Closing in on COVID

The magnitude and consequences of the COVID-19 pandemic will be all too clear to everybody. While writing this article, the number of people infected worldwide has topped 5 million and the number of deaths is over 300,000. In the United States alone, 100,000 people have died from the disease. It is natural for us to wonder what we can do about it. After all, this is a medical problem and so, like other medical problems, it should not be beyond humanity to devise ways of preventing the virus spreading and for curing people who are unfortunate enough to become infected. As has been widely stated, an effective vaccine would be a major step forward and efforts are underway to produce one. But vaccines are not necessarily easy to make. Here we should remind ourselves of the last major viral pandemic, the spread of HIV-1. A vaccine would also be an effective way of dealing with that problem. But people have been working on an effective HIV-1 vaccine for decades and nothing has come of it yet. So, while we wait and hope for a vaccine for treating COVID-19, we also need to consider other approaches. Here again we can take heart from thinking about the AIDS epidemic. A viral disease for which there was initially no cure, gradually became something we could control through the use of antiviral drugs. And it is in the area of pharmacology that many of our major hopes lie at the moment. It is the role of pharmacologists to come up with new drugs for treating diseases. So if, like me, you are a pharmacologist, then this is your moment. This is what you were born for. Come on pharmacologists—what have you got! The answer at the present time is not very much. But also not nothing. The first drugs that appear to make a dent in the course of SARS-CoV-2 infection (the name of the virus that produces the COVID-19 syndrome) are with us and the signs are that others may be on the way soon. So, what kinds of drugs are already being developed, how do they work and what might we expect in the future?

There are really two kinds of approaches to treating COVID-19 that might be amenable to drug development. The first of these is to produce drugs that attack the virus itself and prevent it infecting cells and replicating. Drugs such as these would be the best kinds of treatment. A second type of drug answers a slightly different problem. Let us assume that someone has an active infection; how can drugs target the consequences of this infection? SARS-CoV-2 infections can be fatal because they trigger adverse events that attack the body, leading to fatality. Drugs that target the molecules that enable these adverse events would also be extremely helpful and would save many lives.

To understand these two approaches we first need to understand the biology of the SARS-CoV-2 virus. Viruses are really the simplest forms of life. One might argue that they aren’t really alive at all in the conventional sense of the word, because in order to go through their normal life cycle, replicating to produce further viruses, they need the help of host cells. In effect they are tiny parasites that cannot live independently of their hosts. Viruses exhibit a range of preferences for infecting different species and different types of cells. There are over 200 types of viruses which show a preference for infecting humans rather than other animals, plants or even bacteria. The first of these to be discovered was Yellow Fever virus in 1901, and three to four new species are still being discovered every year. Some, like SARS-CoV (the virus that causes Severe Acute Respiratory Syndrome), MERS-CoV (the virus that causes Middle East Respiratory Syndrome) and SARS-CoV-2 (the virus that causes COVID-19) are extremely recent additions. Why pathogenic human viruses continue to appear isn’t completely clear, although it seems likely that viruses like SARS-CoV-2 originally existed in other species, such as bats in this case, and then mutated to produce new varieties that were able to utilize human hosts perhaps by passing through several other species first. The appearance of the HIV-1 virus in the latter part of the 20th century was another example of this kind of transmission, in that case initially from monkeys before jumping to humans. Coronaviruses were first identified in chickens in the 1930s and in humans in the 1960s. The viruses look like little balls with multiple spike-like structures sticking out of them and so resemble crowns, the feature that gave rise to their name. Initially, coronaviruses were thought to only produce mild symptoms in humans, such as the common cold. However, the appearance of the SARS-CoV, MERS-CoV and SARS-CoV-2 viruses has clearly demonstrated that newer members of the family can be much more pathogenic and dangerous. The SARS-CoV-2 virus has evolved to infect human cells (and possibly the cells of some other animals). Viruses normally consist of some genetic material, RNA or DNA, packaged into a protein coat, sometimes embedded in a lipid membrane. The purpose of the protein coat is to enable the viral nucleic acid to enter the host cell. Once inside, the viral genetic material takes over the host’s synthetic machinery, diverting it to the task of making more viruses which then lyse the cell and are free to infect further cells. Of the viruses that attack humans, SARS-CoV-2 is very large, being around 125 nanometers in diameter. SARS-CoV-2 viruses use a single-stranded RNA as their genetic material and have very large genomes consisting of 30,000 genetic bases. In fact, coronaviruses have the largest genomes of all RNA viruses. They are three times as big as HIV-1, for example.

