Tolerance and Withdrawal

20.02.2021 |

Episode #3 of the course Introduction to drugs and behavior by Dr. Daniel McGrath

 

Welcome back! In yesterday’s lesson, we discussed how drugs enter the body, reach the brain, and affect the brain’s reward system. In this lesson, we are going to focus on two key components of drug use and abuse: tolerance and withdrawal.

Many of us can remember the first time we had a little too much to drink. There is a good chance that it wasn’t a great experience in the end. People who are novice substance users lack the tolerance that more experienced users have acquired over time. Tolerance refers to the reduced effectiveness of a drug after its repeated use. It is the body’s way of fighting off the drug in order to continue functioning normally. Acute tolerance means that a drug can lose effectiveness in a single session. For instance, when we drink alcohol, we may feel the “buzz” early on in the evening; however, our body begins to adjust as we continue to drink, and we don’t feel as intoxicated as we actually are.

Chronic tolerance refers to the reduced effectiveness of a drug over many substance use sessions, usually over an extended period of time. This happens in three ways. First, pharmacokinetic tolerance occurs. This is where the body begins to more effectively metabolize drug molecules by creating more enzymes. Second, pharmacodynamic tolerance occurs. Neurons begin to adapt to drug molecules by changing the number of receptors available on neurons, making it more difficult for a drug to bind with them. Third, behavioral tolerance or conditioned tolerance happens. As we use drugs, we also begin to associate objects in the environment with drug use. For example, if someone is using heroin, the drug paraphernalia becomes conditioned with the drug after repeated use. When the individual sees the paraphernalia, their body begins to prepare to take the drug. With each of these types of tolerance influencing the user, a greater and greater quantity of the drug is required to achieve the same effect.

In the early 1980s, a psychologist named Shepard Siegel at McMaster University in Canada published a significant discovery. In his experiments using rats, he found that not only is the drug itself critical in drug overdoses, but also the environmental stimuli that becomes associated with drug use. He found that learning is at the heart of behavioral tolerance. Rats given increasing doses of morphine over time would develop a tolerance to the drug. Eventually, the rats could tolerate high doses that would have killed them before they developed tolerance. However, Siegel found that if you remove rats from their “home cage” and place them in a new cage, their tolerance substantially decreased. The rats would then die from overdoses in much larger numbers than rats that were not removed from their home cage. Outside of the home cage, familiar external cues (e.g., lights, smells, sounds) were absent. It turns out these cues tell the body to “get ready for a large dose of morphine”, and without them, the rats were not prepared to defend against a possible overdose.

Siegel’s brilliant insights help to explain heroin overdoses in people too. Many overdoses occur away from home. If you stop and think about it, how many high-profile celebrity overdoses occur in hotels or when they were away from home? Quite a few. There is a good chance that when a person takes a large dose of heroin in a novel place, they have lost some (or most) of their conditioned tolerance to the drug. When this happens, it’s almost as if they have minimal experience with the drug. Their body is not cued; they are not prepared to handle their normal dose of heroin and subsequently are more likely to overdose.

As people use drugs, they also become susceptible to withdrawal symptoms. The changes in the brain that occur with tolerance also make it increasingly difficult to stop taking the drug. Withdrawal symptoms are physiological changes that range from mild to very uncomfortable. They are usually the opposite of the drug effect. For instance, cocaine makes you stimulated, but a common withdrawal symptom of cocaine use is “crashing”. Interestingly, many drugs can have very uncomfortable withdrawal effects, but they are not life-threatening. Yet, withdrawal from alcohol or benzodiazepines can be fatal. Withdrawal effects can contribute to drug use and addiction, but are not the sole cause of why people continue to use drugs. We will discuss withdrawal symptoms for individual drugs in later lectures.

In tomorrow’s lesson, we will cover how some people can become dependent and addicted to drugs. See you in the next lecture!

 

Recommended book

In the Realm of Hungry Ghosts: Close Encounters with Addiction by Gabor Mate

 

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