Is Heath Ledger's Death a Drug Addict's Overdose?

Jan 24 2008 Published by under Drug Abuse Science

The death of 28-yr old actor Heath Ledger is in the news, provoking a cynical "What, another celebrity drug overdose? Big deal!" response in some corners. Ledger fans, OTOH, are no doubt right there with the media reports which are going way, way out of their way to not speculate that this was indeed a drug overdose and, more to the point, whether this was the result of an addiction to drugs. Gasp. Of course it was.


Or so suspects the drug abuse scientist anyway. (Some may have another take on such an unhappy event.) What do we know so far? Let's take it from the above linked AP report because there appears to be little variance in the current reporting.

Ledger told The New York Times in November ...that he was struggling with sleeplessness and had taken the sleep aid Ambien...There were six different types of prescription drugs in the room, including pills to treat insomnia and anxiety, and an antihistamine, according to two law enforcement officials who spoke on condition of anonymity because the investigation is ongoing.

Okay, so we're talking about Ambien (zolpidem; clinical-type warnings here) which is a non-benzodiazepine (Valium being the most familiar of the benzodiazepines) tranquilizer or hypnotic drug (Wikipedia does okay on Zolpidem). To quickly overview, zolpidem interacts with the GABAA receptor type to increase release of GABA, a generally inhibitory neurotransmitter. The benzodiazepines have similar effects. Most importantly, zolpidem, like Valium, et alia, is readily abused and repeated use can result in dependence.
This brings us to the opinions of Ledger's pals, which are interesting:

Lee Daniels, who produced the critically acclaimed 2001 movie "Monster's Ball," in which Ledger starred, strongly disputed any notion that Ledger had a drug problem.
"The definition of substance abuse is really up to one's perspective," Daniels said. "I didn't see him as a drug addict. I saw him as someone who enjoyed life. I know drug addicts -- he was not a drug addict."

Now if that isn't a backhanded way of saying "Yeah, he takes some recreational drugs but not too much", I don't know what it is. And sorry, no, you don't know "drug addicts". And the definition is not "up to one's perspective", given that we have formal diagnostic criteria for drug abuse. There's a nice little overview here. Some general points about drug dependence for today's discussion are:

1. Tolerance, as defined by either of the following:

(a) A need for markedly increased amounts of the substance to achieve intoxication or the desired effect
or
(b) Markedly diminished effect with continued use of the same amount of the substance.

2. Withdrawal, as manifested by either of the following:

(a) The characteristic withdrawal syndrome for the substance
or
(b) The same (or closely related) substance is taken to relieve or avoid withdrawal symptoms.

3. The substance is often taken in larger amounts or over a longer period than intended.
-snip-
7. The substance use is continued despite knowledge of having a persistent physical or psychological problem
that is likely to have been caused or exacerbated by the substance

Six prescriptions drugs (although we don't know the identity of the others other than "an antihistamine"). An admission that drugs were needed for "anxiety" and "insomnia". A report from a friend that he was "edgy and anxious" and "couldn't really relax" over the past weeks. Sure, maybe he was distressed over not seeing his kid, unknown professional woes, doesn't like the holiday season, had jetlag and job stress. Sure. However the evidence is not inconsistent with a guy addicted to hypnotics, who may have been trying to get off them, losing his tolerance and, when relapsing taking a previously well-tolerated dose that is now dangerous.
Or it could have been some complex drug interaction. Theres a nice little overview from Cubala et al. in British Journal of Clinical Pharmacology's pre-press list.

