The poisonous mushrooms, or so-called toadstools, may be grouped in two classes: (1) Those containing minor or irritant poisons, which act locally on the gastro-intestinal tract, such as the Clitocybe illudens, Lepiota Morgani and others, and (2) those containing major poisons which act on the nerve centers after absorption, causing symptoms to appear a long time after the poison has been taken and very often terminating fatally. This group includes the Amanita muscaria, the Amanita bulbosa or Am. verna and the Amanita phalloides.

From the prompt way in which vomiting and purging begin after eating the toadstools of the first group there seems to be no doubt of the local irritant action on the alimentary canal. Grave symptoms from any constitutional effect or any serious disturbances of the circulation do not occur. Although intensely disagreeable, such poisoning terminates in recovery and may not be regarded as dangerous unless the poison be taken in enormous quantity or by one in poor health.

In poisoning by the deadly toxic AmanitÆ vomiting and purging may also occur as prominent symptoms, but generally only occur late—ten to fifteen hours after eating the toadstool—and are due to the action of the poison on the nerve centers. This is clear from the fact that these symptoms appear when the poison is given either hypodermatically or intravenously to animals.

It is exceedingly unfortunate that these deadly poisonous toadstools do not give some warning either in an unpleasant taste or contain an irritant which would act locally to cause emesis and purgation, for in that case the patient would get rid of the poison before such large quantities were absorbed and fatal poisoning would be less frequent. They are not at all unpalatable and sometimes large quantities are eaten by mistake.

Formerly frequent allusion was made to the possibility of poisoning by decomposition products from putrefactive changes in mushrooms. Not a single case has come to the writer’s notice where this form of poisoning has actually occurred. In many reported cases of poisoning it is distinctly stated they were eaten soon after gathering; in none does the reporter mention any suspicion of poisoning of this nature.

At one time very many mushrooms were supposed to be poisonous. We now know that there are only a few dangerous ones, and where serious poisoning occurs it seems clearly to be due to some definite and constant poisons contained in certain fungi. We shall not deal here with the irritant poisons, as they are not dangerous and usually Nature gets rid of them easily, but shall consider the poisons of the Amanita muscaria or “Fly mushroom,” the A. bulbosus vernus Bull. or A. verna, and the A. phalloides or “death cup.” The writer has not had any personal experience with poisoning by these in man, but bases his observations upon over one hundred experiments made upon lower animals.^[C] This is a distinct advantage in reaching any conclusion, as the facts are definite without any doubt as to the kind or quantity of the poison taken. In many of the reports of poisoning by mushrooms in man no mention of the species is made. In all these cases many kinds have been mixed together in preparing them for the table and it has never been known how many of the poisonous and how many of the edible ones have been eaten by any one individual partaking of the dish. Of course the fluid in which they are cooked contains some of the poison. This explains why some patients recover after having eaten several mushrooms while others die from a part of one only. (See report of six cases by Dr. G.E. Caglieri, New York Med. Record, August 28, 1897; also Dr. Berry’s cases reported by Prentiss, Philadelphia Med. Journal, September 24, 1898.) Then, too, different poisonous species may be mixed together. The symptoms produced by the different AmanitÆ poisons are quite different. Those containing irritant poisons may be taken with those containing deadly poisons. This accounts for the great variety of symptoms presented in cases reported.

The symptoms of poisoning by this fungus usually appear from eight to twelve hours after it has been eaten, unless it has been taken in enormous quantities, as in the cases reported by Prentiss (Phila. Med. Jour., September 24, 1898), where they came on in half an hour.

These begin with cramp-like pains in the extremities, colicky pains in the abdomen, burning thirst, vomiting and purging. The pulse may be very slow and strong at first, but later becomes rapid, small and feeble. The blood pressure is low and, as a result of this disturbance of the circulation, faintness is a common early symptom. Extreme pallor is often noticed. The secretions are increased, and the sweat and the saliva may be secreted in abnormal quantities.

The pupils are strongly contracted and dullness of the vision or double vision may be noticed early.

The respirations are slow and become shallow and stertorous when the poisoning is severe.

The mental state may be clear at first, but becomes dull, deepening into unconsciousness and deep coma if a large quantity has been taken.

