This chapter focuses on the pharmacological interactions between opioids or psychoactive substances, such as cocaine, amphetamines, products containing tetrahydrocannabinol and cathinones with anesthetic drugs, and provides recommendations during the perioperative period for recognizing risks and reducing complications. Substance use can be suspected or confirmed in the preoperative phase via physical examination, anamnesis and toxicological tests. Assessment of appropriate timing of surgery is necessary, requiring, in case of opioid dependence, careful evaluation of treatment. Regional anesthesia is preferred in opioid users. General anesthesia could control cardiovascular alterations due to the central and peripheral neurotransmitter effects of psychostimulants. Indications and contraindications regarding anesthetic drugs and intraoperative strategies are discussed. Important postoperative implications include the use of intensive care unit; close respiratory and cardiovascular monitoring; multimodal analgesia and pain control; and withdrawal prevention. Finally, the review provides suggestions on how to approach the patient with other healthcare providers for offering opportunities to treat substance use disorder.