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.

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