Beautiful Ladies

There are two subjects that most people probably know very little about: Mennonites and the country of Bolivia. Nevertheless, as discussed in a recent BBC report, over the last 10 years Mennonites living in Bolivia have been involved in an extremely serious scandal in which the use of  psychotropic drugs played an essential part. These bizarre events took place in the small Mennonite village of Manitoba (population approximately 1,800) buried deep in the South Western Bolivian countryside.

First some background. What are Mennonites and how did they end up living in Bolivia? Mennonites are a religious group of what are known as “anabaptists”, Hutterites and Amish are other examples. Anabaptists are individuals who believe that baptism is only appropriate when carried out by adults who understand how it affects their relationship with Jesus Christ. These groups arose in Germany during the early 16th century as the Protestant Reformation was developing and evolving its different modes of expression. Anabaptists were always considered to be a radical element of the Reformation and they were frequently persecuted for their beliefs. In order to be able to practice their religion freely, many anabaptist groups were forced to leave their original homeland and migrate to other parts of the world in search of religious tolerance.

The Mennonites were founded by a priest named Menno Simons around 1520. Simons not only encouraged adult baptism but also pacifism and living as simple a life as possible. Because of religious persecution in Western Europe, the Mennonites migrated from Northern Germany to  Russia where land was plentiful and they could live an undisturbed existence. Around 1870 however, persecution of different minority religious groups became widespread in Russia and so the Mennonites moved on to Canada, another  country with abundant natural resources which welcomed pioneering settlers. Following their move to Canada, different factions began to arise within the Mennonite community. Some became assimilated into Canadian society adopting a contemporary lifestyle whereas others, known as the “Old Colonists”, decided to cling to their traditional way of life. As their forefathers had done, the “Old Colonists” felt a need to move on and left Canada in the 1920s, traveling to South America. Original areas of Mennonite settlement in South America included Paraguay and Mexico, but ultimately many also moved to Bolivia and Belize, two countries that were relatively “out of the way” with plenty of space where they could live in peace. At the present time there are over 50,000 Mennonites living in Bolivia scattered over more than 50 settlements. The Mennonite settlement of Manitoba was founded in 1993. The residents of Manitoba live a radically simple life, far removed from typical 21st century existence. There are no cars, cell phones or other modern forms of technology. “Entertainments” like music and shows are discouraged. Although they live in the middle of South America, the residents of Manitoba do not speak Spanish. They speak Plattdeutsch, a low German dialect related to Dutch and Friesian (think Thomas Mann’s Buddenbrooks). Mennonites work very hard on their farms and have become important elements of the Bolivian farming community, particularly in the area of dairy produce.

Horse-drawn transport in contemporary Manitoba

Because of their highly traditional lifestyle, men and women have strictly defined social roles. Women wear conservative clothes and are basically “homemakers”. Relationships between men and women are highly regulated. Over the years there has been very little crime in Mennonite communities and, as far as the Bolivian government was concerned, Mennonites were about as law-abiding as people could be. The government basically left them alone to look after themselves—which was exactly what they wanted.

But then something strange happened. Around June 2009, reports began to circulate in Manitoba concerning nighttime attacks on young women. These incidents were all similar. Girls in their early teens would wake up with pounding headaches. They would find their bedclothes soiled with blood and semen and they would feel sore between their legs. In other words, they had been raped but appeared to have no memory of the events or who the perpetrators might be. Other members of their families would also wake up feeling hung over and nobody seemed to know how the events of the previous night had transpired. The frequency of the attacks began to increase to epidemic levels totaling over a hundred victims. Don’t forget that because the Mennonites do not use electricity, there is no street lighting and at night it is really pitch black, making it difficult to see anybody moving around outside. Moreover, because of their conservative attitudes towards sex, attacks like these also produced profound feelings of shame in the victims and were generally not discussed outside the families where they had occurred. Eventually, a man was apprehended one night sneaking into a house and, upon questioning, gave details of several accomplices from the village who had also been involved in these nighttime rapes. The men were reported to the Bolivian authorities. People began to discuss the events more broadly. It turned out that some of the girls had hazy memories of waking up during the night and having the impression of a man lying on top of them before falling back into a deep sleep. A trial ensued and, after a great deal of persuasion, some of the victims testified in court. Eight men were sentenced and sent to jail. Nevertheless, some 10 years later the echoes of these events continue to reverberate in the Bolivian Mennonite community.

