The Death of Marilyn Monroe: Pharmacological and Medical Notes

I've taken a hiatus from my posts regarding Robert F. Kennedy, Jr. and his attacks on Dr. Anthony Fauci and science in general to evaluate some other conspiracy theories.

The Death of Marilyn Monroe.

In this post, I apply my experience in pharmacology to the death of Marilyn Monroe, another person whose official determination of death by suicide has been challenged, and whose actual means of death has been claimed to be part of a conspiracy.

Spoiler alert: I cannot say definitively that Marilyn Monroe was not murdered. I can comment on whether the pharmacological evidence is consistent with a self-administered and suicidal drug overdose. 

The Case

The undisputed facts. Alright, some conspiracy theorists out there dispute everything, and to be fair, some "undisputed" facts turn out to be incorrect. Some diversions from the presented times are apparent in different primary sources. Nevertheless, I have to proceed from some platform, and for the purposes of my analyses, there is little difference.

Marilyn Monroe's lifeless body was discovered at approximately 3:05 a.m. on August 5, 1962. She was pronounced dead at 3:35 a.m. From advanced rigor mortis, she was determined to have been dead for several hours, sometime during the evening of August 4. She weighed 53 kg (117 lbs.) at time of death. 

Medical Examiner's Death Report, Thomas Noguchi

According to the Los Angeles Police Department Death Report. "A bottle marked 1½ grains Nembutal [pentobarbital], prescription #20853 and prescribed by Dr. Engelberg, and referring to this particular bottle, Dr. Engelberg made the statement that he prescribed a refill for this about two days ago and he further stated there probably should have been about 50 capsules at the time this was refilled by the pharmacist." One and one-half grains equals 100 mg pills. Another source says the bottle contained 25 100 mg pills.

The following values of drugs were found, postmortem. 

Plasma levels of pentobarbital (Nembutal): 45 ug/mL. Hepatic tissue levels of pentobarbital: 130 ug/mL suggesting an accumulation over time. (Note: plasma levels, rather than blood levels, are what are commonly reported. For the purposes of any analysis relevant to this case, plasma levels equal blood levels.)

Plasma levels of chloral hydrate: 80 ug/mL. (Note: this probably referred to trichloroethanol. Chloral hydrate has a half-life of approximately 5 minutes and then becomes its active form, trichloroethanol.)  

Pertinent to the absorption of the drugs, the gastrointestinal tract, the stomach, small intestine, and colon were examined and described in the autopsy. 

"The stomach is almost completely empty. The contents is brownish mucoid fluid. The volume is estimated to be no more than 20 cc. No residue of the pills is noted. A smear made from the gastric contents and examined under the polarized microscope shows no refractile crystals. The mucosa shows marked congestion and submucosal petechial hemorrhage diffusely. The duodenum shows no ulcer. The contents of the duodenum is also examined under polarized microscope and shows no refractile crystals. The remainder of the small intestine shows no gross abnormality. The appendix is absent. The colon shows marked congestion and purplish discoloration. The fecal content is light brown and formed." Source.

The Drugs

Pentobarbital is a barbiturate, popular in the 1960s as a sleep and anti-anxiety medicine. It is highly addictive and easy-to-overdose. These pills had the nickname "yellowjackets" due to the yellow coloring of some of their doses (although the 50 mg capsule was orange). They were available as 30, 50, and 100 mg capsules. 

Pentobarbital was recommended for no more than short term use as a sleep aid: beyond addiction, the patient becomes tolerant to its effects, requiring more to obtain the same effect. Although 100 mg was commonly given as a sleep aid, up to 500 mg per use could be prescribed. 

The fact that it was commonly prescribed at the time was poor medicine on the doctors' part. A special drug-dependence committee set up by President Kennedy in 1962, concluded that there may have been as many as 250,000 Americans addicted to barbiturates.

Pentobarbital has largely been replaced by the safer (but far from perfect) benzodiazepines.

To determine the significance of plasma levels of drugs in the blood, several properties of the drugs are required. These are the volume of distribution, the bioavailability, the half-life, and the toxic and lethal levels. These can be obtained from the literature. For pentobarbital, the volume of distribution is 0.6 L/kg, or, for Ms. Monroe at time of death, 31.8 liters. The bioavailability (percent absorbed) is 95%, close to the entire dose. The half-life is 5.1 days. The toxic and lethal levels will be discussed in the next section. Oral or rectal pentobarbital takes approximately 20 to 60 minutes to induce sleep. 

