSD is to set off an interference pattern superimposed upon basic hypothalamico-cortical rhythms. This is seen clinically in the visual disturbances which amount less to formed hallucinations than to complicated perceptual distortions. Disturbed orien- LYSERGIC ACID DIETHYLAMIDE IN REGRESSED SCHIZOPHRENICS 199 tation for space, for time and for body image might originate in the same fashion, but of course, may be described adequately only by those who have the gift of good expressive powers. Premedication of chronic schizophrenics with iproniazid and methyl amphetamine for periods of 5 to 33 days did not increase or prolong the response to LSD. The intensity of the autonomic features was about identical to that of those elicited without premedication. Intramuscular methyl amphetamine at the height of the LSD reaction similarly had no effect. Both iproniazid and methyl amphetamine are inhibitors of monoamine oxidase. Their action in increasing wakefulness in normals is thought to be mediated indirectly by permitting an increase in central norepine- phrine. There is agreement that methyl amphetamine and iproniazid make chronic schizophrenics worse, increasing restlessness, hostility and regressive phenomena. This was so in the present study. Premedication with these substances was ineffective in modifying the LSD reaction either because iproniazid, methyl amphetamine and LSD all produce effects in the same direction, or because LSD does not interact with monoamine oxidase. In this respect, Rothlin'" has pointed out that of all the amides of lysergic acid only the mono and diethyl derivatives possess psychogenic effects. This suggests a mechanism unconnected with amine metabolism. Diethazine [10 (2 diethylamino ethyl) phenothiazine] 0.25 Gm., given intramuscularly at the height of the LSD reaction showed itself to be an efficient blocking agent. Autonomic features subsided within 45 minutes of administration. This efficacy of diethazine in blocking the LSD reaction is perhaps not surprising, considering its structural resemblance to chlorpromazine, whose antagonism to LSD has been shown by Hoch. On the other hand, Denber" has reported that diethazine premedication exacer- bates some features of the mescaline state. The point requires further study. Hoch has asked the important question, "Does a patient under sodium amytal reveal different psychodynamic material than with benzedrine or LSD?" A partial answer may be given. Contrasting with the "normalizing" effect of intravenous sodium amytal in early schizophrenia, in the patients studied, the severe impoverishment of the mental life was underscored. Underproductiveness, stereotyped replies, lack of affective response and poverty of ideation were the rule. Occasionally it was possible to touch upon a fragmentary complex and hence to elicit some affect. For example, one patient who had been in hospital for 30 years was very attached to an iron curtain ring she always wore. Inquiry directed towards this was at once met by hostility and a repetitious "warning off," in which some hitherto repressed four letter words were delivered in an Irish accent to which I cannot do justice here. Further pressure led to a catastrophic 200 BIOLOGICAL PSYCHIATRY reaction, which could be only triggered by this one subject. Findings of this kind have been reported by Kant." and go some way to explain, at least in psychological terms, the limited response of chronic schizophrenics to the psychomimetic drugs. Denber" has emphasized the need in any experimental situation to assess the psychodynamics of the investigator and of the subjects. The inability of LSD to bring forth dynamic responses in chronic schizophrenia contrasts markedly with the effects of, for example, mescaline upon so developed a mind as that of Mr. Aldous Huxley. Mr. Huxley in his account of his experience in The Doors of Perception+ wrote engagingly of the mystical and cosmic aspects of taking mescaline. At one point mescaline had the effect of saturating his grey flannel trousers with "isness." This reminds one of the efforts of William James to describe what nitrous oxide did to him, and of the inability of other mystics (Pascal, St. Teresa) to find language adequate to describe the undescribable. Because, at best, chronic schizophrenics are such poor communicants, even with the aid of drugs, like sodium amytal, which increase verbal responsiveness, it seems that the stunting of their mental life is an important factor in their lack of dynamic response to LSD. As we know very little about the cause of schizophrenic deterioration, it is not yet possible to account for the chronic schizophrenic's loss of psychodynamic response to LSD. It may be due, as Hoagland>" has suggested, to the production of some endogenous metabolite blocking the pathway of LSD to enzyme receptors elsewhere in the brain. The biochemical actions of LSD continue to be studied with intensity, and several hypotheses which appeared attrac- tive recently are now in the process of demolition. Although evidence is accumulating that the site of action of LSD is in the hypothalamus, at present we can only return a verdict of "not proved" regrading its intrinsic pharmacodynamic action.

