The neurobiological and behavioral impacts of adulterants in drugs of abuse

• Adulteration of drugs of abuse exacerbates the substance use disorder crisis. • Common adulterants have standalone effects on brain mechanisms. • Adulterants in combination with the primary drug of abuse can potentiate its effect. This review examines how the presence of adulterants in drugs of abuse can disrupt the neurobiological, behavioral, and physiological processes associated with substance use disorder (SUD). Adulteration, the practice of adding foreign substances to illicit drugs to increase potency or profits, has dangerous and often life-threatening consequences for users. These pharmacologically active ingredients interact with neurobiological pathways in both brain and body, altering the addictive properties of the primary substance and complicating treatment efforts. This includes changes in neurotransmitter activity and alterations in brain circuitry, which increase the likelihood of continued substance use and relapse. In turn, behavioral outcomes are significantly affected, with individuals often experiencing cravings, impaired decision-making, precipitated overdose, and stronger compulsive drug-seeking behaviors. This review primarily highlights the non-abused adulterants and how pairing them with drugs of abuse can alter wide-ranging brain mechanisms. The analysis focuses primarily on preclinical studies while drawing connections to relevant clinical data when available to offer a comprehensive understanding of the impact of SUD on behavioral and physiological outcomes. Graphical diagram outlining common adulterants binding sites, regions of interest and neurobiological and behavioral outcomes following consumption with drugs of abuse. represents toxicity; represents increased neuronal activity; ↑ represents an increase; ↓ represents a decrease; = represents no change; represents a recovery of function; represents reactive oxygen species reaction; represents oxygen; represents cannabis; represents cotinine. nAChR: nicotinic acetylcholine receptors; GCPR: G-coupled protein receptor; k-opioid: kappa opioid; VTA: Ventral tegmental area; COX: cyclooxygenase; CYP2A6: cytochrome P450 2A6 variant; CYP450: cytochrome P450; ROS: Reactive oxygen species; ETOH: ethanol; GA-mix: Green apple mix.