Chloral hydrate has been around since the 19th century when it was a common addiction among those using it as a sleep aid. It is notorious for being a "black-out" drug, a "Mickey Finn" slipped into drinks to kidnap and sequester sailors, into victims' drinks as an early sort of "Ruffie," and it made a great additive to a drink in action stories when the bad guy wanted to knock out the detective. 

The volume of distribution of chloral hydrate is similar to that of pentobarbital, 0.6 L/kg. The half-life of its active form is approximately 9 to 10 hours. Its bioavailability is nearly 100%. Source. An oral dose takes approximately 30 to 60 minutes to induce sleep. 

Analyses

Question #1. Approximately how much of a dose of pentobarbital had to be absorbed into Ms. Monroe's blood to achieve her plasma level of 45 ug/mL? 

First of all, it cannot be said from the available evidence when she took her dose. Could she have had a lingering value of pentobarbital in her blood from a previous dose which was supplemented by a fatal dose? Possibly. 

However, the total dose she took, as seen in her plasma concentration, can be calculated: concentration x volume of distribution/bioavailability. (31.8 liters x 45 ug/mL (or 45 mg/L) / 0.95) This would work out to approximately 1500 mg. (1.5 grams or fifteen of her pills) (Note: people are variable and literature figures do not necessarily match an individual.) 

Question #2. Was that dose lethal? 

This is a more complicated case than that of Kurt Cobain. Monroe took two drugs, two CNS depressants, and the combination of drugs is possibly what caused her death. When determining lethal doses, few, if any, studies look at multiple drugs taken at the same time (much less a specific pair of drugs), so studies that examine single entities and their lethal dose values are only suggestive.

What do studies say about the lethal dose of pentobarbital? Ms. Monroe had 45 ug/mL of pentobarbital. Pentobarbital can put a person into a deep coma with cardiovascular compromise at 30 ug/mL although one case study found a patient surviving a dose of 116 ug/mL (ibid). Conclusion: by itself, it could have caused death.

Question #3. How much chloral hydrate did Ms. Monroe likely take? 

Figuring in her weight and the trichloroethanol concentration, I estimate she took 2500 mg (2.5 grams) of chloral hydrate, between four to six times the recommended dose. One thing to note here is the term "average." After dosing, people do not necessarily have the average concentration. What can be said is that Ms. Monroe did not have an absurdly high number and could have well have taken chloral hydrate at her usual dose for sleep, rather than trying to kill herself through the dosage. From the rate at which she used chloral hydrate from her prescription, it appears not unusual for her to take ten at a time. Unlike the figure given for pentobarbital which has a relatively long half-life, her dose of chloral hydrate was probably taken recently and does not reflect an accumulation from previous days.

This article states that 4 grams of chloral hydrate is typically toxic to an adult and 10 grams typically fatal. However, as the article points out, people vary with some surviving up to 28 grams. 

The chloral hydrate by itself was not likely fatal.

 

Question #4. What is the significance of the empty stomach and the lack of discoloration of the feces? 

As mentioned above, the stomach is a way station. Any ingested pills would have to be dumped into the small intestine before being absorbed. 

The medical examiner Thomas Noguchi (still alive at 98) addressed the lack of pills or pill residue in her stomach in an interview. 

Noguchi: The autopsy found a large amount of Nembutal and chloral hydrate [in her blood and liver], but the case wasn't typical because the stomach was empty. I did not see any residue, although the stomach and gastric lining were much reddened. But this is standard for barbiturate abuse. And this was not the first time we'd seen an empty stomach. Like the liver, it gets used to handling the drug and passes it quickly into the small intestine. 

Marilyn Monroe biographer Donald Spoto, argued it was significant that the stomach did not show any pill residue, suggesting that the drugs were delivered by enema. No drug residue was described in the colon and the feces were firm and of normal color.

My Best Estimate of What Happened.

Marilyn first took her primary sleeping agent: chloral hydrate. She took several times the regular dose so that she would not wake up from any effects from the drug with which she intended to end her life: pentobarbital. 

When a lethal dose of drugs are taken orally, the effects are not immediate. In this case, even the sedation would have taken a half-an-hour. 

There are many studies that look at the transition of drugs in overdose from the stomach to the intestines. This is an important field of research. If the drugs are still in the stomach, a stomach pump will still be helpful and so would induced vomiting. Once the drugs transit to the intestines, these interventions are marginally helpful.