But how exactly had the perpetrators of these crimes managed to sexually assault a large number of women without them really being conscious of what was going on and, moreover, why were the other members of the household also oblivious to these events? The answer is that prior to entering the victims’ homes, the criminals used a spray to aerosolize a drug into each house through open windows. The drug employed had the effect of narcotizing their victims, producing a state resembling deep anesthesia together with amnesia the following morning. As things turned out, the drug was one that was already used by some people in the local area to anesthetize cattle prior to surgical procedures. The drug had been adapted for use as a spray. What was the drug? According to several reports it was “isolated from a local plant”. According to one report it was “belladonna”.

Does this make any sense? Quite possibly, although the precise details are unclear. The drug referred to as belladonna is commonly known as atropine. Atropine and a related drug known as scopolamine can produce a huge number effects and can be employed for many different purposes. At higher doses both drugs are deadly poisonous. Indeed, the traditional source of atropine, the plant Atropa belladonna, is commonly known as the “Deadly Nightshade”. Atropine and scopolamine can actually be obtained from a large number of plants which grow in many parts of the world. These plants are all members of the Solanaceae or Nightshade family (which also includes tobacco, bell peppers, eggplants, tomatoes and potatoes) including the genera Atropa, Brugmansia, Datura, Duboisia, Hyoscyamus and Scopolia, as well as Mandragora, the Mandrake plant which was discussed in a previous blog post. Many species from these genera contain the same active drugs. It isn’t clear that in Bolivia it would actually be Atropa belladonna that was the plant source in this case but more likely a member of the Datura or Brugmansia genus, all of which grow abundantly in parts of Bolivia. Nevertheless, whatever the source, the drug purified from the plant and its effects would be more or less the same. Indeed, as we shall discuss, these drugs have been used for many purposes for thousands of  years. One famous historical figure, the Jesuit monk Bernardino de Sahagun, who became part of the Spanish administration of Mexico in the 17th century and wrote widely about the habits of the indigenous population, called attention to Datura in the following words: “It is administered in potions in order to cause harm to those who are objects of hatred. Those who eat it have visions of fearful things. Magicians or those who wish to harm someone administer it in food or drink. This herb is medicinal and its seed is used as a remedy for gout, ground up and applied to the part affected.”

Brugmansia arborea, native to Bolivia

The chemical substances responsible for the effects of these plants are known as tropane alkaloids. Atropine in a mixture of the two stereoisomers of the molecule hyoscyamine, and scopolamine is the molecule hyoscine. As you can see, they only differ in structure by one oxygen atom and their pharmacological properties are very similar. However, it is worth pointing out that not all tropane alkaloids derived from South American plants have similar properties. Indeed, the drug cocaine, which is derived from the plants of the Erythroxylaceae family, has a similar chemical structure but completely different pharmacological properties, being a powerful psychostimulant.




It is interesting to note that the use of drugs like scopolamine to produce a profound state of anesthesia, amnesia and compliance to the wishes of another individual is not unique to the Mennonite community in Bolivia. According to other reports, the same drug is all the rage  in different parts of South America being used for  similar purposes. For example, a recent somewhat over-the-top report from the online news service Vice illustrates the situation in Bogota, Columbia, where it seems scopolamine is widely used by criminal gangs (see video below). In these cases, the gangs slip some of the drug into the drink of an unwitting individual and then when the victim becomes intoxicated they can be made to empty their ATM or give away all their worldly goods. If the victim is a woman they may also be raped. When subsequently asked what happened to them, the victim seems to have completely forgotten. It seems that people in Bogota are widely aware of the effects of scopolamine and, according to the report on Vice, it is generally regarded as the “most dangerous substance known to man”.

