Substance use disorders (SUDs) can be defined as patterns of symptoms caused by the abusive consumption of recreational or prescribed substances that an individual continues to use despite their negative effects. Oxidative stress is one of the main pathophysiological processes occasioned by SUDs in different brain areas. Oxidative damage and subsequent deleterious symptoms can happen because of the consumption of psychoactive drugs, both stimulants and depressants. This chapter focuses on SUDs associated with depressant drugs, such as alcohol, opioids, benzodiazepines, and their effects on the central nervous system (CNS). We present the main characteristics of the SUDs and later explore endogenous mechanisms of repair, such as neuroglia and the endocannabinoid system. We also examine the neuroprotective effects of exogenous substances such as phytocannabinoids (e.g., cannabidiol) and N-acetylcysteine (NAC), which have shown important roles in anti-inflammatory pathways and antioxidative cascades, and how these molecules can be potential tools in the treatment of neurological symptoms of SUDs.