Mescaline Unlocks the Doors of Perception

One afternoon in the autumn of 1969 I visited Lewis’ medical bookstore on Gower St in London, just a few blocks away from University College. I had been doing so for several years because Lewis’ always displayed copies of the scientific journal Nature for the public to read or purchase. While at the bookstore that afternoon I read what I consider to be the most remarkable scientific paper I have ever encountered (1). The subject of the paper was the hallucinogenic or “psychedelic” drug mescaline. I had just returned from spending the spring and summer working and traveling around the USA prior to attending university to study biochemistry, and I wanted to catch up on the latest scientific news. My travels in the USA had included visiting San Francisco and also attending the famous Woodstock rock festival in upstate New York. Needless to say, I was overflowing with enthusiasm for hippie culture and the associated music and psychedelic drug taking. In fact, I had become interested in psychedelic drugs prior to that time while I was still at high school in the late 1960s. I had read Aldous Huxley’s books “The Doors of Perception” and “Heaven and Hell” and was fascinated by his descriptions of the effects of the drug mescaline. I even tried to make some of it in the school laboratory but didn’t get very far. Surely, I thought, if we could understand how this drug worked it would lead to a better understanding of the phenomenon of human consciousness.

There was a theory circulating at that time that certain people produced an abnormal endogenous psychedelic molecule which elicited the symptoms of schizophrenia. Indeed, many people thought that the effects of hallucinogenic drugs closely resembled schizophrenic behavior. The abnormal molecule could be detected in the urine of schizophrenic patients as a chromatographic pink spot. Theories such as these were known as “Orthomolecular Psychiatry”—the idea that diseases like schizophrenia were caused by abnormal chemical factors, not by social factors like interactions with one’s parents. Hence, if one treated patients with the correct chemical compounds, you could prevent them making their own “psychotogens” and cure the disease. At the time, this seemed to me to be an entirely reasonable idea. One day I read a small advertisement in the Times newspaper saying that a Mrs. Gwynneth Hemmings was going to found a society to investigate Orthomolecular Psychiatry. People who were interested were invited to attend an organizational meeting at a church in Kensington. I decided to go along and became a founding member of the new British Association for Schizophrenia. At the meeting, there was considerable discussion about the pink spot and what it could mean. The chemical structure of the pink spot was supposed to be 3,4 dimethoxyphenylethylamine (DMPEA), which was very close to that of mescaline (3,4,5 -trimethoxyphenylethylamine). Even though synthetic DMPEA wasn’t able to reproduce the psychedelic effects of mescaline, it was thought that it might be derived from another molecule produced by schizophrenics which was hallucinogenic but hadn’t yet been identified. It seemed that understanding the drug mescaline could be a key to understanding diseases like schizophrenia.

File:3,4-Dimethoxyphenethylamine.svg - Wikimedia Commons
DMPEA
Mescaline - Wikipedia
Mescaline

The paper that I read in Lewis’ bookstore that afternoon was authored by Alexander Shulgin and his colleagues, Thornton Sargent and Claudio Naranjo. Although both Shulgin and Sargent were American, Naranjo was from Chile and the experiments had been carried out at the University of Chile in Santiago. What Shulgin and his colleagues had done was this: in order to begin elucidating how mescaline produced its effects, they had synthesized 44 different versions of the mescaline molecule, each one slightly different from the parent drug, and asked how this had changed its hallucinogenic activity. To answer this question they had done what I considered to be a very brave thing, and something that was completely in keeping with the zeitgeist of the time. They had tested each new chemical compound on themselves and, it was rumored, a number of students. Shulgin realized that the type of mental activity that was produced by hallucinogenic drugs like mescaline and LSD was something that was uniquely human. There are presumably effects that occur in animals as well, but they are not in a position to tell us about them. Even humans often struggle to describe the ineffable effects of psychedelics. It should be recalled that when Albert Hofmann discovered LSD in 1938, he tested it on mice and saw no obvious effect. It was only when he accidently ingested some of the drug himself several years later that he discovered its amazing properties. There is no adequate way of assessing the effects of psychedelic drugs except by testing them on humans. Even today, the behavioral assays that many scientists use involving mice to examine the effects of psychedelic drugs are mostly useless and don’t even represent eidolons of the actual experience.