How does SARS-CoV-2 infect humans and produce the particular symptoms associated with the COVID-19 syndrome? When somebody breaths in virus-laden droplets, SARS-CoV-2 enters the nose and throat. Many of the cells that line these regions express a protein receptor for the virus on their surface, called angiotensin-converting enzyme 2 (ACE2). ACE2 normally helps to regulate blood pressure, but the virus has evolved to be able to use it as a portal for entering target cells. It is the glycoprotein spikes that surround the virus and are made of a protein called “S-protein” that seek out and interact with ACE2 on the surface of target cells. SARS-CoV can also use the same protein as a receptor, but the interaction between SARS-CoV-2 and ACE2 is about 100 times stronger than that of SARS-CoV, providing one reason why it is highly infectious. Once the interaction between the virus S-protein and ACE2 has occurred, proteolytic enzymes on the cell’s surface—including furin or another enzyme called TMPRSS2—cleave the viral spike, exposing small peptides that help to fuse the viral membrane with the membrane of the host cell. Fusion allows the virus’ RNA to enter the host cell where it hijacks the host’s cellular machinery, diverting it from its normal role to producing viral RNA and proteins. These then get assembled into new virus particles which exit the host cell and can now attack other cells or leave the body and infect other people.

The SARS-CoV-2 virus

As the virus can only enter cells that express ACE2, it is important to understand exactly where in the body this receptor protein is expressed. The first cells to become infected are often in the throat and pharynx. The virus then moves along the windpipe (trachea) to attack the lungs and particularly the distant branches of the lung’s respiratory tree, which end in tiny air sacs called alveoli. These alveoli are lined by a single layer of cells that also highly express ACE2 receptors and so are easily infected by the virus. Infection of the lungs gives rise to many of the cardinal symptoms of SARS virus-related diseases. However, there are many other parts of the body that also express ACE2, including the cardiovascular system and brain. Some COVID-19 patients have strokes, seizures, confusion, and brain inflammation, indicating that the virus may also be able to directly attack the brain. The virus may also directly attack the lining of the heart and blood vessels, and so explain the cardiovascular symptoms displayed by many patients.

The different phases of the lifecycle of SARS-CoV-2 are well understood at this point and each one represents an opportunity for producing a drug that could be effective in blocking viral infection and replication. For example, one might imagine drugs that block the interaction between the virus S-protein and ACE2, drugs that interfere with the transcription and translation of viral genes and proteins, and drugs that interfere with the way that new virus particles are put together and exit cells. Experience with other viruses that are pathogenic in humans suggests that these approaches may also be possible with SARS-CoV-2. The era of antiviral drug development began with the first antiviral drug, idoxuridine, which was approved in June 1963. Now there are over 90 antiviral drugs that target 9 human infectious diseases including things like HIV-1 and influenza. Interestingly, some antiviral drugs have been approved for the treatment of more than one infectious disease, suggesting an underlying commonality in the processes through which different viruses replicate. This, of course, raises the hope that some existing antiviral drugs might be repurposed for treating COVID-19. Indeed, most of the initial drugs proposed for treating SARS-CoV-2 infection have been repurposed in this way. This is true, for example, in the case of remdesivir, a drug which has been widely discussed in the press as a potential COVID-19 treatment. Remdesivir is a novel small-molecule adenine nucleotide analogue antiviral drug that has shown efficacy against Ebola virus, another single-stranded RNA virus. Remdesivir also displays antiviral activity against other single-stranded RNA viruses, including filoviruses, pneumoviruses, paramyxoviruses, and the coronaviruses MERS-CoV and SARS-CoV. Remdesivir is what is called a “prodrug”, meaning that it has to be metabolized into its active form, another molecule called an adenine nucleotide triphosphate analogue that interferes with the activity of viral RNA-dependent RNA polymerase, the enzyme which transcribes the viral genome. Normally, the SARS-CoV-2 virus has a “proofreading” capacity, which allows it to detect potential mistakes in duplicating its RNA, but remdesivir can avoid this activity, leading to inhibition of viral RNA synthesis and termination of viral replication. It was found that patients with advanced COVID-19 and lung involvement who received remdesivir recovered faster than similar patients who received placebo, according to a preliminary data analysis from a randomized, controlled trial involving 1,063 patients, which began on February 21. Preliminary results have indicated that patients who received remdesivir had a 31% faster time to recovery than those who received placebo. Specifically, the median time to recovery was 11 days for patients treated with remdesivir compared with 15 days for those who received placebo. Results also suggested a survival benefit, with a mortality rate of 8.0% for the group receiving remdesivir versus 11.6% for the placebo group. Clearly, therefore, although remdesivir does not represent a way of completely curing the disease, it does appear to produce significant benefit to patients and is an interesting example of a drug that has been repurposed to treat COVID-19, a trend that will surely continue.