Like most drugs that produce profound psychotropic effects, the effects of atropine and scopolamine are produced by interacting with neurotransmitter systems in the brain—neurotransmitters being the chemical messengers that carry information from one nerve cell to another or from a nerve cell to a target tissue. In this case, the neurotransmitter involved is acetylcholine, the very first neurotransmitter ever to be discovered. Acetylcholine produces its effects by acting on two different types of receptors known as nicotinic and muscarinic receptors. Both types of receptors are widely distributed in the peripheral nervous system and also in the brain. In this instance, it is the muscarinic receptors that are the targets of interest. Both atropine and scopolamine are potent blockers of muscarinic receptors and as both drugs can enter the brain, they have effects on both the central and peripheral nervous systems. In the peripheral nervous system, the muscarinic effects of acetylcholine mostly involve actions on smooth muscle contraction and glandular secretions. At appropriate doses, atropine and scopolamine (or nowadays, their semisynthetic derivatives) are extremely widely used in medicine. The drugs can produce effects such as the relaxation of muscles, effects that can be extremely useful. For example, they are used therapeutically in treating asthma where muscarinic blockers produce relaxation of the lungs. Their antispasmodic actions are useful in the treatment of bladder spasms, irritable bowel disease, peptic ulcer, colic, cystitis and pancreatitis. The drugs are also widely used for producing dilation of the pupils prior to an eye examination. In ancient times women would use atropine to dilate their pupils, which was thought to make them look more attractive, and this is the reason why atropine got its original common name of belladonna (beautiful lady). It seems that Cleopatra was a fan. At more elevated doses, however, effects on the central nervous system begin to show up. Indeed, even today student doctors all learn that the salient features of atropine use are “Hot as a hare: increased body temperature, Blind as a bat: mydriasis (dilated pupils), Dry as a bone: dry mouth, dry eyes, decreased sweat, Red as a beet: flushed face and Mad as a hatter: delirium”.

The deliriant effects of atropine and scopolamine have been well known for thousands of years, leading to their use in witchcraft and magic. It has been widely reported that when under the influence of these drugs one has the impression that one is flying, and that they were key ingredients in witches’ flying ointments. The ability of the drugs to put a patient into a stuporous state have also been widely described throughout history. It is said that the sponge offered to Jesus on the cross contained these drugs. Also, ancient physicians would employ a “soporific” sponge in which hot water and extracts of plants containing drugs like scopolamine would be held under the noses of patients who were undergoing surgery.

It is therefore not surprising that their use for this purpose was “rediscovered” in the early part of the 20th century. In 1903 Dr. Carl J. Gauss, a doctor in Freiburg Germany, devised a procedure which he named “Dammerschlaff” which is usually translated as “Twilight Sleep”. This involved giving a pregnant women a mixture of morphine and scopolamine prior to delivery. Under these circumstances the woman would be more or less unconscious while giving birth, would feel little discomfort and would remember almost nothing about the entire experience. The idea became something of a craze. Women in the USA, for example, demanded the treatment and a society named the National Twilight Sleep Association was founded in order to put pressure on physicians to provide it. Generally speaking, physicians were obliging and the procedure became widely used in the first two decades of the 20th century. It turned out that although women didn’t remember their experiences during twilight sleep, quite a lot was going on. The deliriant effects of scopolamine were frequently apparent with women flailing around and vocalizing while delivering. They were placed in special ‘birthing cots’ with their wrists and ankles strapped to the sides so that they wouldn’t harm themselves while they tossed and turned, sometimes in their own vomit, until their baby had been safely delivered with forceps. Another issue with the twilight sleep procedure was that the drugs would  frequently cross the placenta and depress the behavior of the newborn. This resulted in the practice that the doctor would give babies a brief slap on the bottom as soon as they were delivered to make sure they were breathing. The unfortunate side effects of twilight sleep were the subject of a celebrated article in the Ladies Home Journal in May 1958, in which many patients and nurses spoke out about their experiences. As a result, the use of the procedure gradually declined and the pendulum began to swing in the opposite direction as natural birth procedures came into vogue. 

