Indian summer, the autumn crocus, and colchicine

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By KARL KSNIG, M.D. (Vienna) "The great and the small and everything is part of the whole. Men, wanting and valuing only a single thing, rushing into onesidedness--in order to find satisfaction--make themselves

unhappy."--A. STIFTER. 1. THE ALKALOID DITRINOthe last ten years a star of the first magnitude has risen in the night-sky of researches into the nature of substance: the alkaloid colchieine. Attempts have been made from various angles to explore the effective mechanism of this substance. Botany, pharmacology, clinical medicine, and cytology have accumulated a considerable amount of material, and yet until now the "living idea" is missing which tries to link all these single observations into a harmonious whole. DVSTIN recognized colchicine as a mitotic poison in 1934, and since then his researches have been greatly enlarged and confirmed. LETTR]~ in particular has published some fundamental facts and has shown, besides other things, t h a t in the course of cell-division it is the spindle in particular which is affected b y colchicine. The substance is therefore also described as a spindle-poison, and MARQUAI~DT(1) gives an exact description of its effect; he says: "The symptoms are: (1) Failure to develop a true spindle, so t h a t both the arrangement of the chromosomes in the equatorial plate, and an anaphasic movement with the regular formation of daughter-nuclei are impossible. (2) The extreme contraction and thickening of the chromosomes during longitudinal division which proceeds very slowly from the chromosomeends towards the spindle attachment. (3) The separation of the daughter chromosomes which finally hang together only at the spindle attachment. They usually remain lying at little distance from each other. (4) The formation of a single resting nucleus instead of two daughter nuclei on conclusion of the disturbed mitosis, which has only a pro-phase, and no clearly defined meta-, ana-, and telo-phases. This 'restitution nucleus' contains twice the number of chromosomes." LETTR]~ (2) also believes t h a t it is the spindle-apparatus which is affected b y colchicine, and most other investigators agree with this. SCHERER and BERG~ANN (3) were able to show t h a t the mitochondria themselves are not affected by colchicine. I n plant-growing experiments very definite and well-defined malformations were produced with colchicine (H~,EGER and POETHKE (4), BOAS (5), and others). That such results induced cancer research to take possession of colchicine is very understandable. As early as 1939, BRiSCKE and HUEBER (6) reported on the combined colchicine and radiation therapy of skin metastases in a ease of cancer of the stomach. Since then a great number of such findings and a t t e m p t s have been published. So far no final results are available, however, and the problem is as yet open and unsolved. I m p o r t a n t for the effective application of colchicine are the new attempts at a therapy of leukaemia which go back to investigations made as early as 1908 b y DIXON and MALDEN (7). They observed t h a t the subcutaneous use of eolchieine on rabbits causes at first a leukopenia and about six hours later a strong leukocytosis. * Translated from Hippokrates, 24. gahrgang, Heft 24, S.725-734, with the kind permission of the Hippokrates Verlag, Stuttgart.

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WIDMANN (8) has been able to show that a leukocytosis m a y arise without there having been a previous leukopenia, and that the latter only occurs if the amount of colchicine given has acute toxic effects. At any rate, the bone marrow is a very sensitive barometer for the effect of colchicine and can react to the alkaloid with a decrease or increase in the production of granulocytes. Further research led WIDMANN (9) tO believe that the points of attack for colchicine in the bone marrow are not identical with its effect as a cytostatic substance. The investigations made by KEIBL and LOTSCH (10) which are based on m a n y earlier observations point in the same direction. They found that if colchicine is used in cases of myeloid leuk~emia the number of leukocytes is lowered for a short time. They found aggregates of chromatin in the nuclei of the mature cells and in the nuclei of the myelocytes. The results of their investigations they give in the following sentences: "Although colehicine does not provide a therapeutic agent to influence the white blood picture, it is able, by means of a specifically selective action, to make the young cells of leuk~emia more sensitive to X-rays." All these researches constantly emphasize that neither the lymphocytes nor the red elements of the blood can be influenced by the administration of colchicine. I t is rather the whole system of granulocyte-formation and decomposition in particular which seems to be affected by this substance. SELYE (11), on the other hand, has shown that colchicine and other mitotic poisons lead to a disintegration of the thymolymphocytes in those cases where the activity of the adrenal cortex is maintained. The hyper-function of the adrenal gland has altogether shown itself to be causally connected with lymphopenia (VALENTINE,GRADDOCKand LAWRENCE(12)); I mention this here because during recent years the similarity between the effects of colchicine and ACTH has often been pointed out. HELLMANN (13), for instance, showed that ACTH is capable of inducing as well as stopping the acute attack of gout. ACTH produced a decrease of chloride and sodium and at the same time an increase of uric acid in the urine. MARGOLIS and CAPLAN (14) reported remarkable therapeutic successes in cases of acute gout, with the use of ACTH followed by colchicine. I do not at this point want to touch the hypotheses connected with these effects, but let the phenomena speak for themselves. SPIES and STONE (15) are convinced that ACTH, in a way similar to that of colchicine, has a specific effect on the acute attack of gout. ]~r (16) then tried to describe the parallel modes of action of colchicine and ACTH in more detail, and he comes to the conclusion that both substances are anti-allergic and antiphlogistic. This explains the clinical experience t h a t both substances show their instantaneous action only in acute attacks of gout, and HARKAVY(17) has recently again been very definite about the allergic component of gout.* MUGLERthen tries to trace the "biological" efficacy of colchicine and ACTH. Both substances he describes as blood-pressure-raising agents; at the same time they effect an involution of the thymus and the other lymphatic organs; they cause a relative leukopenia and a decrease in cosinophils. All these symptoms can be interpreted as originating from the adrenal gland. This gives a first picture of the three main fields of action of colchicine. (1) Colchicine is a cytostatic substance (HEILMEYER) and has a particular influence on the spindle formation in mitosis. In this respect it belongs to one group together with arsenic (eaeodylates), urethane and other substances. (2) Like other cytostatic substances, colchicine has a particularly sensitive relationship to the bone marrow and especially to the granulocyte-system. * F. HOFF (18) also mentions the allergic component of gout and refers to G~DZENT, SCH1T~nNHET.M, HANH~T, and others. However t h a t may be, the assumption of an allergie factor does not resolve the great problem of gout itself.

