The Opioid Crisis Crisis

News concerning the “Opioid Crisis” has been extremely widespread over the last year and nearly everybody these days will be at least somewhat familiar with what is going on. A combination of factors, including over-prescription of opioids under inappropriate circumstances, have helped to fuel the crisis which is now responsible for the deaths of more than 70,000 people in the USA every year, even as we come to understand the phenomenon better and engage in better ways to stop it. There are numerous aspects of the crisis that demand our attention, but one which is of paramount importance concerns the properties of opioid drugs themselves. Morphine and other opioids are the pain killing drugs par excellence and they are indispensable to many areas of medicine such as surgery and anaesthesia. However, in addition, we know that outside a strict clinical setting the drugs are extremely dangerous. They are highly addictive and are easily abused. They also have powerful effects on respiration. Opioid inhibition of breathing is the reason why people actually die from taking high doses of these drugs. Because opioids generally work so well as pain killers, there has been a tendency to hand them out in a “one size fits all” fashion for treating all kinds of pain. This is the case even though their chronic use is dangerous and, in fact, they don’t work all that well for treating some chronic pain syndromes. So, the question arises –Why don’t we just make better opioid drugs? Why don’t we make drugs that kill pain as effectively as opioids but are free from their addictive and other dangerous side effects? Come on scientists, how hard can it be to do that?

The idea that this was an achievable goal arose in the 19th century, fueled by results on the drug cocaine. Cocaine is an addictive psychostimulant drug but it is also a good local anaesthetic. So, why not separate these two activities? Note that the chemical structure of cocaine consists of a “tropane” group attached to a “benzoic acid” group. What would happen if the two were separated? When this was done by scientists at the Hoechst drug company, they found that derivatives of the benzoic acid portion alone, things like procaine and lidocaine, worked very well as anaesthetics but were free of psychostimulant activity. Job done! So, all we needed to do was the same kind of thing with morphine and obtain a really good analgesic drug that was no longer addictive or suppressed breathing. Unfortunately, this aim has proved to be much harder to achieve. In fact, nobody has ever been successful in achieving it—and thereby hangs a tale.

Attempts to improve the profile of drugs like morphine began in the 19th century once the first pharmaceutical companies had been established. Researchers at these companies began to use the tools of the newly developing science of organic chemistry to modify the structure of morphine. In 1897, researchers at the Bayer company in Germany, who had had good luck acetylating salicylic acid to produce aspirin, tried the same thing on morphine and produced diacetyl-morphine. On performing some self-experimentation, one of the scientists declared that the drug made him feel very strong and powerful, or “Heroisch” in German. The name stuck and the drug became known as heroin. Heroin was originally marketed as a cough suppressant, like morphine and codeine, but, in contrast to these drugs, it was supposed to be non-habit forming. This is obviously quite untrue and one wonders how they ever came to such a conclusion. The reason, it appears, was that the drug was mostly used to treat tuberculosis patients. As their condition never improved, patients never really stopped taking heroin and so their dependency on the drug wasn’t really evident. Nevertheless, after a few years, the first heroin addicts started to appear and the real dangers of the drug became manifest.

Original 1898 Bayer poster advertising aspirin and heroin

However, this original rather spectacular failure has never dissuaded people from trying to produce non-addictive but effective opioid analgesics, even prior to the present crisis. The obvious attraction of such a drug to the pharmaceutical industry and humanity in general will be clear. Over the years, hundreds of papers have appeared in the scientific literature claiming to have solved the problem. These papers have often received a lot of attention and have been published in important “high profile” scientific journals, which garnered the authors a huge amount of science recognition. Inevitably, however, they all ultimately ended up in disappointment when tested further.

Let us examine a few of these attempts to try and understand what is going on. First of all, a few words about how opioid drugs work. All of these drugs activate a receptor called the μ-opioid receptor (MOP), which is expressed by nerve cells at various points up and down the neuraxis, including nerves that are situated at various points in the spinal cord and the brain, as well as nerves in the peripheral nervous system that are involved in sensing pain. MOP is one of a family of 4 receptors that are responsible for mediating the actions of the peptide neurotransmitters known as endorphins or related neuropeptides known as nociceptins. Apart from MOPs, there are also δ (DOP) and κ (KOP) opioid receptors and a nociceptin receptor (NOP). When these receptors are activated by agonists, they produce biochemical signals that reduce the firing rate of neurons and inhibit neurotransmitter release. It just so happens that, out of all the hundreds of receptors that exist in the genome, MOPs have a unique expression pattern that allows them to produce the profound analgesic effects that are observed. So, as far as we know, activation of no other receptor will be able to produce the same array of effects on the nervous system that would allow a drug to be as effective an analgesic as something like morphine. This doesn’t mean that drugs that activate other receptors, such as receptors for cannabis, might not produce some useful analgesic effects, but they are unlikely to match the profound analgesic effects observed with opioids that have resulted in these drugs becoming the cornerstone of surgery and pain treatment in general. Hence, trying to make a better version of morphine has a lot of appeal.

