http://exhibits.library.stonybrook.edu/mfp/files/original/c577bc7f069484c31c474ab088079b96.pdf ecc528f0eb233cc9aa9e8503f0092d28 PDF Text Text OF' THE EFFECTS CERTAIN DRUGS ON CEREBRAL SYNAPSES By Amedeo S. Marrazzi Reprinted from ANNALS OF THE NEW YORK ACADEMY OF SCIENCES APR 3 0 1qt§9 ‘ ‘ Volume 66, Article 3, Pages 496—507 March 14, 1957 DEPARTMENTOF . EXPERIMENT” PSYBH‘HRY SIDE HOSPlTN- Hug-LEN OAKS. N- Y- �THE EFFECTS OF CERTAIN DRUGS ON CEREBRAL SYNAPSES By Amedeo S. Marrazzi Velerans Administration Research Laboratories in Neuropsye/ziatry, Veterans Administration II ospital, Pittsburgh, Pa. As Edward Evarts has so clearly indicated in his contribution to this volume, we are all interested in determining the neurophysiological correlates of mental disturbance in the hope of thereby gaining an inkling of its underlying mech— anisms and developing a rational therapy for it. Humphry Osmond has drawn a dramatic picture of the opportunity presented by the situation made possible by the psychotomimetic drugs, which afford us the means of inducing at will a reversible model psychosis. This model psychosis, even though it bears only a fragmentary resemblance to schizophrenia, nevertheless simulates certain aspects of mental disturbance by perhaps similar mechanisms. Furthermore, the so-called model psychosis also can be shortened and terminated is in effectiveness clinical which for schizophrenia will the tranquilizers at by claimed. The use of drugs as tools thus creates favorable conditions for studies of mental illness. Our efforts, as investigators, are directed more toward an intelligent applica— tion of the hypotheses of mechanism rather than toward simple clinical evaluation. The conditions that we wish to interpret are fully and truly exhibited in man but, before we can take full advantage of controlled conditions induced in humans, it is necessary to perform some prototype experiments in animals since, in such experiments, more procedures are permissible and in them those experiments intended for man can be constructed and rehearsed. This pur— is be humans with work before done, needed can the my groundwork pose, justification for presenting some data on animals and making comparisons with clinical conditions and experimentally induced conditions in man. FIGURE 1 summarizes the data that led my co—workers and me to a hypothesis that served as the point of departure for studies in this field.1 It shows that in our survey of a variety of sites in the nervous system we find, as far as we have gone, that a consistent reciprocal relationship exists between excitation or enhancement by acetylcholine and acetylcholinelike substances, including anticholinesterases, on synaptic-transmission phenomena and inhibition by epinephrine, norepinephrine, all sympathomimetic amines in varying degrees, and related substances.2 It seemed plausible that any perversion of metabolism that would distort the balance of endogenous chemical or neurohumoral control of synaptic-transmission processes could lead to abnormal cerebral performance or mental disturbance, and that chemicals or drugs could alter the equilibrium of transmission and thereby alter cerebral and mental function in the direction of health or disease. The limitations of communication with animals make it exceedingly difficult, though not impossible, to relate the behavioral disturbances that can be produced in them with mental disturbance in man. Since our basic premise, however, is that all cerebral function, including both behavior and mental proc— in series and in accumulated parallel of units is functional made esses, up 496 �Marrazzi: Effects of Certain Drugs on (‘erebrztl Synapses 497 SIMILARITY OF CHOLINERGIC EXCITATION AND ADRENERGIC INHIBITION AT VARIOUS SYNAPSES ACETYLCHOLINE ATROPINE 0R CURAFIE ANTICHOLINESTERASE TEA EPINEPHRIQJE mnzpmepuamz AMPNETAMINE Epnsonms (-) CORTEX ‘MIDBRAIN (—) ~n£spmnoav (_) CENTER PARASYMPATNETIC GANGLIA (-) svunmznc GANGLIA (_) ”c/ (-I 6.23536: * ----------- 553%? ( - 4 ENHANCEMENT 3' BLOCK ‘I HONOLOGUE OF SVMPATHETIC mcounzn OF ** GANGLION FIGURE an. , _______ (-) INHIBITION CNOLINERGIC EXPERIMENTS 2‘ DEPRESSION EFFECTS IN PROGRESS 1 combinations to form patterns, I believe it of value to study such units, that is, the synapses. The transparent model of the brain of the cat (FIGURE 2) illustrates a relatively simple synaptic* preparation that we have found convenient for study. I must emphasize, at the outset, that we consider the experiment pertinent to the extent that it deals with visual pathways, since the powerful psychotomi— metic drugs exhibit an important Visual component in the hallucinations, dramatically so with mescaline. More important than that, our findings im— press us with the similarities rather than the differences between synaptic per— formance and susceptibility to chemicals, either endogenous or exogenous (drugs). Therefore, we are really using the transcallosally activated cerebral synapses in the visual area of the cat merely as representative of cerebral synapses in general, all of these synapses having qualitative similarities and varying principally by differences of threshold. We do not intend to suggest that an alteration in this specific pathway is necessarily responsible for mental disturbanceT A little later I shall outline a general working hypothesis based ‘ “Synapse” is used throughout in the sense of designating the total complex involved the functional arat ticulation of 2 neurons, that is, presynaptic nerve ends, transmission process, postsynaptic dendrites, and soma. ’r Chronic interruption in a system such as the transcallosal. as mentioned by Edward Evarts, should not necessarily be expected to produce the same changes as an acute interruption by drugs unaccompanied by surgical trauma and subsequent degenerative processes. �498 Annals New York Academy of Sciences 93 .5“ .Qafida 05 mm 399% @003 .3235 029533 33. Saginaw Qumozaumqnbv 18:38.35 gobs—Tm wagon? £35 2: we 1:58 “223359 .12.— . .N 35c 5:... ~ A 688.: . �Marrazzi: Effects of Certain Drugs on Cerebral Synapses 499 patterns that results from alteration in amounts of synaptic regulators or in the thresholds of the neurons upon which they act. Since Edward Evarts has already outlined our technique I can be very brief in pointing out certain features. Because the brain is a communication system it seems most appropriate to measure function by recording the handling of a test message. The test message is supplied in the form of a submaximal elec— trical stimulus applied to 1 optic cortex in a cat that has received a. light dosage of pentobarbital sodium. This stimulus initiates a conducted response in the association or transcallosal tract that connects the stimulated point to a sym— metrical point in the contralateral cortex where, after synaptic. transmission, the stimulation evokes a cortical potential, as first described by Curtis and Bard.3 To help distinguish between peripheral effects that would contribute to the afferent drive constituting the background against which the impulses are elicited and the strictly central effects, we take advantage of the fact. that an intracarotid injection will achieve a transient, higher concentration of drug on the ipsilateral or recording side but, when diluted by the blood in the general circulation, the concentration of the drug is brought down to levels that are below the threshold for the peripheral effects. Under the conditions of our experiment, the amounts of the drug passing through the circle of Willis to the other cortex are unimportant. In this way it becomes possible to demonstrate (FIGURE 3) that epinephrine, a chemical natural to the body, one known to produce anxiety when accumu— lated in sufficient amounts, either endogenously or exogenously, also produces cerebral synaptic inhibition, as indicated by the reduction in the signal (surface on a disruption of normal negative wave) corresponding to outflow, while the inflow (surface positive wave) is essentially unaltered. The same type of synaptic inhibition is shown for another cerebral neurohumor, norepinephrine, in the next line of the same IOO LIV. IOO ”\4 The cerebral synaptic action of epinephrine and norepinephrine in a 2-neuron intercortical (transcallosal) system. Potentials are evoked in the optic cortex by the electrical stimulation of a symmetrical point m the contralateral cortex. Epinephrine (10 lag/kg.) was injected into the i silateral carotid artery after A. and norepmephrine (150 lug/kg.) was injected after D. A and D are centre 5, B and E represent inhibition, and C and F show recovery. FIGURE 3. �500 Annals New York Academy of Sciences 0-9-? H I HO H0 H I OH H I H -N\ CH3 EPINEPHRINE (dihydroxy-phenyl—ethonol methyl amine) h‘h‘,“ ”'9?" HCH3H AMPHETAMINE (phmyl-isopropyl amine) _*.+ H __'.+ H CHSO MESCALINE (trimethoxy-phenyl-ethyl om'ne) FIGURE 4. Types of phenyLethyl amines producing mental effects. figure, but this action is evidently weaker than the other, requiring a larger dose to produce approximately the same degree of inhibition. In FIGURES 4 and 5 are shown some structural chemical similarities of compounds with which other contributors to this volume have already dealt. Attention is called to the close structural similarity (FIGURE 4) of epinephrine to amphetamine, which is also capable of producing anxiety, and mescaline, which does so regularly and with dramatic intensity, producing a full-blown “model psychosis.” These drugs in turn are related to the group shown in FIGURE 5, in which epinephrine15 once more presented alongside a first— oxida— tion product, adrenochrome, which is an indole. Below these are pictured d- lysergic acid diethylamide (LSD- 25), the very highly potent psychotogen which can be considered to be built on an indole nucleus, and 5- hydroxy— tryptamine, or serotonin The epinephrinelike psychotogens thus can be chemically related to the indolelike ones, including established drugs such as LSD— 25, reputed drugs such as adrenochrome, described at the beginning of this monograph by Humphry Osmond, and by myself elsewhere,2 and the b which is 4“ in the postulated by Woolbrain, naturally occurring indole found ley and Shaw5 to be sufficiently related to LSD- 25 possibly either to compete with or to add to its action. We now looked to see whether there was any functional parallelism or neurophysiological correlate of this relationship by using the objective test of cerebral performance afforded by the evoked- potential ac— IS FIGUR126 the that data there an showing the c.at presents in technique tual correspondence111 structure, and that all the compounds produce synaptic �Marrazzi: Effects of ("ertain Drugs on Cerebral Synapses - EH-c-("6"3 no no on 0 ——> 0 501 N has EPINEPHRINE H CON ADRENOCHROME /\ Cat's C2H5 N-CH3 -c-c-NH2 HO N N SEROTONIN D-LYSERGIC ACID DIETHYLAMIDE (LSD-25) FIGURE. 5. inhibition identical in kind to that produced by epinephrine, but vary in degree of effectiveness, so that for the approximately equivalent effects shown it re— quired milligram amounts of mescaline, but only microgram quantities of LSD-25, which duplicates the relative potency of these compounds as found in clinical experience. The dosages used throughout our experiments are inten— tionally of a size selected to produce incomplete actions, so that recovery back‘ to the control level can be secured more readily. Very interesting is the finding with serotonin, which turns out to be the most effective cerebral synaptic inhibitor of all, being effective in as little as l—ug. doses. Accordingly, rather than being an antagonist, this indole, or something like it, may represent the type of endogenous substance that is instrumental in bringing about some forms of spontaneously occurring mental disturbance. b and is brain48h is in the serotonin since so naturally present Furthermore, highly potent (about 20 to 25 times as potent as epinephrine in the same experiment), serotonin becomes, as we pointed out over a year ago,2 an even better candidate than either epinephrine or norepinephrine, which are also found 6 1" for the role of inhibitory neurohumor.* This finding would in the brainfi‘“ must penetrate the blood-brain barrier at least in the small amounts required to exercise the cerebral action described. ’ Serotonin �Annals New York Academy of Sciences 502 IOO MESCALlNE IOO UV. IOO ’D 100‘: UV. / 4" A A A A '°°” A A SEROTONIN CONTROL MAXIMUM EFFECT RECOVERY FIGURE 6. point even more closely to a derangement of neurohumoral balance at synapses as a potential mechanism of cerebral or mental derangement. Unfortunately, except for the intraventricular injections described by Sherwood,7 there have been, thus far, no documented reports of serotonin—induced mental disturbance* in man that are clearly separable from the natural anxiety initiated by the profound peripheral effects such as circulatory disturbance, other autonomic effects, and emesis. There are, however, such reports for a close analogue of serotonin, dimethyl-serotonin, or bufotenin, which is used for its mental efiects by some primitive peoples and has been observed by Fabing8 to produce such disturbances in man experimentally. These 2 subof metabolite epinephrine that well presumed adrenochrome, a as as stances, ‘ The fact that patients with carcinoid have large amounts of circulating serotonin without showing marked has develsym toms of mental derangement could represent an adaptation to very high levels of serotoninofthat such patients ope and accumulated gradually. This suggestion would account for the relative immunity to the possible central effects of high doses of serotonin injected intravenously. �Marrazzi: Effects of Certain Drugs on Cerebral Synapses 503 CONTROL MAXIMUM EFFECT SEROTONIN IO pg RECOVERY nomcwcnmn, N H0 /hCH- /kg. CH 3 CHEN'CH’ ./\N H BUFOTENIN 0= 0: 5 pg /kg MON / N H ADRENOCHROME 2000 pg/kg. FIGURE 7. (‘erebral synaptic inhibition by indoles in a _2-neuron intercortical (transcallosal) system. The potentials evoked in‘the cerebral cortex of the cat by electrical stimulation of the contralateral cortex every 2 seconds. The injections were given in the 1psxlateral common carotid artery. Hoffer, Osmond, and Smythies9 report as reproducing some aspects of the clini— cal syndrome of schizophrenia when injected intravenously in man, are com— pared in the cat in FIGURE 7. Again, all these compounds have the identical qualitative effect, namely, synaptic inhibition, but bufotenin, tested in the same animal, exhibits twice as much effectiveness as does serotonin, which required 10 pg. for its effect on this occasion. Adrenochrome, though it does induce synaptic inhibition, requires so large a dose, 2 mg, that it seems an unlikely candidate for the role of endogenous psychotogen responsible for a form of mental illness, although a substance somewhat like it might be responsible. The great effectiveness of serotonin not only suggests that this is the type of chemical structure implicated, with the reservations already noted, but that it constitutes 1 link, another being its natural occurrence in the brain, in the chain of evidence identifying it as a cerebral neurohumor. A required piece of information to round out this evidence would be the measurement of the actual liberation of serotonin during, or prior to, the recorded synaptic activity. This is a tedious and difficult type of experiment, and it is attended by special handicaps in work on the brain. Another approach leading to a similar conclusion, however, is quite readily followed. This approach is the accumulation of what must be naturally occurring serotonin, strategically located at the synapses, by the poisoning of the enzymes that normally lead to the destruction of serotonin and account for the ready reversibility and short duration of the action of serotonin. This is the technique that has been used so successfully in the study of the function of acetylcholine in the brain, and it is in this manner, by the use of a powerful anticholinesterase, that we demonstrated the presence and operation of acetylcholine at cerebral synapses.1 Serotonin is known to be very susceptible to destruction by monoamine oxidase, which is abundantly �504 Annals New York Academy of Sciences CONTROL EFFECT RECOVERY FIQURE 8. The cerebralsynaptic action of iproniazidin a 2-ncuron intercortical ttranscallosal) system. potentials evoked in the optic cortex of the cat by electrical stimulation of the contralatcral cortex every onds. The iproniazid (S mg./lu;.) was injected into the ipsilateral carotid artery. MAXIMUM The 2 sec- present in the brain.10 We therefore attempted to inhibit. this enzyme by iproniazid (Marsilid). FIGURE 8 shows the result of a preliminary experiment in which we injected iproniazid into the common carotid artery of the cat. in the same way that we had done previously with serotonin. The effect produced duplicated the serotonin effect as if, indeed, the serotonin at the synapse had been preserved by the inhibition of monoamine oxidase by the iproniazid. I believe this finding offers another piece of important evidence that serotonin is present naturally, not only in the brain, but at strategic sites where it is capable of influencing synaptic transmission. We have not as yet measured, as we need to do, how much this dose of iproniazid, given in this way, inhibits cerebral monoamine oxidase in the cat. We believe that the somewhat discouraging attitude of some investigators toward basing clinical prediction on animal experimentation is not, entirely justified, since this procedure is a natural result of the comparison of objective criteria such as we have just described with clinical evaluation based upon questionnaires and much undoubtedly shrewd clinical observation, both of these types of data being very difficult, indeed impossible, to quantitate. Ac— cordingly, we are more impressed by the degree of correspondence obtainable rather than by the discrepancies that are to be found. Thus our evoked-potential experiments in the cat rank the psychotogens and psychotomimetic substances studied so far, in general, in the order of clinical effectiveness, and they suggest that at least part of the mechanism responsible for mental disturbance is to be found in an imbalance in the regulation of synaptic transmission. One such imbalance we have already described. If this hypothesis is truly useful, and if the animal preparation used bears other than a merely empirical relation to the clinical data, we should expect that. the various tranquilizers for which varying degrees of clinical success have been claimed would have some action here also. “'e proceeded to test this extension of our thinking, and we found that all of the several types of tranquilizers are capable, when administered prophylactically to cats, of partially preventing, in the doses used, the cerebral synaptic inhibition of a test dose of mescaline. this reaction, using chlorpromazine ('l‘horazine). 'l‘he figures now read from top to bottom instead of from left to right, as in the previous FIGURE 9 shows �Marrazzi: Effects of Certain Drugs on Cerebral Synapses 505 MESCALNE 2.5mg/kg MESCALINE AFTER CHLORPROMAZINE CHLORPROMAZNE 0.05mg./kq. CONTROL MAflMUM EFFECT RECOVERY 60’\. 200 UV. The_prevention of the mescaline effect by chlorpromazine in a 2-neuron_intercortical (transcallosal) system. The potentials evoked in the cerebral cortex ofthe cat by electrlcal stimulation of the contralateral cortex every 2 seconds. The injections were made in the 1psrlateral common carotid artery. FIGURE 9. The first column shows the control, the mescaline inhibition at B, and the recovery at C. After this, chlorpromazine is given in doses which, per se, have no apparent effect on synaptic transmission, as shown by the new control D in the second column, but now when mescaline is given again, the synaptic inhibition E is much reduced when compared to B. Without the tranquilizers, the same degree of inhibition of mescaline can be repeated several times in succession, provided that complete recovery is allowed between in— jections. Records G and II show again that this dose of chlorpromazine did not impede synaptic transmission despite the ability of the drug to protect against mescaline. If the dose is increased twentyfold it does have a depressant figures. MESCALINE A 2.5 mg./kq. MESCALINE AFTER RESERPINE D CONTROL B MAXIMUM EFFECT C RECOVERY n E RESERPINE 0.lmg./kg. G m I The prevention of the mescaline effect by reserpine in a 2-neuron intercortical (transcallosal) system. The potentials evoked in.tlie cerebral cortex of the cat by electrical stimulation of the contralateral cortex every 2 seconds. The anCCtlonS were given in the ipsilateral common carotid artery. FIGURE 10. �506 Annals New York .‘Xcademy of Sciences MESCALINE CONTROL MAXIMUM 2.5m/llq. MESCALINE AFTER FRENOUEL FRENOUEL tqu/kq. m The prevention-of the mescaline effect by It‘renquel in a Z-rieuron intercortical (transcallosal) system. The potentials evoked In the cerebral cortex of the cat by the electrical stimulation of the contralateral cortex every 2 seconds. The unections were given in the ipsilateral common carotid artery. FIGURE 11. action on synaptic transmission. The same prophylactic action is obtained with reserpine (Serpasil), as shown in FIGURE 10, and with azacyclonol (\lt‘renquel), as shown in FIGURE 11. Another point of correspondence with clinical findings is that the margin of safety, in this case the range between the prophy— lactic and the synaptic-depressant, dose, is large, the depressant dose being 15 to 20 times the prophylactic. dose with both chlorpromazine and azacyclonol, but the factor is only 2 with reserpine. The latter drug approximates the action of the barbiturates, which can reduce the degree of demonstrable inhibition from mescaline by reducing synaptic transmission in the first place. I feel justified in saying, then, that the preparation described is pertinent to the clinical situation in that it ranks the psychotomimetic substances in the order of their clinical eli'ectiveness, and that the action of mescaline, the only drug that we have tried so far, is prevented by the tranquilizers. By use of the evoked—potential technique, we have demonstrated that: (1) There exists an equilibrium of neurohumoral control of transmission at cerebral synapses and throughout the nervous system, as far as I have surveyed it, that is susceptible to distortion and imbalance by disturbance in the amounts of chemical regulator or the susceptibility of neurons. (2*) The psychotogens and psychotomimetic substances discussed. structurally and functionally resemble the actions of the fairly well-established inhibitory synaptic neurohumors, epinephrine and norepinephrine, and of sero— tonin, the new one that we have described. (.3) Serotonin or its dimethyl derivative, bufotenin, comes close, even closer than does LSD-25, to representing the type of endogenous psychotogen that might be a natural cause of some forms of mental disturbance. We speculate that such disturbance can be produced by direct perversion of normal patterns of neuronal activity by the undue influence of synaptic inhibitors or, indirectly, by such inhibitors impeding the flow of impulses from higher controlling centers and releasing the more 1,)rimitive, simpler, and less well—adapted patterns of activity that we call abnormal. �Marrazzi: Effects of Certain Drugs on Cerebral Synapses 507 References 1. MARRAzzr, 118: 367. A. S. 1953. Some indications of cerebral humoral mechanisms. Science. E. R. HART. 1955. Relationship of hallucinogens to adrenergic cerebral neurohumors. Science. 121: 365. 3. CURTIS, H. J. & P. HARD. 1939. lntercortical connection of the corpus callosum. 126: 2. MARRAZZI, A. S. & 473. B. B. CRA\\'F()RD & J. H. GADDUM. 1954. The distribution of substance P and 5—hydroxytryptamine in the central nervous system of the dog. J. Physiol. 126: 596. 4}). PAGE, I. H. 1954. Serotonin (5—hydroxytryptamine). Physiol. Revs. 34: 563. 5. WOOLLEY, D. W. & E. SHAW. 1954. A biochemical and pharmacological suggestion about certain mental disorders. Science. 119: 587. 6. VOGT, M. 1954. The concentration of sympathin in different parts of the central nervous system under normal conditions and after the administration of drugs. J. Physiol. 123: 451. 7. SHERWOOD, S. L. 1955. The responses of psychotic patients to intraventricular injections. Proc. Roy. Soc. Med. 48: 855. FABING, H. D. 1955. Personal communication. 99° HOFFER, A., H. OSMOND & J. SMYTHIES. 1954. Schizophrenia: a new approach. II. Result of a year’s research. J. Mental Sci. 100: 29. 10. KOELLE, G. B. & A. DE T. VALK, JR. 1954. Physiological implications of the histochemical localization of monoamine oxidase. J. Physiol. 126: 434. 4a. AMIN, A. H. T., '1‘. �APR 23 ‘959 DEPARTMENT OF EXPERIMENTAL PSYBHMIRY HILLSIDE HOSPITAL GLEN OAKS, N. Y. �PSYCHOTOMIMETICS, CLINICAL AND THEORETICAL CONSIDERATIONS: HARMINE, WIN-2299 AND NALLINE 17%;»4” M :9 HARRY H. PENNES, M. D., PHILADELPHIA, PA., AND PAUL H. HOCH, M. D., NEW Reprinted from AMERICAN JOURNAL OF PSYCHIATRY Vol. 113, No. 10, April, 1957 YORK CITY �PSYCHOTOMIMETICS, CLINICAL AND THEORETICAL 1 WIN-2299 AND CONSIDERATIONS: HARMINE, NALLINE HARRY H. PENNES, M.D.,2 PHILADELPHIA, PA., AND This report describes the clinical effects of 3 psychotomimetics in mental patients. The results will be related to nosological and certain biological aspects of the “model psychoses” in general. The agents are (I) harmine, an alkaloid present in plant prepara— tions ingested by some South American tribes(1) ; (2) Win-2299, a synthetic cholinolytic(2) and (3) N-allylnormorphine (Nalline), a synthetic morphine antagonist (3, 4, 5). MATERIAL AND METHODS Single dosages of the drugs were given to 32 voluntary, physically normal mental patients, at the New York State Psychiatric Institute; 29 were in the 18-35 year age range; 19 were males and I 3 females. Twenty-two were schizophrenics of the pseudoneurotic and other nondeteriorated types, with only the primary symptoms of the disorder. Five additional schizophrenics had auditory hallucinations or delusions be— fore the drugs. The remaining 5 subjects had severe psychoneuroses or recurrent depressions. No patient had clouding of consciousness. Each drug was given about 9: 00 and breakfast after a 48-hour light a am, medication-free period. Examination by the authors and nurses were made for the remainder of the day in a shaded private room and also in the succeeding 72 hours. No patients were informed of the probable effects of the procedures. Most subjects showed excellent cooperation in reporting drug effects. In most cases, each patient received one drug of the 3 tested, but some received different doses of harmine on differRead at the 112th annual meeting of The American Psychiatric Association, Chicago, Ill., April 30May 4, 1956. 2 Director of Clinical Research, Eastern Pennsylvania Psychiatric Institute, Philadelphia, Pa. 3 Commissioner of Mental Hygiene, New York State. The actual study was performed at the New York Psychiatric Institute, New York, Department of Experimental Psychiatry. 1 PAUL H. HOCH, M. D.,3 NEW YORK CITY ent days. Each drug was given in salt form but for brevity will be referred to as the base. RESULTS GENERAL Since the new manifestations under the drugs were not present in the pre-administration period, they were clearly distinguishable from the patients’ baseline symptoms. At low dosage, each drug produced slight drowsiness, either with or without other symptoms. With medium or high dosage, the reactions qualitatively resembled those in a former series of similar subjects who received mescaline or LSD(6, 7, 8). Thus, diffuse alterations usually occurred in many realms—autonomic, motor, perceptual, emotional, intellectual, and be— havioral. Unlike mescaline or LSD (cf. Discussion for dosages), the present drugs regularly elicited some degree of clouding of consciousness in addition to the preceding changes. The characteristic reaction at medium or high dosage was a semidelirioid or confusional state with intermittent drowsiness or sleep. The confusional periods were cyclic. Their intensity and time of occurrence correlated only partly with drowsiness or sleep. Major symptoms were impairment of contact, attention, grasp, responsiveness, and concentration, with general “dreamy” or twilight quality. Full delirioid reactions occurred in 2 subjects at the highest dosages of 2 drugs (Win-2299, Nalline). Most subjects had intermittent amnesia during the reaction itself but were able to provide adequate descriptions of the major events. A spotty defect in recall was usually present in the 72-hour follow-up period. Visual hallucinations (cf. Discussion for alternative terminology) occurred at medium or high dosage with all 3 drugs. Subjects were easily roused after the onset of drowsiness or sleep and reported some of the hallucinations that had occurred in the “dream887 �888 CONSIDERATIONS OF PSYCHOTOMIMETICS ing” state. In all cases, the hallucinations occurred only with eyes closed and disappeared promptly when the eyes were opened. Hallucinations other than visual were infre— quent. Perceptual distortions of body and environment were moderately frequent. Neurological changes included varying degrees of subjective vertigo, light—headedness, subjective and objective ataxia, and sluggish speech. Like mescaline and LSD, these drugs produce a variable degree of intensification of different types of baseline symptoms. Harmine also occasionally produced a shallow euphoria. Nalline often produced relaxation of rather marked degree. After a few initial hours of peak intensity, reac— tions usually subsided gradually between the fourth to eighth hours, often with fluctuations in degree before complete remission. No subject reported effects after 24 hours except for minor, nonspecific “hangover” feelings. INDIVIDUAL DRUGS Harmine.——Turner, Merlis, and Carl have recently pointed out that the alleged hallucinogenic activity of pure harmine is a complicated issue on the basis of the previous literature on crude plant extracts(9). The threshold hallucinogenic dose of the pure drug in the present study ranged from I 50.0— 200.0 mgm. intravenously. With this route, 5 of 11 subjects reported visual hallucinations of varying degrees of complexity and organization. Bradycardia and hypotension occurred with all doses of intravenous harmine despite a 20- to 30-minute injection time, thereby limiting maximum dosage to 300.0 mgm. Average maximum changes were a pulse rate of 18 beats per minute and systolic blood pressure fall of 16 mm. mertermi— in was one subject Injection cury. nated at 210.0 mgm. because pulse rate dropped from 82 to 48 per minute and blood pressure from 118/78 to 88/60. Recovery occurred in about 30 minutes. The drug was not hallucinogenic by the oral or subcuta— neous routes. However, ingestion of crude plant extracts by natives does produce visual hallucinations according to field observations(10, 11, 12). In an experimental study by Cardenas(13), normal subjects also reported visual hallucinations and other effects [Apr. noted here, after ingestion of an aqueous solution of yahé (Banisteria caapi, a source of harmine). Visual hallucinations might have occurred in the present study with higher oral (loses, the maximum oral amount (960.0 mgm.) being 4.8-6.4 times greater than the intravenous threshold hallucinogenic amount (150.0-200.o mgm.). The amounts of harmine taken orally under field conditions and in Cardenas’ study are unknown, precluding comparison with the present study. Further analysis of the hallucinogenic activity of harmine is complicated by nu— merous botanical and chemical considerations(1, 10, 11, 14). Additional reactions to harmine which occurred frequently were: nausea and vomit— ing; slow, coarse, spontaneous tremor of the extremities of an “extrapyramidal” appear— ance; humming and buzzing noises (no voices); “waviness” of the environment; “sinking” sensations of the body; subjective sense of body vibration; and subject numb— ness, accompanied by objective evidence of reduced sensitivity to light touch and pinprick. These reactions, plus all the preceding, occurred in almost every patient with the intravenous route; and (except for hallucinations) some occurred with oral dosages higher than the threshold of 3000-4000 mgm. The reactions were generally more intense by the former route. Win-2299.—The mental effects of Win2299 in man have apparently not been described previously. The 2 subjects receiving 2.0 mgm. had the sedative effect. One of these subjects in addition became “hypersensitive” to light and sound, and spots on the wall moved and changed form. At the 6.0 mgm. level, all 4 subjects had severe mescaline- or LSD-like reactions plus a confusional state of moderate degree. These mescaline-like effects included bizarre perceptual distortions of soma and environment, unreality feelings, and synesthesias in one case. The single subject at 10.0 mgm. had a full delirioid episode with complete loss of contact, disorientation for time, place, and person, and responses to complex, organized visual and auditory hallucinations. This reaction occurred in brief but cyclic episodes; partial contact and lucidity were restored after persistent comments and questions. �I957] HARRY H. PENNES AND PAUL H. HOCH Most subjects had a moderate degree of mydriasis; blood pressure and pulse rate changes were insignificant. Nall-ine.