Convulsions are reported to have occurred in some cases from poisoning by this toadstool in man. The dried Amanita muscaria or extracts of the fresh fail to produce convulsions in the lower animals, even in frogs, which are very susceptible. Either there is a considerable difference in the susceptibility to this poison or there is some poison present in the fresh fungus which is lost by drying.

Small amounts of the dried Amanita muscaria are said to be used by inhabitants of northern Asia for the stimulating effect upon the nervous system, producing, like other narcotic poisons, a dreamy state of intoxication, deepening into sleep (Von Boeck in Ziemssen’s Cyclopedia of Medicine, Vol. VII).

In animals the most striking effect is upon the circulation. When injected intravenously it causes tremendous inhibition of the heart’s action—a moderate amount causing the heart to beat slowly and powerfully; a large amount causing complete arrest. Even with the partial inhibition there is an enormous fall of pressure. The slowing of the heart soon passes off, and when a moderate amount has been injected, the circulation quickly returns to normal.

In one of my experiments on a dog, the heart stopped for 1¾ minutes and then began beating again, the circulation soon recovering.

Late in the poisoning the heart beats may be rapid and feeble and the blood pressure low. The lowered blood pressure is largely due to dilatation of the small blood vessels resulting from a loss of control over them by the nerve center which normally keeps the arterioles in a state of partial contraction.

The inhibition of the heart is due to the action of the well-known alkaloid muscarine upon nerve ganglia in the heart. The contraction of the pupil and the increased secretory activity of the glands are also due to this substance which was discovered by Schmideberg and Koppe in 1869.

It was soon found that although dogs recovered from the immediate or early effects (i. e., from the muscarine) of enormous quantities of toadstools, they succumbed from the late effects of much smaller quantities. Atropine fails to avert this result from the late effect, whether given before the poison, with it, or after it. The inhibition of the heart passes off long before death occurs. Late death does not appear to be due to muscarine.

All these facts put together point to the existence of some other poison or poisons in the Amanita muscaria to which atropine is not an antidote.

This peculiar poisoning causing death so late will be discussed again after considering the other poisonous mushrooms as they act similarly.

Gastro-intestinal symptoms were not as common in my experiments with Amanita muscaria as with the Amanita phalloides. Vomiting and purging occasionally occurred early, but much more frequently late in the poisoning and often not at all.

Convulsions did not occur in any of the animals poisoned by this fungus. Convulsions are recorded in some cases of poisoning in man, but not so constantly as with the A. phalloides and A. verna. Where they occurred either a large amount had been taken (as in Prentiss' case) or there is some doubt about the Amanita muscaria having been the only toadstool eaten (as in Caglieri’s cases). Frogs are very easily thrown into spasms, but no spasms were observed, even in fatal poisoning of them by this toadstool.

Regarding cerebral symptoms, little can be said except that unconsciousness and coma may come on early and persist till death. In cases terminating fatally the animal seemed to be conscious, but so depressed that it was unable to stand or even move when called.

Concerning differences in the susceptibility of different animals to the poisons of Amanita muscaria, cats seemed to be more susceptible than dogs in the earlier experiments with extracts of the fresh fungus, but more numerous experiments with the dried fungus failed to show any greater difference than can be observed between different animals of the same kind.

As to the nature of the poisons very little can be stated from the experiments, as they were undertaken as a preliminary step to chemical studies to be carried on later. The alkaloid muscarine is one of our best known poisons and nothing can be added to what is already known about it. The poisons are extracted by distilled water as well as by a solution of sodium chloride; they are soluble in glycerine and in alcohol and very little difference can be seen in the action of these extracts, unless the alcoholic extract contains more of the muscarine, while the glycerine extract contains more of the other poisons.

It is stated that muscarine is not poisonous to flies; that the Amanita muscaria contains a volatile poison which is poisonous to flies (hence the name “Fly mushroom”), and which is lost by drying; that inhabitants of northern Asia use the dried fungus (after the volatile poison has been lost) for producing intoxication (Von Boeck in Ziemssen’s Cyclopedia, Vol. VII, p. 927). My experiments have been entirely with mammals and frogs, and unfortunately those performed with the fresh toadstools were not numerous enough to enable me to draw positive conclusions as to any loss of toxicity by drying. A single experiment with a cat seemed to indicate that boiling of the fungus lessened the toxicity but subsequent experiments indicated that a boiled solution was no less toxic than one not boiled.