Attempts to achieve this aim fall into several categories. The first category might be called “Let’s see what Nature has come up with.” After all, Nature came up with morphine and codeine which are derived from poppies, and so maybe it also came up with other things as well. Perhaps, we just need to look around carefully. Moreover, human beings have had tens of thousands of years, at the very least, to experiment with plants and other natural products, so if there was something out there we might well have stumbled across it. In fact there are such things. The best example is the tree Mitragyna speciosa, a tropical evergreen tree in the coffee family native to Southeast Asia. Extracts of the leaves of this tree, commonly known as kratom, have been used as a traditional folk medicine in Southeast Asia. And kratom really does seem to be effective. The tree produces chemicals, particularly mitragynine and 7-OH mitragynine, which, when tested, appear to be perfectly good MOP agonists and produce effects that are strikingly similar to those of morphine, although, interestingly, their chemical structures are quite different from other known classes of opioids. Mitragynine and 7-OH-Mitragynine can produce strong opioid-like analgesia, but they are also addictive and produce respiratory depression just like other opioids. In spite of the fact that kratom is very similar to morphine, its use is more or less legal in most parts of the USA (depending on the state) and deaths due to respiratory depression appear to be rare. It should be recognized that kratom is usually used as a tea or other type of extract and so it is unlikely that, in everyday use, it ever reaches the doses that would produce really dangerous morphine- or heroin-like effects, and so some benefit may be obtained by using kratom tea for general pain relief. However, it is unlikely that kratom is actually a “better” drug than morphine in terms of its core pharmacological properties. It would also be wrong for people to think that kratom is some “natural” non-dangerous alternative to morphine. Really, it’s just another opioid as far as anybody can tell and so it is as potentially dangerous as any other opioid.

Mitragyna speciosa
Mitragynine

Another kind of approach to making a superior version of morphine involves trying to get morphine to work better by playing around with its chemical structure and resulting pharmacological properties, as was attempted during the original synthesis of heroin. There are several types of theories in this area. One hypothesis goes this way: When MOPs are activated, they produce different kinds of biochemical signals in nerve cells. One kind of signal is called G-protein activation. Another kind of signal is called β-arrestin activation. Perhaps, it is argued, one kind of signaling is responsible for the good effects of opioid drugs, such as analgesia, and another kind of signaling is responsible for the bad effects, like addiction and suppression of breathing. Drugs like morphine produce both types of signaling and therefore produce both good and bad effects. However, our experience with receptors like MOPs is that it should be possible to synthesize molecules that only activate one signaling pathway or the other. These types of molecules are called “biased” agonists. So, what would happen if we made biased agonists for MOPs: would the good/bad idea really be true in practice? The results are that it is. Or, at least, that was how the story was originally told. Several publications reported results showing that mice in which the gene for β-arrestin had been “knocked out”, still exhibited strong morphine-induced analgesia, but did not exhibit effects like morphine-induced respiratory depression. This suggested that MOP agonists that were “biased” towards producing G-protein but not β-arrestin activation should be free of dangerous side effects. Buoyed by these exciting results, drug researchers launched an intense search to find such molecules and were successful in reaching this goal. Several reports demonstrated that MOP agonists that were biased towards G-protein activation did, indeed, produce considerably less in the way of respiratory depression, constipation and other side effects but were still good analgesics. So, it seemed that the great search for an improved opioid drug had at last been successfully concluded. Unfortunately, when the leading drug in this category (TRV-130, or Oliceridine) was tested in humans in a clinical trial, the promising results didn’t seem to hold up and the drug appeared to be just another MOR agonist. So, what happened? The problem here, which is certainly not unique to this set of investigations, but has often plagued the search for improved MOP agonists, is what is called lack of “translation.” This can mean a couple of things. In the first case, it means that results found in one laboratory do not “translate” to another laboratory. In other words, an initially exciting result fails to be repeated in other laboratories and eventually fizzles out. Why does this happen? Nobody knows, but it probably has more to do with the sociology and culture of science than science per se. Another type of lack of translation refers to the inability of results obtained in rats and mice to translate to humans. This is another common observation that is certainly not unique to the opioid field. The fact is that pain is a complicated phenomenon. There are triggers for pain that elicit rapid reflexive movements of limbs away from potentially tissue damaging events like the intense heat of a flame, strong acid or sharp objects. Secondly, there are affective, conscious aspects of pain that are enabled by higher conscious brain function. As mentioned above, MOPs are uniquely distributed in the nervous system so that they dampen all aspects of pain, both reflexive and affective, and so they are extremely effective overall. But what is pain to a mouse? This question echoes Thomas Nagel’s famous 1974 essay “What is it like to be a bat?” We don’t really know the answer to this question. A mouse has an inner life and presumably feels something akin to pain, but its appreciation of this phenomenon might not be the same as that of a human being. Hence, its reactions to drugs that involve effects on the higher regions of the central nervous system responsible for consciousness and cognition may well differ from those of a human. Indeed, it is a general problem in the field of drug research that mice are not good models for human cognitive functions and that drugs that show effects in mice seldom translate exactly to humans in these kinds of situations. Tests in monkeys may be more reliable, even though monkeys aren’t exactly human either.

