According to the WHO, 2 billion people drink alcohol, 1.3 billion smoke, 182 million consume cannabis, and almost 250 million use illicit drugs. Many of those alcohol, tobacco and drug users become addicted. Substance use disorders (SUDs) generate the largest disease burden and are categorized by DSM-5 and ICD11. SUDs are defined by compulsive drug use, craving, and relapses that can occur even after years of abstinence. SUDs encompass several drug classes including alcohol, nicotine, cannabis, opioids, and stimulants. One fundamental question in psychiatric research is: “How distinct are the different SUDs and what are the shared pathological phenomena? Here we aim to determine the extent to which alcohol, nicotine, heroin, cannabis, and cocaine use disorders share genetic, epigenetic, transcriptomic and neurochemical mechanisms. In a convergent approach, multiple system levels will be studied concurrently in humans and rats in the approach of SysMedSUDs.