Schizophrenia

A New Approach

It is possible, however, to approach the illness from another direction. Suppose that we start with the signs and symptoms and natural history of schizophrenia and ask ourselves how these could be produced, refusing to be diverted by the existing schools of thought.

The Synthetic Illness

The first question that one asks is whether any known substance could produce results of this sort ; not merely confusion with secondary delusions, but a disturbed mental state which could be mistaken for schizophrenia. It has been known for over fifty years that mescaline, the alkaloid extracted from the peyotl—Anhelonium Lewinii, an American cactus—produces symptoms almost identical with schizophrenia, including catatonia and thought disorder. The symptoms differ in different subjects, but not more markedly than different cases of schizophrenia differ. No account of the effect of altering the dosage of mescaline in the same subject has come to our notice, so that it is impossible to decide whether the difference in symptoms is due to differences in rates of absorption, or the ratio of body weight to dose, or to other factors. It has been taken for years by psychiatrists who wish to experience schizophrenic symptoms and to investigate synaesthesia. From time to time investigators have mentioned that it is unfortunate that more is not known about it. Klüver (6) in America and Eric Guttmann (7) in this country drew attention to our ignorance on this subject and to its importance respectively ; but are we really so ignorant ? The formula of mescaline has been known for at least twenty-five years, and probably much longer. It had not, however, been published in a psychiatric paper for many years until Mayer-Gross's recent lecture (8). Unfortunately in this paper the formula was misprinted, and in addition the structural diagram was so arranged that its most remarkable quality was obscured. Organic chemists have, of course, known its biochemical affinities for many years, but they have rarely been interested in its psychological properties.

There are many other hallucinogenic drugs, but none has either such striking properties or such a simple chemical constitution as mescaline. It would therefore be an excellent candidate for a schizophrenic agent, if there were any likelihood of its appearing in the body.

Before discussing this question it is necessary to examine a widely held view whose most recent proponent is Mayer-Gross. To quote his own words: "The symptoms of mescaline intoxication have been compared to those of schizophrenia, but it is much more the strangeness experienced by the patient suffering from schizophrenia and the difficulties of describing what is happening in the two conditions which is similar. Many typical schizophrenic symptoms, especially in subacute and chronic states, are never seen in mescaline intoxication. Early psychotic phenomena in acute schizophrenia show certain analogues, especially in the field of hallucinations and other sense abnormalities" (8). Surely, in trying to lump together acute and chronic schizophrenic reactions and compare them with the laboratory observations of trained psychiatrists taking mescaline voluntarily, Mayer-Gross is comparing two innately different situations. It is highly unlikely that the unheralded schizophrenic psychosis of indefinite duration in an unprepared victim, and the experiences of a voluntary mescal taker who knows what to expect and how long his ordeal will last, would be exactly similar. The remarkable thing is that these acute reactions have so much in common. In the accompanying table it will be seen that mescaline reproduces every single major symptom of acute schizophrenia, although not always to the same degree.

[The article's Table I -- a symptom-by-symptom comparison of mescaline intoxication and acute schizophrenia across categories of sensory, motor, thought, and mood disturbance -- is omitted here; the table shows the two conditions overlapping on nearly every listed symptom.]

The Chemical Link to Adrenaline

To return to the chemical constitution of mescaline, which is—

[Structural diagram of the mescaline molecule omitted.]

it is a fairly simple compound, and those with biochemical knowledge will realize that it is not very dissimilar from adrenaline. This observation was made by one of us in June, 1950, with the assistance of Dr. Julian Redmill, then a medical student at St. George's Hospital. The adrenergic qualities of mescaline and many similar drugs were investigated by Dr. J. Harley-Mason, M.A., F.R.I.C., University Demonstrator in Organic Chemistry at Cambridge. He has been good enough to allow the following biochemical observations on this aspect of the subject to be published.

Harley-Mason's Biochemical Note

He writes: 'It is extremely probable that the final stage in the biogenesis of adrenaline (II) is a transmethylation of nor-adrenaline (I), the methyl group arising from methionine or choline.

[Structural diagrams comparing nor-adrenaline and adrenaline omitted.]