—The results with Nalline in the main confirmed previous observations of others in different types of subjects, includ— ing normals( 3, 4, 5). Past and present findings included varying degrees of relaxation or euphoria, anxiety and dysphoria, miosis, nausea, drowsiness and sleep, thought disturbances, feelings of heaviness or lightness of limbs, and visual hallucinations. In the present series, visual hallucinations occurred in the single subject receiving 10.0 mgm., in 7 of 8 at 20.0 mgm., and in 2 of 3 at 30.0 mgm. In 4 cases (and in 2 with harmine) the hallucinations were Lilliputian in type, a not infrequent feature of acute toxic psychoses in general. So far as can be judged from the literature, a possible major difference from previous observations consisted in the occurrence of frank mescaline-like or delirioid reactions. At 20.0 mgm, 3 subjects had typical diffuse, bizarre per— ceptual disturbances, severe unreality feelings, and other signs of psychic disorganization. At 30.0 mgm., a similar reaction occurred including auditory hallucinations and synesthesias. In another subject at this dose the effect was overtly delirioid, with a strong resemblance to the Win—2299 toxic psychosis previously described. The intravenous route probably accounts in part for the appearance of these reactions, since previous reporters of the mental effects of Nalline have used the subcutaneous route, usually at dosages of 10.0-15.0 mgm. and sometimes higher( 3, 4, 5). DISCUSSION Relatively high doses of harmine by the intravenous route were required to produce the full psychotomimetic effect with visual hallucinations. The same was probably true of Nalline. It is conventionally stated that acute toxic psychoses occur in apparently normal individuals after high dosages of various other drugs, for example, atropine and cocaine(I5). There is a dearth of precise data on the number of such drugs, dosages required, and regularity of effects. However, not all drugs in relatively high dosage produce the diffusely abnormal men- 889 tal changes which are the criteria of psychotomimetic action. For example, clinical differentiation may be made between a confusional-hallucinatory state and a simple, progressive depression of level of consciousness elicited by narcotics and other agents. High dosage alone would therefore not preclude the classification of the present or other drugs as psychotomimetic in a selective or specific sense. Transient cerebral anoxia could have resulted from the hypo— tension and bradycardia with intravenous harmine or a respiratory depressant action of Nalline, which has been reported at dosages used in this study(3, 5). The florid and diffuse reactions elicited by these 2 drugs would certainly not appear to be characteristic of those in cerebral anoxia. In addition, the circulatory effects of harmine usually disappeared about 20 minutes after termination of injection, whereas the mental re— actions lasted at least several hours at peak intensity. Harmine, Win—2299, and Nalline fundamentally produced an acute organic reaction type, because of the basic mental clouding and confusional effects. Harmine and Nal— line each produced mental clouding together with systemic toxicity (cf. above) ; on the other hand LSD and mescaline elicit neither clouding or toxicity in major form within a certain dosage range. However, Win-2299 did not display this association of the 2 effects, since severe mental clouding occurred without obvious systemic toxicity. It is possible that confusional aspects may be more prominent for a given agent whose threshold psychotomimetic dosage is high relative to threshold dosage for any effect. Quantitative data relevant to this proposition are lacking for any psychotomimetic but are obtainable in principle. It is very probable, however, that absolute dosage thresholds for psychotomimetic activity correlate poorly with mental clouding. In ascending order, these dosages are very approximately: LSD (oral or intravenous) under 100 micrograms; Win—2299 (oral) and Nalline (subcutaneous or intravenous) 55.0-20.0 mgm.; harmine (intravenous) and mescaline (oral or intravenous) over 100.0 mgm. LSD and mescaline are at opposite extremes of an enormous absolute dosage range, and produce �89o CONSIDERATIONS OF PSYCHOTOMIMETICS practcially no clouding whereas the 3 intermediate agents elicit frank clouding at near threshold. There is evidence, however, that LSD and mescaline may produce clouding of consciousness at dosages well above threshold. Pennes has previously reported a sedative effect of LSD in 26.0% of a series of schizophrenics(8). The drug less occasionally (about 10.0% of cases) produced a confusional state(7). MacDonald and Galvin more recently reported a 58.0% incidence of mental clouding and confusion after LSD in 50 subjects. The psychotic subjects in their series apparently received the drug in dosages (per kilogram of body weight) up to 6.0 micrograms as compared with 1.0-2.0 micrograms orally in Pennes’ series(16). Mescaline sulfate (4oo.o—6oo.o mgm., intravenously) often produces slight drowsiness throughout the entire reaction and occasional confusional states(7). There may be an underlying similarity for all the drugs under discussion in the relationship of the visual hallucinogenic response to visual restriction and hypnagogic mechanisms. First, it will be recalled that visual hallucinations with the present drugs always disappeared when the eyes were opened. Wikler noted the same in post-addicts under mescaline(4). The authors have not noted this effect in frank form with either mescaline or LSD but have occasionally observed that hallucinations are reported as less distinct and vivid when the eyes are opened. Darkening of the room does initiate or intensify visual hallucinations with eyes open under mescaline or LSD. If eye closure and reduction of intensity of external light affect drug-induced hallucinations by the same mechanism, then the difference with respect to this mechanism may therefore be negligible between the present drugs and LSD. Such a mechanism may be related to that presumably operative in hallucinations and other mental disturbances recently reported as occurring with generalized restriction of sensory input(17). Secondly, the abnormal visual phenomena with the present drugs are probably best categorized as hypnagogic hallucinations or even more broadly as hypnagogic imagery or visions. This term is used because of the [Apr. invariable drowsiness (cf. Results, General) ; disappearance on eye opening is also consistent with the hypnagogic quality of the response. According to Ardis and McKellar, spontaneous visual hypnagogic images in normals are usually experienced in the drowsy state and with eyes closed. These authors also found strong resemblances in detail between mescaline visual hallucinations and normal visual hypnagogic imagery (18). Previous workers with Nalline have variously used the terms visual hallucinations, day-dreaming, vivid visual fantasies in a dreamy state, or nightmares. The apparent differences between the present drugs and mescaline or LSD may therefore be quantitative rather than qualitative. The conclusion would be that mescaline and LSD may also basically produce an organic reaction type. It is a familiar ob— servation that the visual hallucinations which are so characteristic of the drugs under consideration are relatively infrequent in chronic schizophrenia. These considerations obviously do not preclude various possible relationships between psychotomimetics and a possible endogeneous “toxic factor” or metabolic disturbance in the “functional” psychoses. Hoch and Wikler have recently and independently summarized the other implications of the drugs and the “model” psychoses for experimental psychiatry(19, 20). The indole nucleus, alleged to be specific for psychotomimetic activity(2I), is absent in mescaline, Win-2299, and Nalline. How— ever, with the exception of mescaline, the remaining 4 psychotomimetics contain a tertiary nitrogen grouping (2 in LSD). Since these compounds are otherwise grossly dissimilar in molecular configuration (fig. I), the entire structure undoubtedly has to be taken into account. Despite this well-known factor and the very small series of drugs, there are certain indications that the tertiary nitrogen grouping may contribute to psychotomimetic activity. In brief, some of the evidence relates to effects of apparently minor changes in the LSD molecule, effects of quaternization of VVin-2299 on its CNS potency(2), and comparison of the actions of serotonin with those of its tertiary amine derivative, bufotenine(22). However, in ad— dition to mescaline, the literature reports �HARRY H. PENNES AND PAUL H. HOCH I957] 891 other psychotomimetics without the tertiary nitrogen groupings: marijhuana, which is n0n-nitr0geneous(9) and 3,4,5-trimethoxy— amphetamine, a mescaline derivative(23). 9 W: "5 Some types of centrally acting drugs other OCH3 \ c2 “5 than psychotomimetics also possess the terFuther of OCH: analysis grouping. tiary nitrogen IE SCALINE on, these relationships will be presented elsewhere(24). There is no apparent common neurophar— macological basis for the psychotomimetic action in general and for harmine, Win—2299, and Nalline in particular(2, 5, 25). Win2299 is qualitatively similar to atropine in animals by virtue of its peripheral cholinolytic and central actions(2). The mechanism of production of abnormal mental effects ‘HCL HO- 0" C- 0' CH2. CH2- / similar be both for N\ drugs, Win—2299 apmay \°2"5 parently having a lower threshold dosage. 2299 (2 2 to recent speculations, some psy— According —-— chotomimetics may produce their effects as antagonists of cerebral serotonin(26, 27'). N-CH20H=CM2 The mental effects of oral LSD and intravenous harmine (both indoles and peripheral antiserotonins) differ in many respects (Results, General and Harmine) . The difference in route of administration is not a factor in 0n View of the finding of Hoch that oral and 0 "CL ' intravenous LSD have the same qualitative effects(28). However, differences in relative Structures of Some Psychotomimetics. levels contribute the to dosage apparent may FIG. I.—Harmine was supplied in 2 forms: as the base isolated from Banisteria caapi(I) and as the dissimilarities between the 2 drugs. c—N CH35 \ \ HARMINE NH LYSERGIC ACID DIETHVLAMDE C2 H5 6- D5 WIN- DIETHYLAMINOETHYL GLYCOLATE CH N CYCLOPENTYL THI‘ENVL) HYDROCHLORIDE G“ CH2 H ALLYLNOHMCRPHINE synthetically-prepared HCl-zHaO. The following dosages refer to hydrochloride form in each case. Harmine: oral, II patients, zoo-960.0 mgm.; subcutaneous, 6 subjects, 40.0-70.0 mgm.; and intravenous, II patients, 100.0-3oo.0 mgm. Win-2299 tablets: 7 patients, 2.0-I0.0 mgm. Nalline: intravenous, 12 subjects, 10.0-30.0 mgm. Intravenous harmine and Nalline were injected over a 20-30 minute period. Mescaline and lysergic acid diethylamide (LSD) were not given in this study. LSD and harmine contain the indole nucleus whereas the remainder do not. The tertiary nitrogen grouping is present in LSD (both in aliphatic chain and cyclic constituent), harmine (non-indole member), Win-2299 (aliphatic side chain), and Nalline (linking allyl side chain with ring member). Cf. Discussion. Both forms of harmine were supplied as the dry compound by Dr. K. K. Chen, Eli Lilly Laboratories, Indianapolis, Indiana. For parenteral administration, solutions in pyrogen-free distilled water, 20 cms.,3 were used several hours after autoclaving. Win-2299 was supplied by Sterling-Winthrop Research Institute, Rensselaer, N. Y., as the racemic mixture of the hydrochloride salt. Nalline was supplied by Merck and Co., Rahway, New Jersey, N- SUMMARY Harmine, Win-2299, and Nalline in single dosage produce many new mental effects in schizophrenics grossly similar to those elicited by mescaline and LSD. Many of the same effects are reported in normals after harmine and Nalline (other workers). Unlike mescaline and LSD at usual dosage levels, the present psychotomimetics regularly produce drowsiness and sleep along with the aberrant mental effects. The resultant state is partly that of “hypnagogic” visual hallucinations or imagery. The results with increased dosage suggest that the basic Allylnormorphine HC1= Nalline HCI; ampoules of distilled, pyrogen-free water containing sodium bisulfate, 0.2% and sodium citrate, dihydrate 1.5%. For intravenous administration, ampoule contents were diluted up to 20.0 cms.3 with pyrogen-free distilled water. �892 CONSIDERATIONS OF PSYCHOTOMIMETICS effect of these agents is to produce an acute toxic reaction type. The difference between them and mescaline or LSD with respect to clouding of consciousness and certain aspects of the hallucinogenic response may be quantitative rather than qualitative. The indole nucleus is not necessary in the structure of psychotomimetics since Win-2299 and Nalline are non-indoles. The tertiary nitrogen grouping may contribute to certain aspects of psychotomimetic action. BIBLIOGRAPHY 1. Chen, A. L., and Chen, K. K. Quart. J. Pharm. Pharmacol., 12:30, 1939. 2. Luduena, F. P., and Lands, A. M. J. Pharm. Exper. Therap., 110:282, 1954. 3. Wikler, A., Fraser, H. F., and Isbell, H. J. Pharm. Exper. Therap., 109: 8, 1953. 4. Wikler, A. J. Nerv. Ment. Dis., 120: 157-175, I954. Lasagna, L., and Beecher, H. K. The Analgesic Effectiveness of Nalorphine and NalorphineMorphine Combinations in Man. J. Pharm. Exper. Therap., 112: 3 56-363, 1954. 6. Hoch, P. H., Cattell, J. P., and Pennes, H. H. Am. J. Psychiat., 108: 579, 1952. 7. Hoch, P. H., Pennes, H., and Cattell, J. P. Proc. Assn. Res. Nerv. Ment. Dis., 32: 287, 1952. 8. Pennes, H. H. J. Nerv. Ment. Dis., 119:95, 5. 1954- 9. Turner, W. J., Merlis, S., and Carl A. Am. J. Psychiat., 112:466, 1955. Perrot, Em, Raymond-Hammett. Bull. Sci. Pharmacol., 34: 337; 417; 500, 1927. 10. 11. 1941. 12. 195513. [Apr. Iberico, C. C. Bol. mus. Hist. Nat., 5:313, Schultes, R. E. Natural History, 64: 120, Cardenas, G. F. Estudio Sobre el Principio Activo del Yagé. Thesis, Universidad Nacional, Facultuaa de Medicina y Ciencias Naturales, Bogota, 1923. 14. Albarracin, L. Contribucion al estudio de los Alcaloides de Yagé. Thesis, Bogota, 1925. 15. Goodman, L., and Gilman, A. Pharmacological Basis of Therapeutics. 2d Ed. New York: MacMillan, 1955. 16. MacDonald, J. M., and Galvin, J. A. V. Am. J. Psychiat., 112:970, 1956. 17. Bexton, W. H., Heron, W., and Scott, T. H. Canad. J. Psychol., 8:70, 1954. 18. Ardis, J. A., and McKellar, P. J. Ment. Sci., 102:22, 1956. 19. Hoch, P. H. Am. J. Psychiat., 111:787, I95520. Wikler, A. Am. J. Psychiat., 112 : 961, 1956. 21. Hoffer, A., Osmond, H., and Smythies, J. J. Ment. Sci., 100: 29, 1954. 22. Fabing, H. D., and Hawkins, J. R. Science, 123: 886, 1956. 23. Peretz, D. I., Smythies, J. R., and Gibson, W. J. Ment. Sci., 101 : 317, 1955. 24. Pennes, H. H. In preparation. 25. Gunn, J. A. Arch. Internat. de Pharmacodynam.. 50 : 379, 1935. 26. Gaddum, J. H. Drugs Antagonistic to 5- Hydroxytryptamine. Ciba Foundation Symposium: Hypertension. pp. 75-77, London, 1953. 27. Wooley, D. W., and Shaw, E. Proc. Natl. Acad. Sci., U. 5., 40: 228, 1954. 28. Hoch, P. H. Studies in Routes of Adminis— tration and Counteracting Drugs. Lysergic Acid Diethylamide and Mescaline in Experimental Psy— chiatry. New York: Grune & Stratton, 1956. ��Psychiatria et Neurologia Internationale Monatssehrltt tiir Psychiatrie und Neurologie Revue Internationale Mensuelle de Psychiatrie et de Neurologie International Monthly Review at Psychiatry and Neurology Editor: J. KLAESI, SchloB Knonau Redactor: E. GRUNTHAL, Bern S. KARGER Basel (Schweiz) New York Printed in Switzerland Vol. 135. No. 4/5, 1958 Separatum Sal-Hulda, 11.; Brunecker, G. 11nd Szdra, SL: Psychiat. Neurol., Basel 135: 285—301 (1958) Aus dem Staatl. Zentralen Neurologisch-Psychiatrischen Institut in Budapest (Frau Dr. M. Gimes) Dimethyltryptamin: ein neues Psychotieum Von A. SAI-HALASZ, G. BRUNECKER und ST. SZARA Einleitung Die ohere Stufe des Entwicklungsprozesses der Fachwissenschaften, die sogenannte experimentelle Stufe, beginnt die Psychiatrie fast als letzte der medizinjschen Féicher nur neuerdings zu erreichen. Den wirklichen Anfang bedeutet Beringers Monographie fiber Meskalin [1927], mit welcher zu gleicher Zeit die HaschischBeobachtungen von Frdnkel und Joel erschienen. Den zweiten groBen Fortschritt auf diesem Gebiet bildete die Entdeckung der Lysergséiurediéithylamid (LSD 25) durch Stall und Hofimann [1943]. Der erste ausfiihrh'che Bericht Stalls [1947] bedeutete den Anfang einer groBen Anzahl von Publikationen. Das Ziel dieses Artikels ist die Bekanntgabe eines neuen Psychotikums bzw. dessen Wirkung auf normale Personen. Die Bewohner Haitis benutzten schon seit J ahrhunderten bei religifisen Festen ein narkotisch wirkendes Schnupfpulver, das «Cohoba» genannt wurde. Mit Hilfe dieses Mittels konnten sie angeblich mit ihren «helfenden Geistern» in Verbindung treten, sogar auch von diesen Ratschlfigen erhalten. Das «Cohoba» wurde aus der Frucht der Piptadenia Peregrina gewonnen und enthjelt unter anderen Alkaloiden auch verhéiltnisméifiig groBe Mengen Bufotenin und N-N-Dimethyltryptamin (DMT), wie dies auch von Stromberg und Fish et al. bewiesen wurde. Bufotenin und DMT sind beide Indolamine und in naher Verwandtschaft mit dem biologisch hfichst aktiven Serotonin: �Sai-Halész, Brunecker und Széra 286 {\/\NH) /\——-—-—CH2—CH2—NH2 0H II |' OH A— 1 n —CH2—CH2—N/CH3 :1 \/\NH/ \cm. Bufotenin Serotonin /CH3 /\————CH2—CH2—N \CH3 b“ J \ \NH N-N-Dimethyltryptamin Bufotenin ist daher ein N-Dimethyl-Derivat des Serotonins, beim DMT fehlt jedoch vorigem gegenfiber eine 5-OH-Wurzel. Das Bufotenin isolierte Handovski aus der Haut von Kroten [1920], Wieland hat es synthetisch hergestellt. Raymond Hamet gab Hunden intravenos Bufotenin und stellte voriibergehende BlutdrucksteigeAfl'en intravenos fest. gréBere Evarts, Tachypnoe Apnoe, spiter rung, Dosen Bufotenin und LSD-25 verabreichend, stellte bei jenen eine beinahe identische Wirkung der zwei Chemikalien fest: voriibergehende Erblindung, Ataxie und ein Zahmwerden. Er erklfirte dies alles durch eine Hemmung der sensiblen Reiziibertragung. Evarts nahm die Wirkung des Bufotenins und LSD-25 als Analog des Serotonins an. Nach Fabing ist Bufotenin ein in der Natur weitverbreitet vorkommendes halluzinogenes Indolderivat, dessen eine Hauptquelle die sogenannten Amanita-Pilzarten bilden. Fabing experimentierte an jungen, intelligenten Verurteilten: er injizierte intravent‘is wéihrend 3 Minuten Bufotenin. Es traten Erroten, Gesichtsperspiration und Kribbelgefiihl im ganzen Korper sowie Oppression in der Brust auf. Die Versuchspersonen sahen einige Minuten lang purpurne Flecke, die Storung der Raumwahrnehmung und Konzentration, daneben Depersonalisationsgefiihl und psychomotorische Unruhe dauerten fort. Bei grofieren Dosen war Erbrechen, Nystagmus und Mydriasis zu beobachten, deshalb hielt Fabing das Mittelhirn zum Teil als Angrifl'spunkt des Bufotenins. Die kardiovaskulfire Wirkung des Mittels war verhiiltnisméiBig gering. Die Versuchspersonen berichteten wéihrend 6 Stunden nach der Injektion iiber angenehmes Relaxationsgefiihl. �Dimethyltryptamin: ein neues Psychoticum 287 Material und Methode Unseres Wissens nach wurde die Wirkung des DMT am Menschen zuerst durch uns gepriift. Das DMT wurde von uns selbst synthetisiert nach der von Speeter und Anthony angegebenen Methode. Die salzsfiurige Losung wurde als Injektion angewandt: die wirksame Dose war 0,7—1,0 mg/kg intramuskuléir, meistens gebrauchten Wir 0,8 mg/kg. DMT wurde an 30 normalen Personen, meistens Arzten, gepriift (I7 Manner, 13 Frauen; Alter zwischen 20 und 42 J ahren). Jede Versuchsperson wurde vorerst somatisch untersucht, und nur jene erhielten DMT, die vollkommen gesund waren und keine starkere vegetative Labilitéit zeigten. Auf den Blutdruck wurde sehr geachtet, da das DMT leicht starke Hypertonie erzeugen kann. I6 Versuchspersonen wurden vor und wéihrend des Versuches mit Rorschach untersucht. (Auf dessen Ergebnisse gehen wir hier nicht ein, da einer von uns1 auf dem III. Internationalen RorschachkongreB in Rom 1956 iiber diese berichtete.) Wfihrend dem Versuch wurden parallel zwei Protokolle aufgenommen und die Versuchs2—3 Tagen die subjektiven Erlebnisse nach aufgefordert, personen aufzuzeichnen; die Protokolle wurden dann durch diese Aufzeich5 Fallen wurde wiihrend des Experimentes EEG In ergéinzt. nungen durchgefiihrt. (Bisher noch nicht verofl'entlicht.) Ergebnisse Schon nach 3—5 Minuten nach der Injizierung ffingt das DMT zu wirken an, und innerhalb einer Stunde léiuft die ganze experimentelle Psychose ab. Die Wirkung ist plotzlich und intensiv, mehrere Versuchspersonen berichten anfangs V011 einem weltuntergangsé‘thnlichen Erlebnis mit Starker Todesangst. In einigen Fillen war jedoch die Angst nicht so ausgepréigt, und die éiuBerst intensiven Illusionen und Halluzinationen fesselten die Aufmerksamkeit. Die Angstperioden wechselten mit solchen Starker Euphoric ab. Wéihrend des ganzen Versuches war das wellenartige Auftreten bzw. die Intensitfitsschwankung der gesamten pathologischen Phéinomene sehr charakteristisch. Wahrnehmungsstfirungen bzw. solche des Korperschemas, Depersonalisationserscheinungen, extrapyramidale Hyperkynesien, objektive Reflex- und Sensibilitfitsstfirungen ffirbten oft das Bild. Natiirlich waren bei den Versuchen auch die kultu1 A. S.-H. �288 Sai-Halész, Brunecker und Széra rellen und Pers6nlichkeitsunterschiede bemerkbar. Bevor wir die einzelnen Symptome naher betrachten, geben wir hier einige typische Protokolle wfirtlich wieder: Dr. J.N., Arzt, 28 Jahre. 10. 5. 1956. 50 mg DMT i.m. P.: 78/Min., RR 130/100 Hgmm. 3! Starker Schwindel und Kribbeln im ganzen Kiirper; hauptsiichlich sind die Lippen geffihllos-eingeschlafen. 4/ «Alles ist glfinzender, die ganze Welt ist bedeutend heller.» 5/ «Als ob meine Stimme aus einer tieferen Kehle kfime. Das Zimmer ist gespensterhaft. Mir schwindelt. Ich amfisiere mich darfiber, wie Ihr mich belauert.» «Ach, wie herrlich sind die Far-hen!» Er lacht und spricht andauernd. (Zwangslachen, Logorrhoea.) Maximal erweiterte Pupillen. RR: 160/120 Hgmm, P: 88/Min. Rhythmische Bewegung des linken FuBes. «Ach, neue Welle! Die Bilder kommen in solchen Mengen, daB ich gar nicht weiB, was ich mit ihnen anfangen soll! Zuvor waren sie noch angenehm, doch jetzt ist es schon zu viel!» Er lacht wiederum auf. «Alles ist so komisch. Die Farben leuchten ganz fantastisch. Die Gesichter sind auch ganz anders. Warum beobachtet Ihr mich so verdachtig ? » 10' «Ich sehe eine Farbenorgie, doch in mehreren Schichten nacheinander. Die Welt bewegt sich immer mehr.» 11' Er schmunzelt, spricht inkohéirent, bewegt sich viel und gestikuliert lebhaft. RR: 165/120 Hgmm. P: 88/Min. Er klagt fiber Dyspnoe. 12' «Ich fiihle in meinem Bauch Leere und trotzdem Ffille, dorthin hat sich alles Schlechte verzogen.» «Hofl'entlich kommt es nicht wieder.» «Man sieht seltsame Sachen, und trotzdem ist alles schnell vorfiber, so wie auf der Wellenbahn.» «Die Wand bewegt sich auch, marchenfilmhaft. Ich ffihle mich ganz so, als ob ich geflogen ware.» RR: 155/120 Hgmm. P: 88/Min. Assoziationen aufgelockert, sucht nach Ausdriicken. Keine Dyspnoe. «Das Zimmer beginnt seine normale Form wieder zurfickzugewinnen! Nein, doch nicht . . . » Er setzt sich auf und sieht zum Fenster hinaus. «Nur wenn ich hinausschaue, ffihle ich, daB ich auf der Erde bin. Mir ist, als oh wir bis jetzt geflogen wfiren! » «Ich habe das Geffihl, daB dies fiber allem ist, fiber der Erde. Es ist beruhigend, zu wissen, daB ich wieder auf der Erde bin.» Pupillen noch maximal erweitert. RR: 145/110 Hgmm, P: 84/Min. Bewegt sich andauernd, gestikuliert viel. Sprache ist fifters inkoh'arent, kaum verfolgbar. «Ich habe inneres Zittern, meine Geffihle kann ich nicht gut ausdrficken. Ich ffihle mich so, als ob ich hetrunken ware.» Er zittert. «Dieses Zittern ist gar nicht so unangenehm, es bedeutet, daB die Reise zu Ende ist, aber alles ist noch nicht vorfiber.» Rhythmische Zuckungen des linken FuBes. «Jeder Anwesende hat gleichmiiBig gelbe Zfihne.» �Dimethyltryptamin: ein neues Psychoticum 289 28' «Alles hat einen fiberirdischen Stich und ist doch so real. Schade, daB alles in einem geschlossenen Zimmer geschieht. Mir scheint, daB ich zusammen mit dem Zimmer fliege. Erlebnis der Reise. . .» Pupillen miiBig erweitert. RR: 140/100 Hgmm, P: 80/Min. «J etzt habe ich schon das Gefiihl, daB alles vorbei ist.» Ziindet sich eine Zigarette an. Die ZigaIette sieht er grfiBer und umfangreicher. «Ich habe das Gefiihl, als oh ich lande. Die gehobene Stimmung léiBt nach.» Assoziationen noch immer gelockert. Hort in der Mitte angefangener Séitze auf, vergiBt was er sagen wollte, spricht iiber anderes. «Alles scheint gelb zu sein, hauptsfichlich die Schatten. Ich weiB, daB dieser Zustand aufhéirt, und doch. fiirchte ich mich, daB er weiterbesteht.» «Ich bin so nervos, als ob ich fiebrig wire. Es ist beruhigend, daB ich dauernd bei BewuBtsein war.» Klagt fiber Miidigkeit. «Alles ist voriiber, nur meine Gedanken schwirren durcheinander.» «Alles ist grau und farblos. Die Welt ist jetzt ganz ode.» AuBer leichter Miidigkeit beschwerdenfrei. Assoziation schon normal. «Ich hatte stets das Gefiihl, daB sich nur die AuBenwelt und nicht ich selhst mich verwandelte.» Dr. Z.J., Arzt, 30 Jahre. 1. 6. 1956. 60 mg DMT i.m. P: 72/Min., RR: 110/70 Hgmm (linkshfindig). 5' Er fiihlt sich ein wenig schwach. «Kollapsartiges Gefiihl.» 6' Ausgesprochenes Schwindelgefiihl. 7' RR: 130/90 Hgmm, P: 84/Min. Pupillen etwas erweitert. 8' Schwache Dyspnoe. «Das ganze ist eher angenehm.» 9' «Die Farben sind unveréindert. Mir schwindelt sehr. Leider geht es mir auch so mit dem Alkohol: mir schwindelt, ohne daB ich mich wohl fiihle.» 10' «Ich habe einen beklemmenden Druck auf der Brust, aber es kommt mir vor, daB ich auch ohne Luft existieren konne.» 11’ «Das silherne Muster der rechten Wand des Zimmers ist ganz reliefartig. Das Beklemmungsgefiihl nimmt ab.» 12' RR: 135/80, P: 88/Min. Rechter Patellarreflex verstfirkt, rechtsseitig Babinski13' 14’ 15’ 16' 17' 18' 19' Tendenz. «Die Gesichter haben sich veréindert, sind ganz mephistoéihnlich geworden.» «Uberall dominiert die silberne Farbe! Die Gesichter sind auch aus Silber und teuflisch. Die silberne Farbe ist schon, nur ein wenig furchterregend.» «Der eine Gummischlauch des Blutdruck-MeBapparates ist violett, der andere silbern.» (In Wirklichkeit schwarz.) «Die Gesichter sind asymmetrisch wie im Kino. Alles verandert sich im Raum, auch die Gesichter und Gegenstéinde.» RR 130/85 Hgmm, P: 88/Min. Reflexdifierem der unteren Extremitiiten ist auch weiterhin vorhanden. «1111' schwebt alle im Raum. Bis J'etzt habe ich noch nicht die Rfiumlichkeit der Dinge bemerkt. Die Anschauung des Menschen veréindert sich vollkommen.» «V01: ungefiihr einer halben Stunde konnte ich die Injektion bekommen haben. Mir kommt es vor, als ob diese Minuten viel reicher wfiren, deshalb erscheinen sie mir linger.» �Sai-Halész,Brunecker und Széra 290 20' «Mein Uhelsein verstfirkt sich wieder, ich fiihle mich sehr schwach. Mir ist, als ob ich keinen Atemreflex hfitte; wenn ich nicht daran denke, wiirde ich zu atmen vergessen. » 21’ «Alles ist statuenhaft. Die Gesichter sind teuflisch.» 22' RR: 130/80 Hgmm, P: 84/Min. Pupillen mfiBig erweitert. 23' «Mir fallen solche Details auf, die ich bis jetzt noch nicht bemerkt babe.» 24' «Ich fiihle mich vollkommen gewichtslos, gar nicht, als ob ich 75 kg wiege.» 25' «Es ist merkwiirdig, daB mir meine Hinde vollkommen fremd sind, als ob sie gar nicht mir gehorten.» 26' «Ich kann die Réiumlichkeit der Dinge besser beobachten; ich glaube, die Kiinstler sehen sie immer so. Wenn es so bliebe, wfirde ich Maler werden.» 27' RR: 130/85 Hgmm, P: 80/Min. Rechtsseitge Babinski-Tendenz besteht weiter. 28' «Die Gegenstéinde haben gar kein Gewicht. Ich glaube, ich konnte viel grijBere Gewichte heben als zuvor.» 29' «Die Gesichter sind noch immer statuenhaft.» 30' Er verlangt schwere Gegenstéinde und versucht, sie aufzuheben. «Die haben alle kein Gewicht.» 331' Er hort Musik mit geschlossenen Augen und lichelt. 32' RR 125/85 Hgmm, P: 80/Min. Keine Reflexdifl‘erenz. Pupillen mfiBig erweitert. 33’ «Die Musik ist schon und fesselnd. Als ich diese (Abendsternarie aus Tannhéiuser) letztes Mal horte, schwebte die Musik fiber mir, ich war jedoch auf der Erde. J etzt schwebe ich zusammen mit der Musik.» 34’ «Die Nebengerfiusche storen mich sehr, schade, daB es Grammophonmusik ist.» 35' «Alles wird schon natiirlicher. Das ganze ist sehr angenehm.» 37' RR: 125/75 Hgmm, P: 76/Min. Pupillen méiBig erweitert. 40' «Ich fiihle mich schon halbwegs in Ordnung. Meine Hand gehort wieder mir.» 45' RR: 120/70 Hgmm, P: 80/Min. 50' «Ich bin ein wenig miide, sonst ist alles voriiber. Das Gewicht der Gegenstéinde kam auch zurfick. Es war merkwiirdig, daB sich am Anfang Angenehmes und Unangenehmes vermischte, in der zweiten Halfte jedoch war alles schon und I gut.» Von den retrospektiven Erinnerungen ist folgende ihres lyrischen und subjektiven Charakters halber von Interesse: Dr. E.Ch., Arztin, 27 Jahre. 50 mg DMT i.m., 27. 8. 1956. Teils fiirchte ich mich, teils bin ich sehr gespannt, was eigentlich auf mich wartet. Mein SelbstbewuBtsein mochte ich gem durchwegs behalten. Was werde ich wohl erfahren? Mit 16 Jahren hitte ich gerne Gott gesichtet — wird das jetzt kommen? Oder wird sich eine andere Zeit meiner Vergangenheit verlebendigen? «Guten Tag, Ihr Versuchskaninchen ist angekommen», begrfiBte ich die zwei jungen Minner. «Ich messe IhIen Blutdruck, dann gehen wir ins andere Zimmer hiniiber. Der Blutdruck 120/90. Sie ffirchtet sich gar nicht», sagt der eine. Ich fiihle einen Stich, jetzt gibt es schon kein Zurfick mehr. «Sehen Sie sich gut im Zimmer um», hore ich, «sehen Sie auch aus dem Fenster.» Fliichtig schaue ich auf den Schreibtisch, die Stiihle und die monotone Wand. Alles ist kahl. Ich schaue durch das eisenvergitterte Fenster und sehe die groBen alten Baume. Ich sehe den déimmerigen Himmel, und auf einmal fing es an... �Dimethyltryptamin: ein neues Psychoticum 291 Mir schwindelt entsetzlich, es trommelt in meinen Obren, mit meiner rechten Hand greife ich zum Hals, da ich dort einen ziehenden Schmerz fiihle. Mir schwindelt. — In diesem Augenblick bedauere ich, mich in dieses Experiment eingelassen zu haben. Ich sehe auf meine Uhr, es sind noch kaum einige Minuten vergangen. GroBer Gott, wann wird dieser Versuch ein Ende nehmen? Der Kopf des einen Kollegen zieht sich in die Lange, er bekommt Schlitzaugen. Das Gesicht des anderen wird flacher und vierkantiger. Dieses eigenartige Licht, als ob der Schein einer Quarzlampe dammere. Meine Hand ist ganz zyanotisch. Ist sie wirklich so ? Ich ho're Sausen. Ich bin irgendwohin unterwegs, aber wohin? «Blutdruck 160», hfire ich, «Puls 100.» Das ist jetzt der Tod. Wie einfach alles ist. Das Sausen hat aufgehort, ich bin angekommen. Vor mir zwei stille, sonnenbeschienene Gfitzen. Freundlich nickend beobachten sie mich. Ich glaube, sie begriiBen mich in dieser neuen Welt. Es herrscht dumpfe Stille, wie in der Wfiste. Ich wage nicht, sie anzusprechen. Das ist doch Agypten, diese die Siihne der Sonne, und ich bin endlich zu Hause. Zu Hause in jener wirklichen und schonen Welt, wo binter den zwei Gotzen sich heitere Menschen zwischen den hohen, gelben Sfiulen und Statuen bewegen. Wie vornehm und einfach sie sind. Ihre sonnengebraunten Gesichter sind verklart, ihre Bewegungen frei und grazios. Weiter drinnen singen die Priester mit brausenden Stimmen. Der eine Gotze — nur seine Augen leben spricht mich an: «Geht es Ihnen besser?» «Es wird mir sehr gefallen, wenn das Ubelsein, welches der hohe Blutdruck verursacht, aufhiirt», antworte ich. Ich sehe mir meine Hand an, ein von mir ganz unabhéingiges, selbstandiges Wesen und dazu sehr schon. Die Form ist so wie zuvor, doch als ob sie mit einem goldbraunen Staub gepudert ware. Und die N age] sind rosa Muscheln. «SchlieBen Sie die Augen. Was sehen Sie ?» Ich gehorche. Aus der Dunkelheit sehe ich durch schwarze Eisengitter in den hellen Tempe]. Griiner Ranch qualmt darin und der Gong tont. China! Ich kann meine Augen nicht geschlossen halten, da mir schwindelt. J etzt zeigt man mir die RorschachTafeln. Ich kann mich so schwer darauf konzentrieren, es ist so langweilig. Jetzt erheben sich die hellen, metallschimmernden Wande, dann sinken sie wieder nieder. Es ist, als 0b das Zimmer atme. Auf der ganzen Flache kreisen vielfarbige — gelbe, hellgriine, rosa und blaue — Fischschuppen. Die glanzende Kugel der Lampe beugt sich kreisend naher. Ich sehe wiederum das Gitter, doch ist jetzt dahinter kein Ranch, sondern nur glatte runde grfine Steine. Auf meinem linken FuB kriecht etwas, doch sehe ich dort gar nichts. Alles bewegt sich und wogt. Im F ensterglas kreisen farbige Kranze und Fackeln mit ungeheurer Schnelligkeit. Ich mochte gerne erklaren, was ich sehe, doch .. . An den Wanden sehe ich das zischende, weiBgekronte, wogende Meer. Einige Wellen erreichen mit gedfimpftem Brausen den Strand. — «Debussy» — sage ich. Ich bin ein ganz kleiner Punkt, wie eine Bliite auf dem Wasser von den Wellen geschaukelt. Doch ich weiB, daB mir kein Leid geschehen kann. «Pupillen sind verengt, Blutdruck sinkt», bore ich. J etzt ist es schon still, die Schuppen kreisen immer langsamer, endlich bleiben sie stehen und verschwinden. Nur die seltsame Beleuchtung wéihrt fort. Das WeiB �292 Sai-Halasz, Brunecker und Szara ist noch auffallend weiB, alle Linien scharfe schwarze Konturen. Die Dimensionen sind sonderbar. Die ganze Welt ist furchterregend realistisch. Das ist die wahre Farbe und Form der Dinge. Geféihrliches Spiel, es ware so leicht, nicht zurfickzukehren. Ich bin mir dunkel bewuBt, daB ich Arzt bin, das ist aber gar nicht wichtig; Familienbeziehungen, Studien, Plane und Erinnerungen sind von mir sehr weit entfernt. Nur diese wirkliche Welt ist wichtig, ich bin frei und ganz allein. Zuriick, zuriick, drange ich mich. Ich muB den Weg zur realen Welt zuriickfinden. Auf dem Weg nach Hause trefl'e ich einen Bekannten im Bus. Ich beginne mjt ihm zu plaudern, damit ich die Realitéit der Beziehungen zu spiiren bekomme. Die am Wege stehenden Baume erscheinen grau und verblichen. Das Leben ist stumpf, unfreundlich und gleichgfiltig. Ich bin ein anderer Mensch geworden, erfahrener und freier. J etzt verstehe ich schon viel mehr. Wenn wir die einzelnen Symptome der DMT-Psychose betrefl's Haufigkeit untersuchen, finden Wir folgendes: 1. Vegetative Symptome wurden in allen 30 Fallen beobachtet. Das bestandigste Symptom war die Steigerung des Blutdruckes, die im allgemeinen 20—40 Quecksilber-mm erreichte, manohmal sogar noch mehr. Die hochste von uns beobacbtete Blutdruckerhohung betrug 70 mm, in einem Falle, wo der systolische Druck vor dem Versuch 140 mm zeigte und sich wéihrend des Experimentes bis auf 210 mm steigerte. Der diastolische Druck erhohte sich regelméiBig, doch in kleinerem MaBe als der systolische (meistens 10—20 mm, in einem Falle sogar 40 mm). Fast regelmaBig war die Pupillenerweiterung. Die Mydriase schien parallel mit den farbigen Halluzinationen zu erscheinen. Ob jedoch zwischen diesen ein kausaler Zusammenhang bestand, ist kaum wahrscheinlich. Eine Pulsbeschleunigung geringeren MaBes war auch in fast allen Fallen festzustellen. Objektive Atmungsstorungen fanden wir nicht, doch wurden von 23 Versuchspersonen (76 0/0) fiber Atemnot berichtet; diese wurde von einem Oppressionsgefiihl des Herzens begleitet. Dieses klinische Bild erinnert stark an das durch Serotonin hervorgerufene; es konnte vermutet werden, daB die molekuliire Ahnlichkeit der zwei Substanzen diese Erscheinung erkléirt: DMT verursacht auch wie Serotonin einen Krampf der pulmonalen Arteriolen. Die sympathicomjmetische Wirkung des DMT unterstiitzt diese Vermutung. Zur volligen Klarung dieses Mechanismus miiBten natiirlioh weitere Tierexperimente durchgefiihrt werden. Die sympathicomimetische Wirkung des DMT konnte nicht an allen Organen nachgewiesen werden. So fanden wir z.B. keine be- �Dimethyltryptamin: ein neues Psychoticum 293 deutende Hyperglykéimie und Tachypnoe. Die ganze vegetative Wirkung des DMT iihnelt mehr derjenigen des Serotonins als der des Adrenalins. 