Another approach to the problem is to produce drugs that can modify the effects of MOP activation through a separate pharmacological pathway. The idea here is to make a drug that activates MOPs and produces all of the good and bad effects, but build into the drug a second activity that allows the good effects to proceed as normal but the bad effects to be suppressed. There are many variations of this kind of approach. Certainly, some analgesic drugs produce more than one effect. For example, the analgesic drugs tramadol and tapentadol both block the uptake of the neurotransmitter norepinephrine into nerve terminals in addition to activating MOR. Enhanced norepinephrine action in the spinal cord is thought to enhance the analgesic effects of MOR agonists, although not necessarily improve their profile.

But could a secondary action of a drug actually improve the profile of MOP agonists? This may be a possibility. For example, it has been reported that agonists that activate NOP receptors reduce the side effects of MOP agonists. So, why not make a drug that activates both of these receptors at the same time? This has been achieved and the initial results do appear to be very promising. The first NOP/MOP bifunctional drug of this type, named cebranopadol, appears to have good analgesic effects but few side effects, including lack of respiratory depression or abuse potential when tested in animal studies and, moreover, this desirable profile was also seen in human clinical trials to date. Such a drug would be a considerable advance if these results were confirmed. Encouragingly, a second NOP/MOP agonist named AT-121 has now been synthesized. The investigators tested the effects of AT-121 in monkeys using a tail withdrawal paradigm. The investigators placed monkeys’ tails in some uncomfortably warm water, which the monkeys normally only tolerated for a couple of seconds before removing their tails. However, after receiving AT-121 injections, monkeys kept their tails in the water for much longer periods of time, indicating that they didn’t feel the same degree of discomfort or pain. Even at higher doses, AT-121 did not cause the side effects that make most opioids so dangerous—suppression of breathing and heart rate, itch and physical dependence or tolerance. These results seem to be extremely impressive. So are NOP/MOP bifunctional agonists the answer to everybody’s opioid dreams? The results are certainly interesting. My problem with them is that there is no clear mechanism suggesting why NOP agonists should modify MOP effects in this way. There are numerous possibilities, of course, but the fact that there isn’t a clear answer makes me wonder. Nevertheless, the continued clinical progress of these drugs will be of considerable interest.