Zolpidem metabolism is mediated by human cytochromes P450 (CYP), with a dominant role of CYP3A4 and a contributory role of CYP2C9, 1A2, 2D6 and 2C19 in decreasing order of importance, but not of 2A6, 2E1 or 2C8 [1, 5]. Thus the pharmacokinetic interactions may occur in patients receiving a number of concomitant treatments, including analgesics, antiarrythmics, antibiotics, antiepileptics, antihistamines, antineoplasm, antiparkinsonian drugs, antiprogestorone agents, antirejection drugs, β-blockers, calcium-channel blockers, HMG-CoA reductase inhibitors, non-nulceoside reverse transcriptase inhibitors, protease inhibitors, proton pump inhibitors, steroids and triptans

Okay, the point here is not to scream that Ledger was a drug addict...precisely. It is to ask why our prejudices against mental disorders, behavioral disorders and drug abuse in particular lead to a certain kind of limited and illogical reporting. Why his buddies are quick to assert he wasn't addicted to drugs when any of you who have actually known, say even an alcoholic, realize that they are really. good. at. hiding. their. drug. intake!
When a 28-yr old guy dies mysteriously in his bedroom there are only so many likely hypotheses to pursue. Congenital defect in heart or brain vasculature leading to cardiac arrest or some sort of intracerebral vascular accident (stroke, etc). Foul play (no evidence apparently). Drug overdose. And there is plenty of evidence for this latter. I should have mentioned, perhaps, that the mechanism of death, were it related to the zolpidem would be, as the Wikipedia entry describes it for benzodiazepines, a suppression of central nervous system, cardiac and respiratory function. The effect would be similar to "putting your pet to sleep" for those of you who have had this unhappy experience although in veterinary practice they would typically use the somewhat-related barbiturate class of drugs (benzo's were popularized as having barbiturate-like effects without the same level of risk of nasty side effects such as death, btw). It is the most likely scenario that this was a drug overdose.
Of course, then we have to get into the question of why. Was it suicide (ohh, bad on him)? Drug addiction (ohh, bad on him)? Accidental drug interaction (wasn't reading his pamphlet, ooh, bad on him)? So the media acts like we couldn't possibly rank possible reasons for Ledger's death so why talk about it? This is stupid. We are missing an opportunity to communicate some important principles of recreational and therapeutic drug pharmacology to the essential population.
The Monitoring the Future survey (you might as well bookmark this if you plan to keep reading my stuff on drug abuse) tells us (see Volume 2, Table 2-3) that our target 12th grade through young adult (19-28) slices of the US population run 30-day prevalence rates for "tranquilizers" of 2-3% (with about 10% using annually). They could stand to be better educated on the nature of respiratory suppressant effects of some drugs that they find enjoyable, about drug metabolism interactions, about drug pharmacodynamic interactions (for example two compounds acting at different sites on the same receptor to produce a potentiated effect over one alone) and, yes, tolerance and loss of tolerance that occurs over the course of chronic drug use and abstinence. And that requires some science.
--
Update 1/25/08: I somehow missed the claim from TMZ that the benzodiazepines Valium (diazepam) and Xanax (alprazolam) were among the drugs found. More support for the "trying to get clean from substance abuse" hypothesis here and here.

26 responses so far

  • PhysioProf says:

    "[W]hen relapsing taking a previously well-tolerated dose that is now dangerous."
    Ding!

  • I was really hoping that someone with expertise on Science Blogs would comment about this aspect of Ledger's death. We're awfully quick to medicate in this country, and the number of prescription drugs found with Ledger's body are a testament to that. no wonder so many people get addicted. Thanks for an excellent post.

  • DrugMonkey says:

    Well, Jennifer, do keep in mind that I'm waaaaaay out in front of the evidence on this one. Which is part of my point, namely that normal journalists should be getting the science answers out. What does an "inconclusive" supposed "autopsy" mean and what info will be coming back in a fortnight? Like perhaps they don't have a tox screen back yet? That's almost like they got the chest cavity done but not the cranium and said "well we're done with the autopsy, it's inconclusive. but we'll have more info in a couple of hours." The concept should be "incomplete" rather than "inconclusive" perhaps.
    "We're awfully quick to medicate in this country, and the number of prescription drugs found with Ledger's body are a testament to that"
    Not necessarily. People who ARE addicted to prescription meds and don't have a street source like Limbaugh did are extremely good at doctor shopping and manipulation. Yes there are systems in place to try to combat this but still, these people are good at it. The comment that "some of the prescriptions were from Europe" is fairly interesting in this regard. Although better info would have been something like "4 scripts for the same or closely related drugs from 4 different docs" versus "just the one doc prescribed a bunch of different stuff".

