Turn On and Tune In

Psychedelics, Narcotics and Euphoriants

John Mann, John Emsley, Philip Ball, Philip Page, Joseph P Michael, Henry Oakeley

• Publisher: Royal Society of Chemistry
• Year: 2019
• Edition: 1
• eBook ISBN:
  9781788018234
• Topic: Philosophy
• Subtopic: Higher Education

Timothy Leary's advice to "tune in, turn on and drop out" was a 1960s exhortation to experiment with LSD, but humans had been consuming ergot alkaloids related to lysergic acid diethylamide for at least a thousand years. Opium has been around even longer with its medicinal uses being known to the Ancient Sumerians as long ago as 3400 BC. This is the first book to cover all of the major psychoactive drugs (both natural and synthetic) in one volume, and the only one to cover all aspects of these drugs from their anthropological and sociological influences through to their chemistry and pharmacology. It covers a range of substances including LSD, opium, heroin, cocaine, cannabis, peyote, belladonna, mandrake, and absinthe. The book is highly readable and concentrates on the characters (e.g. authors, painters, pop stars, hippies, politicians and drug barons), both famous and infamous, who have ensured that psychoactive drugs hold an enduring fascination and interest for everyone. The basic chemistry and pharmacological activity covered together with a brief account of useful drugs that have emerged from a study of the psychoactive ones.

CHAPTER 1

From Ergotism to LSD

Timothy Leary’s advice to ‘turn on, tune in, drop out’ was a 1960s exhortation to experiment with LSD and other psychedelics, but humans had been consuming ergot alkaloids related to lysergic acid diethylamide for at least a thousand years, and perhaps since the time of the ancient Mesopotamian empires. The fertile alluvial lands that lie between the mighty Euphrates and Tigris rivers were the cradle of some of the great early civilisations including those of the Sumerians, Assyrians and Babylonians. These large and sophisticated nations developed agriculture on a vast scale with huge annual harvests of wheat and barley, and perhaps rye (which was probably first domesticated in what is now Turkey at least 4000 years ago). For the first time in the Middle East, a well-developed leadership and infrastructure could harness the energies of a large peasant workforce for irrigation projects that provided large annual grain surpluses. These could support a non-nomadic lifestyle and with it the spare time to develop new crafts and written languages. And it is on an ancient Assyrian cuneiform tablet from around 600 bc that we first learn of the ‘noxious pustule in the ear of grain’. This may refer to the purplish black sclerotium (the over-wintering form) of the ergot fungus Claviceps purpurea, which resembles a cock’s spur (ergot in French)(see Figure 1.1). Crop damage is also mentioned in the bible:

Figure 1.1 The ergot fungus growing on rye – note the spur-shaped dark sclerotium. © Blackthorn Arable.

‘I smote you with blasting and with mildew…’(Haggai, 2, 17); and
‘If there be in the land famine, if there be pestilence, blasting and mildew…’(Kings, 8, 37).

However, although the serious health problems associated with consumption of contaminated grain were undoubtedly known in ancient times, we do not know if the link to the ergot fungus was made. We do know that rye – the usual grain host for the fungus – was not introduced from Turkey into Europe before about 1800–1500 bc, and we have to wait for the reports of the mediaeval chroniclers for our first glimpse of ergotism. Perhaps the earliest description can be found in the diaries (the Annales) for ad 857 from the convent of Xanten close to Duisberg on the Lower Rhine in Germany. These relate that a great plague of swollen blisters consumed the people by a loathsome rot so that their limbs were loosened and fell off before death. The gangrene that is so graphically depicted here was one of the two types of ergotism – the gangrenous type – while the other form was most often described as convulsive ergotism and led to so-called ‘dancing epidemics’. The chroniclers agree on the range of symptoms associated with these two disease types. Gangrenous ergotism began with itching and a crawling sensation in the feet with associated sensations of hot and cold in the extremities leading to extensive blistering and gangrene of hands and feet. Loss of these limbs was sometimes followed by recovery but death from septicaemia was the more common sequel. The convulsive form of ergotism was associated with effects on the central nervous system giving rise to tingling in the hands and feet, convulsive movements of the muscles giving rise to staggering and involuntary movements – hence the ‘dancing epidemics’.