This study of stomach contents after the ingestion of an overdose shows that the emptying time of the stomach is highly variable. Even within an hour after ingestion, sometimes you'll find the remnants of pills, sometimes you won't. 

After the pills reached her small intestine, they would have been absorbed until the point of death, when blood circulation, and therefore absorption, would stop.

The amount of pentobarbital in her blood was sufficient to kill her on its own, although death would not have been certain. The chloral hydrate added to its efficiency.

One surprise that came to me while performing this analysis is that Ms. Monroe's plasma levels of pentobarbital were equivalent to having taken 15 pills. Enough to kill her, but where were the rest? It is possible they were dissolved in the intestines, unabsorbed because absorption stopped the moment she had a lethal dose of the drug in her blood. With the prescription being two days old, it is possible she ingested some the previous evening. Finally, the 15 pills is not written in stone: such drug parameters as half-life and volume of distribution vary between people.

A final note. Pentobarbital has very different properties from the similarly named phenobarbital. I have seen the two confused in non-scientific commentaries.

Martin Hill Ortiz is a professor of pharmacology and author of several novels. 

My new novel, The Missing Floor, is now available from Oliver-Heber books. The first in the series, Floor 24, is newly available in audio book format. The audiobook has quite a complimentary review here.

The Missing Floor

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Some Notes on Conspiracies: Kurt Cobain and Marilyn Monroe's Deaths.

 

General Notes on Conspiracies and Notes on the Deaths of Kurt Cobain and Marilyn Monroe.

I've written 20 posts and over 35,000 words now on Robert F. Kennedy, Jr.'s book on Anthony Fauci. I'm halfway through the book and frankly I've skipped over a lot, in part because Kennedy repeats himself. What quickly became clear to me is that RFK Jr. is a conspiracy theorist, and a low-grade one at that. He consistently makes hyperbolic and tortured arguments that don't stand up to the slightest degree of scrutiny and which are often contradicted by the sources he cites. When the sources do agree, they are often books from other conspiracy theorists, YouTube videos, and websites. On one occasion I found him citing a neo-Nazi site.

I've begun reading Voodoo Histories by David Aaronovitch. I publicized it in my previous post. It has some good points but as I've continued on, I find it dissatisfying. 

After discussing conspiracy theories in general, he sets about tackling famous conspiracies, one after another. I feel as though by surveying so many, he fails to provide the depth that is needed to address any one of them.

My first disagreement came when he mentioned the case of Julius and Ethel Rosenberg in passing, saying they are both guilty. My understanding is that the general historical belief is that Julius was caught dead to rights, while Ethel was charged to make him confess. If his point was that there really is enough evidence to point to the guilt of both, he should have presented it. 

In one extended chapter he goes over JFK's assassination, and Marilyn Monroe and Princess Diana's deaths. In doing so, some of his dismissals of conspiratorial evidence comes across as glib.

Not that I blame him. The reason for such glib dismissals is built into conspiracy theories: they are near infinite in their scenarios and quite often those promoting the theories just make up crap. Trying to disprove infinite crap is problematic.

Let's look briefly at JFK's Assassination.

First of all, let me say that I am agnostic on whether JFK's murder was a conspiracy. I think there are aspects that point to a conspiracy and things that do not. I am not often humble, but I will say that I, pretending to know for certain what happened in JFK's assassination would be claiming insights beyond my sphere of knowledge.

Nevertheless, several things strike me. First of all, there are a thousand completely (or at least mostly) contradictory theories as to what happened. This means that 999 of these are wrong. If it was not the mob, then all those overheard mob confessions were boasts (lies) or inventions. If it was the mob, then those CIA second gunmen stories were false. I realize this is being simplistic. Some theories have the CIA by way of the mob. But there are also theories about pro-Castro, anti-Castro, Soviet Union, Illuminati, right wing, left wing parties, Lyndon Johnson, Richard Nixon (who was in town that day), George Bush, Woody Harrelson's and Ted Cruz's fathers, among many others. I read a book about an accidental round being shot by a member of the Secret Service entourage: a theory that negates all the others.

Which gets to the main problem: how to debunk the 999 false theories. It can't be done. Believing in Oswald as the lone gunman does have the advantage that it is a singular theory. 

Which gets down to this. Even if there is a true conspiracy theory, nine-hundred-and-ninety-nine other conspiracy theorists are selling you snake oil. 