Fig. I

A second drug which has received a good deal of publicity is hydroxychloroquine. Hydroxychloroquine is president Trump’s drug of choice, and he is said to take it daily. As the Trump administration has pointed out, the fact that, as far as anybody knows, the president has not come down with COVID-19 is sufficient to prove its effectiveness as far as they are concerned. Like remdesivir, hydroxychloroquine is metabolized in the body to produce chloroquine, a drug with which humanity has had a great deal of experience. During World War II, the Japanese conquest of the Far East had cut off supplies of quinine, leaving the combatants desperate to find effective antimalarial drugs for their troops. Both the Germans and the Allies found that a synthetic drug called resochin, which had been made by the Bayer pharmaceutical company, was quite effective in controlling malaria but was initially considered too toxic for general use. Eventually, however, resochin (now renamed chloroquine) proved to be useful and, after many years of trials, became the most widely used antimalarial drug in the world. As one scientist put it, “The main story of chloroquine, 1934 to 1946, involves investigators in six countries on five continents and embraces its initial discovery, rejection, re-discovery, evaluation and acceptance.” Chloroquine proved to be a breakthrough drug, much more effective than any synthetic drug produced previously for the treatment of malaria. It was used throughout the world to treat many forms of malaria and also as a prophylactic measure. In some areas, it was even added to cooking salt to ensure everybody took it. Malaria isn’t caused by a virus but by a group of infectious organisms called Plasmodium spp. These are actually protozoans (single-cell organisms) rather than viruses but, like viruses, they lead a parasitic existence. Chloroquine kills malaria parasites by interfering with the way they dispose of the heme molecule in the red blood cells they infect, heme being toxic to Plasmodium spp. Hydroxychloroquine and chloroquine have subsequently proved to have other useful effects, including in the treatment of arthritis and lupus as well as general antiviral effects. Indeed, it is clear that these drugs can kill coronaviruses in “test tube” experiments carried out in a laboratory. An initial small clinical trial with hydroxychloroquine conducted in France in March appeared to show some beneficial effects in COVID-19 patients. Since that time however, further trials have proved discouraging. A large study in hospitalized COVID-19 patients in New York found that the drug had no impact on the risk of the most severe outcomes from the disease. Of the 1,446 patients admitted to the hospital from Mar 7 through April 8, 811 (58.9%) received HQ, with 45.8% of patients receiving treatment within 24 hours of presenting at the emergency department and 85.9% within 48 hours. Many of the patients who received HQ were classed as severely ill. No benefit was associated with HQ administration and this agrees with other trials that have also been carried out, and so enthusiasm for using the drug to treat COVID-19 patients appears to be poorly based in fact. Indeed, as I write this (May 26th, 2020), the World Health Organization has just announced that it was halting worldwide trials testing hydroxychloroquine for COVID-19. Last week, a study in the medical journal The Lancet reported that there were no benefits to treating coronavirus patients with hydroxychloroquine, and that taking it might even increase the number of deaths among those in hospital with the disease.

Other substances, mostly repurposed from previous applications, have shown activity against SARS-CoV-2 in the laboratory and are also being considered but have not yet been extensively tested in the clinic. These include compounds that inhibit the viral protease that is important for processing the proteins that constitute new viruses, compounds that block the interaction between viral S-proteins and ACE2, and compounds that inhibit proteases like TMPRSS2 that are involved in cleavage of the S-protein or molecules which, like remdesivir, interfere with the RNA-dependent RNA polymerase that transcribes the viral genome. These strategies all seem reasonable from a scientific point of view and could certainly ultimately turn out to produce something therapeutically useful.

