11.6: Tolerance, Withdrawal, and Dependence

Pharmacologically speaking, tolerance can be defined as a decrease in the action of a drug due to repeat exposure. This phenomenon happens as a result of homeostatic adaptations that the body undergoes when it has been exposed to a substance for a prolonged period of time. In a person who is tolerant, they must take progressively higher doses of the drug to experience a desired effect.

Tolerance can be represented graphically by a rightward shift in the dose response curve. For a drug naive person, someone with no experience with the drug, a low dose of drug may have a strong effect. However, for a person who has become tolerant to the effects of the drug, that same low dose will produce a small drug effect. (The other way to think about the dose response curve is the following: For two people to experience the same magnitude of effect, a drug tolerant person would require a higher dose than Figure 11.22 The liver breaks down alcohol in a two-step enzymatic process. Frequent alcohol use upregulates the speed by which degradation happens, causing tolerance. someone who has never taken the drug before.)

There are different forms of tolerance that a person can experience.

In metabolic tolerance (sometimes also called dispositional tolerance, or pharmacokinetic tolerance), there is a decrease in the amount of the drug that gets to the site of action. The body becomes more efficient at eliminating the substance. Since exogenous substances usually get degraded by enzymatic reactions, an increase in the activity or number of enzymes will decrease the amount of the substance that is capable of acting.

The most common example of metabolic tolerance is seen in frequent alcohol use. The main psychoactive substance found in alcoholic beverages like beer, wine, or liquor is ethanol. Our liver, which filters circulating blood, contains enzymes which break down chemicals in the blood. Specifically, the standard degradation process of ethanol uses two enzymes. The first of which, called alcohol dehydrogenase, oxidizes molecules of ethanol into the toxic byproduct acetaldehyde. The second step uses the enzyme acetaldehyde dehydrogenase to convert the acetaldehyde into acetic acid, a generally harmless compound (the same chemical structure as vinegar) that is used by the body in a biochemical reaction that drives the citric acid cycle. Because most alcohol is taken via oral consumption, ethanol is subject to first-pass metabolism before reaching systemic circulation.

However, after prolonged exposure to alcohol, the body undergoes homeostatic compensatory changes. The two liver enzymes responsible for degradation of ethanol increase in either function or amount. When these metabolic enzymes become upregulated, the circulating ethanol in the bloodstream becomes broken down more rapidly and more efficiently, resulting in a decrease in the amount of ethanol that reaches general circulation, and consequently, the brain. This explains why people who have never drank alcohol (low amounts / function of enzymes) may experience a stronger drug effect compared to someone who drinks regularly. It also accounts for why there is some genetic variation between a person’s sensitivity to alcohol’s intoxicating effect, as enzyme efficiency is partially encoded by genetics.

Another way by which tolerance can manifest itself is through changes at the level of the molecular components of cells. This type of tolerance is called a functional tolerance, or pharmacodynamic tolerance. This tolerance leads to a decreased sensitivity to the substance. This functional tolerance can be characterized by a decrease in receptor expression after chronic exposure to an agonist. When the opioid etorphine is present in the body, it activates the opioid receptors. Frequent exposure to etorphine causes a molecular change in the receptors, which leads to internalization, the process by which cell surface-expressed receptors become taken into the cell. Since etorphine is only able to activate receptors on the surface, these internalized receptors diminish the strength of the etorphine signal, which manifests as tolerance. By downregulating the number of receptors that are expressed on the surface, the cell reacts to the environment by becoming less responsive in the face of drug.

Sometimes, the body physiologically prepares for the drug effect before the drug is even present. The way it does this is to initiate an opposite somatic effect from what the drug is expected to do. This “reverse” effect is likely a protective mechanism to minimize the drug effect, and these anticipatory bodily changes can be precipitated by drug-associated cues. For example, heroin causes analgesia. Cues that predict administration of the drug, such as preparation for an intravenous injection or being in a physical environment where drug is frequently administered, can cause the reverse physiological effect, hyperalgesia. Because of this, a person may need to take more drug to overcome the anticipatory changes. This unconscious form of learning leads to a form of tolerance that is dependent on Pavolvian cues; this is called conditional tolerance.

If not accounted for, conditioned tolerance can have potentially lethal side effects. A clinical description (Siegel, 2001) of a patient with pancreatic cancer describes one such “failure” of tolerance. Bedridden and suffering from tremendous pain, a man was regularly given morphine in his bedroom, dark and filled with humming apparatus for his medical care. As expected, he developed a tolerance towards the morphine, requiring higher and higher doses in order to inhibit pain. One day, he went into the brightly lit living room to receive his normal dose of painkiller. Soon after, he died from opioid overdose.

Sensitization is a phenomenon related to tolerance, but the polar opposite: instead of a drug effect being lessened after chronic exposure, a sensitized person experiences an increase in drug effect. It is sometimes called “reverse tolerance.” Nicotine as well as many psychostimulants such as cocaine or amphetamine can produce psychomotor sensitization after repeated dosings.

Since mechanisms of tolerance result in long lasting homeostatic changes, they may lead to withdrawal, a set of symptoms that a person experiences when they are abstinent from the substance. This produces a highly aversive state that can be relieved by administration of more drug. The symptoms of withdrawal are frequently the opposite of the side effects of the drug. One example is the physiological response to heroin. When heroin is present, a person may experience euphoria, analgesia, relaxation, and constipation. But after the homeostatic changes have taken place resulting in downregulation of opioid receptors, a person may experience withdrawal symptoms such as dysphoria (depression), pain hypersensitivity, restlessness, and diarrhea.

It is good to note that tolerance does not only happen in the presence of agonists like ethanol or morphine. In fact, antagonists are well known to produce tolerance and withdrawal. If you have ever had difficulty staying alert or a headache without your morning coffee, you are experiencing the effects of withdrawal. Caffeine is an antagonist for the adenosine receptors. When the body is used to a certain amount of caffeine that blocks adenosine signaling, there are mechanisms that lead to homeostatic upregulation of adenosine receptors. And so when caffeine is no longer present, the endogenous levels of adenosine overactivate adenosine signaling, leading to the withdrawal symptoms.

When someone is withdrawing from a drug, they often feel the urge to take the drug. This is a sign of drug dependence. Dependence can be a physical dependence, where the person seeks drug in order to either relieve the physical symptoms of withdrawal, or to experience the positive sensations associated with the drug. Alternatively, a psychological dependence can also develop, where the person has intense cravings for the drug such as a fixation on drug acquisition, or mood or behavioral changes in the absence of drug.

Long term drug use may cause people to become heavily dependent. These people often engage in recurring patterns of drug seeking and drug taking. Their patterns of use can be highly destructive, as they make drug acquisition as their main objective, fixating on drug taking even at the cost of their jobs, relationships, and even their own health. Because this form of pathological drug use is extremely harmful, much attention is focused on understanding the mechanisms that underlie this condition.

---