I Wanna Be Sedated: Drugs for the Age of Anxiety

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”

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.

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

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 20^th and 21^st 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 20^th 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 19^th 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.

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 12^th 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.

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.

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…