Of course, the ability of drugs like atropine and scopolamine to produce a state of delirium and amnesia was something that came to the attention of the CIA in the 1950s. Drugs like these, or others including psychedelics such as LSD that could produce altered states of consciousness, were intensively investigated as possible weapons in the Cold War. These aims were generally pursued as part of the CIA’s MK-ULTRA program which was concerned with potential chemical brainwashing and subversion a la Manchurian Candidate. Of course, the CIA didn’t stop with scopolamine and atropine. Much better weapons were soon available. After the war, the Hoffman La Roche company in Basel had a program to make better spasmolytic agents based on the tropane alkaloid structure. One of the molecules they came up with in 1951 was 3-quinuclidinyl benzilate (QNB), a semisynthetic tropane alkaloid which, as you can see, does look a lot like atropine.

3-quinuclidinyl benzilate

The drug company tested it as a treatment for ulcers. It turned out that however good it was for ulcers, it was certainly better at making people delirious. What was more, the drug was fantastically potent. You only need microgram amounts to precipitate hallucinations. Soon the drug was in the hands of the CIA where it was renamed BZ or “Buzz”. From the mechanistic point of view, Buzz proved to be a really potent antagonist of muscarinic receptors, much more potent than atropine or scopolamine. Moreover, Buzz gets into the brain very  easily. Once it is in there it hangs around for a long time producing extended effects. Dr. James Ketchum, one of the people who did secret work on the drug for the army and CIA at the Edgewood Arsenal in the early 1960s, wrote about Buzz,

“Not only did it work, but its effects lasted a long time. At just above half a milligram volunteers consistently became stupefied. After 4-6 hours, they were usually ‘out like a light’. By 12 hours they were moving around again, but were totally disoriented and unable to do much of anything. Forty eight hours later, they were usually approaching normal on their performance tasks. A day or two after that they had completely recovered….it took almost three years and an estimated 100,000 hours of professional effort by physicians, nurses, technicians and volunteers to learn all the things we wanted to know about Buzz”.

And just what were those things? What could the CIA want to know about what was one of the most powerful deliriants ever invented? It was the 1950s and anti-communist paranoia was very much in the air. The CIA played around with a lot of sci-fi ideas as to how Buzz aerosols might incapacitate entire populations or groups of soldiers on the battlefield. As far as we know, this never actually came to anything. However, the subject has recently resurfaced with reports that terror groups like ISIS have now got their hands on materials like Buzz and are actively employing them on the battlefield. And it wasn’t only the CIA who recognized that the delirium induced by drugs like Buzz might be used for mind-control purposes. It is quite clear that drugs of this type have been used by several cult-like groups in efforts to control the minds of their adepts. One notable  example was their use by Charles Manson, perpetrator  of the Tate/La Bianca murders, to maintain psychological domination over the members of his “family”.

So, although the CIA never used tropane alkaloids to incapacitate the armies of their enemies, it seems as though some members of the Mennonite community of Manitoba came up with the similar idea for equally nefarious purposes. As with so many ancient drugs, each generation rediscovers them and uses them for its own purposes.

