How Drug Tolerance Develops

How does one go from liking drugs to needing them? The explanation lies in the brain’s ability to monitor and correct imbalances in order to maintain harmony.

Psychoactive drugs significantly overstimulate dopamine and cause long-lasting changes in the brain’s Limbic “reward” system. This over-stimulation has a cost; it depletes dopamine pathways long after the last dose. For example, disruption of dopamine in the brain’s frontal cortical area (involved in rational thought, motivation, and controlling impulses) is evident as long as 100 days after cocaine use.1 Dr. Nora Volkow, a neuroscientist who studies addiction, is the researcher who demonstrated this long-lasting impact. She says, “The disruption of the dopamine pathways leads to a decrease in the reinforcing value of normal things, and this pushes the individual to take drugs to compensate.”2 This explains why addicts lose interest in activities and people they once valued as they slide into addiction.

If the brain encounters drug or alcohol-induced overstimulation occasionally, it responds defensively to each as an individual event. That’s what hangovers are. (For more click on Hangover versus Withdrawal.) However, if the reward system is overstimulated regularly, it learns to anticipate the over-stimulation and primes defensive systems to respond with a much more powerful and long-lasting protective reaction.

One defensive response is to make the reward system less efficient. This is accomplished by reducing the number of receptors available for docking with dopamine, as if removing extra seats in a game of musical chairs while keeping the same number of players. Addiction researchers found, for example, that alcoholics’ brains contain fewer dopamine receptors than non-drinkers. In experiments on monkeys allowed to self-administer cocaine for a year, researchers found they had 15%-20% fewer dopamine receptors.Former methamphetamine abusers showed an average of 24% fewer dopamine transporters than non-users in the striatum, a part of the reward system.4 (For more on dopamine and tolerance, click on the Dopamine DRD2 Gene.) Similarly, chronic daily marijuana smokers had approximately 20 percent fewer of one (of two) subtypes of cannabinoid receptors than control subjects did.5

In other words, the brain’s defensive response to drug abuse causes physical and structural changes in receptor and neurotransmitter activity which significantly alters neural function. The repeated shocks of continuous and predictable drug abuse cause the brain to reprogram itself in defense.

Tolerance induces a counter-reaction by the user, however. Since it dulls the high that drugs evoke, users take more: only by increasing the amount of dopamine through increasing the dose or frequency of drugs, or both, can the addict feel the same reward she used to feel before tolerance developed.6

Increasing drug use releases more dopamine, the users’ retaliation to the brain’s defense. The brain then responds by making the system even less efficient. A vicious downward-spiraling cycle develops as the brain tries to counteract drug abuse by gumming up the reward system ever more, while the user compensates by taking more and more drugs. This prompts further brain change, accelerating the downward spiral. The process of increasing tolerance is a key reason addiction is a progressively-worsening disease.

Tolerance re-sets what’s “normal” to the brain. Instead of experiencing an overstimulated reward system as an anomaly, the “new normal” of tolerance means that the brain needs the overstimulation provided by drugs to reach the balance it requires.

Reducing the number of dopamine receptors significantly affects neurons’ ability to transmit and receive messages. As neurons go, so go their neural networks: “Ultimately, adaptations that drug exposure elicits in individual neurons alter the functioning of those neurons, which in turn alters the functioning of the neural circuits in which those neurons operate. This leads eventually to the complex behaviors…that characterize an addicted state.”7

Without the dopamine boost provided by drugs, abusers suffer a dopamine deficit, resulting in withdrawal and depression. “Eventually, the dopamine circuit becomes blunted; with tolerance, a drug simply pushes the circuit back to normal, boosting the user out of depression, but no longer propelling him or her toward euphoria.”8 The essence of the addict experience, neuroscientists say, is that they eventually have to take drugs not to get high, but to maintain an ever-harder-to-achieve “new normal” in which the brain, having developed tolerance, now requires them to maintain the “new normal.” It now needs drugs to stave off withdrawal.

A byproduct of increasing tolerance is worsening physical withdrawal. Repeated binge-and-withdrawal cycles also impels a corresponding defensive reaction, causing detoxes to become progressively longer and more severe — hangovers stretch from one to two days, then to three and four.9 The fear of withdrawal escalates as well, with good reason.

Long-term drug abuse can also force brain cells to adapt to what the brain perceives as a permanent change in its reward system. This can trigger genetic change, which is why tolerance can be inherited. For more click on Genetic and Environmental Components of Addiction).

For the next article in the Why Drugs Can Be Addicting series click here.

To go back to the Addiction Science Menu click here.

1. Seeing Drugs As A Choice Or As A Brain Anomoly, New York Times, June 24, 2000.

2. Seeing Drugs As A Choice Or As A Brain Anomoly, New York Times, June 24, 2000.

3. Genetic Studies Promise a Better Path to Treatment of Addictions, New York Times, Nov. 14, 2000.

4. “Speed” Causes Long-Term Brain Damage – U.S. Study, Reuters, Mar. 2, 2001; Drugs Effect on the Brain is Extensive, Study Finds, New York Times, Mar. 6, 2001.

5. Chronic Marijuana Smoking Affects Brain Circuitry, June 7, 2011

6. An Anti-Addiction Pill?, New York Times, June 25, 2006.

7. Molecular and Cellular Basis of Addiction, Science Magazine, October 3, 1997.

8. Addiction: A Brain Disease, Not a Moral Lapse, New York Times, Sept. 30, 2003.

9. A Range of Research-Based Pharmacotherapies, Science Magazine, October 3, 1997.

Subscribe to the Addict Science Newsletter


cover of A Whole Lot of Medicine

One Response to “ How Drug Tolerance Develops ”

  1. Good article, i got a new idea what are the effects of drug addiction

Leave a Reply