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We discussed the pharmacokinetics (PKs) and pharmacodynamics (PD) of currently prescribed direct antiviral agents (NSA5 inhibitors: daclatasvir, elbasvir, ledipasvir, pibrentasvir, velpatasvir; NS5B inhibitor: sofosbuvir; NS3\/4A protease inhibitors: glecaprevir, grazoprevir, voxilaprevir) and most common substances of abuse (opioids: buprenorphine, fentanyl, heroin, methadone, morphine, oxycodone; stimulants: amphetamines, cathinones, cocaine; cannabinoids; ethanol). Overall, most direct\u2010acting antivirals (DAAs) are substrates and inhibitors of the transmembrane transporter P\u2010glycoprotein (P\u2010gp), and several of them are metabolized by cytochrome P450 enzymes. Clinically relevant interactions are associated with P\u2010gp and CYP3A modulators. Most substances of abuse are eliminated by Phase I and Phase II metabolizing enzymes, but none of them are either major inhibitors or inducers. PK studies did not show any relevant interactions between DAA and methadone or buprenorphine. Based on pharmacological considerations, neither efficacy loss nor adverse drug event associated with detrimental interaction are expected with opioids, stimulants, cannabinoids and ethanol. 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