LSD 202 I Europharmaco!Ogy. Transactions of the 2Nd Confe

LSD 202

I_europharmaco!ogy. Transactions of the 2nd Confe- • rence_ 14ay 25-27_ 1955. Princeton_ N.J. Ed.by H.A. Abramson. Josiah i{acy Jr. Foundation_ _,IewYork 1956 R_SEARCH ON SCHIZOPHRENIA * p.183. bn£

_7_ HUMPHRY OSMOND _0 SaskatchewanHospital dqi Weyburn, Saskatchewan,Canada

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{_ing_L and interesting work., The psychiatrist, approaching. them. through •ieurology, neurophys,ology, pharmacology and biochemistry, and .< t_r0ugh elegant and frequently astoundingly brilliant techniques, comes tgl a point where he begins to wish to find out more about this illness or group of illnesses of these sick people, some of whom we call "schizophrenics. ,, It is here of course, that difficulty arises, because now it becomes uncertain (a) whether there is such a condition at all, (b) Whether this condition is so all-embracing that we are all schizophrenics, {'_) whether this is simply a normal mode of people responding to a _6rtain type of sociological setting, or (d) whether this is, in fact, an Hifiess which exists like other illnesses, of which there are more or less SeVere cases and different cases. :_So numerous are the references and so varied are the opinions among _chiatrists as to what is meant by "schizophrenic," that it is essential _,_ me to give some idea of what I think it means; otherwise, we may b:gtalking about something quite different. . To begin with, I do not accept the view that schizophrenics are to be iSoked upon as any but the end process of an illness, nor do I take the view which some hold, that schizophrenic people are necessarily either antisocial or not useful. On the contrary, there is ample evidence that some of the most brilliant and gifted and valuable people who have ever lived have suffered from mental illness. I immediately think of William Blake (1,2,3) and of Sir lsaac Newton (4). The latter's strange ailment would certainly have led him to a psychiatrist if he had lived three hundred years later, and one has the feeling that as his illness

• The work discussed here was done under the auspices of the Saskatchewan Committee for Schizophrenia Research c/o Psychiatric Services Branch, Dept. of Public Health, Regina, Saskatchewan. Funds were provided by the Provincial Government of Saskatchewan, the l_aderal Government of Canada through the Department of Health & Welfare, and the Rockefeller Foundation. .-i_[ t83

1 / / 184 N euro pharmac ology continued on and off for about fifteen years, he might have ha_ _ leukotomy. However, Sir Isaac got very well after about 8 months, and was governing the Mint at the time and, he produced one of his more famous books many years after he had had his first bout of severe paranoid illness. Simultaneously, he was devoted to his work on numerology and discovering "The Beast," among other things. One can think of many contemporary people from the rather less satisfactory Rudolph Hess (5) to the genius and wonder of Franz Kafka (6,7). Many would be prepared to say this is complete nonsense on my part, because schizophrenia has _he unique virtue of being an illness from which there is no recovery. It has been said that if the patient does re5 cover, he really did not have it. Of course, if this is true, it is extreme_ unfortunate, but, luckily, common observation does not suggest thisi:_fi! fact, from time to time, one has the extraordinary experience of seeing someone who has been ill for 10, 15, 20, or even 25 years leaving the hospital and apparently recovering. My picture of schizophrenia is that it is an illness which is characterized by disturbances in thinking, in mood, and in perception (and sometimes in posture, which may or may' not be a result). These three great groups of disturbances may be combined or may not be combined, and they may be congruous or incongruous. I do not see any reason why they should necessarily be combined, but, as a matter of common observation, they quite often are. Clearly, where there is incongruity between thinking, mood, and perception, one would suppose, at any rate, that corn: plete social disintegration is practically certain, though this is not certain, as a matter of fact. On the other hand, where there is a little incongruity; one would believe that social integration is possible. Unfortunately, the information available as to what makes for social integration is very small. We have no reason to think that this simple picture of the degree of congruity, being very important, is, in fact, what keeps people in our large mental hospitals. But my picture of an illness is one which I personally see. Dr. Kallmann's work* suggests, as do field studies, that for every schizophrenic patient treated in mental hospitals, there are at least two or three out of the hospital. I would say that even this is an understatement, bu_ I have done very little field work. However, I know a few schizophrenic people who are living happily in a community and who are keenly interested in things around them. One end of the parameter shows the schizophrenic person lying in

*Prof. Franz J. Kallmann, Department of Medical Genetics of the New York State Psychi- atric Institute, Columbia University, New York, N. Y.: Personal communication, 1954. Research on Schizophrenia 185 dismal conditions, in some hospital where this word is almost a courtesy and where the great tradition of American psychiatry and of British- Quaker psychiatry and of French psychiatry of the early nineteenth century has been forgotten, where Kirkbride and Dorothea Dix, Tuke (8), and Pinel would be scourging those who are responsible for it. This is one end of the parameter. The other end shows someone rare like Blake or Franz Kafka, outside an institution and carrying on useful activity. This is my picture of the strange, mysterious, and really, very odd illness. I came to it through seeing many of these illnesses, being puzzled by them, and finding them incomprehensible some of the time, but incredibly fascinating. I have always been unable to find any formula, apart from this very rough one, which, even among the great classics, such as Bleuler (9) and Kraepelin (10), and the numerous neoclassicists that followed them, seemed to fit in with what I saw. And every so often I have seen things which did not seem to fit in anywhere. This terrible illness, which invariably led one to a mental hospital for many years, could suddenly turn out to be a highly benign illness that lasted a short time. Or an illness that was supposed to be highly benign could suddenly become malignant. On the other hand, a patient suffer- ing from a long-term illness that appeared to be diagnostically extremely malignant and considered hopeless, might recover in 10 years or so. Some years ago, when I was in London with John Smythies (11,12,13, 14), a colleague of mine, I found that he had interested himself in mescaline. Dr. Smythies is a philosopher, and his other interests lie in the fields of neurophysiology and, to a lesser extent, in psychiatry. He was deeply interested in the reality of the phenomena of schizophrenia. It was in connection with this that he became interested in mescaline and, while experimenting with it, he made the observation which we now know was a very old one, that mescaline has some resemblance to epinephrine. Since neither of us knew any biochemistry, we became tremendously excited about this. It was, of course, a very naive observation on our part, but interestingly enough, although chemists have known this for a long time, chemically minded psychiatrists have very rarely pointed out that, for this reason, it would be an extremely interesting thing to correlate the mescaline phenomenon and the schizophrenic phenomenon. If they have done it I have never known it. Also, if they have done it, they have never made any systematic correlation between the effects of epinephrine and the effects of mescaline. Nor have they, except for sporadic forays, made any very systematic investigations of the effects of mescaline and similar compounds, and then correlated them with the effects of schizophrenia. 186 N europharmac ology

We then carried out a sort of rough correlation. I think it is, again, of interest to say that although the pure alkaloid was isolated and its psychological effects described very clearly by Heffter (15) in 1896, we have never seen a paper that gave a really clear picture of the effect of different doses of the alkaloid in the same and in different people. Neither did we find any comparison of these effects with those of schizophrenic illness. It must have been done but we have never run across it. There was no map to guide us so we made our own. From this it seems that if a wide range of schizophrenia and mescaline intoxication is studied, the great majority of symptoms is found in both. The more the range is narrowed, the smaller is the overlap. One of the interesting things about schizophrenia is the fact that at one end of the parameter there can be a man in whom apparently only one area of experience has been altered, and at the other end of the parameter there can be a man who is totally out of touch with everything. There is a curious distinction which we made between the toxic confusional illnesses, those intoxications in which clouding of con- sciousness occurs, and the schizophrenic illnesses. In the former there is unawareness of immediate surroundings, such as not knowing the date or the time, disorientations. The latter are said not to include this, but in actual fact, they appear to be a continuum. Many psychiatrists do not seem to be able to make a distinction between the two. We could find nothing in the huge continuum of mescaline phenomena which could not also be found in certain schizophrenic illnesses. We then tried to find out whether many had suggested looking for substances that had the power of epinephrine and its derivatives, and the psychoactivity of mescaline but not its pressor effects. Again, this was an extremely naive idea, but it did not do us any harm. Sherwood: You started by stating that for your definition of schizophrenia, it was necessary to have a disorder in one or more of the following classes: thought, mood, perception, and posture. Osmond: Posture came in as a fourth because I am not sure that it is not a derivative. I am inclined to think it is not a derivative. Sherwood: You say that any of these may affect only one area or more ? Osrnond: No. Sherwood: You didn't say "area," you referred to those classes. Osmond: I referred to these things as classes, yes. This is a bad definition on my part, but I have deliberately made this wide because, not being a psychologist and not being a philosopher, I find the definitions of these things difficult, and I go in the tradition of William James, (16), who, whenever definitions came, took the greatest care to avoid Research on Schizophrenia 187 them. When he was reproached at the time, he said that he was not made that way. Fremont-Smith: May I support you ? I think that definitions, unless made for a specific and limited goal, have no value other than to be restrictive and to interfere with thought and experimentation. I think that definitions, on the whole, are to be avoided, except a working definition for a specific, limited, and stated goal. Sherwood: I only wanted to make sure that I knew what you meant by"area." Fremont-Smith: And you gave us a chance. I am very much in agree- ment with you. Osmond: As to posture, there is a good deal of neural evidence. I think that there are specific disorders of posture that occur, but, here again, occasionally you get an interpretation of a catatonic posture in a person that makes one feel that, in fact, as one would expect, these are psychological entities. Certainly, to the catatonic person, his posture may represent holding up the earth or punishment for cutting his father's throat, or something of that sort. But, again, in this particular instance, if one makes too narrow a definition or if one narrows oneself, it does not help, and I feel that the posture entities are very important. At any rate, we started our investigation from this, not really having any idea what to do, but making numerous consultations. We obtained a great deal of help from Dr. J. Harley Mason, University Demon- strator in Organic Chemistry, Cambridge, England, and from Dr. C. M. Scott, Director hnperial Chemical industries (Pharmaceuticals), Black- ley, Manchester, England. We decided to collect numerous compounds, starting with mescaline and working slowly and progressively toward epinephrine. Leake: Did you by any chance run into Louis Lewin's Phantastica (17)? Osmond: Yes, but never in an English translation, unfortunately. It went out of print in England in about 1935. Leake: Did you go into Sigmund FrSnkel's Die Arzneimittel-Synthese (18)? Osmond: No. Leake: That, again, is not available in English. So much of this was rather clearly anticipated in connection with type of activity, many years ago, but unfortunately, in a narrow, restricted field, in relation to chemical constitution and biological action. It did not come into clinical attention, so the possible value of it, either from the standpoint of experimentation or even of clinical investigation, was not appreciated. Another work of similar interest is Lewin's Die Gifte in der Well- 188 N eur op harmac olo g y geschichte (19) which has a lot of incidental information all along these lines. It is not a popular item, but much more detailed. Osmond: At any rate, we started on this orderly progression, or so it seemed to us. Dr. Scott made methyl mescaline and some other related compounds for us, and fortunately at about this time, I went to Canada and started to workwith my colleague,Abram Holler (20,21,22). We had not done any simple arithmetic, because, otherwise, I think it would have struck us that the orderly progression that we had in mind repre- sented something like ten thousand compounds. There was the further detriment to this orderly progression that each compound, as we soon discovered, takes a long time to try, and we had no animal methods worked out in our minds. Only recently, Dr. Mirsky has been working on some animal methods, but we did not know about these, and it would have been a very long journey. There is the added fact, of course, that the number of people who are prepared to engage in taking ten thousand unknown compounds is limited, and, therefore, on a volunteer basis alone, one is soon going to run out of subjects. I took mescaline in 1951 and I found this a most extraordinary experience which I will describe later. My experience was recorded and in order to find other subjects, my colleague, John Smythies, thought that we would play this recording to others in order to encourage them to try it (23,24,25). We at length found a man who we thought would be a very good subject. He was a young history professor, and we felt that he would be intelligent, interested, and able to make a clear report. We also thought that he might produce aspects of experience that would be interesting for us to study. As this man listened to the recording, he appeared rather ill. When asked what was the matter, he said that the recorded reactions were familiar to him. He said that he was a severe asthmatic and that when he suffered from asthma badly, if he took epinephrine, some of these things happened to him. We interpreted that, rightly or wrongly, I am not certain, to mean that if there are people in whom the pressor effects of epinephrine do not take place, then either epinephrine itself or some of its metabolites could produce this type of disturbance, and this began to shift our attention a little bit. We found that this was not very uncommon with asthmatics. As you know, there is a curious relationship between asthma and psychosis in a small group of people. We found that quite a few asthmatics, in fact, have these very curious disturbances, often in affect and sometimes in Research on Schizophrenia 189 perception. One very interesting reaction was described to us by a medical student. He said that he used to use an epinephrine nose spray for asthma and, as he never had much money, he used to keep his nose spray a long time and it would get yellowish and off-color. He found, at the time of using this off-color epinephrine, that he got a curious feeling of indifference toward people which really only worried him in retrospect; it did not worry him at the time. For example, when he was driving, if he saw a child in the road, he would suddenly find that it was an intellectual process, and not an affective process, as to whether or not he would slow up. He did not worry, as you or I would if we saw a child in front of the car; he merely wondered if he would get into trouble if he did run it down. As you can see, this tiny change is, in fact, an enormous change, psychologically, and this gave us a clue. Finally, Dr. E. Asquith* who is an anesthetist at Regina General Hospital, told us that while in Eng- land during the war and his co-workers had some epinephrine that had "gone off," and was a sort of pinkish color. The anesthetists used it and found that it had very inadequate pressor effects. They gave a considerable amount of it and, of course, they were giving it to people who had been given atropine which fact I think may be important. They found that many of these patients would go quite crazy. This effect lasted for only a day or two, but it upset the anesthetists. When the patients came out of the anesthetic, they would be visually hallucinating. We asked Dr. Asquith why he didn't inquire into this, and he gave what seemed to him a very satisfactory reply--they just gave up using this epinephrine. We therefore began to think that it might be of value to look more closely into epinephrine. Another idea that came to us was, why should we not find out all the substances that produce psychological effects similar to mescaline, with minimal biological effects ? We felt that if, as we had hypothecated, the body itself might produce something which produced obvious and gross changes in the sympathetic and parasympathetic systems, they would have been found out a long time ago, and therefore there would not be any argument. In fact, the literature is full of arguments as to whether the sympathetic or the parasympathetic system predominates, and what, in fact, is happening. We felt that it was an essential part of the thing we were looking for, that it should have very little obvious effects, and that effects had not yet been classified; therefore, we started to look at the known substances that produce these conditioning disturbances. The substances that I know of up to the moment are mescaline,