Cebranopadol
AT-121

Another strategy that has been suggested relies on the relative distribution of MOPs in the nervous system. Many MOPs are situated in the central nervous system which is protected by what is known as the blood brain barrier (BBB). Many chemicals do not penetrate this barrier very easily, meaning that a chemical you eat or inject may not actually get into the brain, or will only do so with difficulty. However, some MOPs are also situated outside the BBB, on peripheral sensory nerves called nociceptors, whose job it is to send painful information into the spinal cord and the brain. How much of the analgesic effect of a drug like morphine depends on activating MOPs within the BBB and how much is due to activating the MOPs situated outside the BBB? If peripheral MOPs can produce significant amounts of analgesia, then one could potentially design a drug that only activates peripheral MOPs because it doesn’t pass through the BBB. As effects like drug abuse and respiratory depression are all mediated by MOPs within the central nervous system, a drug of this type should be able to produce a degree of analgesia with no central side effects. The only side effects it should produce would be things like constipation which result from the activation of MOPs outside of the brain. The potential success of this kind of selective targeting can be seen with the drug Targinact, which is a mixture of oxycodone and the opioid antagonist naloxone. Naloxone doesn’t get through the BBB very easily unless injected intravenously. Because of this, if it is given orally it will only block MOPs in the periphery and so will relieve the constipating effects of oxycodone which are produced by activating MOPs in the gut. There are animal studies which do suggest that activating peripherally located MOPs can produce some degree of analgesia. Moreover, MOP agonists already exist that don’t penetrate the BBB very easily. These are drugs like loperamide which are used as anti-diarrheal agents precisely because of their peripherally directed constipating effects. So, we might ask, do drugs like loperamide also produce analgesia? The answer is that they do appear to produce some degree of analgesia, and these effects may actually be more apparent under conditions of injury. Nevertheless, the degree of analgesia observed doesn’t seem to be in the same range as the profound effects of morphine. Some added benefit may be obtained by using peripherally directed MOP agonists that also activate other opioid receptors (KOPs and DOPs) or receptors for other agonists as well. For example, the drug DN-9, which is reported to be an effective and side-effect-free analgesic, activates peripheral MOPs, KOPs, DOPs and receptors for Neuropeptide F. However, human trials for such compounds are lacking.

It is clear that the goal of producing a version of morphine that is free of undesirable properties may be extremely challenging, and drugs for relieving pain may ultimately be better pursued on a disease-by-disease basis. For example, if we consider a painful disease like osteoarthritis, we know that the triggers for pain have some unique aspects, in this case degeneration of joint tissues, and this is also the case for other chronic pain syndromes. Thus, it may be that targeting the specific nociceptive triggers for different pain disorders will provide selective answers to ongoing pain issues. Of course, it may ultimately be possible to produce analgesic drugs that rival morphine and that are free from side effects like respiratory depression—but don’t  hold your breath.

The Newcomers

It is difficult to think of a time since the 1960s when public interest in neuropharmacology has been as intense as it is at the moment. There are several reasons for this, including the new cannabis laws, the opioid epidemic and reviving interest in the utility and legal status of psychedelics. Naturally, these cultural reverberations are picked up by the authors of TV shows, movies and plays where psychotropic drugs are turning up with ever increasing frequency as important plot points. I have already covered the stories of the ultra-amnesia inducing drug employed the TV series Homecoming (Jan. 2019) and the use of ergot alkaloid poisoning in the TV period drama Poldark (Feb. 2019). This last week I watched another really good example of a psychotropic drug story, an example of what might be called “communist paranoia” or, these days, “Russian paranoia” fiction. Indeed, the story took me right back to the good old days when there was a red under every bed.

The TV series in question was Homeland (series 7). Homeland depicts the lives of a CIA operative named Carrie Mathison (Clare Danes) and her mentor, Saul Berenson (Mandy Patinkin). As it turns out, one of the main reasons why the USA still exists today as a functioning democracy is because, unbeknownst to the vast majority of people, these two CIA operatives have foiled one dastardly plot after another designed to bring the country to its knees. Many of these threats reflect current stories in the news. In series 7 of Homeland, it turns out that the country has been infiltrated by Russian spies—both real people and cyber-operatives—who are trying to sow havoc by bringing down the recently elected president Elizabeth Keane. But not to worry! Carrie realizes what is going on and, together with Saul, who is now director of National Security, they set out to deal with the Russkies. This actually turns out to be quite difficult because the Russian leader Yevgeny is both very smart and ultra-ruthless and is aided by his beautiful and seductive sidekick Simone, who has had no trouble infiltrating the White House by becoming the mistress of the president’s chief of staff.

