Tolerance develops when the body adapts to the continued presence of a substance. The underlying mechanisms vary by substance class and include receptor downregulation (a reduction in the number or sensitivity of receptors available to bind the substance), changes in intracellular signalling pathways, and increased metabolic clearance. These processes are distinct, and more than one may operate simultaneously.
Three subtypes are commonly distinguished in the pharmacological literature. Pharmacokinetic tolerance (also called dispositional tolerance) refers to accelerated metabolism of a substance, meaning less of it reaches the target site. Pharmacodynamic tolerance refers to reduced responsiveness at the target receptor or tissue, even when drug concentrations remain unchanged. Behavioural tolerance describes learned compensatory responses , for instance, a person adapting their movements or conduct in ways that offset a substance's observable effects.
Tolerance is not equivalent to physical dependence, though the two may occur together. Physical dependence refers to the emergence of withdrawal signs or symptoms when a substance is discontinued or reduced; tolerance may be present without dependence, and vice versa. The distinction matters in both clinical and regulatory contexts.
In Australian scheduling and prescribing frameworks, tolerance is a recognised factor when reviewing dosing for controlled substances listed under the Poisons Standard (the legislative instrument made under the Therapeutic Goods Act 1989). Prescribers operating under the Authorised Prescriber scheme or Special Access Scheme (SAS) are expected to take documented tolerance into account as part of clinical assessment, particularly for Schedule 8 (controlled drug) medicines.
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