Defects in processing speed and memory are common in multiple sclerosis (MS) patients. In other populations, amphetamines have been shown to enhance cognition, but their use is limited by adverse behavioral effects. The L-isomer may have equivalent cognition enhancement with less adverse effects due to decreased potency in subcortical areas. The aim of this study was to assess the safety and efficacy of L-amphetamine sulfate in the treatment of cognitive dysfunction in MS. This was a 2:1 randomized, placebo-controlled, double-blind trial, involving 33 MS clinics across the USA. One hundred and fifty-one clinically definite MS patients with documented cognitive dysfunction who were relapse free for >or=90 days, with an Expanded Disability Status Scale (EDSS) <or=6.5, and with no other medical/psychiatric condition that may cause psychological dysfunction were randomized to 30 mg of oral L-amphetamine sulfate or placebo for 29 days, including a dose escalation period. A history of cardiac disease, uncontrolled hypertension or electrocardiograph abnormalities resulted in exclusion. The primary outcomes were the Subject Global Assessment of Change and Symbol Digit Modalities Test (SDMT). Secondary outcomes were the results from the California Verbal Learning Test, second edition (CVLT2), Brief Visual Memory Test-Revised (BVMTR), and Paced Auditory Serial Addition Test (PASAT). One hundred and thirty-six subjects completed the study. No differences were found at baseline in demographics or in the results of the neuropsychological tests. After treatment, the active group performed significantly better for total learning (P = 0.041) and delayed recall (P < 0.01) on the BVMTR, and for delayed recall (P = 0.012) on the CVLT2. Five patients (four from the treatment group, one placebo) withdrew due to intolerable adverse events. L-amphetamine sulfate was associated with improved learning and memory and was well tolerated in this study. However, because the positive findings were observed on secondary outcome measures, the study requires replication before L: -amphetamine sulfate can be recommended for the treatment of cognitive impairment in MS.