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(3) In its action colchicine is remarkably similar to ACTH. I t is antiallergic and antiphlogistic, and thus shows a close relationship to the whole adaptation-syndrome as described by S~LY~. I t is difficult even today to say whether all these effects come from a single source, or whether colchicine has several points of attack in the organism. All the same, an attempt should be made to try and bring these various results together in such a way that a picture arises which takes us closer to an understanding of the whole colchicine problem. From ancient times, Colchicum and colchieine have been with mankind as a medicament as well as a poison, and only now, during the last few years, are we given a new insight into its action. Why does colchicine act the way it does? W h y does it interfere with the processes of cell-division as a spindle-poisou and act so much like ACTH? A purely quantitative investigation will hardly be able to reach a true image; a qualitative one, however, aiming at the pure phenomenon, might lead a good step further. We shall therefore describe the living medium in which the substance colehicine is constantly created, and start by observing the plant Colchicum Autumnale itself. 2. THE PLANT This flower which is usually Called the autumn crocus is common and well known in the central parts of Europe. I t grows all over Germany and France, spreads down to Spain and Italy, follows the Danube into Hungary and also into the Balkans, and surrounds the western and northern shores of the Black Sea. The latter seems to be its native place, and its name comes from Colchis. "Botanists today know that in those and neighbouring regions of the Caucasus, and altogether on the shores of the Pontus, the autumn crocus appears in several large-flowered varieties" (UsTERI (19)). I t is believed that Colchicum has gradually spread across the remaining parts of Europe from those regions. There is a legend that Medea the Colchican sorceress knew how to prepare the poison of this plant. I n Rome and Athens the plant was called Hermodactylos; this did not refer to the fingers of the messenger of the gods, but to those of the great magician and initiate Hermes Trismegistos, the legendary founder of Egyptian culture. He knew how to prepare the poison and taught his pupils how to use it as a love or death potion. The ancients took it as an aphrodisiac, but they could also use it for public or secret death-sentences. Procreation and death, whose common origin is so often hidden from the outer eye of man, are both rooted in this plant. I n Germany the plant is called "Herbstzeitlose" which is the Germanized version of the Italian words cittola (maid) and osa (naked). Its original name therefore was "naked maiden", and in some rural districts the peasants use the even more candid term "naked whore". More religious souls call it the Michaelmas flower; and here indeed nomen is omen. For it blooms in the autumn when the meadows have been mown and the brown earth begins to shine through. Then the pale lilac flowers come up from the soil in hundreds, similar to the spring crocus; they really do look naked for there is no leaf around them, and the whitish neck of the flower arises unprotected from the earth. After a few days it has ceased flowering and looks miserably pale and ragged. Underneath the earth, the neck leads to a brown corm from which it arises on a short stem. The corm is not, as commonly believed, a bulb, but a stem node, so that Colchicum in fact is a plant which grows and flowers underground. The corm is an internode from which the flower arises first of all, in the autumn. Self- or cross-pollination occurs above ground, and the pollen tubes grow down through the extraordinarily long style, which often reaches a length of 15-20 cm., until they meet the ovary below ground. This takes many months, through the whole of autumn and winter. For only in May do the pollen-tubes combine with the ovules for fertilization.

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I n the meantime, three leaves have developed on the corm below ground, which come up from the earth in March or April, together with the syncarpy. The fruits need until J u l y to develop; then they are ripe, fall from the seedcapsule and are distributed b y grazing cattle, adhering to their hooves. That is more or less the life-history of a Colchicum corm. The plant itself has a subterranean rhizome which forms new internodes every year. Two things are significant and remarkable in this: the plant, flowering and sprouting below ground, has, like Demeter's unhappy child Persephone, t a k e n refuge in the darkness of the earth. But Colehicum does not, like Persephone, rise up in the spring, but in the autumn. I t begins to flower at a time when other plants are dying. Its flowers are bereft of leaves for those only appear during the next period of vegetation, in the following spring. The fruit ripens slowly during the summer. I t takes almost nine months from fertilization to ripeness, for a plant a disproportionately long time. Everything here is, as it were, out of place; the flower rushes ahead before the leaves can unfold and, instead of in the spring, breaks through in the preceding autumn. The leaves follow at their convenience and at the right time. The fruit, however, is particularly late and out of time. This distortion of the periodicity becomes even more obvious when the plant is seen against the background of its family, the Liliaceae; these belong to the very earliest plants to flower in the course of the year; they appear in March and April, and are not naked, like their strange sister, but clothed in leaves, joyful, and gay. The a u t u m n crocus does not only grow underground, it also develops against the periodicity common to its family. In m y opinion such behaviour should not be disregarded; for this is the language in which Colchicum tries to express itself. Within the sphere of this distorted rhythm colchicine is constantly being formed, and to want to see the one without the other would mean an arbitrary separation within a biological whole. Colehicum and colchicine are a unity and should only be regarded as such. I f Colehicum belonged to the late flowering plants, like asters and chrysanthemums, its behaviour would not be so obvious; for in t h a t ease it would be p a r t of an annual environment which is always there at the same time: the early autumn, or Indian summer. T h a t is a period when for a very short time a kind of second blossoming occurs in temperate regions. I f it is especially warm even the lilac and chestnut flower again, and a kind of second spring wafts over the land. The great Austrian poet Adalbert stirrer says in one of his novels about this time of the year: "In the spring, the most frivolous birds become serious, t h e y are busy without pause in feeding their offspring, educating and teaching them, so t h a t t h e y will be capable of the great task of the big journey before them. Towards autumn, again a time comes when t h e y are more free. Then they have, so to speak, an Indian summer and play for a while before they go away." Not only the birds but also the insects and m a n y plants have this Indian summer period when they can still "play for a while". And although it has not yet been described in detail, this time does exist, and m a n y poets have spoken and sung of it most beautifully. Into this time of Indian summer the Colchicum has sneaked. I t takes p a r t in it and uses it for pollination and thus for its perpetuation. But because it misuses an environment which does not belong to it, it turns into a plant which produces poison. For poison arises only where otherwise disease would develop. A natural process arising at the wrong site and at the wrong time is poison in the plant; in the animal and in man, however, it can be poison as well as disease. Both are synonyms of the created world. Only for this reason can a poison cure a disease as well as cause it. This becomes truly manifest in the autumn crocus. I t lives unnaturally in the cycle of the seasons, and therefore produces the alkaloid which acts as a poison. Pollinated during a period when otherwise nature is dying, it bears within itself death as well as procreation; the ancients knew of this.