I do not have expertise regarding rifles, the possibility of the trajectory of the "Magic Bullet," how the CIA or a dozen other organizations handle secret plotting. Using a common sense approach, Occam's Razor, etc., only gets me so far. 

This works both ways. I don't give credence to either those who debunk the Magic Bullet or to those who claim what happened by way of the bullet's trajectory was ordinary. I'm not saying who is right or wrong. I'm just saying I can't tell. Life is like that. All of us live in a limited bubble of knowledge. I have to accept that and yet I'm not ready to totally devote myself to some conspiracy guru and glom on to conspiracy theories just because I don't know.

Ultimately, I tend to fall back on a couple of maxims. I don't believe a conspiracy theory just because some expert has claimed it so, and I tend to believe incompetence explains more world events that supercompetent conspirators. I think it is useful for maintaining mental health to believe in the fewest conspiracies possible. 

Which also gets to the fact that I do have an area of expertise, much of which I have used in my critique of RFK, Jr.'s book. I am an expert in pharmacology, AIDS, and in a general sense, health sciences. I can sniff out phony statements in these fields. RFK's claims regarding hydroxychloroquine, AZT, ivermectin, his advocacy of injecting ozone, etc.: I can make definitive statements about these. 

I decided to direct my expertise to what can be said and what can and can't be said in regards to the pharmacology in two famous cases, both of which fit into conspiracy theories and books: the deaths of Kurt Cobain and Marilyn Monroe. Kurt Cobain is the simpler one, and I'll start there.

The Death of Kurt Cobain: Smells Like Bad Journalism.

When I teach my students the concept of the fatal dosing of drugs, I discuss the Kurt Cobain case. 

LD 50, lethal dose 50, is the dose of a drug that will cause death in 50% of individuals. It is measured either as dose administered, or as how much drug is found in the plasma. This latter number, given by concentration, is determined by post-mortem assay (if the subject died) or else the concentration that appears in the blood of high-dose survivors.

From a slide I present in class:

The author of "Who Killed Kurt Cobain?" said Cobain's death could only be murder. Cobain's blood contained 1.52 ug/mL heroin/morphine. (Heroin spontaneously breaks down into morphine by the time it is measured.)

The LD50 of morphine is 0.5 ug/mL.

The author states "This level [Cobain's 1.52 ug/mL] is widely known to represent three times the lethal dose of heroin. . ." and "a blood morphine level of 0.5 ug/mL is . . . the established maximum lethal dose, even for severe addicts." The author argues that the high dose of heroin would have been nearly instantly fatal or incapacitating and would not have permitted Cobain time to employ a shotgun to kill himself. 

I ask my students: What’s wrong with this argument?

There is a whole lot wrong with the author's brief statements. 

1. There is no such thing as a "maximum lethal dose." If you double that "maximum," it is still lethal. This book invented this nonsense term.
2. LD50 is the dose that kills 50% of individuals, not all of them.
3. Three times the LD50 has nothing to do with three times the lethal dose for any individual.
4. LD50 is not adjusted for "even in severe addicts."
5. LD50 does not address what is "nearly instantly fatal or incapacitating." Heroin kills by respiratory arrest. Not breathing does not cause instant death. He would have plenty of time to employ a shotgun, especially if it was already loaded and prepared.
6. The cited figure of 0.5 ug/mL is the LD50 determined in rats. Lethal dose studies do not generally take place in humans. The number determined in rats does not directly correspond to humans: it is an extrapolation.

Conclusion: the toxic values of heroin/morphine did not in any way prevent Cobain from committing suicide. I've not read the rest of the conspiracy book on Kurt Cobain's death. I do have a prejudice against his work due to the arguments in the field in which I am an expert, pharmacology.

Kurt Cobain's Suicide Note

Next Up: Marilyn Monroe.

Martin Hill Ortiz is a professor of pharmacology and author of several novels. 

My new novel, The Missing Floor, is now available from Oliver-Heber books. The first in the series, Floor 24, is newly available in audio book format. The audiobook has quite a complimentary review here.

The Missing Floor

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The Coronavirus: Potential Treatments and Drugs to Potentially Avoid

Pharmacology and SARS-CoV-2

I have taught pharmacology, the science of drugs, going on thirty years. Several matters related to pharmacology have appeared regarding SARS-CoV-2. I will address two broad questions. First: do some drugs work against the virus? Second: do some drugs make the infection worse?