Figure from Shulgin et al. (1) showing the structure of mescaline and the derivatives prepared. The second to last column shows the relative activity of each molecule

Shulgin, of course, had realized this fact and so had traveled to Chile where the constraints on human drug testing were a little more “relaxed.” Shulgin subsequently became the high priest of psychedelic drug research in the 1960s and 1970s. He continued to prepare hundreds of mescaline derivatives at his home laboratory in California and tested them out on himself and his friends, eventually publishing all of his findings in his book “PIHKAL: A Chemical Love Story”—PIHKAL standing for “Phenethylamines I Have Known And Loved.” The book is considered to be one of the bibles of the psychedelic drug literature and describes the chemical synthesis of each drug along with notes as to the effects they produced on Shulgin and his friends. Shulgin discovered many important things about mescaline and also about drugs that were closely related to it from the chemical structural point of view, but which turned out to have different interesting properties. This included the molecule methylenedioxymethamphetamine (MDMA or Ecstasy), a psychotropic drug with a similar structure to mescaline but an entirely different mechanism of action, which produces a different spectrum of psychotropic effects. Shulgin continued along these lines until his death, but others have continued to make new versions of mescaline up until the present day seeking, perhaps, the ultimate psychedelic molecule, one so powerful that it could deconstruct all forms of normal thinking permanently after just one dose. Indeed, in a paper published just last month in the journal Cell (2), a group of scientists has used one of the latest versions of mescaline to probe the ultimate truths of its mechanism of action.

Like many drugs throughout history that have come to us from nature, the roots of mescaline use are extremely ancient; remains of mescaline-containing plants have been found in the Americas going back around 6,000 years. This was prior to the development of writing in Mesopotamia around 3–4,000 years ago, and so we don’t know what the drug was being used for at the time. However, we have every reason to believe, based on its subsequent history, that it was being used for shamanic purposes during religious ceremonies. Mescaline is obtained from certain types of cacti found in central and south America, particularly Lophophora williamsii (peyote cactus) and Echinopsis pachanoi (San Pedro cactus). The traditional method of consuming mescaline is to chew the dried tops of peyote cacti known as peyote buttons, although it is also used by making infusions and decoctions of various types.

The peyote (left) and San Pedro (right) cacti

The use of mescaline was unknown to Europeans until the Spanish conquistadors encountered it in the 15th century when they conquered the Aztec empire in Mexico. Indeed, the Spanish discovered that the indigenous American peoples used a wide variety of psychotropic agents in addition to mescaline. These included hallucinogenic mushrooms (psilocybin), morning glory seeds (lysergic acid amide), ayahuasca (N,N-dimethyltryptamine), tobacco (nicotine) and jimson weed (atropine/scopolamine). Their use was studied by the Spanish monk Bernardino de Sahagun. He learned the local language (Nahuatl) and taught his Aztec students Spanish and Latin and so could communicate with them very accurately and was able to compose a detailed account of their habits and beliefs, including the way they used hallucinogenic drugs in their religious ceremonies. De Sahagun used his findings to compose the Florentine Codex, one of the greatest works in the history of anthropology. He describes the use of mescaline as follows:

“There is another herb like mountain prickly pear,
named peiotl, which is white and can be found in the north.
Those who eat or drink of it see terrifying or absurd visions;
this inebriation lasts two or three days and then subsides.
It is a delicacy often enjoyed by the Chichimeca, for it is
sustaining and spurs them to fight with no thought of fear,
thirst, or hunger, and they say that it protects them from all
danger.”

De Sahagun aside, the conquistadors went out of their way to suppress the religious practices of the American peoples they encountered in a wholesale effort to convert them to Catholicism. As can be imagined, there was a great deal of reluctance to doing this and the use of hallucinogenic drugs was forced underground. Interestingly, Spanish proselytizing eventually resulted in the development of syncretic religions that were ostensibly Christian but maintained a good deal of their original American Indian character and incorporated the use of drugs like mescaline and psilocybin in the celebration of Christian ceremonies. However, very little was heard about these practices for several hundred years. During this time, the use of mescaline by indigenous peoples started to spread northwards and, by the 19th century, it was being used by “Indians” in the Texas/New Mexico/Arizona region. A few reports of its use began to circulate in the American press including, for example, a report that during the United States Civil War, Texas Rangers soaked peyote in water and drank the resulting hallucinogenic liquid.