  • PhysioProf says:

    "Which is part of my point, namely that normal journalists should be getting the science answers out."
    I think you need to recalibrate your conception of what is "normal" for so-called journalists in this country.

  • This is an absolutely superb teaching post and public information resource. Thanks so much for taking the time to not only put Ledger's case in proper context, but also to comment on the needless and incredibly unnerving social stigma of mental illnesses and substance dependence.
    Yes, even with the whiz-bang ABI mass specs we see on CSI it'll take a few more days to know exactly what was in his bloodstream and GI tract.
    You folks are a fabulous addition to ScienceBlogs - congratulations and welcome.

  • Brownian says:

    Just came over from Pharyngula.
    As someone who has experimented with various street drugs in the past, has friends who still use marijuana regularly, and is now being treated for depression with SSRIs and cognitive behavioural therapy, I look forward to more posts like this.

  • Cpl. Cam says:

    Thanks for this illuminating post. I also came over from pharyngula and I must thank P.Z. for the introduction. I had been firmly in the suicide camp, mainly because of an anti-msm bias I've developed. When I heard they found an empty bottle of Ambien and an empty bottle of over the counter sleep aid and were calling it a drug-related death my first thought was "If they find me hanging from a noose in the basement will they call it a rope-related death." My loathing of our society's tendancy to blame drugs for human failings clouded my objectivity. Thank you for opening my eyes to the fact that this could very well have been an accidental overdose, if that's the case this is tragic.

  • LeeLeeOne says:

    "We are missing an opportunity to communicate some important principles of recreational and therapeutic drug pharmacology to the essential population."
    FINALLY! PULEEEZE! communication! - OPEN communication!
    Um, humbly thank you for my rant.

  • Julie Stahlhut says:

    Great post -- this could definitely be a teaching moment. More than a few people have died from drug overdoses when they weren't trying to either kill themselves or have a good time, but just trying to knock themselves out because of anxiety or insomnia. Some of us are old enough to remember the writer Dorothy Kilgallen, who (conspiracy theories aside) probably just made the mistake of taking too many drinks and too many sleeping pills on the same night. Also, Heath Ledger had been quoted as saying he'd at least once taken a double dose of Ambien just to get an hour of sleep.
    The public needs to be made aware that prescribed controlled drugs aren't evil, but are simply chemicals that have both benefits and risks. An acquaintance of mine was killed in a freak accident because she'd been dealing with bipolar disorder, wasn't exactly diligent about taking her meds, and had purportedly been using sleeping pills sporadically and reacting to them in some unpredictable ways. She left her house at night in a confused state, wandered into the street, and got run over.
    Of course, most people who use medications for pain, insomnia, or anxiety do not get addicted, don't kill themselves with the drugs, and don't die of accidental overdoses. Any of us who have ever taken necessary pain meds after surgery or an injury would hate to see people needlessly refuse them.

  • wenchacha says:

    I appreciate your commentary on Heath Ledger's death. The science behind what happened is something we should all know more about, rather than less.
    "Just say NO" or "Drugs are Bad!" lessons rarely discuss the science or biology involved in drug use. While it's great that a pharmacy promises to alert us to drug interaction issues with our prescriptions, it would be better to know what could actually happen and the risks involved.

