This common pharmacokinetic reaction will help you manage many bad medication reactions in psychiatric practice. But did it lead to Elvis Presley’s death? For Part 1 of this podcast, click here.

Publication Date: 2/6/2023
Duration: 23 mins, 26 seconds

Transcript: 

KELLIE NEWSOME: Last week, we ruled out amphetamines as the direct cause of Elvis Presley’s untimely death at the age of 42. Although he was a lifelong user of these dopaminergic drugs, he did not have them in his system at the time of his death. Instead, he had opioids and sedatives – mainly barbiturates and benzos. But did Elvis die of a sedative-opioid overdose?

Elvis did have a history of drug overdoses. In the 4 years before his death in 1977 he had four accidental overdoses, mainly on barbiturates, one of which put him in a 3-day coma. Opioids and sedatives cause death by stopping respiration, and Elvis’s multiple health problems – particularly COPD – put him at greater risk for respiratory suppression. 

But several teams of forensic pathologists have investigated his death, including one by the former president of the American Pathology Association, and their findings point to sudden death from a heart attack, not the slower death of respiratory suppression. The details are a little beyond the scope here – this is a psychiatry podcast – but they have to do with the timing of rigor mortis and cellular changes in the organs.

CHRIS AIKEN: So far, everything points to a heart attack caused by a sudden arrhythmia, something he was already at risk for because he had an enlarged heart or hypertrophic cardiomyopathy. Stimulant use and poor diet may have worsened his cardiac health, but hypertrophic cardiomyopathy is largely a genetic disorder that follows pretty straight-forward Mendellian inheritance. It is an autosomal dominant gene, which means you only need to inherit one copy of the gene to develop the disease.

We know that Elvis had this gene in the most – well, the most Elvis kind of way. It is a tale of tabloids, barbers, and kissing cousins. Bear with us.

KELLIE NEWSOME: Homer Gilleland was Elvis’s personal hair stylist for 20 years and collected clumps of the famous black hair. After Elvis’s death, Homer gave these strands away to friends and fans. Homer died in 1994, but in 2014, one of those friends sold a clump of hair to the tabloid-eque Dead Famous, a TV show that digs up the DNA sequences of the famous and infamous, from Marilyn Monroe to Adolph Hitler. When they unraveled Elvis’s DNA, they found the tell-tale code for an enlarged heart.

Elvis probably inherited this gene from his mother’s side. Several people on that side of the family died young, including his mother. Consanguineous marriage may have also played a role. Elvis’s maternal grandparents were first cousins, and marriages involving first cousins and closer are about twice as likely to result in congenital heart diseases like hypertrophic cardiomyopathy.

CHRIS AIKEN: Sounds like a solid case. The genetics line up with the coroner’s report – death by an arrhythmia caused by a congenital heart disease that enlarged Elvis’s heart. But what about Elvis’s lifestyle – the daily pounds of bacon and fried sandwiches – and the drug use? Could that have played a role? And what role did his other medical problems play. Elvis had 4 hospitalizations in the 4 years before his death for various medical problems, and the list of his diagnoses covers nearly every system in the body:

• Megacolon, gastric ulcer
• Fatty liver
• Traumatic brain injury
• Arthritis and herniated discs
• Hypertension and cardiomyopathy
• Prostatitis
• Glaucoma and labyrinthitis
• Prediabetes and high cholesterol
• COPD
• Antitripsin deficiency
• Tooth decay
• Anemia

KELLIE NEWSOME: Presley’s doctors suspected that he suffered from a multisystem disease but could not find it despite testing. Dr. Forest Tennant had special access to Elvis’s medical history as an expert witness in Presley’s wrongful death case, and he believes he has found it: Ehlers–Danlos syndrome, a genetic deficiency of collagen that affects connective tissue throughout the body. 

CHRIS AIKEN: Ehlers–Danlos may have led to Presley’s rise as well as his fall. Elvis had an unusual ability to hyperextend his joints, allowing him to swivel his hips, bend, and gyrate his legs all at the same time. It was a move that people have rarely seen before or since, but Elvis’s mother was known to do the same move in community dances. Remember, Ehlers–Danlos is a genetic disorder of connective tissue, and the primary symptom is loose, hyper-extendable joints that often become displaced from their sockets. 

Ehlers–Danlos may have also contributed to Elvis’s good looks, according to Dr. Tennant. By interfering with collagen production, the disorder leads to soft, smooth skin. Elvis also had unusually charismatic eyes – they were more spaced apart than average, with a dropping of the eyelid or ptosis. The overall impression is a sultry, sexy stare, but it is also a soft sign of Ehlers–Danlos. Elvis’s mother had similar facial features. Even Elvis’s voice – which covered two octaves with a wide, flexible range of vocal contours – might have been enabled by loosening of the connective tissue in his larynx.