Carrie and Saul have a secret meeting

Then there are the drugs. There are two stories here. One concerns Carrie herself who, as watchers of the series will know, suffers from bipolar disorder. In fact, the series implies that the manic phase of the disorder actually increases Carrie’s effectiveness as an agent, although it certainly compromises to her ability to carry on normal relationships with her family and other people. Unfortunately, the lithium which Carrie takes to control her mania has become ineffective and so she is prescribed Seroquel (the antipsychotic drug quetiapine) to calm her down and help her sleep—which it does. However, Carrie is suddenly thrown into the middle of an international spy plot and needs to have her wits about her. So, she buys some methamphetamine from a drug dealer in an attempt counter the effects of the Seroquel—an “upper” to counteract a “downer.” The combination of lithium, Seroquel, methamphetamine and a considerable amount of alcohol causes Carrie’s behavior to veer wildly from one state to another, finally culminating in PTSD-fueled paranoid psychotic hallucinations resulting in her hospitalization.

However, this isn’t the most interesting drug-related story in the current series. One of the schemes that the Russian spies have cooked up is the assassination of an important US general who is being kept under guard while he is investigated for possible criminal acts. The assassination is carried out by a “medic” who is giving the general a routine medical exam while he is being incarcerated awaiting trial. At some point, the medic touches the general with a rubber glove he is wearing on which the poison has been placed. The small amount of poison is then absorbed through the general’s skin. Soon, he collapses, writhes around a bit (maybe he has a seizure), and finally dies of a “heart attack.” Although the story that is put out to the public indicates that the general has died of natural causes, the government operatives working behind the scenes don’t think this is true and actually believe it is more evidence of Russian interference. But that isn’t the end of the drug story. Further investigation leads Carrie and Saul to a suspect member of the FBI named Dante Allen, supposedly working with Carrie, but who may actually be another Russian agent. Of course, he denies it but his testimony is needed within a couple of days to prevent a complete government meltdown. Carrie has an idea. She will poison Dante and hope that he will admit what he has done before he dies and then, in the nick of time, she will administer an antidote to him allowing him to survive and testify (a bit risky, this!). The poison is administered to Dante when some ink on a pen he is using to sign a document touches his finger. Again, just as in the death of the general, the poison is rapidly absorbed through Dante’s skin and then produces what seem to be seizures and possibly a heart attack. Carrie and her colleagues quickly administer the antidote and eventually Dante recovers only to be murdered by Yevgeny. But, are there really poisons that are so potent that a tiny amount absorbed through your skin can be fatal in the manner described in these TV shows? You bet there are and, what is more, they have been used for exactly the purpose described.

The identities of the poisonous drugs used in Homeland are fairly clear from what we know about how they were employed and the effects they produced. The way they work is based on the fact that, if you want to fatally poison somebody very quickly, the best thing to do is to use a chemical that attacks their nervous system. This strategy is well known to the vast majority of creatures on the planet Earth that use nerve toxins to kill their prey. Humans are not intrinsically venomous creatures and so, if we want to do what most other creatures do, we have to invent our own nerve poisons and figure out ways of effectively deploying them. One obvious use of such chemicals would be by the military. Toxins might be conveniently “weaponized.” For example, they could be packed into artillery shells that would then burst over enemy positions, distributing the contents widely so they can be breathed in by enemy soldiers or possibly absorbed by their skin. We know this works because, among other things, Nature has already done this experiment for us. For example, in areas like Florida, toxic red tides are caused by blooms of tiny organisms named dinoflagellates that synthesize toxins that can poison the nervous system. When waves crash against the shore, these tiny organisms break open releasing their toxins into the air. The aerosolized toxins are then breathed in by people and animals on land producing adverse effects on respiration and other functions.

Not to be outdone by Nature, human beings also tried this out in World War I when shells containing poisonous mustard gas were fired at enemy positions to devastating effect. Immediately after the World War I, nobody doubted that the next war would include the use of such “chemical warfare agents” (CWAs). But what kind of agents might be the most devastating? Here we might again take note of experiments performed by Nature. What are the targets used by poisonous insects and snakes who want to incapacitate their prey? The targets are frequently ion channels and receptors expressed by nerves. Consider, for example ,the toxins produced by poisonous snakes such as cobras, that block the effects of the neurotransmitter acetylcholine (Ach), producing paralysis of muscles involved in breathing, which leads to asphyxiation and death. Indeed, disrupting Ach-mediated neurotransmission would be an ideal target for a CWA. Ach acts as the neurotransmitter at many peripheral nerve synapses that regulate muscle contraction and the functions of many of the organs that are vital for life. Moreover, Ach controls important synapses in many parts of the brain and can be responsible for the induction of seizures under some conditions. Indeed, giving animals the cholinergic drug pilocarpine is a reliable and widely used method for producing seizures in animal experiments. So, interference with the actions of Ach might be expected to have devastating effects for multiple reasons.

