The dose of alcohol administered in combination with the drugs or the use of alcohol by the participants in the studies (e.g., moderate versus heavy users) can modify the findings in the results. For example, at a high BAC (~0.8–1.0 g/L), alcohol inhibited the hepatic first-pass metabolism of amitriptyline (TCA), which markedly increased amitriptyline plasma concentrations (274). However, a study that used a more moderate alcohol exposure (BAC~ 0.3 g/L) found that alcohol had no effect on amitriptyline’s pharmacokinetics (275) (but delayed the time of absorption of trazodone). The pharmacokinetics of bupropion, which is extensively metabolized by the CYP450 (CYP2B6), was not affected by moderate (~ 0.3–0.4 g/L) nor by high (~0.8 g/L) BACs (276). Most antidepressants are metabolized by CP2D6, but alcohol neither induces nor inhibits hepatic clearance via this specific enzyme (277). Interestingly, clinical studies show that CYP2D6 (and CYP2E1) is also expressed in the brain and is upregulated in people with AUD (137, 278). This suggests that some alcohol-drug interaction may arise from altered drug metabolism in the brain without affecting systemic drug concentrations.
