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

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 GABA_A 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.