Many of the chronicles describe plagues giving rise to symptoms that might well be ascribed to ergotism. For example, the account of Frodoard of an ignis plaga(fire plague) in Paris around ad 945 which attacked various limbs of the body (diversa membra ignis plaga peradunta) with relief only coming with death of the sufferer. Though Frodoard goes on to report that some were saved by the local leader Hugo who supplied daily rations of (presumably) bread free of ergot contamination:

Asserantur ab hoc peste salvatii (saved from the plague): quos Hugo quoque Dux stipendiis aluit quotidianis (daily rations from Duke Hugo).

Salvation was also provided by the local clergy and there are various accounts of plagues in Aquitaine and Limousin during the period ad 950 to 1000 where the bones of St Martial were shown to the victims with positive results. One can only assume that these clergy had supplies of uncontaminated bread to give to the victims, thus reversing the effects of the ergotism in those lightly affected. Alternative saintly relics were used in other regions including those of St Génévieve in Paris and St Martin in Tours; but it was the remains of St Anthony that were most widely touted as an effective means for the cure of holy fire or ignis sacer.

The origins of the myth of St Anthony, like much of the early history of ergotism, have to be viewed with a degree of scepticism. It is usually accepted that he was born near Koma in Egypt around ad 250 into a wealthy Christian family. He was converted to the life of a hermit following the death of his parents, and by ad 270 had given away all of his worldly goods and had retreated to a tomb near his village. Many paintings show him tormented by visions of wild beasts during his period of seclusion, though he also seems to have been tormented by people seeking his advice (see Figure 1.2), and he eventually retreated to the depths of the Sinai desert and lived in an old abandoned fort. After about 15 years of contemplation and prayer, he emerged to found a cult of Christian monasticism, and spent the rest of his long life devoted to these religious activities. Following his death, probably in ad 356, his remains were hidden locally only to be discovered some years later and then transferred to St John’s Church in Alexandria. Here they lay for several centuries but they were transferred to Constantinople before the Arabs overwhelmed Alexandria in ad 641. They remained undisturbed in the Church of St Sophia for about 400 years.

Figure 1.2 An imagined meeting of St Anthony and a patient suffering from ergotism – note the amputation and the burning hand. © Wellcome Images.

After this the story becomes even more hazy though it is usually assumed that what little remained of him was taken to France by crusaders returning from Constantinople. Jocelin, the Count of Dauphiné, is usually credited with taking the relics back to the Dauphiné region in south-eastern France – but the truth remains elusive. The location of the church where the remains were deposited around ad 1070 is also in doubt, though the one in the tiny village of St Didier de la Motte (now St Antoine l’Abbaye, near Marcellin, Isère) is most often cited in the chronicles. What seems more certain is that the first hospital dedicated to the treatment of victims of ergotism was erected nearby in around ad 1090 by Gaston, a local nobleman whose son Guerin had been cured of ergotism following a pilgrimage to St Didier de la Motte. This hospital with its team of dedicated brothers of the order of St Anthony served as a model for dozens of other hospitals that sprang up all over France (e.g. in Besançon and Chambéry). The great significance of the association of St Anthony with ergotism has been celebrated in many fine paintings and other religious artefacts, most notably the wonderful sixteenth-century altar painting by Matthias Grünewald in the church at Colmar, a small town between Strasbourg and Basel.

Obviously all of these activities occurred in the depths of the Middle Ages, and it is worth looking at some of the more reliable medical and historical records to try to untangle fact from fiction. One fact quickly emerges and this concerns the greater prevalence of the necrotic form of ergotism west of the Rhine, primarily in France, while the convulsive type – often mistaken for epilepsy – seems to have been more common in Germany and Russia. Presumably these differences correspond to the levels of the various ergot alkaloids present in the geographically distinct strains of fungus, and to the mode of preparation or cooking of the bread. The major ergot alkaloid is usually ergometrine, which is a potent vasoconstricting agent and this would be expected to have a significant effect on the blood vessels of the extremities (hence the gangrene) and on neurotransmission within the central nervous system (hence the neurological effects). The vasoconstrictive effect was certainly recognised and used as early as the sixteenth century when the German physician Adam Lonitzer described the use of the sclerotia of ergot to stimulate contraction of the uterus and thus ‘quicken labour’. In his Kräuterbuch (four editions between 1557 and 1577)– actually the title was Book of Herbs and Artificial Counterfeiting, With the Art of Distillation– he provided specific instructions for this new medication: three sclerotia to be administered with repeat doses if necessary.

