How Drug Tolerance Changes the Brain

Dopamine is a neurotransmitter. Neurotransmitters are released from neurons and travel in the microscopic spaces (called “synapses”) to inter-connected neurons to send messages from one brain cell to another. To accomplish this, neurotransmitters “dock” with “receptors” on the surface of message-receiving neurons, stimulating them via an electro-chemical exchange. Dopamine creates the feeling of pleasure by docking with neurons in  the Reward System, stimulating those neurons and the Reward System as a whole.

Excessive drug use can cause permanent change to Reward System neurons. This results from increasing drug tolerance, a process of accelerating change that makes the Reward System less efficient and requires users to take more drugs to obtain the same high they used to get from less. Tolerance alters brain cells physically, changing their function. Eventually, as tolerance deepens, it alters the nature of the drug-using experience, from liking drugs for their euphoric effects to needing them simply to feel normal and hold off withdrawal.

How does this happen?

The brain must be balanced to operate properly and has defensive systems to monitor and correct imbalances. If the brain encounters drug-induced overstimulation occasionally, the brain’s defensive systems respond to each as an individual event. However, if the Reward System is overstimulated regularly over a long period, the brain learns to anticipate the overstimulation, prompting a much more powerful and long-lasting — even permanent –defensive reaction.

The correction to repeated overstimulation is to make the Reward System less excitable restoring a more normal balance. One way this is accomplished is by reducing the number of receptors available for docking with dopamine. It’s like removing extra seats in a game of musical chairs while keeping the same number of players — fewer players get a seat. Likewise, the fewer receptors there are for dopamine to dock with, the less stimulation of neurons occurs, blunting the high.

Addiction researchers found, for example, that alcoholics’ brains contain significantly fewer dopamine receptors (called D2 receptors) than non-alcoholics. Similarly, monkeys allowed to self-administer cocaine for a year had 15%-20% fewer dopamine receptors.3 Non-dopamine receptors can also be involved in tolerance. For example, marijuana impacts both dopamine and the brain’s cannabinoid system. (The psychoactive component in pot is THC, a cannabinoid compound.) Chronic daily marijuana smokers were found to have 20% fewer cannabinoid receptors than control subjects.1

Tolerance also operates on other critical parts of the Reward System to make it less efficient. One study found that methamphetamine abusers, for example, had an average of 24% fewer dopamine transporters than non-users in a key part of the Reward System.2 (Transporters are involved in shuttling neurotransmitters to and from receptors.)

In other words, in the face of chronic overstimulation by drugs, the brain’s defensive systems cause physical and structural changes in Reward System neurons: “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.”3 Essentially, long-term, predictable drug abuse causes the brain to reprogram itself in defense. That’s what tolerance does.

However, since tolerance dulls the high that drugs evoke, users retaliate by taking more. They increase the amount of dopamine by increasing the dose or frequency of drugs, or both, so they get the same reward they used to feel with less, before tolerance developed.The brain, in turn, responds by making the system even less efficient, deepening tolerance. A vicious downward-spiraling cycle develops as the brain tries to counteract drug abuse by gumming up the reward system ever further while the user compensates by taking more and more drugs. This prompts further brain change, which in turn elicits increasing drug taking, accelerating the downward spiral. That’s a key reason addiction is a progressively-worsening disease.

The neural changes caused by tolerance establish what scientists refer to as a “new normal” for the addict brain — a less efficient Reward System. 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.”5 The essence of the addict experience, neuroscientists say, is that addicts have to take drugs not to produce euphoria, but to maintain an ever-harder-to-achieve “new normal” in which the brain, having developed tolerance, now requires a drug-induced dopamine boost to maintain the “new normal.” It now needs drugs to stave off withdrawal, instead of just wanting them to get high.

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 — withdrawal stretches from one to two days, then to three and four.6 The fear of withdrawal escalates as well, with good reason, a central reason addicts keep using drugs in spite of worsening physical, social and psychological consequences.

For more on tolerance, click on Tolerance Is Capable of Being Inherited.

Click here to return to the Questions About Addiction Menu.

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

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

3. “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.

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

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

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

Subscribe to the Addict Science Newsletter


cover of A Whole Lot of Medicine

2 Responses to “ How Drug Tolerance Changes the Brain ”

  1. […] change to make you less receptive to those feel good neurotransmitters – this is known as tolerance. Dopamine tolerance can be short-term (usually), or permanent (in the case of serious drug abuse), […]

  2. […] […]

Leave a Reply