2. Sinnestiiuschungen wurden in 27 F fillen (90%) beobaohtet. Diese waren in der Mehrheit optischen Charakters: helleuchtende, farbige Illusionen und Halluzinationen, die sich stets im schnellen Wechsel befanden. Bei geschlossenen Augen vermehrten sich die Halluzinationen und nahmen szenenhaften Charakter an. Eine unserer Versuchspersonen erzéihlte mit geschlossenen Augen: «Ich sehe F elsen, Téiler, méirchenhafte Gegenden, mit kaum einem Schein von Rot als belebende Farbe. Watteau-artige Bilder, dort sind jedoch die Gestalten griiBer. Diejenigen, die ich sehe, sind ganz winzig und verlieren sich in den Felsenrissen, kleine Anhiinger der furchterregenden Umgebung.» Oder spéiter: «Orthodox-griechische Einsiedler, die in F elsen gehauenen dunklen Hfihlen leben. An den Wéinden leuchten Ikone. Man spiirt, daB ihr ganzes Leben auf diese Heiligenbilder zentriert ist.» AuBer den optischen fanden wir auch — wenn auch seltener — akustische und haptische Halluzinationen fliichtigen Charakters, die ebenso plfitzlich verschwanden, wie sie erschienen. 3. Stb'rungen der Raumwahrnehmung wurden in 22 Féillen (73 %) beobachtet. Die Dimensionen des Zimmers finderten sich am auffallendsten. Nahes und F ernes verschmolz ineinander. Die Form des Zimmers wurde ganz neu: oval oder vielkantig. Es konnte festgestellt werden, daB sich eben jene Dimensionen finderten, auf welche die Aufmerksamkeit gerichtet wurde. Wie auch in Meskalinund LSD-25-Psychose veréinderte stets jene Mauer die Lage, die eben angeschaut wurde. In einigen Fallen, in denen die Versuchspsychose Starker ausgeprfigt war, gingen die Raumdimensionen vallig verloren. Es stellte sich dann immer ein subjektives Erleichterungsgefiihl ein, sobald die richtige Riumlichkeit der Dinge wieder wahrnehmbar wurde. 4. Stb‘rungen des Kb'rperschemas erschienen fast immer gleichzeitig mit denen des Raumes. Es handelte sich um Symptome, die an den parietalen Symptomenkomplex erinnerten: die Versuchsperson bemerkte z.B., daB ihre Hand schon nicht ihr gehiire; oder wenn auch die GewiBheit bestand, daB es doch ihre eigene Hand sei, hatte diese doch etwas Selbstéindiges und Seltsames an sich. 0ft waren die St6rungen des Kérperschemas halbseitig; in 4 F fillen dehnte sich die St6rung auf die ganze linke Kiirperhfilfte aus. �294 Sai-Halész, Brunecker und Széra 5. Zeitstc'irung war in geringerem MaBe in allen Fallen vorhan- den, erreichte aber nie eine grijflere Intensitéit. Solche Erscheinun— wie beim Meskalin-Versuch berichtet — daB Zeitsinn der ganz gen, verlorengegangen ware, haben wir nicht bemerkt. Die Dauer des Versuches wurde immer etwas fiberschfitzt. Eine Versuchsperson fiihrte das «auf die reichere Fiille der Minuten» zuriick. 6. Denkstb'rung. In 21 Fallen (70 0/0) fanden Wir eine ausgesprochene Auflockerung der Assoziationen. Die Sprache wurde inkohéirent, angefangene Siitze konnten nicht beendigt werden, da schon der néichste Gedanke im Vordergrund stand. Diese Inkohéirenz verursachte auch beim Protokollfiihren Schwierigkeiten. 0ft schwiegen die Versuchspersonen fiir einige Minuten, antworteten auch nicht auf Fragen; sie erkléirten spéiter, daB sie ihre Gedanken nicht genug beherrschen konnten, um etWas Verstéindiges zu antworten. In 5 Fallen hatten wir es mit paranoiden bzw. wahnéihnlichen Gedanken zu tun. Diese Versuchspersonen berichteten erst 1—2 Tage spater, daB sie wéihrend des Versuches fiberzeugt waren, man wolle sie tfiten bzw. vergiften. DMT war das Gift, die Versuchsleiter die Mfirder. Eine Versuchsperson wurde Wéihrend des Experimentes sehr unruhig und muBte mit Gewalt niedergehalten werden. Sie erkléirte am néichsten Tage folgendes: «Ich fiihlte, daB ich vergiftet wurde und sterben werde und schon nichts dagegen tun konnte. Trotzdem kéimpfte ich einen seelischen Kampf, ob ich bis zum letzten Moment am Leben hé’mgen Oder ruhig sterben soll; das letztere war sehr verlockend, da ich mich sehr wohl fiihlte. Dieser seelische Kampf éiuBerte sich in meinem Motorium als Unruhe; ich spiirte und wuBte alles.» In anderen Fillen waren die Beziehungsideen nicht so ausgeprfigt, doch berichteten die Versuchspersonen nach einigen Tagen, daB sie betrefi's der Aufrichtigkeit und Zuverléissigkeit der Versuchsleiter ein wenig unsicher waren. Am nichsten Tage war dieses Gefiihl mit den eventuellen aggressiven Einstellungen zusammen verschwunden. 7. Afi'ektive Verdnderungen. Euphorie ist eine verhfiltnismfifiig 0ft zu beobachtende Erscheinung der DMT-Psychose. In 8 Féillen (27 0/0) war sie stark ausgeprfigt, in 12 Fallen (40%) milderen Grades Oder nur auf kiirzere Zeit bemerkbar. 0ft trat sie zusammen mit Zwangslachen auf, in anderen Féiflen war sie mit Introversion verbunden; letztere wurde durch ein «verkléirtes» Lficheln begleitet, das manchmal fast wéihrend dem ganzen Versuche dauerte. Die �Dimethyltryptamin: ein neues Psychoticum 295 Versuchsperson lag mehrere Minuten lang wortlos mit geschlossenen Augen und léichelte; manchmal jedoch weinte sie vor Seligkeit und seufzte: «Oh, wie wunderbar ist doch alles!» Wie schon bemerkt, ist die Angst eine der héiufigsten Erscheinungen der DMT-Psychose. Am stéirksten ist sie einige Minuten nach Verabreichung der Injektion bemerkbar, wenn sich die Umwelt so plfitzlich und intensiv veréindert, daB die Versuchsperson die feste Umgebung verliert. Nur 4 Personen berichteten, keine Angst gehabt zu haben. In der zweiten Héilfte der Psychose tritt Angst Viel seltener auf. Nur eine Versuchsperson klagte wfihrend des ganzen Versuches iiber Angst und sagte: «DaB es nur nicht zuriickkomme ! » Was nicht zurfickkommen sol], konnte sie nicht erkléiren; sie antwortete: «Na ja, das Ganze!» 8. Bewufitseinstb’rungen. Nur in 7 Fallen (23 0/0) haben wir eine BewuBtseinstriibung beobachtet. Sie war stets am Anfang des Experimentes bemerkhar, d.h. 8—15 Minuten nach Verabreichung der Injektion und dauerte nicht léinger als 2—5 Minuten. Wéihrend dieser Periode sprechen die Versuchspersonen nichts, und auch spéiter bestand eine Amnesie der Ereignisse, die inzwischen geschahen. Es blieb ihnen nur das Gefiihl, daB etwas Schreckliches vorging. 9. Neurologische Verc‘inderungen. Die Reflexe waren wéihrend des Versuches 0ft (63 %) erhtiht oder lebhaft. Voriibergehende pathologische Reflexe (Babinski usw.) fanden wir nur in 3 Fallen (10%). Im Motorium zeigten sich ausgepréigte Veréinderungen. Fast alle Versuchspersonen hatten eine hyperkynetische Zeitspanne, in der sich unwillkiirlich-extrapyramidale und Willkiirliche Bewegungen mischten. Nur einmal war die Hyperkynesie so stark, daB Gewalt angewandt werden muBte, um einen Unfall zu verhiiten. Sensibilitéitsstfirungen gesellten sich oft zur Stfirung des K6rperschemas. Meistens waren die Fehlleistungen seitens der Tiefensensibilitéit, Gewichtsschfitzung, Kfirperlage usw. zu beobachten. Die Oberflfichensensibilitéit war relativ viel besser erhalten. Sensibilitéitsstfirungen fanden wir in 18 Féillen (6000). 10. Halbseitigkeit der Symptome. Eine der interessantesten Beobachtungen beziiglich der DMT-Psychosen war, daB in Mehrzahl der F fille die Symptome halbseitig ausgepréigter waren. Dies war ebenso bei den neurologischen Symptomen wie bei den Halluzinationen und Kfirperschemastfirungen bemerkbar. Die linke Seite war stets die stéirker betroflene. Wir hatten Gelegenheit, 3 Linkshéindige unserem Experiment zu unterziehen; bei diesen dominierten �Sai-Halész, Brunecker und Széra ___—____—_——_—————————————-—-———~ 296 Abb. 100 % 1 80% 40% 20% s-aaa°a°-Eaa°a:a°§-Eé°-EE g be :1 :5 a; s: >., a "-4 0 '8 A: H m "‘ {-11 o I: cu 3'3 E,” H o9-1 >5 no 3:: g: .H .0 gcu 8 0 .=: :2 53 Q '8 au :5 uo .5.” 0 aa o 0 m C121 :o ‘53 a:3 (I) 1 :1 '-' :5 an .... f:O m flw m a a)” ‘ M o CIT-I o a: ‘9 '8 w "" ho” s 2": cc 94 aH :o 2; 4.: '-' fl tan 5:: 5 4:: 0 m F ‘3 w Q 5 E75 b; <‘. :1 H :o E E :1 «a p: '5cs o :1 g 3 g .... < g v-c an E o A4 v “-1 = 4 Q. m :1 I- :o gm 4-» ' 53 rd a a E :3 .ao _. g m o "=1 ° [—1 an g g c: "" ‘9 *8 6) u m g cc a 5.0 c: .2 s m die Symptome rechtsseitig. (Auf diese Erscheinung kommen wir in der Besprechung noch zuriick.) 11. Nachwirkungen. Alle Versuchspersonen klagten am Experiment folgenden Tage iiber Miidigkeit. Diese dauerte manchma] nur einige Stunden, bei einigen jedoch 1—2 Tage. Wéihrend dieser Periode 2 Nach ein 7 Tagen depressiv. %) (23 wenig Versuchspersonen waren Die in betrefl's alle 30 Ordnung. Personen vfillig Stimmung waren 1 der in wir Abbildung einzelnen der gehen Symptome Hfiufigkeit wieder. Besprechung Durch die DMT-Versuche ergeben sich 3 Tatsachen, die fiir das weitere Verstéindnis der sogenannten Modell-Psychosen éiuBerst interessant sind: und kurze Dauer der DMT-Psychose. 2. Halbseitigkeit gewisser Symptome. 3. Nahe chemische Verwandtschaft zwischen DMT und Serotonin. 1. Pliitzlicher Anfang �297 Dimethyltryptamin: ein neues Psychoticum Wirkung des DMT ist etwas ganz Neues unter der Psychotica. Meskalin fingt nach fast einer Stunde zu wirken an, Haschisch und LSD-25 wirkt noch langsamer. Aber auch die Dauer der Psychose ist beim DMT auffallend kurz, und zwar 40~60 Minuten. Um diesem Problem nfiherzukommen, haben wir — wie schon berichtet - die Ausscheidung von DMT und 3-Indolessigséiure wéihrend und nach dem Versuch untersucht. Wir fanden, daB nach Verabreichung von DMT die Quantitéit der 3-Indolessigséiure im Harn stark zunjmmt und in den ersten 6 Stunden schon ungeféihr das Zehnfache der normalen Ausscheidung erreicht; ebenso erhfiht sich — jedoch nur in geringerem MaBe — die Ausscheidung der 5-hydroxy-3-Indolessigséiure, was auf einen Zusammenhang mit dem Serotonin-Stoffwechsel hinweist. Im Harn fanden wir jedoch kein unveréindertes DMT, was bezeugt, daB das DMT im Korper sehr schnell und vollig abgebaut wird. Dies kann uns erkléiren, warum die Wirkung so schnell abléiuft und auch das DMT peroral unwirksam ist: wahrscheinlich wird es in der Leber abgebaut, bevor es die psychische Wirkung ausiiben konnte. Es bleibt aber noch immer die Frage ofl'en, warum das DMT so schnell wirken kann. Nach der Theorie von Rothlin und Patzig veréindert sich das Meskalin und LSD-25 im Organismus, bevor es eine Wirkung ausiiben konnte; es wéire eigentlich ein Umbauprodukt dieser Substanzen, das die psychotische Wirkung habe. Beim DMT kann kaum von so einer Transformation die Bede sein; das plotzliche Auftreten der Symptome unterstiitzt die Vermutung, daB das DMT selbst die psychotische Wirkung ausiibt. DMT wéire demgemfiB das erste Psychotikum auBer Bufotenin — das selbst ohne Abbau oder Umbau die experimentelle Psychose verursacht. 2. Die Halbseitigkeit einiger Symptome ist eine der interessantesten Erscheinungen der DMT-Psychose. Es treten gleich zwei Fragen auf: a) wie ist es moglich, daB eine chemische Substanz auf eine Hemisphfire stéirkere Wirkung ausiibt als auf die andere, und warum stets auf die nichtdominante Hemisphéire ? b) hat die nichtdominante Hemisphéire eine wichtige Rolle im Auftreten der experimentellen Psychose oder wenigstens einiger Symptome ? Diese Fragen kann man heute noch kaum beantworten. Es wfire zu oberfléichlich, sich auf die erste Frage mit der Antwort zu begniigen, daB die nichtdominante Hemisphéire chemischen Intoxi1. Die rasche -— Psychiat. New-0]., Basel. Vol. 135, No. 4—5 (1958) 20 �298 Sai-Halész, Brunecker und Széra kationen gegeniiber mehr «verwundbar» wire; dies sollte sich doch dann auch bei anderen Vergiftungen zeigen. Oder aber ist der Kreislauf der dominanten Hemisphéire im Notfall zu besserer Regulation ffihig ? Die zweite Frage, 0b néimlich die rechte Hemisphfire im Auf— treten psychopathologischer Syndrome eine wichtige Rolle habe, wurde schon in anderen Zusammenhéingen beriicksichtigt. Hofi und Pfitzl fanden, daB das Zeitrafi'er-Phéinomen nur bei rechtsseitiger Lfision zu beobachten war and meistens bei parieto-okzipitalen Schfidigungen. In der DMT-Psychose zeigt sich ein groBer Tei] der Erscheinungen eben als parieto-okzipitale F unktionsstfirungen (visuale Halluzinationen, Kfirperschemastfirungen, Raumwahrnehmungs-Stfirungen usw.). Es scheint, daB die Halbseitigkeit bei der DMT-Psychose uns einen weiteren Beweis bietet, die Theorie von Hofl und Pb’tzl zu unterstiitzen: eine rechtsseitige Gehjrnschéidigung iibt eine «bahnende» Wirkung beim Auftreten gewisser psychopathologischer Phfinomene ans. 3. In den letzten J ahren héiufen sich die Publikationen, die eine zentrale Rolle des Serotonins in der Funktion des zentralen Nervensystems annehmen (Brodie et al.). Es wurde auch angenommen (Woolley), daB der Serotonin-Stoffwechsel in der Genese der Psychosen, hauptséichlich der Schizophrenic, einen wichtigen Anteil habe. Wie schon erwéihnt, fanden wir im Harn der Versuchspersonne ungeféihr 4—5mal mehr 5-hydroxy-3-Indolessigséiure als bei Normalen; diese Substanz ist, wie bekannt, das Hauptabbauprodukt des Serotonins. Es gibt wiederum zwei Mfiglichkeiten: entweder wird die 3-Indolessigséiure, also das Abbauprodukt des DMT, sekundfir oxydiert, oder aber mobilisiert das verabreichte DMT eine bedeutende Menge des gebundenen Serotonins. Im letzteren Falle ware die experimentelle DMT-Psychose im strengsten Zusammenhang mit dem Serotonin-Stofl'wechsel verbunden. Hier k6nnte man nach gewissen Analogien einen in den zentralen Synapsen abspielenden kompetitiven Antagonismus der zwei Aminen vorstellen. Es miissen noch weitere mit radioaktiven Isotopen gezeichnete DMT-Experimente vorgenommen werden, um diese Fragen zu lfisen und auch damit einen Wichtigen Schritt zum biochemischen Verstéindnis der psychotischen Zustéinde im allgemeinen zu tun. Durch unsere ohigen Beobachtungen kfinnen wir auch feststellen, daB auBer dem Bufotenin das DMT auch eine bedeutende R0116 in der Gesamtwirkung der Piptadenia-Extrakte zu spielen habe. �M“— Dimenthyltryptamin: ein neues Psychoticum 299 Insofern unsere Ergebnisse mit den spfirlichen an Menschen gewonnenen Bufotenin-Beobachtungen zu vergleichen sind (diese sind wegen der intravenosen Anwendung des Bufotenins kaum moglich), ist es auffallend, daB das DMT eine periphere-vaskulfire, serotoninartige Wirkung in geringerem MaBe als das Bufotenin ausiibt. Dies kann vielleicht der strukturelle Unterschied, d. h. die beim Bufotenin vorhandene 5-OH-Wurzel erkléiren. Diese und die iibrigen Detailfragen konnten bloB weitere, an denselben Personen und unter gleicher Anwendung der 2 Indolamine durchgefiihrte Versuche kliiren. Z usammenfassung Dimethyltryptamin wurde synthetisiert, und dessen psychotische Wirkung untersucht. Nach intramuskuléirer Verabreichung von 0,7—1mg/kg Dimethyltryptamin tritt schon nach 3~5 Minuten ein psychotischer Zustand auf, der in vielen Erscheinungen denen ahnelt, die durch Meskalin und LSD-25 verursacht wurden. Die Dimethyltryptamjn-Psychose lauft innerhalb einer Stunde ab. AuBer der Beschreibung der Symptome werden 3 Probleme nfiher untersucht: 1. Was kann die Ursache des plotzlichen Auftretens und schnellen Ablaufes der Dimethyltryptamin-Psychose sein. 2. Welche Rolle spielt die Halbseitigkeit der Symptome, also die stiirkere Schiidigung der rechten nichtdominanten Hemisphéire beim Auftreten der psychopathologischen Erscheinungen. 3. Welche F olgerungen konnen beziiglich der Bedeutung des Serotonin-Stofl'wechsels im zentralen Nervensystem betrefl's der nahen cliemischen Verwandtschaft zwischen Dimethyltryptamin und Serotonin gezogen werden. Die Ahnlichkeiten und Unterschiede zwischen den Bufoteninund Dimethyltryptamin-Psychosen sollen weitere Experimente klarstellen. Re’sumé On a synthétisé la diméthyltryptamine et étudié son action psychotique. Aprés une administration intra-musculaire de 0,7—1 mg/kg de djméthyltryptamine, un état psychotique est apparu aprés 3 a 5 minutes déja. Il ressemhlait par beaucoup d’aspects a ceux qui sont �300 Sai-Halasz, Brunecker und Széra provoqués par la mescaline et le LSD 25. La psychose a la diméthyltryptamine dure une heure. A part la description des symptfimes on a étudié de plus pres 3 problémes: 1. Quelle peut étre la raison du début brusque et de la fin rapide de la psychose a la diméthyltryptamine. 2. Quel role joue la latéralisation des symptémes ainsi que l’atteinte prépondérante de l’hémisphére droit, non dominant, lors de l’apparition des symptomes psychopathologiques. 3. Quelles conclusions on peut tirer de la proche parenté chimique entre la diméthyltryptamine et la sérotonine pour la signification du métabolisme de la sérotonine dans le systeme nerveux central. D’autres expériences montreront les ressemblances et difl'érences entre les psychoses a la Bufotenine et a la diméthyltryptamine. Summary Dimethyltryptamin was synthesized and its efi'ect on psychosis investigated. An intramuscular injection of 0.7—1 mg/kg Dimethyl3—5 minutes a psychotic condition after and was given tryptamin was induced which in many respects resembled those phenomena induced by mescalin and LSD 25. This Dimethyltryptamin psychosis lasted less than an hour. Besides a description of the symptoms we have investigated three problems: 1. The reason for the swift start and rapid departure of the psychosis. 2. What is the significance of the one-sided nature of the in of the disturbance the right degree is, that greater symptoms, non-dominant hemisphere when the psychopathological phenomena begin to show. 3. Having regard to the close chemical affinity between Dimethyltryptamin and Serotonin, what conclusions could be drawn as to the import of serotonin metabolism in the C.N.S. Further experiments should clarify the similarities and differences between psychoses induced by Bufotenin and those by Dimethyltryptamin. LITERATUR Beringer, K.: Der Meskalim'ausch, Springer, Berlin 1927. — Brodie, B. B. et al.: Science 122, 968, 1955. — Erspamer, V.: Pharmacol. Rev. 6, 425, 1954. — Evarts, E. V.: Arch. Neurol. Psychiat. 75., 49, 1956. — Fabing, H.D.: Amer. J. Psychiat. 113, 409, 1956. — Fabing, H.D. and Hawkins: Science 123, 886, 1956. — Fish, M. S., �m Dimethyltryptamin: ein neues Psychoticum 301. N. M. Johnson and D. C. Homing: J. amer. chem. Soc. p. 77, 1955. — Fraenkel, F. und E. Joel: Z. ges. Neurol. Psychiat. 111, 84, 1927. — Hofi, H. und 0. Po'tzl: Z. Neurol. 151, 599, 1934. — Page, I.H.: Physiol. Rev. 34, 563, 1954. — RaymondHamet: Compt. rend. Soc. biol. 135, 1414, 1941. — Rothlin, E.: Experientia 12, 154, 1956. — Speeter, M.E. and W. C. Anthony: J. amer. chem. Soc. 76, 6208, 1954. — Stall, A. und A. Hoflmann: Helv. chim. Acta 26, 944, 1943. - Stromberg, V.L.: J. amer. chem. Soc. 76, 1707, 1954. — Stoll, A.: Schweiz. Arch. Neurol. Psychiat. 60, 1, 1947. — Szdra, SL: Experientia 12, 441, 1956. — Wieland, H. und H. Mittasch: Ann. Chem. 513, 1, 1934. — Woolley, D. W.: Brit. med. J. 1954, 122. Adresse der Autoren: Dr. A. Sai-Halész, Dr. G. anecker, Zentrales Neurologisch-Psychiatrisches Institut, Budapest-Lipétmezb‘ (Ungarn). Dr. St. Széra, 113 Hesketh Street, Chavy Chase 15, Md. (USA). �, u '1‘ �Copyright, 1958, by the Society 'for'Experimental Biology and Medicine. Reprinted from PROCEEDINGS OF THE SOCIETY FOR EXPERIMENTAL BIOLOGY AND MEDICINE, 1958, v97, 4837486 A New Group of Psychotomimetic L. G. ABOOD, A. M. OSTFELD Agents.ale AND (23782) JOHN BIEL Divisions of Psychiatry and Preventive Medicine, University of Illinois College of Medicine and Lakeside Laboratories, Milwaukee During the past few years, much interest has developed in psychotomimetic agents, particularly with regard to LSD 25 and mescaline. At the same time, considerable emphasis has been placed on the possible role of adrenalin and serotonin in psychoses, particularly because they are structurally related to the psychotomimetic agents and are pharThe, role Of macologically antagonistic. acetylcholine and acetylcholine- like sub'stances, on the other hand, has received relatively little attention. Knowledge of the hallucinogenic properties Of cholinergic blocking agents,,such. as atroh pine and hyoscine, dates back to thetime of the ancient Hindus. Recently, a group of piperidyl benzilates possessing anticholinergic properties were synthesized by Biel and associates(l) as possible antispasmodics in the treatment Of duodenal ulcer(2). In the course of therapeutic trials, it was found that the tertiary amine hydrochlorides of the benzilate esters, although active anticholinergics, produced undesirable side effects, particu- larly hallucinations. The quaternary ammonium salts, on the other hand, were entirely devoid of such effects. We have recently, Obtained a series of such substances and examined their psychotomimetic effects on animals and human subjects(3). Methods. The psychotogenic effects of the N—methyl-3-piperidyl benzilate and related congeners were tested on over 40 human volunteers who were either normal or patients complaining of minor disorders. Although some of the patients had limited knowledge of the psychotogenic action of the drugs, the majority of subjects were completely unaware Of their nature. Ceruloplasmin determinations were made on many subjects, employing a method described previously(4). All of the agents were tested for their behavioral effects in animals, including some 30 Siamese fighting fish, 50 rodents, and 5 cats. The action of these agents on the Siamese fighting fish is comparable to those described 'for LSD by Abramson(5). In rodents there were marked behavioral changes, such as initial excitement and marked' hyperactivity, spon* Supported by grants from Mental Health Fund, taneous squealing, lack Of ”responsiveness to State Of Illinois, and Teagle Fn. stimuli, muscular weakness, (and lethargy. , _ 4 _ �NEW PSYCHOTOMIMETIC AGENTS The anticholinergic effect of the agents was determined on isolated smooth muscle preparations and the rectus abdominus according to the method of Chang and Gaddum(6). Results. Experimental findings have indicated that the compounds are extremely powerful hallucinogens, in many respects more interesting than LSD and mescaline. When administered in 5-15 mg doses, orally, to human volunteers, distinct auditory and visual hallucinations occurred within one hour in for recurred and periodically individual every periods up to 10 hours after administration of the drug. Hallucinations were accompanied by gross distortions of visual images and severe alterations in feeling state. A number of subjects exhibited paranoid and megalomanic delusions, while the affective states ranged from a feeling of unpleasantness to extreme terror. Some of the subjects actually carried on conversations with imaginary individuals involving situations dating back 10-20 years. The following are almost exact quotations from different subjects: “People from India are standing outside a tent. They have turbans and those are camels.” “I see six people sitting around a table playing cards . a monkey is over the table hanging by his tail.” “I am walking down a narrow corridor and suddenly stop and cannot move is beating . . . a band is playing . . . a drum 3/4 rhythm.” The subjects receiving 10 mg (orally) of N-methyl-3-piperidyl benzilate were in complete loss of contact with the environment for vis— dramatic While hours experiencing many ual and auditory hallucinations. In many respects these anticholinergic agents come closer to simulating clinical psychoses than do mescaline and LSD. Thus far, a number of congeners have been tested for both hallucinogenic properties and anticholinergic effect on the isolated colon (Table I). Of all the compounds tested for hallucinogenic properties, N-methyl-3-piperidyl benzilate is the most potent, with the Nethyl derivative being somewhat less effective. The tetramethyl derivative is considerably less effective than the N—ethyl derivative. The quaternary derivative is devoid of , psychotogenic effects. As for the antispasmodic potency, although the 3 substances possessing psychotogenic properties are perhaps the most potent, the remaining compounds are still quite effective. Ceruloplasmin determinations were made on all subjects, since this enzyme was shown to be increased in the serum of acute schizophrenics(4,7). The method used has been described previously(4). Preliminary observations have indicated that as much as a 50-75% elevation in the blood ceruloplasmin accompanies the hallucinatory episode produced by these agents. The enzyme increased only when marked psychogenic disturbances were apparent, returning to normal shortly after the psychogenic effects disappeared and while peripheral autonomic effects, such as mydriasis, muscular weakness, and dryness of the mouth, still persisted. A rise in ceruloplasmin has been shown to accompany changes in affective or feeling states, regardless of the mechanism by which the effects are produced (3 ) . Discussion. A discussion of the relative antispasmodic properties of this group of compounds appears elsewhere(1). It is apparent from the present study that in this series of compounds there is no direct relationship between the anticholinergic effect on smooth muscle and psychotogenic potency. The presence of the hydroxyl group in the acid moiety to yield the diphenylacetate ester is undoubtedly essential for hallucinogenic effect, while only slightly enhancing the anticholinergic effect. Since both the diphenylacetate and the benzilate derivatives penetrate the blood brain barrier, it would appear that the hydroxyl group is an absolute require— ment. The presence of a quaternary nitrogen in the piperidine ring only slightly influences the anticholinergic effect, but apparently pre— vents the compound from penetrating the blood—brain barrier. As a rule, quaternary ammonium compounds are not able to enter the central nervous system through the blood stream. Preliminary observations have shown that intrathecal injections of the quaternary compound into rats produce much the same kind of neurological and behavioral disturb- �_,,' _ a \ 4 l NEW PSYCHOTOMIMETIC AGENTS TABLE I. Structure-Activity Relationships of. Some Piperidyl Benzilate Congeners. Anticholinergic effect was determined on isolated rat colon with concentrations of about 10“ M. \ / Ill/Q ox R—O—C—C \ \/\O — Relative Relative halantilucinogenic cholinergic potency potency Name R X N—methyl-3-piperidy1-benzilate m 0H ++++ ++++ OH +++ +++ OH — + +++ I \N/ CHs N -ethyl-3-piperidyl—benzilate \/ N 02115 1,2,2,6 tetramethyl-4-piperidyl benzilate CH3 \N/(CHS) 2 CH3 N-ethyl-3-piperidyl-diphenylacetate \/ H 0 +++ OH 0 +++ N 02H5 m \/ /\ N-dimethyl—3-piperidyl benzilate N+ CH3 ances observed with the tertiary benzilates. At present, numerous other congeners are being examined for their hallucinogenic properties. Future synthetic work is contemplated in an effort to explore other structureactivity relationships from the point of view of hallucinogenic effect. In view of the work of others on anticholinergic substances, it may be predicted that the distance between the hydroxyl group and the piperidyl nitrogen is critical( 8,9). Introduction of alkyl groups into the molecule would, therefore, presumably diminish the anticholinergic potency, and it will be of interest to determine the relationship of such a change to hallucinogenic effectiveness. Summary. A series of synthetic anticholin- C'H3 ergic agents have been shown to possess potent psychotomimetic properties. Chemically, the agents are esters of piperidine and benzilic acid. Among the effects produced are megalomanic and paranoid delusions, visual and auditory hallucinations, and a partial loss of contact with the environment. A number of congeners of the compounds have been examined with regard to structure-activity relationships. J. H., Sprengler, E. P., Leiser, H. A., Horner, 1., Drukker, A., Friedman, H. L., J. Am. Chem. 1. Biel, Soc., 1955, v77, 2250. 2. Ewing, P. L., Seager, L. D., Keller, G., Dodson, D., J. Pharmacol. Exp. Therap., 1954, v110, l7. 3. Ostfeld, A. M., Abood, L. G., Marcus, D. A., �NEW PSYCHOIOMIME’TIC AGENTS Arch. Neurol. Psych. in press. 4. Abood, L. G, Gibbs, F. A, Gibbs,E ., ibid., 1957, v77, 643. 5. Abramson, H. A., Evans, L. T., Science. 1954. V120: 9906. Chang, v79, 255. H. C., Gaddum, J. H., J. Physiol., 1933, . t ' ' 7‘Akerfeldt, M., J. Pharmacol. Exp. Therap., Lands, 8. S., Science, 1957, v125, 117. A. 1951, v102, 219. 9. Goodman, L., Gilman, A., The Pharmacological Basis of Therapeutics, ed. Macmillan Co., N. Y., 1955. Received December 23, 1957. P.S.E.B.M., 1958, v97. DEPARTMENT OF EXPERIMENTAL rsvcumm HlLLSlDE HOSPITAL GLEN OAKS. N. v. MAY1 4'53 '- �Reprinted from the A. M. A. Archives of Neurology (5“ Psychiatry March 1958, Vol. 79, pp. 317-322 Copyright 1958, by American Medical Association Studies with Ceruloplasmin and a New Hallucinogen ADRIAN M. OS'I'FELD, M.D.; LEO G. ABOOD, Ph.D., and Knowledge of the hallucinogenic prop—erties of atropine—like compounds is cer— tainly as old as that concerning the effects of mescal and marihuana. It has been pos— tulated that the oracle at Delphi induced her prophetic vision with belladonna. Hughes and Clark1 quote a lively description of a 17th century American epidemic of atro— pine poisoning. Readers of English detec— tive novels or American Western stories are familiar with the deadly nightshade and Jimson weed, respectively. The recent synthesis of N-ethyl-3-piper— idyl benzilate hydrochloride, JB 318*,2 an agent chemically related to atropine (Figure), led to the present studies. Originally intended as an autonomic—blocking agent in the treatment of peptic ulcer, the drug exhibited hallucinogenic properties, so prominent as to merit further investigation.3 At the close of the conference of the Brain Research Foundation on blood tests in mental illness in 1957,4 several unan— swered or partly answered questions were raised or implied. What are the serum ceruloplasmin levels in disturbed behavior not of psychotic proportion? Does the con— centration of this protein vary with the severity of the mental disorder? Is its concentration in the blood increased during Submitted for publication Sept. 16, 1957. Department of Preventive Medicine and Division of Psychiatry, University of Illinois College of Medicine. Now at the Institute for Psychosomatic and Psychiatric Research and Training, Michael Reese Hospital (Dr. Marcus). This research was supported in part by the Mental Health Fund, State of Illinois; the Brain Research Foundation, and the Dan Crego Fund. *The material was supplied by Drs. John Biel and H. L. Daiell, of Lakeside Laboratories. Dr. John Biel cooperated in the study and made helpful suggestions. DAVID A. MARCUS, M.D., Chicago N—ETHYL—B-PIPERIDYLBENZILATE (JB 3l8) CHz—7CH—CH2\ N—CH: \ CHz——- CH——-CH2 / CHzOH l CH—O-C H ATROPINE drug—induced psychoses? And, finally, since ceruloplasmin attacks certain pyrocatechol (catechol) amines in vitro, what effect does an increase in these pyrocatechol amines in the blood have on ceruloplasmin? The present study, then, had the dual purpose of examining the psychotomimetic properties of ]B 318 and assaying the effects on serum ceruloplasmin of (1) JB 318—induced “psychoses,” (2) intravenous infusion of some pyrocatechol amines, and '(3) naturally occurring behavior disturb— ances of moderate severity. Experimental Methods and Results Studies with J B 318.—In all, 45 volunteer nonpsychotic subjects were studied. JD 318 was administered orally to nine subjects in doses of 10 or 15 mg. Three who took the agent were professional persons employed in the hospital; six were medical ward patients, selected only because their general state of health was satisfactory. The three 317 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY professional persons had prior knowledge of anxious to repeat the experience. Seven the effects of the drug, whereas none of experienced visual hallucinations, and four the patients were told what to expect. Blood of these also described auditory hallucina— was drawn for serum ceruloplasmin deter— tions, which were especially prominent in mination before and at the peak of the three. The visual hallucinations usually consisted hallucinatory phase. Ceruloplasmin was measured by the method of Abood5 in of amorphous colored forms, whereas eight of the nine subjects. brightly colored, elaborate images were inThe determination was done as follows: frequent. In the five cases in which animal One-tenth milliliter of fresh serum was and human forms were reported the images incubated with 0.1 ml. of 0.1% p-phenylene— were usually related to specific events in the diamine and 1.0 ml. of 0.2 M tris(hydroxy— recent past experience of the subject. Most methyl)ethanolamine buffer (pH 6.8) for hallucinations lasted only a few seconds, al— a period of one hour at 37 C. After the though one subject reported images persist— addition of 2 ml. of distilled water the mix- ing for many minutes. Generally, but not ture was read at 490m“ on the spectro- always, the maximum hallucinatory effect photometer. An optical density reading of was attained when subject was kept alone 0.100 corresponds to an activity of IOMM in a darkened, quiet room. The auditory hallucinations consisted of substrate (p—phenylenediamine) oxidized of musical such mainly sounds, stand— 0.1 as whistling, hour ml. The of one serum. per ard curve was determined by oxidizing the singing, and band playing. A few reported substrate with purified human cerulo~ noises, such as sirens and hammering or banging radiators. Emotional disturbances, plasminrt such fear and as bewilderment, seem to acReactions related to the autonomic activ— visual whereas hallucinations, the company the 30 of about minutes ity drug began after oral administration and consisted of auditory experiences were not usually disthe following: dry mouth, blurred vision in turbing. Two be subjects to appeared paranoid all cases, usually tachycardia, facial flushing, hallu— the during or immediately following and disappearance of the carotid sinus re— ef— While the cinatory central responses. flex. There was no appreciable effect on fects ofthe drug persisted, the subjects blood pressure. Nausea occurred in two pa— showed reduction of intellectual a capacity, tients, vomiting in one. The autonomic recharacterized rela— short attention by span, actions began 15 to 60 minutes before the tive and anomia, inaccurate time grossly hallu— and outlasted the psychic phenomena All remained in judgment. contact with cinations by l to 24 hours. The peak auto— the actual environment, but the presence of nomic effects preceded the peak psychic familiar a person or object was required to effects in every case. enhance orientation and allay apprehen— Perceptual responses were characterized sions. by distortion of Visual images, visual and The following are taken essentially verauditory hallucinations, and alterations in batim from the comments of dur— a patient feeling state. All nine subjects reported dis— ing the period of hallucinogenic effect: tortion of visual images and an initial change “My arms are heavy and everything feels far in mood, characterized by apprehension and away. My head feels light. I’m very weak. . . .” “Lots of people are talking incoherently. I think lethargy. The general feeling tone was re— it’s Spanish.” ported as unpleasant by eight of the nine “The room feels distant. I wish I could lift my subjects, and none of the subjects were left is arm but I can’t. The and Dr. G. D. Cummings, of the Michigan Department of Health, supplied the purified human cerulo— plasmin. 