A more scientific description was given by the German physician Paulizky in 1787 in a paper to the Neues Magazin für Arzte, and here he described his extract of ergot as pulvis ad partum as providing a more rapid and powerful quickening of labour than any other known drug. Crude ergot became very popular amongst the midwives and physicians in much of Europe, though it was less enthusiastically adopted in America. So, although John Stearns, a physician from Saratoga County in New York State, extolled the virtues of administration of 5–10 g of crude ergot to produce a rapid delivery of the baby, he did warn of the severe adverse effects of nausea and vomiting and admitted that the uncertain constitution of the extracts could affect the outcome. Writing to a Mr Akerly in January 1807 he says:

In compliance with your request I herewith transmit you a sample of pulvis parturiens, which I have been in the habit of using for several years, with the most complete success. My method of administering it is either in decoction or powder. Boil half a drachm of the powder in half a pint of water, and give one third every twenty minutes till the pains commence… If the dose is large it will produce nausea and vomiting. In most cases you will be surprised with the suddenness of its operation; it is, therefore, necessary to be completely ready before you give the medicine, as the urgency of the pains will allow a short time afterwards.

And he went on to discuss the source of his material:

It is a vegetable, and appears to be a spurious growth of rye. On examining a granary where rye is stored, you will be able to procure a sufficient quantity from among the grain. Rye which grows in low, wet ground, yields it in greatest abundance.

Oliver Prescott produced a pamphlet in 1813 for the Massachusetts Medical Society along the same lines, and such was the enthusiasm for ergot that it was included in the US Pharmacopoeia in 1820. However, other physicians were more cautious and as early as 1824 the New York physician Hosak had warned of the serious risk of rupture of the uterus and death of the mother. He even suggested that crude ergot should be renamed pulvis mortem, and the rising toll of deaths resulting from its use provided the death knell for ergot, at least in America, and by the end of the nineteenth century it was no longer in use.

Two strange occurrences often blamed upon the neurological effects of ergotism are worth considering, even if the links to contaminated rye have never been conclusively established. The first concerns la Grande Peur, or the Great Fear, which gripped whole cohorts of the French peasantry for about 18 days at the end of July 1789. There is little discernible pattern to the riots in which the peasants rose up against the tyranny of the French landowners who controlled almost every facet of their lives. It is suggested that they were responding to rumours that brigands from the north had been sent to steal or damage their crops. Certainly the concurrent agitation against the aristocracy that was occurring in Paris and its environs, which marked the start of the French Revolution (the Bastille had fallen on July 14th), had given rise to widespread fear and uncertainty amongst the peasant class. In regions as far apart as Normandy, Dauphiné, Provence and Aquitaine, the peasants looted and burned local châteaux but (for the most part) stopped short of murder, and most eyewitness accounts imply that this was uncoordinated madness rather than a revolution. A tentative link between the various outbreaks of vandalism and ingestion of ergot-contaminated rye has been made. In particular, the weather records for 1788–1789 reveal that a cold winter was followed by a cold and damp spring, which would have been ideal growing conditions for the fungus. Early summer was then warm and dry, favouring airborne spread of the fungal spores, and the warm and wet summer completed a weather cycle that was hugely favourable for growth of the sclerotia. To make matters worse, the previous year’s harvest had been poor so the peasants were probably less assiduous in their cleaning of the rye harvest. Of course this regional madness brought on by ergot-contaminated rye could be pure fantasy apart from the fact that certain regions of France escaped this epidemic. One of these was the Sologne which had been badly affected by the gangrenous form of ergotism throughout the Middle Ages, so the peasants could be expected to be more careful in rooting out ergot from the harvested rye. We will never know what caused la Grande Peur but it is clear that the landowning aristocracy failed to respond to the genuine grievances that were voiced, and they soon faced a much larger conflagration which had nothing to do with ergotism – the French Revolution.

The second episode of unexplained behaviour concerns the Salem witchcraft trials of 1692. Starting in December 1691 a number of villagers began to behave in a peculiar way suffering from what were described as ‘distempers with disorderly speech’ and ‘odd postures and convulsive fits’, and these led to a suspicion of witchcraft. At their trial some of the defendants complained of hallucinations and ‘crawling sensations in the skin’, and all of these symptoms could, in principle, be ascribed to ergotism. Rye was certainly the most successful cereal grown by the New England settlers, and as with La Grande Peur, the weather records for 1691 reveal early spring rains followed by a hot and stormy summer which could have encouraged the growth of Claviceps purpurea. Harvesting and threshing of the crop would have been over by Thanksgiving Day, so the bread baked in December would have been the first to contain ergot if indeed it was present. Whatever the cause of the strange behaviour – and the evidence for ergotism is highly tenuous – by September 1692, 20 villagers had been found guilty of witchcraft and executed.