REFERENCES 1. Abramson, H. A.: Neuropharmacology. In Transactions of the Second Con- ference. New York, Josiah Macy, Jr. Foundation, 1956, p. 259. 2. Adrian, E. D.: The Physical Background of Perception. Oxford, England, Clarendon Press, 1947. 3. Anderson, E. W. and Rawnsley, K.: Clinical studies of lysergic acid diethylamide. Mtschr. Psychiat. u. Neurol. 128: 38-55, 1954. 4. Axelrod, J" Brady, R. 0., Witkop, B. and Evarts, E. V.: The distribution and metabolism of lysergic acid diethylamide. Ann. New York Acad. Sc. 66: 435, 1957. 5. Brodie, B. B.:Neuropharmacology. In Transactions of the Third Conference. New York, Josiah Macy, Jr. Foundation, 1957, p. 323. 6. Brown, B. B.: Lysergic acid diethylamide antagonism of certain drugs. Ann. New York. Acad. Sc. 66: 677, 1957.

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7. Cholden, L. S., Kurland, A. and Savage, C.: Clinical reactions and tolerance to LSD in chronic schizophrenia. J. Nerv. & Ment. Dis. 122: 211, 1955. 8. Denber, H. C. B.: Studies on mescaline. VII. The role of anxiety in the mescaline induced state and its influence on the therapeutic result. J. Nerv. & Ment. Dis. 124: 74, 1956. 9. --: Psychodynamic considerations of the research worker in psychiatry. Pre- sented at the Conference on Psychodynamic, Psychoanalytic and Sociologic Aspects of the Neuroleptic (Tranquilizing) Drugs in Psychiatry, Queen Mary Veterans Hospital, Montreal, April 11, 1958. 10. Evarts, E. V.: A review of the neurophysiological effects of lysergic acid diethylamide (LSD) and other psychotomimetic agents. Ann. New York Acad. Sc. 66: 479, 1957. 11. Forrer, G. R. and Goldner, R. D.: Experimental physiological studies with lysergic acid diethylamide (LSD-25). A.M.A. Arch. Neurol. & Psychiat. 65: 581-588, 1951. 12. Himwich, H. E.: The effect of Frenquel on EEG changes produced by LSD and mescaline. In Cholden, L., Ed.: Lysergic Acid Diethylamide and Mes- caline in Experimental Psychiatry. New York, Grune & Stratton, 1956, p. 19. 13. Hoagland, H.: A review of biochemical changes induced in vivo by lysergic acid diethylamide and similar drugs. Ann. New York Acad. Sc. 66: 445, 1957. 14. Hoch, P. H.: Experimental psychiatry. Am. J. Psychiat. Ill: 787, 1955. 15. --: Studies in routes of administration and counteracting drugs. In Cholden, L., Ed.:Lysergic Acid Diethylamide and Mescaline in Experimental Psy- chiatry. New York, Grune & Stratton, 1956, p. 8. 16. --: J. Nerv. & Ment. Dis. 125: 442, 1957. 17. --, Cattell, J. P. and Pennes, H. H.: Effect of drugs; theoretical considerations from psychological viewpoint. Am. J. Psychiat. 108: 585, 1952. 18. Huxley, A. L.: The Doors of Perception. New York, Harper, 1954. 19. Isbell, H., Belleville, R. E., Fraser, H. F., Wikler, A. and Logan, C. R.: A.M.A. Arch. Neurol. & Psychiat. 76: 468, 1956. 20. Isbell, H. and Logan, C. R.: Studies on the diethylamide of lysergic acid (LSD-25). II. Effects of chlorpromazine, azacyclonal, and reserpine on the intensity of the LSD-reaction. A.M.A. Arch. Neurol. & Psychiat. 77: 350- 358, 1957. 21. Kant, 0.: Clinical analysis of schizophrenic deterioration; investigation aided by sodium amytal interviews. Psych. Quart. 17: 426, 1943. 22. Katzenelbogen, S. and Fang, A. D.:Narcosynthesis effects of sodium amytal, methedrine and LSD-25. Dis. Nerv. System 14: 85-88, 1953. 23. Kies, M. W., Horst, D., Evarts, E. V. and Goldstein, N. P.: Antidiuretic effect of lysergic acid diethylamide in humans. A.M.A. Arch. Neuro!. & Psychiat. 77: 267, 1957. 24. MacDonald, J. M. and Galvin, J. A. V.: Experimental psychotic states. Am. J. Psychiat. 112: 970, 1956. 25. Murphy, J. P. and Gellhorn, E.: Further investigations on diencephalic-cortical relations and their significance for problem of emotion. J. Neurophysiol. 8: 431, 1945. 26. Murphy, J. P. and Gellhorn, E.: Influence of hypothalamic stimulation on cortically induced movements and on action potential of cortex. J. Neuro- physiol. 8: 341, 1945. 202 BIOLOGICAL PSYCHIATRY