In 1888 the pioneering psychopharmacologist, Louis Lewin, author of the book Phantastica, visited the United States and received a sample of a peyote cactus which he took home to Germany. He gave it to the Berlin Botanical Museum, who named it Anhalonium lewinii (although as we have seen the modern name is Lophophora williamsii). Lewin obtained a crude extract of the alkaloids contained in the cactus. Naturally, cacti like peyote contain thousands of chemicals including a large number of substances that are related to mescaline biosynthetically but are not psychoactive. Lewin probably succeeded in isolating some of these but not mescaline itself. However, in 1896, mescaline was isolated from peyote by Arthur Heffter, who also reported its psychedelic properties based on some self-experimentation. These reports stimulated a good deal of interest in mescaline and several people experimented with its psychotropic effects resulting in the publication of books such as Der Meskalinrausch—“The Mescaline Rush”—by Kurt Beringer. The pioneering sex psychologist Havelock Ellis extracted several peyote buttons, drank the resulting decoction and wrote a poetic account of his experience describing it as a “saturnalia of the specific senses, and chiefly an orgy of vision.” Mescaline was eventually synthesized by the Austrian pharmacologist Ernst Späth, in 1919, and from that point in time the pure substance was available for experimentation.

Widespread modern interest in the use of psychedelic drugs had to wait until after the Second World War. In particular, it was the publication of The Doors of Perception and the essay Heaven and Hell by Aldous Huxley in 1954/6 that introduced the properties of mescaline to the public at large. Indeed, the modern recognition of the properties of psychedelic drugs was well underway in the 1950s. In addition to Huxley’s books, the American banker and ethnobotanist Gordon Wasson journeyed to Mexico and “discovered” psilocybin use by Mexican Indians during religious ceremonies in out-of-the-way villages where they had secretly been using it since the time of the conquistadors. In 1957, he wrote a widely read essay in Life magazine entitled Seeking the Magic Mushroom. One of the people who read this essay was Timothy Leary, then a young faculty member in the psychology department at Harvard, who decided to go down to Mexico and try psilocybin out for himself. Leary was very impressed and when he returned to Harvard switched his research program to investigating the effects of hallucinogenic drugs. Topping all of this off, of course, was the discovery of the hallucinogenic effects of LSD by Albert Hofmann working at the Sandoz drug company in Basel in 1943.

The hallucinogenic drug revolution was now well on its way. One of major participants in this revolution was actually the CIA, who tested different psychotropic drugs, including mescaline, in their MK-ULTRA “brainwashing” program. They had received information that the Nazis had been testing the drug on concentration camp inmates during the war and even imported the Nazi scientist Kurt Plotner, who had performed the work, to help them out. By the early 1960s, however, it was clear that LSD was by far the most powerful hallucinogen available and it became the drug of choice by members of the counterculture movement of the 1960s. Of course, many people had read about mescaline, particularly from Huxley’s book, but nobody ever used it. When I was in the USA in 1969, I never encountered a single individual who had actually tried mescaline.

Mescaline is not that difficult to make. It is actually much easier to synthesize than LSD. The problem with mescaline is that it isn’t actually a very good psychedelic drug. If you want to trip you might take around 100 μg of LSD, but you would need more than 1,000 times that amount—over 100 mg—of mescaline to get a similar effect. So, when Shulgin performed the study he published in 1969, he quickly realized that it was quite simple to make improvements to the biological activity of the drug. You can already see some of these innovations in his 1969 paper. What happens if instead of mescaline, which is 3,4,5-phenethylamine, you make 3,4,5-amphetamine which is a very closely related structure in which the propylamine side chain has a methyl group added to it? This drug was twice as good as mescaline. Then how about the 3,4,5-methoxy groups—how necessary are they? The 2,4,5-methoxy analogue of amphetamine was even more effective, about 17 times as good as mescaline. Now what happens if you keep the 2,5-methoxy groups and put a methyl group rather than a methoxy in position 4? The resulting molecule named DOM turned out to be a whopping 80 times better than mescaline! If a bromine (Br, DOB) or iodine (I, DOI) atom was placed in the 4 position instead of the methyl group, the resulting compounds were even more potent. This was also true if one went back to the original mescaline-like phenylethylamine structure to yield substances like 2C-B. But that wasn’t the end of the story. What would happen if you traveled down to the other end of the molecule and started playing around by substituting the nitrogen atom? Addition of a benzyl group to 2C-B (25B-NB) produced a further increase in activity, and adding an ortho-methoxy to the benzyl group increased the activity even further. The resulting compound 25B-NBOMe is about 1,000 times more potent than mescaline and is even more potent than LSD, making it one of the most potent psychotropic substances ever made. In addition to their potency, some of these substances such as (S,S)-DMBMPP and 25CN-NBOH are highly selective at interacting with the 5-HT2A receptor, the most important mediator of the hallucinogenic effects of these drugs in the brain.

