Translational research suggests that agonist replacement may be a viable treatment approach for managing methamphetamine dependence. This study sought to determine the effects of d-amphetamine maintenance on methamphetamine self-administration in stimulant using participants. A cognitive battery was used to determine the performance effects of methamphetamine alone and during d-amphetamine maintenance. During each maintenance condition, participants first sampled a dose of intranasal methamphetamine then had the opportunity to respond on a progressive ratio task to earn portions of the sampled dose. Subject-rated drug-effect and physiological measures were completed prior to and after sampling methamphetamine. Methamphetamine was self-administered as function of dose regardless of the maintenance condition. Methamphetamine produced prototypical subject-rated effects, some of which were attenuated by d-amphetamine maintenance. Methamphetamine was well tolerated during d-amphetamine maintenance and no adverse events occurred. The self-administration results are concordant with those of clinical trials that show d-amphetamine did not reduce methamphetamine use. Generally, there was no difference in cognitive performance after methamphetamine administration during both placebo and d-amphetamine maintenance. Overall d-amphetamine does not appear to be a viable treatment for preventing methamphetamine relapse, but translational literature suggests that other agonist medications or the combination of pharmacotherapy and behavioral therapies may be effective.