Ergot was first mentioned by the German physician Lonitzer in as a remedy used by midwives for quickening childbirth. The isolation of pharmacologically useful alkaloids started in with the discovery of ergotoxine and its adrenolytic activity by Barger, Carr and Dale. In , Stoll isolated ergotamine, the first chemically pure ergot alkaloid, which found widespread therapeutic use in obstetrics and internal medicine.
After that, Stoll ended his research in this area. In , Hofmann was looking for a new project and suggested to Stoll that he resume investigation of ergot alkaloids. Based on what was known about them so far, Hofmann believed things looked promising.
Stoll approved, but warned about the difficulty of working with these unstable substances. The required ergot was grown by farmers in the Emmental region as a secondary income and shipped to Sandoz in Basel in one hundred kilogram barrels. There, it would be milled, extracted with benzene, and concentrated. The components would be fractionated6 and delivered to the experimental laboratory to be tested for purity before further processing.
Safety measures in laboratories of the thirties did not compare to present day standards. The workers had no effective protection against highly poisonous chemicals and solvents. Consequently, there were frequent accidents and health hazards, especially with toxic and highly volatile solvents that often led to fainting. Controls at Sandoz became ever more stringent. Arthur Stoll watched to see that raw materials were treated sparingly and criticized Hofmann for his allegedly wasteful methods.
I needed to adopt microchemical procedures if I was to work with his costly substances. The Synthesis In , American scientists W. Jacobs and L. Craig succeeded in determining the chemical structure of lysergic acid, the basic component of many ergot alkaloids. Lysergic acid proved to be a substance that easily decomposed. It was before Hofmann applied the Curtius Synthesis, a method which enabled him to combine and stabilize lysergic acid with basic groups for further ergot research.
From lysergic acid he began synthesizing the indole derivative ergobasine. This gave him a more rational method of producing a substance that is present only in extremely small quantities in ergotamine. Moreover, the synthesis led to the eagerly sought clarification of its structure, which had previously remained unresolved.
Hofmann achieved the first synthesis of a natural ergot alkaloid by combining lysergic acid with propanolamine. This partial synthesis made it possible to convert the other alkaloids in ergot into ergobasine, which was valuable in obstetrics.
Hofmann subsequently produced many more lysergic acid derivatives, among them the twenty-fifth on November 16, , which was lysergic acid diethylamide; hence the designation LSD He was planning to synthesize an analog to the cardiovascular agent Coramine which was produced by Ciba, a competing pharmaceutical firm on the opposite bank of the Rhine.
It was delicious. I had just finished and had begun to pace back and forth and think about my work. Suddenly, I thought of the circulatory stimulant, Coramine, and had the idea of producing an analog compound based on lysergic acid, the building block of ergot alkaloids. Chemically, Coramine is nicotinic acid diethylamide so I decided to produce lysergic acid diethylamide.
The chemical and structural relationship of these two compounds led me to suspect they might have similar pharmacological properties. I hoped that lysergic acid diethylamide would be a new and improved cardiovascular stimulant. The trial audit mentioned slight restlessness in lab animals. Because the effects observed were less than expected, the physicians and pharmacologists at Sandoz quickly lost interest in the new substance.
For the next five years, nothing more was done with LSD This led me to produce LSD again five years after the first synthesis and pass it on to the pharmacological department for further trials. This was unusual, because test compounds were normally struck from the research program once declared to be of no pharmacological interest.
It was a matter of producing a few tenths of a gram. Again, things were orderly and clean and all the safety measures required for work with poisons were followed. At home I lay down and sank into a not unpleasant intoxicated-like condition, characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed I found the daylight to be unpleasantly glaring , I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.
After some two hours this condition faded away. The First Trip Albert Hofmann had to know and decided to undertake a series of experiments, beginning with a test on himself on April 19th, Again he proceeded with great caution and chose a dosage of micrograms, the smallest amount of ergot alkaloid deemed to have a noticeable effect. But once again, strange and, initially, decidedly frightening images overcame the chemist, this time more acutely than before. To be taken thinned with ca.
He is at once certain that his experiences on April 16th stemmed from unintentional ingestion of a small amount of LSD The experiences were the same, but this time more intense and profound. During the war, fuel was difficult to find. Gasoline was rationed and available for very few private vehicles. Indispensable commercial vehicles such as tractors and trucks were fitted with wood gasifiers.
At that time, even in Switzerland only a few wealthy could afford an automobile and taxis were not available. That is why Hofmann did not have someone drive him home; instead, his lab assistant, Susi Ramstein accompanied him by bicycle. He had the impression that they made little headway, but she later assured him that they cycled very fast and she had to pedal hard to keep up with him. The rows of houses took on threatening forms, the street seemed wavy, and the few persons they met changed into distorted shapes.
Some causes could be immediately eliminated. It seemed unlikely that the fresh country air and sunshine could be responsible for the disease, and the country and city folks all drank from the same source of water could not be the cause. Thus, he thought diet was the key to the disease. On his visits to his patience, in the country, he noted the food that was set out on the tables.