*Private communication, 1952. 190 N europharmacolo gy lycergic acid, harmine, norepinephrine, indole (found in ibogaine), epinephrine, adrenochrome, and adrenolutin. The first and most striking thing, of course, is the extraordinarily small number of these substances; however, they are widespread throughout the world, and some of them have enormous antiquity and tremendous social importance. Marrazzi: Would you clarify what you were saying about looking for substances which I thought you said did not have obvious autonomic effects ? Osmond: What we were looking for was substances that were known to have more or less obvious psychological effects and less obvious autonomic effects, such as would not be easy to classify. This is why we ruled out atropine. There is no doubt that an individual can be made quite psychotic when given atropine if he is given enough, but, at the same time, it is quite obvious that he has had atropine. And so this could hardly be a substance of the sort that would produce this extremely fugitive and strange illness: The earliest one that we have on record is soma. No one knows what soma is, because, apparently, it was introduced into India from the north, between two and three thousand years ago. The high caste Indians also called it homa, suma, funa, and a great many other names. The only person who appears to know much about it is Dr. Andreyi Puharich, of the Round Table Foundation, Glen Cove, Maine, who is making a study of it and has started with Herodotus and early Egyptian sources. Soma has an enormous and very ancient history. Its story, according to India, is this: It used to be imported, and the high caste Indians took it as part of religious ceremonies. They went on taking it for many gen- erations, and apparently it was dangerous. It was said to be a creeping plant, supposedly coming from somewhere in Central Asia. Eventually it was no longer possible to obtain so the devotees took up yoga as a way of trying to produce the same sort of experience. Since then, they have been carrying on with yoga. I do not know whether or not this is completely accurate, but I understand that Philippe de Felice (26) claims that is what happened. At any rate, we were certainly not able to obtain soma and so, of course, we do not know what it was. I believe the next one in antiquity of which we are certain is Indian hemp, hashish, which, again, is very old, and to which we did not pay too much attention, because, the battle about the active principle still seems to be in progress. We felt that it would be quite useless to enter into that. It may have been solved by now, but we came to the conclusion from the literature available that there was almost no end to this. Research on Schizophrenia 191

Furthermore, the hemp is extremely variable; even samples from the same crop differ greatly. But it has a long and noble history. Then came peyotl. Peyotl, again, has a great history, and we, naturally, started off with the papers of Havelock Ellis (27) and S. W. Mitchell (28). As you know, peyotl has been, from the psychiatric point of view, one of the more curious incidents in psychiatry, because there is tremendous ambivalence among psychiatrists toward it. At one moment, they are tremendously interested, and they are being urged on by the scientists and the poets to do something about it, every so often. Heinrich Kl_ver (29), for instance, has spent years urging psychiatrists to interest themselves in mescaline. Leake: May I interrupt for a moment to say that it is wise to remember the slow development of appreciation of the euphoric and dream- producing effects of opium ? This drug was well known to the early Romans, and has a long history of gradual understanding of its hallucinating properties. One should also remember the long popular my- thology associated with the mandrake or mandragora (30). In this connection there was also the ancient recognition of hallucinations from atropine-containing plants. Probably older than peyotl is the use of tobacco as an intoxicant among the Amerinds. In the South Seas, the natives used kava, and in the Andes, the Incas chewed coca leaves. On the other hand, in India, rauwolfia, was recognized by the Hindus as an antiphrenetic. Dioscor- ides, the Greek medical writer, described this as "serpentina," also noting its antiphrenetic action. Many other similar native agents are described in Lewin's Phanlastica (17). Osmond: We ruled out opium because of its extremely narcotic effects. Leake: I know; but it produces many of the symptoms. Osmond: Yes; it does. Leake: It produces many of the symptoms that are involved in some degree of loss of touch with reality. Osmond: But the ones we had to rule out were those that did not pertain to the clinical picture with which we were faced. But, on the other hand, I entirely agree with you that these others are clearly of extreme importance in the total psychological picture. However, we felt, from the clinical picture, it was less likely that those opium-like substances-- Leake: But even of greater antiquity, and with wider distribution than any of these, are the fermented drinks, such as beer and wine. Beer was well known to the old Egyptians, and wine from the utmost antiquity. Their intoxicating properties were well recognized by the ancients. 192 N europharmacolo gy

Many phases of their intoxicating action resemble various types of mental disturbance, at least from the standpoint of unusual behavior, including disturbances of thought, mood, and perception. Abramson: How about wormwood ? Leake: No; wormwood was always used, as far as I know, for expell- ing worms. Abramson: What about pernod ? Leake: Absinthe is derived from wormwood, but its effect, as far as I know, did not become known generally until the distillation process developed during the Middle Ages. Then, this peculiar use of absinthe developed somewhere in the seventeenth or eighteenth century. Abramson: But that would disturb thought, mood, perception, and posture. Leake: Yes; but it certainly did not come out of antiquity. Cerletti: I would say that it is a certain danger to think that all possi- bilities of mental disturbances by drugs have to do with your problem. I think we should try to limit the problem to more specific drugs and make a distinction between, let us say, intoxication by alcohol, as an example on the one side, and what Dr. Gerard calls psychosomimetic drug effects on the other. Otherwise, we must cover the whole field of pharmacology. There are several other examples. Perhaps you remember, that during the war between Italy and Abyssinia the story became known that the Abyssinians drank a special tea t)efore going into battle. This tea was made of Catha edulJs, the active principle of which is known to be closely related to ephedrine and amphetamine. This might be a more typical example for your field, but I still doubt if it is possible to take into consideration all kinds of drug intoxication. Leake: I know the problems. Nevertheless, let me defend my position. In considering the relation of chemical constitution to action on the central nervous system, let us remember the enormous scope of the type of chemicals that are active. It is important to select those that produce the most striking effects, and to investigate them most thoroughly. But I certainly think that we would be unwise, in a general discussion of neuropharmacology with particular reference to mental disorder, if we neglected addiction drugs, or if we neglected the whole scope implied by the consideration. Cerletti: I am also thinking, for example, of Schmiedeberg's old description (31) of urethan as a drug producing something like a psychotic state in animals. When urethan was used for the treatment of leukemia, some cases of mental disturbances in patients were described. Research on Schizophrenia 193

Leake: If we are interested in obtaining any clue regarding possible chemical disturbances occurring in mental illness, we cannot really for- get or neglect any drug that may produce some abnormality in that regard. It may give us an important clue. Osmond: I limited our work, as far as I could to those drugs that did not produce disorientation and confusion, not because any of these things occurred even with the large doses with which we worked, but we sought essentially disturbances in perception, thinking, and mood. If the person who doesn't get DT's takes a sufficient quantity of alcohol, he becomes unconscious. Again, if he takes opium, he is on the fringe of the curious narcotic state that De Quincey (32) described. He is not this way if he takes peyotl or mescaline. That, therefore, was our rough way of division, and that is why it brought us down to this small group. Whether, in the long run, this will prove to be of any use or not, we do not know, of course. After peyotl came mescaline. Of others that followed, one of the most respectable and one of the oldest is, of course, cohoba, which is derived from the seeds of Piptadenia peregrina (33). It appears that it was merely an accident that tobacco and not cohoba was introduced to the West. It is interesting to speculate on the psycho-social consequences had cohoba been substituted. Ramon Pane, who sailed with Columbus, seems to have been the first to notice it. In Cuba, the natives used two types of snuff, one of which was tobacco snuff and the other cohoba. One suspects that when they came across the predatory white men, they came to the conclusion that they would give them the less potent of the two. This decision was a fortunate one for them, because in South America and Central America, where the Indians interested the white man in their own invention--peyotl--the white man's immediate response was to forbid it. This is characteristic of the white man: Those activities in other cultures of which he does not approve he bans as vices, but his own vices he spreads determinedly. So we see the disappearance of the home-grown methods of altering psychic experience, and the imposition of the white man's own method--alcohol, although there is not the slightest evidence that his own is either better, safer, or more desirable than the native's method; rather to the contrary. The evidence before the Commission on Indian hemp held by the British in the 1890's in India (34) seemed to show that, on the whole, the hemp is less objec- tionable than alcohol, except, of course, where it is occasionally used in combination with datura, when it turns out to be very powerful. This will be discussed in more detail later. Rh_kel: Dr. Osmond, the natives use a special machine for the snuff which they make out of cohoba, and one of the original pieces of appara- 194 N euro pharmacology tus is at the museum in Philadelphia and another one is in Heidelberg. As far as I know, those are the only original ones which exist. Osmond: Dr. Schultes (35) sent me a very good paper of his dealing with another substance which is taken as a snuff. This is called yopo or yarge and it is made by heating the resin exuded from a certain nutmeg- like tree, once it has been barked. This snuff is very powerful and we would like to obtain some, but it would mean taking an expedi- tion a considerable distance up the Amazon. The Indians who live near white men pretend to be ignorant of it. I do not know of anyone who is' working on it and only heard about it recently. Now, I don't know of any work on bufotenin, but I am told there is some being done. We did not know this at the time of our work. Rinkel: Bufotenin, as far as I know, does not produce any particular mental symptoms. Is that correct, Dr. Cerletti ? Cerletti: That is just what I wanted to ask. Has it been shown that bufotenin can produce the symptoms of cohoba ? Osmond: It is alleged that it can. Cerletti." It has been isolated from cohoba, but it has not yet been found that it produces the symptoms of cohoba, as far as I know. Osmond: It is so claimed, in monkeys. Cerletti.. I know that in monkeys effects similar to those produced with LSD have been described, but with very large doses bufotenin produced some unspecific toxic symptoms, just like the ones I described in the dog. Osmond: I have had no experience with it. We have been trying to obtain some. Dr. Marrazzi, have you had an), ? Marrazzz: No. Cantoni: I think, with bufotenin, the experiments were mostly done in a scientific manner, and this is most unfortunate in that this drug was not used by the Indians in a scientific manner. The real way to test the drug would be to apply it with a snuffer, that is, one of these pieces of apparatus Dr. Rinkel has described. I think that this experiment has been planned, or is being planned, in Bethesda, and until such time as it is actually carried out, all one can tell is that bufotenin, when injected intravenously, does not produce psychic effects. This is not particularly significant. If the same negative results should be observed when bufotonin is applied in the more usual way, that would be quite significant. Osmond: This business of the snuffer is a fascinating sort of anomaly, isn't it, Dr. Cantoni, because there are connections between the nerve endings that go right into the nasal area, do they not ? Fremont-Smith." They are very short, only a few millimeters, right tip into the olfactory bulb. Research on Schizophrenia 195

