Friday, 28 September 2012

Why Addicts Overdose: Learned Tolerance

At first glance, the question of why addicts overdose seems absurd given the apparent straight-forwardness of the situation; an addict enjoys taking a drug, over time takes more of it, and eventually takes more than his body can handle which results in an overdose. However, things are not quite so simple. Since the victims of overdose are typically long-term users rather than novices, we can expect that they would have an extensive history with the substance and as a consequence will have developed a significant tolerance to the drug, and (looking specifically at heroin) this means that the user would need high levels of the drug to induce a fatal respiratory depression. When we compare heroin addicts who died from an overdose versus those who died through homicide, we find that the majority of victims in the "overdose" group had no higher levels of morphine in their blood than the comparison group1. The conclusion of this study was that, for the majority of overdose victims, the death could not be attributed to a toxic quantity of morphine in the blood. Even 30 years ago, the problems with the standard "overdose" story were succinctly summarised by Brecher2, who said:
  1. the deaths cannot be due to overdose,
  2. there has never been any evidence that they are due to overdose,
  3. there has long been a plethora of evidence demonstrating they are not due to overdose.

To understand why people have claimed that it is a misnomer to attribute these deaths to the traditional understanding of "overdose", we have to look at the factors that influence the development of drug tolerance and why the usual processes of tolerance failed. Tolerance is usually defined as the decreasing effects of a drug through repeated administrations, but even as far back as the 60's researchers were arguing that a complete explanation of tolerance requires an element of learning. This was argued on the basis that there were findings that could only be explained from a learning perspective; for example, the observation that the analgesic effect of morphine can persist in rats even after a number of drug-free months3.

Due to the way we normally conceive of 'tolerance' and our reliance on the purely physiological model, the idea that learning affects our biological tolerance to drugs can be quite a difficult concept to get our heads around. However, after looking at how classical conditioning can affect our response to the placebo effect (and the functioning of our immune system), we can look at how classical conditioning could play a role in drug tolerance. By looking at how classical conditioning was proposed to work by Pavlov, with a previously neutral stimulus (e.g. a bell) being paired with a unconditioned stimulus (e.g. food) and the neutral stimulus taking on the value of the unconditioned stimulus to produce the same effects (the sound of the bell becoming capable of making a dog salivate in the same way food does), we can begin to understand how classical conditioning could affect drug tolerance.

Instead of treating this as speculation or an elaborate metaphor for how learning could explain these anomalies in tolerance research, Siegel (in his seminal paper "Evidence from Rats that Morphine Tolerance is a Learned Response"4) set about testing the proposal and presenting evidence for the notion of behavioral tolerance. His demonstration involved heating up the paws of rats to induce a pain response and administering morphine across sessions to observe how their tolerance developed. Control rats (with no pain relief) started experiencing pain at around 12 seconds, whereas the morphine rats didn't experience it until around 24 seconds. However, by about the fourth session, what we find is that the 'morphine rats' started experiencing pain at around 12 seconds, like the control group.

So far, this is entirely expected - repeated exposure to drugs commonly produces a tolerance effect where we start needing more of the same drug to produce the original effect. This is where it gets interesting though, as on the fifth session, after the rats had demonstrated complete tolerance to the drug, Siegel moved the rats to a new location and ran the exact same procedure again. This time the morphine response produced the same effect as it did in rats that had never received a morphine injection, and the rats did not experience pain until around 28 seconds. In other words, simply changing the location of the rats completely removed the tolerance that had been built up to the morphine.


In terms of drug users, what this means is that their tolerance is not only a product of the physical substance and its interaction with their physiological structures, but it is also partly a function of the context cues that become associated with it through repeated exposure. This means that if a heroin addict repeatedly injects themselves in a similar environment, like their bedroom, then the cues associated with their bedroom will take on the ability to elicit a biological response that prepares the body for the drug (thus producing tolerance). The problem occurs when the heroin addict takes the drug elsewhere, like in a park or at the house of an acquaintance where, without the additional environmental cues to produce the tolerance response, the addict unknowingly "overdoses" by taking the same amount of the drug as they normally would. As we now know, the tolerance that they have developed over the years has now disappeared and so taking the level of drug that they have become accustomed to will be in far excess of what their behavioral tolerance can account for.

To better understand this effect, look at what happens when people who are used to drinking beer and wine in bars go on holiday and have a few drinks on the beach or at a barbecue in a park. After a couple of drinks, a few people will comment on how tipsy they are getting and often attribute it to the 'heat', but as we can see from the above discussion, it seems more likely that the culprit is the change of environment. The tolerance level of the drinker here is not the same as what it is when they are in the pub and it has effectively been reset back to a state of near-zero tolerance. They have, more or less, reverted to 15-year olds trying to keep up with their dad's drinking schedule.


1. Monforte, J. R., (1977). Some observations concerning blood morphine concentrations in narcotic addicts. Journal of Forensic Sciences, 22, 718-724.

2. Brecher, E. M., (1972). Licit and Illicit Drugs. Boston: Little, Brown.

3. Cochin, J. & Kornetsky, C. (1964). Development and loss of tolerance to morphine in the rat after single and multiple injections. Journal of Pharmacology and Experimental Therapeutics, 145, 1-10.