There was usually pork or beans, but the main staple and what always seemed to be present was a loaf of rye bread, which always seemed to be prominently displayed in the center of the table.
A few families began eating potatoes by this time and Thuillier initially believe that this was the possible cause of this disease, but at this time it had not yet become popular enough to be a standard fare in family meals and St.
Anthony's Fire had been known hundreds of years prior to the introduction of the potato to Europe. As farmers brought their goods to market, Thuillier also noted that the city dwellers consumed rich beef, poultry, truffles and white bread.
All the information that he required to solve the puzzle of St. Anthony's Fire was there and Thuillier must have had it for quite some time before all the pieces of the puzzle would fall into place. The answer came one day while he was walking through the country as he had done on so many occasions before. Passing through fields of rye infected with ergot, Thuillier suddenly realized that he had walked by this answer countless numbers of time.
The ergot or what the French farmers called cockspurs, were well known, but have never been considered harmful. Thuillier also knew of these structures from his readings. He knew that they had been used by alchemist in their potions to hasten child birth.
However, he also realized that even medicine must be carefully measured out in their dosage for too much of a good medicine could just as well be a poison. He then looked into his records and found that in years when ergot infection was high, the "Fire" raged and thousands died.
Although he was convinced that this was the answer, the evidence at hand was still not conclusive and Thuillier could not convince the farmers that this was the cause of this dreaded disease. It would be another two hundred years before Ergot was demonstrated to be a fungus that was causing gangrenous and convulsive ergotism. In , Louis Tulasne, an early mycologist and illustrator, worked out the life cycle for the Ergot of Rye. In his examination of the development of the Rye flower, he concluded that the ergot was a fungus that was growing on the inconspicuous flower of the Rye and that the fungus, and not the Rye itself, was the culprit.
The sclerotium or ergot that grows on the Rye is an over wintering stage and not met for consumption by either man or animals. In fact, we now know today that the ergot, as is true of many other fungi and plants, has evolved with numerous alkaloids as protection against such events occurring. Once the ergot stage has survived the winter, it will germinate to form mushroom-like structures that will produce the sexual spore stage, during the spring.
This spore stage will be ejected from the fruit bodies by the fungus and dispersed by wind to the Rye flower where a new infection will begin. However, the probability that a spore will happen to come to rest on a Rye flower is very remote, but only a few infections are necessary for the lifecycle to continue.
Once the infection does occur, a new, asexual spore stage is now produced, which is far more effective in infecting the Rye flowers. This is called the Spacelia stage, which produces its spores in a "honey dew" exudates that will attract flies and beetles.
As they visit each flower, looking for more honey, they carry the ergot spores from Rye flower to Rye flower, causing new infections with each visit, throughout the spring and summer months. When winter approaches, sclerotia are formed that will allow them to survive until the following spring. The plague of Holy Fire gangrenous ergotism was also responsible for some of the geographical boundary of Europe today.
France suffered many waves of ergotism throughout its history beginning around the eight and ninth century and continuing for the next years. During the one hundred years between A. This was a part of Europe that was populated by the Franks and during this period thousands of peasants ate bread made from the infected grain and thousands died as a result of Holy Fire.
With their superior size and fighting ability, and of course the fact that a large population of the Franks had just suffered from ergot poisoning, they easily defeated the Franks who lived along the coastal regions.
Before this time, the Vikings had already settled permanently on the northwest coast of France and had already exerted pressure on the Holy Roman Empire with their numerous raids.
Because of the constant successful raids in this area, Charles the Third was forced to abdicate the throne of the Holy Roman Empire by and this led to the split of the Holy Roman Empire into two kingdoms. Through it all the Northmen were unaffected by the ergotism because Rye was not their staple food. By , the Northmen's hold on the northwest coast of France was complete, and the king of France ceded to them what would become Normandy.
The people that settled Normandy adopted the French religion, language and culture, and would eventually become assimilated by France. Today, Normandy is a part of France, but its recognition as a region is still recognized.
Without question the Northmen were warriors of superior size and fighting skill, but it is impossible to say how successful their invasion, against the Franks, would have been if the wave of ergotism had not occurred at this same time.
However, it is difficult to imagine that with much of the Frank population sick with ergotism that they were able to put up much of a fight regardless of the fighting prowess of the invading army. Ergotism and the Bubonic Plague.
Matossian believed that while deaths could ultimately be attributed to Bubonic Plague, the consumption of grains infected with T-2 or related mycotoxins compromised the immune system and increased the likelihood of death in human and rats. Because of the increase in death of rats, the fleas carrying the disease would require a new host, which in heavily populated area, often was a human host. This led to a higher death rate than might have normally occurred.
She also presented evidence, based on what seemed to be selectivity of the disease, based on age and wealth, grain storage and environmental moisture. Due to the cold and wet years that occurred in , in certain areas of Europe, grain crops, which were the staple for Europe at this time, were thought to have been contaminated with T-2 or related toxins that damaged the immune systems of both rats and humans.