DMBMPP - Wikipedia
(S,S)-DMBMPP
25CN-NBOH

One has to wonder about such super-potent psychotropic drugs. Medicinal chemists are so sophisticated these days that they can usually achieve these kinds of results with any class of drugs that we originally discovered from nature. In the field of opioid drug research, for example, substances like some of the derivatives of fentanyl are thousands of times more potent than morphine and are extremely deadly as street drugs. Synthetic analogues of the archetypal cannabinoid drug tetrahydrocannabinol (THC) are also much more potent and have resulted in deadly effects as street drugs. In the last few years, hallucinogenic drugs like 25I-NBOMe and 25B-NBOMe have been reported as being used as street drugs under the name N-bombs. Serious overdose problems and some fatalities have been reported. Sophisticated medicinal chemistry together with the Internet is a very effective way of spreading new chemicals throughout society and there is no end of substances that can potentially be made, and perhaps no end to the potency that can be achieved. We can therefore see how mescaline has journeyed from being a religious sacrament thousands of years ago to becoming the blueprint for synthesizing some of the most potent hallucinogenic drugs ever made.

Structure of mescaline and various key molecules prepared from it (3)

Whatever the future holds in store for these substances in recreational drug circles, their extreme potency and selectivity make them ideal tools for basic scientists investigating the mechanism of action of psychedelic drugs. As we have discussed, psychedelic drugs like LSD and mescaline interact with 5-HT2A receptors in the brain. These receptors are mostly expressed in the cerebral cortex, which makes them well placed for regulating phenomena connected with the higher cognitive functions of the brain. But how exactly does a drug like LSD activate a 5-HT2A receptor? Answering this question is clearly of considerable importance if you want to really understand how the drug works. To do this, it is important to study the chemical structure of the 5-HT2A receptor in its active conformation, that is when it is being activated by an agonist drug such as LSD. In their recent paper in the journal Cell, Kim et al. (2) achieved this aim. The authors decided to use two methods for conducting their studies, X-ray crystallography and a technique that is being used increasingly for structural studies of this type: “single particle cryo-electron microscopy (cryo-EM).” The results of these studies produced molecular structures at “near atomic resolution” and represent the most sophisticated structural picture of hallucinogenic drugs activating 5-HT2A receptors available to date. Not only are the results very interesting if you are a molecular pharmacologist, but they can also be appreciated by professionals and amateurs alike because of their aesthetic appeal, the figures and structures being presented in distinctly trippy hues of pink and purple. It should be noted that the drug chosen to activate the 5-HT2A receptor for the cryo-EM study was the highly selective and potent mescaline derivative 25CN-NBOH. The story of mescaline has followed an arc of discovery lasting many thousands of years. The drug has helped human beings discover themselves and scientists to discover the secrets of the brain. And so to the future when mescaline will surely continue to help us unlock the doors of perception.

References

1) Structure–activity relationships of one-ring psychotomimetics

Shulgin AT, Sargent T, Naranjo C. Nature. 1969 Feb 8;221(5180):537-41. doi:10.1038/221537a0. PMID: 5789297

2) Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor

Kim K, Che T, Panova O, DiBerto JF, Lyu J, Krumm BE, Wacker D, Robertson MJ, Seven AB, Nichols DE, Shoichet BK, Skiniotis G, Roth BL. Cell. 2020 Sep 17;182(6):1574-1588.e19. doi: 10.1016/j.cell.2020.08.024. PMID: 32946782

3) DARK Classics in Chemical Neuroscience: NBOMes

Poulie CBM, Jensen AA, Halberstadt AL, Kristensen JL. ACS Chem Neurosci. 2019 Nov 12. doi: 10.1021/acschemneuro.9b00528. Online ahead of print. PMID: 31657895

Herbs for Hamnet

Like many people, I have had ample opportunity to read a large number of books during the pandemic, both fiction and non-fiction. I was given a copy of Maggie O ‘Farrell’s book “Hamnet: A Novel of the Plague” and the title certainly caught my attention. Along with The Decameron and Camus’ The Plague, both of which I reread, the title of the novel clearly states its relevance to our current situation. It turned out to be a very interesting book. The story is about a playwright who lives in Stratford-upon-Avon at the end of the 16th century, but who is never named (I wonder who that might be?) and concerns the fate of his son Hamnet. Apparently, the names Hamnet and Hamlet were considered equivalent at the time. One of the things the book achieves very effectively is a vivid description of what it was like to live in an English town during the Elizabethan period. Something that I found particularly interesting was that Hamnet’s mother (whose name is Agnes in the book) is a healer (as opposed to a doctor) and is constantly using different types of medicinal herbs which she grows and prepares herself. Agnes makes a living by dispensing her remedies to the citizens of Stratford when they are ill and come to consult her. It is very interesting to see what kinds of things she used and how these were part of the practice of medicine at the time.