Let's start off with some perspective. All of this is new. Even a quick study rushed to publication takes months: and we are not many months into this infection. There is no definitive statement regarding any of these matters, just a handful of very recent publications along with too many anecdotal reports. In the early days of AIDS (of which I have some familiarity), a lot of the original information about treatment candidates proved to be born out of desperation rather than usefulness.

Coronaviruses, along with rhinoviruses and adenoviruses, are among those that cause the common cold. That's the bad news: common colds are common. They are readily transmissible and, as we all know, there is no cure for the common cold. Beyond that, SARS-CoV-2 is much more dangerous than a typical cold or flu.

On the other hand, treating the SARS-CoV-2 virus is not the same as curing the common cold. We are not targeting all of the potential "cold" viruses here: just one. That provides hope for vaccines, and perhaps, pharmaceutical agents. (Strictly speaking, vaccines are pharmaceutical agents, but for the sake of this piece, I'll only be talking about non-vaccine drugs.) Some of the drugs mentioned here were tested during previous SARS outbreak.

Potential Drugs to Treat Coronavirus

These are some of the drugs that have been put forward as to helping with COV-19 infection.

Oseltamivir (Tamiflu). This drug is taken orally to help curtail influenza disease course. It is useful only if the drug is taken within the first two days of symptoms. Even then, it will only briefly shorten the recovery time. Oseltamivir helps prevent newly-formed viral particles from escaping an infected cell and therefore infecting new cells. It does this by inhibiting the neuraminidase enzyme. It is available orally and that's probably why it is prescribed a lot: convenience. In contrast, zanamivir (Relenza) is an inhalant that also inhibits neuraminidase used for flu. It has less side effects than oseltamivir because it is an inhalant: less gets to the blood, more hangs around the lungs where it is needed. Perhaps the best thing about oseltamivir is that it can be used for prophylaxis of the flu, which is especially helpful in high intensity infection settings such as nursing homes.

I've never been a big fan of oseltamivir. Its window of use is brief, its maximum effect is limited, and its side effects are potentially problematic. When I was hospitalized for bacterial pneumonia I was started on oseltamivir -- six days after arrival. That made no sense to me unless there was a concern I was coming down with a secondary infection. I experienced hallucinations. I can't be sure it was the oseltamivir, but delirium is one of its side effects.

Oseltamivir has not been shown to be effective in the previous SARS outbreak, nor did it change long-term outcomes of previously infected SARS patients. It is unlikely that it will work for the current coronavirus.

Favipiravir (Avigan) is fascinating. It has been shown to have efficacy for a variety of RNA-viruses. It has been approved for use in China, Japan, and Italy and has made it through a pair of Phase 3 studies in the US for the treatment of influenza. (China and Italy approved it just this past week.) Its mechanism of action is similar to that of ribavirin and remdesivir (below): they all inhibit RNA virus RNA polymerase.

On March 17, China announced that they had completed clinical studies for favipiravir and that it was helpful in recovery from the disease. To quote:

"The Third People's Hospital of Shenzhen in Guangdong province conducted a clinical trial on 80 patients, with 35 receiving the drug. The results have shown patients treated with favipiravir took four days before being tested negative, whereas the control group took 11 days."

That's a pretty dramatic difference. It is said to not be helpful in severe disease. As I discussed in my pharmacology class, with severe viral diseases such as influenza, all the cells that are going to be infected are infected.

I am surprised by their description of "no obvious adverse effects," same source as above, however, Phase 2 trials in the US showed a low degree of side effects.

Phase 3 studies against influenza virus were finished in 2015. No results have been presented. That suggests the results were not good, at least against the flu virus. Good results get published and the drug is put in for approval.

Remdesivir is much like favipiravir, only earlier in being studied. It has the same mechanism of action. Studies are beginning now.

Lopinavir/ritonavir (Kaletra in combination). These are anti-HIV protease inhibitors. There is no reason to believe they should work on coronavirus and an initial study indicates that they don't.

Chloroquine (Araclen) and hydroxychloroquine are classical antimalarial drugs. For decades chloroquine was the drug of choice against malaria due to being effective while being safer than the others. Now chloroquine-resistant malaria dominates the world and, we have some newer choices that are more powerful, the artemisinins. Hydroxychloroquine is also an antiinflammatory and is used for rheumatoid arthritis.

When I said these are safer than other antimalarials, I didn't mean that they don't have any toxicities. Like quinine, chloroquine and hydroxychloroquine can affect blood sugar. It can cause headaches, diarrhea, and hemolytic anemia in patients with G-6-PD deficiency.

