Tolerance is associated with various drugs and involves a number of different body systems; it is particularly noticeable where addictive substances are concerned. It is a phenomenon whereby the body develops an ability to tolerate the effects of a drug. This means that the body has made adjustments to overcome the drug’s effects, which then causes the rebound effect referred to above.

With alcohol, there may also be a built-in tolerance in some people who have a family history of alcoholism. This accounts for the low response factor explained in the section on genetics.

Tolerance to alcohol and the depressants involves adaptive changes that up-regulate systems activating the central nervous system. In other words, the brain becomes hyperalert and hypersensitive in order to compensate. Tolerance to the opiates involves a similar process, although different pathways are in use.

Another type of tolerance involves the body’s ability to metabolize the drug. Some drugs, such as the barbiturates, stimulate cells in the liver which break down and help eliminate drugs of all types. The rate of elimination of the drug goes up, so the amount needed to produce a clinical effect goes up as well. For this reason, people who are addicted to some types of drugs require higher than normal doses of other drugs to achieve an effect.

Cross-tolerance to similar substances is quite common. For example, if you develop tolerance to one type of depressant drug, you will have increased tolerance to other depressant drugs. Alcohol, barbiturates, and benzodiazepines are all cross-tolerant, so benzodiazepines such as Librium can be used to treat alcohol withdrawal and phenobarbital can be used to treat withdrawal from benzodiazepines. But this can also lead to cross-addiction. For example, an alcoholic might be inappropriately treated by a doctor’s prescribing tranquilizers for “nerves” (really chronic withdrawal), which results in a cross-addiction. The person might not need to drink alcohol anymore, but the addiction is still there and active. Exposure to barbiturates or benzodiazepines can also trigger a relapse in a person who has been abstinent from alcohol, or vice versa.

One important system involved with alcohol and the depressants involves the overall electrical stability of the brain.

Seizures, or convulsions, are episodes of unregulated electrical discharge within the brain. In order for a seizure to occur, one of two things has to happen. The first is that there has to be a strong stimulus. The second is that this stimulus has to override the regulatory mechanisms in each cell membrane.

Seizures can be produced in two ways, by the addition of a strong electrical stimulus or by a decrease in the cell membranes’ ability to resist the stimulus. When a person develops tolerance to alcohol or to the depressant medications, alterations in the function of a chemical that regulates the movement of calcium in and out of the cells causes these cells to be very sensitive to any kind of stimulation. The cells are unstable, so it takes little provocation to produce a seizure.

The withdrawal symptoms that we typically see in those who have used alcohol or the depressants expose the changes that the brain made when it developed tolerance to the effects of the substance. Shakiness, anxiety, irritability, and sometimes psychotic reactions are seen in people whose bodies are reacting to the absence of a depressant drug. Fatigue, sleepiness, depressed mood, and increased appetite are the symptoms in someone whose brain is reacting to the absence of stimulants.

Withdrawal symptoms emerge as the drug clears the system. With drugs that clear quickly, such as cocaine or alcohol, there is a fairly rapid onset of such symptoms. Other drugs clear very slowly, marijuana being the best example. This drug clears the body over the span of days to weeks. There has been much controversy over whether or not marijuana is physically addictive because of the lack of a distinct withdrawal syndrome. It has, however, been demonstrated that such a syndrome exists; it is simply hard to detect, because, as the drug slowly clears the system, the body gradually adapts.

Nonetheless, it is probably just uncomfortable enough to make the resumption of use psychologically reinforcing.

It is also important to note that tolerance to drugs develops unevenly. Tolerance may develop to one effect of the drug and not to another. All drugs have a number of effects other than the desired ones. For example, tranquilizers such as the benzodiazepines (Valium and others) are useful for the short-term treatment of anxiety. However, they consistently cause drowsiness, and this is a “side effect” when the drug is prescribed for anxiety. Some drugs in this same class, though, are marketed for sleep. In this case the intended effect is the sedation. Tolerance to the sedative effects of these drugs will develop over time, which limits their long-term use as sleep aids. However, tolerance to the effect of relieving pathological anxiety does not develop to any substantial degree. Many people with severe anxiety disorders, therefore, are effectively maintained on these (and other) medications without a need to substantially increase the dose. Since tolerance to the drowsiness occurs over time, this side effect diminishes. So here is a situation where tolerance to one effect - sedation - is a problem in one type of case and an advantage in another.

However, development of tolerance to the desired effect of the drug can leave the person vulnerable to problems with other effects. For example, one of the effects of the opiates (such as heroin) is euphoria - an abnormal elevation of mood. Tolerance to this effect occurs rapidly, so that higher and higher doses are required to achieve the effect. Another effect of opiates is the depression of the respiratory reflex in the brain. Tolerance to this effect does not occur rapidly, if at all. As increasing doses of opiates are used, the person comes nearer and nearer to the toxic level. Death from an overdose of opiates is frequently due to the depression of the respiratory reflex.

Another example is cocaine, which also causes euphoria.

Tolerance to this effect develops rapidly, leading the user to increase the dose or the frequency of use. Cocaine, however, also has what is known as a chronotropic effect on the heart, meaning that the drug speeds up the heart rate by stimulating that muscle to contract more rapidly. This can lead to heart damage. In fact, before the epidemic of cocaine dependence that reached its peak in the late 1980s, heart attacks in people under the age of thirty-five or forty were considered extremely rare. Then emergency rooms were suddenly seeing heart patients in their twenties, or even in their teens, because of the toxic effect of cocaine on the heart.

So the development of tolerance increases the dangerousness of the drug and also creates a situation in which the body becomes uncomfortable without it.

Elizabeth Connell Henderson, M.D.

Glossary

Appendix A: Regulation of Addictive Substances

Appendix B: Sources of Additional Information