The action of the book takes place around the year 1583. At that time, one of the worst fates that might befall you was being treated by a medical professional, what we would call a doctor today. Such a thing would usually ensure your hasty demise because very little was actually known about medicine from our current perspective. Most of the things doctors did to you made no scientific sense whatsoever and were liable to make your illness worse. The major reason for this was that the general theory of disease in Tudor times was completely incorrect. Medicine in the 16th century was based on the work of the great Greek/Roman doctor Aelius Galen who lived in the third century CE and was certainly, along with Aristotle and Hippocrates, one of the most influential figures in the history of medicine. Galen was responsible for the development of experimental medicine in antiquity and he discovered many interesting facts about the nervous and cardiovascular systems. Unfortunately, he interpreted all of his results according to the humoral theory of disease, something that he appropriated from Aristotle. This theory postulated that the effective functioning of the human body depended on the actions of four humors—blood, phlegm, yellow bile and black bile—which were obtained from eating food and breathing air. These humors also had other properties. Blood was hot and wet, phlegm was cold and wet, yellow bile was hot and dry and black bile was cold and dry. Good health depended on these humors being “in balance.” Galen developed the concept of plethora, or an overabundance of a particular humor as the cause of a disease. As manifestations of disease, the presence of blood and phlegm were obvious. Yellow bile was found in the gall bladder and was observed when the patient became jaundiced. The effects of black bile were apparent in conditions where the skin became black. The recommended treatment for any disease was to redress the balance between the humors through purging, starving, vomiting or bloodletting. Bloodletting was a very common treatment during the Tudor period. It is said that the barber’s red and white pole commemorates this fact—the red stripe representing bloodletting, and the white stripe the tourniquet to stem the bleeding. Cupping was also used to remove excess bodily humors. A small glass was heated and applied to the skin. The vacuum created by the glass cooling was supposed to suck harmful substances out of the body. Purging was used for problems of the stomach and alimentary canal. Emetics or laxatives were administered for cleansing the body of an overabundant humor. Based on ideas like these, if somebody had a fever, for example, the explanation was that the patient was suffering from an overabundance of hot blood and so the treatment was bloodletting using leeches or a similar method. Galen wrote a great deal and his work was widely respected. Following the fall of Rome in 476 CE, his ideas spread from Western Europe to the great Arab empires that stretched from Baghdad to Spain and became an entrenched medical doctrine throughout Europe and the near East for at least the next 1200 years. Very little changed over that vast period of time.

In addition to the treatments administered by doctors, there was also a tradition of folk medicine— natural cures derived from plants—and, whereas the treatments performed by doctors seldom worked, many valuable naturally occurring drugs had been discovered over thousands of years of informal human experimentation. These included things like opium (morphine) for pain, willow bark (salicylic acid) for pains and fevers, and foxglove (digoxin) for dropsy (edema—a primary symptom of heart failure). The effects of these plant extracts were interpreted through the concepts of humoral medicine as being the result of a redistribution of humors and, even though this was not the reason for their effects, they certainly could be very helpful in practice. In general, medicines like these were administered by healers such as Hamnet’s mother Agnes. Indeed, as illustrated in the book, healers and doctors were often in competition with one another for the same patient population. When Hamnet’s sister Judith comes down with bubonic plague, she is visited by a “plague doctor” in his traditional regalia.

Plague doctor in his traditional costume with mask

In order to cure Judith of the plague, the doctor gives Agnes a package to tie to her daughter’s abdomen. The package contains a dried toad. As the doctor explains to Agnes, “you must trust that I know more about these matters than you do. A dried toad, applied to the abdomen for several days, has proven to have great efficacy in cases such as these.” Agnes declines his offer. It is hard to know why ineffective remedies such as these persisted over so many centuries but, of course, there were always patients who improved spontaneously, and doctors could point to them as being genuine successes.