There has been one smallish study that found that azithromycin (an antibacterial protein synthesis inhibitor, Zithromax) and hydroxychloroquine helped to dramatically reduce the length the patient carried the virus and the amount of the virus. The drop out rate was high (6 out of 26) among those initially treated with three of those going to the ICU and one dying. All in all, the study is open for interpretation as either hopeful or problematic. As is usually the case, more studies are needed.

Another study from China found efficacy from chloroquine and remdesivir, in vitro. 

So how does chloroquine or hydroxychloroquine help? That's unknown. Perhaps it is the anti-inflammatory effect. The azithromycin might be preventing secondary bacterial pneumonia infection or it might be due antiviral properties that azithromycin is claimed to have. Furthermore, azithromycin is also an antiinflammatory. On the other hand, since chloroquine has been shown to be effective in vitro, that suggests its effect is more than the antiinflammatory actions.

Concerns about what drugs not to use.

ACE inhibitors / Angiotensin Receptor Blockers (ARBs)

These drugs are standard care for high blood pressure and are used as adjuncts in congestive heart failure. Do they make coronavirus symptoms worse? There are three reasons why this is suspected.

1) SARS-CoV-2 uses the angiotensin coverting enzyme type-2 as a cell receptor for infection.
2) ACE inhibitors, in particular, have been shown to upregulate angiotensin converting enzyme. 
3) Among the co-morbidities for death in Italy in one study, 74% of patients had high blood pressure. This might simply be because high blood pressure and age have a strong association. Age also presents a strong association with SARS-CoV-2 lethality.

In a recent commentary, it was strongly suggested that patients do not stop using these popular blood pressure medicines: the evidence for bad outcome with SARS-CoV-2 infection is not clear. The authors disclosed pharmaceutical ties. Nevertheless, the advice is generally sound.

Ibuprofen / NSAIDs / Acetaminophen.

Ibuprofen in particular was mentioned as something that might be avoided. The director of the National Institute of Allergy and Infectious Diseases, Anthony Fauci, suggests that this is an alarmist extrapolation from aspirin in viral infections causing Reyes' syndrome in children. Others have suggested that fever has a place in the body's fight against infections, and that NSAIDs and acetaminophen lower fever.

Let's take these one by one. The Reyes' concerns should not carry over to other NSAIDs and should not affect decisions in adults. For children, for pain and fever, it is generally recommended to avoid aspirin. Some physicians recommend acetaminophen. Acetaminophen overdose is so common, I would go with a non-aspirin NSAID.

Is lowering the fever in the case of a viral infection a bad strategy? Is the body fighting the infection with fever? In the case of bacterial infections this makes more sense to me. When culturing human pathogenic bacteria, the classic temperature of the heating device is 98.6 F (37 C). This concept to  doesn't pass over to viruses. Viruses in the blood are not going to affected by a fever. Viruses perform their main functions, including replication inside of cells, which I suspect are less susceptible to overall body temperature changes. That said, there is an argument that the induction of heat-shock proteins is protective. In the cited study, the temperature was raised to 40 C (104 F), which is a fairly heavy duty fever, the upper range below emergency.

Asthmatics are advised to avoid NSAIDs. This is because NSAIDs block the production of prostaglandins and the action of blocking the production of prostaglandins shunts the precursors over to leukotrienes, some of which mediate inflammation, and, in particular, mediate inflammation in asthma. If those leukotrienes are exacerbating symptoms in coronavirus patients with compromised respiration, this may be a concern. Of course, some asthma patients will have coronavirus. Perhaps using a leukotriene synthesis blocker such as zileuton could be helpful to overcome this.

The FDA is stating that there is not enough evidence to exclude the use of NSAIDS in coronavirus.

So, what's the bottom line? This is my take. If you have mild symptoms of fever and aches and you don't know if you have coronavirus, and you are over 12 years of age and don't have asthma, take an aspirin or other NSAID. The most significant exception to that rule is if you are allergic to aspirin. In the same situation if you're under 12, then try acetaminophen or ibuprofen. If you have coronavirus and you are not actively have problems breathing, then the NSAIDs are okay. For asthma, acetaminophen will not cause the problems with peripheral leukotrienes.

NSAIDs may be contraindicated if the infection is severe and with active respiratory problems. Even then, the evidence is out.

