What is Drug Tolerance and Why Does it Matter?

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Addictive substances all have one thing in common: their effects grow increasingly weaker the longer a person keeps using them. People who’ve used drugs or alcohol for extended periods of time may or may not notice the “need” to ingest increasingly larger doses with ongoing use.

According to the National Institute on Drug Abuse, drug tolerance exists as one of the four criteria that sustain a substance abuse disorder. In effect, addictive substances have a chemical make-up that enables them access to the brain’s chemical system. Once inside, drug tolerance develops as the brain becomes acclimated to the drug’s effects.

For anyone concerned about the potential long-term effects of drug abuse, drug tolerance plays a pivotal role in converting a casual drug user into a hardcore addict. Drug tolerance remains an ongoing process throughout the course of drug use, so the sooner a person comes to terms with his or her drug-using practices the better.

Psychoactive Substances and the Blood-Brain-Barrier

The blood-brain-barrier appears as a wall of endothelial cells that regulates what types of substances go in and out of the brain. Within this wall of cells sits a network of capillaries through which the brain receives oxygen and nutrients and eliminates waste materials.

The blood-brain barrier works to protect the brain’s delicate chemical system from foreign substances or contaminants carried in from the bloodstream. Psychoactive drugs, however, can permeate this barrier and wreak all sorts of havoc on brain chemical processes.

In general, psychoactive drugs have a fat-soluble chemical make-up that allows them to pass through the blood-brain-barrier and interact with the brain’s chemical system. The potential for drug tolerance lies in the chemical make-up of these drugs and the brain’s inability to distinguish them from its own neurotransmitter chemicals.

The Effects of Drugs in the Brain

What most characterizes psychoactive drugs is their ability to blend in with the brain’s chemicals, all of which act as information messengers between the brain’s various regions. More specifically, drugs interact with the brain cell receptor sites that secrete neurotransmitter chemicals.

Drug tolerance develops out of this interaction between psychoactive drugs and chemical-producing cell sites. With each dose, a drug’s effect will either stimulate chemical production and/or block chemical production processes.

Over time, drug tolerance takes shape as over-stimulated cell sites develop structural damage, making them less responsive to drug effects. When this happens, users must keep increasing drug dosage amounts to experience the desired drug effects. These interactions continue for as long as a person engages in drug use.

Drug Tolerance – Mechanisms of Action

While weakening brain cell sites play a central role in increasing drug tolerance levels, other mechanisms of action also contribute to changes in tolerance levels. According to the California State University-Fullerton, a total of four mechanisms (including cell damage) contribute to rising drug tolerance levels:

  • Metabolic tolerance
  • Behavioral tolerance
  • Conditioned tolerance

Metabolic drug tolerance has to do with the rate at which the liver breaks down drugs in the system. With continued use, this rate increases, shortening the length of time a drug remains in the bloodstream.

Behavioral tolerance involves the emotional response of the user in terms of his or her expectations of the drug’s effects. These expectations drive a person to increase dosage amounts in anticipation of the drug’s “high” effects.

Conditioned drug tolerance has to do with the environmental cues that trigger the desire to use drugs where cues take the form of certain people, places, activities or mood states. All four of these mechanisms feed into one another, further increasing a person’s drug tolerance over time.

Drug Tolerance & the Drug Abuse Cycle

Physical Dependence

As brain cells grow weaker, they become more dependent on a drug’s effects to maintain an even balance of neurotransmitter chemicals in the brain. The structural damage brought about by ongoing drug use leaves cells unable to function normally in the absence of the drug. Since physical dependence develops out of growing drug tolerance levels, a cycle of drug abuse takes shape as users continue to increase dosage amounts while damage to cell structures grows increasingly worse.

Withdrawal Effects

Once chemical imbalances reach a certain point, the brain loses its ability to maintain normal bodily functions. When this happens, withdrawal effects start to develop.

In effect, increasing drug tolerance levels and withdrawal effects go hand-in-hand as withdrawal effects only develop when needed amounts of the drug are lacking. Consequently, a person will likely use drugs in an attempt to self-medicate uncomfortable withdrawal symptoms. With continued drug use, withdrawal effects become yet another trigger within the drug abuse cycle.

Psychological Dependence

Psychological dependence becomes yet another stage of decline brought about by increasing drug tolerance levels. According to Harvard Health, after a certain point, neurotransmitter imbalances start to disrupt the brain’s reward system, the center that regulates a person’s motivations, drives and priorities.

Once a person becomes psychologically dependent, a fundamental shift has taken place within his or her thinking and emotional responses. Ultimately, drugs take top priority in a person’s life, at which point relationships, work and any and all former interests fall by the wayside.

The Addiction Cycle

The addiction cycle develops out of psychological dependency in terms of a person’s total preoccupation with getting and using drugs. At this point, a person has organized his or her lifestyle around drugs, which only works to perpetuate ongoing drug use.

Once addicted, a person believes he or she needs the drug’s effects in order to cope with everyday stressors and pressures. This belief system takes root within the chemical imbalances brought about by chronic drug use.


Over the course of chronic drug use, drug effects essentially restructure the brain and reconfigure its chemical pathways. While these changes can be undone, the longer a person engages in drug abuse the longer it takes to undo the damage.

In cases of long-term, chronic drug abuse, the extent of damage done can become permanent leaving users in an incapacitated state even after stopping drug use. In effect, drug tolerance increases become the driving force behind the potential damage drugs can have in a person’s life.