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But we have gone one step further and come to know the exact spot where these forces act; there where growth originates and creates anew, in the formation of new cells, this poison strikes. I t takes its revenge at the very place where it is not allowed to appear. The spring forces of sprouting cell-growth are struck by the deadly breath of the plant which flowers in the autumn. The spindle formation comes to a standstill and instead of forming daughter cells the mother cells remain distorted. This same deathly autumnal breath appears in Colchieum where it acts as an anti-allergic and antiphlogistic agent. For inflammation is a heightened defensive force of the organism; it is an enhanced life force, either concentrated on a certain region of the body, or displayed over the whole of the organism. This defensive power is dampened b y colchicine and often extinguished altogether. Thus a first understanding can arise of these effects. But colchicine has not only been investigated experimentally, it has also been tried in its clinical effects, and the symptoms appearing in the patient and in drug provings will now be taken into consideration. 3. THE D ~ u o I:)ICTUI~E A few years ago WIDMAIqlq (20) published an exact and detailed account of a case of subacute colchicine poisoning. The symptomatology he gives differs from the acute forms of poisoning, but confirms very clearly m a n y of the symptoms found in the drug provings of the homceopathic school. W I D ~ A ~ ' S patient gives a highly instructive proving not of the whole plant, but of the alkaloid alone. The various symptoms were briefly as follows: A woman of 27, in a poor state of nutrition (it was 1947, in Germany) takes 45 rag. of colchicine with intent to suicide. No signs of poisoning during the first six hours; then severe vomiting occurs which repeats itself m a n y times; after another hour she feels very ill, with increased vomiting; after 14 hours "sitting up unaided is no longer possible". Restlessness, headache and palpitations set in. Strong sensation of cramps behind the sternum; the legs appear as if paralysed. Vomiting and retching continue, and on the 5th d a y "a fleeting painfulness and swelling was observed in the large joints." Contrary to the usual indications, there is continual constipation. On the sixth day the patient is admitted to the clinic. The findings are: a sluggish reaction of the medium wide pupils: mouth, throat and the white-coated tongue are dry; there is a tachycardia of between 110 and 120 beats per second, and the blood pressure is 150/95 mm. Hg. The limbs show a pronounced lack of tone. Gross muscular power is diminished; no reflexes can be obtained from the legs, but arm reflexes are normal. No abnormal reflexes are found. There is a definite leukocytosis with "shift to the left" (9,800 leukocytes). No pathological findings in the urine; no albumin, sugar, urobilinogen. On the 10th and 12th days epileptiform spasms occur which start as clonus in the facial region, extend to the upper extremities, and finally are generalized. "Pupils contracted, lips cyanosed, frothy mouth, deep coma. Even between the attacks the patient does not react." On the 14th day, great improvement. The patient is orientated and lucid, has however a complete retrograde amnesia. On the 16th day the hair begins to fall out rapidly, and in the course of the next two weeks all the hair was lost from the head. The general improvement continues, and after five weeks the woman is dismissed from the hospital as cured. T h a t is the dramatic story of a subacute colchicine poisoning, and, as we have said before, it agrees very well with the findings of homceopathic provings. Usually the three main points of action for colchicine are the gastro-intestinal tract, the large joints, and the heart. Added to this is "great exhaustion", with the typical sign "too weak to hold up the head". The hyper-sensitivity of the sense-organs is very marked. "Nausea and disgust even at the smell of