Some of Elvis’s medical problems could also be explained by Ehlers–Danlos: Arthritis, colonic distension or “megacolon,” the early onset of glaucoma (that is why he wore sunglasses in the 1970’s), the and the frequent trips to the dentist (Ehlers–Danlos causes gum disease). Add to that the non-specific symptoms that often brought Elvis do the doctor: joint pain, fatigue, and headaches. Ehlers–Danlos is linked to higher rates of anxiety and mood disorders, ADHD, and chronic pain, which could explain his opioid use. Dr. Tennant even speculates that the connective tissue disorder allowed Elvis to eat unnaturally large quantities of food by distending his stomach just as it enlarged his colon 

But if Elvis had this genetic disorder, why wasn’t this discovered when the tabloids unrolled his DNA? There are 13 types of Ehlers–Danlos, and the most common form – hypermobile Ehlers Danlos, has no genetic test, although researchers at MUSC are closing in on a candidate gene. 

KELLIE NEWSOME: Another possible contribution to Elvis’s death was traumatic brain injury. Elvis had several concussions in his adult life, from various fights and accidents, but one in particular turned things for the worse. In 1967 he fell and hit his head on the bathtub. He lost consciousness and was found with a golf ball sized bruise on his forehead. 

Friends and family describe a change in Elvis after the TBI. He cursed more, and was difficult to talk to, often going off on obsessive tangents. This is when Elvis developed an obsession with law enforcement, collecting badges from different police precincts which he used to pull people over on the road, if only just to chat with them. 

He began to behave in ways that stretched the bounds of acceptability, even for a rock star. A few days before Christmas in 1970, he impulsively boarded a commercial jet with a gun and flew to Washington DC, where he wiggled his way into the White House, all the while with a loaded gun, and offered his services to Nixon in the war on drugs. Nixon gave Elvis what he wanted – a DEA badge – in exchange for a photo op. Maybe you’ve seen the black and white shot of the perplexed president shaking hands with a dazed Elvis – it is the most requested item from the National Archives. 

Whether or not these personality changes were due to the head injury, the drug use, the fame, or something else, we don’t know. But here’s a pearl to take with you. Nearly all medical problems worsen after a TBI. The brain does more than host our thoughts, feelings, and behavior. It regulates nearly every organ in the body, from the skin to the immune system. This is probably why chronic psychiatric illnesses and traumatic brain injury both take about 10 years off the lifespan. 

As the 1970’s progressed, Elvis’s physical health worsened in lockstep with his mental decline. He was sluggish, slurring his words, forgetting lyrics, and depended on a cocktail of steroids, amphetamines, barbiturates, and opioids to get through performances. By 1977, Elvis’s body was like a building on the verge of collapse, and a toothache may have tipped it over the edge. 

CHRIS AIKEN: On the day before his death, Elvis visited the dentist to fill a nagging cavity. After the procedure, he was sent home with a prescription for codeine. Unfortunately, Elvis had an allergy to codeine. A lot of patients who report this allergy, and these patients are also at risk for bad reactions to many psych meds at well. Here’s why. 

Codeine is a prodrug, which means it doesn’t do anything except cause side effects until it is converted into the active opioid morphine in the liver. That conversion takes place in the p450 system, mainly at the CYP-2D6 enzyme. If you’ve studied drug interactions or ever read a pharmacogenetic panel, you probably recognize 2D6 as the enzyme that metabolizes many psychiatric medications, including antipsychotics, tricyclics, venlafaxine, trazodone, and duloxetine.

When this enzyme is blocked, those psych meds will shoot to unusually high levels, causing lots of side effects. Two things can block it: drug interactions and poor metabolizer status on a genetic test. In the case of codeine, blockage at 2D6 causes the prodrug codeine to rise and it doesn’t get converted to morphine. When that happens, patients get all the side effects of codeine - itching, nausea, headache, fatigue – and none of the pain relief. A similar thing happens with tramadol.

We suspect that enzyme was one of the 7% of Caucasians who are poor metabolizers at CYP 2D6. When he died, codeine had barely converted to morphine. Codeine was at 10 times the normal level, and the codeine to morphine ratio was 36 to 1. In contrast, none of the other 8 controlled drugs in his system were elevated, indicating he took his meds as prescribed. 

