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.

TOLERANCE

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.

WHAT DOES THIS MEAN?

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.

REFERENCES:

<sup>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.↩</sup>