As it turns out, around the time that the novel takes place, the science of therapeutics was undergoing a great change. This was due to the influence of alchemy, whose general aims of turning base metals into gold or discovering the philosopher’s stone—a source of immortality—were based on the science of chemistry. The high priest of this approach at the time was one Philippus Theophrastus Aureolus Bombastus von Hohenheim, usually known as Paracelsus. Paracelsus was brought up in a southern region of Austria known as Carinthia, which was a center of the burgeoning mining industry where new chemical elements were being discovered. Paracelsus was an iconoclast and completely disagreed with Galen and the way he practiced medicine. For example, he replaced Galen’s set of four humors with three humors of his own: salt (representing stability), sulfur (representing combustibility), and mercury (representing liquidity). More importantly, the way Paracelsus went about treating disease was completely different. Rather than attempting to rebalance the humoral state of the body, he suggested using particular chemical agents, often highly purified through the use of distillation and related chemical techniques, for treating specific diseases which, he hypothesized, might be the result of problems with individual organs rather than due to humoral imbalance of the entire body. Paracelsus recognized that the drugs he used, which were typically metals or extracts prepared from plants and other natural sources, would have different effects according to the dose employed, saying “All things are poison and nothing is without poison; only the dose makes a thing not a poison,” which is, of course, a classic tenet of the science of pharmacology. Something like mercury could be extremely toxic at one dose but might have selective benefits at a lower dose. The introduction of the use of chemistry to prepare drugs, the idea that dosage was important and the concept that drugs should target particular organs, all presaged a much more modern approach to therapy, one which was completely different from the Galenist theories employed by the Plague Doctor. Agnes’ methods were much more in line with the coming chemical approach to medicine, even though neither she, nor Paracelsus, had any real idea as to the mechanisms underlying a drug’s beneficial effects. Paracelsus’ insights had probably not reached Stratford in 1583, but they would soon. In the meantime, Agnes’ ideas concerning the beneficial effects of her preparations were based on Galenic interpretations.

For example, at the start of the book Agnes’ daughter becomes seriously ill. As soon as Agnes becomes aware of the physical symptoms of her daughter’s disease, she rushes downstairs to prepare a remedy. She begins with rue and cinnamon which are “good for drawing out the heat,” to which she adds bindweed root and thyme. Then she adds rhubarb “to purge the stomach and drive out the pestilence.” Her thinking relies on drawing out and purging excess humors. Nevertheless, she is attempting to achieve these aims by using plants that do, in truth, contain active chemical ingredients. No dried toads or magic incantations. Unfortunately, Agnes is really up against it because her daughter’s infection with the bacterium Yersinia pestis (bubonic plague) is not easily treated except with an antibiotic.

Harvesting Rue (Ruta graveolens)

We all know about cinnamon, thyme and rhubarb. But how about rue and bindweed root? Rue has a particular resonance in this story because it also features in Shakespeare’s Hamlet when the mad Ophelia declares, “There’s rue for you; and here’s some for me; we may call it herb of grace o’ Sundays. You must wear your rue with a difference.” Rue refers to Ruta graveolens,which was often used as an ornamental plant owing to the color of its blue/green leaves. Rue has a bitter taste and, in former times, was used a symbol of regret and repentance. It was often used to signify these sentiments in phrases such as “rue the day.” Ophelia also refers to the plant as a “herb of grace on Sundays.” This was because when entering a church on a Sunday, the wearer dipped the rue in Holy Water—which always stood within the portals—and blessed himself with it, hoping to obtain God’s grace or mercy. Rue not only symbolized bitterness but was a major cause of abortion in its day, which is why it was also associated with adultery. Ophelia keeps a rue flower for herself but also gives one to Gertrude and says that she “must wear her rue with a difference.” Clearly Gertrude’s rue symbolizes something different than Ophelia’s. One might conclude that Ophelia was filled with bitterness due to the awful things Hamlet said to her as well as her father’s death, and that Gertrude’s rue represented adultery.

The chemical constituents of rue have been widely studied. Of course, like any plant it contains thousands of natural products that have interesting chemical structures and which might have effects on humans. When Agnes gives somebody an extract of rue as a remedy, this will contain a huge number of different chemicals mixed together, and trying to elucidate which one is responsible for any observed effect would be a very difficult problem, even today using the most up-to-date analytical techniques. Rue has a particularly high alkaloid content, which presumably accounts for its bitter taste—alkaloids like strychnine, morphine and nicotine are always bitter. It is also the source of the chemical rutin, which was named after the plant and has been investigated for its therapeutic potential. A recent review considered some 50 possible uses for this compound! However, at this point in time, none of these applications are well established according to the strictest modern criteria. Nevertheless, Agnes would have had a great deal of experience using rue, and this is a key consideration, because she certainly would be aware of its effectiveness in the context of her practice.