We know that after acetylcholine is released at a synapse and has finished the job of activating its target receptors—there are two types of these named nicotinic and muscarinic receptors—it is rapidly destroyed by an enzyme called acetylcholinesterase (AchE). The activity of this enzyme is essential for restricting the normal effects of acetylcholine to a quick burst, thereby avoiding receptor desensitization and other phenomena. What would be the effect of inhibiting the action of this enzyme? If acetylcholine wasn’t destroyed, its synaptic levels would build up rapidly leading to activation and desensitization of nicotinic receptors as well as long lasting activation of muscarinic receptors. Given the importance of acetylcholine as a neurotransmitter in the autonomic nervous system, for example, the normal physiology of the body would be completely thrown into disarray. The functions of vital organs such as the heart, lungs and kidneys would be compromised. Given the importance of these organ systems, the effects could easily be deadly.

However, this doesn’t necessarily mean that AchE inhibitors would be useless. Interestingly, Ach also has important functions in the lives of insects and so inhibiting AchE might also be a way of producing an insecticide. Indeed, this is precisely what happened. In 1925, all the important German pharmaceutical and chemical companies formed themselves into a giant cartel called IG Farben (Interessengemeinschaft Farbenindustrie—“The combined interests of the dye making companies”). This giant company was responsible for many innovations in drug development in the early 20th century, although it was subsequently taken over by the Nazis and used to support their war effort. In 1932, two IG Farben scientists discovered a group of molecules called organophosphates that acted as effective inhibitors of AchE and were subsequently developed as insecticides. By performing a small amount of self-experimentation, these scientists also noted that these novel substances had effects on their breathing and vision. Inspired by these results, in 1936, the German scientist Dr. Gerhard Schrader produced an extremely potent organophosphorous-related agent named tabun. At that point in time, the German government was very interested in the discovery of new chemical weapons and, after some experimentation, it became clear that tabun might be just what they were looking for. Tabun was the first of a group of substances which have become known as Nerve Agents (NAs), and which were designed to act as weapons rather than insecticides. NAs were secretly developed in many Western countries during and after the Second World War. The original group of NAs—tabun (GA), sarin (GB), soman (GD) and cyclosarin (GF)—were known as “G” agents, “G” standing for German. Subsequently, even more lethal substances were developed, initially in the UK in the early 1950s, and were designated ‘‘V’’ agents (VE, VG, VM, VX, and VR), “V” standing for venomous. The most familiar of these is the ultrapotent molecule VX. However, the most recent and most deadly development of this technology has been the synthesis of the Novichok agents by scientists in Russia. Novichok means “newcomer.” Novichoks were produced in the 1980s at the State Institute for Organic Chemistry and Technology at Shikhany near Volgograd in the Soviet Union. More than 100 compounds fall into the Novichok category, with Novichok 5 and Novichok 7 being the best known. All of these agents are extremely potent and basically irreversible inhibitors of AchE and can produce deadly effects in humans.

“Newcomers.” Structures of two Novichoks

It should be noted that many of these NAs are easily absorbed through the skin or can be breathed in as aerosols, making them easy to deploy on the battlefield or surreptitiously to an individual. Once AchE is inhibited, stimulation of muscarinic receptors causes defecation, urination, miosis, bradycardia, bronchorrhea, bronchospasm, emesis, lacrimation, and salivation (made easier to remember by the mnemonic DUMBBBELS). Nicotinic receptor stimulation leads to m-ydriasis, t -achycardia, w-eakness, h-ypertension, and f-asciculations (remembered with the mnemonic, M- onday, T-uesday, W-ednesday, T-hursday, F-riday). NAs are not that expensive or difficult to produce, but they are certainly extremely poisonous and so they make ideal weapons for terrorists. There are now a large number of incidents in which NAs have been used, or are suspected to have been used, in wars and assassinations around the globe. For example, nerve agents were certainly used in the Iran-Iraq war and by Iraq against its Kurdish population. NAs have also been used in the Syrian civil war—sarin in particular killing 1,400 people in one incident. Terrorists in Japan have used nerve agents, including in the Tokyo subway attack on March 20th 1995. The idea that such potent and devastating poisons are in the hands of different radical factions throughout the world is a very scary prospect. One might wonder if there is any way of treating somebody who has been poisoned in this way? The traditional treatment involves a triad of drugs—an antiepileptic, typically a benzodiazepine, atropine to block muscarinic acetylcholine receptors and a chemical such as pralidoxime (2-PAM) that may help to reactivate the inhibited enzyme, although this doesn’t work very well in many instances. Come what may, even if the victim lives he may suffer many serious health issues for the rest of his life.