1' 318 room a narrow, band is playing. The rhythm is M. . . .” “The room is a long corridor, and I’m in it and I’m 8 or 9 years old. I wonder how I’ll get out. I Vol. 79, March, 1958 �I CERULOPLASMIN AND NEW HALLUCINOGEN of .18 318 on Serum Ceruloplasmin’l‘ of Normal Volunteers TABLE l.——Eflect Before JB Ceruloplasmln Approximately Two Hours After J B 318 Subjects Who Hallucinated 318 230 242 304 224 188 230 241 2l 1 115 120 155 315 * 160 170 Subjects Who Did Not Hallucinate _ «——~ - _ _ -_ . __ -_ 143 296 The values are expressed as optical density X10 8. know I’m in bed and also in that other place. There must be more than one of me, and one is a little girl.” “People from India are standing outside a tent. They have turbans, and those are camels.” An electroencephalogram taken on one subject revealed no abnormality, even dur— ing a series of vivid hallucinations. Ceruloplasmin levels uniformly increased in the six subjects who experienced hallucinations and decreased slightly in the two who did not (Table 1). The parallelism of ceruloplasmin levels in schizophrenic psy— choses and those induced by JB 318 is evident. There was, however, no propor— tionality between the per cent increase in ceruloplasmin and the severity of the psy— choses. Nor were the ceruloplasmin levels during the drug psychoses as high as commonly occurs in acute schizophrenics?6 Studies with Pyrocatechol Amines and Human Subjects.—Pyrocatechol amines and their breakdown products have been increas— ingly implicated in schizophrenic psychoses. Since ceruloplasmin has been shown to at— tack epinephrine and serotonin in vitro,7 it was deemed worth while to infuse certain pyrocatechol amines intravenously and to gauge their effects on behavior and serum ceruloplasmin. There was a uniform slight decrease in serum ceruloplasmin with each agent, as well as with control dextrose in— fusion. The subjects were general medical patients who were either convalescing or not seriously ill. None had rheumatoid arthri— tis, liver disease, acute infections, or known carcinoma, conditions sometimes associated Oxtfeld at (11. with high cerulopla51nin.4'6 The infusions were all administered by an unfamiliar physician in a new setting. Apprehension was initially evident in the behavior and Speech of each subject. Common were such comments as “We’re on the same side, aren’t we, Doc. . .you won’t hurt me”; or “lf the test comes out bad, will I have to stay here [in the hospital] longer?” With a single exception, the subjects were relaxed, beginning about 15 minutes after perfusion was started. About half slept, and nearly all commented on how comfortable and tranquil they felt. None of the subjects on levarterenol, serotonin, or dex— trose reported any unusual sensation. The subject on isoproterenol U. S. P. and the two who received epinephrine experienced a rapid heart rate but no emotional disturb— ances. One subject who received epinephrine grimaced, tossed about, and was agitated during the infusion. Since the effects of the infusion on ceruloplasmin were identical regardless of the agent administered, the parallel decline in anxiety and in ceruloplasmin attracted our attention. It was postulated that if there were a parallelism between feeling state and ceruloplasmin, then both would be ex— pected to undergo an increase during peri— ods of disturbed behavior. 2.—E[fect of Various Agents“ onSerum Creruloplasmin of Normal Human Subjects TABLE Agent Levarterenol Epinephrine Dosage 10 jug/min. 10 jig/min. 20 jig/min. 5 pg/min. 10 ug/min. 10 ug/min. 15 Isoproterenol Serotonin Iproniazid 5% dextrose with water jig/min. pg/min. ng/min. 15 15 5 ug/m‘m. mg/min. mg/ min. 100 mg. orally 0.25 0.50 Ceruloplasmin Control 186 213 292 228 350 144 235 220 188 211 222 196 During Drug Eflect 140 232 225 191 347 102 205 200 214 189 224 1' 177 230 225 240 278 182 228 236 160 187 170 __- 141 150 TThis subject alone was markedly agitated during the infusion. N onpsychotic at present, he had been previously hospitalized six times for acute schizophrenic episodes. 319 �A. M. A. ARCHIVES OF NEUROLOGY AND PSYCHIATRY Ccruloplasmin* of Disturbed and Tranquil Subjects Who Were Not Psychotic TABLE 3.——Serum Disturbed Tranquil 262 250 220 222 136 157 154 272 240 lVlean * S. l). 348 230 282 410 263 202 170 181 118 186 156 230 170 120 166 The values are expressed in terms of optical density X10 5. This thesis was tested in 26 consecutively referred clinic patients. Previously, one pa— tient who could not speak English and three whose psychological states were not clearly discernible to the observer were not included, leaving a group of 22 patients. Each subject was interviewed in order to determine his general psychological state. Eleven exhibited disturbed behavior, such as weeping, pacing the floor, sweating, and tachycardia and/0r admitted to prominent feelings of anxiety and depression. An equal number whose illnesses were not viewed by them as unduly threatening were calm in the clinic setting. Ceruloplasmin levels for the two groups are shown in Table 3. No attempt was made to determine a pre— cise psychiatric diagnosis, but the behavior disturbances in the one group were of neurotic proportions. Increased ceruloplasmin levels in the disturbed group are evident and are significant at the 0.001 level of probabil— ity. Comment The correlation of elevated ceruloplasmin with particular types of behavioral disturb~ ances apparently involving an alteration in “feeling state” raises the problem of the mechanism of ceruloplasmin production. In- asmuch as hallucinogenic agents, such as the present one (see also Alkerfeldtfi Abood“) seem to stimulate ceruloplasmin production only during the hallucinatory or psychogen— ically disturbed phase, a central mechanism would appear to be involved. It is of par— 320 ticular significance that the onset of the enzyme elevation is within minutes after the occurrence of hallucinations or anxiety, suggesting a rather unique mechanism for enzyme production. Contrary to our origi— nal expectations, an elevation in blood pyrocatechol amines, which are apparently endogenous substrates for ceruloplasmin, was not, in itself, a stimulus for increased production of ceruloplasmin, but, rather, caused a decrease in many instances. What increases were noted in the infusion studies were apparently related to anxiety reactions to the manipulative procedures involved’in handling the subjects. Since, in the present studies, no noticeable alterations in feeling state resulted directly from the pyrocatechol amines, it remains to be seen whether in those instances in which such reactions have been attributable to infused epineph— rine8 an elevation in ceruloplasmin does occur. Future studies are aimed at the clarification of many of these points. The suggestion that changes in cerulo— plasmin may reflect alterations in emotional state has been proposed by others. Leach and associates9 have postulated that many environmental factors, including stress, can alter the enzyme level. Meduna4 described a patient who exhibited a high serum cerulo— plasmin >during an acute schizophrenic psychosis and a normal value during a lucid interval. Hoffer10 has noted an increase in a serum pyrocatechol oxidase (presum— ably not ceruloplasmin) during the acute phase of a schizophrenic attack. Schizophrenia is a genetic limitation involving par— ticular enzymes within the brain or elsewhere in the organism. In the face of environmental stress, such limitations be— come prominent, and metabolic products with psychotomimetic properties accumu— late." The psychosis itself is ushered in by the sensory distortions, altered feeling state, and hallucinations so induced. Sub— sequently, when the patient attempts to reconcile his present state with his past ex— perience, the disorganization of cortical function begins. Vol. 79,‘ March, 1958 �CERULOPLASMIN AND NEW HALLUCINOGEN Numerous reports”12 are available on the psychogenic properties of the bella— donna alkaloids, but the effects were quite variable and difficult to interpret because of the many peripheral side-effects, particularly with atropine. JR 318 possessed about one—third of the cholineric—blocking effect of atropine on smooth muscle,‘3 and at the doses used in the present study produced a slight, if any, effect on blood pressure, heart rate, or gastrointestinal tract. Even the more superficial peripheral effects ob— servable with atropine, such as mydriasis and dryness of the mouth, were occasion— ally absent with the doses of JB 318 used. With regard to the possible mechanism of JR 318 and other cholinergic—blocking agents on the central nervous system, very little'can be said. Although the evidence in support of the role of acetylcholine as a chemical transmitter in the central nervous system is not convincing“:15 disturbances in its concentration or action within the central nervous system result in a wide variety of psychic and neurological symp— toms. Many cholinergic agents, such as isofluro— phatef“,17 produce central nervous system disturbances which are apparently associated with the accumulation of acetylcholine in the brain. The observations of Pfeiffer et al.18 that the “muscarinic” component of acetylcholine—like agents, such as arecoline and physostigmine, are of value in the treat— ment of catatonic schizophrenia, suggest a role of acetylcholine in mental disease. There would appear to be a conflict between the argument that a cholinergic agent is beneficial in schizophrenia, while a choliner— gic—blocking agent is psychotomimetic; but the neural mechanisms involved in psycho— genic phenomena are much too obscure to justify the comment on this apparent dis— crepancy. What is significant is the fact that acetylcholine does seem to influence psychogenic phenomena and may be of im— portance in the study of mental disease. Ostfeld at al. Summary A recently synthesized atropine—like compound, N-ethyl—3—piperidyl benzilate, induced altered feeling states, visual and auditory hallucinations, and increased se— rum ceruloplasmin in seven of nine patients. Infusion of four pyrocatechol amines— epinephrine, levarterenol, isoproterenol, and serotonin—appeared to have no effect per se on serum ceruloplasmin. Iproniazid, an amine—oxidase inhibitor, was likewise inef— fective. Serum ceruloplasmin undergoes small, but significant, increases during psychiatric disturbances of neurotic type and proportions, and decreases by a similar amount during periods of tranquility. Department of Preventive Medicine, University of Illinois College of Medicine (Dr. Ostfeld). REFERENCES Hughes, J. D., and Clark, J. H., Jr. Strontium Poisoning: A Report of 2 Cases, J. A. M. A. 112: 1. : 2500, 1939. J. H.; Sprengeler, E. P.; Leiser, H. A.; Homer, J.; Drukker, A., and Friedman, H. L.: Antispasmodics: II. Derivatives of N—Substituted— 3-Piperidols, J. Am. Chem. Soc. 77:2250, 1955. 3. Biel, J. H.: Personal communication to the authors. 4. Brain Research Foundation, papers read at Medical Conference, Chicago, Jan. 12—13, 1957, by Akerfeldt,5 Abood,8 and Meduna. 5. Akerfeldt, S.: Oxidation of N,N-Dimethyl—p' plienylenediamine by Serum from Patients with Mental Disease, Science 1252117, 1957. 6. Abood, L. G.; Gibbs, F. A., and Gibbs, E.: Comparative Study of Blood Ceruloplasmin in Schizophrenia and Other Disorders, A. M. A. Arch. Neurol. & Psychiat. 772643, 1957. 7. Holmberg, C. G., and Laurell, C. B.: Investigations in Serum Copper: IlI. Ceruloplasmin as an Enzyme, 'Acta chem. scandinav. 5:476, 1951. 8. Hoffer, A.: Epinephrine Derivatives as Potential Schizophrenic Factors, Quart. Rev. Psychiat. & Neurol. 18:27, 1957. 9. Leach, B. E.; Cohen, M.; Heath, R. G., and Martens, 8.: Studies of the Role of Ceruloplasmin and Albumin in Adrenaline Metabolism, A. M.A. Arch. Neurol. & Psychiat. 762635, 1956. 10. Hoffer, A.: Conference on Biochemistry and Mental Disease, University of British Columbia, Vancouver, B. C., Canada, June, 1957. 2. Biel, 321 �A. M. A. ARCHIVES OF NEUROLOGY AND 11. Quigley, J. P.: Mental Disturbances from Atropine or Novatropine to Subjects Under the Influence of Insulin, J. A. M. A. 10921363, 1937. 12. Wangeman, C. P., and Hawk, M. H.: The Effects of Morphine, Atropine and Scopolamine on Human Subjects, Anesthesiology 3:24, 1942. 13. Ewing, P. L.; Seager, L. D.; Keller, G., and Dodson, D.: Cardiovascular Effects of Some Derivatives, J. Diphenylacetate 3-Piperdy1 Pharmacol. & Exper. Therap. 110217, 1954. 14. Eccles, J. C.: The Physiology of Nerve Cells, Baltimore, Johns Hopkins Press, 1956. 15. Feldberg, W. S.: Central and Sensory Trans— mission, Pharmacol. Rev. 6285, 1954. 322 PSYCHIATRY Koelle, G. B., and Gilman, A.: The Chronic Toxicity of Di—Isopropylfluorophosphate (DFP) in Dogs, Monkeys and Rats, J. Pharmacol. & 16. , Exper. Therap. 872435, 1946. 17. Rowntree, D. W.; Nevin, S., and Wilson, A.: The Effects of Diisopropylfluorophosphonate in Schizophrenia and Manic Depressive Psychosis, J. Neurol. Neurosurg. & Psychiat. 13:47, 1950. 18. Pfeiffer, C. C., and Jenney, E. H.: The 111- hibition of the Conditioned Response and the Counteraction of Schizophrenia by Muscarinic Stimulation of the Brain, Ann. Nevv York Acad. Sc. 662753, 1957. '- Printed and Published in the United States of America �DEPARTMENT OF PSYCHIATTY EXPERIMENTAL HILLSIDE HOSPITAL GLE. CAKS. MAY-1 4's; N Y. �Vol. 167, No. l MEDICAL LITERATURE ABSTRACTS neuralgic pain from herpes zoster, and in patients with tabetic crisis. R 875 was then given to 8 patients with psychalgia in whom a diagnosis of cenesthopathia associated with depression had been made. In these patients the drug proved to be ineffective; it was tolerated badly and the cenesthopathia frequently was increased. Thus, the effectiveness of the drug in patients with organic syndromes contrasted with its complete ineffectiveness in those with psychalgia. R 875 may be administered orally or subcutaneously; the intravenous route of administration is contraindicated because of the risk of respiratory accidents. Certain undesirable side-effects of the drug, such as malaise, nausea, vomiting, and oc— casionally drowsiness, require care in administering it; rest in bed is advisable, at least for the initial phase of the treatment. the Hearing Level Following Severe Poliomyelitis. R. Batson and F. McConnell. A. M. A. J. Dis. Child. 95:139-145 (Feb.) 1958 [Chicago]. A Study of The authors report on 87 selected, extensively paralyzed patients, between the ages of 5 and 37 years, with poliomyelitis who underwent detailed audiological assessment in order to determine the precise status of auditory acuity. The audiograms obtained from these patients were compared with those obtained during the same period from 2 groups of young adults without poliomyelitis. Near— ly all the pure-tone thresholds in the patients with poliomyelitis departed from the zero decibel reference level by more than 10 db., indicating some depression of hearing acuity as compared with the levels in the control subjects, which adhered ex— tremely closely to the zero decibel reference level, denoting normal threshold of audibility. Inspection of the pure-tone and speech thresholds in the patients with poliomyelitis revealed that more than 75% (28 patients) showed at least a slight depression of acuity which would be considered deviant from the norm. Numerous factors were considered in an effort to clarify the causative significance of the reduction in sensitivity to auditory stimuli in the patients with poliomyelitis. Factors such as age, sex, and possible drug therapy were not thought to influence these results. It was believed that depressed hearing responses could not be attributed to emotional disturbances or lethargy accompanying serious illness, since the patients gave oral responses to speech-hearing tests which required more physical energy than the effort required for signaling in response to pure-tone stimuli. It was found that the duration of disability did not correlate well with the extent of hearing loss. Several patients who were ambulatory and others who were in a wheelchair throughout the day demonstrated the same defect. A significant correlation, however, was observed between loss in hearing and loss in 117 vital capacity, in that patients with marked decrease in vital capacity were apt to show significantly greater hearing loss. The significance of this is not clear, and it may be only a reflection of the severity of the disease in a particular patient. Because there are many other clinical symptoms more distressing to the patient and the physician, and since communication with such patients is usually at close range, reduction in sensitivity to auditory stimuli can be easily overlooked even when it reaches moderate proportions of severity. The causative significance of this finding is not clear. New Group of Psychotomimetic Agents. L. C. Abood, A. M. Ostfeld and J. Biel. Proc. Soc. Exper. Biol. 8: Med. 97:483-486 (Feb.) 1958 [Utica, N. Y.]. A group of piperidyl benzilates possessing anticholinergic properties were recently synthesized as possible antispasmodics in the treatment of duodenal ulcer. In the course of therapeutic trials, it was found that the tertiary amine hydrochlorides of the benzilate esters, although active anticholinergics, produced undesirable side-effects, particulary hallucinations. The quaternary ammonium salts, on the other hand, were entirely devoid of such effects. The authors recently obtained a series of such substances and examined their psychotomimetic effects on animals and human subjects. The psychotogenic effects of the N-methyl-S-piperidyl benzilate and related congeners were tested on more than 40 human volunteers. Although some of the patients had limited knowledge of the psychotogenic action of the drugs, the majority of the subjects were completely unaware of their nature. All the agents were tested for their behavioral effects on animals, including some 30 Siamese fighting fish, 50 rodents, and 5 cats. The action of these agents on the Siamese fighting fish is comparable to the action described for lysergic acid diethyl amide (LSD) by Abramson. In rodents there were marked behavioral changes, such as initial excitement and marked hyperactivity, spontaneous squealing, lack of responsiveness to stimuli, muscular weakness, and lethargy. The compounds proved to be extremely powerful hallucinogens, in many respects more interesting than LSD and mescaline. When administered in oral doses of 5 to 15 mg. to human volunteers, distinct auditory and visual hallucinations occurred within 1 hour in every individual and recurred periodically for periods up to 10 hours after administration of the drug. Hallucinations were accompanied by gross distortions of visual images and severe alterations in feeling state. A number of subjects exhibited paranoid and megalomanic delusions, while the affective states ranged from a feeling of unpleasantness to extreme terror. Some of the subjects actually carried on conversations with imaginary individuals involving situations datA _ �118 MEDICAL LITERATURE ABSTRACTS ing back 10 to 20 years. The subjects receiving 10 mg. (orally) of N-methyl-S—piperidyl benzilate were in complete loss of contact with the environment for many hours while experiencing dramatic visual and auditory hallucinations. In many respects these anticholinergic agents come closer to simulating clinical psychoses than do mescaline and LSD. Of all the compounds tested for hallucinogenic properties, N-Methyl-S-piperidyl benzilate is the most potent, with the N-ethyl derivative being somewhat less effective. The tetramethyl derivative is considerably less effective than the N-ethyl derivative. The quaternary derivative is devoid of psychotogenic effects. As for the antispasmodic potency, although the 3 substances possessing psychotogenic properties are perhaps the most potent, the remaining compounds are still quite effective. Recurrence of Glioma of Cerebral Hemispheres: Histological Features and Therapeutic Possibilities. I. Papo and R. Tritapepe. Minerva chir. 12:144-31446 (Nov. 30) 1957 (In Italian) [Turin, Italy]. A second surgical procedure was performed on 34 patients with a recurrent supratentorial glioma. At the first operation this tumor appeared to be an astrocytoma in 7 patients, an oligodendroglioma in 7, a glioblastoma in 16, and a changing type of tumor in 4. Histopathological changes from astrocytoma to glioblastoma were observed in 1 patient 11 months after the first operation. It is possible, however, that areas of glioblastoma were originally present. Atypical areas were found in sections of the oligodendroglioma in 4 patients, who were operated on, from 35 to 103 months after the first operation. This phenomenon could justify the differentiation of the oligodendroglioma. The immature and atypical features of glioblastoma became more evident at the second operation. A type of glioma, which originally appeared to be oligodendroglioma with atypical areas, changed into glioblastoma in 1 patient 25 months after the first operation. The longest postoperative survival period in patients with astrocytoma was 19 months, in those with oligodendroglioma 21 month, in those with glioblastoma 26 months, and in those with a changing type of glioma 6 months. The authors point out that in most instances there is reappearance of the symptoms of glioma rather than its recurrence. Astrocytoma and oligodendroglioma often change into glioblastoma. There is no evidence to show whether this is due to the intrinsic character— istics of the tumor, to the surgical intervention, or to the x-ray therapy. A gradual higher degree of malignancy seems to develop even in those gliomas which did not originally present a neoplastic structure. Surgical therapy, with rare exceptions, affords no benefit to patients with recurrent glioblastoma but may be considered in patients with recurrent astrocytoma and oligodendroglioma. ].A.M.A., May 3, 1958 GYNECOLOGY & OBSTETRICS Induction of Ovulation in the Human: Therapeutic and Diagnostic Importance. H. S. Kupperman, J. A. Epstein, M. H. G. Blatt and A. Stone. Am. ]. Obst. 8: Gynec. 75:801-309 (Feb.) 1958 [St. Louis]. The authors explain on the basis of a diagram the current status of knowledge of the normal cyclic functioning of the pituitary-ovarian axis. A defect or alteration in any one of this normally sequential series of interactions can result in menstrual irregularities, ovulatory failure, and/0r amenorrhea. It was felt that specific hormone therapy in properly selected cases of failure of ovulation might artificially trigger the defective ovulatory mechanism. Since the proposed therapy theoreti— cally was to be specific for an isolated defect in ovulation, patients with other hormonal imbalances that secondarily influence the pituitary-ovarian axis were not included in the series. The patients who were euthyroid with normal adrenal function and who menstruated fairly regularly or who menstruated after therapy with progesterone and showed an absence of pregnanediol with a flat basal body temperature were judged as having ovulatory failure and fulfilled the criteria established for the “potentially responsive” cases. Those whose only endocrinopathy was failure of ovulation received 20 mg. of conjugated estrogens (equine), administered intravenously as a single dose, not sooner than the 18th day of the menstrual cycle. Of the 40 patients treated, 31 were barren, and 9 were either single women with menstrual irregularities or married women practicing contraception. Nine pregnancies resulted among the 17 infertile patients in whom ovulation was induced after no more than 2 injections of estrogens given intrave— nously at intervals determined by the patients’ own basal body temperature charts. The history of infertility in the 9 women in whom treatment resulted in pregnancy ranged from 2 to 7 years. One of the nonpregnant patients had her first spontaneous ovulatory menses in 3 years in the cycle subsequent to the menses induced by estrogens given intra— venously. Three other patients with a history of only infrequently occurring spontaneous ovulatory menses also had normal 28-day cycles for 1 period after that induced by estrogen. Moreover, 4 of the 9 pregnancies occurred during the cycle subsequent to the estrogen-induced ovulatory response. The negative responses were due to mechanical inability of the ovaries to respond to pituitary stimulation, i. e., polycystic ovaries of the Stein-Leventhallike syndrome, where the thickened fibrous tuniCa presents a mechanical barrier to ovulation. Surgical exploration with bilateral ovarian wedge resection was advised in 8 of 12 infertile patients who were negative responders. In each of the 8 patients op- �COUNCIL ON DRUGS 1634 Orphenadrine Hydrochloride.—N,N-Dimethyl-2(o-methyl-a-phenylbenzyloxy) ethylamine hydrochloride—The structural formula of orphenadrine hydrochloride may be represented as follows: [CH3 CH Cy 0 CH2CH2N\ CH3 ' HCI CH3 ~ Actions and Uses.—Orphenadrine hydrochloride, the o-methyl analogue of the antihistamine, diphenhydramine hydrochloride, produces a reduction of voluntary muscle spasm. The effect is central, presumably by an inhibitory action on cerebral motor areas, and resembles the central effects of atropine. Orphenadrine exerts only weak antihistaminic and sedative eHects. It is not primarily a peripherally acting anticholinergic agent since, in therapeutic doses, it produces few of the typical effects on smooth muscle, the eye, or secretory glands which characterize atropine and other peripheral para— sympathetic blocking agents. The skeletal muscle relaxation is not of the type produced by mephenesin or zoxazolamine, since there is no evidence that it interrupts transmission through peripheral neuromuscular pathways. Nor is there any indication that it acts at the myoneural junction in the manner of the curariform drugs; it does not cause ganglionic blockade. Orphenadrine has been used for the symptomatic management of paralysis agitans (Parkinson’s disease). Subjective observations seem to indicate that the drug may bring about beneficial effects in approximately half of the patients so treated. Rigidity is apparently relieved much more readily than is tremor; in occasional patients with severe spasticity, tremor may even be accentuated as the spasticity is relieved. Other salutary effects ascribed to the action of the drug include relief of oculogyria, sialorrhea, diaphoresis, blepharospasm, and disturbances in gait and balance. The drug also exerts a euphoriant effect which is useful in combating the depression and fatigue that frequently accompany this syndrome. In common with other antiparkinsonian drugs, the therapeutic effectiveness of orphenadrine diminishes with prolonged use. For this reason, and because it is considered somewhat less active than other antiparkinsonian drugs, orphenadrine is probably best employed as an adjunct to such other agents as procyclidine, trihexyphenidyl, cycrimine, or benztropine for the treatment of paralysis agitans. It may, however, be tried alone for patients who have become refractory to the other antiparkinsonian drugs. Because of its antispastic effect on voluntary muscle, orphenadrine has been proposed for use in a variety of clinical conditions which may be unrelated in etiology but in which pain due to J.A.M.A., July 26, 1958 skeletal muscle spasm is present. These have been described as sprains, strains, fibrositis, whiplash injuries, noninflammatory rheumatic and arthritic states, and torticollis. Although such use might be considered a logical clinical application of the drug’s pharmacological action, the evidence available to date is not adequate to permit a sound conclusion as to the ultimate effectiveness of such therapy. Further studies are also needed to confirm the possible usefulness of orphenadrine in the treatment of the extrapyramidal involvement associated with high doses of reserpine or phenothiazine-type tranquilizing agents. The clinical toxicity of orphenadrine hydrochloride appears to be low, at least with therapeutic doses. Thus far, side-effects have been limited to nausea, dryness of the mouth, dizziness, mild excitation, and occasional hallucinations. Most of these effects tend to subside or disappear with a reduction in dosage. Because of its anticholinergic classification, orphenadrine should be administered cautiously to patients with glaucoma, tachycardia, or urinary retention. Dosage—Orphenadrine hydrochloride is administered orally. The usual initial dose is 50 mg. given three times a day. This dosage should then be ad— justed according to the clinical response of the individual patient and the appearance of sideeffects. Preparations: tablets 50 mg. Applicable commercial name: Disipal. Biker Laboratories, Inc., cooperated by furnishing scientific data to aid in the evaluation of orphenadrine hydrochloride. Pancreatic Dornase.—A stabilized preparation of the enzyme, deoxyribonuclease, prepared by fractional precipitation of aqueous acid extracts of beef pancreas followed by dialysis, sterilization by filtration, and lyophilization. The activity of pancreatic dornase is determined by measuring the rate at which it reduces the viscosity of thymus deoxyribonucleic acid, potency being expressed in terms of units. One unit is an amount of enzyme which causes a drop of one viscosity unit in 10 minutes at 30 C, where the flow-time of water is taken as one viscosity unit. Actions and Uses—Pancreatic dornase is derived from beef pancreas, and, in contrast to the deoxyribonucleases produced by hemolytic streptococci (streptodornase), it is a single nuclease. Like streptodornase, it acts directly upon a substrate of deoxyribonucleoprotein (and deoxyribonucleic acid). The action of pancreatic dornase has been characterized as one of rapid depolymerization, with a resulting decrease in viscosity of purulent material. Pancreatic dornase degrades deoxyribonucleoprotein to relatively large-sized fragments, thus differing from streptodornase, which continues �Vol. 167, No. 13 COUNCIL ON DRUGS Mepazine Hydrochloride. — 10—[(1-Methyl-3—piperidyl ) methyl] phenothiazine hydrochloride—The structural formula of mepazine hydrochloride may be represented as follows: N-CH; < CH2 (II) .3 - HCI Actions and Uses—Mepazine hydrochloride is a phenothiazine derivative with actions and uses similar to, but not identical with, those of chlorpromazine. Although less potent, mepazine is not merely a weak chlorpromazine. Pharmacological studies indicate that it differs from chlorpromazine in that it does not lower the body temperature in rats as does chlorpromazine; it does not antagonize the waltzing syndrome in mice as does chlorpromazine; and it augments carotid sinus reflexes in cats whereas chlorpromazine inhibits them. The significance of these differences with respect to its clinical usefulness is, at present, unclear. The drug is used principally for its calming or tranquilizing action in the management of neuroses and psychoses in which anxiety, tension, agitation, and increased psychomotor activity are predominant; it is said to exert a selective action to normalize the thinking process of mentally or emotionally disturbed patients. Because mepazine is less potent than chlorpromazine, it does not produce the excessive sedation, drowsiness, and depression which frequently accompany therapy with the latter drug. On the other hand, the diminished potency of mepazine makes it less effective than chlorpromazine for the long—term control of the most severe forms of agitation and tension; it has little or no immediate effect on acute psychotic disturbances. In terms of over-all psychotherapeutic effectiveness, mepazine might be considered to be intermediate between the most potent agents such as chlorpromazine and the milder agents such as meprobamate. Like chlorpromazine and other phenothiazine derivatives, mepazine hydrochloride exerts an antiemetic effect and may be used for the control of nausea and vomiting from a variety of causes. The drug has also been used for its calming effects in surgery, in obstetrics, and in anesthesia. Other reported clinical applications include use in narcotic withdrawal to control restlessness and agitation, in chronic alcoholism to lessen anxiety and tensions, and in advanced neoplastic states to reduce the 1633 quantity of narcotics needed for control of pain. However, sufficient evidence is not available to establish its usefulness for the latter purposes. The acute toxicity of mepazine hydrochloride in experimental animals is less than that of chlorpromazine hydrochloride, and, in general, its clinical use is followed by a somewhat lower incidence of side-effects and untoward reactions. As already indicated, the usual doses produce a calming effect, with little sedation and drowsiness. Although jaundice has not as yet been observed with administration of mepazine, physicians should be alert to its possible occurrence. The drug should not be given to patients with a history of jaundice or liver damage. The most frequent side-effects of mepazine are atropine-like in nature and include blurring of vision, dryness of the mouth, and constipation. Since constipation can lead to more serious forms of intestinal obstruction, it should not be neglected; if necessary, laxatives should be prescribed. Less frequent side-effects include occasional dizziness, tremor, urinary retention, and transient hypoten— sion. The most serious toxic reaction to mepazine is referable to hematopoietic depression. As with chlorpromazine, the drug can produce leukopenia and granulocytopenia. It should, therefore, be used with discretion; peripheral blood cell counts are indicated at frequent intervals during therapy, and patients should be advised to report to the physician immediately upon the onset of fever, sore throat, or marked weakness. Because it potentiates the action of other central nervous system depressants, mepazine is contraindicated in patients under the influence of large doses of narcotics, barbiturates, or unknown large quantities of alcohol. Dosage.