Abigail Kay, MD, MS, joins host Lorenzo Norris, MD, to discuss the treatment of patients with substance use disorders. Dr. Kay is an addiction psychiatrist at Thomas Jefferson University Hospital in Philadelphia and is associate dean of academic affairs and medical student education at Sidney Kimmel Medical College. Dr. Norris is assistant dean of student affairs, and assistant professor of psychiatry and behavioral sciences at George Washington University, Washington. Dr. Kay disclosed no conflicts of interest for the past year. Before that, she reported receiving payment from the American Society of Addiction Medicine, through a grant from the Substance Abuse and Mental Health Services Administration, to teach a free training to clinicians to be certified to prescribe buprenorphine. Dr. Norris, who also serves as medical director of psychiatric and behavioral sciences at George Washington University Hospital, disclosed no conflicts. Take-home points Substance use disorders have genetic and environmental factors. The genetic component is sometimes overlooked because the environmental factor – the exposure to using a substance – is heavily focused as the only trigger for addiction. Methadone is a pure agonist at the mu-opioid receptor so the higher dose the greater the effect. The average dose of methadone to achieve blocking of cravings, withdrawal, and opiate intoxication is 80-120 mg. Buprenorphine is a partial agonist: At low doses, it acts as an agonist, and at high doses it acts as an antagonist with quite high affinity for the receptor. As a partial agonist, it has a ceiling effect with more than 90% of opiate receptors occupied at 24 mg. Dr. Kay suggests a helpful rule of thumb is to assume that, if patients have an addiction, there’s a 50/50 chance that they have another psychiatric disorder and vice versa. With this in mind, all patients with substance use disorder should be evaluated for comorbid psychiatric disorders and underlying medical conditions. Summary Dr. Kay breaks down human cognition into the primitive brain and thoughtful brain. The primitive brain keeps us alive by preferentially focusing on sleeping, drinking, and eating. Addiction to a drug hijacks the primitive brain, making it prioritize the substance of choice above all else. Methadone is the “gold-standard” treatment for opioid use disorder in the sense that all treatments are compared with its efficacy and mechanism of action. Methadone is a pure agonist at the mu-opioid receptor, meaning the higher dose the greater the effect; the average dose of methadone is 80-120 mg. The goal of treatment is to achieve a blocking dose, meaning a dose that blocks the craving, the withdrawal, and the high if people were to use illicit opiates on top of their methadone. Methadone is administered only at federally approved sites, and one advantage is that additional services, such as counseling, can be offered on site after daily administration. Buprenorphine as a partial agonist can play both “roles” on the mu-opioid receptor. At low doses, it acts as an agonist, and at high doses, it acts as an antagonist with quite high affinity for the receptor. In addition, as a partial agonist buprenorphine has a ceiling effect: At 24 mg of buprenorphine occupies 92% of opiate receptors and at 32 mg only an additional 1% of receptors are occupied. Buprenorphine must be administered when the person is already in withdrawal, because its affinity to the receptor dislodges other opiates from the mu receptor thus precipitating withdrawal. Buprenorphine works well for individuals who would require an average 40-60 mg of methadone to achieve their blocking dose. Because of the ceiling effect, some individuals continue to crave opiates while on buprenorphine. This means that, despite the greater convenience offered by buprenorphine, it is not the treatment of choice for everyone. Naltrexone is a pure opioid antagonist requiring 10-14 days of abstinence from opiates to prevent