Yohimbine in erectile dysfunction: would an orphan drug ever be properly assessed?

The systemic use of adrenergic antagonists in the treatment of sexual dysfunction has originated more controversy than results. Among the various agents, yohimbine has acquired an unenviable reputation in the treatment of erectile dysfunction. The drug is pharmacologically well characterized as an alpha2 adrenoceptor antagonist with activity in the central and peripheral nervous systems. In-depth, systematic studies in animals have shown that yohimbine has a remarkable positive effect on sexual performance. Meta-analyses of the few controlled, randomized human studies have consistently shown an advantage of yohimbine over placebo. Despite such a long history and encouraging activity, the drug has not yet been subjected to scientifically rigid human clinical trials. Although relevant basic pharmacological and animal research information has been available for over 15 years, recent studies have been designed with a lack of insight and complete disregard of those fundamental studies. Currently, dose-response investigations are not available, alternative routes of administration (i.e., sublingual) have not been investigated, nor has continuous versus "on-demand" administration been explored. Synergistic activity with other drugs was last studied nearly four decades ago. Assessments of various populations were carried out in very limited cohorts and only in the most general terms. In short, properly designed trials in humans have not been performed. This apparent lack of scientific and financial interest has various roots. First of all, yohimbine is an old drug. As such it does not enjoy patent protection or commercial viability. Until molecular/formulation changes can be brought about (as recently happened with two other venerable agents: phentolamine and apomorphine) serious investigation of the drug will remain in limbo. Another promising avenue is the potential for synergistic effect of yohimbine with other compounds. When all is said and done, it could be that the naysayers are right and yohimbine indeed lacks clinical activity as a treatment for the phallodynamically challenged. As long as it remains an orphan drug we will never know. One hopes that interest can be eventually generated for the proper assessment of yohimbine in a different formulation or in combination with other agents.