Drug Tolerance, A Hallmark of Addiction
“Tolerance is one of the most obvious effects of abused drugs,” wrote the first director of the National Institute on Drug Abuse (NIDA), Robert Du Pont, in The Selfish Brain. “Most non-users are impressed by how much drug use tolerance permits. They cannot imagine liking the feelings produced by smoking 40 cigarettes a day or drinking 26 ounces of vodka a day.” How can long-term substance users tolerate such enormous amounts? According to NIDA, “Tolerance occurs when the person no longer responds to the drug in the way that person initially responded. Stated another way, it takes a higher dose of the drug to achieve the same level of response achieved initially.”
According to the current edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), tolerance has two aspects, a need for a markedly increased amount of a substance to achieve the desired effect and a diminished effect from the same amount of a substance. The addicted person is increasingly held captive in a vicious cycle in which the powerful euphoria caused by the initial substance use can never be reached again while he or she feels compelled to take ever-larger amounts of the drug just to maintain a normal emotional state. “Addiction is, first and foremost, a disease of the brain’s reward system,” concludes Nora Volkow, Gene-Jack Wang, et al. in a 2010 addiction study.
Here’s how it works. The substance interacts with the relevant receptors in the brain, triggering a dopamine release. Dopamine is the main neurotransmitter in the brain’s reward system. This release creates a feeling of pleasure for the user. The drug-induced dopamine surges resemble—and often dramatically surpass—the increases triggered by natural stimuli such as tasty food or sexual activity. Other regions of the brain register the pleasurable experience and motivate the user to repeat it. This is called “positive reinforcement,” normally a very useful behavior that enables humans to remember where they found nutritious food or—in the case of negative reinforcement—what dangerous situations to avoid. But with repeated use of drugs and alcohol, the reward system can go into a pathological downward spiral. The addict learns to love the substance and to fear its absence. A three-stage addiction cycle sets in. 
This is where tolerance comes in. “The positively reinforcing effects of substances tend to diminish with repeated use,” the Surgeon General writes in his new report on addiction. “Eventually, in the absence of the substance, a person may experience negative emotions such as stress, anxiety, or depression, or feel physically ill. This is called withdrawal, which often leads the person to use the substance again to relieve the withdrawal symptoms.” Why are the effects of the substance diminished over time? By its nature, the brain doesn’t like persistent over-stimulation and will start to modulate the effects of the substance. In response to continued drug use, the brain will seek to re-establish equilibrium by reducing the number of dopamine receptors and transporters. Excessive drug use eventually changes the makeup of the entire reward system.
Addicted users will typically respond by increasing the dosage to get the same high or even just to get back to normal. In this hellish game of musical chairs, more and more players are now competing for fewer and fewer chairs. This process of adaptation has limits, though. At some point, the tolerance effect levels out and the daily intake of the substance reaches a plateau. The drug and alcohol use is now mostly focused on counteracting withdrawal symptoms. Should the addicted person decide to go through detoxification and addiction treatment, she will usually experience a return of the tolerance reaction to more normal levels. Ironically, this presents a danger for the addict in recovery. Should a relapse occur at this point, she might overestimate her ability to tolerate the drug, thereby leading to an overdose.
