Loperamide is an over-the-counter antidiarrheal for which increasing cases of abuse or misuse are described. We report the onset of opioid use disorder associated with low to moderate doses of loperamide in an intellectual disability patient without previous history of substance use disorder (SUD). Our patient presented strongly reduced activities of CYP3A and P-glycoprotein, which are mainly involved in loperamide metabolism and transport. We suggest that this led to an increase in bioavailability, systemic exposure, and brain penetration thus allowing loperamide to act on the central nervous system and contributing to the development of SUD. Slow release oral morphine (SROM) was chosen as opioid agonist treatment, which successfully contained loperamide use and globally improved her clinical condition. This situation highlights the need for caution and awareness when prescribing loperamide, particularly in vulnerable patients with few cognitive resources to understand the risks of self-medication and little insight into its effects.