Far FAAH Out

Cannabis is an extremely ancient drug. Its widespread use is mentioned in the earliest Chinese pharmacopeias as well as the Rig Veda and Avesta, the founding texts of Hinduism and Zoroastrianism respectively. Many uses are listed for the drug including beneficial effects on pain, inflammation and a variety of psychiatric problems. Indeed, the Avesta says that cannabis is the most useful of all known drugs. Cannabis has been used in Asia for medical purposes for thousands of years. The drug eventually arrived in Europe by various routes including being brought back from Egypt by Napoleon’s troops and by the British such as Dr. William O’Shaughnessy from the British Raj in India. From Western Europe cannabis spread to the United States where it was beloved by people such as the writers  Fitzhugh Ludlow and Louisa May Alcott. Throughout the 19th  and early 20th centuries cannabis was widely appreciated in Europe and America for its medical properties. Cannabis tinctures were sold by most of the major European and American drug companies and it was a component of many patent medicines.

But then something happened. The 19th century saw the first attempts to regulate and tax the distribution of drugs. The introduction of heroin (marketed by the Bayer company in 1898) and the appearance of heroin addiction in the first decades of the 20th century,  as well as increased use of opiates by the military and addiction to purified cocaine, resulted in the first international attempts to legislate the trade and use of highly addictive substances. In the USA the result was the Harrison Tax Act of 1914. Eventually the US government set up the Federal Bureau of Narcotics (FBN) in 1930 which was supposed to have overall control of drug issues. Their choice of the man to run the FBN,  Harry Anslinger, was an unfortunate one. Political issues and corruption made it difficult for Anslinger to pay much attention to illegal heroin operations. So, in order to provide some kind of rationale for the Bureau’s activities, Anslinger decided to turn his attention to the use of cannabis. The drug had now become widely known by its Spanish name “marijuana” because it was used by immigrant Mexican workers with little political influence. Through the use of a spectacularly ridiculous “fake news” campaign, Anslinger spread the idea that cannabis/marijuana was actually the most dangerous substance in the world and that its use was the trigger for an enormous number of serious criminal activities, including rape and murder. In reaction to all of this, strict laws were passed restricting the availability of cannabis and its use for any sort of respectable medical purpose completely disappeared. The eclipse of cannabis was absolute.F

The situation began to change in the 1960s when cannabis use became associated with the very lively counterculture movement. Gradually  “grass roots” organizations began to agitate for the legalization of cannabis once again. These efforts have met with increasing success in the 21st century and now cannabis use is legal for medical or recreational purposes in many parts of the USA as well as in several other countries such as Canada and Uruguay. There is every indication that this trend will continue to expand in the coming years. There is now a vigorous discussion as to which of the many claims concerning the health benefits of cannabis are actually true as a whole new generation begins to rediscover things that humanity has really known for thousands of years. Of course, the societal context for cannabis use has now changed somewhat and advances in science and technology are able to make more sophisticated judgements as to cannabis’ true medical potential.

Really the debate about cannabis concerns the properties of the two major pharmacologically active  chemical components of the cannabis plant -the “phytocannabinoids” tetrahydrocannabinol (THC) and cannabidiol (CBD). Although they are related chemically, these two molecules have very different properties. As we shall discuss, THC is responsible for the known psychoactive effects of cannabis as well as several of its well-established pharmacological effects. CBD, on the other hand, is devoid of psychotropic properties. Generally speaking CBD has been viewed by regulatory agencies as being much less “dangerous” than THC. Because CBD is now widely available there are a huge number of claims as to its health benefits, many of which are undoubtedly spurious. Nevertheless, it appears that CBD does produce some interesting pharmacological effects (e.g. in the treatment of childhood epilepsies). Unfortunately, there is no real understanding as to how CBD works in terms of a molecular mechanism ,making it difficult to really evaluate it.The situation with THC is quite different. Here there is a very well described molecular context for understanding the mechanism of action of the drug, meaning that the basic tools of pharmacology can be brought to bear on refining any potential health benefits it might produce. Indeed, these benefits have recently been highlighted in a spectacular manner.

