Classical Conditioning of Drug Tolerance

In the case of psychoactive drugs, drug tolerance is a condition in which repeated use of a drug leads to reductions in its psychological effects, thereby requiring progressively larger doses in order for similar effects to occur. Many factors affect the development of drug tolerance, and learning is one of them. A classic study by Siegel, Hinson, Krank, and McCully (1982) was one of the first to demonstrate this. The researchers found that rats can be classically conditioned to develop tolerance to heroin.

Siegel, et al. (1982) wanted to understand why some addicts died after taking a dose of the drug that they had taken many times before. The official cause of death in these cases usually was said to be a “drug overdose” because the dose was high enough to kill most people not addicted to the drug. These addicts, however, had developed a high level of tolerance to the lethal effects of the drug, so ascribing their deaths to an overdose couldn’t be correct.

The researchers hypothesized that the addicts’ tolerance was due, in part, to classical conditioning. That is, the situation is which they typically took the drug had become a conditioned stimulus (CS) that elicited a conditioned response (CR) involving a change in biological processes that prepared their bodies to counteract the lethal effects of the drug. This explanation may be easier to understand by looking at a case study described in Siegel (2001). The study was of a man suffering from severe pain because of pancreatic cancer. In order to reduce the pain, he received four injections of morphine per day. Over time, the dosage had been increased to a high level because of the tolerance he had developed to morphine’s pain-reducing effects.

The patient stayed in his bedroom (which was dimly lit and contained apparatus necessary for his care), and received injections in this environment. For some reason, after staying in this bedroom for about a month, the patient left his bed and went to the living room (which was brightly lit and different in many ways from the bedroom/sickroom). He was in considerable pain in the living room, and, as it was time for his next scheduled morphine administration, he was administered his usual dose of the drug. The patient quickly displayed signs of opiate overdose (constricted pupils, shallow breathing), and died a few hours later. (p. 510).

The explanation given by Siegel and his colleagues involved the classical conditioning of tolerance to the lethal effects of morphine. The explanation is outlined in Figure 1:

Figure 1. Classical conditioning of tolerance to morphine

As shown in Figure 1, the stimuli in the bedroom comprise a CS that produces a CR consisting of physiological changes that counteract the effects of morphine (i.e., are opposite to the physiological changes caused by morphine). This CR is part of the change in biological processes that causes tolerance to drugs, thereby requiring people to use higher doses in order to experience the same psychological and physical effects of drugs. The CR develops because the CS is followed by the drug, which can be thought of as a UCS — in this case, the injection of morphine. The UCS causes a UCR consisting of physiological changes associated with the drug. By counteracting the physiological effects of the drug, the CR reduces its lethality (i.e., the probability that the drug will result in death).

When an addict takes a high dose of a drug in a different environment — in the case of the man taking morphine, the different environment was his living room — the CR does not occur and, therefore, the drug now has its full effect on the body, which makes it more likely that the person will die.

Siegel, et al. (1982) designed an experimental study to test the classical-conditioning theory of drug tolerance. They gave rats injections of heroin every other day for 30 days (a total of 15 injections). They increased the dose gradually over time so that the rats eventually could tolerate relatively high doses. On the days the rats didn’t get heroin,they were injected with a sugar solution (see Table 1 below).

Siegel, et al. (1982) tested two heroin-injected groups:

  1. Group 1. These rats received their heroin injections in Room 1, which was the room that housed all the rats (the “colony room”). They received their sugar injections in Room 2, which was a room that differed from Room 1 in two ways: (a) no rats were housed there;(b) a machine generated constant “white noise.”
  2. Group 2. These rats received their heroin injections in Room 2, and their sugar injections in Room 1.

The researchers also included a placebo-control group (Group 3) that received injections of the sugar solution in both Room 1 and Room 2 on the same schedule as the other rats. Table 1 shows the schedule for each group on the first four days of the 30-day experiment.

Table 1. The schedule of heroin and sugar injections over the first four days of the experiment

At the end of the 30-day period, rats in all three groups were given a very large dose of heroin (almost twice as much as those in Group 1 and Group 2 had received before). Figure 2 shows the results.

Figure 2. Mortality in heroin-tolerant and control rats after receiving a very high dose of heroin

The label Different in Figure 2 refers rats in Groups 1 and 2 that received the very large dose of heroin in the room in which they had been injected with the sugar solution during the first part of the experiment. The label Same refers to in Groups 1 and 2 that received the very large dose of heroin in the room in which they had been injected with heroin during the first part of the experiment. The label Control refers to rats that were injected only with the sugar solution during the first part of the experiment.

As can be seen in Figure 2, almost all the rats in the Control Group died after being injected with the large dose of heroin because they had no tolerance for its lethal effects. About 64% of rats in the Different condition died, whereas only 32% of the rats in the Same condition died. Siegel, et al. (1982) interpreted these results as supporting their theory: the environmental stimuli in which drug addicts usually take the drug serve as a CS that produces a CR that increases tolerance for the drug’s effects.

The researchers concluded that the sensory stimuli from the room in which the rats were injected with heroin made up a CS. The rats developed a CR to that room–a CR consisting of changes in biological changes that counteracted the effects of the drug they were about to receive. When they received the final injection in a different room, the CR didn’t occur, which increased their chances of dying from the overdose.

Another point I want to make is that, although in most experimental studies of classical conditioning, the CR and UCR are the same or very similar, the responses also may be very different. In fact, in the study by Siegel, et al. (1982), the CR and UCR were completely opposite from each other.


Siegel, S. (2001). Pavlovian conditioning and drug overdose: When tolerance fails. Addiction Research & Theory, 9, 503-513. doi: 10.3109/16066350109141767
Retrieved October 18, 2011, from

Siegel, S., Hinson, R. E., Krank, M. D., McCully, J. (1982). Heroin “overdose” death: Contribution of drug-associated environmental cues. Science, 23, 436-437.  doi: 10.1126/science.7200260