Cross tolerance is the phenomenon that can develop between natural and synthetic opiates.

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Cross tolerance occurs when tolerance to one drug reduces the response to another drug with a similar action. Natural opiates like morphine and synthetic opiates such as heroin or fentanyl both primarily act on the μ-opioid receptors. When someone uses one opiate chronically, the brain adapts—receptor changes and downstream signaling adjustments—so the same dose no longer produces the previous effect, and this diminished response carries over to other opiates that use the same receptor. So tolerance to morphine typically extends to heroin or other opiates, because the mechanism is the shared receptor target and compensatory changes in the nervous system. This differs from cross dependence (which is about withdrawal-related effects between substances) and from metabolic tolerance (which would involve changes in how the drug is processed in the body). While cross tolerance is a specific instance, it reflects the broader pharmacodynamic adaptations that underlie tolerance to related drugs.