tolerance

Tolerance is the body learning to shrug off a drug. The first coffee of someone's life jolts them; after a few years the same cup barely registers. With many drugs, repeated exposure makes the same dose do less, so a person needs more and more to get the original effect. It is the response fading, not the drug weakening.

It arises through several distinct routes. The body may break the drug down faster (metabolic or 'pharmacokinetic' tolerance, so less drug reaches the target); the target itself may adapt — receptors becoming less responsive or fewer in number (pharmacodynamic tolerance); or the whole system may rebalance around the drug's presence. Because these mechanisms differ, tolerance to one effect of a drug can develop while tolerance to another effect does not, which is why an opioid's painkilling effect may fade faster than its dangerous suppression of breathing.

Tolerance is not the same as addiction, nor the same as physical dependence, though they often travel together. It is a measurable shift in the dose–response relationship — the curve moves to the right (more drug needed) and sometimes downward (a lower achievable ceiling). The opposite can also happen: occasionally repeated exposure makes a response stronger, called sensitization. From a design standpoint, tolerance is a key reason a drug that works beautifully on day one may disappoint after weeks of use.