Abuse and dependence potential of sphingosine-1-phosphate (S1P) receptor modulators used in the treatment of multiple sclerosis: a review of literature and public data

Abuse and misuse of prescription drugs remains an ongoing concern in the USA and worldwide; thus, all centrally active new drugs must be assessed for abuse and dependence potential. Sphingosine-1-phosphate (S1P) receptor modulators are used primarily in the treatment of multiple sclerosis. Among the new S1P receptor modulators, siponimod, ozanimod, and ponesimod have recently been approved in the USA, European Union (EU), and other countries. This review of literature and other public data has been undertaken to assess the potential for abuse of S1P receptor modulators, including ozanimod, siponimod, ponesimod, and fingolimod, as well as several similar compounds in development. The S1P receptor modulators have not shown chemical or pharmacological similarity to known drugs of abuse; have not shown abuse or dependence potential in animal models for subjective effects, reinforcement, or physical dependence; and do not have adverse event profiles demonstrating effects of interest to individuals who abuse drugs (such as sedative, stimulant, mood-elevating, or hallucinogenic effects). In addition, no reports of actual abuse, misuse, or dependence were identified in the scientific literature for fingolimod, which has been on the market since 2010 (USA) and 2011 (EU). Overall, the data suggest that S1P receptor modulators are not associated with significant potential for abuse or dependence, consistent with their unscheduled status in the USA and internationally.