—Mepazine hydrochloride is administered orally. For the treatment of ambulatory neurotic patients, the usual initial dose is 25 mg. three or four times daily. This dosage can be increased every week by increments of 25 mg. per day until the desired effect has been attained. For those psychiatric conditions which are severe enough to require hospitalization of the patient, the initial dose is 100 mg. per day; this may be increased by 50 mg. every five to seven days. Maintenance dosage for such patients is usually 400 mg. per day or more. For the treatment of nausea and vomiting, the dosage ranges from 50 to 100 mg. per day. Dosage for use in surgical and obstetric patients has not been firmly established; single doses ranging from 50 to 200 mg. or more have been employed. Preparations: tablets 25, 50, and 100 mg. Applicable commercial name: Pacatal Hydrochloride. ’ �COUNCIL ON DRUGS 1632 the bacteria, as such, responded to the antibiotics, i. e., a transformation of the original bacterial arthritis into a chemical arthritis occurred. If the nodules were originally situated only in the skin (as clinically described) and only later appeared in the subcutaneous fat tissue (as described in the biopsy specimen and at autopsy), one could postulate that originally circulating trypsin caused vascular alterations in the deeper layer of the corium, with resultant skin nodules, and later the circulating lipase resulted in subcutaneous fat necrosis and subcutaneous nodules. Summary A chronic alcoholic patient had episodes of abdominal pain for two years, on the basis of a relapsing pancreatitis. Four weeks prior to his death, he developed swelling and tenderness of the various joints, with chills and fever. This could have been due to a bacterial polyarthritis associated with an acute pulmonary lesion such as pneumonia. The bacterial infection could have precipitated an acute pancreatic fat necrosis, on the basis of a Schwartzman phenomenon. Excessive amounts of circulating enzymes (trypsin and lipase) caused a striking involvement of the extrapancreatic fat tissue, cutaneous and subcutaneous nodules of fat necrosis, and necrosis of the periarticular fat tissue, initiating a chemical polyarthritis. The abdominal symptoms that appeared later were due to extensive J.A.M.A., July 26, 1958 mesenteric fat necrosis. The terminal jaundice was due to hepatocellular damage (toxic hepatitis) secondary to the pancreatic and extrapancreatic fat necrosis. The depression of blood calcium level was characteristic for extensive pancreatic fat necrosis and was due to saponification of the fatty acids liberated from neutral fat by the enzymatic action of pancreatic lipase. References 1. Roberts, N. J.; Baggenstoss, A. H.; and Comfort, M. W.: Acute Pancreatic Necrosis: Clinicopathologic Study, Am. J. Clin. Path. 20:742-764 (Aug) 1950. 2. Balser, W.: Ueber Fettnekrose, eine zuweilen todtliche Krankheit des Menschen, Virchows Arch. f. path. Anat., 90:520-535, 1882. 3. Hansemann, D.: Discussion in Verhandlungen arzt- licher Gesellschaften, Berl. klin. Wchnschr. 26:1115, 1889. Blauvelt, H.: Case of Acute Pancreatitis with Subcutaneous Fat Necrosis, Brit. J. Surg. 34:207-208 (Oct.) 1946. 4. Ponfick, E.: Ueber die sympathischen Erkrankungen des Knochenmarkes bei inneren Krankheiten, Virchows Arch. f. path. Anat. 56:534-556, 1872. Scarpelli, D. 0.: Fat Necrosis of Bone Marrow in Acute Pancreatitis, Am. J. Path. 32: 1077-1087 (Sept-Oct.) 1956. 5. Vogel, F. S.: Cerebral Demyelination and Focal Visceral Lesions in Case of Acute Hemorrhagic Pancreatitis, with Consideration of Possible Role of Circulating Enzymes in Causations of Lesions, A. M. A. Arch. Path. 52:355-362 (Oct) 1951. and Brakney, E. L.: Acute Hemorrhagic Pancreatic Necrosis Produced by Local Schwartzman Reaction: Experimental Study on Pancreatitis, J. A. M. A. 1553569574 (June 5) 1954. 7. Richman, A.: Acute Pancreatitis, Am. J. Med. 21:2466. Thal, A., 274 (Aug) 1956. COUNCIL ON DRUGS NEW AND NONOFFICIAL DRUGS Monographs and supplemental statements on drugs described here and in subsequent editions of New and Nonofficial Drugs are based on the evaluation of available scientific data and reports of investigations. H. D. KAUTZ, M.D., Secretary. Mepazine Acetate.—10-[ ( l-Methyl-S-piperidyl) methyl]phenothiazine acetate—The structural formula of mepazine acetate may be represented as follows : N " CH3 < 0 CH2 ‘ u CH3C OH Actions and Uses.—Mepazine acetate has the same actions and uses as mepazine hydrochloride, except that it is administered parenterally. (See the monograph on mepazine hydrochloride.) Dosage—Mepazine acetate is administered by intramuscular or intravenous injection. For severely agitated psychotic patients, the dose by either route is 50 mg. three or four times daily. For the treatment of severe nausea and vomiting, daily doses of 25 to 75 mg. are injected intramuscularly. Dosage for use in surgical and obstetric patients has not been firmly established, but single intramuscular or intravenous doses ranging from 50 to 200 mg. or more have been employed. Mepazine acetate may be injected parenterally either as the full-strength solution or as a diluted solution. Chloride or alkaline solutions should not be used as diluents since they cause precipitation of mepazine acetate. Oral therapy with the hydrochloride salt should be substituted for parenteral injection as soon as possible. Preparations: solution (injection) 50 mg. in 2 cc. Applicable commercial name: Pacatal Acetate. �1631 DIAGNOSTIC PROBLEMS Vol. 167, No. 13 with antigenic properties may cause a Schwartzman reaction, and antigenic specificity is not involved, i. e., the provocative antigen need not be identical with the sensitizing antigen. It may be recalled that, in the case under discussion, the joint involvement was conspicuous early in the course of the disease. There was no definite evidence of rheumatoid arthritis, either clinically or pathologically. Bacterial polyarthritis, specifically of gonorrheal origin, should be considered, although a most careful search failed to reveal any evidence for a gonorrheal infection of the genital organs. Gonorrhea] polyarthritis in the early stages shows a serous type of synovitis, and cultures of synovial fluid may be negative. The association of polyarthritis with periarticular fat necrosis and pancreatic fat necrosis raises the following possibilities: 1. There may have been a rheumatoid of coincidence polyarthritis a pure with pancreatic fat necrosis, whereby the peri- The interesting feature of this case was the onset, with polyarthritis followed by the appearance of disseminated subcutaneous nodules, while the abdominal symptoms appeared later. The involvement of the pancreas proper, revealed at autopsy, TABLE 3.—Etiology of Acute Pancreatitis“ I. The common channel theory: reflux of bile into pancreatic duct secondary to obstruction of ampulla of Vater a. Calculus at ampulla of Vater b. Spasrn of the sphincter of Oddi c. Edema II. Obstruction of pancreatic ducts by 1. Stone 2. Spasrn of sphincter of ampulla of Vater 3. 4. 5. 6. Fig. 5.—Relatively well-preserved body and tail of pancreas. Large hemorrhagic, chalky, mesenteric mass extends downward from pancreas. III. Alcohol A. Acute B. Nutritional IV. Metabolic disturbances 1. Malnutrition (as it has been produced experimentally by ethionine) was not too extensive; it is possible that extrapancreatic involvement occurred early and was limited to the retroperitoneal space, enabling the escape of pancreatic lipase into the circulation by way of the lymphatics, circumventing the enterohepatic circulation. The resultant high lipase levels may account for the extensive involvement of the joints and skin. The various theories about the etiology and 2. Site Trauma VI. Vascular changes (Necrotizing arteriolitis; periarteritis nodosa) VII. Infection (e. g. mumps, scpticemic, acute cholecystitis?) VIII. Allergic a. Schwart7m3.n phenomenon * Extrapancreatic Fat Necrosis In Literature In Our Case + + ....................... Retroperitoneal fat tissue .................. + + Mediastinal tat tissue ...................... + — Subepicardial fat tissue .................... + Subcutaneous fat tissue ................... + + — Bone marrow ............................... + Central nervous system + (perivascular demyelinization) ........... + — Periarticular fat tissue ..................... + necrosis at the site of the original intradermal Mesenteric fat tissue Hyperlipemia V. pathogenesis of acute pancreatitis are summarized in table 3. An interesting recent theory6 relates acute pancreatitis to the Schwartzman phenomenon, whereby intradermal injection of a cell-free filtrate of Salmonella, followed by intravenous injection of the same filtrate, results in hemorrhagic TABLE 2.—-Sites of Edema of papilla of Vater Tumor of pancreas Squamous metaplasia of the epithelium in the ducts Surgical ligature —— V injection. Using this principle, injection of a bacterial endotoxin in sublethal doses into a pancreatic duct, with a subsequent provocative intravenous injection of the same endotoxin, has produced a fulminating pancreatitis in rabbits. Any substance Richman" (modified). articular fat necrosis occurred in a site of decreased resistance; but, despite the high incidence of rheumatoid arthritis and the relative frequency of pancreatitis, such a coincidence of these with periarticular fat necrosis has never been reported. 2. The pancreatic fat necrosis in the early clinically latent phase of the disease, with liberation of lipase into the circulating blood, may have led to a chemical polyarthritis due to extensive periarticular fat necrosis. 3. A bacterial (gonorrheal?) polyarthritis preceding pancreatitis cannot be excluded, despite the negative bacteriologic findings. One might speculate, on the basis of morphologic evidence of a chronic pancreatitis, that the pancreas was already sensitized. A bacterial polyarthritis could then have provided an antigenic provocation for a Schwartzman phenomenon, which led to an acute pancreatic fat necrosis, in the course of which large amounts of circulating trypsin and lipase were liberated. The circulating lipase caused a peri— articular fat necrosis, which in turn caused a proression of the polyarthritis, despite the fact that DEPAR MENT OF EXPERIMENIAL PSYCHIATRY HILLSIDE HOSPITAL GLEN OAKS, N. Y. JUL3 1 ‘5. �elements. 3. The rhythm of 4 -6 cycle/sec in the sub- cortical area disappears completely following administration of chlorpromazine in the dosage of 7.5—10 mg per kg, and does not appear even in response to painful stimulation with electric current; which undoubtedly indicates an inhibitory effect of chlorpromazine on adrenergic elements of these structures. 4. Administration of epinephrine against a background of a pronounced chlorpromazine effect produces a temporary decrease in symptoms of the chlorpromaaine effect on the organism. Accompanying this, there is a tendency to activation of electrical activity in all parts of the brain. 5. Comparison of our data with those in the literature leads us to the conclusion that the adrenergic substrate of the reticular formation exerts a complex influence on individual structures within the reticular formation as well as on the cerebral cortex. This action is apparently associated with metabolism of adrenergic substances, and for this reason it changes in a reciprocal manner as a result of the action of epinephrine and chlorpromazine. RE FERENCES 1. 2. AGAFONOV, V.G., Zhurn. nevropatolog. ipsikhiatr., 56, ANOKHIN, P.K., No. 2, 94, 1956. XX Mezhdunarodnyi kon— v Briussele (Collected gress fiziologov papers, 20th International Congress of Physiologists in Brussels), 151, M. , 3. 4. 5. 6. ’ 7. 8. 1956; Fiziolog. zhurn. USSR, 43, No. 11, 1072, 1957; Zhurn. vyssh. nervn. deiat.. 9, No. 4, 489, 1959. ANOKHINA, I.P., Zhurn. nevropatologi psikhiatr., 56, No. 6, 478, 1956. BAN'I‘SEKINA, M.M., Biull. eksper. biolog. i med., No. 8, 3, 1959. VERSHININ, N.V., Farmakologiiamchobnik) 137, M., 1952. GAVLICHEK, V., Fiziolog. Zhurn. USSR, 44, No. 4, 305, 1958. DOBRZHANSKAIA, A.K., Zhurn. vyld. nervn. deiat.. 9, No. 1, 22, 1959. POPOV, E.A. and T.A. NEVZOROVA, Zhurn. nevropatolog. No. 7, 559, 1956. 9. SHUMILLNA, 11. 12. 13. 14. 15. 56. A.I., Zhurn. nevropatolog. ipsikhiatr, 56, 10. ipsikhiatr.. No. 2, 118, 1956; Kinf. po vopr. elektrofiziolog. ts. n. s.. Tez. dokl. (Abstracts of Confsnnes on Problems of Electrophysiology of the C.N.S.), 144, M., 1958. BRADLEY, P.B. and A.I. HAUCE, EIG clin. Neurophysiol., 9, 2, 191, 1957. DELL, P., M. BONVALLET and A. HUGELIN, Journ. Physiol., 48, 403, 1956. GANGLOF‘F, H. and M. MONNIER, Physiol. et Pharmacol., acta, 15, l, 83, 1957. RINALDI, F. and H. HIMWICH, Dis. Nerv. System, 16, 5, 1955. ROTHBALLER, A.B., EEG clin. Neurophysiol., 8, 603, 1956. VOGT, M., Journ. Physiol.. 123, 451, 1954. THE ANTAGONISTIC ACTION OF CHOLINOMIMECTIC AND CENTRAL CHOLINOLYTIC AGENTS ON THE EEG OF THE RABBIT P.P. DENISENKO, Division of Pharmacology, Institute of Experimental Medicine, Um}! Academy of Medical Sciences, Leningrad (Received January 21, 1959) Today the presence of cholinerglc synapses in the central nervous system, particularly in the cerebral cortex, is considered an estab— lished fact. The cerebral cortex can be stimulated with acetylcholine (Markosian, 1937; Feldberg, 1950) and various "cholinopositive" substances — cholinomimetics (nicotine, arecoline) and anticholinesterases (physostigmine and diethyl p-nitrophenyl phosphate, or phos- phacol) — which, like acetylcholine, are capable of causing excitation of choline-roactive systems (Rizzolo, 1929; Miller, 1037; Stewart, 1952; Michaells, Finesinger, Ver— ster, Erickson, 1954). The rate of profile- tion of acetylcholine in the cortex depends on the functional state of the cortex (Macintosh and Oborin, 1953). The establishment of the role and significance �of aeetylcholine in the activity of the cortex and other parts of the brain has aided in the under— standing and the correct evaluation and interpretation of the influence of cholinolytic drugs such as atropine, scopolamine, etc. upon psychic activity. ()1 the other hand, it has given rise to the synthesis and investigation of new sub- stances with cholinolytic action, inasmuch as this opens up an opportunity for entirely new methods in drug therapy of psychic and nervous diseases and increases the armamentarium of sedative and anticonvulsive drugs, as well as antidotes for poisoning with anticholinesterases. Among the cholinolytics known today there are a considerable number of substances capable of exerting a blocking influence chiefly on cholinergic structures in the central nervous system. Owing to the obvious predominance of central cholinolytic action over peripheral, substances of this type have, at the suggestion of S.V. Anichkov, been classed in a separate group — central cholinolytic agents.1 In chemical structure, central cholinolytic agents in most cases are complex esters of amino alcohols and aromatic acids, such 'as diethylaminoethanol and diphenylacetic acid. Pharmacologic studies of central cholinolytic agents are conducted by various methods, especially the methods of conditioned reflexes and electroencephalography; among others are experiments with convulsions produced by nicotine, arecoline, pentylenetetrazol, and other ' drugs. As research, electroencephalography is being increasingly widely used. However, out of the large group of cen— tral cholinolytic agents, this method has been used only for partial investigation of caramiphen (Pentaphen, Parpanit), benactyzine (IEMa method of 22, Diazil), and Z—diethylaminoethyl diphenylacetate (Diphacil, Trasentine) (Schallek and Smith, 1952; Paskov, 1958). In the current study an electrophysiological investigation was made of five new substances synthetized by S. F. Torf in the chemical lab— oratory of the Division of Pharmacology, In— stitute Fxperimental Medicine, USSR Acad— emy of Medical Sciences: Preparation IBM263 (benzene sulfonate 0f l—diethylaniinoisopropyl methoxyd l pheny lacetate . Preparation IEM-265, or Methyldiphacil (racemic l—diethylaminoisop ropyl diphenylacetate hydrochloride), Preparation [EM—268 (racemic 1-dimethyl aminoisopropyl diphenylacetate hydrochloride), Preparation [EM—273 (benzene— sulfonate of 2-methylcholine diphenylacetate), Preparation IBM—275, or Methyldiazil (racemic l «timethylaminoisopropyl benzilate hydrochloride». We also made a comparative study of the influence of certain other central cholino1 ‘The term "central cholinolytic agent" was approved and accepted at the 9th All-Union Conference of Physiologists, Biochemists, and Pharmacologists in 1959. 125 olytic agents, namely Diphacil, Diazil, Pentaphen, Aprophen (fl-diethylaminoethyl diphenylpropionate hydrochloride), Diprophen w—di-Npropyl thiodiphenylacetate hydrochloride), and Tropacin (tropine diphenylacetate hydrochloride) upon the bioelectrical activity of the brain. METHOD Experiments were conducted on rabbits weighing 3 —4 kg with implanted nichrome or platinum electrodes. Potentials from the cortex (temporal and occipital areas), thalamus, and hypothalamus were recorded unipolarly. Experimental equipment consisted of a differential amplifier from the Moscow experimental shop and either an ink-writing or a type MPO—2 oscillograph. The amplitude—frequency characteristic of the ink-writing apparatus in the O — 70 cycle/sec range was flat to within 20%. The influence of the central cholinolytics, as well as of acetylcholine and cholinomimetics (nicotine and arecoline), on the spontaneous electrical activity of various parts of the brain was investigated. In addition, electroencephalography was used to show the existence of antagonism between these two groups of substances. No substance was administered to the same animal more than once a week. EXPERIME NT A l. RESULTS Before proceeding with the study of the in— fluence of central cholinolytic agents on the electrical activity of various parts of the brain, we considered it necessary to determine how it changes under the influence of acetylvholine and cholinomimetics (nicotine and arecoline). This was essential because one of the tests in the study of substances of central cholinolytic action involves a determination of their anticonvulsive activity in nicotine and arecoline convulsions (Bovet and Longo, 1951; Kharauzov. 1954; Artem'ev, 1955. 1957; Zeimal', 1955, 1957; Golikov, 1956; Liberman, 1956; Sokolova, 1957; Smirnov, 1957; Fedorchuk, 1958; Jacobson, 1958). Intravenous injection of nicotine and arecoline (0.4 mg/kg) produces tremor and convulsions in the animal due to the stimulating effect of these substances on the choline—reactive systems of the brain. For further evaluation and analysis of the influence of central cholinolytic agents on the bioelectrical activity of the brain it was important to compare the picture of general excitation of the animal with the changes in the electrical potentials of the brain. Normally, the electrocorticogram of the rabbit was made up chiefly of waves of medium amplitude (30 -60 uv) and a rate of 4 —9 per second. Superimposed on these we re fast small waves with an amplitude of up to 15 av. Occasionally single high-amplitude waves appeared (5 —8 per min). As a rule, potentials �large doses (0.4 -0.5 mg/kugi. 1.9. .dosos which usually cause a convulsive seizure is animal. In the last case we recorded simultaneously the champs in brain potentials and of the thalamus and hypothalamus, were faster than those of the cortex but of considerably smaller amplitude (Fig. 1. 1-3; Fig. 2, 1-3; l-‘ig. 3). .l FIG. 1. Influence of nicotine and Diphacil on the RH; - - - somatosensory cortex; B hypothalamus. l normal EEG; 2 — 3 min after intravenous administration of nicotine in a dose of 0.43 mg/kg; 3 — prior to administration of Diphacil (6 days after the initial application of nicotine); 4 — 5 min after intravenous administration of Diphacil in a dose of 5 rug/kg; 5 — absence of stimulating action of nicotine (0.43 mg/kg) administered after Diphacil; 6 — 4 hours after administration of the preparations. A Cholinomimetics (nicotine and arecoline) were used in small doses (0.25 mg/kg) and the contractions in the hind limb. After the administration of choiinomimstios 126 �no FIG. 2. Antagonism of cholinomimetic arecoline and choline— lytic Methyldiazil displayed in the rabbit EEG. A — - somatosensory cortex, B thalamus. 1 — normal EEG; 2 — 3 min after administration of arecoline in a dose of 0.45 mg/kg; 3 restoration of original state; 4 — 5 min after intravenous- administration of Methyldiazil (0.5 mg/kg); 5 — absence of stimulating influence of are coline in the same dose after Methyldiazil; 6 — 8 hours after administration of the preparations. - the animal's behavior changed abruptly, espe— cially if administration occurred against a background of general depression which was usually observed after the rabbit had temporarily been in a darkened room. Whereas prior to the ad— ministration of the preparations the rabbit lay quietly in its stand with its head between its paws and at times even semi-asleep, following administration of nicotine or arecoline it exhibited unrest, turned its head, jerked, pricked up its ears and reacted keenly to any external stimulation. Mter epinephrine was given intravenously in the dose of 0.4 mg/kg, severe convulsive movements were observed lasting, with interruptions, for several min— utes. Along with the changes in the behavior of the animals already mentioned, there were also marked changes in the spontaneous elec— trical activity of the brain (Figs. 1 and 2). These changes took the form of an increase in amplitude and number of the high—frequency potentials and quantitative diminution, to and including complete disappearance, of high- �FIG. 3. EEGs in various parts of the rabbit brain before (upper oscillograms) and 5 min after (lower oscillograms) intravenous administration of central cholinolytic agents in the following doses: Diazil 0.5 mg/kg (A), Diphacil 5 mg/kg (B), Aprophen 2 mg/kg (C). Left, cortex; right, subcortical structures. amplitude slow waves. Changes in the EEG appearing after administration of nicotine evidently are not the result of induction of muscle currents but reflect changes in the electrical activity of the brain. inasmuch as they precede motor excitation of the animal. Such a supposition appears to be even more probable because 10 — 15 min after the strongest general excitation produced by administration of nicotine, the rabbit calms down (muscle tone becomes normal, movements decrease or disappear, and the animal reposes quietly in its stand) . Simultaneously with this, lowering of general EEG activity is observed, with an increase in the number of abrupt high waves and a diminution of the high-— frequency discharges. Comparison of changes in the EEGs of different parts of the brain discloses that follow— ing administration of nicotine cortical potentials show the first and strongest changes. Changes in the EEGs of the hypothalamus, thalamus, and other subcortical structures are less pronounced and appear later than the cortical changes. The other cholinomimetic, arecoline, in doses of 0.4-0.5 mg/kg also had a stimulating action: it caused unrest. convulsions, and tremor, which, as is generally recognized, are the result of the stimulating action of are— coline on the choline-reactive systems of the brain. The stimulating action of arecoline on ~ 128 the brain is reflected in the EEG to the same extent as is that of nicotine. As shown in Fig. 2, the amplitude of the fast oscillations, especially in the subcortex, rises sharply and the number of oscillations increases appreciably. Typical changes characteristic of excitation appeared in the EEG following intravenous injection of acetylcholine in doses of 0. l - 0. 8 ‘y/kg. In doses of 1 ~50 'y/kg acetylchouno produced such changes only du ring the first, very brief timevinterval after the injection; this was followed by a pronounced depression of electrical activity. Thus, in experiments with cholinomimetics (nicotine and arecoline) and acetylcholine. a characteristic picture of EEG changes a» crease in amplitude and number of fut rhythms and a decrease in slow waves) was produced which in combination with changes in the general condition and behavior of the rabbits (excitation, tremor, convulsions) permits us to regard, with a high degree of probability, the observed picture of EEG changes as a roll..tion of cerebral excitation. In addition, a clear—cut distinction was observed between the action of nicotine and arecoline on the cholinergic systems of the brain: the first and most marked changes uder the influence of nicotine are in the cortical EEG, but under the influence of arecoline, in the subcortical structures. The changes produced by �arecoline and nicotine are not identical in duration. The intensification of activity prochiced by administration of nicotine lasts a maximum of 10—15 min and is often succeeded by a general dqreesion of electrical activity. Potentials of normal magnitude and rhythm appear in l - 1 1/2 hours, but the sensitivity of the cholinsrgie systems to nicotine and mani— festation of the corresponding reaction to nicotine are not restored for 4 -—5 days. Arecoline a more lasting excitation which is succeeded by the normal EEG picture. 0n repeated one hour after the first injection, one may observe complete restoration of sensitivity b arecoline. Ahinistration of central cholinolytic agents gave opposite results. General calming of the animal was observed following administration of cholinolytic agents. This was manifested especially prominently when central cholinolytic agents were administered to animals which had not yet become accustomed to the stand and the experimental conditions, or when the prepara— tions were administered at the very beginning of the experiment when the rabbit remained somewhat excited. In such instances the ad— ministration of a cholinolytic agent caused jerking of the paw, attempts to escape the stand, head movement, and reactions to external stimuli (noise, light, and sound) to disappear immediately. Two to five minutes following admin— istration of Diphacil, Diasil, Pentaphen, Aprophen, and other substances in the group under investigation, the state of unrest was succeeded by general depression. of an intensity which depended on the dose of the cholinolytic agent. The rabbit lay quietly in the stand and reacted feebly to external stimulation. Simultaneously with the change in the state and behavior of the animal, characteristic changes were also observed in the electrical activity of the brain: slow waves (1 - 2 per sec) lg) to ”0 v predominated in the EEG. High— a potentials disappeared entirely or marke‘y decreased in number (Figs. 1, 2, 3). These cheapo in electrical activity following the injection of central cholinolytic agents could be registered in all portions of the brain which were under study. The intensity and duration of theee depended on the dosage of the agents admhistened as well as on their properties. This. similar changes could be observed following intravenous administration pm Motion frwy We of Diphacil. 5 mar/ks. Wen, Mammal-oil. 2 mar/ks; mg/kg; Diaail, 0.6 mg/kg; Methyl— easu. 0.1 mg/kg; and Diprophen, 15 mg/kg. other hand, intravenous administration cholinolytic agents in identical heee redted in dissimilar changes in the thalamus. and hypothalad cortex, such as Diazil and Methylmus. Motions dis-ll greater changes in the potentials of the structures than of the cortex. whereas administration of Methyldiphacil and Difllacil renlted in greater changes in the cortex. Under the influence of Pentaphen. 1 it.eeet ~ ‘ I” h a“ Meal 129 131’ Aprophen, and to some extent Methyldiphacil, changes in the EEGs cf the cortex and subcortex were approximately identical (Fig. 3). Duration of the action of the preparations under study varied between 2 and 30 hours depending, apparently, on the dosage and their physico-chemical properties. The strongest and most lasting effect was observed after the administration of Diazil and Methyldiazil, and the weakest and shortest after administration of [EM-268 and Diprophen. Thus, experiments with central cholinolytic agents showed that they cause general depres— sion of the animal, a decrease in reflex activity and characteristic changes in the EEG (predominance of slow, high-amplitude potentials). Comparison of changes, following administra— tion of central cholinolytic agents, in behavior, general condition, and EEG, which were oppo— site to those seen after administration of cholinomimetics (nicotine and arecoline), per— mits the conclusion that the EEG changes produced by central cholinolytic agents reflect a state of cerebral depression due to blocking of the cholinergic systems of the brain. From our own and published data we knew of the antagonistic relationships between cholino— lytic and cholinomimetic agents that have been demonstrated on peripheral structures as well as in experiments with conditioned reflexes and with nicotine and arecoline convulsions. It was of interest to find out whether these antagonistic relationships are exhibited in the EEG. A special series of experiments were therefore carried out for the purpose of investigating the influences of central cholinolytic agents on the EEG already altered by the administration of cholinomimetics, and vice versa. It was found that central cholinolytic agents in definite doses prevent and cancel the action of cholinomimetics. As shown in Fig. 1, Di— phacil prevented the action of nicotine administered in a dose which usually produced a pro— nounced rise in electrical activity. Convulsions were the external manifestation of the stimulating influence of nicotine on the brain. Nicotine administered after Diphacil, Methyldiphacil, Pentaphen. and other preparations never pro— duced convulsions. Similar results were obtained wifli arecoline: preliminary administra— tion of Methyldiazil prevented the effect of a convulsive dose of arecoline (Fig. 2). Figs. 1 and 2 show that normally both of these cholinomimetics exerted a pronounced influence on the EEG. Their administration in the same doses against a background of action by central cholinolytic agents was without effect; the EEG remained the same as after administration of central cholinolytic agents Diphacil and Methyldianil. In these experiments there were also data indicating a certain preferential antagonism batman arecoline and Diazil or Methyldiazil and between nicotine and Diphacil or Methyldiphsoil. Preparations such as Pentaphen and Aprophen prevent and cancel the action of - �arecoline and nicotine equally effectively. as application clinical for agents tion of these cholinolytics and tranquilizers. DISC U$ION REFERENCES experi— the of the course in clear It became experito an administration following ments that (Diphacil, preparations older of animal mental as and others) Aprophen. Pentaphen, Diazil, S.V.. In the book: Novye i eksperimente v sredstva lekarstvennye 1. ANICHKOV. and in experiments klinike (New drugs clinic), 5. L.. 1958. protivosudo— Izyskanie V.S., ARTEM'EV, 2. rozhnykh sredstv metodom eksperimental'anticonvulsive for search (A noi terapii agents by the method of experimental 1955; L. Dissertation. , therapy). i atsetilkholina rol' Fiziologicheskaia izyskanie novykh lekarstvennykh of role physiological (The veshchestv new for search the and acetylcholine drugs), 1. L.. 1.957. soveshch. dokl. Tez. GOLIKOV, S.N., 3. i claim. strukt. mezhdu sviazi p0 probl. the of (Abstracts veshchestv lekarstv. between Connection the on Conference 13, of Drugs), Action and Structure Tarw, 1956. dokl. Tez. iref. 4. DENISENKO, P.P., deiat. nervn. vyssh. probl. soveshch. p0 Problems on Conference the of (Abstracts of Higher Nervous Activity). No. 1, ‘6, 1... 1958. 1 mom. 5. ZEIMAL‘, E.V., Biuli. eksper.book: the in 1955. 42, 1, 39, med., Fiziologicheskaia roi' atsetilkholinai izyskanie novykh 106m rstvennykh of veshchestv (The physiological role new for search the and acetylcholine drugs), 79, 1... 1957. itoksiFarmakolog. LIBERMAN, 5.8., 6. kolog.. 6, 10, 1956. bioBiull. eksper. A.A., MARHEIAN, 7. 1937. 4 119, (2), med., log. Farmakoiogicholtm D.S., PASKOV', 8. GEM-275), Methyldiazil — agents well as newer — sigIBM-268 and (IBM-265), Methyldiphacil slow EEG: large the in develop nificant changes be— waves medium and waves appear and small be may changes These come less numerous. of cere— state of a manifestations regarded as confirmed interpretation an bral depression, the of experibehavior and condition the by mental animals. The depressant effect of central cholinolytic nature, cholinolytic of a is brain the agents on action the cancel and prevent inasmuch as they (nicotine, cholinomimetics and of acetylcholine stimu— a exert themselves which by arecoline), some is There brain. the on influence lating already which was antagonism, preferential discussed earlier. more one as serve hand, one on These data, synapses cholinergic of existence the of proof other the on system; nervous in the central the that proof convincing hand, they provide not characteristic is central cholinolytic effect of an but agents, cholinolytic individual only of of esters (complex entire class of compounds acids) which have amino alcohols and aromatic been called "central cholinolytic agents." and new that hope to Our data permit us found be posmay agents cholinolytic powerful Two action. central sessing a predominantly —- [EM-265 (Methyl— of the preparations studied — are (Methyldiazil) IBM-275 and diphacil) and tranquilizers as trials undergoing clinical cholinolytic drugs. 1 CONC LU SION'S to used was Electroencephalography 1. of properties cholinolytic establish the central complex representing of substances a number and aromatic diethylaminoethanol of esters acids. in manifested 2. A pronounced antagonism, central between exists EEG, their action on the agents. cholinomimetic and cholinolytic be— interdependence 3. There is a definite of action the and tween the chemical structure to the degree cholinolytic agents. According study under the preparations of vigor of action, of diminorder following the in may be arranged ishing strength: Methyldiphacil, and Aprophen phen, Diprophen. and IBM—268, Preparation chocentral the 4. The EEG data regarding esters complex of series of this ytic action recommenda— the which permits investigations u kharakteristika alkaloids Mann antikholinesteraznogv sredstva (Pharma— alkaloid of the characterizatmn cological Disantichoiinesterase), an nivaline as sertation, L.. 1958. rol' Fiziologicheskaia 9. SOKOLOVA, LA. . atsetilkholina i izyskanie novyldl vennykh veshchestv (The phydol“ role of acetylcholine and the 1957. 