Rather than considering these traditional targets, recent study published in the journal Nature took the approach of going “back to the drawing board” and trying to come up with entirely new targets for drugs to combat SARS-CoV-2. Gordon et al. (2020 Apr 30. doi: 10.1038/s41586-020-2286-9: online ahead of print) cloned the majority of the proteins that constitute the SARS-CoV-2 virus and then expressed them in human cells and measured which cellular proteins they interacted with. The authors argued that many of these interactions could be important in the normal processing of the virus and so drugs that inhibited them might have therapeutic effects. A large number of interactions were observed. However, after applying several other criteria, the authors whittled these down to a few targets that they deemed particularly interesting. After all the experimental dust had settled, the authors had a winner: sigma (σ) receptors! So, what are σ receptors and how might they be important? Back in the 1970s, there were many ongoing efforts to discover how many different types of receptors existed for opioid drugs. In addition to μ, κ and δ receptors, one categorization based on interactions with the drug N-allylnormetazocine (SKF10047) also came up with a class called σ, although in many respects this proposed receptor didn’t display properties that suggested it mediated the primary effects of opioid drugs. For one thing, the general opioid antagonist naloxone didn’t bind to the site and, moreover, in the case of many σ-selective drugs, the (+) isomer of the drug, which was usually devoid of opiate-like properties, proved to interact much more potently than the biologically active (-) isomers. Further studies using (+) pentazocine as a defining ligand showed that the σ binding site could not be defined as an opioid receptor but must have some other function. Indeed, the σ receptor proved to have affinity for a spectrum of chemicals that had been previously shown to exhibit a wide range of pharmacological effects. Moreover, a second binding site (σ2) was also defined and subsequently found to be identical with a previously known protein called TMEM97, which had been suggested as being a transport protein involved in cholesterol biosynthesis. In spite of a lot of work done over the years—including structural work, the preparation of knockout mice and many other important studies—nobody has ever pinned down exactly what the biological functions of σ receptors might be. There is a strong impression that they may be involved in modulating biochemical signaling pathways in cells that are activated by other receptors such as G protein-coupled receptors, but really nobody knows and σ receptors remain a biological mystery. Nevertheless, Gordon et al. demonstrated that several molecules that bind to σ receptors were powerful inhibitors of SARS-CoV-2 production in cultured cells, suggesting that they may be a novel therapeutic target in this case. Although these experiments are very interesting and suggestive, it should be pointed out that historically σ receptors have been “discovered” as being novel targets for most of the diseases that afflict humanity, including pain, amyotrophic lateral sclerosis, Alzheimer’s disease, Parkinson’s disease, retinal disease, stroke, cocaine and alcohol addiction and, of course, cancer. Unfortunately, σ-specific drugs have yet to be translated for any useful therapeutic advantage in human patients. Hence, whether σ receptors are really the answer to the SARS-CoV-2 problem awaits further testing, particularly in COVID-19 patients.

As indicated above, another important method for potentially intervening in COVID-19 is to find a way of ameliorating the destructive effects that result from viral infection. The viral receptor ACE2 is also expressed in some immune cells, including monocytes, macrophages and dendritic cells. SARS-CoV-2 infection of these cells results in their activation and secretion of IL-6 and other inflammatory cytokines. IL-6 has particularly powerful proinflammatory properties and has been implicated as a key mediator of many inflammatory syndromes. The receptor for IL-6 consists of an IL-R protein combined with a second protein named gp130. Soluble forms of IL-R can combine with circulating IL-6 and then this complex can associate with gp130 proteins, which are very widely expressed by many tissues including endothelial cells. The resulting IL-6-mediated signaling triggers the synthesis of many other inflammatory cytokines, producing a “cytokine storm” that can lead to vascular permeability and leakage, which participate in the pathophysiology of hypotension and pulmonary dysfunction in COVID-19. Cytokine storms have been shown to produce pathology in a variety of situations such as during CAR-T cell treatment for cancer, where they can produce very dangerous and ultimately fatal effects. This has led to the suggestion that cytokine storms may be controlled by treatments that neutralize circulating IL-6, such as the humanized monoclonal antibody tocilizumab which has been shown to be effective in reducing these problems during CAR-T cell therapy. Cytokine storms have been suggested as being triggered by SARS-CoV-2 infection and are thought to be responsible for many of the far-reaching effects of the virus in tissues that it doesn’t primarily infect, and so treatments with agents such as tocilizumab may be helpful, something that appears to be the case in some early clinical trials.

The arrival of the COVID-19 pandemic, as well as the government funding that goes with it, has meant that many scientists have converted their laboratory efforts to researching this problem, resulting in an enormous worldwide effort to produce novel drugs for combating the disease. Hopefully, some combination of new drugs and vaccines will reduce the SARS-CoV-2 problem to just another manageable infection. Nevertheless, the appearance of SARS-CoV, MERS-CoV and SARS-CoV-2 in rapid succession means that there are many lessons about preparedness to be learned before the next new pathogen turns up.