It is just possible that a pathological disordering of its transmethylation mechanism might lead to methylation of one or both of its phenolic hydroxyl groups instead of its amino group, leading to the formation of (III) and (IV). Methylation of phenolic hydroxyl groups in the animal body is of rare occurrence, but a significant case has been reported recently by Maclagon and Wilkinson (10). It is particularly interesting to note that out of a series of phenylethylamine derivatives tested by Noteboom (11), 3.4-dimethoxyphenylethylamine (V) was the most potent in producing catatonia in animals, and that this substance

[Structural diagrams of the phenylethylamine derivatives under discussion omitted.]

differs from (IV) only in the absence of its side chain hydroxyl group. It is however doubtful, in view of the relatively high dosage of (V) required to produce a catatonic effect, whether enough of a compound such as (IV) could be elaborated in the body to produce mental symptoms, having regard to the normal capacity for adrenalin production. It may be, however, that in chronic intoxication smaller amounts would be effective.

" The extremely high activity of lysergic acid diethylamide is remarkable, the dosage level of 30-50 mgm. being one-tenth the amount of adrenalin or thyroxin required to produce an observable response. The compound bears no relationship to any substance at present known to occur in the animal body and the mechanism of its action is wholly obscure."'

The Hypothesis

Surely it is significant that a single biochemical failure could occur in the stress mechanism and produce these dangerous toxins, one of which is already known to be a powerful catatonic agent ? Mescaline itself is not, of course, the toxic agent in schizophrenia. It is not nearly active enough, and the adrenals could not possibly make 500 mgm. or more daily, which would be necessary to produce symptoms. It is, however, thought that mescaline itself is non-toxic, and that the toxic agent in mescalism is a breakdown product.

We therefore suggest that schizophrenia is due to a specific disorder of the adrenals in which a failure of metabolism occurs and a mescaline-like compound or compounds are produced, which for convenience we shall refer to as "M substance." The striking implications of the relationship between the bizarre Mexican cactus drug and the common hormone have, so far as we know, never been recorded before. Psychiatrists appear to have been unaware of its biochemical structure, biochemists to have been uninterested in its production of an artificial psychosis. The close clinical connections between schizophrenia, anxiety states and stress have been known for a long time, and the process involved may be that in certain people when the adrenals are overworked (due perhaps to an inherited latent fault as Kallman has suggested) (12) the process of methylation becomes disturbed and highly toxic substances are produced. This M substance, once produced, would naturally set up a vicious circle, since one of the prominent features of both the mescal "psychosis" and of many cases of schizophrenia is the stress and terror experienced by the victim. There is already a certain amount of evidence for the presence of such an agent (13). This hypothesis could also account for the somatic manifestations of schizophrenia—the excessive adrenocortical activity perhaps generated by Vogt's mechanism, the vascular changes, the disturbances of carbohydrate metabolism, the overloading of the detoxicating mechanisms of the liver, and the pigmentation (melanin and adrenaline metabolism are linked).

Discussion

It is easy enough to speculate about an illness which has been the subject of so much investigation and remains so barren in established aetiology, but the first essential for any directed programme of research is a hypothesis based on fact, otherwise observation hardly progresses beyond the stage of cataloguing. It seems to us that the advantage of this new approach lies in its combination of the clinical and the biochemical, which allows one to substitute a definite plan of campaign in place of the present state of speculation about unknown substances. Mescaline is the simplest agent producing a schizophrenic-like psychosis, and the only one that closely resembles a substance found naturally in the body. The proper course of action to test this hypothesis is clear. It would consist in the pharmacological investigation of mescaline, its breakdown products, and the range of compounds between it and adrenaline (especially 3.4-dimethoxyphenylethylamine), and the attempt would have to be made to isolate these substances from the body-fluids of acute schizophrenics. Once these investigations have been done our hypothesis will either join the large number of plausible theories which have failed to stand up to the test of experiment and are now to be found on the scrap-heap of psychiatry in the pages of old journals, or the cause of schizophrenia will be known.

Summary

After a brief survey of the present state of our knowledge regarding schizophrenia we have drawn attention to the close biochemical relationship between adrenaline and mescaline. This, taken in conjunction with the clinical relationship between acute mescaline intoxication and acute schizophrenia, and between the latter condition and stress, appears to us to be significant. The clinical and biochemical implications of this are discussed.