My primary sources in putting this together were (a) Anthony Fauci's March 18 podcast with the editor of the Journal of the American Medical Association, and (b) Derek Lowe's In the Pipeline blog as part of Science Translational Medicine, his March 6th and (c) March 19th entries.

(a) https://youtu.be/EXY76TKNy2Y
(b) https://blogs.sciencemag.org/pipeline/archives/2020/03/06/covid-19-small-molecule-therapies-reviewed
(c) https://blogs.sciencemag.org/pipeline/archives/2020/03/19/coronavirus-some-clinical-trial-data

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A Mystery Writer's Guide to Drugs and Poisons. Part One.

I have a doctorate in Pharmacology--the science behind drugs--and have taught the subject to medical students for twenty years. I have also taught Toxicology, the science of poisons. The two subjects overlap. As any pharmacologist can tell you, every drug can be a toxin, it just depends on the dose.

Drugs and Poisons.

Drugs and/or poisons take their place in mystery literature as murder weapons, as addictive substances related to character flaws or criminal ventures and, in thrillers, as potential terrorist threats which can wipe out whole cities.

On a less dramatic note, characters use drugs for their various ailments and may suffer from their side effects and it is important to get the details right.

Pharmacology and Toxicology are vast subjects with issues related to the thousands of drugs and poisons. In this series I will try to deal with some of the most common situations the mystery writer may encounter. First, however, some basics on how drugs and toxins work.

What Makes Drugs and Toxins Work.

The human body is run by chemicals that it produces. These can be hormones that are released by glands which act elsewhere in the body on organs and tissues or else they can be locally acting substances such as neurotransmitters. What's a neurotransmitter? Nerves, both those that run like wires around the body, and those that comprise the brain, act by releasing stimulants and depressants which affect tissues or act at another nerve. These chemicals are neurotransmitters and run the communication system of the body, giving orders to both the automatic systems that govern functions such as breathing and digestion and the voluntary system that controls movement and willful actions. Neurotransmitters also control the brain functions: consciousness, memory, wakefulness, euphoria, etc.

So, what does a drug do? In most cases* it either acts like the natural chemical or blocks the effect of the natural chemical at its site of action.

Let's have a couple of examples. You are probably familiar with adrenaline (also called epinephrine). It is a chemical released by the body in response to stress or danger. Among other actions, it opens up the lungs for breathing, it makes the heart beat faster, it raises the blood pressure and it directs blood flow to the skeletal muscles. The set of effects from adrenaline are often described as preparing you for "fight or flight."

Adrenaline can be given as a drug. Shock involves a precipitous drop in blood pressure. A doctor may want to raise blood pressure using adrenaline in the case of anaphylactic shock (the type of shock that occurs with a severe allergic reaction such as bee-sting allergies).

Adrenaline was formerly given for asthmatic attacks: it relaxes the bronchiole muscles of the lungs to make breathing easier. In this case, we get to a toxicity: adrenaline not only opens up the bronchioles, it causes the heart to race. It can cause death in those prone to heart attacks. As a general principle of toxicity, some people are more susceptible than others. There are other drugs which can be used for asthma that do not have this effect.

To get back to what I noted above, some drugs mimic while other block the effects of natural compounds. Instead of raising the blood pressure with adrenaline, you might want to lower the blood pressure by providing a drug that blocks the action of circulating adrenaline (and its companion which is released by nerve endings, noradrenaline). Such drugs are often called blockers or inhibitors or else by the more technical term, antagonists.

How Do Drugs Achieve Their Effect?

Drugs, and their natural chemical counterparts, work by binding to receptors which turn on or off cell processes. What is a receptor? The following analogy is over a century old. A drug is the key, the receptor is the lock (or ignition switch). The receptor is typically on the outside of a cell. The drug is carried by blood to the outside of the cells where the drug turns on the cells causing a tissue effect. Why a particular tissue? That's where the receptors are which fit the keys: adrenaline on the heart tissue (and blood vessels and elsewhere where it has its actions).

Let's look at another example. Acetylcholine is a neurotransmitter with many effects throughout the body. Nerves which go to the skin release acetylcholine causing a person to sweat. Nerves which go the salivary glands release acetylcholine causing a person to salivate.

Acetylcholine is also released at the nerves which connect the brain to the skeletal muscles. The skeletal muscles are those that control voluntary movement. Drugs that act like acetylcholine are given to patient with myasthenia gravis. Why? Myasthenia gravis is a disease in which a person's immune system attacks the acetylcholine receptors on the outside of skeletal muscles. The person thereby loses muscle strength. By acting like acetylcholine, a drug can activate some of the remaining receptors.