In order to understand these new revelations we should first briefly discuss what is known about the mechanism of action of THC. Like most drugs with well understood mechanisms, THC acts by interacting with a receptor-or actually two receptors. These are known as “cannabinoid” receptors-the CB1 and CB2 cannabinoid receptors. Both of these are what are known as G-protein coupled receptors, which constitute the largest family of receptors and one of the largest families of proteins in the genome. THC acts as a partial agonist at cannabinoid  receptors. CB1 receptors are very highly expressed in the nervous system, whereas CB2 receptors are more highly expressed in cells like white blood cells. Of course,  cannabinoid receptors do not exist in nature just to mediate the effects of  THC. In reality, they are the receptors for what are known as “endocannabinoids”, endogenous substances that are found in all animals and which normally activate CB1 and CB2 receptors. In the brain, for example, endocannabinoids act as neurotransmitters that carry information from one  nerve cell to another.  

Now that the potentially useful pharmacological effects of THC have been “rediscovered”, there is a great deal of interest in making synthetic cannabinoids that stimulate or inhibit cannabinoid receptors for treating different disease states including pain, inflammation and nausea associated with chemotherapy. But, of course, in principle there is another way to achieve these same effects. What if you could make your body raise its own levels of endocannabinoids? This should produce a similar effect to giving a drug that activates cannabinoid receptors. Indeed, such an approach is certainly possible in principle. The two major endocannabinoids are known as anandamide and 2-arachidonoyl-glycerol (2-AG). They are derivatives of a molecule called arachidonic acid which is known to play a central role in many biologically important processes. The two endocannabinoids are synthesized and destroyed by specific enzymes. For example, the enzyme that destroys anandamide is called Fatty Acid Acyl Hydrolase (FAAH). Supposing we had a drug that inhibited this enzyme. The result might well be that levels of anandamide would rise because it is no longer being destroyed efficiently and this would result in increased activation of cannabinoid receptors. This kind of approach has many precedents in pharmacology. For example, if we believe that biogenic amines like norepinephrine and serotonin are important for the maintenance of  normal mood, then raising their levels might be good for treating depression. As these substances are normally destroyed by the enzyme monoamine oxidase (MAO), then a drug that blocks the activity of this enzyme should raise biogenic amine levels and counter depression. This turns out to be broadly true-monoamine oxidase inhibitors like iproniazid were the first successful antidepressant drugs. Blocking FAAH to raise levels of anandamide would be an equivalent procedure.

Figure 1: Anandamide

As the biology of endocannabinoids became clearer many drug companies were attracted to the idea that FAAH antagonists might be useful drugs. Take pain, for example. We all know that treating chronic pain with opiates produces addiction -that’s why we have an opioid crisis at the moment. Because we know from much historical and recent evidence that activation of CB1 receptors might be helpful for pain, maybe a FAAH antagonist would be good for this purpose, making it a really useful new drug ?

So, the race was on.  Several big pharmaceutical companies such as Pfizer produced a range of potent FAAH inhibitors. Another company that was in the game early on was a Portuguese drug company called Bial. The company began a series of preclinical trials on its new compounds and picked a drug called BIA 10-2474 as its lead molecule for further development.  After conducting a series of tests the company decided that the drug seemed promising enough to begin clinical trials in humans. Human trials usually begin  with “Phase 1” trials that are run to assess the general safety of the new compound and to collect some basic data on drug metabolism. In order to carry out this trial Bial hired an experienced company in Rennes, France, named Biotrial Research that uses hospital facilities at Rennes University for carrying out trials such as these. Six doses  of BIA 10-2474 were to be tested on human volunteers – 2.5 mg; 5 mg; 10 mg; 20mg; 50 mg and 100 mg. Each dose was to be administered for 10 consecutive days. Nothing untoward was expected. But things didn’t go according to plan. In fact the trial was a complete disaster. On the evening of day five  (10 January 2016) and the fifth administration of the 50 mg dose, the highest dose category tested at that point, one of the 6 volunteers who had  received the drug rather than the placebo had to be hospitalized in  serious condition. This patient sank into a coma and died. Four of the other five men in the same dosage group were also hospitalized between 10th and 13th of  January displaying similar symptoms to those of the man who died. The symptoms experienced by the affected participants were all of a neurological nature resembling those associated with a stroke. These included severe headaches and problems with consciousness  ranging from sedation to coma and memory impairment. The trial was immediately abandoned. The four hospitalized patients that didn’t die all eventually survived, although several of them had severe symptoms over an extended period of time. Brain imaging studies demonstrated that these individuals had several structural anomalies in their brains strongly suggestive of  a toxic or metabolic mechanism for the adverse effects of the drug.

