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In particular, activation of the hypothalamo-pituitary-adrenal (HPA) axis by stress results in the somatostatin-mediated inhibition of thyroid-releasing hormone (TRH) and thyroid-stimulating hormone (TSH) release and in reduced conversion of thyroid T4 to T3 (active hormone) that in humans, displays a negative control on various CYP genes including those belonging to the CYP3A subfamily ( Figure 1 The impact of stress on drug metabolism is unique and distinct from that of medicines that usually display dose- and time-dependent specificities ( CYP2E1 and CYP2B constitutive expression, whereas it up-regulated most of the other CYPs including those belonging to CYP1A, CYP2A, CYP2C, CYP2D and CYP3A subfamilies and metabolize over 70% of prescribed drugs ( There is also an indirect involvement of stress in drug metabolism as long-term exposure to uncontrolled stress may trigger several pathophysiological states including cancer, depression, inflammatory diseases, diabetes mellitus and other diseases within the spectrum of metabolic syndrome, which comprise modified hormonal, nutritional, immune and psychological states compared to healthy population ( Age-related modifications of critical parameters determining hepatic drug metabolism Although a comprehensive definition of ageing is not possible, several characteristic alterations including the time-related loss of functional units of organs, the disruption of functional integration between cells and organs and the failure in preserving homeostasis under stress are recognized