There have been some very high-profile political assassinations using NAs that have received wide coverage in the media. For example, on Feb 13th 2017, Kim Jong Nam, the estranged brother of North Korean leader Kim Jong Un, was approached by 2 women in the Kuala Lumpur airport, who wiped his face with a liquid which turned out to contain a high concentration of VX. Kim Jong Nam died within minutes. However, by far the most notorious incident took place in England. On March 4th 2018, Sergei Skripal, a Russian double agent who had been given political asylum in the UK, and his daughter Yulia, recently arrived from Russia, collapsed on a park bench in the middle of the town of Salisbury. They were found by a passing doctor and nurse and were taken to the local hospital. It was obvious from the start that they had been exposed to a toxic substance but “what, how and where?” Investigations by British officials found that they had been poisoned by a Novichok, perhaps spread on the handle of Mr. Skripal’s front door. On entering the hospital, Mr. Skripal and his daughter were in very critical condition and there was considerable doubt as to whether they would survive. Eventually, after some weeks of intensive treatment, they were both able to go home, although it isn’t clear whether there will be long-term health effects resulting from the attack. The British government made it very clear that they considered the Russians responsible for the attack. A huge diplomatic row ensued, the Russians repeatedly declaring that they weren’t involved. However, this wasn’t the end of the affair. A few weeks later, on June 30th 2018, Charlie Rowley, a British citizen who had nothing to do with Russia, was walking through a park in Amesbury, some 8 miles from where the Skripals had been poisoned, when he came across what looked like a bottle of perfume wrapped up in an expensive-looking package. Rowley took the package home and, a couple of days later, showed it to his girlfriend Dawn Sturgess when she came to visit. She recognized the name of the “perfume,” took it out and applied a drop to her wrists which she rubbed together. Rowley also took out a drop to smell but then washed it off his hands. Within 15 minutes, Sturgess was feeling extremely ill and was rushed to the hospital. Rowley then became ill and was also admitted. On July 8th, Sturgess died. Rowley eventually recovered. The bottle proved to be full of a Novichok NA. It is speculated that this was the source of the material that had poisoned Mr. Skripal and his daughter, and the bottle had just been thrown away without any regard for the danger of its contents. It is certainly disturbing that, in spite of international treaties aimed at banning NAs, they may well still be stockpiled by renegade countries that have little regard for their dangers.

As a matter of fact, NAs aren’t the only attempt to nefariously manipulate Ach-mediated neurotransmission. As shown in Homeland, the CIA has always been in the vanguard when it comes to using dangerous chemicals for diverse “patriotic” purposes and, in the 1950s/60s, had a secret program named MK-ULTRA whose job it was to investigate such possibilities. Rather than investigating AchE inhibitors, the MK-ULTRA program was more concerned with weaponizing psychotropic drugs that would send populations of enemy troops (or possibly civilians) completely out of their minds. Here again we can take a cue from Nature. Powerful inhibitors of muscarinic Ach receptors such as atropine and scopolamine are made by plants such as Deadly Nightshade (Atropa belladonna) and Black Henbane (Hyoscyamus niger) and are well known for their disorienting or even deadly effects. In 1951, the Roche drug company synthesized an analogue of atropine named 3-Quinuclidinyl benzilate (3-QNB) for use as an antispasmodic agent. It did work but also had spectacularly profound disorienting side effects. The drug was taken up by the CIA, who performed considerable human experimentation on what was now called “Buzz” and became very impressed with its effects on the human psyche. The drug was therefore weaponized and stockpiled for possible future use. It is unlikely that this was ever done by the US army, but it may well have been employed by other countries, particularly by the Russians against Chechen revolutionaries. Rumor had it that Saddam Hussein also stockpiled weapons of this type, although there was ultimately never any proof of this.

The use of NAs of various types for recent political assassinations, terrorism and also, quite possibly, in warfare in various parts of the world, is a matter of considerable concern given the extremely poisonous nature of these substances. Let us hope that we won’t need to call upon Carrie or Saul to help us out any time soon.