BIA 10-2474

A subsequent investigation as to the causes of the fiasco revealed several interesting things. As it turned out BIA 10-2474 wasn’t a very good FAAH inhibitor, particularly when compared to other clinical candidates that had been produced by the likes of Pfizer and Johnson and Johnson. The potency of the drug wasn’t very high and its selectivity, that is its propensity to act on FAAH rather than other targets, also wasn’t that clear. It  appears that the animal testing done by Bial with respect to effects on pain, the supposed major endpoint to be examined, was rather rudimentary and the doses calculated for use in humans were based on animal experiments which turned out to be misleading. A key question was whether the toxicity of the drug was due to its effects on FAAH or due to  other “off target” effects resulting from its lack of specificity. Without going into all of the evidence , it seems most likely that the latter alternative was the correct one. Nevertheless, it was not surprising that ongoing programs at other drug companies to develop clinically effective FAAH antagonists came to an abrupt halt. The idea that this might be a route for the production of a novel analgesic drug seemed dead as a doornail…or was it?

Mrs. Jo Cameron

About 6 years ago Mrs. Jo Cameron, a woman living in Inverness in Scotland, came to her local hospital with severe osteoarthritis of the hip. Interestingly, Mrs. Cameron didn’t seek medical help because her arthritis hurt -it didn’t. Rather she was having mechanical issues resulting from hip degeneration. Asked if she needed pain killers following her hip replacement, she declined. A year later she was back in the hospital for an operation on her hand. Once again she said she didn’t need pain killers. Needless to say the doctors involved were puzzled by Mrs. Cameron’s lack of pain under circumstances in which other people invariably report extremely severe pain. On investigating Mrs. Cameron further several other interesting facts about her came to light. She had quite extensive scarring resulting from an abnormally large number of previous injuries from burns, cuts and other types of trauma. As it turned out she was frequently unaware when her skin was burning, only being alerted to the situation by the smell of burning flesh rather than any pain. Mrs. Cameron also told the doctors that the birth of her two children had not been painful at all. She had felt some stretching sensations but no discomfort. All in all she thought that the experience had been a uniformly pleasant one. The doctors then asked Mrs. Cameron if she would eat a habanero chili pepper. Habanero or Scotch Bonnet peppers are among the world’s hottest. No human being can just pop one in their mouth, chew it and swallow it without experiencing excruciating pain. But Mrs. Cameron could do it with no trouble at all, merely remarking that the habanero produced a nice warm feeling in her mouth. Another curious thing about Mrs. Cameron was that she had a remarkably calm, mellow and cheerful personality. When given questionnaires to assess her levels of anxiety and depression, she scored zero on each of them. Finally, Mrs. Cameron declared that she frequently forgot things like where she had put her keys. One can watch Mrs. Cameron discuss these matters live on You Tube:

