Drugs for stroke recovery: the example of amphetamines.

Clinical trials of pharmacological agents in stroke have mainly focused on events that need to be modified in the very acute stage, such as restoration of blood flow with thrombolytic therapy or reducing the effects of ischaemia with neuroprotective therapy. Thrombolytic therapy is, however, only effective within the first few hours of stroke onset and so far, no neuroprotective therapy has proven to be efficacious in humans. Thus, there is a great need for new pharmacological strategies to improve outcome after stroke. Accumulating evidence supports the assumption that the brain is plastic and improvements can be expected after permanent injuries. Acute and chronic alterations in neurotransmitter regulation after injury affects plasticity and may thus provide a basis for new pharmacological targets for stroke recovery. The search for pharmacological therapies that affect the recovery process after a permanent injury has been intensified during the last decade. Amphetamines, in combination with training, are currently one of the most promising pharmacological strategies studied for recovery after stroke. Several non-mutually exclusive hypotheses, more or less supported by experimental studies, have tried to explain the mechanisms underlying the facilitation of recovery of function with amphetamine treatment. Amphetamines are believed to hasten the processes in the brain, such as plasticity mechanisms and resolution of diaschisis. The combination of amphetamine and task-specific training seems to be of importance to the outcome. Results from animal studies are consistent between different models and species, and mainly show an increased rate of recovery but there are a few exceptions, with some studies reporting no effect or even a decreased recovery rate. In humans the number of randomised controlled studies of amphetamines is growing rapidly. Results from a Cochrane systematic review indicate a faster motor and language recovery rate with treatment, but the number of studies is too few and studies are too small to draw definite conclusions about the effect on recovery of stroke. Data in the systematic review also indicate that the mortality rate is higher in amphetamine-treated patients compared with placebo-treated patients. However, this is most likely because of baseline imbalances between the treatment groups with patients with more severe strokes being allocated to amphetamine treatment. Further clinical trials are justified, but at present amphetamines should not be used in clinical practice.