Magoun: My guess would be that this was brought into the mucosal vessels and thus into the circulation. Kety: May I summarize the situation on cohoba to avoid confusion about what is known of this substance? Horning's laboratory at the National Heart Institute in Bethesda isolated bufotenin (33), which is dimethyl serotonin, from cohoba. Evarts at the National Institute of Mental Health (36) found that bufotenin given intravenously, in large doses, to monkeys produces the same symptoms as do large doses of LSD; these symptoms seem to be blindness and certain disturbances in motor behavior, but there was no evidence of subtle mental aberrations with small doses. Bufotenin cannot be given to man intravenously in large doses because of its profound circulatory effects, which resemble those of serotonin. Dr. Homing tells me that there are other substances in cohoba besides bufotenin which may very well be the active principle. Harris Isbell, at the United States Public Health Service Addiction Research Center in Lexington, is administering bufotenin by the intranasal route, in order to test the possibility that this may be the mode of administration necessary. He is going to prepare it the way the Indians used it, and to administer it that way. He is having great difficulty because his subjects sneeze violently when given the crude drug, while pure bufotenin by aerosol has not yet shown any mental effects (37). To the best of my knowledge, that seems to be the situation at the present time. Abramso_e: I might add that the sneezing might be connected with the particle size of the aerosol which it produces in the snuff. Kety: That is an interesting point. Fre,mnt-S,zith: _rould a tiny speck of anesthetic of some sort prevent the sneezing ? Kety: That is another good point. Marrazzh How large were the doses of LSD and how did you detect the blindness ? Ketj: These were appreciable doses, something of the order of milli- grams. Cerletti: I have seen 1 mg./kg, in a report. Kety." And the blindness was obvious from the behavior of the monkey. The monkey would run into things, and did not seem to react to visual stimuli. Cer/etti: Should not the possibility also be considered that, if something is applied by snuffing, the stimulation of olfactory endings could influence the psychic functions? Such studies have been made with special products of the perfume industry. Perhaps there is an effect only in certain people with abnormal or psychopathic tendencies. 196 N europharmac ology

Kety: Of course, to a number of us, it seemed that there might be a blood-brain barrier problem here, and that the introduction by the intranasal route might get the substance immediately into the cerebrospinal system without having to pass the blood-brain barrier. Marrazzi: You say the intranasal route would get in directly ? How ? Kety: Aren't there fairly direct communications between the olfactory nerve endings at the top of the nose and the rest of the brain ? Sherwood: It is a well known fact that particles of India ink will migrate from the nose through the cribriform plate and into the area of the olfactory bulb. Marrazzi: I don't know that drugs would necessarily. Kety: We didn't know, either, but it was a possibility. Cantoni: That is what they want to find out. I might add that one of the substances which Homing has identified in cohoba seeds is the quaternary derivative of serotonin, the trimethyl serotonin, which is a positively charged compound, and this might have some properties which might aid penetration and be, perhaps, advantageous in that respect. One doesn't know. Osmond: It hasn't been experimented with yet, really. Kety: Obviously, the reason for the great interest in cohoba is the fact that (1) the active ingredients, or should I say an important ingre- dient, is so closely related to serotonin (2) because Page (38) has isolated from normal human urine substances which appear to be methylated derivatives of serotonin. Cerlettk Why did you not include bulbocapnine in this comparative chemical list ? Osmond: Because we had all done such an enormous amount of work on it and also because we had very little information about its psychological effect. However, its effect was shown in cats. We felt though, that the dosage involved seemed to be a very large one. Sherwood: Yes; it is something of the order of 20 rag. Ingrain and Ranson (39) used that amount to obtain their experimental catatonia in cats. But this, incidentally, is the only drug that Feldberg and I (40) have found to do much the same thing whether it is given through the ventricles or subcutaneously. The only difference is the dosage; good effects are obtained with a dose of 500 /_g. to 1 rag. in the ventricle. Some experimental work along these lines has been described by de Jong

Osn_ond," And, of course, all the time, we were looking for something that we thought might turn up in the body, which limits one's field. We could find substances at that time--and we didn't find cohoba then. Since then, we have found one o1: two more that we would have liked to Research on Schizophrenia 197 investigate, and one that we did investigate; that was ololiuqui (an Aztec name) which comes from the seeds of Rivea corymbosa. I will come back to ololiuqui later in the discussion. I found it very interesting as it was the primary narcotic of the Aztecs, and peyotl was, in fact, their secondary narcotic. They esteemed ololiuqui highly and kept it secret from the Spaniards while they allowed the invaders to learn about peyotl. It is odd that although they had this extraordinary substance, peyotl, to work with, they preferred to work with ololiuqui, but there is little doubt that they did. For many years the inquisitors used to ask whether the Indians had taken the "devil's root," and also ololiuqui, the "devil's seed," but all they managed to get was peyotl. Rinkel: Dr. Osmond, since you have talked about ololiuqui, will you please elaborate on it a little more? I know from your work that there are some quite intriguing facets to it. I thought we might have some details. Osmond: I thought it would be more logical to return to ololiuqui later, and for the present, to discuss harmine, about which there is a good deal in the literature. I have never found any satisfactory psychological experiments with it, however. It was not easy to obtain. I have some seeds of the harmala and have eaten some of them. They are very unpleasant, and they do not seem to produce any effects, but I think that may be because we have not eaten enough. Ibogaine is the next one. I wrote to Dr. Albert Schweitzer to try to get information about ibogaine. I believe Lewin (17) has information about it, also, doesn't he ? Leake: Yes. Janot and Goutarel (d2) have isolated voacangine from Voaca_2ga africaIza, which is related to ibogaine. Voacangine is a methoxy indole. Osmond: We have tried to obtain a supply of that from the S. B. Penick Company of New York, but it is apparently quite difficult to collect the right bean, and the Penick Company was concerned that we might get a supply of the wrong bean, and, of course, so were we. For that reason, we have never taken ibogaine. Albert Schweitzer's (43) account of it certainly suggests that it should be tried and experimented with. We got a group of these substances together, and then it seemed to us that there was a possible pattern here. It was conceivable that if mescaline joined into some sort of indole-like compound, possibly, there might be some sort of unit),. Armed with this idea and with the pink epinephrine idea, we went to our colleagues in the University of Saskatchewan, Prof. Charles McArthur and Prof. Vernon _roodford of the Department of Bio- 198 N europharmac ologj chemistry, and Prof. Duncan Hutcheon of the Department of Pharma- cology, and asked their advice. We were thinking of a breakdown product of epinephrine that would be active but without its pressor qualities. We had not, however, reached a firm decision as to what this might be, so we asked them. Dr. Hutcheon, who is now with Chas. Pfizer & Co., suggested adrenochrome, which he and his pupil, Mr. Eade, made. They tested it on mice, and we began to go into the literature on it and found that there is an extensive literature in many directions except on its psychologic effects. Apparently, it has always been known to be rather unstable and difficult to deal with. Dr. Leake tells me that it is always resonating and becoming something else, so that it is clearly an interesting substance. Also, Chevremont (44) has done some work on it in relation to the mitosis of cells. If we were right in our supposition that there is a toxic substance in human beings, those already loaded with it, i.e., abnormal humans, psychotic patients, would obviously be entirely unsatisfactory subjects for study, so for that reason we have always felt that it was essential to study the effect of the drug on normal human beings. In the same way, if you give someone a large dose of LSD and then another there appears to be very little effect. I think L. Cholden* has shown that if LSD is given at short intervals, eventually it becomes quite ineffective, something, presumably, having happened. Abramson: Tolerance to LSD-25 was first observed by Dr. Harris Isbell and his group (45) at Lexington, Kentucky. I think that is important for the record. Osmond: Yes. The difficulty was that, although in actual fact, it is rather nontoxic with mice (46), we did not know what it would do when administered to human beings, and we did not know how to administer it. We gave it initially by subcutaneous injection, which is very painful, and we started at what we thought were extremely low doses, about 0.5 mg. I have some reason to suppose that the dosage which we used was larger than we intended as we had a new electrical balance which I do not think we were using properly. I suspect that our initial doses were at least ten times what we supposed they were, and that we started off first with 1 mg. and then with about 5 mg. Certainly our later experiments suggest that about 10 mg. is about the lowest effective dose. Then, of course, we began to run into some of the difficulties with methodology because, ideally, one should really have all these things