I Wanna Be Sedated: Drugs for the Age of Anxiety

20, 20, 20, 4, hours to go
I wanna be sedated
Nothing to do, nowhere to go, oh
I wanna be sedated

– The Ramones

The “Red Death” had long devastated the country. No pestilence had ever been so fatal, or so hideous. The opening of Edgar Allan Poe’s “The Masque of the Red Death” seems prophetic given the situation we find ourselves in today.

In response to the pandemic, Prince Prospero, the main protagonist of Poe’s story, decides to “shelter in place”

But the Prince Prospero was happy and dauntless and
sagacious. When his dominions were half depopulated, he
summoned to his presence a thousand hale and light-hearted
friends from among the knights and dames of his court, and
with these retired to the deep seclusion of one of his
castellated abbeys. This was an extensive and magnificent
structure, the creation of the prince’s own eccentric yet
august taste. A strong and lofty wall girdled it in. This wall
had gates of iron. The courtiers, having entered, brought
furnaces and massy hammers and welded the bolts. They
resolved to leave means neither of ingress nor egress to the
sudden impulses of despair or of frenzy from within. The
abbey was amply provisioned. With such precautions the
courtiers might bid defiance to contagion. The external world
could take care of itself. In the meantime it was folly to
grieve, or to think. The prince had provided all the
appliances of pleasure. There were buffoons, there were
improvisatori, there were ballet-dancers, there were
musicians, there was Beauty, there was wine. All these and
security were within. Without was the “Red Death”

The Masque of the Red Death by Aubrey Beardsley (1895)

And, of course, that is how most of us find ourselves at the moment. It’s hard to be stuck at home most of the time. Naturally, many of us are anxious about our health, our jobs and many other facets of our lives that seem to have all but disappeared. I thought about how others had responded under similar circumstances. In the Decameron, Boccaccio had seven young women and three young men escape from a pandemic raging in Florence and retreat to their country estates where they spent their time eating, drinking and telling each other stories. This seems like a great idea although, I suspect, most of us don’t have country estates to flee to, requiring us to think of something else.

A Tale from the Decameron by John William Waterhouse (1916)

In 1976 Joey Ramone sang songs that might suggest some solutions. Perhaps, pharmacology could provide a way of helping us? How can we control our anxiety? “I wanna be sedated” provides us with one alternative. The words of another song are as follows:

Now I wanna sniff some glue
Now I wanna have somethin’ to do
All the kids wanna sniff some glue
All the kids want somethin’ to do

Joey Ramone, possibly considering sniffing some glue

It seems to me that these words perfectly encapsulate the current situation. Yes, adults and kids are bored out of their minds and they really want something to do—but what? Before considering the potential benefits (or otherwise) of glue sniffing, let us look at other possible ways that we can use pharmacology to intervene in states of anxiety.

Anxiety, used in the broadest sense of the word, is probably the most prevalent of all human psychiatric problems. In the Western world, the lifetime prevalence of anxiety-related disorders is approximately 20–30% in the general population. Psychiatrists now define a large number of anxiety-related disorders, of which Generalized Anxiety Disorder (GAD) is the most common and amorphous. In addition to GAD, there are also phobias, social anxiety disorder (SAD), posttraumatic stress disorder (PTSD), panic disorder (PD) with/without agoraphobia, and obsessive-compulsive disorder (OCD) as well as many others.

It’s no wonder that we are all anxious. In olden times we had religion to guide us and tell us exactly how to live our lives. But we don’t anymore and science has been able to prove it. Uncertainty, Relativity and Incompleteness set the scene for 20th and 21st century angst, something that we have all inherited. Now, on top of it all, we have to deal with a terrible pandemic.

Interestingly, until the 20th century, anxiety wasn’t even classified as a psychiatric problem, more a personality defect which just needed to be overcome through the application of will power. But once the medical establishment labelled anxiety as an official medical condition, the door for discovering drugs that would take care of the problem was wide open.