122, L., drugs), new 1 Parmakolog. 10. FEDORCHUK, IU. G.. 130 imh m ' toksil<olog., 4, 52, 1953. 11. KHARAUZOV, giperkine zov N.A., Farmakoterapfll tsentral'nogo proiskhoal- hyper“ deniia (Pharmacotherapy of of central origin). Dissertation. L.. 1954; Izbiratel'noe vliianie lekar not.” tsentral'nuiu na veshchestv nykh of influence (Selective nuiu sistemy -_., L.. system). nervous central the on ' ‘ �13. FELDBERG, W., Brit. Med. Bull., 6, 11, 312, 1950. 14. JACOEON, E... Antibiot. Med. a. Clin. Therapy, 5, 2, 89, 1958. 15. MACINTOSH, F. and P. OBORIN, Abstr. Comm. XIX Intern. Physiol. Congr. 580, Montreal, 1953. 16. MICHAELIS, M., J.E. FINESINGER, F. VERSTER and R.W. ERICKSON, Journ. Pharmacol., III, 2, 169, THE EFFECTS OF 17. 18. 19. ' 20. 1954. MILLER, F.R.. Journ. Physiol., 91, 2, 212, 1937. RIZZOLO, A., Arch. Farmacol., sper.,50, 16, 1929. Tsit. p0: Chem. Abstr., 24, 1158, 1930. SCHALLEK, W. and 1LT. SMITH, Journ. Pharmacol., 104, 3, 291, 1952. STEWART, W., Brit. Journ. Pharmacol., 7, 2, 270, 1952. HYPOCAPNIA ON THE FUNCTIONAL STATE OF THE RESPIRATORY CENTER G.L. FEL’DMAN, Department of Human and Animal Physiology, State University, Rostov-on-Don (Received January 8, 1960) METHODS The question of the physiological mechanism and biological function of sleep has long interested investigators (Legendre and Pierron, 1913; von Eoonomo, 1925; Hess, 1949; and others) and has also been the subject of syste— matic study in experiments conducted at the Pavlov Laboratory (Pavlov, 1911, 1923, 1935; Krasnogorskii, 1911; Rozhanskji, 1913; Petrova, 1941; Asratian, 1953; Anokhin, 1958). Ole method adopted for exploring the nature of sleep inhibition and its effect on normal behav— ior of the brain is that of artificial sleep depri— vation. Thus, as early as 1891, M.I. Manasseina demonstrated that keeping puppies awake for a period of 4 to 5 days will lead to death by degeneration of the nervous tissue of the brain Legendre and Pierron (1913) described histo— logical changes of the neurons in the region of the motor analyzer in the cerebral cortex of adult dogs deprived of sleep for 7 days. Prolonged sleep deprivation produces severe derangement of brain function, manifested in a derangement of the processes regulating biochemical activity (Fedorov and Sikolskaia, 1M1), nervous breakdown (Ukolova, 1959), and so on. Reports by N. Kleitman (1923), N. Kleitman and M. Li (1923), Tyler (1955), Bredlend (1955), and others, describe changes during experiments in sleep deprivation in The present study was conducted on 34 ani— mals (10 kittens between 18 and 30 days old, 13 kittens between 35 and 55 days old, 6 adult cats, and 5 puppies between 25 and 40 days old), with electrodes chronically implanted according to the method described by A. B. Kogan (1952). The electrodes were implanted in the region of the motor and visual analyzers of the cortex and in the subcortical sections of the brain. Potentials were recorded bipolarly with an interval between the electrodes of 3 mm for the surface electrodes, 1.5 mm for the depth electrodes. Recording was done with a two—channel electroencephalograph with optical recording or a four—channel ink-writing electro— encephalograph. Physiological tests were made of the effects of a sound stimulus (intermittent siren twice per second) and a tactile stimulus (an air current). Parallel with this, and with the same chronically implanted electrodes, determinations were made of the thresholds for direct electrical stimulation of the correspond— ing points in the brain. For purposes of comparison, we studied the intensity relationships for the motor components of the natural conditioned food reflex (Varukha, 1954) and coordination tests in which we analyzed the placement of the footprints made by the animals in walking. Throughout the period of wakefulness the animals were permitted to move about without restraint and were constantly observed under natural light by day and bright elect‘ric illumination at night. We kept the humans. Thus a study of the effects extended wake— fulness has upon brain function as revealed in the EEG and other indicators of. the functional state of the brain is a matter of definite interest. 131 �may be somewhat wider than the actual distribution, due to analytical errors and biological variation in the ratio of single bone to whole skeleton. It is predicted that in 1966 the average young child in the world will have a skeletal concentration of strontium-90 of about 4 MIC of strontium-90 per gram of calcium; that 10 percent may have a concentration of 8 one; that 1 percent may have a level of 20 uuc; and that none will have a level exceeding 80 one of strontium-90 per gram of calcium. References and Notes 1. Lamont Geological Observatory Contribution No. 347. This research is being supported by the Division of Biology and Medicine of the U.S. Atomic Energy Commission. Many individuals have contributed valuable suggestions and criticism. These include E. C. Anderson, C. L. Dunham, M. Eisenbud, H. Hollister. W. H. Langham, W. F. Libby, J. F. Loutit, L. Machta, W. G. Marley, N. G. Stewart, H. L. Volchok, and H. Q. Woodard. We also express our gratitude to the many medical doctors around the world who have assisted in essential sample procurement. Rieta Slakter is in charge of the Lamont analytical laboratory. R. Alley, W. Blake, T. Bott, J. Brokaw, D. IO :55» 5. 6. 7. 8. 9. 10. 11. 12. Harlin, M. Mandel,.._G. Markle, J. Rippey, J. Sonderburg, and R. lWoehr assisted in various aspects of the techniCal and secretarial work. J. L. Kulp, W. R. Eckelmann, A. R. Schulert, Science 125, 219 (1957). W. R. Eckelmann, J. L. Kulp, A. R. Schulert, ibid. 127, 266 (1958). The two commercial laboratories were Isotopes, Inc., Westwotid, N.J., and Nuclear Sci— ence and Engineering Corp., Pittsburgh, Pa. H. L. Volchok, J. L. Kulp, W. R. Eckelmann, J. Gaetjen, Ann. N;.Y. Acad. Sci. 71, l, 293 (1957); H. L. Volchok and J. L. Kulp, Nucleonicr 13, 49 (1955). D. L. Thurber, J. L. Kulp, E. J. Hodges, P. W. Gast, M. Warhpler, Science 128, 256 ' (1958). A. R. Schulert, E. A. Peets, D. Laszlo, H. Spencer, M. Charles, J. Samachson, Intern. ]. Appl. Radiation and Isotopes 4, 144 (1959). A. R. Schulert, E. J. Hodges, E. S. Lenhoff, J. L. Kulp, Health Phys., in press. J. L. Kulp and R. Slakter, in preparation. F. J. Bryant, A. C. Chamberlain, G. S. Spicer, M. S. W. Webb, Brit. Med. ]. l, 1371 (1958). Health and Safety Lab. U.S. Atomic Energy Comm. Publ. No. HASL—42 (16 June 1958). J. L. Kulp and R. Slakter, Science 128, 86 (1958). D. V. Booker, F. J. Bryant, A. C. Chamberlain, A. Morgan, G. S. Spicer, Atomic Energy Research Establ. (G. Brit.) Publ. No. HP/R 2182 (1957); F. J. Bryant, A. C. Chamberlain, A. Morgan, G. S. Spicer, Atomic Energy Research Establ. (G. Brit.) Publ. No. HP/R 2056 (1957). H. H. Mitchell, T. S. Hamilton, F. R. Steg~ 13. 14. Isosterism and Competitive Phenomena in Drugs q_ A study of structure-activity relationships in agents acting upon autonomic effector cells Daniel Bovet Making use of the considerable means offered by organic synthesis, many investigators have directed their efforts to the field of therapeutics and have sought to lay the groundwork for a pharmaceutical chemistry or, better, for a chemical pharmacology. If such an ambitious program has not yet been fully realized, nevertheless, during the last five decades, one can notice the emergence of a few basic concepts whose usefulness continues to be confirmed. This is particularly true of the concepts of isosterism and of competition. Numerous drugs were first derived from products of biological origin, par- ticularly the alkaloids. The elucidation of their structure helped chemists to embark on syntheses of analogous compounds. In this respect cocaine, atropine, 8 MAY 1959 and morphine are good illustrative examples. The molecules synthesized according to their models exhibited clinically useful anesthetic properties, spasmolytic activity, or pronounced analgesic effects. In each case, chemical similarity produces in-some-way-related physiological properties. Analogous observations have subsequently been gathered in many other fields, but it has also become evident that sometimes very different, even antagonistic, pharmacological properties may be found in chemically similar molecules. Despite the fact that the concept of “antimetabolite” is based on rather old experiments, it was defined essentially in the field of “antivitamins”; the work of Woods (1940) and Fildes (1940) on 15. 16. 17. 18. gerda, H. W. Bean, J. Biol. Chem. 158, 625 (1945). H. Spencer, D. Laszlo, M. Brothers, ]. Clin. Invest. 36, 680 (1957); “Deposition and Retention of Ingested Strontium-90 in the Skeleton" (Washington, D.C., 23 Apr. 1957), committee report (official use only). C. L. Comar, R. H. Wasserman, M. M. Nold, Proc. Soc. Exptl. Biol. Med. 92, 859 (1956). C. L. Comar, I. B. Whitney, F. W. Lengeman, ibid. 88, 232 (1955). Consumer: Repts. 24, No. 3, 102 (March 1959). 19. J. L. Kulp, A. N. Kaufman, R. S. Slakter, W. R. Eckelmann, in preparation. 20. Health and Safety Lab. U.S. Atomic Energy Comm. Publ. No. HASL-5I (10 Nov. 1958). 21. L. Machta and R. J. List, “Stratospheric data and meteorological interpretations,” paper presented at a meeting on “ABC—sponsored Research and Development Related to the Collection and Classification of Atmospheric Particulates,” held in Minneapolis, Minn., Oct. 1958. 22. W. F. Libby, Proceedings symposium on Noxious Eflects of Low Level Radiation, Schweizerischen Akadcmie der Medizinischen Witsenschaften 27-29 Mar. 1958, p. 309. 23. R. S. Russell, Nature 182, 834 (1958). 24. Unpublished data from the Lamont Geologi8—9 25. 26. 27. 28. cal Observatory, Palisades, N.Y. A. M. Brues, Science 128, 693 (1958). M. P. Finkel, ibid. 128, 637 (1958). E. B. Lewis, ibid. 125, 969 (1597). F. J. Bryant, E. H. Henderson, G. S. Spicer, M. S. W. Webb, Atomic Energy Research Establ. (G. Brit.) Rept. No. C/R 2583 (May 1958). the antisulfonamide component of yeast and its identification as p-aminobenzoic acid found a large acceptance. The idea that a compound structurally similar to one normally present in the organism is able to interfere with the function of this metabolite could be applied in many ways. Its success, especially in enzymology [where, for the first time, it was clearly formulated by Quastel (1925— 1928)], in chemotherapy, in vitaminology, and in endocrinology, obviates a detailed discussion of the underlying physi-L cochemical and biological principles. Instead, I would like to draw your attention to the importance of studies of competitive phenomena in pharmacodynamics, especially in the pharmacology of drugs of the autonomic nervous system. I would like to show how a very large part of therapeutical chemistry depends on the relations between many alkaloids or synthetic compounds and a few hormones, chemical transmitters, and products of tissue metabolism of rather simple chemical structure: epinephrine and norepinephrine, acetylcholine and propionylcholine, histamine, and 5-hydroxytryptamine (Table 1). Dr. Bovet is head of the department of therapeutic chemistry at the Istituto Superiore di Sanita, Rome, Italy. This article is a translation of his Nobel lecture, presented 11 December 1957, when he was awarded the Nobel prize for medicine and physiology for 1957. It is reproduced here with the permission of the Nobel Foundation. We are indebted to Dr. Ernest Schoffeniels of the department of neurology. College of Physicians and Surgeons, Columbia University, for the translation. 1255 �Drugs of the Autonomic Nervous System The history of the research in this field is one of the most spectacular and successful chapters in the chemistry and physiology of the alkaloids and hormones. As far as transmitters of the sympathetic system are concerned, one may recall that the isolation of epineph— rine by Takamine (1901) was preceded both by empiric application of ephedrine-rich mahuang by the Chinese, and by the fortuitous discovery of the properties of tetrahydronaphthylamine by Bamberger (1888). The exact significance of norepinephrine has been established only recently, by von Euler (1946). In the field of parasympathomimetic agents, the observation of the properties of muscarine (1811) and the synthesis of acetylcholine (1866) preceded, by a century and a half century, respectively, the discovery of acetylcholine of Loewi (1921) and its isolation from tissues (1931). Histamine was synthesized (1907) shortly before its identification in the products of animal and plant origin and before Dale and Dudley (1910) began their well-known studies of its pharmacological properties. The recent discovery of 5-hydroxytryptamine (Rapport, 1949) is the culmination of the work of Erspamer on enteramine isolated from enterochromaflin cells (1937—1952) and the work of Rapport, Green, and Page (1947— 1948) on the vasoconstrictor factor of serum, serotonin. The relationship between epinephrine, (CH2) /COO.CH2.CH2.N(CH3)31 “\COO.CH2CH2N(CH3)3 1 £5 E I34 8 0- 3 7 a% 2 w .=‘ - 3 g . 0 Fig. n=12345 Curarizing effect of choline esters 8 1. and dicarboxylic aliphate acids with normal chains. Curarizing activity was established in rabbits by measuring the “head dro P ” dose of the various compounds given intravenously. Curarizing activity reaches a maximum with succinylcholine and decreases with higher homologues of the series. [Bovet, Bovet-Nitti, Guarino, Longo, and Marotta, 1939] 1256 Table 1. Drugs with a competitive action with respect to epinephrine, acetylcholine, histamine, and 5-hydroxytryptamine. Adrenaline (noradrenaline) H \ CH0H.CH2rN/ , CH 0H Hydroxytrypt amine . . Histamine Acetylcholine CH 3 K CH3.COO.CH2.GH2.N\ 6213 CH/ H H \\N—c CH3 ’H NH-CH . OH CH 2. CH 2. H- cHz.CHz.N\H N/ \H H Sympatholytic Antihistaminics : Parasympatholytic Antihydroxytryptaagents : agents : .mines ” Ergotamine 929 F Atropine (spasmolytic Yohimbine 2339 R.P. (Antergen) agents ) Benzodioxane Curares: Pyrilamine d-Tubocurarine (933 F) Diphenhydramine Dibenamine Gallamine Antazoline Phentolamine Decamethonium Promethazine Succinylcholine Ganglioplegic agent: Hexamethonium Central ganglioplegic agents: Antiparkinson agents Antiphobic agents _ , tissue acetylcholine, and the nervous system was recognized early. In 1904, Elliot, struck by the similarity existing between the pharmacological action of epinephrine and the effect of stimulating the sympathetic system, proposed the hypothesis according to which epineph- rine is released from sympathetic nerve endings and transmits the impulse from nerve cell to smooth muscle fiber. Wieland in 1912 and Le Heux in 1919 tried to demonstrate that choline and acetylcholine were local hormones. Their hypothesis, we know, was successfully developed by Loewi, Dale, Cannon, and Bacq, whose experiments established the concept of chemical transmitters. The hypothesis of chemical transmission by acetylcholine first proposed for viscera innervated by the parasympathetic system was later extended by Dale, Feldberg, and Vogt (1936) to the neuromuscular junction. Recent investigations on the physiology of the end plate have, in sum, confirmed this mechanism. The reaction between acetylcholine and its receptor located at the postsynaptic mem— brane can now be integrated within the framework of electrophysiological findings, particularly those demonstrating electrical nonexcitability of this membrane and its great sensitivity to the transmitter (Kufller, 1948; Castillo and Katz, 1956). To turn now to substances antagonizing these various hormones and transmitters, models for the synthesis of adrenergic and cholinergic blocking agents were furnished by compounds of biological origin, such as ergotoxine, atropine, and curare. The antihistaminics were studied later and represent syn- ' thetic products of completely original design. In practice, these drugs have been widely used in the symptomatic treatment of dysfunction of organs which are dependent on the activity of the autonomic nervous system: heart, blood vessels, bronchi, gastrointestinal tract, and uterus. The antagonists of epinephrine found their major application in the treatment of vascular disorders and hypertension. The antagonists of acetylcholine are used primarily as spasmolytic, mydriatic, and muscle-relaxing Table 2. Structural relations between and sympathomimetic Sympatholytic agents. [Raymond-Hamet, 1937; Bovet and Simon, 1936; Druey, 1936; Bovet, de Lestrange, and Fourneau, 1942; de Beer and Fassett, 1938; Hartmann and Isler, 1939; Gross, Tripod, and Meier, 1951] SYMPA'HOMIMEIIC AGEN’S /’ H0 \0H SYMPAYNOlVYIC AGENYS CHOHCHZNHCHg ACHECHENHE CH2CH2N(C2H5)2 V AC CH2CH2NHCH3 \v OCHZCH2N(C2H5)2 OH ANHCHECHzNH: N< V CH 2 mm L c (2115).? 93*” HUM HOMNH CH3 NCH3 o/\I~1chzc{r\m-<':H2 CHJDV OCH3 \N—CH; N CH2 C<NH—(IIH2 \N—CHg CH3 0H SCIENCE, VOL. 129 �agents. The antihistaminics are most useful in the treatment of urticaria, rhinitis, asthma, and other allergic diseases. For specific illustrations, I shall use examples from three different pharmacological groups. For the epinephrine group, I will consider ergotamine; for the antiacetylcholine group, curare; and for histamine, I will consider the syn— thetic antihistaminics. “ifssfim " , '" CH? C3 Synthetic Sympatholytic and Ergotamine-Like Compounds Sympatholytic drugs form a group characterized by common pharmacological properties. They act as competitors—or blocking agents, in AngloSaxon terminology—by opposing the effects of epinephrine and norepinephrine. Most characteristically, they block the hypertension and vasoconstriction produced by epinephrine. As is often the case, various drugs of this class were introduced empirically into therapeutics long before their pharmacological actions were established. As long ago as 1909, Froelich noticed that animals pretreated with small doses of the dextrorotatory isomer of epinephrine became resistant to the effects of the natural isomer. Today we explain this observation as resulting from a partial block of the receptors by a pharmacologically much less active enantiomorph of the compound. Later Loewe (1927), Kiilz (1936), and Raymond-Hamet (1937) described N-alkyl derivatives of phenylethylamine with sympatholytic properties; analogous properties were described in the phenoxyethylamine series (Anan, 1930; Levy and Ditz, 1933; Bovet and Maderni, 1933; Bovet, Simon and Druey, 1937), the phenylethylenediamine series (Bovet, de Lestrange, and J. P. Fourneau, 1942), the isoquinoline series (Hjort, de Beer and Fassett, 1938), and the phenylaminoethylimidazoline series (Meier and M'Liller, 1939; Hartmann and Isler, 1939). In each of these groups the structural similarities between the antagonistic molecules with either sympathomimetic or sympatholytic properties are evident (Table 2); the degree of substitution on the amine, the suppression or displacement of the phenolic function, the closing of a ring, are sufficient to reverse the pharmacological action. It is very important to notice that while the distance betWeen the amine function and the aromatic ring remains constant in both sympathomimetic and sympatholytic agents, the inhibitory 'molecule has always, in con: 8 MAY 1959 {gags seems i} {We casing mag, Fig. 2. Pachycurares. (Left) d-Tubocura- rine; (above) gallamine. Table 3. Classification of the main groups of sympathomimetic and sympatholytic agents. ©-c-c—N ©—o-c—c—N ©mc-c-n Phenylethylamines Phenoxyethylamines Phenylethylene diamines Tiiii r i Sympathomimetic agents Phenolic derivatives of Phenylethylenediamine and Epinephrine its phenolic derivatives Phenylethylamines and their phenoxyethylamine phenolic derivatives Sympatholytic agents (aromatic series) N-Diethyl-N’-propyl-N’N-Diethylphenylethylamine N-Diethylphenoxyethylamine phenylethylenediamine Dibenamine Dibenzyline Tetrahydronaphthylamines, N-substituted Sympat/tolytic agents (heterocyclic series) N -MethyltetrahydroBenzodioxane: Phenylpiperazine Phentolamine isoquinoline Prosympal Benzylimidazoline Piperoxan Sympatholytic alkaloids Yohimbine Ergot alkaloids Table 4. Structural relations between sympathomimetic and sympatholytic agents: from epinephrine to ergotamine. [Marini-Bettolo, Chiavarelli and Landi, Vittory, 1950—1953; Bovet, Bovet-Nitti, Virno, Longo, Marotta, and Sollero, 1953] [NH _ CH3 CHOH-CHZ NH 2 ,NH2 / (31+2<:H2 NH2 GHz'ct' 0H3 OH OH Adrenaline Phenylethylamine Amphetamine Tetrahydronaphtylamine CH30H‘I3H2 IcorchH5 CH3 _ 843 LS alibi-c co C H2 -0H \Nz—CH 2 H 5-» 3 9| 6 1.5. _ CIH2 CH\ N/CHZ c,o\lI NH— N\ COG N‘ X30 ERGOTAMINE 1257 �The most active natural and synthetic tradistinction to the excitatory one, an amino group substituted by more, and heavier, radicals. Generally the inhibitory molecules also have a more stable structure and a higher molecular weight. sympatholytic compounds, whose effectiveness is sufficient to permit their use in the clinic, are generally polycyclic or heterocyclic, with structures analogous Table 5. Investigations of synthetic oxytocic agents, derived from phenylglycinamide. [Bovet-Nitti, 1952, 1954] CH CH 3 3 NH- CH- CHZOH co- CONH-CIZHCHZOH CH2' CH2 N— CH3 CZ H5 NHCOCH2N< c2*‘5 8331.8. Ergometrine 62' " s CZ H5 NHCOCH2 N 1048 I €sz 1.3. ,6sz NHCOCHZN. H 0sz‘N- co- CHz-N c ’2 5 |062 |058I.S. 1.5. Table 6. Natural and synthetic curares: d-tubocurarine (King, 1935; Wintersteiner and Dutcher, 1943); 3381 RF. (Bovet, Courvoisier, Duclos, and Horclois, 1946) ; gallamine (Bovet, Depierre, and de Lestrange, 1947) ; succinylcholine (Bovet, Bovet-Nitti, Longo, and Marotta, 1949; Fusco, Palazzo, Chiavarelli, and Kniisli, 1949). “3‘0 <300 H 3 ‘ E"? 06H; on / ;.. C2H5 \ /"x I 1‘ ————©—o O—(CH2)5-—-0 I °2H5 3381 R.P. d-Tubocurarine ' O‘CHZ-CHZ'N(CZH5)3I ' on 2coocnzc H2N(CH3)BC! - , . o-cwcwmcm-I' 2 2. 253 or 0 Hz- CH2*N(CZH5)3'I ] _ . CHz-COOCHZCH2N(CH3)3C!‘ Succinylcholine Gallamine Table Subject Mammals Birds Amphibians (rectus abdominis) 1258 7. Pharmacodynamic properties of synthetic curares. Pachycurares (competing agents) : tubocurarine, gallamine Curarization Curarization Antagonism to acetylcholine Leptocurares (depolarizing agents) : succinylcholine, decamethonium Curarization (muscular fibrillation) Contracture followed by curarization Acetylcholinic contracture to the above-mentioned compounds despite their complexity. Benzylimidazoline (Meier and Miiller, 1939) and dibenamine (Nickerson and Goodman, 1947) are related to the phenylethylamines; the aminomethyl-benzodioxanes (Fourneau and Bovet, 1933), to the phenoxyethylamines; and phentolamine (Gross, Tripod, and Meier, 1951) to phenylethylenediamine derivatives (Table 3). Studies conducted at the Istituto Superiore di Sanita by Marini-Bettolo and Chiavarelli, on the chemical aspects, and by F. Bovet-Nitti, Longo, Marotta, and Guarino on the pharmacological aspects, illustrate the usefulness of the concepts of isosterism and of competition in this kind of investigation. When the isolation and structural determination of the ergot alkaloids was achievedwresearches for which we are largely indebted to Stoll and Jacobs—— much work was done to prepare derivatives by partial or total synthesis; thus, dehydrogenated derivatives (Rothlin, 1947) and oxytocic derivatives closely related to ergometrine (Rothlin, 1947) were prepared, and the diethylamide of lysergic acid with hallucinogenic properties was discovered (Stoll). Since we proposed to investigate the structureactivity relationships of ergotamine, we used as our working hypothesis the con— cept relating structure to antagonistic action. At first sight, the structure of the ergot alkaloids seems to be very different from that of epinephrine or of sympathomimetic derivatives of the phenylethylamine series. Nevertheless, since the skeleton of B-tetrahydronaphthylamine (2-aminotetralin) can be recognized in'the structure of lysergic acid, we decided to study compounds of this group (Table 4). Pharmacological tests with derivatives of relatively simple structure demonstrated the sympatholytic activity of 2-diethylaminotetralin (843 1.5.). Studies with more complex molecules, in particular the amide and amine derivatives of 2-tetralin, are a new step in the attempt to reproduce the essential portion of the lysergic acid skeleton. Using molecules of increasing complexity, one may go by successive stages from phenylethylamine to tetrahydronaphthylamine or to N-(2-tetra1yl) -N-methyl-N’-ethylB-alaninamide (916 LS.) and the ergot alkaloids, with a resulting progressive diminution at each stage of sympathomimetic properties and the appearance of sympatholytic properties. Oxytocic activity was observed in a large number of synthetic derivatives, SCIENCE, VOL. 129 �and this class of compounds seems very broad compared to that of adrenolytic substances (Table 5). In the course of experiments performed on rabbit uterus, isolated or in situ, several derivatives of aminotetralin and of aniline and even some aliphatic compounds showed strong activity. We may single out such examples as N,N-diethyl-N’- ( 2-tetralyl ) glycinamide (621 I.S.); N,N-diethyl-N’-3( 1048 4-dimethylphenylglycinamide LS.) ; and N,N,N’,N’tetraethylglycinamide (1062 LS.) (Bovet-Nitti, 1953). The main difficulty, apparently encountered also by other investigators, was the lack of parallelism between effects observed in laboratory animals and in man. Generally speaking, a satisfactory solution to the problem of syn— thetic oxytocies has not yet been reached, and the question is still under study. Antagonists of Acetylcholine: Synthetic Curares The problem of competitive agents that antagonize acetylcholine activity is rather complex, due to the multiple functions of this transmitter. Acetylcholine is the chemical transmitter in viscera innervated by the parasympathetic system; it has a role at the neuromuscu— lar junction, and it is liberated in ganglia during the passage of a nerve impulse. A surprising fact, which has been profitably exploited in pharmacological investigations of competitive agents, is that compounds antagonizing acetylcholine differ according to the site of action of the local hormone. Thus, atropine and benzoylcholine neutralize the muscarinic effects of acetylcholine on cardiac receptors, on the intestine, or on secretions; tetraethylammonium iodide or hexamethonium block the nicotinic action of acetylcholine on sympathetic and parasympathetic ganglia. Finally, curares are specific antagonists of acetylcholine in striated muscle. With respect to the structure of antagonists, synthetic curares furnish us with a succession of examples comparable to those we have reviewed in the sympatholyticgroup. These investigations were begun in 1946, after King’s elucidation, in 1935, of the structure of one of the physiologically active constituents of Amazonian curares, and after the introduction by Griffith and Cullen in 1942 of the chemically pure alkaloid as an adjuvant in anethesia. d-Tubocurarine, which is extracted from a menispermum, Chondodendron tomentosum, is found in curares prepared by the natives of the Upper Ama8 MAY 1959 , emcageugcagcagefcam Mammengmécm {1:39} CHQCG B Ci‘iéci‘ig ‘ ’ R;C8313 (CH333NCHgCRgu C0 CHg Fig. 3. Leptocurares. (Left) Decamethonium; (right) succinylcholine. zon. It is an alkaloid of the group bis ( benzyltetrahydroisoquinoline) , whose molecule has two quaternary ammonium ity, and this was also true for polyphenol ethers and aromatic esters. The latest investigations on the path to ultimate simplification are concerned’ with the activity of aliphatic derivatives. In England, Barlow and Ing and Paton and Zaimis (1948) reported extremely interesting observations on the curare-like effect of decamethylene—w- functions. In research done with our colleagues, Viaud, Horclois, and de Lestrange, we first looked for molecules structurally close to the selected model. By successive transformations, we were able to synthesize relatively simple derivatives with analogous properties (Table 6). From a series of new compounds with two quinolinic rings bearing quaternary ammonium functions, we first selected the diiodoethylate of 8’ ,8’ ’ -diquinolyloxy1,5-pentane (3381 R.P.). This was the first synthetic compound with curarelike action in mammals showing a specificity comparable to that of natural alkaloids isolated from curare (1946). It was then found that aminophenol derivatives which have neither quinoline nor isoquinoline rings had similar activ- bis-trimethylammonium hydrate (decamethonium). In our Laboratory of Therapeutical Chemistry at the Istituto Superiore di Sanita, the curare-like action of succinylcholine was first recognized. This compound was synthesized by Hunt in 1911. The number and variety of compounds with curare-like action, the relative simplicity of their mode of action, and the possibility of precise pharmacological assay permitted a careful study of structure-activity relationships of synthetic curares. Solveni front D Iodine Carboxylic reagent Bromothymol blue 0 000 @%s + 60 O Enzymic hydrolysis (5%) 01 cm.{ R; 1 o O o @ @s....,...ho.... @ @ @ ® + a 2 § § Choline Succinylmonocholine Succinate 3 20 Control Non-enzymic hydrolysis (96) Fig. 4. Chromatograms of (a to e) succinlycholine at various stages of enzymic hydrolysis; (f) a mixture of succinylcholine and its products of hydrolysis; (g) 0.1 mg of succinylcholine after nonenzymic hydrolysis. [Whittaker and Wijesundera, 1952] 1259 �Fig. 5. Comparison between curarizing effects of d-tubocurarine (left) and of succinylcholine (right) given intravenously as a single fol— muscle of the Contraction anesthesia. gastrocnemius chloralose under (First line) the dog, continuous perfusion on injection or by lowing the.rhythmic stimulation of the sciatic nerve; (second line) control of the speed of injection; (third line) blood pressure. The record shows clearly the difference between the duration of neuromuscular paralysis following a single injection of succinylcholine (370 1.8., 0.05 mg/kg) and of d-tubocurarine (0.1 mg/kg). Also, on comparing the effect of a single injection of d—tubocurarine with continuous perfusion of succinylcholine (initial injection of 0.05 mg followed by repeated injection of 0.0062 mg at each signal), one sees that, for the duration of subtotal and reasonably uniform eurarization (about 80 percent, for 20 minutes), the reversibility of the effect is quick (about 10 minutes) after infusion of succinylcholine while it is slowly progressive (about 50 minutes) after injection of d-tubocurarine. [Reuse, 1953] I will mention only two important factors which influence the activity of bis-quaternary derivatives: the distance between the quaternary ammonium groups and the massiveness of the molecule. The first factor is illustrated by comparison of polymethylene-bis-trimethylammonium derivatives (Barlow and Ing; Paton and Zaimis, 1948) as well as of aliphatic diesters of choline (Bovet, Bovet-Nitti, Guarino, Longo and Marotta, 1949) (Fig. 1). Careful pharmacological study showed that the action of new synthetic derivatives was sometimes quite different from that of the natural alkaloids. The differences between the action of decamethonium iodide and succinylcholine iodide on the one hand and the action of d-tubocurarine and of the tri— iodethylate of gallamine on the other were carefully studied by Paton and Zaimis, Brown and Dias and in our own laboratory. The British authors have proposed calling these two groups depolarizing agents and competitive curares. We proposed designating decamethonium and succinylcholine as leptocurares, and tubocurarine and gallamine as pachycurares (Figs. 2 and 3; Table 7). The advantage of our nomenclature lies in the fact that it does not presume the mechanism of action. The main differ— ence between the pharmacodynamic effects produced by the two types of curares is determined by the responses of amphibian and bird muscles. In birds, the pachycurares are typical curarizing agents, while leptoeurares induce con- ESHWEH H . CH, C“Cf~iLCHNH }; fag; \g‘fsfmwx ‘ as? N 1260 y 2‘ ecu, '2 CHECHEMCHM Fig. 6. (Left, top) Histamine; (left, bottom) pyridylethylamine; (above) pyrilamine. tracture that is followed by eurarization. In mammals the differences between the two groups are less sharp. The responses of muscle from different species or of different muscles from a single species are not always comparable. Also, intermediary steps seem to exist between depolarization and curare competition. The distinction between the groups, though relative with respect to the mechanism of action and the type of preparation used, are, nevertheless, useful if we want to compare relations between chemical structure and pharmacological activity. Clinically, the most important factor in classification of curares is duration of effect. In this respect, the introduction of a short-acting curare, particularly succinylcholine, is an important step forward. The relative ease with which suc— cinylcholine is hydrolyzed by pseudocholinesterase and the very low toxicity of the products choline and succinic acid account for the brevity of action and the remarkable tolerance of the organism for this curare (Fig. 4; Table 8). The first clinical observations concerning short-acting curares were published by Valdoni (1949) and Scurr (1951) and deal with suxethonium. The introduction of succinylcholine into anesthesiology was first proposed in Sweden, by Thesleff (1951), Holmberg and Thesleff ( 1951), Tammelin and Low (1951 ) , and von Dardel (1951), and in Austria, by Briicke et al. (1951), Mayrhofer and Hassfurther (1951), and Holzer (1951). In the light of these various investigations, one may today recognize two methods of using succinylcholine: single injection when very short action is required (as for endoscopy or electroSCIENCE, VOL. 129 �Table 8. Hydrolytic products of succinylcholine. (CHgaN‘CiECi-izococ Hacib c OOCHZC HZN ’(c 1493.1’ -Succiny|choline 1'. (CH3)? CHZCHZOCOCHZCI‘ECOOH + OHCHZCHZN (cl-1‘3)3 I Choline Succinylmonoct‘oline l lrl(.7H3)3N CH2 CH 2OH+ HOOCCHZCHZCOOH Succinic acid Choline shock) or continuous infusion in surgical procedures of long duration. Two recordings from a study in our laboratory demonstrate results obtained with the two types of application. They show the superiority of continuous infusion of short-acting curares over