BackgroundWhile the mandate to check patients’ prescription history in Prescription Drug Monitoring Program (PDMP) database before prescribing/dispensing controlled drugs has been shown to be an important tool to curb opioid abuse, less is known about whether the mandate can reduce the misuse of other commonly abused prescription drugs. We examined whether PDMP use mandates were associated with changes in prescription stimulant and depressant quantities.MethodsUsing data from Automated Reports and Consolidate Ordering System (ARCOS), we employed difference-in-differences design to estimate the association between PDMP use mandates and prescription stimulant and depressant quantities in 50 U.S. states and the District of Columbia from 2006 to 2020. Limited PDMP use mandate was specific only to opioids or benzodiazepines. Expansive PDMP use mandate was non-specific to opioid or benzodiazepine and required prescribers/dispensers to check PDMP when prescribing/dispensing targeted controlled substances in Schedule II-V. The main outcomes were population-adjusted prescription stimulant (amphetamine, methylphenidate, lisdexamfetamine) and depressant (amobarbital, butalbital, pentobarbital, secobarbital) quantities in grams.ResultsThere was no evidence that limited PDMP use mandate was associated with a reduction in the prescription stimulant and depressant quantities. However, expansive PDMP use mandate that was non-specific to opioid or benzodiazepine and required prescribers/dispensers to check PDMP when prescribing/dispensing targeted controlled substances in Schedule II-V was associated with 6.2% (95% CI: -10.06%, -2.08%) decline in prescription amphetamine quantity.ConclusionExpansive PDMP use mandate was associated with a decline in prescription amphetamine quantity. Limited PDMP use mandate did not appear to change prescription stimulant and depressant quantities.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12889-023-16256-9.