Since the middle of the 19th century, a series of drugs have been invented which seem to have genuinely “anxiolytic” or anxiety-treating effects. These drugs all have the same specific mechanism of action: they target the effects of the neurotransmitter γ-amino-butyric-acid (GABA). Nerve connections in the brain, known as synapses, regulate the flow of information from one nerve cell to another. Synapses come in two types, excitatory, which make nerves fire more electrical signals called action potentials, or inhibitory, which make them fire fewer action potentials. The vast majority of excitatory effects in the brain are initiated by the neurotransmitter glutamate, and most of the inhibitory effects are produced by GABA. As things turn out, drugs that enhance the inhibitory effects of GABA have found many uses in medicine. Consider, for example, the situation in epilepsy. Epileptic seizure activity in the brain results from an abnormal degree of excitation. Hence, one would predict that drugs that increase the degree of inhibitory activity, perhaps by increasing the effectiveness of GABA in the brain, might reduce seizures by resetting the normal excitatory-to-inhibitory balance. And in fact, that is precisely how many anti-epileptic drugs work. We might also imagine that, in some less obvious way, anxiety results from the brain being “over excited” and so the same strategy might work for anxiety-related disorders. In 1831, Justus von Liebig discovered a substance called chloral hydrate through the chlorination of ethanol, and it was subsequently observed that this substance had a “sedative” action on mood and behavior.

Early advertisement for barbiturates transforming the patient from “afraid and anxious” to calm

The drug became very popular and was used by the likes of Dante Gabriel Rossetti, the leader of the Pre-Raphaelite group of avantgarde artists to help him sleep. However, as Rossetti and others discovered, in addition to its useful qualities, chloral hydrate was extremely habit forming. Then, in 1863, Adolf von Baeyer, the great German chemist (he won the Nobel Prize), performed a chemical reaction in which he reacted urea with malonic acid. As he performed this experiment on St. Barbara’s day, he named the resulting product barbituric acid—from Barbara and urea. Some years later, Emil Fischer (another Nobel Laureate) and Josef von Mering, working for the Bayer pharmaceutical company, observed that when they synthesized the diethyl derivative of barbituric acid it had sedative properties that were very similar to those of chloral hydrate. The drug was marketed in the US under the name barbital—it was the first barbiturate drug. Many similar drugs followed. They were found to have a large number of medical uses. A small dose would act as a sedative, a somewhat higher dose as a hypnotic (it would put you to sleep), an even higher dose could produce profound anaesthesia, enabling many kinds of surgery to be performed for the first time and, as mentioned above, the drugs were also useful for treating seizures. Unfortunately, they also had serious problems associated with their use. If the dose was too high, barbiturates could be fatal and they were also very addictive. All of these effects actually reflect the ability of drugs like barbiturates to increase the inhibitory actions of GABA in the brain. Generally speaking, increasing GABAergic transmission produces a spectrum of effects from lowering anxiety, to sleep, to anaesthesia and then, at high doses, to death. In spite of their negative properties, barbiturates were a huge breakthrough in medicine—if used appropriately. But, of course, because they were very addictive, they weren’t always used appropriately and, after the sensational news broke in 1962 that Marilyn Monroe had died of a barbiturate overdose, it was clear that better, less dangerous drugs were needed.

And better drugs were soon forthcoming. Right after the war, Frank Berger, a Czech immigrant in the UK and then the US, developed a new drug called meprobamate from preservatives that he was using in research on penicillin. Sold under the name of Miltown, this was the first drug to be targeted specifically for treating anxiety—the first “anxiolytic” drug. Miltown was very effective at reducing general anxiety and was much safer to use than barbiturates. Miltown was an enormous success and highlighted the fact that general anxiety was really something that afflicted many individuals in society. Miltown was developed and sold by a small drug company called Carter Wallace and soon attracted the attention of “Big Pharma” companies who wanted to position themselves in the new anti-anxiety market. The Swiss giant Hofmann LaRoche started a program at their laboratory in Nutley, N.J. led by a Polish immigrant scientist named Leo Sternbach. After several years without success, Sternbach and Roche were about to shelve the project when, while cleaning up his bench, Sternbach discovered a compound he had made but had never gotten around to testing. It’s lucky that he did. When tested on animals in the company’s laboratories, the drug—a benzodiazepine structure named chlordiazepoxide—appeared to produce clear anxiolytic effects and, furthermore, it was superior to Miltown tested under the same conditions. Of particular interest was its specific calming effect on a colony of wild monkeys while, at the same time, their general level of alertness was not affected. Roche summarized the results as follows: “The substance has hypnotic, sedative, and anti-strychnine effects in mice similar to meprobamate (Miltown). In cats it is about twice as potent in causing muscle relaxation and ten times as potent in blocking the flexor reflex.” Before being tested on humans, chlordiazepoxide was also tested on leopards, lions, panthers, tigers, and pumas at the San Diego and Boston zoos, and it was reported to have a calming effect on all of them. Soon Roche had tested the new drug, now called Librium, on humans in a series of clinical trials and it became clear that the company had a real winner on their hands. They also began to develop substances in the same benzodiazepine chemical series and soon came up with another promising molecule called diazepam which was also developed as the drug Valium. Once they went on sale, Librium and Valium were an immediate success, catapulting Roche to becoming the largest drug company in the world.