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food" (MEzoE~ (21)). "The patients are extremely irritable at even the smallest outer impressions, such as light, noise, and strong smells; pain appears to be unbearable" (FARRINGTON (22)). STAUFFER (23) sums up the leading symptoms most admirably and says: "Rheumatic-gouty inflammations of the serous membranes and fibrous tissues. Exhaustion in body and spirit, feels deathly weak. At night, restlessness and sleeplessness because of pain, with dry mouth. Hyper-sensitivity to noises, and especially to the smell of food. Disgust, nausea, retching until he faints at the smell of cooking, or thought of food; a leading symptom. Burning or ice-cold sensation in the stomach. Flatulence in stomach and intestines; eructation, colic, singultus. Inflammation of heart and kidneys, with dropsy and irregularities of the bladder. Very marked aggravation from evening towards morning. Aggravated b y touch, movement, exertion, cold, draught. Ameliorated b y warmth of a n y kind, and rest." This reveals the drug picture of the autumn crocus. I t shows a fairly wide range of indications which, adding the signs of poisoning, includes almost the whole of the organism, with the exception of the sexual sphere. To enable one to survey such variety it will be necessary to decide on a natural order for all the given symptoms. I t does not seem to me t h a t Colchicum can do "everything", but that under various conditions it can have various effects. The span from mitotic poison to the s y m p t o m of hyper-sensitivity in the sphere of the senses is one sphere in itself; it is merely necessary to recognize this unity b y arranging it in its appropriate order. I n the various reports and observations one is repeatedly struck b y the fact t h a t the dose in which Colchicum or colchicine is given does not seem to be of very great importance. WIDMANN (20) writes: "The indications given in the literature about the amount of colchicine lethal to m a n v a r y from 20 to 50 mg. SUF]rET and TRASTOUR even describe a case of lethal poisoning after a dose of 3 mg. The latest statement b y Fi~gN~R gives 20 mg. of the pure substance, which corresponds to about 5 g. of the seeds of the a u t u m n crocus, as the average lethal dose." The acute poisonings with Colchicum which terminate in the death of the patient do however present a picture differing from the subacute forms, and I think t h a t it is necessary and justified to divide the symptomatology into three parts, arranging it according to the symptoms of the acute, the subacute, and the chronic poisoning. With chronic poisoning I mean here the drug picture obtained through homoeopathic drug provings. So far the investigators are all agreed that in an acute case of poisoning which ends in death the main point of action for the poison is the gastrointestinal tract. There occurs diarrhoea and vomiting. DUSTIN JR. (24) reports a case, for instance, with profuse diarrhoea and vomiting becoming bloody on the third day, which ended in death. I n animal experiments the gastro-intestinal syndrome again is in the foreground. MEZGER (21), following FfrHNER, is of the opinion " t h a t colchieine should be regarded as a capillary poison. I t causes a marked distension and even paralysis of the capillaries, with hypersemia followed by h~emorrhages. I n cases of acute poisoning the point of action is the gastro-intestinal tract where it causes severe inflammations with swelling and hypermmia of the mucous membranes, and ulcers. The effect on the kidneys manifests itself in hmmaturia, albuminuria, and anuria; the joints are painful, and hmmatorrhcea and extravasation into the articular cavities occur. Hypermmia of the cerebral meninges has also been observed. Hsemorrhagie exudates have been noted in the pleura, pericardium, and peritoneum." This gives a first impression of the acute syndrome, and not much needs to be added. Diarrhoea and vomiting are the main features, until bleeding from the capillaries occurs in all the tissues and organs. In tests with animals, motor and

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sensory paralysis occurs as well, and death m a y set in accompanied by suffocation. " I n man, severe and particularly lethal cases of colchicine poisoning show a complete loss of all the reflexes of the limbs. Anomalies of the reflexes in the upper extremities are rarely seen" (W~D~IANN (20)). All the authors emphasize that consciousness is maintained until death. With the description of the nervous symptoms we have already reached the sphere of the symptomatology of subacute poisoning. Here, and I am referring to the case described above, vomiting m a y still occur, but no diarrhoea; instead there is constipation and the whole picture of the poisoning process moves upwards. Now the sensorium is paralysed and there m a y even be loss of consciousness together with epileptiform convulsions. There is a tachycardia present (in cases of acute poisoning it is bradyeardia), and the pulse is threadlike. The blood picture shows a definite 'shift to the left', with leukocytosis. Fleeting pains in the large joints. I t is difficult to say whether the loss of all hair from the head is a common symptom. WID~_A~ in his paper mentions a tumour case described b y SEED which showed loss of hair of the head following an a t t e m p t at colchicine therapy, and LUDFORD describes the loss of hair in mice, the cause of which he sees in the interruption of mitotic activity in the cells of the hair roots. As regards the chronic poisoning, I consider the hyper-sensitivity of the senses to be one of the most important symptoms; the irritability to the smell of cooked food, the irritable sensitivity to noise and light, are particularly obvious and repeatedly mentioned b y these patients. I n addition there are the changed gastro-intestinal symptoms. There is no diarrhcea or vomiting, but instead a tendency to flatulence in the epigastrium. Much eructation, singultus, and either a strong burning sensation or one of cold in the stomach (NAs~[). Very definite and described b y m a n y authors are the typical anginal pains and signs of oppression behind the sternum. Dyspncea and cardiac anxiety occur in connection with these symptoms. Mentally the patient is irritable; he is easily annoyed, sullen, and again hyper-sensitive. This threefold order of the main symptoms (there are m a n y others which can easily be fitted in) gives a clear picture of the clinical as well as the toxic symptomatology of Colehicum. The division into the three stages of acute, subacute, and chronic signs of poisoning brings clarity into a drug picture which until now was confusing. I t shows the rise from the lower pole of the organism towards the upper one, and thus brings order into separate facts which until now were scattered. I t seems that only such a sifting and ordering can produce an appropriate picture of the characteristics of the a u t u m n crocus. I n this threefold order the three periods of growth of the plant itself can be distinguished clearly in their characteristi.c traits. There are first of all the naked flowers of the a u t u m n which perish quickly yet are necessary for the process of propagation. Their pale colour and their relation to the time of Indian summer are characteristic. These, to me, reveal the image of the process of chronic poisoning. I t shows the hyper-sensitivity of the sensory organs; are not the blossoms of Colchicum in their nakedness and vulnerability a picture of this symptom? These flowers, breaking through the dark ground towards the fading light of the Indian summer, do they not indicate t h a t aggravation tends towards the morning hours? And a mere glance at the tender, almost shivering blossom explains the aggravation-symptoms to cold, movement, and touch. W a r m t h and rest on the other hand ameliorate; in the same way does the "naked maiden" unfold on still and sunny days, and close on cold and stormy ones. After the flowering is over, all the activity of propagation moves into the corm. For months the pollen tube grows down towards the ovules, and the leaves begin their first growth, as yet still underground. The corm itself thickens during the winter period. Here the pictorial images of the subacute poisonings