  • BlazingDragon says:

    My experience is that Ambien is not nearly as "addictive" as benzodiazepines. I've had both. I have used Ambien off and on for years (for over a year at a time) with little tolerance developing. Maybe I'm unusual (wouldn't be the first FDA approved substance I have unusual reactions to). I don't think it's fair to put Ambien in the same sentence as true benzodiazepines. They are similar, but there are very important differences. I noticed tolerance within a few weeks when I was put on a true benzodiazepine. Ambien will still knock me on my ass at the same dose after using it every night for a year. As a rule, I strongly dislike the way benzodiazepines make me feel, whereas Ambien doesn't do much at all to the way I feel (the amnesia from the time between when I take it and when I go to sleep is disconcerting once in awhile).
    Please don't scare people away from Ambien. People do need to be warned about the side effects of FDA-approved medicines (people seem to assume that if it is FDA approved, it is somehow safe). Please don't go into hyperbole over Ambien while trying to educate the public.
    As for Ledger's death, I dunno if he unwittingly combined incompatible medicines (my initial thought) or if he was an actual addict that had an accidental overdose (which I think is more likely after reading your post), or if he committed suicide (I don't think it's likely). I did cringe a bit when I read "inconclusive autopsy with further test results to follow." Why couldn't the press reports just report what happened (which is that Ledger died of some kind of poisoning/overdose that wouldn't leave any signs in a physical autopsy and they were waiting for toxicological screens)? The state of journalism is almost as pitiful as the scientific literacy of the general population.

  • raised by wolves says:

    Thanks for the good discussion. I also wondered if he might have taken some of
    the other drugs while in that odd but well documented sleepwalking, eating, pill-taking reverie so often described by Ambien users. Coupled with the amnesia, it would be as dangerous as Jack Nicholson warned him. Also, do you think a quicker 911 call could have saved him? I think it was about 20-30 minute delay.

  • miskwaa says:

    Thank you for your site. There is very little which speaks honestly to this subject. Being a recovering addict for many years now, I have seen and watched many drop dead slowly or quickly. In this case the victim is legitimate(liked), so he gets sympathy. Terms like "tragedy" will be used. If it was an accident, we will get warnings. If it was an overdose, we will have the tortured artist effect. Then the Doctors will be blamed, unless we find out he was chasing multiple scripts. Alcohol still kills so many more than anything else discussion need not even begin. One person I knew went through a spinal tap to get a large dose of loritab, which he promptly took all at once. He is dead from an overdose now. He was illegitimate; even his fellow addicts said " if he'd just go to meetings..blah blah blah". I used to think the same way. Finally, after staying away from condemnation,observing for a bit, and becoming a scientist myself, I asked some questions. Would an organism knowingly threaten its own survival without some underlying drive? Would a woman, by natural choice, choose to spend her money on a crystalline dopamine (meth) enhancer rather than buy her children supper? In this case, it is bio-chemical, meaning merely neurotransmitters. Scientists, of course, have known this for years, but the larger culture, including the recovering community, still sees this within as a choice. If they had just done this or that...My observations tell me some adddicts have a degree of disease less then others. Someone who drinks themselves to death at 30 despite intervention has the equivalent of stage 4 lung carcinoma; I, with intervention at a young age ( luckily I was in the state which first invented in-patient treatment, was able to arrest and go into remission. Maybe I was in the equivalent of an early stage 2 or 3. Ok, enough of my rant. I merely think we need to chnage our metaphor for understanding what we see.

  • Monado says:

    It's conceivable that he did commit suicide. At 28 your life can seem to be over. His marriage had broken up and it seeems he was unsure of his professional abilities. I doubt we'll ever know.

  • Jewel says:

    I also came over from Pharyngula and I want to thank you for such an informative article. My first thought when the press mentioned possible overdose was bad drug combining. However, after reading your article, it makes more sense for it to be a tolerance issue. A little more time will tell.
    I've always thought the "Just say NO" campaigns were way off base. People need to be educated so that they can make better informed decisions.
    Anyway, thanks.

  • btw, I didn't really mean ABI way up there - must have RT-PCR on the brain. I meant Agilent. Speaking of which, The Scientist blog has a nice post on how instrumentation manufacturers get their stuff on CSI, really.

  • Dawn says:

    I haven't read all of the posts but I DID read that he was prescribed drugs here in the states and abroad in Europe. Why would a Doctor prescribe MULTI benzo's? It's a rule of thumb that you NEVER mix benzo's. I don't understand. Perhaps Heath didn't tell both Doctor's about the other drugs he was taking. It could have lead to his ultimate demise. Very sad.