One thing we can state definitely; that boiling the dried A. muscaria does not destroy its toxicity. This indicates that the poison is not of an albuminous nature, which would be coagulated by heat.

Whether or not any volatile poison is lost by boiling a solution of the fresh fungus or by drying at 40° C. can not be stated definitely as the experiments made with the fresh fungus were few in number on account of the extreme difficulty in getting them perfectly fresh.

The average of six observations in which it was possible to weigh the toadstools before and after drying at 40° C. showed a loss of 84.4 per cent. of water. In other words, 1 gram of the dried equals 6.4 grams of the fresh.

Comparing the lethal doses of the dried with the lethal doses of the fresh extracted by glycerine and alcohol, it does not appear that there is any great loss of the toxicity by drying as is shown by the following: Lethal dose of dried in Experiment 31 was .085 gram. per kilo of body weight; in Experiment 55, .033 gram. per kilo caused early death, while .223 gram. of dried per kilo and .120 gram. per kilo caused death from late effects (Exps. 32 and 57). The lethal doses of the fresh were .91 gram. per kilo (Exp. 29) and 1.055 gram. per kilo (Exp. 36) when a glycerine extract of the fresh growth was used, while 1.222 gram. per kilo (Exp. 16) made from an alcoholic extract failed to kill.

It may be well to introduce here the results of an experiment which shows there is no highly poisonous volatile material given off from the A. phalloides. This is rather an important fact to determine, as the opinion is held by some that there is a volatile poison, and most of my experiments were made with the dried fungus. A 1 per cent. solution of fresh A. phalloides was distilled until three-fourths of the fluid had passed over as distillate. The latter was injected into the vein of a dog and found not at all toxic. The opportunity has not been afforded me of repeating this experiment personally, but Dr. J.P. Arnold has kindly repeated it for me, injecting the distillate into rabbits and frogs and failed to find it toxic. Certainly if there is any volatile poison in the A. phalloides it must be either in very minute quantity or very slightly toxic.

ANTIDOTAL VALUE OF ATROPINE.

In arriving at any conclusion we must bear in mind the variation of different animals in their susceptibility to poisons. Thus, to give the greatest difference observed, .085 gram. dried Amanita muscaria per kilo of body weight killed one dog in an hour, while in another dog .223 grams. of the same preparation per kilo only killed after 24 hours, the cardiac inhibition having disappeared one-half hour after the poison was injected. However, an average of six (6) experiments on cats and dogs with dried A. muscaria in which no antidote was given shows the lethal dose to be .103 gram. per kilo of body weight. The average of four (4) experiments, in which the fungus, dried in the same way, was used but atropine was given as an antidote, gives the lethal dose of .335 gram. per kilo and death only occurred late in each case. There can be no doubt, therefore, of the antidotal value of atropine for poisoning by Amanita muscaria.

It should be borne in mind, however, that it is not an infallible antidote even when given early, and that it does not prevent death from the late effects in severe cases, although given in large doses. In some experiments atropine was administered at the same time the poison was given and in others before it.

The important practical lesson is that too much reliance should not be placed upon atropine. It will be shown later that it has little value as an antidote to A. verna and A. phalloides. Probably these fungi contain less muscarine than A. muscaria. Although there is no drug so antagonistic in its physiological action to the poison of the A. muscaria as atropine, the use of other remedies should not be neglected. The symptoms have to be treated as they arise. Strychnia, alcohol in moderate amounts and suprarenal extract could all be used to advantage in restoring the circulation, especially late in the poisoning. Atropine merely removes the inhibition of the heart which occurs as an early symptom.

External heat should be applied if the body temperature is subnormal. The treatment of gastro-intestinal symptoms will depend upon the conditions of each individual case. The injection of a large amount of warm physiological salt solution (.6-.7 per cent. sodium chloride) into the subcutaneous tissues should also be tried in severe cases seen late in the poisoning.