*Unpublished data. Research on Schizophrenia 199 set up with double-dummy experiments and things of that sort. I gave the first dose of this to Abram Hoffer, and the only reaction he had was a long pain. Marrazzi: Where ? Osmond: In his arm. Fremont-Smith: This injection was subcutaneous ? Osmond: Yes, subcutaneous. Then, Dr. Hoffer gave me an alleged 0.5 rag. dose also in the arm, and I got a lot of pain. I should say, and I think the blood pressure records suggested this, that I had no dryness of the mouth, so I do not think there was any epinephrine in the dose. Secondly, I do not think I was unduly expecting anything, because I was quite convinced that it would not work, for two reasons: I believed the dose to be 0.5 rag., and it seemed extremely unlikely that anything so small would produce any effect. The other thing was that I was somewhat preoccupied by the pain. Fremont-Smith: It kept on hurting, did it ? Osmond: Yes; it continued to hurt all through the night but, as time passed, I did not seem to worry about it. Leake: Was this subcutaneous ? Osmond: Yes; it was. Fremont-Smith: How large a volume ? Osmond: We originally made up about 2 ml. Leake: In distilled water ? Osmond: Yes, in distilled water. Abramson: That produces the pain ? Osmond: Yes ; I found out something here. Fremont-Smith: But not persistent pain from distilled water. Osmond: I think that the substance itself produced some pain, too. Anyway, of course, in any sort of experiment of this kind it is necessary to ask whether or not the subject frequently has experiences of this sort, if so, the value of the experiment is reduced, of course. You should know, then, that I developed a mild delirium when I had a fever of 104° F. and was being heavily treated with sulphonamides; however, I do not normally develop a delirium under 104 ° F., and I do not appear to have any specific sensitivity to any of the various drugs. I am not particularly sensitive to barbiturates, for instance. I am somewhat sensitive to benzedrine, but not in the direction of my becoming grossly overexcited or psychotic with it; I merely become very depressed. I think that these things are important because I suspect that people have a wide range of psychological differences in their reactions to all these substances and we have very little information with which to work at the moment. At any rate, I felt nothing much, and I was convinced that nothing 200 N europharmacolo gy much would happen; in fact, we were discussing what dose we really could next use with safety when I began to feel that the lighting in the room had changed. I can normally improve on my hypnagogic phenomena by taking a few drinks in the evening after having had a hard day. Under these cir- cumstances, with my eyes closed, I can see patterns of blues and blacks but nothing very vivid; if I am very tired, I can sometimes see more vivid coloring. I have to have the lights off to do this, incidentally. What happened on this occasion, however, was something different. In our particular laboratory, the light is quite bright, and the place seemed to be painted a very bright blue color. I closed my eyes, and had the very odd feeling of being at the bottom of an aquarium and of seeing curious things like sea anemones and bright flashing colors; I was becoming preoccupied with this. Of course, I felt at the time that this must clearly be some sort of odd imagination, but the fact that I went on looking was an indication of how odd it was, because normally I would have quickly opened my eyes and stopped this. Meanwhile my colleagues were urging me to let them know what was happening but I found myself getting less and less interested in them. She,'wood." Did you have any disturbances in other sensory rnodalities, or only in the visual? Osmond: No. Just visual. I opened my eyes again, and I felt the lighting had changed in the room. Of course, I was not an unsophisticated subject for this; I had taken mescaline, for instance. But I began to think that it was odd. I noticed that a van Gogh picture on the wall had a peculiar plasticity and depth about it which I had not noticed before. I think this is quite important because I am not normally very sensitive to pictures. This particular picture had never struck me very much, except, as is true of some of the pictures van Gogh painted when he was in the asylum ; they can be very unpleasant. However, the picture now began to become highly plastic and highly unpleasant. I began to feel uneasy, and I wanted to get out of the place. I found it depressing. My colleagues kept urging me to begin a Rorschach test which they had. I was not anxious to but finally did. This is interesting because I have always deliberately refrained from doing the Rorschach test but on this occasion I did not feel any particular reason for not doing it. Moreover, when I looked at the test I found it much more interesting than ever before, and also I saw things in it which I have never seen before nor have I seen since. There were parts of it that were really quite fascinating, particularly card 10 in which I saw a shrimp salesman. In the laboratory I was fairly happy although I didn't like the ques- Research on Schizophrenia 201 tioning, I didn't much like the colors, and I didn't like the van Gogh, but then we went outside and there was a curious sensation of the place having changed. We were driving along a familiar road but it didn't seem familiar. I would look into a house and see a lamp there, and this would seem significant; then I would begin to think and brood about it. The other thing I noticed was that I was extremely disinterested in my colleagues. They kept saying how interesting this was and I felt that I ought to feel that it was fascinating, but I didn't. Marrazzi: This was different from the feeling of being at the bottom of an aquarium ? Osmond: Yes. This was while I was out in the outer world. I didn't return very much to the aquarium sensation. I should say, again, that this was an unscientific experiment because we did not have any particular intention of doing the experiment that night. We finally arrived home and some people came in. I sat there for the best part of 3 hours, quite disinterested in them. I didn't want to talk. I found that I could be interested in and preoccupied with things and really felt happy with them, but people were a great strain. They seemed to make very silly remarks which they always wanted to press on me. It was almost as though they were intruding upon me. The only other time I have had an experience in any way similar was after I had taken mescaline. I normally do not feel this extreme reluctance to relate to people. Sherwood: Would you care to say whether what you experienced then was caused primarily by an impairment of memory of a relatively recent kind or was it the cognitive power that was impaired ? Osmond: The memory was excellent. I could name the street quite easily, but it did not look just the way it normally did. It wasn't a case of being disoriented and not knowing where I was. Sherwood: So the significance of things was your difficulty ? Osmond: Yes; that is it; the significance. Fremont-Smith: It doesn't seem to me that this quite describes it, either, because the significance would mean from one point of view. You recognized the street was leading you to the place where you expected to go, b{atthen it also seemed strange. It seems to me that what you are describing is the quality of a strangeness combined with the fact that it was still the street it was supposed to be. Leake: Were you in any way disoriented in time ? Osmond: No; I knew where I was. I knew, if pressed, I could verv well say what time I took this drug and that we were making an experiment, but this appeared to be very unimportant. 202 N euro pharmac ologj

Sherwood: Did you have any difficulty in understanding what ,people were saying to you ? Osmond: No; I understood very well what they were saying, but I had great difficulty in being interested in it. Leake: But you did not feel hostile to them ? Osmond: I felt hostile when they kept on talking because I didn't want to talk to them. It was a feeling of being intruded upon. At any rate, on the first occasion when I took this drug, the effect wore off by the next day; however, the following morning and all that day I felt extremely lively and active and interested, in fact, rather hyperactive. About a week later I took a second dose and I assumed that the effect would all be gone by the next day, as before, but a curious thing happened. I was supposed to go to a meeting and at this meeting I was to undertake certain discussions about mental health propaganda. I also wanted to drive to the meeting. I had taken the dose the night before at eight, and this was the second dose. That morning, at seven, I got up but I was extremely slow in dressin_ and getting out. There seemed to be a great deal of time and it did not seem to matter if I was late. When I got my car out I decided that I couldn't drive so persuaded someone else to drive for me as far as there was heavy traffic. Then I thanked him and drove on, not giving him a tip for this service, although, normally, I would have done so. When I got to the meeting, I felt all right, but I suddenly began to realize that I couldn't relate to these people, that I couldn't talk to them, and I had a queer feeling that somehow there was a sort of glass between them and me. I made one or two remarks--as I felt I had to do something, but it was a great effort. I was beginning to get preoccupied about driving the car as it was a 70-mile journey back across the prairies. Fortunately, I was able to arrange for a friend to drive me home. As we drove along, I realized that the reason why I couldn't possibly have driven the car before was that I didn't know where other cars were. 1 would see a car on the horizon and I would think it was going to run into us. Then I would think again that this was nonsense; it was a half mile away. Then there would be a queer panic, a sort of shuffling between not knowing whether it was close and intellectually knowing it was far away but not feeling that it was far. It really proved to be a very unpleasant journey back. About halfway home we stopped at a restaurant and another curious and rather unpleasant thing happened. There were two cars nearby which had obviously been in an accident and were badly damaged. I went inside for coffee but found that I did not like the place. In particular, there seemed to be a lot of unpleasant-looking individuals present, Research on Schizophrenia 203 so I went out. Then I found that I just couldn't get myself away from the two wrecked cars. There was a feeling that I was involved with them, that the accident they had been in had something to do with me. I wondered what had happened to them and then I came to think that I knew, which, of course, was not true. This effect, I am glad to say, wore off completely after about 24 hours. We then carried out two more experiments with Dr. Hoffer, one of which he assured me at the time had produced no results. He told me that some of his things had been stolen by people in the building and that there were many fiendish people about. Of course, this was not true. In fact, the things were there and I was able to find them. Later on that day he made arrangements to buy an expensive picture when he didn't have the money to pay for it. He did not need the picture, and, in fact, he had to go back the next day and tell the rather disappointed artist that he did not want it. We came to the conclusion that this substance produced peculiar changes in affect and perception of the subject and which, when you knew him were easy to spot and very obviously were there. One of the effects really worried us. Dr. Holler gave his wife 10 rag. of adrenochrome, and 2 days later I found her in what was quite clearly a clinical depression. She had lost insight in us. She said that she was sure it had nothing to do with the injection, but that everything seemed so hopeless and she didn't have any energy. We both were certainly alarmed; however the depression went away after 3 days. Another curious thing was the fact that about eight or nine years ago Mrs. Hoffer had had a quite severe jaundice. Evidence has been ac- cumulating with LSD and with mescaline that in some people, there are prolonged reactions after jaundice.* Again, this is not a thing on which anyone has done much systematic experimenting. It may not be jaundice; infectious hepatitis seems to be the relevant one, but, again, we do not know. Fremont-Smith: It would be a good point, though for anyone working with LSD or these other compounds, to make a historical note for each subject, as to whether or not there was a history of jaundice. Osvmnd: We are very careful about it. Fremont-Smith: This really, I think, might go on the record for all of us. Pfeiffer: Dr. Osmond made a comment about an apparent change in

*Dr. Roland Fischer (Research Biochemist in the Schizophrenia Research Unit of the Dept. of Psychiatry at the l.Jniversity of Saskatchewan) reported in a persnnal _ommunication a prohmged reaction to mescaline lasting 3 days in a subject who had severe jaundice some years previously. 204 N europharrnac ology the lighting with the use of this compound. We, too, have noticed that one of the first effects of LSD is an apparent change in the lighting. If you look at the subject's pupils, however, they are going up and down, and, of course, their interpretation of "the powerhouse failing" can very well be this change in pupil size, which occurs very rapidly. Another thing which occurs is that there may be dilation of one pupil before the other, in which case they may have a Pulfrich effect (47) in which things appear to be traveling in arcs instead of straight lines. If these patients are tested with a pendulum, it will seem to them that it is going in a circle instead of in its single plane. This is explained by the fact that the light from one retina gets to the visual cortex ahead of the other. The ophthalmologist puts a patch over one eye in order to get rid of this disturbing phenomenon, which can be interpreted, of course, as a central nervous system effect but it is actually a phenomenon originating in the eye. Fremont-Smith: I don't quite understand why a change in the pupil would make light or the impulse get to the visual cortex faster. P]eiffer: It is presumably a greater intensity of light on one retina than on the other. Osmond: Clearly, there are several other important directions in which this work might lead us: The first thing we wished to do was obtain more information about adrenochrome, and, to do this, we carried out a rather small number of experiments because, unfortunately, we ran out of our supply and it has been most difficult to obtain. Also it can deteriorate. Quaste]: What do you mean ? Osm(md: It ended up as melanin. Quaslel." You mean, it has gone a stage further ? Osmond: Yes. Quastel: Why should it do that ? Was it present in solution ? Osmond: No; this substance was under nitrogen and made by com- petent people. Ouastel: It was supl_osed to be a purified product ? O.rmond: It was supposed to be a purified product, yes. This has happened on several occasions when it came from a reliable place. Rinket: I have been told that it is extremely unstable. Quaslel: Was the substance kept under nitrogen ? Rheke]: It has to be handled with the greatest of care. The laboratory (Eli Lilly Research Laboratories) which produced it for Dr. Hoch and me sent it to us in packed ice just the day before the experiment. We used it quite fresh. Kety: Dr. Osmond, in the light of this, do you feel that the results Research on Schizophrenia 205 which you gave us and which I have no doubt are valid resulted from adrenochrome or from some yet unknown, unidentified substance ? Osmond: I only know that this was a red substance, like adrenochrome, and when it went a bit further, it was quite different. It became a black compound; as long as we were using that red compound we felt fairly confident. Dr. Duncan Hutcheon who made our adrenochrome for us was an expert at working with members of the epinephrine family. His co-worker, Eade (46), has published a description of his method and Dr. Hutcheon himself will be publishing in the near future. As I said he is now with Chas. Pfizer & Co. and they are generously supplying us. I know, however, that even with Dr. Hutcheon some batches quickly became melanin. Kety: Have you been able to obtain similar results with your adrenochrome since ? Osmond: With the next lot, we obtained similar results again, but it is only recently that we have been able to get our adrenochrome from the same source. Leake: Had Dr. Hutcheon any idea of the impurities in the first batch ? Osmond: I don't know. There were certainly no pressor impurities, but he does not say what impurities there were. Cantoni: Do I understand you to say that it was only with adrenochrome made by this particular man in this particular laboratory that you obtained these effects ? Osmo,zd: That is correct. We did not obtain any effects with the other substance because it was wrong; it was black by that time. We never use it if we can see any black in it at all, and we have had at least two or three lots like that. Now, we have a third lot, but made in a different laboratory by Dr. Hutcheon. That is the position, at present. Marrazzi: Dr. Osmond, this adrenochrome has been chemically characterized as pure ? Osmond: I gather that Dr. Hutcheon has done it. He says that he is certain, and his paper will come out and say exactly how it was prepared. I would not like to give you my views on it. Marrazzi: My question is a little bit different. It is not only this prep- aration, but the final characterization after it has been prepared, as a pure substance ? Osmond: I think so, but I would not like to say definitely, because, again, he is writing this now and soon you will be able to read his whole account of exactly what it is. Reynolds: At any rate, there was nothing intentionally added to it as a stabilizer ? 206 Neuro pharmacology

