Neurologic, psychological, and aggressive disturbances with sildenafil.
BACKGROUND
Anecdotal reports and case studies have described psychological disturbances and aggressive behavior in some men taking sildenafil. In the course of assisting the defense in a trial in which a man was alleged to have committed rape and in which sildenafil was implicated, a mechanistic hypothesis was formulated by the first author for central nervous system (CNS) adverse effects associated with the use of sildenafil.


OBJECTIVE
To examine whether there was any scientific information available to suggest a possible mechanism for or an association between exposure to sildenafil and aggressive behavior.


METHODS
The scientific literature on sildenafil, nitric oxide (NO), and the NO-cyclic-guanosine monophosphate (cyclic-GMP) signaling pathway was reviewed. Adverse event reports that referenced sildenafil and were filed with the Food and Drug Administration Adverse Event Reporting System between January 4, 1998, and February 21, 2001, also were examined.


RESULTS
Published studies reported that sildenafil crosses the blood-brain barrier, that it exerts various biochemical and physiologic effects in the brain, and that it affects information processing. Other published reports indicated that phosphodiesterase type 5 (PDE-5), NO synthase, and guanylyl cyclase are present at highest activities in areas of the brain responsible for behavior, sexual drive, and emotion, and that NO modulates aggression and sexual behavior in male mice. In addition, 274 adverse event reports designated sildenafil as the primary suspect of various neurologic disturbances, amnesia, and aggressive behavior.


CONCLUSIONS
Evidence has been presented for an association between sildenafil and various CNS adverse effects, including aggressive behavior. Whether sildenafil causes these effects by inhibiting PDE-5 in the brain, accumulating cyclic-GMP, decreasing NO, and affecting cell-cell signaling and modulation of aggressive behavior requires further investigation.


CONCLUSIONS
It is recommended that, before prescribing sildenafil for erectile dysfunction, clinicians should caution their patients and their partners on the possibility of neurologic, emotional, or psychological disturbances; amnesia or loss of consciousness; or aggressive behavior.
Milman
Harry A
HA
ToxNetwork.com, Rockville, MD 20853-2345, USA. hmilman@erols.om
Arnold
Suzanne B
SB
D016907:Adverse Drug Reaction Reporting Systems; D000374:Aggression; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects*; D001921:Brain / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology; D010879:Piperazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D011687:Purines; D012726:Sexual Behavior, Animal / Q000187:drug effects; D000068677:Sildenafil Citrate; D012920:Social Behavior Disorders / Q000139:chemically induced*; D013450:Sulfones
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D000068677:Sildenafil Citrate