POISONING BY AMANITA VERNA OR A. BULBOSUS VERNA BULL.

The symptoms appear from six to fifteen hours after the ingestion of the poison and may be largely choleraic in nature, i. e., vomiting and purging, the discharges from the bowel being watery with small flakes suspended and sometimes containing blood.

The disturbance of the circulation is somewhat similar to that caused by A. muscaria, viz., slow, strong pulse early, but rapid and weak later. Dizziness and faintness may be early symptoms. Sometimes the skin is pale and covered with cold, clammy sweat; at others there is great cyanosis. The body temperature is subnormal, unless nervous symptoms are very severe. Very prominent among the symptoms are tetanic convulsions, which may appear comparatively early and persist until the end.

In animals the effect of this toadstool is entirely different from that of A. muscaria. Perhaps the most striking difference is the frequency with which convulsions appear. Convulsions occurred repeatedly in mammals and in nearly every frog to which the toadstool was given. This fungus seems to contain some poison that acts upon the spinal cord very much as strychnia does, though less powerfully, of course.

The circulatory conditions are also different. The inhibition of the heart may be pronounced as an early condition, but the pressure does not return to the normal after this disappears, either from giving atropine or from cutting the pneumogastric nerves. Section of these nerves removes the cardiac inhibition much more completely than after poisoning by the A. muscaria. There is often a fall of pressure without cardiac inhibition. In other words, there is a much greater permanent fall of blood-pressure due to paralysis of the nerve center controlling the blood vessels (vaso-motor center). This condition will last a long time and does not show the same tendency to disappear as after A. muscaria. Moreover it is produced by comparatively small amounts of the A. verna.

The respirations are very slow. The blood is poorly oxygenated and this probably causes the cyanosis sometimes observed in men poisoned by this fungus.

Bloody fluid is sometimes vomited or comes from the nose. It may also occur in the discharge from the bowel.

Retching and purging occurred more frequently as early symptoms than in animals poisoned by A. muscaria.

Coma appeared early and continued until death. The administration of atropine soon after giving the poison when cardiac inhibition was present, caused a slight temporary rise of blood pressure but did not affect the dilated condition of the blood vessels. The pressure continued low notwithstanding the atropine. Although the experiments with this fungus were not as numerous as with the A. muscaria because of difficulty in obtaining it, yet it seems clear that atropine is of very little value as an antidote. Death very rarely resulted from the cardiac inhibition occurring early but usually came on late after that condition had disappeared. The lethal dose was no larger when atropine was given than when no antidote was used.

Amanita verna is very much more toxic than A. muscaria, the average of four experiments in which the former was given without an antidote being .034 gram. (dried) per kilo of body weight, while .103 gram. (dried) per kilo, was the average for the latter fungus.

POISONING BY AMANITA PHALLOIDES.

The symptoms described in man are very similar to those caused by the A. verna, except that the convulsions are less constant and cyanosis is not mentioned. In some cases vomiting and purging are prominent symptoms. There is dizziness and fainting, extreme ashy pallor, cold skin covered with sweat, subnormal temperature, muscular twitchings and occasional convulsions and somnolence which deepens into coma and lasts until death, which usually occurs two or three days after eating the poison. Sometimes the gastro-intestinal symptoms are less severe or may be absent, though they are usually present; in that case the nervous symptoms are more prominent, particularly the convulsions and circulatory disturbance.

In experiments upon animals the convulsions were not observed so constantly as with the A. verna. Out of twenty-five dogs poisoned by the Amanita phalloides, convulsions only occurred twice, while twelve frogs injected with different preparations (dried toadstool and glycerine and alcoholic extracts of the fresh) failed to show a convulsive seizure in a single instance. It seems to be difficult for mycologists to draw a sharp line between the A. verna and the A. phalloides and say to which of these two certain fungi belong. This may explain why convulsions are recorded more frequently in persons poisoned by this toadstool than in animals poisoned by it. Frogs are very susceptible to poisons acting upon the spinal cord, and all of those poisoned by lethal doses of A. verna had convulsions, while none of those poisoned by the A. phalloides had any. It would therefore appear from this striking difference in the physiological actions that the two are separate and distinct.