the classical technique (Fig. 5). Antihistamines The last example I will use to illus— trate the concept of competition is concerned with compounds that antagonize the third local hormone, histamine. This particularly rich field since the usefulness of these compounds has stimulated a great many investigations within a very few years. In 1937, in Fourneau’s laboratory, we began—A. M. Staub and I—to look for compounds antagonistic to histamine. Considering the number of features that histamine, acetylcholine, and epinephrine have in common, we looked for antagonism comparable to that exhibited by sympatholytic compounds toward epinephrine and by parasympatholytic compounds toward acetylcholine. We obtained the first positive results in 1939 with thymoxyethyldiethylamine (929 F). Our experimental work was then directed toward defining criteria for antihistaminic activity. Staub (1939) extended her observations to phenylethylenediamine derivatives. In 1942, the syntheses by Mosnier, the pharmacodynamic studies of Halpern, and the first therapeutic results of Cuilleret, Thiers, Gaté, Celice, Perrault, Decourt, and Durel with dimethylaminoethylbenzylaniline, or Antergan, definitively established interest in compounds of this group. The role played by histamine in many allergic affections assures a broad area of clinical application of these compounds. After the pio— neers (Maderni, de Lestrange, and Benoit in Fourneau’s laboratory in Paris; is a Table 9. Principal groups of synthetic antihistaminics: 929 F (Bovet and Staub, 1937) ; Antergan (Halpern, 1942); antazoline (Meier and Bucher, 1946); diphenhydramine (Loew, Kaiser, and Moore, 1945); promethazine (Halpern and Ducrot, 1946); chlorphenamine (Tislow, La Belle, et al., 1949) ; pyrilamine (Bovet, Horclois, Walther, and Fournel, 1944); tripelennamine (Mayer, Huttrer, and Scholz, 1945) ; thonzylamine (Reinhard and Scudi, 1947). Antihistaminics related to: Sympatholytic agents onQ [OHS CH ocnac H2N(62H5)2 CH3 929F ”Q CH ‘0H 2 0H 2 Maria) 2 Antergon Q Spasmolytic agents 0 \ZCH CH Diphanhydramine O cuzcnmcusiz N \ N-CH2 _ Antozoiine 8 MAY 1959 :EH GHZCH2N(CH3)2 Chlorphenamino 2N(CH3) Pyrilamine N‘cnacnzmchu 3 CH— @001 ECHocH ZCHZNKSH 3’2 Promethazine \C Histamine Tripulennominc flZOOCHS N/ \ZCHZCHZNCHa) Thonzylamino Table 10. Structural relations between histamine and antihistamines. [Walter, Hunt, and F osbinder, 1941; Nieman and Hays, 1942; Bovet and Walthert, 1943] NH /\ / / ’I CH2 CH2 NHZ , I, HISTAMINE Histamine action 2. N I Antihistamine action HQ": CH2 CHZN: (/\n-CH2.GH2.NHZO KEV) /J Nona \ ,/<CH 2 .0H 2 .NH 2 \ "[0142 A" (7N1ii KN 6H2 ii; N’0 2 ‘01:: CH 0 o \N ~ /-CH2CH2. NH2 “3 + K I R N: N [CH3 CH2.CH .N\ * CH% Viaud, Horclois, Mosnier, and Charpentier in French industry; Hartman and Hofman in Switzerland; Rieveschl, Scholz, Huttrer, and Roblin in the United States; Cavallini in Italy), about 500 chemists synthesized, in less than ten years, more than 5000 compounds in the antihistaminic group. Pharmacologists were easily able to recognize the competitive nature of the antagonism exerted by these antihistaminics toward histamine. Chemists, however, could not perceive any relation between the structure of antihistaminics and histamine which logically might explain such activity, nor could they find a relationship among the various active compounds. It was therefore impossible to escape the conclusion that most of the results were rather empirical. From the pharmacological viewpoint, it was possible to distinguish three groups of substances (see Table 9) with antihistaminic action and relate them to (i) the sympatholytic group; (ii) the parasympatholytic-sympatholytic group; and (iii) histamine itself. To the first group belong the phenolic esters (929 F) and the phenylethylene— diamine derivatives (1571 F) studied at the Pasteur Institute, Halpern’s Antergan, and the antazoline of Meier and Bucher. The compounds of the second group, from a chemical point of view, have more homogeneous structures, in 1261 �common with atropine-like drugs and other spasmolytics; some of these are, in fact, spasmolytic as well as antihistaminic (diphenhydramine). In derivatives of a-aminopyridine, which form the third group, the antihistaminic action is more specific and almost free of secondary effects. It is interesting to note in this group the isosteric reactions which account for the pharmacological activity. Walter et al. (1941) and Niemann and Hays (1942) have shown that a-pyridylethylamine derivatives have histamine-like activity, and that a fundamental difference exists between a-, [3-, and y-substituted pyridines in this respect. In this case, the analogy of structure which is not evident between histamine and pyrilamine (Neo-Antergan) may be seen between the groups a-pyridylethylamine and (it-pyridine ethylenediamine (Table 10, Fig. 6). A typical compound from this group is pyrilamine (see Fig. 7), but many other synthetic compounds of similar design have also proved to be active. Central Action of Transmitters The compounds considered so far do not exhaust the ranks of competitive agents. Pharmacologists are to some extent les enfants terrible: of physiology. They did not wait for the battle of the neuromuscular junction to be won before engaging in a more difficult encounter. They proposed that the available evidence suggested the action of a chemical transmitter in the central nervous system, exactly as in the autonomic nervous system. Analyzing the collective results from various laboratories, Feldberg (1950) concluded that the theory ascribing a transmitter role to acetylcholine in the central nervous system was the only one able to offer convincing and satisfactory interpretations. Even if intervention of noncholinergic chemical transmitters in the central nervous system is not excluded, we must admit that our knowledge about the probable roles of norepinephrine, epinephrine, histamine, and 5-hydroxytryptamine is still quite incomplete. The physiological role of the reticular formation in the brain stem has been clearly defined by Moruzzi and Magoun (1949). In the last few years, a considerable number of investigations have shown that compounds affecting the autonomic nervous system also affected this formation. Paradoxically enough, cholinergic as 1262 HISTAMINE 0.001 cm/H 0 20 .mm/Hg 200 100 0 15 PYRILAMINE HISTAMINE 1.0 0.001 “ j 1 V. 10 5 0 0 ‘_3lOsec Fig. 7. Antagonistic action of pyrilamine with respect to the vasodilating effects of histamine in cerebral circulation. The subject was a dog under chloralose anesthesia. (A) Blood pressure, femoral artery (mm-Hg); (V1) pressure recorded through a catheter introduced in a centrifugal direction into the external maxillary vein (mm-H20) ; (V2) pressure in the internal maxillary vein (mm-H20). Injection was made into the saphenous vein; dosages are given in milligrams per kilogram. [Virno, Gertner and Bovet, 1956] well as adrenergic substances affect the electrical activity of the cortex in the same way that direct electrical stimulation of the reticular formation does. Under well-defined experimental conditions, acetylcholine (Bonnet and Bremcr, 1937) and epinephrine itself (Bonvallet, Dell, and Hietzel, 1954) provoke a transient activation in the electroencephalogram. The administration of either an anticholinesterase (eserine, diisopropyl fluorophosphate) or of amphetamine (Bradley and Elkcs, 1953) produces an intense and prolonged desynchronization. From a strictly pharmacological viewpoint, the major interest in this type of investigation stems from the similarity in observed antagonisms between various groups of drugs in the central nervous system and in viscera innervated by the autonomic nervous system. As early as 1947 we suggested that in extrapyramidal syndromes some relation might exist between the central, “antiparkinson,” effect of certain tertiary amines and their ganglioplegic properties in peripheral ganglia (Sigwald and Bovet; Dumont; 1947). “Antiparkinson” drugs form a relatively homogeneous group comprising diethazine (Diparcol), isothazine (Parsidol), caramiphen (Parpanit), and trihexyphenidyl (Artane), as well as some antihistaminics (diphenliydramine and promethazine). Electroencephalographic studies (Fig. 8) have shown that three groups of compounds produce an electroencephalogram similar to that recorded during sleep: the parasympatholytics (scopolamine and atropine), the central ganglio— plegic or “antiparkinson” drugs (Table 11), and the neuroleptics (chlorproma- w; mwgwmmwww W MWMvM 51mm ‘ . -..,: p‘, 51%; g‘fi‘kfifig‘fi’?‘ “if“?'9““(high ‘) K $3.)wa ai’zfiig'f$6,133?3.25% “ if: (3:1‘331“ ii 4, ,. “‘ ;.§l(¢t {brave-112m}? Fig. 8. Antagonistic action of diethazine against convulsive patterns caused by nicotine on the electroencephalogram of curarized rabbit. (A) Blocking reaction after acoustic stimulation (black line). (B) Convulsive seizure by nicotine (2 mg/kg) in normal animal. (C) After injection of diethazine (5 mg/kg) a second injection of nicotine no longer produced the electrical changes observed previously. and the acoustic stimulus fails to produce the blocking reaction. [Longo and Bovet, 1952] SCIENCE, VOL. 129 �zine, reserpine). These also antagonize the cortical reaction elicited by external stimuli (stress) or by desynchronizing agents (eserine and amphetamine) (Bovet and Longo, 1956). The effect of such synchronizing agents may, as a first approximation, be localized in the reticular formation and thus be comparable to the importance of chemical transmitters at this level. Many observations suggest that specific receptors fOr epinephrine, acetyl- choline, and histamine are specific proteins with a structural configuration complementary to that of the transmitter. This concept was first proposed by Fischer, who illustrated it with the now famous model of key and lock. his mechanism has been invoked to explain observations in physiological and chemical studies of taste and smell. Recently, Landsteiner and Pauling applied this idea of “complementary configuration” in the field of immunological reactions. At this point it would not be possible to consider the various aspects of reactions between chemical transmitters, inhibitors, and receptor proteins without taking more space than is available. The particularly simple case of binding acetylcholine with cholinesterase has been studied by Nachmansohn (1953— 1954) and Wilson (1954). They consider acetylcholine to be attached at two points, one electronegative and the other elcctropositive, and have drawn valid conclusions with respect not only to various anticholinesterases but also to a new group of drugs that reactivate the phosphorylated enzyme. If I cared to develop the extensive areas covered in this article I could include other topics and point out that different groups of compounds affect the metabolism of mediators because they are precursors or because they inhibit synthesis, slow down or accelerate liberation, or interfere with destruction. In every phase, investigations have been successful and the results appear to be very promising. Conclusion The composite picture I have tried to present, at the risk of relating many al— ready well-known facts, appears, despite inevitable gaps, very certain. If, in concluding, we rapidly retrace our path, we will see that in covering the vast field of pharmacology, the structures of a small group of remarkably simple biogenic amines have led us, like the thread 8 MAY 1959 Table 11. Central ganglioplegic agents: diphenhydramine (Loew, Kaiser, and Moore, 1945) ; diethazine (Sigwald, Bovet, and Dumont, 1946; Bovet, Fournel, and Charpentier, 1947); caramiphen (Domenjoz, 1946; Griinthal, 1946); trihexyphenidyl (Doshay and Constable, 1949). / \ / \ CH-O-CHz-CH2~N(GH3)2 Diphenhydramine (Benadryl) -GO'O‘ OHZ'GHZ'N(02H5)2 Caramiphen <// \\> S N'CH2'CH2N(02H5)2 :COH'CHZCHZN > Diethazine Trihexyphenidyl of Ariadne, through the labyrinth of very a name always well-known and sometimes very close to us. The future of pharmacodynamics is, nevertheless, so rich and promising, and diverse physiological actions and chemical structures. It has been said that the art of the orator is to speak about what he knows and to hide his ignorance. I do not feel any need to resort to such an artifice in presenting the current picture of the chemical pharmacology, because it is, in final analysis, only a kind of “natural history” and classification of organic molecules. I would say that the results obtained so far give rise to optimism because they let us catch a glimpse of the pharmacology to come as a well-ordered and well-defined science in which foods, drugs, and poisons will be integrated in the metabolism of the simplest constituents of living matter. Finally, in recalling the great names associated with studies of the pharmacological agents that made it possible for us to reach our present level, I can only speak with emotion of all those who preceded me, particularly of my teacher, Ernest Fourneau, who wrote such a great and glorious chapter of therapeutic chemistry and whose name will forever be written in the history of this science. My feelings are sincerely divided between the immense pleasure I feel at the honor which is bestowed on me and my sense of inadequacy at being unable to repay my teachers and colleagues all that I owe them. This feeling is the more vivid because therapeutic chemistry is a very young science that has developed amazingly during the past half century; perhaps in no other domain does the part played by each individual appear so clearly and with such continuity as in our studies, where every formula bears it bears so many theoretical and prac— tical possibilities, that I cherish the hope that my future work will justify not only the marvellous distinction I have received today but also the confidence and the friendship of my teachers and colleagues, whose works cannot be separated from those I pursue with confidence, enthusiasm, and love. Bibliography The following bibliography includes mainly general reviews; concerning studies published prior to 1948, the reader is referred to the work published in collaboration with Mme. F. Bovet-Nitti. Z. M. Bacq, “La pharmacologie du systeme nerveux autonome, et particuliérement du sympathique, d’apres la théorie neurohumorale,” Arm. physio]. physicochim. biol. 10, 467 (1934). D. Bovet, “Introduzione allo studio fisiologico e farmacologico del curaro,” Boll. soc. ital. bio]. sper. 25, 539 (1949). , “Introduction to antihistamine agents and Antergan derivatives,” Arm. N.Y. Acad. Sci. 50, 1089 (1950). , “Some aspects of the relationship between chemical constitution and curare-like activity,” ibid. 54, 407 (1951). and F. Bovet-Nitti, Structure et Activite’ pharmacodynamique des Médicaments du syrtéme nerveux vége’tatif (Basle, 1948). “Curare,” Experientia 4, 325 (1949). , “Rapports de structure entre sympathomimétiques et sympatholytiques. De l’adrénaline a l’ergotamine,” Actualités pharmacol. N0. 6 (1953), p. 21. , “Le chlorure de succinylcholine, agent curarisant a breve durée d’action,” Sci. Med. Ital. 3, 509 (1955). , S. Guarino, V. G. Longo, R. Fusco, “Recherches sur les curarisants de synthése. III, Succinylcholine et dérivés aliphatiques,” Arch. intern. pharmacodynamie 88, 1 (1951). D. Bovet and V. G. Longo, “Pharmacologie de la formation réticulée du tronc cerebral,” Oomph-rend. 20éme Congr. intern. physiol. Bruxeller (1956), pp. 306—329. D. Bovet and P. Viaud, “Curares synthése: Chimie et pharmacologie,” Aneslhésie et analgésie 8, 328 (1951). F. Bovet-Nitti and D. Bovet, “Recherches sur les ocytociques de synthése: dérivés de la phenylglycinamide,” Arch. intern. pharmacodynamic 6, 327 (1954). F. Briicke, “Dicholinesters of -dicarboxylic acids ‘ 1263 �and related substances,” Pharmacol. Revs. 8, 265 (1956). W. B. Cannon and A. Rosenblueth, Autonomic Neuroeflector System (New York, 1937). J. Castilljo and B. Katz, “Biophysical aspects of neuro—muscular transmission,” Progr. in Biophys. and Biophys. Chem. 6, 122 (1956). H. H. Dale, “Transmission of nervous effects by acetylcholine,” Harvey Lecture Ser. 32, 229 (1937). L. Donatelli and U. Serafini, Gli antistaminici di sintesi (Naples, 1951). J. C. Eccles, “The electrophysiological properties of the motoneurone,” Cold Spring Harbor Symposia Quant. Biol. 17, 175 (1952). V. Erspamer, “Pharmacology of indolealkylam~ mines,” Pharmacol. Revs. 6, 425 (1954). U. S. von Euler, “The nature of adrenergic nerve mediators,” ibid. 3, 247 (1951). S. M. Feinberg, S. Malkiel, A. R. Feinberg, The Antihistamines (Chicago, 111., 1950). W. Feldberg, “The role of acetylcholine in the central nervous system, Brit. Med. Bull. 6, 312 (1950). R. Fusco, G. Palazzo, S. Chiavarelli, D. Bovet, “Ricerche sui curari di sintesi, IV,” Gazz. chim. ital. 79, 836 (1949). L. S. Goodman and M. Nickerson, “Clinical ap- plication of adrenergic blockade,” Med. Clin. N. Am. 34, 379 (1950). H. R. Griffith and G. E. Johnson, “The use of curare in general anesthesia,” Anesthesiology 3, 418 (1942). B. N. Halpern, “Les antihistaminiques de synthese, essais de chimiothérapie des états allergiques,” Arch. intern. pharmacodynamie 68, 339 (1942). , “Sur le mécanisme d’action des antihistaminiques de synthése,” Presse Med. 57, 949 (1949). H. R. Ing, “The curariform action of onium salts,” Physiol. Revs. 16, 527 (1936). S. W. Kufller, “Physiology of neuro-muscular junctions: electrical aspects,” Federation Proc. 7, 437 (1948). O. Loewi, “Problems connected with the principle of humoral transmission of nerve impulses,” Proc. Roy. Soc. (London) 1188, 299 (1936). G. B. Marini~Bettolo, “Contribution a l’étude des alcaloides des Strychnos du Brésil,” Festschr. Arthur Stoll (Basel, 1957), pp. 257—280. , S. Chiavarelli, D. Bovet, “Ricerche sui simpatolitici di sintesi della serie dell’ergotammina,” Gazz. chim. ital. 80, 281 (1950). A. R. McIntyre, Curare. Its history and clinical use (Chicago, 111., 1947). D. Nachmansohn, “Metabolism and function of Manuel Luz Roxas, Agricultural Chemist Manuel Luz Roxas was one of the foremost scientists in the Philippines. His valuable services to the University of the Philippines as a teacher of chemistry in the College of Agriculture and the important role he played in the creation and organization of the National Research Council of the Philippines will be long remembered. Almost immediately after Dr. Roxas’ graduation from the University of the Philippines in 1911, with a BS. degree Hg? ‘ \ ._ Manogmmm OF in Agriculture, his first research work appeared in the Philippine Agriculturist and Forester under the title “The pandan industry in Majayjay.” This was soon followed by three other articles in the same journal: “The cultivation of coconut,” “The effect of some stimulant upon rice,” and “The coffee industry in the island of Luzon.” Dr. Roxas pursued further studies in his chosen field and in 1913 obtained his MS. degree at the University of the Philippines, where he then served as instructor in chemistry until he was appointed a university fellow to the United States. Evidently this appointment was in recognition of his unusual endowment with the “divine spark” to perform research. He enrolled in the University of Wisconsin and received his Ph.D. there in 1916. On his return to the Philippines, Dr. Roxas resumed his position in the Col-' lege of Agriculture in the University of the Philippines, where he was later appointed assistant professor, then professor of chemistry, and ultimately, professor emeritus of agricultural organic chemistry. He was also named Distinguished Alumnus of the University of the Philippines in 1932 for achievement in scientific research. All these deserved 11111111111111 131111111111 HILLSIDE HOSPITAL QLEN omsm. v. ' recognitions were due to his active labor in the field of research, especially in agricultural chemistry and food technology; his 95 scientific papers were published in various journals, including the Philippine Agriculturist and Forester, the [ournal of Biological Chemis— try, Sugar News, and the Journal of the Philippine Islands Medical Association. The National Research Council of the Philippines owes its origin to the leadership of Dr. Roxas. He headed a committee that worked continuously in preparing the draft of the bill for its creation which was introduced in the House of Representatives. With the support of Manuel L. Quezon as Senate President and other leaders of the Philippine Legislature, and the cooperation of the then Governor General Frank Murphy, Act 4120 creating a National Research Council for the promotion of research along scientific lines was approved on 8 December 1933. Elected as first chairman of the National Research Council, Dr. Roxas did a great deal in the organization of the different divisions integrating the Executive Committee of the council. For his distinguished and outstanding contributions in scientific research in the Philippines, Dr. Roxas may well be considered the “father of the National Research Council of the Philippines.” Manuel Luz Roxas was a man of sterling character, a good Filipino and patriot, simple and humble; all these qualities enhanced his merit as a true man of science. Our country can never repay what it owes him for his scientific labor and devotion to research. ANTONIO G. SISON National Research Council of the Philippines, Quezon City SCIENCE, VOL. 129 _ 3.1u1111959 the nerve cell,” Harvey Lecture Ser. 49, 57 (1956). W. D. M. Paton and E. J. Zaimis, “The methonium compounds,” Pharmacol. Revs. 4, 219 (1952). M. Protiva. “Chemie antihistaminovych latek a histaminové skupiny,” Nakladatelstvi L'eskolovenske’ Akademie véd (Prague, 1955). M. M. Rapport, “Serum vasoconstrictor (serotonin) : IV,” ]. Biol. Chem. 180, 961 (1949). Raymond-Hamet, “Sur un nouveau cas d’inversion des eflets adrénaliniques,” Compt. rend. acad. sci. 180, 2074 (1925). Rend. ist. super. sanita‘ 12, 1-264 (1949) (numero speciale sui curari di sintesi). Ibid. 15, 723—1040 (1952) (numero speciale sugli ergotamminici di sintesi). E. R. Rothlin, “The pharmacology of the natural and dihydrogenated alkaloids of ergot,” Bull. schweiz. Akad. med. Wiss. 2, 249 (1947). A. M. Staub, “Recherches sur quelques bases synthétiques antagonistes de l’histamine,” Ann. inst. Pasteur 63, 400 (1939). S. Theslefl', “Succinylcholine iodide. Studies on its pharmacological properties and chemical use,” Acta Physiol. Scand. Suppl. 99, 1 (1952). D. W. Woolley, A Study of Antimetabolites (New York, 1952). �Cultural Determinants of Response to Hallucinatory Experience ANTHONY F. C. WALLACE. Ph.D. PHILADELPHIA �Reprinted from the A. M. A. Archives of General Psychiatry July 1959, Vol. 1, pp. 58-69 Copyright 1959, by American Medical Association Cultural Determinants of Response to Hallucinatory Experience ANTHONY F. C. WALLACE, Ph.D., Philadelphia Hallucination attracts the attention of the anthropologist for several reasons: First, because, as one of the most ancient and most widely distributed of the modes of human experience, most, if not all, human cultures provide definitions of and responses to it which are of interest to the descriptive ethnographer; second, because a vast quan— tity of content has been introduced into the cultural repertoire of mankind by halluci— natory ideation in dreams, visions, and hypnogogic imagery, and hallucination must therefore be considered in relation to culture change; and, third, because hallucination is often defined in Western societies as a symptom of mental and/or physical disease, and anthropologists play a role in medical research in these societies. It is in the last context, particularly in the area of mental health research, that the present inquiry is undertaken. Cross—cultural materials on hallucination may be of interest in a mental health re— search context in at least two ways. First, and rather obviously, both psychiatrist and anthropologist will expect the manifest con— tent of hallucination to vary, as does the content of other behavior, to some degree with cultural setting, and they may be interested in the range, frequencies, and associations of various types of manifest content. Differences of opinion exist in Submitted for publication Sept. 3, 1958. This study was in part supported by Grant M-1106 from the National Institute of Mental Health, U. S. Public Health Service. Research assistants were Fred Adelman, Josephine Dixon, Joan K055, and Robert J. Smith. The writer has benefited from discussion of methodological problems in psychopharmacology with Dr. Harry Pennes and Dr. Harold Rashkis, of the Eastern Pennsylvania Psychiatric Institute. 74/58 regard to the supposed variability of latent content: Lincoln, in his study of dreams in primitive cultures, and other psychoanalyti— cally oriented scholars have emphasized the universal presence in dreams of Oedipal themes and the classic “Freudian” sym— bols 13; less strictly psychoanalytic ethnolo— gists have not emphasized the presence of these themes so much as culturally and personally idiographic onesfi2'3 In any case, however, we shall not be primarily concerned with the content per se of hallucina— tions. Rather, we shall deal with the problem of the definition of and response to the experience, by the society, by the scientific observer, and by the hallucinator himself. The rationale for such an approach, in a mental health context, is twofold: First, knowledge of the range of definitions and response, and their cultural associations, may help in diagnosis and in communication with patients; and, second, it is likely that in some cultural subgroups in our society the nature of definition and response to hallucination entertained by hallucinator and his associates may aggra— vate or precipitate other mental disabilities in the hallucinating person. Indeed, the mental patient may suffer from added anx— iety precisely because of the nature of the definition of hallucinatory experience which he entertained prior to experiencing it him— self. Certainly among hospitalized patients in our society, the attempt to conceal halluci— natory experiences from the staff is both chronic and, in one sense, realistic: Staff members frequently take a negative View of hallucinations, and hallucinating patients are subject to measures which, from the pa— tient’s standpoint, may be punishments (de- �RESPONSE TO HALLUCINATORY EXPERIENCE lay in discharge, restriction of privileges, questioning on sensitive issues, subtle contempt, and even ridicule, from both staff and other patients) .23 Problems of Definition Uncertainties of definition impede re— search in the area of hallucinatory experi— ence. Although hallucination is commonly treated by psychiatrists as a symptom of mental disorder, its occurrence is neither a necessary nor a sufficient condition for such a diagnosis. Most psychiatrists, furtherword the restrictions two on impose more, “hallucination,” excluding from its exten— sion those ideational experiences which oc— cur during sleep and assigning to it a generally negative valence. These restric— tions are useful in psychiatry in our own cultural setting, but they are not helpful in establishing a cross—culturally applicable definition (nor need they be, for a Western psychiatrist’s definition is to be regarded as only one cultural variant), since in some societies dreams and waking visions may be for many purposes treated as equivalent. For the purposes of this study, “hallucina— tion” will be defined, very broadly, as pseu— doperception, without relevant stimulation of external or internal sensory receptors, but with subjective vividness equal to that aroused by such stimulation. Included in its extension, therefore, are dreams, the ter— of “hallucinations” psychiatric waking minology, and hypnogogic imagery; excluded is the fainter audiovisual imagery of reflective thought. There remains a some— what dubious category, occasionally referred to as hallucinations in the psychiatric lite-ra— ture, of perceptions whose subject matter is unambiguously provided by external stim— ulation but whose form displays subtle or gross distortion. The most familiar exam— ples are the undulating floors, stretched perspectives, echoing sounds, and other dis— tortions experienced by some subjects on administration of the so—called hallucino— genic or psychotomimetic drugs, and by normal subjects who have consumed nar— Wallace or alcohol, have been breathing anesthetics, or are in process of losing consciousness (fainting). We shall leave these phenomena out of the range of our definition, on the ground that a “hallucina— tory” dimension already exists, of vividness of subjective imagery in the absence of sensory stimulation, at all points of which the pseudoperception may be equally undis— torted, and relate these dubious cases, rather, to a logically independent dimension of perceptual distortion. The relationship between the two dimensions may, of course. be investigated empirically. A second major problem, in addition to the concept of hallucination itself, is that perennial flower of confusion, the word “possession.” Casual observers and many anthropologists alike use this word in two very different senses: as a label for some person’s overtly observable behavior, and as a label for a native theory to explain this be— havior. These two uses are, unhappily, often confused. It may be best to state flatly, at the outset, that I shall use the word “possession” to denote any native theory which explains some event of human behavior as being the result of the physical presence, in a human body, of an alien spirit which takes over certain or all of the host’s executive functions, most frequently speech and control of the skeletal musculature. A phe— nomenon of possession does not, therefore, for me exist; the word merely labels a theory. Now the possession theory happens to be frequently applied, in folk beliefs, to three very different classes of phenomena, for each of which other terms exist. One of these is hallucination; the second is hysteri— cal dissociation (including multiple personality, fugues, somnambulism, conversion hysterias, and hypnotic states); the third is obsessive ideation and compulsive action. Clinically, these are distinguishable phenom— ena. But any one, or group, of them can be, in folk theory, explained by the mecha— nism of possession. Unfortunately, some observers have, in their eagerness to empa— thize with their subjects, used the word cotics, 75/59 �A. M. A. possession to denote not only a type of folk theory but also whatever phenomenon their folk happen to use the theory to explain. In other words, if a people use the concept of “possession” to explain certain hysterical dissociations (such as the stereotyped fugues which are so commonly induced in many religious rituals), the anthropologist tends to say that the dancers in the ritual are “possessed”; similarly, if a people use the theory to explain hallucination (which is, incidentally, a less common use of the concept), the anthropologist may refer to hallucinators as “possessed” persons. Even more confusingly, the ethnographer may use the word to denote any person who is thought to be persistently influenced by a supernatural being, whether located inside or outside the person’s body. A third problem of conceptual ambiguity is the notion of trance. There would seem to be at least two major uses of this term: (1) to denote physiological collapse with coma or the occasionally concomitant delirious hallucinations; and (2) to denote (again) states of dissociation. The possi— bilities of semantic confusion are manifest. Problems of Methodology At first, it was hoped that the Human Relations Area Files (HRAF), including the old Cross—Cultural Survey Files at New Haven and the completed portions of HRAF at New Haven and Philadelphia, would provide a sample of societies various of whose cultural features could be sta— tistically related to the phenomena of hallucination. The data contained in HRAF, however, even when supplemented by mate— rial from sources not tapped by HRAF, and by data on societies not included in HRAF, proved to be not amenable to statistical treatment, for three reasons: A sample which included representative cul— tures from all major culture areas was not available; the data were not comparable from society to society, because of the extreme unevenness of the reporting (rang— ing from no report at all to careful, exten— 76/60 ARCHIVES OF GENERAL PSYCHIATRY sive, and psychiatrically informed study), and the data provided were usually too crude to permit the discriminations which I regarded as significant for statistical cate- gories. N0 quantity of time or money spent in HRAF and other library compilations can remedy all of these defects of the eth— nographic literature, and only a vast expenditure of funds in field work could amass new and adequate data on a sufficient num— ber of societies. The inference to be made is, rather, that the ethnographic literature available for areal or world samples, of the sort envisioned by Murdock 14 and others in connection with HRAF, is not suitable for statistical analysis with respect to all dimensions of anthropological interest, but is suitable only with respect to certain highly formalized and conventionally re— ported dimensions, such as kinship and subsistence activities. The cultures on which data were collected from HRAF in the abortive statistical phase of the study are the following: Abipone Achewa Ainu Andamanese Apiaca Apinage Aranda Arikara Assiniboin Balinese Bena Blackfoot Buka Bushman—Hottentot Canella Chuckchee Creek Crow Cuna Dahoman Easter Island Gros Ventres Hopi Ifugao Indian Yoga Kamilaroi Kwakiutl Lamba Maori Marshallese Plateau area (North America) Sherente Since nontrivial and significant statistics appeared to be unachievable, the obvious next step was to consider what prestatistical manipulations of the data were possible and whether any of these might yield formulations of interest. Experimentation along these lines brought me to construct a rather tedious list of “existence theorems,” which I shall not reproduce here, but which proved later to be valuable in setting up the matrix of concepts. Existence theorems are Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE eminently prestatistical, but they are neces— statistical of description, sort to any sary since they define the relevant and nontrivial categories. An existence theorem is merely a statement that of the class A: there is at least one member concerning which the statement [9 in true; thus, for instance, the theorem where “there exists at least one (x) such that . . .” (3x)=df and (x):df “society” and A ber of the society as meaningless concatenations of visual and/or a u d i to r y pseudo-perceptions.” The whole of the theorem would read: “There exists at least one society such that hallucinations are defined by some members of the society as meaningless concatenations of visual and/or auditory pseudopercep— tions.” From the existence theorems, derived from the HRAF cross—cultural ma— terials and from my ethnographic knowledge, the dimensions of hallucinatory experience shown in Table l were con— structed. These dimensions are offered as a formal frame of reference within which to observe cultural definitions of hallucina— tory experience, and as a rough statement of the range of cultural variability evident in the ethnographic record. With the foregoing semantic and methodological considerations in mind, we may proceed to discuss, informally and nonstatistically, certain implications of the ethno— graphic data. Conditions of Hallucination If one were to design an electronic brain which behaved in all respects like a normal human brain, one would have to include in its specifications both a capacity for hallucina— tion and a capacity to distinguish halluci— nation from sensory perception. Most human beings hallucinate (in the broad sense of the term which is employed in Wallace Communication Contains no information but is a meaningless pattern of auditory or visual images (:2 Contains information in the form of observation of phenomena that really exist somewhere (but are not messages) (1. Contains message from a supernatural being (ghost, soul, demon, divinity, etc.) located outside Ego’s body a . Contains message from, or is the experience of, a supernatural being (ghost, soul, demon, divinity, etc.) located inside Ego’s body ((5 Contains message from one part of self (e. g., own soul, conscience, memory, Id, subconscious, etc.) to another (6. g., consciousness, ego, etc.) or to other person as Contains message from a natural being communicating by means of radio, telepathy, or other means of telecommunication (1 1 B p12“hallucinations are defined by some mem- 1.