Osmond: No! We deliberately avoided that. Abramson: I would like to tell of an experiment which I tried with Siamese fighting fish. I added 0.5 gm. of epinephrine base which, as you know, is insoluble, to an aquarium of 2-gallon capacity. The aquarium contained about 20 fish, and they tried to eat the little particles of epinephrine. However, after engulfing them, they spit them out. Then, within an hour or two, the aquarium turned red, probably because of the presence of adrenochrome and possibly other pigmented compounds, I assume, which are formed from epinephrine. The fish lived very happily in this red liquid and with the other products I don't know about, for 2 months, the water becoming redder by the day. I regret that I was unable to observe any new phenomenon at all; they ate and fought as usual. Kety: I would like to ask Dr. Rinkd to indicate what his results were and whether they were with adrenochrome. I remember reading in the literature that he was not able to confirm Dr. Osmond's results with adrenochrome, although I do not know what the nature of his material was. Rinkel: I was greatly impressed by Dr. Osmond's results with adrenochrome. We also had come to a similar concept of psychosis, although from a different angle, as I will elaborate later. Naturally, we tried to duplicate the experiments of Osmond and Hoffer, but at that time, we did not have the pure adrenochrome available. We, therefore, used, perhaps not justifiably so, but for the time being, the stable semicarba- zone of adrenochrome which was available in this country, and is being widely used as a hemostatic in surgery. Since then, however, we received pure adrenochrome from the Eli Lilly Research Laboratories, with a report by Dr. Norbert Neuss,* of the procedure and chemical identification of adrenochrome, and Dr. Hoch received the same adrenochrome. The adrenochrome was packed in ice and in vials each containing 20 mg. This was received on the morning of the experiment. I finally persuaded Dr. J. Jackson DeShon of the Boston Psychopathic Hospital, to give me an injection of this substance. Fremont-Smith: Subcutaneously ? Rinke]: No, intravenously, because we had already had the same experience as Dr. Osmond who stated that the subcutaneous injection was very painful. He had suggested that it be injected intravenously,

*The adrenochrome was prepared for this experiment by Dr, N. Neuss using the method of Sobotka and Austin (48) as modified by Kornfeld. The spectral properties (infrared and ultraviolet absorption) were identical with those reported in the literature. The material was shown *o be free of epinephrine by paper chromatography. Research on Schizophrenia 207 and by withdrawing some blood and mixing it up in the syringe with the adrenochrome, no pain would be experienced. Kety: Dr. Osmond, did you give any of it intravenously and get mental effects. Osmond: Yes; we gave some intravenously and got mental effects, but mostly on epileptic people about whom I am going to tell you later. Rinkel: At that time, we followed the first publication on adrenochrome, and injected it according to Osmond and Hoffer's (22) description: 1 mg. dissolved in 1 ml. of saline solution. Nothing happened to me when I took this dose. I injected one more member of the hospital personnel who volun- teered. I might say this young man approached it with terrific anxiety; he was shaking, but no sooner had he received the adrenochrome than he stopped shaking and felt perfectly fine. Fremont-Smith: But your dosage was limited to 1 mg. ? Rinkel: In the first experiments, yes. We planned to increase the dose, although we were warned that a slight impurity of epinephrine in the compound might have a rather serious consequence, especially if a dose of from 25 to 50 mg. was injected. Fremont-Smith: You mean that you have so far used only 1 rag. ? Rinkel: Yes. Fremont-Smith: And you got no results. Do you think this is a good deal smaller dose than you used, Dr. Osmond ? Osmond: Yes. As I will tell you, we came to the conclusion that probably the effective dose is somewhere between 10 and 50 rag. There seems to be extraordinary individual variation with these things. Why we do not know. We have a few clues, though, as to why this may be. We did a few more experiments, and then we got a group of about 20 epileptics and gave them this substance intravenously in doses of from 10 to 50 rag. Hoffer and Szatmari (49) have published this work and show that adrenochrome undoubtedly produces changes in the brain waves; many slow waves can be altered by giving intravenous nicotinic acid. I am not going to go into that very much as I do not know enough about it. Some interesting work has been done on rabbits at the Mayo Clinic by Dr. B. Schwarz (50) who has given intraventricular adrenochrome and adrenolutin. John Smithies, my colleague in British Columbia, did some work with cats and found nothing much. But shortly after that he reported that his adrenochrome was turning black. Later it turned out to have much silver in it so this work must be discounted. This was not using Hutcheon's adrenochrome. 208 Neuropharmacology

Sherwood: Have you noticed any difference in onset of phenomena in general with different modes of administration? For instance, how long did onset of phenomena take if you put the substance in intravenously ? Osmond: It appears to be about the same time. This was very curious. I think that the EEG changes came on quite quickly, but the psychological changes, such as they were, came on quite suddenly. In work we did on one epileptic, who was given approximately 20 rag. intravenously, there were fairly good indications that there was a reaction. But unfortunately, that evening, she became acutely psychotic and she remained that way for 4 months, after which she became better. Our feeling was that it is possible to alter people who are balanced somewhere between, as it were, this world and the next. Fremont-Smith: Did her convulsions stop during this time ? Osmond: I do not know, unfortunately. She went away from us. Sherwood: That is very important. Fremont-Smith: It is very important, because this does happen. Osmond: Yes; I know. Fremont-Smith: I have seen that happen under psychotherapy. Was she a paranoid ? Osmond: I think she became acutely hallucinatory, almost, with many paranoid phenomena. We moved along rather slowly because of lack of material. We kept trying to get more adrenochrome, and we kept failing. We then had Dr. _toodford* in Saskatchewan working on the _Xrarburg apparatus and trying adrenochrome on rat brain. Here, I am afraid that my information will be extremely unsatisfactory to the pharmacologists and biochemists, because, of course, I simply do not know enough about this to be really accurate. But what I understood happened was that he showed that there is a very major inhibition in a rat brain on the War- burg apparatus. It is apparently something like up to 80 per cent, and it is dramatic and impressive. That work will all be published. I believe this has been shown before but in more detail and with different substrates. Ouastel: I would like to say that this effect of adrenochrome is fairly well known, to us at any rate. Adrenochrome, or the oxidized product of epinephrine, brings about a quite marked inhibitory effect on the respiratory system of isolated brain tissue. I would like to point out that the diketone group, as present in adrenochrome, is a very active group. Such groups have a very high affinity for

*xX,'oodford, V. R.: "Inhibition of Carbc_hydratc Metab_dism in Rat Brain by Adrcn_- clnrome." Paper delivered at the 8th scientific session of the Western Regi_,nal Group of the Division of Medical Research NRC Winnipeg, 1954. Research on Schizophrenia 209

SH enzymes and bring about large inhibitions of their activities. I am inclined to think that the changes you observed in the Warburg respiratory apparatus are largely due to the activity of the diketone groups. Similar inhibitions may be obtained with a variety of orthoquinones. I am, therefore, uncertain whether the respiratory inhibitions observed with adrenochrome are more or less nonspecific effects caused by the ketone groups or whether the molecule as a whole is specifically involved and its effect possibly related to the psychological manifestations you have discussed. You have mentioned, have you not, that you have had samples with various activities ? Osmond: Yes. Quastel: What we would like to know is whether the psychological effects of adrenochrome administration are caused by the activity of the diketone moiety of the molecule, or by the molecule as a whole, acting perhaps as a metabolite antagonist. Might it not be worthwhile injecting a mixture of adrenochrome with an equimolar concentration of cysteine or glutathione to bring about a reduction of the ketone to hydroxyl groups? It is possible that injection of such reduced adrenochrome would not result in the same psychological changes as are obtained with adrenochrome alone. Abramson: Is the activity of those ketone groups dependent upon the pH, and the oxidation reduction potential of the system, and so on ? Ouastel: Their presence affects the entire enzymatic system. Once they attack the SH enzymes present, the metabolic picture is changed. I have been wondering whether adrenochrome enters the red cell ? Does anyone know ? Osmond: There is evidence that it does. OQuastel: If it does enter the red cell, it may be reduced by the free glutathione present. What adrenochrome does not enter the red cell will be taken up by other tissues of the body where it will react with their metabolic systems. Osmond: Bacq (51) claims that it does get into the red cell. O0.uastd; Then the problem is whether or not the reduced adrenochrome will emerge from the red cell and whether or not it is as physiologically active as the oxidized form of adrenochrome. Presum- ably, if all the adrenochrome is absorbed by the red cells, it must emerge from the cells in one form or another to take effect ? Osmond: Yes. Elmadjian." Does it get in the red cell systematically or was it done in vitro ? Ovmond: I do not know. kfarrazzi: You have data on that ? 210 N euro pharmacology

Osmond: Yes. Quasteh Here again we have labile groups to consider. In what form are these groups ? I suppose you are sure of the structure of the molecule. Osmond: I am not quite sure. I was merely assured by Dr. Hutcheon. I understand it is a far from easy thing to be absolutely sure on this thing. Abramson: I should like to ask Dr. Osmond why he restricts his chemical concept to this group of compounds. Clinically speaking, the steroids, we know, do produce psychoses very often. I see them constantly. We know that they are natural products and know that the psychoses they produce lead to suicide, to confusion, and, in fact, meet all the requirements of change in thought, mood, perception, and posture. Why not stress the steroids with just as much interest as this group ? Elmadjian: There may be close relations between the metabolism of adrenal cortical and adrenal medullary hormones. Von Euler and his associates (52) have demonstrated a reduction in the norepinephrine excretion after ACTH and cortisone administration. We have been able to confirm the effect of ACTH on norepinephrine excretion (53). Furthermore, we have studied the effect of whole adrenal acetone powder on the possible conversion of hydroxytyramine to norepinephrine-like material. In the study of the physiological reactions to stress, we know that both the adrenal medulla and the adrenal cortex play important roles. At- tempts at studying together the adrenal-pituitary and sympathico- adrenal systems have been delayed because of the lack of reliable techniques for the measurement of epinephrine and norepinephrine. In brief, the hypothesis may be stated in a general way that it is not just by chance that these two portions of the adrenal gland, medulla, and cortex happen to be together. There may be some functional and metabolic relations between them. Cleg,born: I would like to support that hypothesis. Elmadjian: Table XII shows the results obtained by incubating 25 rag. of whole adrenal acetone powder with hydroxytyramine in addition to £umarate, magnesium, and phosphate buffer. Control incubations in- cluded all factors except hydroxytyramine while the experimental incubations contained 500 _g. of hydroxytyramine. In experiment 1, ATP, DPN, and TPN were omitted. The control and experimental results are the same. However, when these cofactors are added we obtained an increase in the measurable norepinephrine-like material. The iodometric color reaction of von Euler and Hamberg (54) was of limited value because hydroxytyramine gives a color approximately 15 per cent of that of norepinephrine. Research on Schizophrenia 211

TABLE XII

Incubation of Adrenal Acetone Powder with Hydroxytyramine*

Norepinephrine _,g. Experiment Cofactors Bio-assay Iodometric Color

1. C None 28.4 E None 24.5

2. C ATP DPN TPN 24.5 22.0 E ATP DPN TPN 65.5 159.2

3. C ATP DPN TPN 23.5 E ATP DPN TPN 38.5

9. C ATP DPN TPN 33.4 36.0 E ATP DPN TPN 76.4 192.0

C__control without hydroxytyramine Ezexperimental with 500 t_g. hydroxytyramine

Courtesy of R. Ncri, M. Hayano, D. Stone, R. I. Dorfman, and F. Elmadjian.

*Incubations were for 2 hours except for experiment 9, which was for 8 hours.