The damage to the immune systems of both rats and human is is believed to be one the contributing factors that led to the high mortality during the Bubonic Plague. However, other causes of depressed immune systems, other than fungal in origin, may also have occurred at this time.
When the greatest mortality due to the Bubonic Plague had passed, areas that were hard hit with the plague did not recover. This puzzled historians, although there were still some incidents of famine and diseases, after the plague, generally there was not a lack of food nor a great deal of disease since the populations in many areas had been drastically reduced by the plague.
However, there was still a population depression even a generation after the plague, and longer. Populations in many areas had still not reached levels that were present before the plague.
After the plague, the winters were unusually cold. This affected the diet of the poor more than the wealthy. In those years where the winters were cooler, Rye would be more likely to survive than wheat. This made it more likely that Rye would be consumed, and while the Rye survived the cold temperatures, the plants were traumatized and were more susceptible to infections by Ergot.
Evidence that Ergot poisoning was occurring was based on reports of nervous system disorders. People believed that they saw demons. In , a wet year, marked by a lack of food, there was an outbreak of hallucinations, convulsions and compulsive dancing in the Rhineland. Some people imagined they were drowning in a stream of blood. In addition to nervous system disorders such as those described above, Ergot poisoning is also known to reduce fertility and cause spontaneous abortions.
With the greater consumption of Rye, coupled with consumption of grains infected with T-2 and related mycotoxin that is believed to have shortened the consumer's life span by compromising their immune system, were possibly the reason for the population depression during this period of time. It would not be until almost the 15th. Century that an upward trend in population would begin.
Ergotism and Witchcraft. In victims where convulsive ergotism has occurred, during the Dark Ages, what can the uninfected people around them be thinking? It has recently been postulated that such victims of ergotism were often thought to be witches. In talking about witches and witchcraft, just how would one go about deciding that someone is a witch? One thing to keep in mind is that these incidents that we will be talking about happened centuries ago. So, you may think the criteria kind of silly when you hear them.
If you saw someone with the symptoms of ergotism, and you didn't know about ergotism, you may guess that the individual having a muscle spasm, tremors and writhing had some type of physical problem, such as epilepsy, or maybe even be on drugs, especially if they were hallucinating.
Most people wouldn't think that witchcraft was involved. However, you now know that even during the last century the cause of diseases was still not known. Even today, there are people that not only believe in witchcraft, but even practice witchcraft. It seems that people have always been willing to believe in fanciful explanation for a given phenomenon rather than an a simple one. So when there were large number of people that came down with the symptoms of ergotism, it was concluded that they must have been the victims of witchcraft.
It was especially true for convulsive ergotism since some people would claim to hear the devil speaking to them and were thought to be possessed. Matossian linked the occurrence of ergotism with periods where there were high incidents of people persecuted for being witches. Emphasis was placed on the Salem Witch Trial, in Massachusetts, in , where there was a sudden rise in the number of people accused of being witches, but earlier examples were taken from Europe, as well.
How did Matossian arrive at the conclusion that the bewitched individuals were victims of ergotism rather than something else? There are many symptoms that are attributed to ergotism and while together they may be rather unique, there are other diseases, or physical afflictions that may also have some of these symptoms.
However, Matossian did not rely on just one indicator the symptoms to determine that ergotism was responsible for witchcraft hysteria, but looked at several other parameters as well. She looked at where these incidents occurred, the temperature, rainfall, the crops grown in that area and who was affected. In looking at the geography of where witch trials occurred in Europe, Matossian found that a large proportion of the trials were concentrated in the alpine regions of France and central Europe where Rye was usually grown as the staple.
Also, it was in these areas that the best source of "primary" records were kept. In Swabia, in southwestern Germany, they even kept annual records as to the number of trials. Other records such as the price of Rye would give an indicator as to how much Rye was available in a given year and more contemporary research compiling the widths of annual rings of trees in given localities gave an indication as to approximately what the spring and summer temperature may have been.
For example, in years where there were a large number of witch trials, there were usually high Rye prices, indicating that it was a poor growing year for Rye and people may not be as selective in what they consumed.
Trials were also more common during years when the spring and summer months were usually cooler, and even more so if the climate was colder and wetter than the norm.
Cooler temperatures would be more favorable for ergot formation on Rye and even more Ergot would form if the rainfall was greater. How did the witch hunt begin? Once victims of ergotism began exhibiting symptoms of alkaloid poisoning of Ergot, people began to look for the "witch or witches" that caused this sickness and misery to occur.
In Salem, Massachusetts, the witch hunt began, on January 20, when three pre-teen girls began began to exhibit symptoms of what Matossian interpreted as convulsive ergotism. This would, of course, have been interpreted as acts of strange behavior on the part of the people of Salem. They began blasphemous screaming, had convulsive seizures, were in a trance-like states.
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