4. Siegel, S. (1975). Evidence from rats that morphine tolerance is a learned response. Journal of comparative and physiological psychology, 89:489–506.


  1. Interesting, Mr Samsa.

    It is not uncommon to see reports of a rash of overdoses, usually attributed to the arrival of a particularly pure batch of heroin.

    How does this fit?


  2. Hey Goldenmane, thanks for checking out my blog!

    As for your question, sorry if I didn't make this clear enough but learned tolerance obviously isn't the only factor that contributes to overdoses. If someone takes massive amounts of some potentially lethal drug, then it doesn't matter whether they're in their grandma's basement or on a beach - they're probably going to overdose.

    So for the example you've given, I would speculate that it would account for a lot of the overdose cases in the Monforte analysis which were found to be higher than the control group (I think around 25% of the group tested significantly higher levels of the drug in their blood).

    What I was trying to get at in my post is that there are a number of factors that need to be considered when looking at overdose cases, and these can be basically summed up as physical tolerance and learned tolerance. Some overdose cases will likely be due to purely physical tolerance (like the example you give), some will be due to purely learned tolerance, and a lot will be a complex interaction between the two.


  3. Righto. Makes sense.

    I had figured that was what you were getting at - you've never been one to make outlandish statements - but I just felt the need to clarify.

    Nice blog, btw. I've added it to my list of regular reading.

    1. Thanks for raising the issue. It's always good to hear some feedback and criticism of the posts I've made, as I think a lot of people try to be nice when you start a new blog so poorly formed thoughts and badly written posts get the generic "Interesting post" comments, rather than actual feedback I'd need to improve.

  4. I was thinking about this recently, actually, in terms of my own experience as a bit of a drinker.

    What follows is anecdotal only, of course, but it may be interesting if anyone chose to pursue it.

    I spent a decade drinking every night. I could drink quite a lot, and remain quite coherent - when I was drinking at home, alone. But on occasion I did find, when drinking elsewhere, that it seemed to take far less to make me very very drunk.

    So, I wonder if there is anything to that, or if it's just bollocks.

    Would be interesting to see some science on it, actually.

    1. Yeah the effect you're talking about is exactly the same as the one I've discussed in the article. Most of the research in the area is done with animals because it's the easiest way to control for all the variables, but there are human studies looking at the effect of environment and context on alcohol consumption (all consistent with the discussion above):

      Alcohol-Predictive Cues Enhance Tolerance to and Precipitate "Craving" for Alcohol in Social Drinkers

      The Effect of Drink Familiarity on Tolerance to Alcohol

      The Effect of Drink Familiarity on Tolerance to Alcohol (different article with the same name - obviously they're not very imaginative)

      Applying Laboratory Research: Drug Anticipation and the Treatment of Drug Addiction

      The Four-Loko Effect

      Unfortunately the most relevant ones to you there are behind paywalls.. Sorry about that. Basically, they looked at people drinking in familiar environments versus unfamiliar environments, and found that they got drunker faster in unfamiliar environments. The other studies show some other interesting effects, like getting drunker faster on unfamiliar drinks, so that might be relevant to your question.

      Hope that helps anyway!

  5. Thanks, Mike. Very interesting.

    Indeed, it's always nice to see that I'm not completely off base.

    It would be fascinating to explore further, actually, given the context in which I, generally, drank.

    (I trained in an unusual style of Chinese martial art, which involved drinking large quantities of alcohol. Some of the results of that training are, in retrospect, very interesting. Not many people can reliably do a backflip whilst drunk, for example.)

    1. Sounds like an interesting brand of martial arts. I think I may have met a guy who did something similar years ago whilst drunk on a beach with some friends. From the darkness he approached us, singing some drunken song and barely able to stand, then asked us if we'd like to see him do a backwards somersault. We say yes, and he proceeds to flip backwards over and over again all the way into the water.

      He was the weirdest, yet coolest, ninja ever.

  6. there is some truth 2 placebo but i can tell u from experience that heroin quality can easily vary by 1000+% & thats even if u have a regular day just 1 bag can make u 'fall out' or even kill u esp if fentanyl ...the next day a whole bundle can not be enough to get you 'off of E'....this is y ppl OD...U NEVER KNOW the cut %age/purity ....& is y it should be regulated / legal....if u don't agree its just because of a hidden cultural belief(which by definition means u dont know) & u think drug users deserve death....only reason theres such thing as a drug lord/cartel is cuz of the massive $ involved....the stuff gets thru via highest levels CIA etc....then they make $ busting ppl buying it....if it wasn't illegal ..would that cause u 2 use it? certainly NOT....its way past time 2 end the drug war game & have common sense like a few countries do....educate & tax....true anyone is better off without...but the present laws & attitudes only make things much literally creates criminals. So silly to think this a criminal issue & not a social/ spiritual one. & btw the worst drug by far is the one u can get @ any corner liquor store....kills way more then all other drugs combined in just is automotive accident contribution.

  7. Super-Duper site! I am Loving it!! Will come back again, Im taking your feed also, Thanks.
    long term treatment centers for addiction

  8. This comment has been removed by the author.