—Dimensiom of Hallucinatory Experience TABLE Mechanism of control Can be controlled by hallucinator and/or hallucinator’s fellows by manipulating physical condition and/or foreign biochemical factors ()2 Can be controlled by hallucinator and/or hallucinator's fellows by nonphysical means (such as will, prayer, ritual, worry, suggestion, autosuggestion, psychotherapy, etc.) I). Can be controlled by will of alien supernatural or natum being b I) 1 t b5 b. b1 b3 b 1A0 2 0 [Ab 3 b 2N) a I) 1A0 2A1) . Other (fill) [Vb sz 3]) 0 Induction c. Hallucinator seeks to induce or repeat experience C 2 /—"C 1 D Concealment d1 Hallucinator conceals experience from group or denies oc- currence d 2 ,—/d 1 Punishment E e. Group institutes punishment and/or social extrusion e 2 He 1 Therapy 1“ Group or individual institutes therapeutic and/or prophy— lactic measures f1 fz Hf! G Role assignment g1 Experience qualifies individual for valued social role (adult hood, shaman, healer, diviner, priest, etc.) g2 My 1 H Behavior guidance hi Content of experience may be taken as guide for individual and/or group action (other than therapeutic) irrespective of social role of hallucinator h: Content of experience taken as guide for individual and/or group action (other than therapeutic) only when hallucinator already fills certain social roles (e. g. shaman, prophet) h , Content of experience not taken as guide for individual and/ or group action (other than therapeutic) 77/61 �A. M. A. this paper), in one way or another, quite frequently; and there is no society, to my knowledge, in which hallucinatory experience is unknown. Hallucination is, in fact, one of the most widely distributed of the modes of human experience. Explicit re— ports of dreams, visions, and the hearing of voices are found in the sacred literature of the pre—Christian Near East; if mythology, ritual, and other religious behavior be re— garded as in part the legacy of such experi— ences passed on by oral or written tradition, we may suspect an antiquity measured in tens or hundreds of millenia. Under the general rubric of hallucination, however, there can be assembled a wide range of types of experience, from the Vivid and realistic supplanting of reality in ec— static visions and auditory revelations, to a relatively pallid verbal or visual imagery which blends imperceptibly into ordinary “thought.” These experiences are known from Western clinical observations to be prompted by the most various circum— stances: sleep, anoxia, pharmacologic agents, brain tumors, psychological stress, fatigue, sensory restriction, and others. Relatively little seems to have been done to relate the conditions precipitating and surrounding an event of hallucination to the content of the experience; ethnographic investigation may offer a few clues here. The specific conditions under which hal— lucinations have been reported in the ethno— graphic literature may be divided into the following categories : Sleep Fatigue Hunger and thirst Prolonged physical pain Extreme physical illness Social isolation Special exercises (breath control, posture, sensory restriction) Drugs Emotional stress in normal persons Mental illness It should be noted that these conditions are not logically independent, and that frequent— ly (and especially in voluntarily induced hallucination) two or more of the conditions are realized at the same time. Three observations are pertinent. First, in many societies relatively little significance 78/62 ARCHIVES OF GENERAL PSYCHIATRY is attached to differences in the conditions under which hallucination occurs. In par— ticular, dreams during sleep, spontaneous waking visions, and induced hallucinations under drugs or stress may be given equal status and comparable evaluation. Western society is remarkable for the importance it assigns to differences in the precipitating conditions of hallucination; the most strik— ing example, of course, is afforded by the profound distinctions we draw among dreams (in sleep), delirium (in illness or intoxication), and “hallucination” in the restricted sense (in the waking state). Second, we must take note that, although not all hallucinatory experiences are regarded as desirable in any society, in primitive socie— ties it is very common for hallucinations with desirable content to be not only ac— cepted with pleasure but deliberately sought with the aid of such devices as hallucino— genic substances (e. g., some American Indians ingest parts of the cactus peyote and Paleo—Siberians, the mushroom fly agaric) and various sorts of personal disciplines, ranging from breathing and posture exercises, through hunger, thirst, and isola— tion, to prolonged physical self—torture. The tendency to minimize discrimination among hallucinations on a criterion of precipitating condition of course does not imply any inability to discriminate between hallucina— tion and sensory perception; the preferential status of hallucinatory experiences is possible only when it is clearly differentiable from normal experience. Third, it appears that both the subjective feeling tone and the specific content of the hallucination are heavily influenced by a still more pervasive condition: the cultural milieu in which the hallucination, and particularly the voluntary hallucination, takes place. The latter point is worth elaborating here, although it anticipates some of the material to follow, because it is relevant to the methodology and evaluation of clinical research with hallucinogenic compounds under varying experimental conditions. Typically in such research the clinician administers Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE to a group of healthy urban adults, often medi— the with identified themselves persons cal or an auxiliary—medical profession, a substance which induces various instrumentally measurable physiological changes and observable alterations in behavior. The subjects are asked also to report verbally on their subjective experience. These verbal reports reveal a considerable variety of experience: Some subjects are euphoric; some are entranced by the intensity of esthetic pleasure they achieve in the contemplation of color, form, and movement divorced from meaning; many complain of anxiety, physical discomfort, various un— welcome perceptual distortions, and attitu— dinal changes; some hallucinate and some do not. These various reports and observa— tions are taken to indicate the psychological actions of the drug. Similarly variable re— sults, but usually with transient intensification of chronic symptomatology, are given by mental patients from roughly comparable cultural backgrounds (but, of course, by virtue of illness occupying a very different social status). But no cultural controls are employed; and it is possible that to an unknown degree the subjective experience, and hence even the physiological measures, is influenced by the negative attitude toward any distortion of normal sensory and cognitive experience which many members of our society share, at least those people who do not customarily seek such special experi— ences as are afforded by narcotics and alcohol or by mystical or esthetic preoccu— pations. Some indication of the quality and mag— nitude of the possible effect of differing cultural attitudes toward hallucinatory ex— perience under differing conditions of drug administration is given by the differences in the experiences reported by normal white subjects after administration of mescaline and by American Indians after consumption 0d of introduction, and of intragroup per— sonality differences: first, the influence of tains mescaline). The literature on the mescaline experi— ences of normal subjects is rather scattered, Wallace and some of it, particularly if it has an early date of publication, is unsatisfying because of the inadequacy of sample description and the disjointed and anecdotal style of presen— tation conventional at the time. Neverthe— less, the consultation of several prime sources “'25 reveals a reasonably consistent pattern of described phenomena, which con— trasts with the pattern described (also, unfortunately, sometimes in undefined sam— ples) by anthropologists’ American Indian informants.”12'1“"!24 The fact of major contrast has been briefly remarked in print by one of the—foremost anthropological stu— dents of peyotism, Slotkin,21 who observed in the course of discussion of attempts of white persons to suppress peyotism that “the responses described in clinical experi— ments on Whites are so different from the responses described by Indian Peyotists . as to fall into completely different catego— 2.—Contrasts in Prevailing Character of the Responses 0f_Climcally “Normal” White and Indian Subjects of M escaline Intoxication TABLE White Indian Variable and extreme mood shifts (agitated depression, anxiety, euphoria, depend— ing on stage of intoxication and personal characteristics) Initial relative stability of mood, followed by religious anxiety and enthusiasm, with tendency toward feel— Frequent breakdown of social inhibitions and display of Maintenance of orderly and “proper” behavior (“revivalistic" enthusiasm is socially proper in context) No report of suspiciousness “shameless” sexual, aggressive, etc., behavior Suspiciousness of others present in environment (reported to be uniformly present by Guttmann and noted in self by Kliiver) Unwelcome feelings of loss of contact with reality, depersonalization, meaningless“split-personality," ness, etc. Hallucinations largely idiosyncratic in content No therapeutic benefits or permanent behavioral changes ings of religious reverence and personal satisfaction when vision achieved, and often, also, expectation of “cure” of physical illness Welcome feelings of contact with a new, more meaningful, higher order of reality, but a reality prefigured in doctrinal knowledge and implying more, rather than less social participation Hallucinations often strongly patterned after doctrinal model Marked therapeutic benefits and behavioral changes (reduction of chronic anxiety level, increased sense of personal worth, more satisfac» tion in community life) 79/63 �A. M. A. ries; they do not seem to be talking about the same thing.” The salient differences in the reports are displayed in Table 2; the reader should note that a meaningful statis— tical presentation of frequencies of response types, while desirable, is precluded by the nature of the data available. These marked differences would seem to be plausibly explained by two related fac— tors which are independent of possible differences in racial physiology, of chemical action of the drug owing to variations in dosage, mixture with other agents, of meth— od of introduction, and 0f intragroup person— ality differences: first, the influence of the setting in which the drug is taken (the white subject’s experiences occur usually in a hospital or university research setting; the Indian experiences, in a ceremonial lodge during a solemn religious ritual); and, second, differences in the psychological meaning of the primary drug effects when experienced. Certainly, gross enough situ— ational and semantic differences exist: White normal subjects generally take mes— caline once or twice, in a clinical research setting, with definite knowledge of an ex— perimental or a clinical purpose in the investigation, and without any commitment to or interest in peyote, or to mescaline in any form, as a personal religion; Indian peyote users take mescaline repeatedly, in a solemn religious setting to the accompaniment of serious ritual, with definite knowledge of a religious purpose in the usage and, often, with hope for per— sonal salvation, of which the vision is the evidence. The former factor—the setting— 5 been has reported by Fernberger to yield differences in content, which can to some degree be affected both by suggestion by the experimenter and by autosuggestion. The latter, the semantic, factor would seem to be significant at the present stage of theory concerning the action of the hallucinogens, since it is recognized that both personal character and, perhaps, personally or cul— turally determined values concerning the “homeostasis of subjective—experience” may 80/64 ARCHIVES OF GENERAL PSYCHIATRY affect response to experimentally induced changes in sensation and perception.19 We quote the work of Hoch, Cattell, and Pennes 8 in this connection. We have pointed out that the alterations in the vegetative nervous system appear first under the influence of mescaline, lysergic acid, pervitin, etc. This is usually followed by alterations of per— ception, bodily sensations, and changes in body image. In many patients it would appear that the perceptual alterations are conducive in producing anxiety, uncertainty, and, at times, rage. Seemingly, the perceptual alterations lead to a lowering of reality control, thence to tension and anxiety, which in turn lead to depressive, aggressive, and paranoid manifestations. Schizophrenic patients whose reality contact is already impaired are seemingly more vulnerable to drugs that have a disorganizing effect on reality perception. As yet it is unclear whether the emotional alterations seen in these patients are due to a physiological action of the drug per se or due to the experiencing of an alteration of reality and other changes on a psy— chic level. Interpretation of Content In most primitive societies, even if (on other grounds) the hallucinator is regarded as being ill, or the hallucination itself is unpleasurable, the content will not be re— garded as a meaningless concatenation of pseudoperceptions. The content of hallucination is sometimes interpreted as a message introduced directly into the subject’s consciousness by a supernatural being, directed either to the hallucinator himself or to the community through him as an intermediary. More frequently, hallucination will be in— terpreted as a real perceptual experience by the soul, which has wandered from the body and is seeing and hearing events involving real or supernatural persons which are occurring in another place, or which is able to see and hear events and supernatural beings present but imperceptible to others. The message—intrusion theory tends to blend into primitive theories of possession; in our society, it is expressed in the conventional telepathy, radio, radar, brain—washing, and electrical—current delusions and is classed as a paranoid mechanism, while the spiritual— perception theory is associated with extreme Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE religious enthusiasm. But in both theories, the content of hallucination is interpreted as significant information. In at least two culture areas, that of the 17th—century Iroquois Indians of what is now New York State,26 and of Western society after the advent of psychoanalysis, a third theory also has existed as an alterna— tive explanation for hallucination. In this theory, the hallucination conveys an emo— tion—laden message from the soul, or some unconscious part of the mind, to the conscious self, and thus is a process of thought. This view, like the others, regards the content of hallucination as a message containing information. It appears to be a rare idea that the content of hallucination is mean— ingless, and one may hazard the guess that this notion is largely confined to psychiatri— cally unsophisticated, nonparanoid, and tepidly religious, or nonreligious, members of Western society. If a hallucination is regarded as a mes— sage, there are evidently two approaches to its interpretation: to take the manifest con— tent literally, and to regard the manifest con— tent as a symbolic expression of significant underlying ideas. The latter approach may entail various techniques, such as guessing and devices of free association, the consul— tation of a formal list of symbols and their meanings, and the more or less standardized derivation of meaning from the context of circumstances (such as ritual, illness, situ— ational stresses, and the like) in which the hallucination occurred. It is not important here whether or not there are, in truth, universal themes and symbols expressed in dreams and other hallucinatory experiences, as psychoanalytic theory and data suggest. The important point is that most human beings, in most societies, outside Western civilization, regard hallucinatory content as communication bearing significant informa— tion which can be understood either directly or by the use of special methods of interpretation. Now this belief in hallucinatory content as communication, particularly when it is Wallace coupled with the conviction that the com— munication is not merely intrapsychic, seems to have an effect both on the content of hallucination and on the hallucinator’s, and his community’s, response to it. Halluci— nation in itself is not frightening, either to hallucinator or to his community, al— though the content may be; but even if the content is frightening, it is valuable knowl— edge. Hence the overt response to halluci— nation will very likely be markedly affected by its classification as communication. It is to the topic of response to hallucina— tion that we now turn. Response to Hallucination The difference in response between Eng— lish white and Australian black to a course of hallucinations in a mourning woman is vividly illustrated in the following anecdote, reported by Parker,15 the author of a study of the Euahlayi tribe of Australia. Our witch woman was rather a remarkable 01d person. When she was, I suppose considerably over sixty, her favourite granddaughter (lied. Old Bootha was in a terrible state of grief, and chopped herself in a most merciless manner at the burial, especially about the head. She would speak to no one, used to spend her time about the grave, round which she fixed upright posts which she painted white, red, and black. All round the grave she used to sweep continually. More and more she isolated herself, and at last discarded all her clothes and roamed the bush 5. la Eve . . . as she had probably done as a young girl. She dug herself an underground camp, roofed it over, and painted enormous posts which she erected in front of her “Muddy wine,” as she called her camp. She never came near the house, though we had been great friends before. She used to prowl around the outhouses and pick up all sorts of things, rubbish for the most part, but often good utensils too; all used to be secreted in the underground camp. She never talked to anyone, but used to mutter continually to herself and her dogs in an unknown tongue which only her dogs seemed to understand. We thought she was quite mad. One day, while we were playing tennis, she sud— denly, muttering her strange language and dancing new corroboree steps, clad only in her black skin, came up. Matah told her to go away, but she only corroboreed round him and said she wanted to see 81/65 �A. M. A. She danced round me for a little time, then sidled up to me and said: “\Nahl [negative or “no”] you frightened, wahl me hurt you. I only womba—mad—all yowee— spirits—in me tell me gubbah— good—I lib ‘long a youee: bimeby I come back big feller wirreenun [as a medicine woman] wahl you frightened? I not hurt you.” And after crooning an accompaniment to her steps, off she went, a strange enough figure, dancing and crooning as she went towards her camp; and not until the spirits gave up possession of her did she come near the house again. I used to tell the other blacks to see that Bootha had plenty of food. They said she was all right, the spirits were looking after her. Lunatics, from their point of view, are only persons spirit-possessed. Gradually old Bootha, clothed as usual, came back about the place. Strange stories came through the house back to me of old Bootha. She was very ill for a long time, then suddenly she recovered, not only recovered but seemed rejuvenated. We heard of wonderful cures she made; how she always consulted the spirits about any illness; how there were said to be spirits in some of her dogs; how she was now a rainmaker, and, in fact, a fully fledged witch. me. . . . The reader will note a typical Western attitude toward the “lunatic,” a blend of amused contempt, pity, and anxiety, and also the native woman’s awareness of the attitude, and her effort to clarify the white man’s misunderstanding by explaining that her hallucinatory experiences were “good.” Noteworthy also is the satisfactory (both to the woman and to her associates) social remission, which was achieved in the course of becoming a shaman: a remission which, I suggest, was facilitated by her anxiety— free acceptance of hallucinatory experience. This anxiety—free acceptance of, and willing— ness to describe, hallucinatory experience contrasts vividly with the common shamed, fearful, self—doubting attitude of Western patients, who frequently try to conceal the fact that they “see things” or “hear voices,” and sometimes “confess” (as the psychi— atrist puts it) to hallucinations only under very careful questioning. Response to hallucination may be considered both as a matter of the hallucinator’s response to the experience and as a matter of the response of his group (and the two, 82/66 ARCHIVES OF GENERAL PSYCHIATRY of course, may be equivalent). As I have indicated, in primitive societies the fact of hallucination per se is seldom disturbing; but the content itself may be disturbing or not, depending on the nature of the socially appropriate response. Dreamers or vision— aries may resist strenuously the hallucinated suggestion that they undergo an arduous process of becoming a shaman, or that they accept the role of berdache (an institutional— ized inversion of sexual role among the Plains Indians), or that they commit some act, like murder or incest, which violates social norms; they may be stricken with panic at learning of approaching community disaster, or that they have been bewitched, or that they will be captured, tortured, and killed in a future war. Similarly, the hallu— cinator’s associates may respond with dismay, or with enthusiasm, to the wishes of his soul, and may institute protective meas— ures to avert harm from him or from them— selves, may induct him into the special social relationships indicated by his vision, may conduct the indicated medical treatment, or may take his revelation as a code for social reform. The significant point is that it is the content of the communication which is the focus of interest and the fulcrum of action rather than the fact of hallucination itself. Let us now consider, by contrast, the responses to hallucination typical in Western societies. In some social groups, particularly religious sects, hallucinatory experience with supernatural figures ap— parent in the manifest content is interpreted as divine, 0r Satanic, revelation, and is responded to either by acceptance of in— junctions discovered in the content or by repression, or even punishment designed to drive out “possessing” devils. In psycho— analytically influenced groups (which prob— ably include a considerable proportion of the urban population of Western countries), dreams are interpreted and used as a basis for psychotherapeutic action, but waking hallucinations are regarded as symptoms of serious psychic illness. And in the rest of Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE the population at large, waking hallucina— tions are probably regarded primarily as indications of “nervous breakdown,” or even “insanity.’ The latter unfavorable social diagnosis is very commonly followed by the social extrusion of the hallucinator, with or without prior medical advice, into a mental hospital or some other socially restricted environment, or at the very least into a quasiostracism at home or in lodgings. Police force is available and not uncom— monly used to sanction and to effect this extrusion. In medical circles, despite recog— nition that hallucination in many conditions is a secondary symptom, and despite the insistence of workers like Boisen that “what the voices say is the important thing, not 1 hallucina— the mere fact of hearing voices,” tion is commonly taken to be a grave sign. In some of the research literature, indeed, hallucination is treated as if it were the essential feature of psychosis. Now it is reasonable to suppose that most persons, when they hallucinate for the first time (certainly when the first waking hallu— cination occurs), are aware of the culturally standard interpretation of and response to hallucination in their society. Even if they do not accept this interpretation and re— sponse as wise or proper, they will be aware of its probable evocation in others. If this is the case, then it is likely that the person’s interpretation of, and response to, the fact of his own hallucination in a given context (as well as its content) will be a function of the way in which the fact (and content) of hallucination is defined by his culture. The function should determine in part his ’ emotional experience both during and after the event, and possibly (by cultural suggestion) its perceived content as well. 'We may ask, at this point, how much anxiety, self—depreciation, and cognitive dis— tortion are added to the miseries of mental patients by the circumstance that they have learned to fear waking hallucination in the course of living in a society in which waking hallucinatory experience is almost uni— formly negatively valued? (The scientific validity of the valuation is irrelevant.) Furthermore, we must question the completeness of any research into the psychophysiological action of the so—called psychomimetic drugs, of sensory restriction, and of other hallucinogenic procedures which fails to weigh not only the magnitude but also the direction of the probably mas— sive contaminating effect of cultural sug— gestion upon the subjects. For what is measured is not just the action of a drug or other procedure, but the action of the procedure plus the subject’s interpretation of and response to this action, plus the feedback effect on the continuing action itself (Figure); and all of these actions, inter— pretations, responses, and effects are factors with direction, as well as magnitude. There may be much that the therapist can do to alter the internalized cultural defini— tions of hallucinatory experience in his patients, if he wishes. But it is research problems that chiefly concern us here. It would be possible in clinical research to con— trol for the direction of cultural effects by employing as control subjects persons whose subculture differs sharply from that of the Hallucinatory pseudo— perception SPECIFIC HALLUCINOGENIC STIMULUS CONDITION cognition of Situation -””'“°'°‘ , . -39. “—3). _____ Musculofure 1’ Vaugned'gme" "em”s ' . WWW / ‘ . personal-3y . 2‘ .. dynamics , Internalized cultural 15" definition of situation 9 MOTOR vEggAL *{ RESPONSE Mediation of response , , to hallucmOgenic stimulus by facets 0m; subjectlve experience. _ - - 9 NERV° Wallace 83/67 �A. M. A. experimental subjects in its definition of the expected experience, and by ensuring that the experimental conditions for the controls were sufficiently close to culturally normal conditions for them to permit generalization from past learning. Furthermore, it would be possible to select subjects systematically on criteria of personality, of past experi— ence, and of attitude toward the expected events; and it would be possible to vary deliberately the general situational structure with other variables held constant, both by physical manipulation and by deliberate in— struction and suggestion to the subjects. Such procedures, incidentally, should also be considered in relation to other than halluci— nogenic compounds; they evidently would apply to such drugs as tranquilizers, sedatives, and energizers, which on other evidence also depend in part for their effects on relatively unexplored interactions with personal dynamics and sociocultural milieu.18 Methodologically, such manipulations are the reverse images of the controls imposed by the placebo—and—blind (or double—blind) techniques and of analysis—of—variance tech— niques involving multiple pharmacologic agents; whereas the placebo-plus—blind, or variance—analysis, design varies the chemical agent and holds situation constant either by randomization or by laboratory control, the method of cultural and situational controls would hold the drug constant and vary such aspects of situation as the physical experi— mental conditions, instructions to personnel, and character and background of subjects. Drug and cultural controls should ideally be combined in one design. Summary The paper briefly examines the range of cultural variation in conditions inducing, interpretations of, and responses to, hallu— cinatory experience. The published data suggest strongly that internalized cultural definitions of hallucinatory experience have a profound effect on the responses both of mentally ill and of normal persons. Meth— odological controls for cultural differences 84/68 ARCHIVES OF GENERAL PSYCHIATRY are indicated in research with hallucinogenic substances. Eastern Pennsylvania Psychiatric Institute. REFERENCES Boisen, A. T.: The Exploration of the Inner World, New York, Harper & Brothers, 1936. 1. Eggan, D.: The Manifest Content of Dreams: A Challenge to Social Science, Am. Anthropologist 2. 54 :469, 1952. Eggan, D.: The Personal Use of Myth in Dreams, J. Am. Folklore 68 :445, 1955. 4. Fernberger, S. W.: Observations on Taking Peyote (Anhalonium lewinii), Am. J. Psychol. 3. 34 :267, 1923. Fernberger, S. W.: Further Observations on Peyote Intoxication, J. Abnorm. & Social Psychol. 5. 26:367, 1932. Guttmann, E.: Artificial Psychoses Produced by Mescaline, J. Ment. Sc. 82 2203, 1936. 6. Hoch, P. H.: Experimental Induction of Psychoses, in The Biology of Mental Health and Disease, 27th Annual Conference of Milbank Memorial Fund, New York, Paul B. Hoeber, Inc. (Medical Book Department of Harper & 7. Brothers), 1952. Hoch, P. H.; Cattell, J. P., and Pennes, H. H.; Effect of Drugs: Theoretical Considera— tions from a Psychological Viewpoint, Am. J. Psychiat. 1082585, 1952. 8. Huxley, A.: The Doors of Perception, New York, Harper & Brothers, 1954. 10. Klfiver, H.; Mescal Visions and Eidetic Visions, Am. J. Psychol. 371502, 1926. 11. La Barre, W.: The Peyote Cult, in Native American Culture, Yale University Publications in Anthropology, No. 19, New Haven, Conn, Yale University Press, 1938. 12. La Barre, W.: Primitive Psychotherapy: Peyotism and Confession, J. Abnorm. & Social Psychol. 42:294, 1947. 13. Lincoln, J. S.: The Dream in Primitive Cul— tures, Baltimore, Williams & Wilkins Company, 9. 1935. Murdock, G. R: World Ethnographic Sample, Am. Anthropologist 592664, 1957. 14. 15. Parker, K. L.: The Euahlayi Tribe, London, Archibald Constable & C0., 1905. Petrullo, V.: The Diabolic Root: A Study of Peyotism, the New Indian Religion, Among the Delawares, Philadelphia, University of Pennsyl— vania Press, 1934. 16. Vol. 1, July, 1959 �RESPONSE TO HALLUCINATORY EXPERIENCE Radin, P.: The Winnebago Tribe, Washington, D. C., Bureau of American Ethnology, 37th Annual Report to Secretary of Smithsonian In— stitute, 1915-1916, 1923. 17. Rashkis, H. A., and Smarr, E. R.: A Method for the Control and Evaluation of Sociopsychological Factors in Pharmacological Research, Psychiat. Res. Rep. 9:121, 1958. 18. Rubin, L. S.: The Psychopharmacology of Lysergic Acid Diethylamide (LSD—25), Psychol. 19. Bull. 54:479, 1957. 20. Slotkin, J. S.: Menomini Philos. Soc., n. 5. 42:4, 1952. Peyotism, Tr. Am. J. S.: The Peyote Religion: A Study in Indian—White Relations, Glencoe, 111., Free Press, 1956. 21. Slotkin, Wallace 22. Smythies, J. R.: The Mescaline Phenomena, Brit. J. Philos. Sc. 3:339, 1953. 23. Smythies, J. R.: A Logical and Cultural Analysis of Hallucinatory Sense—Experience, J. Ment. Sc. 102:336, 1956. D.: Personality and Peyotism in Menomini Indian Acculturation, Psychiatry 15: 24. Spindler, G. 151, 1952. 25. Stockings, G. T.: A Clinical Study of the Mescaline Psychosis, with Special Reference to the Mechanism of the Genesis of Schizophrenia and Other Psychotic States, J. Ment. Sc. 86:29, 1946. 26. Wallace, A. F. C.: Dreams and the Wishes of the Soul: A Type of Psychoanalytic Theory Among the 17th Century Iroquois, Am. Anthropologist 602234, 1958. Printed and Published in the United States of America 85/69 �� Dublin Core The Dublin Core metadata element set is common to all Omeka records, including items, files, and collections. 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