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can be envisaged. Now all the symptoms become more compact and stronger, for the tender flower has vanished; the open sphere above the earth has been left, and the strong underground corm becomes the main bearer of the further course of the vegetative process. Here the gastric symptoms in the form of vomiting seem to have their place; the sensorium is dimmed, just as the flower has vanished and the plant withdrew into the earth. An outstanding symptom in this second order is the great exhaustion, indicating that the contact with the surrounding world through the spheres of the senses has been lost. The patient can no longer maintain himself in the realm of his environment, he withdraws into himself and into the sphere of his body. At last spring comes when the three leaves break through the earth and carry with them the syucarpy. This corresponds to the phase of acute, lethal poisoning. The plant has now, as leaf and fruit, risen from the underworld, and in the same way, in the course of the acute poisoning, consciousness reappears and is retained until death. I t is important to observe these modalities, for a dimming of the consciousness occurs only in the sub-acute phase which corresponds to the winterly corm underground. But now the alkaloid ripens in the increasing light of the sun and reaches its maximum power. The seed is the most poisonous part of the plant and becomes the force which has such devastating effects on the capillaries and the mitotic processes. The whole cycle of growth of the autumn crocus now becomes even more obvious. The flower itself is still almost innocent; yet by inducing pollination at the wrong time it causes Colchicum to become a poisonous plant. The poison is prepared in the corm and fully ripened in the leaf and peduncle as they rise upwards. All this leads to a first understanding of the three phases of the Colchicum-colchicine action in man and animals. I n parenthesis and without further proof I would just like to mention that the old question of the height of the potency is quite obvious in this case. The high and highest potencies should be used in the acute, the medium in the sub-acute, and low potencies (from D6 to D10) in the chronic stage. One question, however, remains: how could colchicine prove to be a specific for the symptoms of an acute attack of gout and similar conditions, and also during the last few years reveal its close relationship to ACTH? Let us t r y and approach this problem. 4. THE ARCHETYPE STAUFFER (23) ends his treatise on Colchicum by writing: "The autumn crocus does not act on the constitution of rheumatoid arthritis and gout; provings on healthy persons as well as animal tests show no local changes in the joints. This has also been confirmed by the observations of H. Sc~uLz. The remedy does produce pain in the joints, a proof that there is an affinity to the synovial membranes . . . . That the remedy does not really act constitutionally on the uric acid diathesis, but only symptomatically in the case of gout is also borne out b y the fact that homceopathic high potencies are of no avail in podagra and the like. I f we want to be successful in this case we must go back to the low potencies." This shows that for Homceopathy Colchicum is by no means the remedy for gout, whereas used in an allopathic dose it often removes the symptoms effectively during an attack. Here, then, lies a cardinal point for a further necessary sifting, so that perhaps we shall be permitted to decipher the archetype. For this it will be necessary to distinguish between C01chicum on the one hand and colchicine on the other; between the sheath and the alkaloid which is produced within the sheath. As long as in the preparation of the remedy we only dilute or dissolve Colchicum, we are not dealing with the plant itself, but

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with its alkaloid, colchicine. I t is only when the process of potentizing is used that the plant itself begins to unfold its particular powers and possibilities. Then colchicine retreats into the background. The higher the potency the more freely can Colchicum unfold itself, and the less can colchicine come into effect. Just as Colchicum bears within it colchicine, so does also colchicine contain the forces of the autumn crocus; each substance contains the other, but colchiclue is effective only in allopathic preparation, and Colchicum only in the potentized form. I t is as though colchicine were the condensed physical substance of those living forces which act in the forming and shaping of the a u t u m n crocus. That which unfolds itself in the cycles of growth of Colchicum is compressed into matter where the poison is l)repared. I f excessive doses of colchicine are given to the organism Colchicum as a plant can no longer act effectively. The allopathic colchicine grows too powerful and leads to the acute form of poisoning. I n weaker doses, or with increased resistance from the organism, however, colchicine can develop its Colchicumproperties in so far as the gastro-intestinal organs produce just sufficient strength to act as a potentizer and thus liberate the hidden properties of Colchicum; this gives rise to the sub-acute poisoning. I f colchicine or Colchicnm are given in the potentized dosage chronic poisoning occurs. Here the action of the alkaloid is silent and the plant alone speaks. Such considerations show that we have to distinguish between the allopathic colchicine and the homceopathic Colchicum, and t h a t it is the former which has the cytostatic, capillary-paralysing, h~emorrhagic, and toxic effect on the organism. But here we also find the forces which can cure an acute attack of gout. STAUFFER is quite right in denoting Colchicum as not specific for gout; it is the allopathic colchicine alone which does it. The question remains as to why colchicine is a cytostatic poison as well as an anti-arthritic agent. Again and again the hypothesis is put forward which Hoff (18) also mentions when he points out t h a t since the nucleus of the cell consists of nucleoproteins the cytostatic effect simply indicates the common root with gout. A great m a n y substances, however, act similarly in disturbing mitosis, without being remedies for acute attacks of gout. ACTH on the other hand has no cytostatic powers whatsoever, but in the attack of gout appears to help most excellently. When Ft~HNER and LI~PS (25) investigated the toxic effects of colchicine they described it as 'vegetable arsenic' since its symptoms of poisoning were almost exactly alike to those of arsenic. I t is rather striking that arsenic, in the form of cacodylates, also belongs to the same group of cytostatic substances with colchieine. Both are poisons which act specifically upon the formation of the spindle. This parallelism needs to be followed up. As with colchicine, acute cases of poisoning with arsenic lead to vomiting and diarrhcea, produce a d r y mouth, anginal pains, and cardiac anxiety. H~emorrhages occur in all the body cavities and after generalized paralysis and asphyxia death sets in. Like colchicine, arsenic is a capillary poison. The sub-acute phenomena of arsenic poisoning are in m a n y ways similar to those of colchicine, but differ in some symptoms; it is striking that here, too, there m a y be a complete loss of hair, and this seems of pathognomic importance in both substances. LEESER (26) reports t h a t GAUTIER showed in 1903 t h a t arsenic is found mainly in the brain, the thymus, and the thyroid. " I t is reported to be excreted with the hair in men, and with the menstrual blood and the milk in women." I n the same connection LEESER states " t h a t the hair of people living in the industrial towns of England contained regular traces of arsenic, whilst the hair of people from regions where peat is burned always proved free from arsenic." Is there perhaps an important indication in these facts? That in women, arsenic is excreted with the menstrual blood, in men, however, with the hair?