However, in other circumstances you might want to give a drug that blocks acetylcholine at the skeletal muscles. Why would you want to do that? These drugs (skeletal muscle blockers) are given prior to surgery to prevent the patient from flinching. (General anesthesia does not paralyze the patient, anymore than sleep does not paralyze us.) A good plot device: a murderer substitutes or cuts off the skeletal muscle blocker being infused during a delicate life-or-death surgical procedure.

Let's look at the skeletal muscle blockers from the point of view of poisons. Tubocurarine (Curare) paralyzes the muscles and was discovered by a researcher who noted South American tribes using poison-tipped blow darts to capture animals. It can be fatal in animals or humans because one set of skeletal muscles helps us to breathe. (During surgery, the patient is placed on mechanical ventilation.)

After curare was discovered, but well before it was purified well enough from its plant source to be used as a drug, it made for a popular poison in mystery stories. No one interested in murder cares whether a poison is pure enough to avoid additional toxic effects.

Another set of toxins work through the acetylcholine system. Popular as the villainous weapons in thrillers and popular with villains in real life (Saddam Hussein, the Tokyo attacks), the nerve gases first overload and then knock out the acetylcholine receptors. The effects are several fold. First you have the twitching and spasms from having the skeletal muscles activated. You have the sweat glands and salivary glands turned on. Then you have the skeletal muscles shut down, including those that help you breathe. The nerve gases make for the more terrifying sort of poisons in part because they are active in small concentrations, they can be absorbed by breathing and through the skin (not many toxins can), and they can be spread in a suspended gaseous form. They also make for great plot devices because they have specific antidotes—and not many poisons do.

The Differences Between Drugs and the Natural Body Chemicals.

Although human-made compounds such as adrenaline can be used as drugs, a general rule is that the body exquisitely regulates its own compounds, producing them as needed and then quickly stopping the effect. One of the main ways in which the body stops the action is by breaking down the chemical into ineffective parts (metabolites). Adrenaline has a half-life of about 2 to 3 minutes. Acetylcholine, at the nerve ending, has a half-life of seconds. One major difference between synthesized drugs and the natural compounds is that the synthesized drugs act for a longer time. For example, an asthmatic patient might be taking a drug that acts like adrenaline in the lungs but has a half-life of hours.

So what is half-life? Unless the drug (or toxin) overwhelms the body's system of elimination, the body will eliminate half of the drug dose in a given period of time. A simple illustration is this:

Digoxin (for heart failure or arrhythmias). Half-life: 40 hours.

• Concentration in blood. (micrograms per milliliter)

• Zero hour. First measure: 8 ug/mL
• 40 hours later: 4 ug/mL
• 40 more hours later: 2 ug/mL
• 40 more hours later: 1 ug/mL

The drug is disappearing by halves, moving like the traveler on Zeno's bridge.

I provide this table to overcome a misconception. Half-life is not how long a drug acts. It may still be acting the level of 1 ug/mL. -- Or else it may not, it may be at a concentration that is no longer causing an effect. Half-life describes the elimination of the drug. The elimination of its effect is determined by the lower threshold of its effective concentration.

Extending This To Other Drugs.

There are thousands of drugs belonging to hundreds of systems. The differences between them is what receptors they act on, individual toxicities, half-lives, and routes of administration. 

For example, morphine-related drugs act through receptors which are naturally activated by the endorphins. These receptors are located in places which cause pain relief, euphoria, depressed breathing (the main fatal effect with an overdose), and constipation (the common problematic side effect). These receptors are present in other places to provide minor effects such as pinpoint pupils.

Morphine-blockers such as naloxone (Narcan) block the receptors. This won't make much of a difference (they are blocking pain-relief rather than causing pain) unless someone has a dose of morphine-related drugs or endorphins present. In such a case the drug wipes out the euphoria, pain-relief, etc. and restores the breathing.


*A final note on this part. Does every drug either mimic or block the action of a natural human substance? No. One alternative mechanism of action comes with the antibiotics which interfere with the chemistry of microorganisms.

Next. Some Differences Between Drugs and Toxins.

Never Kill A Friend, Ransom Note Press

Never Kill A Friend is available for purchase in hard cover format and as an ebook.
The story follows Shelley Krieg, an African-American detective for the Washington DC Metro PD as she tries to undo a wrong which sent an innocent teenager to prison.

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