Cleghorn: What is the 3 in Table XII and the 9 ? What is the difference between 3 and 2 ? Elmadjian: They are exactly the same type of experiment. Cleghorn: There is a different result, though. Elmadjian." As indicated in the table, experiment 9, the incubation period was for 8 hours, while all other experiments were incubated for 2 hours. Quastel: May I interrupt you for a moment ? How far is ATP necessary for this reaction ? You have got all three together. Elmadjian: We cannot define the specific requirements at this time. The data support the idea that ATP is necessary. Of course we intend to study these aspects in detail. Cantonk What about DPN and TPN ? 212 N euro pharmac ology

Elmadjian: We can only answer that question when ATP is tried alone. Quasteh You mean, this reaction does not go without ATP ? Elmadjian: I would say at the present time that in one experiment conducted to date with DPN and TPN no conversion could be demonstrated. Of course this must be repeated. On this basis we are inclined to believe that ATP is necessary. Quasteh This involves a straight oxidation of a side chain of tyramine, as you know. Elmadjian: Yes. Quasteh One can understand TPN or DPN entering the picture, but I do not yet see the function of the ATP. Is it your point that ATP is necessary ? Elmadjian: Various molds were also shown to have the ability to convert hydroxytyramine to norepinephrine-like material. When cultures of molds (Cunninghamella blakesleeana, Neurospora crassa, and Rhizopus arrhizus) were extracted and assayed, there was no norepinephrine present. However, when the cultures of these molds were grown with hydroxytyramine, norepinephrine activity was demonstrated ranging from 0.50 to 1 per cent conversion. When DOPA was tried, no conversion could be demonstrated. By studying the mechanisms of biosynthesis or epinephrine and norepinephrine, we may be able to show relations between the adrenal cortex and the adrenal medulla. Cleghorn: They contained which ? Elmadjian: These are the molds: Rhizo/_us, Neurospora, and Cunleheg- hamella. Cunnheghamella is quite clearly demonstrated to have 11-_3- hydroxylase in the study with steroids. With Cunninghanzella, and the mold alone gave no activity in the bio-assay. When 500 _g. of hydroxytyramine was added, there was definite activity; with 250, there was definite activity; at 250 again--and these are the volumes in which the growth had occurred--2.78; and then we tried DOPA, to see what would happen to it; but it was inactive and nothing happened. With our present Cunninghamella, we have done other experiments on Rhizopus and NeurosDora , and both of these molds form material which comes out active in the bio-assay of norepinephrine and, furthermore, when DOPA was used as an abstrate, no transformation to norepinephrine occurred. Therefore, the story here is, from what Dr. Abramson said, that when you do get these steroids, they may be doing something or being closely involved and, as I said, we are working with epinephrine, norepinephrine, 17-K and other determinations under various conditions to see just what relationship they have, one to the other. Research on Schizophrenia 213

Osmond: We next began to search for a way to substantiate our theory that there might be some substance of this sort in the body. We have been trying with various methods, using paper chromatography and things of that sort, and so far, we have not been very successful. There was some work by Macht (55,56) in which he showed that the growth of the lupine seed root point has been inhibited by various sorts of sera, and particularly by schizophrenic serum. We therefore thought that it would be quite logical, since adrenochrome is not unlike the auxins or plant hormones, if something like this was around which would interfere with the lupine mitosis. We also knew that there was some evidence that adrenochrome interferes with the mitosis of mouse skin. We therefore began to think of some way by which we could find out if this were so, and we were rather fortunate in that Dr. Rudolph Altschul at the University of Saskatchewan Medical School has a colleague, Dr. S. Fedoroff, who works with cell cultures. He had a cell culture known as the L cell culture, and he also had several others, but this L culture, I understand, came originally from mouse cell. We began to send up samples of acute schizophrenic serum, and later, of a more chronic schizophrenic series F, to Dr. Fedoroff to work with on his cultures. Roughly and briefly, this is what seemed to happen: There is a big split between the sera of normal and the schizophrenic people. At least 80 per cent of the sera of schizophrenic people also seem to be toxic to the mouse cell. The normal people, or most of them, don't do anything much to it, and a few of them do a little. Naturally he doesn't know what the samples are; they are all done under coding; but we do not think there is any question of his suggesting things here and, indeed, the pictures that he shows don't look much like it. In this intermediate group, who represent something like 10 per cent, we have not yet characterized them. Naturally, we would like to make our results more accurate. We have just started doing the same thing with cerebrospinal fluid. The interesting thing is that both chronic and acute schizophrenic patients show much the same pattern. The cerebrospinal fluids seem to be extremely toxic to the mouse cell. Dr. Fedoroff has reported this at the recent anatomical meeting, and I hope that we will press ahead and try to find out what fraction of the serum cerebrospinal fluid does this. Clearly, if it is substantiated, it would be extremely interesting. Fremont-Smizh: How many experiments, roughly ? Osmond: I think he has now worked with about 50 schizophrenic and about 30 normal patients. Fremont-Sn_ith: This is serum or cerebrospinal fluid ? 214 Neuropharmacology

Osmond. This is serum. With cerebrospinal fluid we did only about 10. Unfortunately, we ran into one of those snags which often occur with cell cultures. They got one of their illnesses; the cells got some "bugs" in them. Leake: Who reported this ? Osmond: Fedoroff (57,58). Cantoni: Have any experiments been done with dialyzed serum ? Osmond: That is the next thing to be done and preparations are actually being made to do that now. Naturally we want to know whether or not it is attached to the protein. Fremont-Smith: Would you have an opportunity to measure the cerebrospinal fluid pressure of schizophrenic patients by lumbar puncture ? In this way there could be a double check on this other matter. Osmond: I will certainly try. It is being done in several places. I rather fear that this is a thing where you need to have one man who measures carefully all the time. Fremont-Smith: That is right. Perhaps in one place, one man could measure, and we could get ten or twelve reports after a while. We need them. Sherwood: I would like to add something to that. I think that lumbar puncture pressure measurements are not necessarily the same as ventricular, and, second, if lumbar puncture is done in the same patient often, it becomes insignificant. Fremont-Smith: Because of leakage ? Sheru, ood: Yes, because of leakage. Fremont-Smith.. Quite right, but it is also of considerable importance to look again at what the lumbar puncture pressure is, because we need to know that, or we cannot possibly evaluate what there is or is not in the other. The question of whether your patients had had previous lumbar punctures which had been leaking would also come up. That is why the ventricular pressure was low. Osmond: We have also tried to look in the urine to see whether we could find something else, assuming again that we were looking for something that might be of this family. We have tried a number of things and, so far, with only rather moderate success. We tried, first, to see whether, if there was such a substance here, we could produce some inhibition in plant growth. We did not really succeed there immediately. Then, while paper chromatography was still going on, following Dr. Roland Fischer's (59) suggestion that indolic substances get picked up on wool, we thought we would try to absorb these substances from urine; that is, soak special wool in urine, then dry it under standard conditions and wait and see whether Research on Schizophrenia 215 there was any difference in what was picked up. Dr. Fischer has suggested that since wool is an ectodermal tissue and most of the central nervous system is ectodermal in origin, wool may be a useful and easily handled model of the central nervous system. We pressed on and certainly at the moment, it does seem that you can get differences in what is picked up on wool from schizophrenic people and what is picked up from nonschizophrenic people. Fremont-Smith: Measured by weight ? Osmond: Yes, measured by weight. Fremont-Smith: You mean, more in the schizophrenic people ? Osmond: Yes, more in the schizophrenic people and less from nonschizophrenic people. It is an extremely tedious process, not wholly satisfactory, and technically difficult. Fremont-Smith: Does the urine have the same specific gravity? Osmond: I understand all these points have been carefully considered and allowed for. But this technique is tedious and it is affected by all sorts of things like humidity. I am not satisfied with it, and we want to get rid of it. But I thought I would mention it as one thing that we have been doing. Mirsky: Dr. Osmond, did you or did you not confirm Macht's work (56) ? Osmond: We never confirmed Macht's work (55,56) because we decided not to go into this lupine seed work. We decided on the cell once we knew we had the cell culture available and found it worked. We were thinking of going to see Macht and learning his technique, but we decided not to because it seemed too tricky. Mirsky: Incidentally, has anyone confirmed this work or attempted to confirm it ? Osmond: I think Dr. Jacques S. Gottlieb, now I believe at the Uni- versity of Michigan, said that many years ago, he attempted it but he did not have any success; he said it was a difficult technique and he was not certain that he had got it. It sounded difficult to us. I feel that our wool work is in this category. I think that there are certain techniques that a few people can do but are too tedious or too boring for anyone else to do. These things, of course, are often of no practical use because some more straightforward technique is called for, for general use. Therefore, from the wool work, we went on to see, if we got that substance or if we thought that some substance has absorbed, whether we could grow various things on the wool and see if their rate of growth were changed. We had considerable satisfaction from this and got marked differential growth in wheat seedlings and in oat seedlings. Then, we 216 Neuropharmacolo gy

ran into some difficulty and, for the last months, we have had whole batches going wrong. We don't understand it, but we are trying to find out why this is happening. Fremont-Smith: You mean you are not having the differential growth ? Osmond: No differential growth, and some dying off. We originally thought that we had copper in the water, which is one of the things that often happens in Saskatchewan. We are now trying to avoid this. Therefore, I don't know what happened to that. Certainly, initially, the results were promising. Now, they are far less promising. The wool work itself is still standing up fairly well. A4arrazzi: Do you have any idea what absorbed onto the wool ? Osmond: No. We think indolic substances, but our tests have been very gross, and I would not say. I think it can go on the record as being gross, but I do not think it should be accepted as being that. However, this area of the work is going on, and we are trying now to find out what this substance is that deals with cell cultures. Appar- ently, the evidence so far suggests that if the serum is heated to about 56 ° C. the toxic substance is destroyed and the cells are unaffected. But I understand that it is not thought to be a virus. Then, the next area in which we are particularly interested is in exploring some other substances. The first one that we explored was largely a matter of personal interest, I think. I got some ololiuqui seeds by the kindness of Dr. I. D. Clement, Director of the Atkins Memorial Laboratory and the Harvard Botanical Gardens in Cuba. I was very much interested in these and started to investigate them. Briefly, they are interesting from several points of view: The first is that there is a magnificent monograph on them by Richard Evans Schultes (35), so you start off with the advantage of a fascinating story of how this thing got lost for so long. It is one of the apparently celebrated ethno-botanical cases of a substance getting lost for many years amid great differences of opinion, and Schultes did this very able bit of work in identifying it. Then the Indian accounts, both ancient and modern, have proved to be accurate. Finally, it is queer in itself; the seeds are very hard and must be chewed. Eventually, we invented a little machine for breaking them up, as they taste rather unpleasant. Ololiuqui produces minor changes in visual perception but major changes in affect and volition. When given a close of this substance, the subject does not want to do anything, won't do anything, and gradu- ally he becomes more and more inactive. Then a kind of alert watch- fulness supervenes. I found that with 60 seeds and finally with 100 seeds, this is quite a feature. I sat, noting everything but not cnoving. Research on Schizophrenia 217

It is quite difficult to decide whether I did not want to move or was not able to. I also found that when I did move there was a tendency, once I got going, to keep going. If I stopped, I remained where I was. For example; if I started writing, I would keep on writing; if I stopped writing, there I would stop. But I didn't write the same syllable over and over again. Fremont-Smith: But you kept on writing ? Osmond: Yes; I kept on writing. There were several curious and interesting things. Again, I had this detachment from human beings, but a feeling of great comfort from small animals. We had a little Chihuahua dog, who was particularly comforting and friendly. This makes one wonder how many psychotic people may get great pleasure from small animals. Fremont-Smith: Do they have pets? Do they like pets? Do we know ? Osmond: We know of many strange old people who live alone with pets, and the death of the pet is a terrible catastrophe for them. They may well be right, and the great comfort obtained from this little animal is really extraordinary. I noted in the hospital that many of the patients want to have pets but for administrative reasons many do not have them. I often wonder of how much we are depriving them. Pets were a feature of the famous Retreat at York, England, about 1800. It was considered therapeutic for patients to have helpless creatures depending on them. In retrospect, I found this an intriguing idea because it may be of great clinical interest. As far as I know, the capacity to form relation- ships with animals has received little attention except in the medico- legal field. Nevertheless, it is of some importance. For instance, the human relationship with the dog is immensely old, and not only hunters but many others form a very close reciprocal attachment to these excellent creatures. It seems odd that this survived when human beings were terribly tiresome. I found my little dog far less difficult to relate to than my small daughter then aged 4 and very active. She was darting about, and couldn't understand what was happening. This was annoy- ing to me so I thought I would give her a little shove, but without meaning to I knocked her absolutely fiat. Here was an example of an almost all-or-none response. Also, I got one of my arms up in the air and found myself unable to get it down. Eventually, however, I got it down by pulling it with the other arm. This, I would say was a so-called catatonic phenomenon. Fre/,ont-Smith., You mean, you had a sense of helplessness about getting ),our arm down ? 218 N euroDharmacolo gy