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I f we can make the step towards a comprehensive understanding of the relation between the cytostatic as well as the poisonous actions of arsenic and colchicine, perhaps the h~emorrhagie symptoms should have particular attention: intestinal, renal and cystic bleeding, hmmorrhages into the pericardial and pleural cavities, and probably also into the cavities of the central nervous system. With the arsenic action these symptoms are enhanced further by the peteehial h~emorrhages on the surfaces of m a n y organs and underneath the skin. What are these hmmorrhages like? Suddenly the capillaries fail in their action; a stasis occurs, the boundaries of the blood vessels give way, and blood oozes into the body cavities. Could one not describe this syndrome as a generalized menstruation? That which normally is confined to one organ now extends over the whole organism and creates the dangerous signs. Here, too, we get the desquamation of the epithelium in the gastro-intestinal tract, and the mucous membranes are disposed of. Something which in the uterus is a normal process here becomes a pathological one. This m a y at first seem an audacious way of thinking, but only such a course will help us to bridge a gulf which until now was impossible to cross. Similar to the way in which in the second chapter we called poison and disease a synonym of the created world, we can now hypothetically denote colchicine and menstruation as synonymous. Menstruation is a process which in the woman, during the stage of maturity, periodically interrupts the continuity of her ability to conceive. The uterus oscillates within a four-weekly periodicity of the formation and destruction of its mucous membrane; so flood and ebb follow each other rhythmically. The menstrual floods, however, pervade the whole organization of the woman and the question is as yet fully open as to whether the gonadotrophic hormone of the hypophysis, for instance, autocratically steers this r h y t h m or merely is taken hold of b y the in itself existing periodicity. ASCgNER (27) repeatedly points out the generalized nature of menstruation and gives the following facts which are important in our considerations: " I n old writings we m a y every now and then still hear of "fluxes" and "metastases", but we take these for rather vague notions which we do not really believe in. Yet there are m a n y cases where a missed or too scanty menstruation, quite analogous to pregnancy and the climacterinm, leads to congestions and hsemorrhages into the head, lungs, and stomach, ttsematemesis as a vicarious menstruation was often mentioned besides the much more frequent nose bleeding. Much less known are the connections between tuberculous hmmoptysis and the menstrual processes." This shows with great consistency, and every experienced practitioner will confirm it, that menstrual bleeding is not necessarily confined to the uterine region. The hsemorrhage can, under pathological conditions, change the place in which it occurs. Such considerations can, in due course, lead to the idea of a generalized menstruation. This would be a living process permeating the whole organism and having its coarse physical manifestation in the monthly bleeding; but it also exists without this. For an amenorrhoea does not mean that the woman does not menstruate; the monthly rhythm occurs, but without a uterine hmmorrhage. J u s t as a dumb person is not necessarily aphasic, but withholds, for psychogenic reasons for instance, the manifestation of his ability. Most animals have their cestrous cycles without menstruation; but all the same this periodic ability to conceive has its effects in a variety of different cycles in the various species and families. There are swellings and budding of organs, and a consequent involution when fertilization does not occur. Now it becomes apparent that colchicine bears within itself the concentrated power which represents the menstrual phase in the female organism. This phase is the force which brings to an end the respective cestrous cycle. Is it going too far to say that Colchicum represents the periodic ability to conceive whereas