27. Penfield, W. and Jasper, H.:Epilepsy and the Functional Anatomy of the Human Brain. Boston, Little, Brown, 1954, p. 412. 28. Rinke!, M.: Neuropharmacology. In Transactions of the Second Conference. New York, Josiah Macy, Jr. Foundation, 1956, p. 235. 29. Rothlin, E.: Pharmacology of lysergic acid diethylamide and some of its re- lated compounds. J. Pharm. & Pharmacol. 9: 569, 1957. 30. Whitty, C. W. M.: J. Ment. Sc. 102: 719, 1956.

Discussion by Harold Himuiich, M.D.

Dr. Charatan gave large doses of LSD to chronic schizophrenic patients with deterioration, and observed dramatic autonomic alterations. Though there were changes in mood, on the whole the behavioral reactions were less marked than the autonomic. Even when methyl amphetamine was given in addition to LSD or when iproniazid was given in addition to LSD, the behavioral effects were still on the moderate side. It is of interest that diethazine terminated the LSD-induced state in the psychotic patient though in patients without overt psychotic symptoms diethazine seemed to be psychotomimetic. Dr. Charatan makes the suggestion that LSD works on the part of the hypothalamus which is sympathetic in activity, and therefore the posterior hypothalamus. Dr. Woolley believes that LSD acts by virtue of displacing serotonin and does so because of a similar chemical configuration of a portion of the LSD and of the serotonin molecules. Drs. Everett and Tolman presented evidence in favor of the importance of noradrenaline rather than serotonin as a hormone which affects behavior. These workers suggest that noradrenaline acts both centrally on the brain and peripherally as well, wherever there are depots of noradrenaline and adrenaline. In our laboratory Dr. Costa and Dr. Williamina Himwich have shown that another psychotomimetic drug, bufotenin, acts peripherally and perhaps centrally as well. In Dr. Charatan's work, the autonomic symptoms are not obviously of central origin. They could be entirely a peripheral effect of LSD. The schizophrenic patients reveal less central activity of this drug in terms of behavior which is characteristically a central expression. Among the possibilities to explain Dr. Charatan's meager central results may be included a different status of the adrenaline and noradrenaline deposits in the schizophrenic than in the normal brain. Also to be considered is that schizophrenics with their spontaneously dis- ordered behavior make it more difficult to disclose other abnormalities. This is in contrast to normal volunteers in whom changes in behavior produced by psychotomimetic drugs are more easily ascertained.

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