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 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. 

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. 

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 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 pills. 

Pentobarbital was recommended for only short term use as a sleep aid: beyond addiction, the patient became 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 doctor's 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. 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%. 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 "knock-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 black 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 LD50 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). 

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

Figuring in her weight and the average trichloroethanol concentration given in the above study, 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. Unlike the figure given for pentobarbital which has a relatively long half-life, her dose 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 pill or pill residue in her stomach in an interview. 

Noguchi: The autopsy found a large amount of Nembutal and chloral hydrate, 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 vomiting. Once they transit to the intestines, these interventions are marginally helpful.

This study show that the emptying time of the stomach is highly variable. Even within an hour after ingestion, sometimes you find the remnants of pills, sometimes you don'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. 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.

A final note. Pentobarbital has very different properties from the similarly named phenobarbital.

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