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colchicine is its terminating phase ? That Colchicum as a plant contains the same living forces which in the female organism bear the ability to conceive and to menstruate ? Only thus can we understand why the drug picture of Colchicum does not show any symptoms connected with the sexual sphere. For the autumn crocus in itself is a genital cycle and hence cannot act upon it. This also explains the cytostatic effect of colchicine. For menstrual bleeding interrupts the regular processes of growth and development in the same way as colchicine stops mitosis. The close relationship between colchicine and ACTH is also illumined. This substance belongs to the pituitary-adrenal system and hence to the sphere of menstruation and ability to conceive. The anti-allergic and antiphlogistic action corresponds fully to the character of destruction which is shown in menstrual h~emorrhage. Now t h a t we have gained such insights we can t r y to find a possible explanation for the effect of colchicine on the acute attack of gout. H e r r (18) concludes his discussion of the theories on the genetic factors of gout b y saying: "For the moment one will therefore have to be content with the fact t h a t we kaow various factors in the phenomenon of gout, but have not yet understood its real character." And KRmrL (28), after trying to get nearer to the whole problem of gout from various angles, is forced to say: "As we have already said, the conditions of uric acid in the tissues, in blood and urine, as well as the processes taking place around them are merely a small part of the whole picture of this illness. The disease (sclerosis) of the small and large arteries which plays such a great role in gout, and with it the kidney and heart complaints, could possibly be connected with the poisonous effects of uric acid. However, all t h a t seems rather uncertain. There is not very much and nothing very satisfactory t h a t can be said about gout. One cannot yet speak at all of a theory of the disease, of a comprehension of even the principal processes, because too m a n y of the basic facts are still missing." We can see that twenty years ago and still t o d a y leading clinicians like the two mentioned above are faced with something of a puzzle when approaching the problem of gout. A few years ago some American authors made an important contribution to this puzzle. STEeliER, HElCSH, and SOLOMON (29) have once again occupied themselves with the problem of heredity in families where gout occurs regularly. They examined 201 members of 44 families in order to determine the serum-level of uric acid. They fixed the m a x i m u m level for uric acid at 6.5 rag. per cent. Among other interesting results they found that, quite in contrast to the sons, none of the daughters of gouty patients showed a raised serum-level of uric acid. I n men, no relation was found between age and uric acid level. But in the women, it was striking t h a t not one of them showed a raised serum-level of uric acid under the age of 50. Only after this did the uric acid level rise and it seems more probable t h a t this rise is connected with the beginning of the menopause. This then provides a connection between the problems we have discussed above. I f menstruation can really prevent a rise in the uric acid level and perhaps balance the amount of uric acid in blood and tissues, then our expositions might give an explanation as to why colchicine is effective in the acute attack of gout.* * A f t e r t h e m a n u s c r i p t w a s c o m p l e t e d , a p a p e r o n clinical a n d e x p e r i m e n t a l investigat i o n s b y R . SOUGI~-NIBASHAZq a n d M. H o ~ w I T z of t h e U n i v e r s i t y of C a p e T o w n a p p e a r e d in t h e Lancet of J u n e l l t h , 1955 (No. 6876) w h i c h m i g h t well be a c o n f i r m a t i o n of t h e ideas p u t f o r w a r d here. T h e s e t w o a u t h o r s f o u n d b y c h a n c e t h a t t h e s u b s t a n c e T r o m e x a n (ethyl b i s e o u m acetate) w h i c h is k n o w n for its a n t i - c o a g u l a n t ~ction is able to lower t h e uric acid level c o n s i d e r a b l y w i t h i n a few h o u r s in t h o s e suffering f r o m g o u t a s well as in h e a l t h y persons. T h i s therefore confirms clinically a n d e x p e r i m e n t a l l y t h e c o m m o n root of g o u t a n d h a e m o r r h a g e , i.e. blood w h i c h does n o t clot, or is p r e v e n t e d f r o m clotting a n d h e n c e c o m e s close to t h e p h e n o m e n o n o f m e n s t r u a t i o n . T h e a b o v e - m e n t i o n e d p a p e r c o n t a i n s v a l u a b l e n e w ideas on t h e p r o b l e m o f g o u t w h i c h go in t h e s a m e d i r e c t i o n as in this p a p e r .

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Through the force of "generalized menstruation" it brings about an increased excretion of uric acid and hence a lowering of its serum-level. This explains at once the well-known fact that "men are affected by gout much more frequently than women" (STRi~MPELL (30)). I t seems to me, at any rate, that in this differentiation between the two sexes one m a y find one of the deeper sources for an understanding of the gout-problem. LETTR~ (31) has moreover been able to show that the cytostatie action of eolehieine can be increased by testosterone but not by cestrone. This is a discovery which also points to the possibility that gradually a uniform picture of the colehicine action m a y arise from the points we have put forward. All the above considerations and phenomena can perhaps give a very first picture for the mtiology of gout in the following way: the excretion of uric acid is a continual process which occurs in order to keep the balance of formation and dissolution of the purine substances. I n the female organism this process is greatly supported by the regular menstruation, since this monthly emptying of the organism is like a purification-process. The male organism, however, must have a different way of excreting purine bodies of which we know as yet little. The attacks of gout point to the fact that instead of a monthly r h y t h m there seems to be a half-yearly one; for most acute attacks of gout occur during the time of spring and autumn. I t could well be that this periodicity does not depend on the external seasonal r h y t h m but on an endogenous cycle. Gout itself, which most probably is a case of insufficient elimination of urates, does in the acute attack lead to a kind of "male menstruation" where the uric acid deposited in the joints is removed from the organism. Colehicine, as it belongs to menstruation, encourages this process of excretion. A new field of vision and investigation opens up. I have the impression that uratic arthritis is functionally very closely connected with the activity of the testes, and that their hyper-aetivity, which shows itself in a strong spermiogenesis and hence the formation of copious nuclear purines, is causal for the origin of the disease. Gout is for the male organism what osteomalacia is for the female. Thus the observations on an alkaloid have led to various medical problems in order to arrive at a comprehensive picture of its remedial action. Some of it m a y seem hypothetical, but it is meant to be a first attempt to see the plant and its medicinal force as a living being, and to t r y and understand them under a uniform point of view. Is it not significant that "cittola osa", the naked maiden, was already named in this way for centuries, probably because, to an insight into nature more acute than ours of today, the menstrual character of the plant was evident? Further investigations which may perhaps go into the periodicity of the animal cestrus and the female menstrual cycle in connection with sub-acute and chronic Colchieum and colchicine poisoning, m a y possibly lead to important results. Here only an intimation was intended of such relations. 5. FINALE In conclusion I would very m u c h like to m a k e a few remarks on the autumn crocus which are of more general interest, and m a y help to elucidate what 1 have tried to indicate in the preceding chapters. Although well k n o w n in ancient days, Colchicum was not used as a medicament for the acute attack of gout. Despite the fact that gout was dreaded by poor and rich, in Athens as well as in l~ome, the effectof Hermodactylos was not known. Only love and death potions were m a d e from these "fingers of Hermes" which alchemized the forces of menstruation. Only in the 5th century A.D. was Cotchicum used for gout by JACOBUS PS:CCHORnSTOSwho lived in Byzantium. For a few centuries it remained known to medical practice, hut then it was soon forgotten and only used again at the

