This is an NIH Pilot Clinical Trial Grant designed to provide data to permit the rationale design of a subsequent efficacy study. The purpose of this project is to determine the potential benefit of amphetamine combined with physical therapy in enhancing motor recovery in patients admitted for inpatient rehabilitation between 10 and 30 days after hemispheric ischemic stroke. The study hypotheses are: 1, The addition of treatment with d-amphetamine will result in at least a 12.6 point improvement in the Fugl-Meyer motor score 3 months after stroke. 2, There will be no clinically significant increase in the frequency of serious adverse events associated with treatment with d-amphetamine which would preclude further testing.

The purpose of this Pilot Grant is to collect data critical for the design of a subsequent full-scale clinical trial testing the efficacy of treatment with amphetamine combined with physical therapy to facilitate poststroke motor recovery. When combined with task-relevant experience, a single dose of d amphetamine given 24 hr following a unilateral sensorimotor cortex ablation in the rat results in an enduring enhancement of motor recovery. This amphetamine effect extends to functional deficits that occur following focal lesions produced through a variety of mechanisms including ischemic brain injury, to lesions affecting other areas of the cortex, and to other behaviors. Laboratory studies not only show that certain drugs such as amphetamine may facilitate recovery, but that other classes of drugs may be harmful. Clinical studies suggest similar detrimental drug effects may occur in humans recovering from stroke. Three small studies of the impact of treatment with amphetamine on poststroke recovery have been carried out. Two found a beneficial effect and the third was negative. These studies differed in significant ways as reviewed in the referenced section of the proposal. The present study is designed based on these small studies. Using a multicenter, block-randomized, placebo-controlled design, this pilot study will:

1. Refine the intervention strategy which has been developed for this Pilot Grant based on the best available laboratory and preliminary clinical data.
2. Refine the target patient population.
3. Gain information to permit an accurate sample size calculation (estimated for this pilot study) for a subsequent trial.
4. Refine outcome measures, site monitoring techniques, data consistency protocols, and data management procedures.
5. Obtain data to further support the safety of the proposed intervention.

This study has several hypotheses.

1. Patients treated with d-amphetamine combined with physical therapy will have improved recovery of motor function as compared to similar patients treated with placebo combined with physical therapy measured 90 days after hemispheric ischemic stroke.
2. There will not be a clinically significant increase in the frequency of serious adverse events associated with treatment with d-amphetamine which would preclude further testing of these regimens.

Secondary goals include:

1. Refinement of the target patient population.
2. Gain information to permit an accurate sample size calculation (estimated for this pilot study) for a subsequent trial.
3. Refinement of outcome measures, site monitoring techniques, data consistency protocols, and data management procedures.

Inclusion Criteria:

1. Documented (including neuroimaging) ischemic hemispheric stroke
2. Start treatment between 10-30 days after stroke
3. Independent prior to index stroke (Rankin 0 or 1)
4. Moderate or severe stroke-related motor impairment (Fugl-Meyer motor score <80)
5. Patient (or legal representative) capable of giving informed consent
6. Availability for follow-up evaluation
7. Physically able to receive study drug/ placebo

Exclusion Criteria:

1. Hypertension defined as systolic BP>160, or diastolic BP>100 mmHg at rest determined by 3 readings during the 24 hours prior to randomization. Patients with such elevations of blood pressure on admission who respond to antihypertensive medication before medication phase of the study is to start will be eligible to participate
2. Index or remote intracerebral or subarachnoid hemorrhage
3. History of or active psychosis or bipolar disorder
4. Angina pectoris within the preceding 3 months
5. Myocardial infarction within the preceding year
6. Inducible myocardial ischemia based on exercise or pharmacological stress test if done within the prior year
7. Clinically significant congestive heart failure defined as New York Heart Class 3 or 4
8. Atrial or ventricular arrhythmias including atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation, and Wolff Parkinson White by history, electrocardiogram, or Holter monitor if done
9. History of seizures or seizures associated with index ischemic stroke
10. Allergy to amphetamine
11. Current treatment with L-dopa, other dopamine agonist, or MAO inhibitor
12. Glaucoma
13. Need for treatment with a drug/class thought to impair recovery based on laboratory and available clinical evidence (a1-adrenergic receptor antagonist, a2-adrenergic receptor agonist, benzodiazepine, dopamine receptor antagonist, phenobarbital, phenytoin)
14. Hyperthyroidism
15. Pregnancy
16. Expected rehabilitation stay less than 3 weeks for regimen 1
17. Mild stroke-related motor impairment (Fugl-Meyer motor score >80).
18. Participation in another investigational protocol
19. Any condition which in the view of the investigator would put the patient at risk through their participation in the study.