Osmond: Yes. I couldn't move it one way or the other. Sherwood: You were fully aware, with respect to body image, where the arm was ? Osmond: Yes; I knew exactly where it was, and I knew exactly what I wanted to do. I had previously had, with mescaline, disturbances in the perceived body but this was not the same thing. Sherwood: There was no Parkinsonian feature about it ? Osmond: No, none at all, which is curious; there were no tremors or that sort of thing. At any rate, this is one small exploration that we have made. All I think we can suggest is that, really, it is worth looking into. Fremont-Smith: Did you do more than one experiment at this level ? Osmond: We have done four of them. Fremont-Smith: With this dose ? Osmond: No; I took up to 100 seeds and then, for other reasons, I had to stop. I got up to 60 seeds and got a rather similar thing. Sixty and a hundred seeds seem to be a sort of limit. I am hoping to go back to this work. Leake: How large are these seeds ? Osmond: About the size of a sweet pea. Leake: That includes the shell ? Osmond: Yes. They have a hard shell. I took the shells and all, because there wasn't any way of shelling them very easily. Cantoni: Is there any information as to what material is in these seeds? I mean, what one could attribute these reactions to? Do you have any idea ? Osmond: Yes. Santesson (60) did quite a bit of work on this. He apparently got only a very short distance and, with his mice, found that there are some different fractions which work in different ways. But the work is all in Richard Evans Schultes' monograph (35) and, because we were not able to start systematically on it, we did not go any further. But I am hoping to carry out some more psychological experiments with the seeds themselves, and I hope that somebody may get interested in this and may start sifting out what the active fraction is. Ololiuqui comes from Rivea corymhosa (61), which is a morning glory. Fremont-Smith: Where is it available ? Osmond: The only place I know is from Atkins Memorial Bo- tanical Gardens in Cuba. Dr. Clements, who is extremely obliging, sent it to us. A great authority on it is Richard Evans Schultes at Harvard. Marrazzi: How disturbed were you by the arm incident ? Osmond: I did not like it. But the most peculiar thing was the way Research on Schizophrenia 219 this reaction went away. I am quite used to adrenochrome and the way these reactions go away, but this time I had the impression that with ololiuqui the reaction can go away extremely quickly. I was very much impressed by Dr. Cerletti's dogs which made a very sudden recovery. My impression with the ololiuqui is, and this is borne out by the tapes, that in about 20 minutes, one moves from being really extremely inef- ficient to being thoroughly active and interested, with insight and all these things, and one is left in a very curious condition of well-being. After mescal, and certainly after adrenochrome and adrenolutin, I did not have a feeling of well-being. But, after ololiuqui, I felt very relaxed, cheerful, active, and able to think very clearly and well. Fremont-Smith: For how long? Osmond: This feeling of well-being lasted for about 24 hours. Another interesting thing was that sleep was not interfered with by this substance; I was able to go to sleep, and when I was awakened in the night by my daughter, which normally would make me very irritable, I felt relaxed and calm. I would like to know whether this happens to other people. It seems to me that these little points are interesting in that they may throw light on the very many curious properties of these things. In continuing to look around, we came upon adrenolutin. Abram Hoffer asked Harley Mason at Cambridge for some suggestions which he gave us. Dr. D. Hutcheon in Saskatchewan had worked with this initially and had done with Dr. N. Eade some experiments on mice. The great advantage of it from our point of view is that it is stable and can be stored quite easily. We didn't know how it had to be given, but we didn't feel it was going to deteriorate. This allowed us to work with it more easily, because, after our experience with adrenochrome, which we were still trying to get, we were hoping to find something a bit more stable. Leake: Doesn't this turn color in solution ? Osmond: No; it just goes yellow. It will after you leave it long enough, but we found that it didn't go dark quickly. It meant that we could bring it over from England in a little bottle without having to have it very carefully prepared. At the moment we have done about eight or nine experiments with adrenolutin. In the first one, I took 5 rag. of the lot that Harley Mason gave us. This was the original lot we got from England. I certainly did not expect it to have an effect because we started at what we thought was as low a dosage as possible. I did, however, have certain changes from this. The lot had never been meant for intravenous use. We thought it 220 NeuroDharmacology

wouldn't act, and therefore we took it by mouth, assuming this to be safe. Then, we worked up to 15 mg. in different preparations, because we ran out of our first lot. So far, we have used doses up to 50 rag. on different people, and in two of them, we had no effect at all; one was with 50 and one with 25 rag. In five of them, with doses from 5 to 25 mg. we have had different effects. In one, we have had quite a major change in EEG, with slow waves appearing that did not appear with adrenochrome and did not appear with hyperventilation in this subject. They are quite interesting. We do not know what they mean. We have a suspicion that blondes are more easily affected than bru- nettes; that is, people with dark skin, brown eyes and black hair are much less affected than very fair people. We have rather more than an impression, although I cannot prove this, that in some people at least this substance will go on producing reactions at times for longer than 24 hours, and that it will recur under stress. Fremont-Smith: What kind of reactions ? Osrnond: I will give you some examples. Hoffer took adrenolutin and was quite clearly very different from his normal self. He was with- drawn, irritable, edgy, but the next day, he felt fine. The day after, he became very gloomy and paranoid, that is, in this sense: He came to the conclusion from a letter that he had received that he wasn't very much liked. We looked at the letter and found it to be perfectly non- committal. He even came to the conclusion that it might be a good idea to give up his job on this account. He is not normally a temperamental man, but he became extremely irritable and, finally, he stopped work in the afternoon and went home, which was also unusual for him. This continued for about 2 days. He didn't immediately relate it to anything in particular but ascribed it to outside influences. Finally, he went to bed. When he got up again later that day he was feeling quite different, and only then did he think that this might have some conceivable relationship to the adrenolutin. At that time, one of our colleagues had been urging us to do some double-dummy experiments and we were saying that we would want to know what reaction the substance produced first. Some months previously, I had taken it, and for about 10 days, had had periods of great uneasiness. I also became very anergic and I had periods, particularly under stress, in which I would get something that seemed to me to be derealization, but I am not quite sure what it was. The end of this reaction was very odd, and it is not easy to interpret. I may have been merely ill, but I did not feel ill in the ordinary sense. One morning I got up and while washing felt faint and sick. I feared I might be gravely ill and become quite hypochondriacal, but in a Research on Schizophrenia 221 martyr-like way decided to go to work. In about a half hour I felt very good. Then I knew that I was different. This has now happened with two people. Of course, with our third subject, we took great care to watch him and not let him know something would happen. It is not easy. You do not want to suggest anything. Yet over a period of several days it is not easy to keep a really close watch on them and yet you do not want them to run into grave difficulties either. Our third subject had another perceptive change. He had great difficulty in telling the size of objects, until we let him know he was making mistakes. He judged distances very queerly. For instance, when I held up this pen, he announced that it was 21/_ inches long. We did about six tests of that sort. When we told him he was wrong, then he began to correct very quickly. It comes out quite clearly on the record. He alleged that the floor was sloping downward, but of course it was not. He went home, and he came back the next day and said that he was perfectly well. However, people who work with him said that he was odd and irritable and "bossy." He is normally a rather quiet man. His wife asked what we did to him, and she said that he was so different. The difference, apparently, was that he was extremely irritable and "bossy," which, again, is not like him. Therefore, we have seen some evidence that the effect of adrenolutin may last a little longer than 24 hours, and that this effect may be brought about by tiredness and stress. We are now pressing ahead on this, working with certain changes in the urinary chemicals, and we are trying to see whether there is any constant change with it. We are also trying to relate it to skin color, to see whether there is, in fact, some specific difference in people of different color. This, then, is our work in that direction. In the other direction, my own particular interest lies in seeing the psychological effects of mescaline on gifted people who can describe what has happened. I was lucky enough to be able to give it to Mr. Aldous Huxley, who wrote of it in his book The Doors of PerceHion (62), and I have given it to a few other gifted people, who undoubtedly, are able to make great use of this experience and who believe that it is of both esthetic and psychological interest. Leake: Are you responsible for the suggestion that it be substituted for alcohol ? Osl_ond: No; I do not think Mr. Huxley means that exactly. I think what he means is that we require less dangerous institutionalized narcotics than alcohol, and that mescaline shows us another possibility. Personally, I feel, and I know that Mr. Huxley agrees, that this is a 222 Neuropharmacology field in which we should proceed rather slowly. I do not think that we can ignore the fact that it is at present a largely ignored deep human craving. Marrazzi: May I go back a moment, Dr. Osmond ? Why have you confined yourself to oral administration of adrenolutin? Osmond: Because we have not yet had our substance biologically standardized. We are just having that done now. We had a chemically pure but unstandardized substance. Leake: You didn't want any pressor agent ? Osmond: No; nor did we know what the substance might do. We were told by Hutcheon, in the original work he did, that it was quite as toxic as adrenochrome. We only started giving it by mouth because we had not obtained any substance that we thought was sufficiently pure to give by intravenous injection. Abramson: I would like to bring up a very important point from a methodological point of view. I know that Dr. Osmond is fully aware of the usefulness of the placebo experiment in this kind of work. How- ever, we have found (63,64) it very wise not to avoid inoculating our subjects ahead of time. Actually we revised our original questionnaire technique to acquaint our subjects ahead of time with the possible symptoms they might have with the drug. We have also studied unknowns. For example, we studied successfully many other compounds, the response to which was unknown with our questionnaire method. Abramson: To continue apropos of Dr. Osmond's remarks that there was some fear of inoculating his subjects with what they might be expected to show following an unknown drug, we, in our work at Mount Sinai and at the Biological Laboratory, have taken the reverse point of view. We found it expedient to structure the whole experiment in such a way, using a rather large number of placebos, that the subjects know exactly what they may expect. I have passed around a type of questionnaire (Table XIII) which we found very useful for a period of 3 years. We have had no trouble detecting unknowns at all. We have always been right when an unknown sample of LSD-25 was given to us. We could say with our method whether or not a threshold dosage of LSD-25 was present and, approximately how much the threshold dose had been exceeded. Fremont-Smith: By the answers to the questionnaire? Abramson: Yes. But we always did reject as our test subjects, and this is extremely important, those on placebo dosage who gave more than three or four positive responses consistently. For example, an individual's heart might be faster or his palms might get moist without necessarily excluding him as a subject. We used this first technique, Research on Schizophrenia 223 therefore, to screen out people who were "suggestible" and only then did we use our screened test subjects to test our unknowns. However, we found that even this was not inoculation enough. Dr. Jarvik and Mrs. Hirsch improved the questionnaire (Table XIV). In- stead of having the first question given half an hour after, we give the questionnaire to the subject and he is asked to say ahead of time whether or not he has any symptoms. Table XV illustrates a marked response to zero dosage. This subject would be unsuitable for screening purposes. This, then, will prepare for the part of the work on tolerance which will follow Dr. Rinkel's presentation, because none of our work is done on subjects unless they have been screened and found to be satisfactory. This screening must be done on the same subjects periodi- cally. We always introduce a placebo from time to time. I found one very interesting thing. Mr. B. has been used as a subject for 2 years. At first, I allowed Mrs. B. who helped in the experiments, to know in certain critical experiments whether or not he and other subjects were getting the drug. But by her facial expression and attitude, he could often guess what was going on, even though she did not say a word. So the problem of unconscious communication between the observer and his subject is very important. I think the experiments should be run as blind as possible. Leake: In connection with the experiments described by Dr. Osmond, all of us were impressed by the extraordinary quality of the description of subjective symptoms, and this would suggest the value of a battery of projective tests, establishing for subjects a base line personality profile, as it were, which then could be run almost routinely in connection with the subsequent effect under drugs. Fremont.SmBh: Especially of the normal subjects. Leake: Yes, especially of the normal subjects, of course, and that would give a considerable amount of information that is pretty well standardized as to significance and interpretation, with regard to the sort of projections that are made. Osmond: We have done that with our LSD work modified by niacin, and we have had a lot of work done on this. We found that so far-- we started to work with rather high doses of LSD--our tests have not shown any that worked very well during the procedure, because they are too long, but we are trying to get a series of much shorter tests, such as Lehman* was developing at one time. Leake: Or the Zondi is extremely rapid, and that shows as quick changes in projective personality.