Some physicians think that codeine toxicity was the final straw that broke the singers back. We dug into the science on this and came up uncertain. Although most opioids can cause arrhythmias of the type Elvis had by prolonging the QTc, it’s not clear if the prodrug codeine does this – all we could find was basic science research which suggests it does not. So we searched the literature looking for other reports of death in poor 2D6 metabolizers, and found none. What we did find was the opposite – it is people with ultrarapid 2D6 metabolism who are at risk for death on codeine because their 2D6 enzyme turns out morphine at an alarming rate, leading to sedation and respiratory depression. Ultrarapid 2D6 is about 3 times as rare as poor metabolism – about 1 in 50 people have it. And while there are many drug interactions that can slow down 2D6 – we know of none that can speed it up. 

And those drug interactions – the ones that slow 2D6 down – are among the most important in psychiatry. For one thing, it will raise levels of psych meds that pass through 2D6 – which in the case of tricyclics can be fatal. And in another setting, it can make your patient look like a drug seeker. Imagine if you are giving your patient a medicine that slows down 2D6, like asenapine, duloxetine, bupropion, and all of the SSRIs except the prams – citalopram and escitalopram. If they develop pain and are given codeine, they won’t be able to activate the drug, and may ask their doctor for higher and higher doses.

2D6 is a critical metabolic pathway in psychiatry, and Elvis’s story brings us to a final pearl, a sort of poor man’s genetic test. If your patient reports an allergy to a prodrug like codeine or tramadol and got no pain relief from the med, suspect poor 2D6 metabolism. About 1 in 12 Caucasians have this problem, and the rates are triple in Asians and some Hispanic and African groups. If they have poor metabolism at 2D6, they are going to get lots of side effects on psychiatric meds. Sometimes it may even look like they have bipolar disorder because they feel worse on antidepressants.

We’ve taken you down a lot of rabbit holes, but where do we end up?

Elvis Aaron Presley died on August 16, 1977 at the age of 42. Here’s our best guess of how it happened. He had a genetic heart condition – hypertrophic cardiomyopathy – and as his heart enlarged his risk of fatal arrhythmias rose. This dominant gene likely came from his mother’s side, and consanguineous marriage in his maternal grandparents made its transmission more likely. Sure, Elvis leaned too heavy on controlled drugs and an uncontrolled diet. But his lifestyle also had virtues – he was physically active, and steered clear of alcohol and nicotine.  Elvis’s lifestyle might have caught up with him eventually, but not at the age of 42. We don’t think he died of a drug overdose or poor diet. And although we are unsure of codeine’s contribution to arrhythmias, we can’t ignore the fact that he took the medication within a few hours of his death.

The Bottom Line: Elvis Presley died of cardiac arrest, caused by a genetic defect, and possibly exacerbated by high levels of the codeine-prodrug. End of story, at least for now.

KELLIE NEWSOME: A few weeks ago we mentioned that Rhode Island is one of the states in the US that reports the highest levels of stress. But we’d like to end this podcast in a happier place. For several years the pollsters at Gallop have asked over 300,000 people how much they enjoy life and how stressed they feel. Year after year, one state got the top prize for low stress and high joy: Hawaii, with Louisiana and Mississippi close behind. What do these states have in common? They aren’t wealthy, but they do have lots of stuff that money can’t buy: sunlight, water, festivities, and strong community and family bonds. Between Dr. Aiken and myself, we’ve lived in all 3 of them, and we can testify to that.

Elvis brought joy to millions. Maybe billions. He was born in Mississippi, started his career in Louisiana, and he loved spending time in Hawaii – he filmed 3 films and a concert special there. This year, Dr. Aiken and I spent our Christmas in Hawaii in the hotel where Elvis filmed Blue Hawaii and we got to see the last remaining Elvis impersonator in the state. In the middle of the concert, he walked down and hugged me. For a moment, it felt real, even if he couldn’t shake his legs and gyrate his hips at the same time.

In 2015, a group of psychologists conducted a test of destination memory in older adults. Have you ever had an older patient who felt terribly embarrassed by their memory problems, because they kept telling same stories to people? That’s a problem with destination memory. It is the memory of whom you told something to.

This study had older adults tell proverbs to pictures of faces – either unfamiliar faces or faces of celebrities like Elvis Presley. Later, they were asked which face they had told the proverb to, and their recall was much sharper for proverbs they had shared with the King.

KELLIE NEWSOME: Keep up with the latest research with Dr. Aiken’s DailyPsych feed on LinkedIn and Twitter (handle @chrisaikenmd) where he posts a new research study every day. Today’s study features the surprisingly small effect size of a drug that carries a large amount of hype: Esketamine. 

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The Carlat CME Institute is accredited by the ACCME to provide continuing medical education for physicians. Carlat CME Institute maintains responsibility for this program and its content. Carlat CME Institute designates this enduring material educational activity for a maximum of one quarter (.25) AMA PRA Category 1 Credits^TM. Physicians or psychologists should claim credit commensurate only with the extent of their participation in the activity.