Nowadays we know a great deal about how anxiolytic drugs like barbiturates, meprobamate and benzodiazepines work in the brain. They do all enhance the actions of GABA. GABA actually produces its inhibitory effects on neurons by acting on two kinds of receptors known as GABA-A and GABA-B receptors. Anxiolytics act by helping GABA activate GABA-A receptors. These receptors are ion channels that allow gradients of anions, Cl and HCO3, to redistribute themselves across the cell membrane. It should be realized that although drugs like this are certainly effective in treating anxiety, they are potentially addictive and dangerous. That is why they are only available with a prescription and they can only be used under a doctor’s direction.

Are there any other drugs that work this way for which you don’t need a prescription and so might be more generally available? The answer is “yes,” there is one—it’s called alcohol! Humans have been producing alcohol for recreational use since time immemorial, starting with beer-like drinks made by fermenting sugar or starch-containing fruits, honey, grains and many other materials. Arab scientists in medieval times developed the technique of distillation, enabling the production of spirits with higher alcohol content such as those produced in southern Italy in the 12th century from wine and known as “aqua vita” or, subsequently, in other parts of Europe where they became known as brandy, from the Dutch brandewijn or “burned wine.” It is clear that many of the effects of alcohol are reminiscent of the effects of anxiolytic drugs, such as producing a reduction in anxiety as well as being extremely addictive. In fact, these actions of alcohol are also produced by activating GABA-A receptors. As opposed to drugs like Valium, however, alcohol produces its effects at very high concentrations and it is not at all specific for GABA-A receptors; alcohol also produces effects at numerous other sites on nerve cells, resulting in a potpourri of behavioral effects. Nevertheless, many of us will be aware of the fact that, used in extreme moderation, alcohol can have an effect on mood, making us feel less anxious and more relaxed, and presumably, many of us are indulging in this well-known GABA-A receptor activator these days.

There are plenty of other alternatives as well if we wish to produce mild activation of GABA-A receptors to relieve personal anxiety. Many of these are drugs that are dispensed as plant extracts and tinctures and are generally known as phytochemicals. In many instances, knowledge about these drugs is the result of thousands of years of human experience that have identified folk remedies for virtually every human disease, anxiety being no exception. There are actually a large number of plants that are said to have anxiolytic effects among their properties. One of the best characterized of these is the Kava plant (Piper methysticum). Kava, which is sometimes known as awa, is produced from a plant typically found in the western Pacific and has been traditionally used by many of the island cultures of the Pacific Ocean, including Fiji, Vanuatu, Hawaii, and Polynesia. In Fiji, for instance, Kava is considered the national drink. Kava juice is extracted from the roots of the Kava plant. The roots are first cut into pieces and are then chewed by people who spit out the pulp into a bowl containing coconut or cold water. This mixture is then filtered through coconut fibers prior to being consumed. The ancient origins of Kava drinking is known to go back at least 3,000 years and is associated with both social and ceremonial functions. It was, and is, highly valued for its medicinal uses as a sedative, muscle relaxant, diuretic, and as a remedy for nervousness and insomnia. A historical reference, dating back as far as 1616, suggests that Dutch navigators called Le Maire and Schouten observed Kava drinking ceremonies on the island of Futuna, and the voyages of Captain James Cook to the South Pacific most certainly included the discovery of Kava. The major bioactive constituents of Kava are the six lipophilic kavalactones, of which kawain and dihydrokawain are thought to be the major contributors to the plant’s anxiolytic activity. In keeping with the above discussion, experiments have demonstrated that both of these substances can activate GABA-A receptors, providing a mechanism for Kava’s observed anxiolytic actions.

Kavalactones

A meta-analysis of small clinical trials that have tested the effects of Kava on human subjects came to the conclusion that it did indeed produce a modest anxiolytic effect. The only “fly in the ointment” are some reports that consumption of Kava can cause liver damage and, as a result, its use is restricted in some countries. However, it has also been observed that no such damage has been reported among the indigenous populations of the South Pacific who have used Kava for millenia, suggesting that the reports of toxicity may have been due to inappropriate dosing or some other reason. Just in case you don’t particularly like the idea of somebody chewing up the Kava root and then spitting it out for you to drink, plenty of Kava-related products are available in the US, including Kava-containing teas, so this might really be worth trying.