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turn of the 18th century. I t is significant that, coming from the shores of the Black Sea, it is there again, in Byzantium, made into a remedy. That happened at the time when antiquity came to an end and central and northern Europe began to rise. I n our time, which probably has a significance similar to that epoch of migrations, colchicine again steps into the foreground, this time in connection with its cytostatic effects and thus with the whole problem of cancer. A few years ago there appeared beside the scientific investigations also a poetic work which contains the whole mystery of Colchicum without the author being conscious of this. It is a short story which tells of a woman who has just entered the climacteric. She is still youthful and fresh and lives with her two children, a grown-up, slightly sour daughter, and the younger son who is still a student. She is a widow. I n this Indian summer of her life an affectionate love awakens in her for a young American, and grows so strong t h a t suddenly her menses start again. She feels rejuvenated, filled with an autumnal spring, under the spell of this late loveaffair. After a dramatic crescendo leading to a meeting and mutual confession of the lovers another menstruation occurs. This however is so profuse that the transfer to a nursing home is necessary. There she succumbs and dies; a far advanced carcinoma was the cause of her h~emorrhage. The return of her menstruation was the beginning of her dying. Here the mystery of Colchicum is presented in intuitive perfection; it is as though Medea and Jason appear again in modern guise. The affection of the Indian summer which bears within it the germ of death occurs under the doubleface of menstruation as a bleeding which promises rejuvenation and yet is lethal destruction. This short story originated in the mature art of THOMAS MA~N and is called "The Deceived Woman". One could just as well call it "The Autumn Crocus". I t comes closer than any scientific treatise to the mysterium of this plant which I have tried to approach in the above chapters. Among m a n y other statements which RUDOLF STEINER has made on the a u t u m n crocus there is also one which I shall use to conclude this treatise. I n one of his lectures he says: "Can one really look at the autumn crocus with the eyes of the spirit and not feel slightly ashamed? Does it not remind us that our desires may become unclean, that they may be permeated by a multiplicity of impurities? We might say that the autumn crocuses speak to us from all around as though to whisper constantly: Watch the world of t h y desires, 0 Man, how easily thou mayst become a sinner." With all this I have tried to approach the essence in Colehicum. From how m a n y sides must we labour, from how many places must we approach in order to get on to the track of just one plant! I believe that with this method of approach a very first attempt is taken up again for a possible understanding of the science of signatures. Not of a signature which is content with superficial appearances and vague speculations by comparing colours and forms; but rather of a science of signatures which undertakes to go all over the earth, to reveal the many observations and experiences, and to explore and describe the essential in a substance, a plant, an organ. At first there will be much that is imperfect; but the important thing is not the perfection but the impulse to advance into the land of the true signature.

(1) (2) (3) (4) (5) (6) (7)

REFERENCES MABQUARDT,H.: ~_rztl. Forschung 1947, i, 207. LETTR2,If.: Die Pharmazle 1946, 9. Naturwissenschaften 1946, 33, 75. SCHERER,E., und BE~GMANX,H.; Jt'rztl. Forschung 1954, i, 164. I-IEEGE~,E. F., und POETRKE:Die Pharmazie 1950, 9. BOAS,FR.: Dynamische Botanik, Mtinchen, 1949. BRtiCKEund HUBER:Klinische Wsohr., 1939, 34. DIXONund MALDEN:Zitiert nach WIDMA)rN(8).

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WrDM~_Iqlq, H.: Arztl. t~'orschung 1949, i, 86. - : Naunyn-Schmiedebergs Arch. 1949, 207, 218. KEIBL u n d LSTSCH: Schweizer Meal. Wschr., 1950, No. 9. SET.YE, H.: TheStress, Montreal, 1950. V~ENTINE, GI~ADDOCK and LAWRENCE. Quoted from COrEMAZr W. S. C. Cortisone and A C T H, London, 1953. (13) HELLMAN, L.:Science, 1949, 109, 280. (14) MAR(~OLIS, H. 1~., and C~LAN, P. S.: Journal of American Medical Association, 1950, 142,256. (15) Sl'I~.S, T. D., and STONE, 1~. H.: Lancet, 1950, 6593, 11. (16) MUGLER, A.: Sem. de Hop., 1952, 28, 136. (17) HARKAVY, J.: Journal of American Medical Association, 1949, 139, 75. (18) HOFF, F.: Klinische Physiologic und Pathologic, Stuttgart, 1954. (19) USTERI, A.: Pflanzenskizzen. Dresden, 1935. (20) WIDMANN, H,: Arztl. Forschung, 1948, i, 457. (21) MEZOER: Gesichtete ArzneimitteUehre, Saulgau, 1950. (22) F~RINGTON: quoted from TYLER, M. L.: Homoeopathic Drug Pictures, London, 1942. (23) STAUFFER, K.: Klinische homSopathische ArzneimitteUehre, Regeusburg, 1926. (24) DUSTIN, JR.: Quoted from WID~A~q (20). (25) F#HNER a n d LII"Ps: quoted from WIDMA~N (20). (26) LEESER, O.: Die mineralischen Arzneimittel, Stuttgart, 1933. (27) ASCH~CER, B.: Die Konstitution der Frau, 2 Band. Miinchen, 1924. (28) KREHL, L.: Entstehung, Erkennung und Behandlung innerer Krankheiten, Berlin, 1932. (29) S~ECHER, R. M., HERSH, A. H. a n d SOLOMON, W. M.: Ann. Int. Med., 1949, 31, 595. Berlin, 1934. (30) S~Ri3MPELL-SEYFAR~H: Lehrbuch der speziellen Pathologle und Therapie. Berlin, 1934. (31) LETTRfi, H., LE~TR~, 1~., a n d PFLA~Z, CH.: I~aturwisseusehaften, 1950, 38, 70. Unfortunately the monograph on Colchicum b y EIGS~I and DUsTr~r Jr. (Iowa, 1955) could not be t a k e n into consideration since it only appeared after this manuscript had boon comploted.

(8) (9) (10) (11) (12)