The critical points that must be addressed in evaluating ergotropic drugs are 
exemplified by the current morass of positive and negative results that have 
been obtained in clinical investigations of TRH or its analogues. Appropriate 
subject selection is crucial. These patients may have bulbar symptoms, and those 
features of ALS should be specifically assayed for treatment effects relative to 
placebo. Gender-specific effects of TRH need to be accounted for in study 
design. In addition, electrophysiological techniques such as single fiber 
density may help determine the responsiveness of patients to TRH or its 
analogues. The clinical significance of an increase in fiber density following 
TRH or other drugs should be determined, as it will provide insight into the 
state of motor neurons in the spinal cord of patients with ALS and possibly 
could be important in determining those who may respond to TRH if such a 
response is possible. Clinical studies have quite clearly shown conflicting 
results. Basic studies, however, have shown that response to TRH is state 
dependent, that is, whether the patient is male or female. Clinical studies have 
shown that response to TRH is state dependent, that is, it depends on whether 
the patient has bulbar or nonbulbar signs and is male or female. Future studies 
must take into consideration this state dependence as a specific feature of the 
pharmacological action of TRH and its analogues.