Kava plant (Piper methysticum)

And Kava-related phytochemicals aren’t the only ones that have been suggested as having anxiolytic actions. One should also note the potential effects of Centella asiatica (Gotu cola/kola, pennywort), Humulus lupulus (Hops), Ginkgo biloba (Maiden hair), Matricariarecutita/Matricaria chamomilla (Chamomile, German chamomile), Melissa officinalis (Lemon Balm), Passiflora incarnata (Passion flower), Scutellaria lateriflora (Scullcap, Blue Skullcap), Valeriana officinalis (Valerian), Withania somnifera (Ashwagandha, Indian ginseng, winter cherry), all of which may contain substances that activate GABA-A receptors.

Classical anxiolytic drugs and related GABA-A agonists are certainly not the only choice for dealing with anxiety. Many of us nowadays live in areas where we have access to recreational cannabis, another drug that is well known for its relaxing effects. Cannabis is also an extremely ancient drug and has always been known for its many medical benefits. The drug is mentioned in the earliest pharmacopeias for numerous purposes, including its relaxing effects. The preparations that are sold as cannabis these days are the products of the plants Cannabis sativa and Cannabis indica. Extracts of cannabis contain a large class of phytochemicals called cannabinoids. The two that exist in highest concentrations are called Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). As far as we know, THC is responsible for all of the psychotropic effects of cannabis, whereas we are still working to uncover genuine effects attributable to CBD. THC has a large number of medical uses including stimulating appetite, treatment of chronic pain and producing a relaxed mood. In moderate doses, it doesn’t appear to be beset with the problems associated with alcohol use. It doesn’t produce violence and, if used moderately, is not particularly addictive. Perhaps these things are not surprising considering the fact that the mechanism of action of THC is quite different from that of the anxiolytics. THC acts on two receptors that are quite different from the GABA-A receptors. They are G-protein coupled receptors (GPCRs) known as CB1 and CB2 receptors. The receptor that occurs in the brain is the CB1 receptor. CB2 receptors are mostly expressed by white blood cells, where they may be responsible for the drug’s anti-inflammatory and immuno-suppressive effects. CB receptors are normally involved in mediating the effects of the body’s own “endocannabinoid” molecules which act as agonists for these receptors. THC, then, works by mimicking the effects of these endocannabinoid molecules. CB1 receptors in the brain are usually localized at synapses and control the strength of synaptic transmission, working as a sort of “volume control” device. Activation of CB1 receptors is responsible for many of the effects produced by cannabis including relaxed mood. In humans, this effect was brought into stark relief last year by a report describing a woman from Scotland, Mrs. Joe Cameron, who carries a gene mutation resulting in her having unusually high levels of endocannabinoids. Among other things, neuropsychological testing on Mrs. Cameron revealed that she was an extremely relaxed person who displayed almost no anxiety in the face of clear stressors, something that was consistent with the profile of a person who was using cannabis. Following thousands of years of use, including widespread use in the US in the 1960s and again over the last decade, there is now a good deal of experience with using cannabis, and nowadays many people do find it useful for its relaxing effects.

Which brings us back to glue. Sniffing glue or other volatile “inhalants” is viewed as a serious drug problem throughout the world, particularly in disadvantaged populations and among adolescents. The easy availability of products containing volatile substances (e.g. aerosol sprays, cleaning products, paint and glue) provides a cheap way for producing psychotropic experiences. Unfortunately, serious complications such as brain, cardiovascular, liver, and renal damage or even death can arise from the use of these materials. Adolescents usually perceive the risk as low, and parents are usually unaware of the potential problems. Inhalant abuse and dependence among adolescents is a dangerous and serious issue. So, although glue sniffing may constitute “something to do” as the song goes, it is dangerous and clearly not recommended.

These are challenging times for all of us . Pharmacology may ultimately present us with a way of really treating coronavirus infection through the use of novel anti-viral drugs. This kind of approach has been helpful with pandemics of the past. Hopefully such a solution for our present problems will not be far away. In the meantime, as Joey Ramone sang:

You know it’s generally known you got everything at home
Kisses out of desperation bring you more aggravation
And you don’t come close, you don’t come close, you don’t come close…