What causes tolerance to a drug?

Answer: Tolerance is the phenomenon where chronic exposure to a drug leads to a condition where more drug is needed for the person to experience the same effect.

Tolerance can develop to a drug after multiple exposures. The word drug, in this sense, is used broadly: any substance that changes the body chemistry. This includes both drugs of abuse (such as nicotine or cocaine) and therapeutic drugs (such as antihistamines or sleep aid medication). When a person becomes tolerant to a drug, the normal dosage of the drug does not produce as strong of an effect as before tolerance. As a result, the dosage of the drug must be increased before a therapeutic benefit is achieved.

An animal without any prior exposure to a drug is considered to be in the “naive” state. After first exposure, the drug may produce an some sort of effect. With repeated exposure to the drug, the subject will experience the effects of the drug progressively less over time. Development of tolerance does not happen at the same rate for each drug. For some drugs, particularly hallucinogenic compounds such as LSD or psilocybin, tolerance develops acutely.

Mechanisms of Tolerance

The body produces tolerance through two different mechanisms: Pharmacodynamic or metabolic tolerance. These processes are not independent from each other, as tolerance can occur due to a combination of both of these effects.

Pharmacodynamic tolerance often happens at the level of the receptor. When a receptor is repeatedly activated due to the activity of the drug, the cell tends to adjust to decrease the amount of receptor activation. It can do this in two ways. The receptors themselves may undergo a change to become less responsive to activation by an agonist. Alternatively, the cell may respond to repeated activation of the agonist by downregulating the number of receptors expressed at the cell surface. Both of these reactions result in a decreased effect of the drug in the system.

Metabolic tolerance occurs at the level of the organism. Whenever a drug enters into the system, it can only be cleared from the body after it has been broken down, or metabolized, by enzymes. The liver is predominantly responsible for metabolizing drugs, but almost every bodily organ has some capacity for metabolism. In metabolic tolerance, the organism undergoes a change that allows metabolism for the specific drug to proceed at a faster rate. Because the drug is broken down and removed from the body faster, a higher concentration of the drug must be delivered to the organism for any therapeutic effect to occur.

For an example of an explanation of metabolic tolerance to a drug, consider a chronic alcohol abuser. Ethanol, the primary psychoactive ingredient of alcoholic products such as beer or wine, is degraded in the body by a liver enzyme called alcohol dehydrogenase (ADH). As a result of this degradation process, a byproduct called acetaldehyde is produced. This chemical itself is toxic, but it is quickly degraded by a different liver enzyme called acetaldehyde dehydrogenase (ALDH). After this enzymatic degradation, the resulting byproduct is acetic acid, which is harmless at the concentrations that a person would take in from drinking alcohol.

After chronic alcohol consumption, the body produces more of the enzymes that break apart these chemicals. Alcohol is the only psychoactive product; the other two do not create the pleasurable sensations associated with alcohol consumption. However, because the body has upregulated the function or number of enzymes, the person must consume more of the drug to experience the positive effects of the drug. Therefore, the body has undergone a metabolic tolerance to alcohol.

In many ways, tolerance is an expression of the organism’s tendency towards equilibrium (homeostasis). When a drug is in the system, the body is disrupted from equilibrium. The body will compensate to return the organism to the naive state.

Tolerance can be illustrated by a rightward shift in the dose response curve. In comparing two curves, the same dose of drug for the non-tolerant individual will produce a small effect for a tolerant individual.