Mrs. Jo Cameron eats one of the world’s hottest peppers

It’s a remarkable performance. Overall, one might be forgiven for thinking that Mrs. Cameron was continually high on cannabis. Because of Mrs. Cameron’s  resistance to pain, together with her unusually equanimous personality, the doctors referred her to the Molecular Nociception group at University College in London for a genetic assessment. The surprising results of this investigation were recently published (Habib et al 2019). The bottom line is that Mrs. Cameron has some interesting mutations in her FAAH gene. In fact, Mrs. Cameron has a very unusual genetic profile indeed. The first thing that the investigators discovered was that right next to the FAAH gene was a FAAH “pseudogene”. This is a fairly common occurrence in the genome when a gene is duplicated and the sequence of one copy starts to drift so that it no longer has its original protein coding function. Nevertheless, some pseudogenes have attained new functions concerned with different sorts of gene regulation. The scientists investigating Mrs. Cameron dubbed the new pseudogene “FAAH-OUT”. It appears that Mrs. Cameron carries a microdeletion of genetic material that  has removed the promoter region and the first two exons of the FAAH-OUT gene. For some reason, this deletion has not only crippled the FAAH-OUT gene but also the FAAH gene, indicating that the expression of FAAH is normally controlled by some function of FAAH-OUT, although precisely what that function might be remains speculative at this time. Of course, every human carries two  copies of each gene (alleles). Although the production of FAAH by one of Mrs. Cameron’s alleles seems to have been crippled, she also has another allele that might well compensate for this loss. But, fascinatingly, in Mrs. Cameron’s case, the situation is different. It is well known that every gene contains small changes in nucleic acid sequence throughout the human population. These are called  single nucleotide polymorphisms or “SNPs”. Sometimes these changes make no difference whatsoever, but in other instances they may increase or decrease the activity of the gene. Just as with all genes, there are numerous SNPs in the human FAAH gene, some of which produce a “hypomorphic” phenotype, meaning that the gene functions less well.  As things turn out, Mrs. Cameron’s second allele carries a FAAH gene with a  missense variant converting proline at position 129 to threonine (rs324420). This has been shown to result in lower FAAH activity and is associated with significantly lower  pain sensitivity and less need for postoperative analgesia. Hence, Mrs. Cameron carries two alleles that produce deficient FAAH function. That being the case one would expect Mrs. Cameron to have abnormally high levels of the endocannabinoid anandamide which is normally a substrate for FAAH. This was exactly what was found to be the case. Interestingly, Mrs. Cameron’s son carries the gene microdeletion but not the SNP and Mrs. Cameron’s mother carries the SNP but not the microdeletion. Both of these individuals  have some pain hyposensitivity but it is not nearly as marked as that displayed by Mrs. Cameron who carries both dysfunctional alleles.The results of these studies have important implications for cannabis pharmacology. Mrs. Cameron can be viewed as an experiment carried out by Nature.In effect it is an experiment carried out  in a human rather than in mice where pharmacological results are frequently misleading. The data appear to suggest that drugs that inhibit FAAH activity might well have useful properties. In particular, if Mrs. Cameron is anything to go by, they may have beneficial effects on  pain and mood, two areas of pharmacology where new drugs are urgently needed after little progress in these fields for many decades. Moreover, it also appears that, in addition to FAAH itself, FAAH-OUT may be a novel drug target-although a great deal more work is required before we understand exactly how this gene operates. It appears that the unfortunate results of the BIA 10-2474 trial may in fact be something of a red herring and that now the pharmacological industry might consider reinvesting in this area, even though it has not previously yielded promising clinical results.

The results of the FAAH-OUT investigation also tell us that the interregnum of the last 70 or so years when the use of cannabis has been severely restricted, for what are clearly political reasons, was a medical mistake. History assures us that attention to the medical properties of cannabis will surely yield useful results in the future.


Microdeletion in a FAAH pseudogene identified in a patient with high anandamide concentrations and pain insensitivity. Habib AM, Okorokov AL, Hill MN, Bras JT, Lee MC, Li S, Gossage SJ, van Drimmelen M, Morena M, Houlden H, Ramirez JD, Bennett DLH, Srivastava D, Cox JJ. Br J Anaesth. 2019 Mar 28. pii: S0007-0912(19)30138-2. doi: 10.1016/j.bja.2019.02.019. [Epub ahead of print]. PMID: 30929760