Rachel Ruysch, Flower Still Life, c. 1726 (Toledo Museum of Art)
Note the blue and white Morning Glories

The word bindweed in 16th century England probably refers to the plant Convolvulus arvensis, often known as the “field bindweed,” or possibly Castylegia sepium, the “hedge bindweed.” Another common name for these plants and others in the same family is “Morning Glory.” These plants are characterized by their trumpet-shaped flowers which are normally white or pink but can be other colors such as blue or violet. Morning Glories are usually considered invasive weeds but are sometimes cultivated for show. One particularly interesting thing to note about these plants is that some varieties contain the compound ergine or lysergic acid amide (LSA). This is very close in structure to lysergic acid diethylamide (LSD), which is an extremely powerful hallucinogenic drug. Indeed, chewing Morning Glory seeds was often used by indigenous peoples in South America in pre-Columbian times as a way of inducing a transcendental state of mind. However, LSA is very weakly hallucinogenic compared to LSD and, moreover, the seeds usually contain the highest concentration of the drug. So, whether the bindweed root extract used by Agnes had any hallucinogenic effect is unclear. The plants are also reported to contain tropane alkaloids which are often biologically active—both atropine and cocaine are tropane derivatives. Consumption of crude bindweed root extracts are reported to produce vomiting and have laxative effects, which would be consistent with a desire to use them for purging. The powdered roots of rhubarb, which Agnes also added to the remedy, were also widely used at the time as a laxative purgative. One can therefore see that the combination of plants used by Agnes to treat her daughter would contain a wide variety of bioactive molecules and would likely produce a rather strong purging reaction by eliciting vomiting and diarrhea, as well as possibly producing some mild psychotropic effects. Regrettably, none of these things would really be of much use when trying to treat bubonic plague.

In another example, Agnes attempts to self-medicate when suffering from cramps prior to the delivery of her twins, Judith and Hamnet. She uses a combination of honey, valerian and chickweed which she reports don’t help very much. Honey was frequently added to cover up the unpleasantly bitter taste of many of plant extracts. Valerian root (V. officinalis) has been used since antiquity for the treatment of anxiety, tension and insomnia, and there is some contemporary evidence that it might actually do just that. Extracts of these plants known as “valerian” have a long history of medicinal use dating back to the era of the Greek physicians Hippocrates (circa 460-377 BCE), Dioscorides (1st century CE) and Galen (circa 130-200 CE), who all prescribed it for insomnia among other complaints, and it was still being used for this purpose in Tudor times. It is possible that the hypnotic actions of valerian may be produced in a similar fashion to those associated with benzodiazepine drugs like Valium. The targets for these drugs are the receptors for the neurotransmitter GABA, which has an inhibitory effect on nerve cells in the brain. Benzodiazepines enhance the effects of GABA on its receptors and so inhibit nerve activity. A recent study demonstrated that some of the chemicals that are found in Valerian, such as isovaleric acid (3-methyl-butanoic acid), can inhibit the enzyme GABA-transaminase which normally metabolizes GABA in the brain. Such an action would cause synaptic levels of GABA to rise and might therefore produce a hypnotic effect.

Chickweed (Stellaria media) is a common plant with small white star-shaped flowers employed as ground cover in many parts of the world. It is widely used as a salad ingredient and in folk medicine. Again, as with many herbal remedies, a large number of uses for the plant have been suggested over the centuries, including treatment of gastrointestinal disorders, asthma, diarrhea, measles and jaundice as well as renal, digestive, reproductive and respiratory tract inflammation. Moreover, as with valerian, anxiolytic activity has been reported when extracts of the plant are given to mice. Overall, the use of a mixture of valerian and chickweed might be expected to have some kind of calming effect on Agnes, although it is unlikely to abolish severe cramps associated with delivering a baby ( it turns out she is having twins!).

William Peake, attrib. c 1600.
Portrait of a girl holding rosehips.
Rockingham castle, Leicestershire

Not all the plants mentioned in Hamnet are for treating illness. In another episode, Agnes’ daughters ask her about making their yearly expedition to collect rose hips. The family traditionally made syrup out of rose hips for treating coughs and colds. This particular year, however, following the death of her son, Agnes finds the bright red color of the rose hips difficult to appreciate as they clash with her somber mood and, moreover, the whole business of picking them, preparing them and cooking them seems like something that is beyond her strength to deal with at the time. The harvesting and utilization of rose hips must normally have been very pleasant for the family. Rose hips are the accessory fruits that grow on rose plants after the flowers have fallen off. They are the pods that contain the seeds for propagating new roses. But, if you are growing the plants for their flowers, they are traditionally cut off, because roses produce better flowers that way. Seed pods like these form on many flowering plants and sometimes have interesting properties. Consider the seed pods that form on poppies after their flowers have fallen off, which are the source of the drug opium. Agnes and her daughter were going to search the hedgerows for rose hips that grew on wild roses. Rose hips are very popular, even today, for making syrups, jams and medicines. Just like all the other plants mentioned, rose hips contain many interesting chemicals that might produce useful medicinal effects but these are still under investigation using rigorous modern scientific approaches. One thing that is quite clear, however, is that rose hips are particularly rich in vitamin C, something that is certainly good for treating colds. So, rose hips are a “win-win” crop—delicious and good for you! I remember as a young boy at school going through the ritual of receiving a spoonful of rose hip syrup every day from the matron—something I certainly looked forward to.