The circulatory and gastro-intestinal symptoms were quite similar to those caused by the A. verna.

A. phalloides is less toxic than the A. verna, but more so than the A. muscaria, the average lethal dose of the dried fungus (eight experiments) for dogs, where no antidote was used, being .117 gram. per kilo.

The antidotal value of atropine is very slight, if indeed it has any action other than removing the temporary cardiac inhibition. The animals very seldom died from this, but mostly from the late effects after the inhibition had disappeared. In four experiments on dogs in which atropine was given either at the same time as the poison or before it, the average lethal dose was .198 gram. of the dried fungus per kilo. Two dogs were killed by .1 gram. per kilo without atropine; another was given the same amount and was given atropine hypodermatically a number of times and recovered, though very ill for two days.

Transfusion of physiological salt solution (.6 per cent. table salt) was practiced in three dogs. Although death occurred in all of these and the lethal dose was not unusually high, the pressure was restored for a time at least. It should be employed in treating poisoning in man, and not be depended upon as the only procedure, but used in conjunction with other remedies. This will be referred to again in describing treatment.

It will be seen from the above that poisoning by the A. verna and A. phalloides present symptoms in the lower animals which are quite different from those caused by the A. muscaria, and that in either case poisoning is far more serious than by the latter fungus. This is not only because they are so much more toxic, but also because there is no decidedly antagonistic action by atropine, and hence its value as an antidote is much less.

In treating a case of poisoning by either A. verna or A. phalloides the only thing that can be done is to meet the indications in the individual case. If the heart is beating slowly, atropine should be given in liberal doses. This will not overcome the chief disturbance of the circulation, viz., the tremendous dilation of the blood vessels. Strychnia will do this to a certain extent, but its use may be contra-indicated by twitchings or convulsions from the toadstools. If it can be used it is exceedingly valuable, as it stimulates not only the vaso-motor center but the respiration and heart as well. Caffein or strong coffee may also be used to this end if the stomach will retain it. Suprarenal extract should also be given hypodermatically, as it will restore the blood pressure more nearly to normal than any other drug, according to our experiments. It has the advantage of not increasing the excitability of the spinal cord as strychnia does, and hence would not be contra-indicated by nervous symptoms.

Perhaps the most rational treatment to meet the most serious condition of the poisoning by these toadstools is the transfusion of normal saline solution (.6-.7 per cent. solution of table salt) into the subcutaneous tissues. This should, of course, only be given by a physician, as great care is required in sterilizing the syringe. It can be given with a fountain syringe and aspirating needle beneath the skin of the thigh. Large quantities should be used—at least a quart (1000 cc.) or more. The fluid is rapidly absorbed by the lymphatics and gets into the blood vessels. It restores the blood pressure by increasing the fluid in the vessels and also doubtless aids the organs of excretion in eliminating the poison; at the same time it would relieve the intense thirst patients complain of. Clinicians who have observed cases of poisoning by the A. phalloides in man have suggested this procedure as the most rational one to meet the symptoms presented. From the condition produced in animals poisoned by this toadstool the writer was led to the same conclusion. In two experiments upon dogs, when transfusion of warm physiological salt solution was made directly into the vein after poisoning by the A. phalloides, death occurred in both cases and the lethal dose was not unusually large, although the amount transferred was equal to the estimated volume of the blood of the animal in one case and half that amount in another. In another animal atropine was given before the poison and the pressure had been reduced by the latter to one-fifth of the normal, the transfusion of an amount of normal salt solution equivalent to two-thirds of the bulk of blood restored the pressure to three-fourths of normal in about 15 minutes, but further injection of the poison caused late death.

Although the rise of pressure is not so great from transfusion as from suprarenal extract in large doses, it is more permanent. Transfusion (or transfusion into the subcutaneous tissues by hypodermoclysis which amounts to the same thing) has the additional advantage of increasing the flow of urine, which is often suppressed in these cases. Even if it does no good it can do no harm if done antiseptically and should be tried but always in conjunction with other remedies.