As with many other biologically interesting natural extracts, pharmacists and chemists began to investigate the chemical constituents of ergot early in the nineteenth century. Progress was slow and the first supposedly pure constituent – ergotinine – was not isolated until 1875 by the French pharmacist Charles Tanret, though this proved to be a mixture of alkaloids with little discernible biological activity. It took another 30 years before George Barger and Francis Carr of the Wellcome Research Laboratories in London managed in 1906 to isolate what they believed to be the pure and biologically interesting ergot alkaloid they christened ergotoxine, though this was subsequently shown to be a mixture of active alkaloids, mainly ergocornine. This was followed 12 years later by Arthur Stoll’s isolation of ergotamine (in 1918) at Sandoz in Basel, though it took until 1951 before he and Albert Hofmann established the correct chemical structure. The trio of major alkaloids was completed by perhaps the most medicinally interesting of the ergot alkaloids – ergometrine – isolated by Harold Dudley and John Moir of the National Institute for Medical Research in London in 1935, and independently by Morris Kharasch in Chicago, Marvin Thompson in Maryland and Stoll and Burkhardt at Sandoz. These researchers could not agree on one name, so ergometrine in Europe was called ergonovine in the USA. This was shown to have a pronounced effect on uterine smooth muscle producing increased muscular tone with practical value in the prevention and treatment of postpartum haemorrhage (PPH). Since postpartum haemorrhage is still a major factor responsible for the deaths of as many as 150,000 women each year, especially in developing countries, the introduction of ergometrine for treatment and prevention of PPH in 1935 was a major lifesaver. However, over the last 70 years of use, obstetricians have gradually moved away from ergometrine towards the peptide hormone oxytocin since this also stems PPH but with a more acceptable profile of side-effects for the patient.

Another clinically important alkaloid is ergotamine which was introduced in the mid 1920s by Ernst Rothlin, a colleague of Arthur Stoll, for the therapy of moderate to severe attacks of migraine. Rothlin took the bold decision to inject the alkaloid subcutaneously into two patients with severe migraine who had not responded to any treatment, and fortunately achieved immediate success. A proper clinical evaluation was then undertaken by H. W. Maier at the Burgholzli Hospital in Zurich and he was able to confirm the efficacy of ergotamine. The alkaloid appears to act by vasoconstriction (narrowing) of blood vessels associated with the carotid artery where vasodilation has been produced by over-production of the neurotransmitter serotonin (5-hydroxtryptamine or 5-HT). However, unlike ergometrine which exerts its effects mainly at 5-HT receptors, ergotamine is a non-selective drug and interacts with various neurotransmitter receptors including those for noradrenaline and dopamine. Not surprisingly, prolonged administration of the drug (the maximum recommended dose is 6 mg/day) can give rise to the classic symptoms of ergotism including severe peripheral vasoconstriction leading to gangrene.

All of this interest in the clinical utility of ergot alkaloids necessitated exploitation of various sources of the compounds. Sandoz introduced ergotamine tartrate in 1921, where the ergotamine was isolated directly from the fungus. More recently, a number of other pharmaceutical companies including Novartis (which took over Sandoz), Boehringer Ingelheim, Eli Lilly and Farmitalia all produce ergot alkaloids either by fermentation technology (around 60% of the supply) or from cultivation of triticale, which is a hybrid of wheat and rye. All of these natural products are complex amide derivatives of lysergic acid, and most of this supply of natural ergot alkaloids is converted into lysergic acid through hydrolysis. This parent acid had already been prepared in 1934 by Jacobs and Craig at the Rockefeller Institute in New Yo...

Table of contents

• Cover
• Title Page
• Copyright Page
• Preface
• Contents
• Chapter 1 From Ergotism to LSD
• Chapter 2 Opiates from Opium to Heroin
• Chapter 3 Coca and Cocaine
• Chapter 4 Cannabis: Hashish, Marijuana, Charas and Bhang
• Chapter 5 Belladonna, Mandrake and Daturas
• Chapter 6 Peyote and Amphetamines
• Chapter 7 Fly Agaric
• Chapter 8 Absinthe
• Further Reading
• Glossary
• Subject Index