  • AaronRowe says:

    I cited your post here on my blog.

  • Georgia Dawes says:

    I doubt that Heath Ledger committed suicide. He bought groceries the evening prior to his death, and had booked a massage for 3 p.m. the day of his death. Not indicative of plans to check out. On the other hand, one report stated that his Australian Oscar for Brokeback was found face down at the foot of his bad. Not a great sign. Re: addiction. One drug found with him was Ativan. This is HIGHLY addictive. I took it for only a week once, following surgery, and was shocked at how quickly I felt a dependence (I stopped taking it). I think the most likely scenario is that he went out and got high (alcohol, coke) and then came home and took some meds to sleep, and the combination is what killed him. Such a wonderful talented actor. Touched so many people. Very sad.

  • Tod Crean says:

    I thought this actor was just about as versatile as one can be. He was pretty convincing in pretty much every movie I saw him in. His death was clearly an accident. I was recently rx'd Ativan and only took it for a short time. But strangely, when you take the medication you don't get a "high". I can see maybe somebody taking more than they really need because they think the med is not taking affect. He probably miscalculated by upping the dosage and the pendulum swung too far the other way. Life sure is a fragile gift. This is a terrible shame. Great actor at the top of his game.

  • Just in from AP this afternoon:

    The cause of death was "acute intoxication by the combined effects of oxycodone, hydrocodone, diazepam, temazepam, alprazolam and doxylamine," spokeswoman Ellen Borakove said in a statement.

    I haven't seen a copy of the report itself (maybe Smoking Gun will have it soon) but plasma concentrations of each were not noted. However, this was the statement from the family:

    In a statement released through Ledger's publicist, the actor's father, Kim, said Wednesday: "While no medications were taken in excess, we learned today the combination of doctor-prescribed drugs proved lethal for our boy. Heath's accidental death serves as a caution to the hidden dangers of combining prescription medication, even at low dosage."

    Is it me or would the redundant use of two opioids and three benzodiazepines (plus an antihistamine with good anticholinergic activity) seem to indicate an intentional rather than accidental overdose? Not that it matters and this has already been painful enough for the family but I'm just thinking out loud.

  • N.B. says:

    Great post. I threw in my two cents on the accidental versus intentional issue on Abel's blog already; I really think that this is a no-brainer. Either way, DrugMonkey, you've done a fantastic job illustrating some excellent points. Prescription drug abuse is getting more and more common in America as teens and adults alike come to the conclusion that it's a "safer" way to get their kicks. It's safer than buying heroin in a back alley, but it's not safe. You can still get addicted, and you can still OD and die.
    The public needs to be made aware that prescribed controlled drugs aren't evil, but are simply chemicals that have both benefits and risks.
    Thank you, thank you, THANK you Julie. One of my biggest pet peeves is when people tack morality onto a legitimate medical need just because the drugs in question have been labeled as controlled substances--which is frequently more about politics than it is about science. I've encountered patients who refused to take opioids, even when in pain, because they've been conditioned to believe that it's immoral.
    Drugs are a neutral entity. Used properly, they can be used to alleviate pain and suffering. Used improperly, they can cause harm or death. Instead of teaching the public to fear drugs, we should be teaching them to respect them.

  • m.w. says:

    This is the first time I've seen someone finally take this stance, and I'm thankful that you did.
    The statement released by Ledger's manager stated something about Heath dying from an accidental overdose due to "a combination of doctor-prescribed drugs", which though truthful, seems like they're shaking the blame away from this fact: yes, the drugs may have been been prescribed to him, but he was not using them AS PRESCRIBED.
    I find it striking that very few people in Hollywood are willing to describe Heath Ledger as a "drug abuser" for the only reason that the drugs were from a prescription. IMHO prescription drug abuse is not any more acceptable, nor obviously any less dangerous, than using street drugs like heroin and cocaine (case in point, some of the drugs found in the toxicology report are quite similar, biochemically, to street opiates). Which is why your blog is helpful to illustrate and educate that prescription drug abuse is still drug abuse.
    thanks for letting me share my opinion, and thanks for your blog.

