When people develop tolerance, they have become desensitized to the drug and require more and more of the substance to achieve the same effect. Different drugs vary as to how likely they are to cause tolerance. For example, tolerance for amphetamine and opiates is generally stronger than that for alcohol. In fact, people who abuse opiates, such as heroin or morphine, can develop a tolerance for the analgesic (pain-killing) effects that can last for years after the end of the substance abuse. Consequently, people with a history of opiate abuse or dependence often require much more opiates to treat pain than the average person.

Withdrawal refers to physiological symptoms that occur when the substance is discontinued. Because the brain has become adapted to the chemical, removal of the chemical sends the brain into a disregulated state. Withdrawal can be extremely painful as well as dangerous. Depending on the substance, withdrawal symptoms can include changes in heart rate, vomiting, confusion, pain, and even seizures. The effects of withdrawal are generally opposite to the effects of intoxication. For example, people become energetic and euphoric during cocaine intoxication, but experience fatigue and depression during cocaine withdrawal.