*Unpublished data. 224 N europharmacolo gy

Abramsom We have had considerable experience with projective tests (65,66,67). In any test situation, what you get depends not only on the personality structure, but also on the dosage. That must be considered constantly. You may get no change with a given test with 50 _g. but important changes on 75 _g. Beecber: I would like to say that there is another way of handling this questionnaire problem. It is hardly fair to put in a question, "Do you feel weak," because there is a suggestion there. Of course some suggestion is unavoidable, but you can minimize the effect of suggestion by presenting two opposites simultaneously.

TABLE XIII Questionnaire Section I

i. Half an hour after administration and at hourly intervals thereafter, the following direct ques- tions are put to the subject. His rating is accepted_ if possible on a + to + + + + + basist- Up TO Up To Up To Up To Up To Alter QUESTION Y_Hr. 1_/_ Hrs. I 2½ Hrs. 3Y2 Hrs. 4½ Hrs. 4Y_ Hrs.

1. Do you feel ill in any way?

2. Are you nauseated?

4.3. IsHavesalivyouationa feelincirnegased?of choking? ...... _.

56.. OIsr yourdecreaseappetited? increased? ... i

7. Or decreased? iI J 8. Do you have a "dry" taste in your mouth? ] 9. Do you have a funny taste in your mouth? --[, r "(i lB. Is it a bitter taste? ]

11. Are your lips numb? ] I 12. Or drawn back as if you were smiling? [

13. Does your head ache? 1" ]4. Are things moving around you?

15. Do you feel dizzy?

16. Or unsteady?

17. Is there difl3culty in breathing?

18. Do you pass more urine than usual?

19. Are you aware of your heart heat?

20. Is it faster than usual? 21. Are you sweating?

22. Are you hot? 23. Or cold?

24. Are your palms moist?

2.5. Or dry? 26. Or'cold? I

27. Is your skin sensitive? / 28. Do you have funny feellngs on your skin? l Research on Schizophrenia 225

Up To 'Up To Up To Up To Up To After QUESTION ½ Hr. I% Hrs. 2% Hrs. $½ Hrs. 4_/2 Hrs. 4½ Hrs.

29. Do your handJ and feet feel peculiar?

30. Do they feel heavy? ..... 31. Or light?

32. Is there pressure in your ears?

33. Is _our bearing abnormal? 34. Is _t more acute than usual?

35, Is your eyesight blurred?

36. Do you have dit_cul_in focming your vislon ?

37. Do you see double?

38. Are shapes & colors altered in any way?

39. Does light bother you?

40. Do things seem too close?

41. Or too far away?

42. Do you tremble inside?

43. Do yOU feel weak?

44. Or fatigued?

45. Do you feel drowsy?

46. Do you feel as if in it dream? i 47. Are you anxious? I

The following are tested and rated by the experimentor, and scored normal - -; abnormal + +.

Up "to Up _o ] Up To Up To t Up To j After QUESTION Y7 Hr. IE/2Hrs. , 2J/_ Hrs. 3Y: Hrs. r 4½ firs. t 4½ Hrs. 1. PalIor I

2. Flushing -I 3. Restlessness I

4. Tremors !

5. Twitching

6. Fasiculation

7. Fibrillation

8. Pupillary Reactions

9. Visual Fields (to confrontatlon) (Decreased)

10. Hearing

11. Respiration 12. Pulse

13. Perspiration 14. Blood Pressure

15. Tendon Reflexes (Increased)

16. Coordination (Impaired)

t18.9. Ha_llusindwonsriting I TABLE XIII (Continued) Questionnaire--Section II

The _ol]owil_ are tested by the experimentor's oblervatJonp plus the subject's statementL Rating is qualitative. |. Molo_ Bdmvi0_ 6. Atdlude to Envit

_4 Hour: .,, ½ Hour:

2½ Hour*: , 2½ H'oen: 3½ Hours: 3_ Horn's:

4_ Hours: 4½ Horn.st Late_ Late_:

s+ Comtroh 7. O-"+_,,,t_mt > ½ Hour: ½ Hour: J !% Hours: J' l½ Hours:

2_ Hours: _/ 2% Hours: S½ Ho..: _ 3½ Houri:

4% Hours: 4½ Hours: Later: Later:

3. Omsciommtu: 8. Memory: i

½ Hour: ½ Hour: 1½ Hours: 1½ Hours:

2½ Hours: 2% Hours:

3½ Hours: f 3½ Hours: 4½ Hours: _ 4_ Hours:

4. Concentration: _ 9. Ha|lucinatiom: L..... _ } L..... I ½ Hour: / % Hour: / 1½ Hours: _ 11/I Hours:

3V_ Hours: g½ Hours:

4% Hours: 4% Hours:

2Later½ Hours:: _ 2Lat½ eHours:r: t

_. Mood (Euphoria . Depression):

V2 Hour:

1½ Hours:

2V_ Hours:

43_½/_HouHours:ri:

Later: TABLE XIV

Revised Questionnaire

Subject Dose Data Time of Administration

Indicate time you first feel any kind of changes Answer the fallowing questionswith "O" if your answer il "no"; "1'" for slight; "'2" for moderate; and "3" for severe positive answers. HOURSAFTERDRUG QUESTION PRI_ _ 2t/t 4th 1. Do you feel peculiar in any way? 2. is your eyesight blurred? 3. Does it take long to focus your eyes? 4. Do colors seem changed? 5. Do shapes seem changed? 6. Do things look too dose? 7. Do things feel too close? 8. Do things look,too for away? 9. Do things feel too far away? 10. Do objects look distorted? ] 1. Do you see anything which isn't there? 12. Do you have visual hallu¢lootions? 13. Are things moving to and from you? 14. is your hearing abnormal? 15. Do you have auditory hallucinations? 16. Is your hearing lessacute than usual? 17. Is your skinsensitive? 18. Do you have funny feelings on your skin? 19. Do your clothes feel peculiar? 20. Doyour arms foel peculiar when you move them? 21. Do your legs feel peculiar when you move them? 22. Do you feel dizzy? 2_. Do you feel unsteady on standing? 24. Do things seem to move? 25. Does the room seemto move around you? 26. Do you feel ill? 27. Are y coted? 28. Do you fee[ abnormal4y hungry? 29. Are you hat? 30. Are you cold? 31. Are you sweating? I 32. Are your palms moist? 33. Are you aware of your heartbeat? 34. Have you a headache? 35. Do you tremble inside? 36. Is breathing difficult? 37 Is swallowing difficult? ]8. Do you have trouble moving about? )9. Do you feel weak? 40. Do you feel muscular fatigue? 41. Do you feel drowsy? ¢2. Do your movements lack control? 43. Are your movementsincoordinated? 44. Are you laughing more than usual? |5. Are you crying more than usual? 46. Do you feel more happy than usual? 47. Do you feel more sad than usual? t8. Are you unsure of where you are? t9. Do you have difficulty in concentrating? 50. Do strange things seem familiar? $1. Do famihar things seem strange? S2. Do you feel as if in a dream? $3. Are you anxious? 54. Does time seem to be passing more quickly than usual? ______l 55. Does t me seem o be passing more slowly than usual? $6. Do thoughts crowd your mind? 57. Do unpleasant thoughtsoccur more often? 58. Doyou feel friendlier? 59. Do you havedimcuity expressingyourself as clearly as usual? SO _syour memorydifferent for recent events? 51 Is it difi:erent Forpast even!s? i 228 N euro pharmacology

TABLE XV A Completed Questionnaire on a Subject with Zero Dosage LSD-25

FoodPrior:_-,'_?_ _ _'."_-o_ _.e_. _A_ ,q._

Food During •

I. Half an hour after administration and at hourly intervals thereafter, the following direct ques- tions arc put to the subject. His rating is accepted, if possible on a + to + + + + + basis:- - - Up lo Up io Up To Up To Up To Af(er QUFSTION VI Hr. |=/_ Hrs. ] 2*/'=Hrs, 3_/I Fir*. 4'/_ Hrs. 4Vt HH. ,. |. Do you feel ill in •ny way? '4'

2. A ...... ed? ' i .Ib ]

_,.3,...,,tio_ _°°• f...... liogodr_ho_ing: +'+ I| ++ ] + I *+' I ]1

Ord6. Is you...... r •ppetltd?e incr,,,d? 4 i , "i 4...... 1 i

l I174 Or d_creased ? "_+

8. Do you have • "dw/" tas.te in _/our mouth? 9. D .... h.... !...... lay ...... h? + I I ++ II 10. Is it • bitter taste? [ +_.

It. Are your lips numb? " • i i 12. Or drawn back ,, if you w_re trailing? - | .. * it • i • ]I÷+*i+ 14. Ate things moving •round you_ t ;

15. Do you feeldi_ty? I 16. Or unsteady? I

..!,7. h there diff*culty in breathing, )

18. ][_,, you p_SSmore urine _n .1renal?

19. _re you •ware o| your heart beat? I 20. ]J it laster *kan wtml? I

21. Are you sweating?

_'). Are you hot? 23. Or cold?

25. Or dry_

2_. ,.Or,,,_cold..?_,.._... ? +-I" i '" + I + It _, _,_.., .... ,...... a.?l ++ I + II Research on Schizophrenia 229

Up To Up To" " Up To UpTo I Up To After QUr.STION 4% Hrs. 4% Hn:. Do Mrh_dt--,,_,.. +* -.r .* I +* J| 30. Do they feel heavy? i 31. Or lillhtP 4'4' +4" ' _ r

32. I, there pressure in yo4ir .e._.rs? . + ++ " +++ I

33. I, your h_lrin, abnorm81_ . + + ... ++ Ji 34. I* it more acute than usual? ++ + ++

$5. Is your e,#eilght blurred? ,,. ',

36, Do you have dlffic_ihy in |m:liiuil yoll vlii_l ?

37. Do _ou tee do u.hJe? ._

38. Are shapes & "c?lon altered,in _ wly? ++ J

39. Does light bother you? + =| l I 40. Do things seem too c|o6e? 41. Or too far nwsy?

42. Do you Urembie inside? 4"4' J 4' ++_ |

43. Do you feel weah?

44. Or fatJil_ed? , .-- 45. Do you feel drowsy?

46. Do you feel al if in a driim?

47., Are you .nxlout, * I * _ * I ** l

The followlng are tested and rated by the exper[mentor, and scored normal- -; sbnonnkl + +.

QUESTION .%upHr.To IVuspHrs.To 2VU=pHrs.To SV_ps flTo_. 4_I_,. 4Y_I-rHrs. I. Pallor

2. Flushing

3. R_tlemne_

4. "]l'remorl

5. Twlicbin#: 6. Fm_uhttion 7. Fibrillation

8. Pupillm7 Reaetlom

9. VisualFie!dl (tocoulromafion) (_) 10. Hearing

11. Resplrmtiom

12_. Pulle .....

15. Persplnti_t . 14. Blood Premure

15. Tendms Refletes (I_) IS. Coo,,,tnJtioe(.l_lm_'l ) ._.

18. Hamdwri_ ...... ll17.. illAurticusion,,lation t .... 230 N euro pharmacology

Abramson: We thought of that. Beecher: We have used, for example, "sad . . . happy", 3, 2, 1, 0, 1, 2, 3. You check the point which applies most accurately. You get opposite suggestions at the same time, and, at least in our experience, this is a better way of handling the thing. Abramson: We weren't looking for the best way. We were looking for a useful way. In our hands this has proven very useful over a period of years, with slight modifications. Beecher: You should, I think, present opposites simultaneously: "strong-weak," "happy-sad." Abramson: Yes; we could. There are many ways of setting up a questionnaire. Sherwood: Would it be worth-while to try to establish the basic personality characteristics, such as Dr. Osmond mentioned? Should we determine if the subject rarely sees hypnagogic shapes. I always do, so I assume that if I took LSD, I would probably get these things much sooner and it would be much less significant than if he sees them. Fremont-Smith: You might not get them at all, but it would be worthwhile. That is the purpose of this suggestion of Dr. Leake's, to establish the personality profile to some extent in advance. Abramson: We have done that in all our subjects, Dr. Leake (65,66,67).

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