  • L.C. says:

    As another visitor from Pharyngula, I too would like to thank you for the incredibly informative article.
    According to one of the many reports I've read on the official cause of Heath Ledger's death, a Pharmacology Professor from Duke University (Cindy Kuhn) has been attributed with the following comment:
    "Kuhn said some of the drugs are long-lasting and Ledger could have taken them over a period of several days."
    Can someone tell me if there is any basis of fact in this, bearing in mind it hasn't been made public what the concentration of each individual drug was in his blood?

  • DrugMonkey says:

    Thanks for the tip LC. From this AP report we get the following

    "This is not rock star wretched excess," said Cindy Kuhn, a pharmacology professor at Duke University. "This is a situation that could happen to plenty of people with prescriptions for these kind of drugs."

    Kuhn said some of the drugs are long-lasting and Ledger could have taken them over a period of several days. The medical examiner's office wouldn't say what concentrations of each drug were found in Ledger's blood.

    Which is an excellent point. The assays to detect drugs are really quite sensitive and it is possible that drugs could have been taken in sequence with sufficient interval between that the cumulative hit is negligible. With that said, however, the reporting I've seen on the Medical Examiner report says the official decision was death resulting from "acute intoxication" which suggests that the ME interpretation of the drug levels found suggests concurrent dosing. or at the least, dosing within a relevant window for cumulative effects.

  • L.C. says:

    Thanks for your response DrugMonkey. It's nice to have found somewhere where some of the "How?" and "Why?"'s surrounding Heath Ledger's passing can be discussed without being subjected to the ignorant, ill-informed and downright tasteless comments that proliferate the mainstream news pages public Comment Boards.
    Having said that, I found another news article at USA Today that could explain the "acute intoxication" you describe above:
    http://www.usatoday.com/life/people/2008-02-06-ledger-drug-side_N.htm#uslPageReturn
    "In addition, Lackner says, "benzodiazepines, even in a relatively healthy person, can cause memory problems." Ledger was found to have taken three of them, Valium and Xanax, prescribed for anxiety, and Restoril, prescribed for sleep. It's possible, Lackner says, that Ledger forgot that he had already taken one or two of the drugs and took a second or a third."
    Mr Lackner is cited in the article as "a professor in the department of experimental and clinical pharmacology at the University of Minnesota College of Pharmacy".
    Again, I have no idea how much of the above is based in fact.
    I would like to state at this point that I'm not some dedicated Heath Ledger fan in denial of what could be a fatal flaw in his personality - his addiction to drugs, prescribed or otherwise. I'm just a casual admirer of his work who is trying to see the whole picture after such a senseless tragedy.
    Some of the most commonly reported points I have seen are:
    1. Six different drugs - two each of sleeping pills, anti-anxiety meds and painkillers. This would suggest to me two separate prescriptions.
    2. Three of the six drugs were sourced "in Europe". I'd speculate that he got these whilst filming with Terry Gilliam here in the UK. Perhaps he just ran out of his usual drugs, or his prescription wasn't helping the suspected "walking pneumonia" that he has been reported to have been suffering from. Whatever the reason, it would explain the doubling up of each of his medications, without him having gone "doctor shopping".
    3. His public admission that a single dose of Ambien wasn't enough to alleviate his sleeping problems, and even a double dose only gave him an hour of sleep. Whether this was because of an addiction to the drug that increased his toleration, or a more deeply rooted psychological problem, we'll never know. However, it appears (at least to me) that for every unnamed source proclaiming his status as a substance abuser and an addict, there are an equal number of people ready to stand up and be named who state that he wasn't even drinking alcohol in the months prior to his death.
    For me, the above points make it difficult to simply accept that he was an addict, although I also wouldn't dismiss the theory entirely. Let's just say I have "reasonable doubt". 🙂
    I'd appreciate any insights into this report you may have. I'm sure you'll be able to help me put all of the facts into perspective.
    Thanks again.

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