A remarkable case of recovery after the injection of a large amount of normal saline solution has been reported by Delobel (Presse medicale September 30, 1899). A man aged fifty-two ate some A. phalloides; he was seen four hours afterward. The skin was covered with cold, clammy sweat; body temperature was sub-normal; shivering and tremors present; had not vomited or purged; urine suppressed; respiration stertorous; pulse 28 per minute and so feeble that it was almost imperceptible. Two full doses of atropine were given hypodermatically as well as 10 cc. of ether and 200 cc. of strong coffee with 20 cc. of rum were given by the mouth and hot bottles applied externally. In spite of all this the symptoms became worse and the patient sank into a condition of profound collapse, the pulse dropping to 24 per minute and the tremors ceased. One liter (1 quart) of normal saline solution was injected hypodermatically and improvement began in 15 minutes after the injection. The respiration lost the Cheyne-Stokes character; the pulse improved in tension and in an hour was 60 per minute; the skin improved and the temperature returned to normal and the patient went to work next day.

The circulatory symptoms are most prominent and demand most attention. Vomiting and purging have to be treated according to the conditions in the individual case and no rule can be followed. As the peripheral vessels are dilated the body temperature is usually subnormal. This should be overcome by applying hot bottles externally.

The suppression of urine should receive attention, and the activity of the kidneys be stimulated as much as possible. It is probable the suppression is largely due to the tremendous fall of blood pressure. If the urine is secreted but retained in the bladder it should be drawn off.

Just as there is no simple way of detecting the presence of poisonous mushrooms in a mixture of mushrooms, so there is no simple way of destroying or removing the poisons. Pouchet stated that boiling destroyed the poison and Chestnut has stated the poison of A. phalloides is a toxic albumen. If this were the case boiling would destroy it. In our experiments, however, boiling has not diminished the toxicity at all and it can be definitely stated that the poison is not an albumen.

There is also a popular impression that vinegar will remove the poison and numerous observers claim to have removed the poison of A. muscaria completely by soaking the fungus in vinegar. We have not had the opportunity of trying this with fresh A. muscaria, but in one experiment in which the A. verna was soaked over night in vinegar it failed to get rid of the poison—any more than would have dissolved in that amount of water.

Toadstool poisoning differs from most poisonings in the long time elapsing before death in fatal cases. The only inorganic poisons causing death after such a long interval produce profound tissue changes. Husemann believed death from poisonous mushrooms to be due to fatty degeneration of the various organs. We have examined microscopically the tissue of dogs and cats dying from the late effects of the A. muscaria and A. phalloides and found them to be perfectly normal.

Mr. V.K. Chestnut, in a bulletin published by the United States Department of Agriculture (Circular No. 13, p. 23), states that death from the A. phalloides is due to a destruction of the red-blood corpuscles. Upon what authority this assertion is made is not stated. The conclusion has probably been based upon the venosity of the blood in cases of poisoning resulting from the disturbance of the respiration and circulation. The blood corpuscles of animals poisoned by all three of the AmanitÆ studied have been counted repeatedly in our experiments and in none of them has there been any appreciable reduction.

It can be positively stated that death is not due to a destruction of the red blood cells.

Further, the coloring matter of the blood (hÆmoglobin), which carries oxygen to the tissues, has been examined with the spectroscope to see if any new compound had been formed which would prevent it from carrying oxygen. No such compound has been found—no alteration could be detected in the hÆmoglobin. It is quite evident that these toadstools do not kill by their action on the blood, for in a number of experiments the blood was examined a very short time before death.

Thinking that they might act upon the nerve cells of the brain and spinal cord very much as certain toxins of infectious diseases do, those structures were examined by special staining methods (silver impregnation), but no greater variation than is normal could be detected in any of those examined.

No statement can be made as to the cause of this late death, but it would appear to be due to some disturbance of nutrition.

Late death occurs not only in animals, but in most of the cases of poisoning in man recorded in medical literature.

The contrast between the early and late symptoms is not so great in poisoning by A. phalloides and A. verna as in the case of poisoning by A. muscaria. In the first two the serious symptoms appear early and continue till the end; in the last the early effects of the muscarine soon passes off or can be removed by atropine, but the late symptoms, strikingly in contrast with the early ones, still appear, and continue till death.