There are numerous other medicinal herbs mentioned in Hamnet. Here are a few others with interesting old fashioned names that might be new to you.

Comfrey (Symphytum officianale) (top left and right) and Borage (bottom): Egerton manuscript

Comfrey: (Symphytum officianale). Comfrey has been used for centuries as a traditional medicinal plant for the treatment of painful muscle and joint complaints. Indeed, the name Symphytum comes from the Greek symphis, meaning growing together of bones, and phyton, a plant. Comfrey is a perennial shrub that is native to Europe and some parts of Asia. It has a thick, hairy stem, and grows two to five feet tall. Its flowers are dull purple, blue or whitish, and densely arranged in clusters. Comfrey roots and leaves contain allantoin, a substance that helps new skin cells grow. Comfrey ointments have been used to heal bruises as well as pulled muscles and ligaments, fractures, sprains, strains, and osteoarthritis. The therapeutic properties of comfrey also include its anti-inflammatory and analgesic effects. Although it is not known exactly which chemical components of comfrey are responsible for these effects, it does contain rosmarinic acid which has been shown to possess anti-inflammatory activity in several test systems.

Hyssop (Hyssopus officinalis): Egerton manuscript

Hyssop: (Hyssopus officinalis). Hyssop is a small perennial plant which grows about two feet tall with slim woody quadrangular stems. The narrow elliptical leaves bear spikes of little flowers—usually violet-blue, pink, red, or white. Hyssop comes from the mint family and has been grown since ancient times for its aromatic properties. The plant has a sweet scent and a warm bitter taste and has long been used as flavoring for foods and liquors, which may be the reason why Agnes was growing it in her garden. It has also been used as a medicinal herb as it contains high concentrations of phenol, which give it antiseptic properties. Interestingly, it also contains high concentrations of thujone, which is an antagonist of GABA receptors. As mentioned above, activation of GABA receptors has a calming effect and so substances like thujone ,which do the opposite, have strong excitant effects. Indeed, taking too much purified hyssop extract (essential oil) can actually produce seizures.

Feverfew (Tanacetum parthenium): Egerton manuscript

Feverfew: (Tanacetum parthenium). Feverfew looks a lot like a daisy and is in the same family of plants (Asteraceae). The name feverfew comes from the Latin febrifugia, meaning a reducer of fevers—again illustrating its ancient use in folk medicine. Indeed, it was documented in the first century CE as an anti-inflammatory drug by the Greek herbalist physician Dioscorides. More recently, it has been evaluated for migraine prophylaxis and it has been shown to produce beneficial effects. Although the exact mechanism of feverfew’s action is unknown, it is believed that a sesquiterpene lactone called parthenolide is the active ingredient and works by inhibition of several potential inflammatory mediators of migraine including cyclooxygenase-2, tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1).

Wormwood (Artemesia absinthium): Egerton manuscript

Wormwort: This one is a bit of a mystery. Plants of the genus Artemesia are sometimes called wormwood or sometimes mugwort or sagewort—but “wormwort” appears to be a combination of the two names and so it is difficult to know exactly what is meant here. Most likely it is Artemisia absinthium (common wormwood), a plant with silver feathery foliage and yellow flowers that appear in early summer. Plants of this genus are famously bitter and some of this flavor is imparted to absinthe, the liquor made from A. absinthium, which may be the reason why Agnes was growing it. Shakespeare referred to wormwood in Romeo and Juliet: Act 1, Scene 3, Juliet’s childhood nurse declaring, “For I had then laid wormwood to my dug,” meaning that the nurse had weaned Juliet, then aged three, by using the bitter taste of wormwood applied to her nipple. A. absinthium also contains thujone and so might have potent excitatory effects if used inappropriately. It is interesting to note that plants from the Artemisia family contain many potent substances, some of which have been extremely useful. The prime example of this was the discovery of the widely used anti-malarial drug artemisinin from the Sweet Wormwood plant A. annua by the Chinese scientist Tu Youyou, something for which she was awarded the Nobel Prize in medicine, the first Chinese woman to receive the award. This discovery shows us that the herbs used by Agnes are still likely to reveal new treasures even after all these years. Many of the herbs Agnes used really do produce interesting effects and, in many instances, we still don’t quite know why.