On-demand SSRI treatment of premature ejaculation: pharmacodynamic limitations for relevant ejaculation delay and consequent solutions

J Sex Med. 2005 Jan;2(1):121-31. doi: 10.1111/j.1743-6109.2005.20112.x.


Introduction: Recently, the idea has emerged that on-demand use of serotonin reuptake inhibitors (SSRIs), particularly short half-life, should be equally effective in delaying ejaculation as daily SSRI treatment of premature ejaculation.

Aim: To provide evidence that SSRI-induced ejaculation delay is mainly dependent on pharmacodynamic properties of the drug and hardly on pharmacokinetic factors, and that combined SSRI administration with specific 5-hydroxytryptamine (5-HT) receptor antagonism leads acutely to stronger ejaculation delay than acute SSRI monoadministration.

Methods: We performed a detailed analysis of serotonin neurotransmission and reviewed animal studies with 5-HT(1A) receptor antagonists. In addition, we critically reviewed existing on-demand SSRI treatments publications and the current debate on a definition of premature ejaculation.

Main outcome measures: Intravaginal ejaculation latency time (IELT).

Results: Acute SSRI administration leads to only a mild or no increase of 5-HT neurotransmission and concomitant stimulation of postsynaptic 5-HT receptors. Existing on-demand SSRI treatment studies suffer from methodological insufficiencies, and the reported high-fold increases of ejaculation time contradict with neuropharmacological insights from serotonin metabolism. Animal studies show that SSRI coadministration with 5-HT(1A) receptor antagonists significantly increases the ejaculation time acutely compared to acute SSRI monoadministration.

Conclusion: On-demand SSRI treatment has less ejaculation-delaying effects than daily SSRI treatment. SSRIs with a short half-life are likely leading to much less ejaculation delay than current registered SSRIs. Combined use of SSRIs with 5-HT(1A) receptor antagonists increases the likelihood of clinically relevant ejaculation delay after on-demand treatment. On-demand SSRIs with short half-life that insufficiently delay ejaculation in men with IELTs less than 1 minute should be called ejaculation-delaying drugs rather than drugs against premature ejaculation.

Publication types

  • Review

MeSH terms

  • Animals
  • Drug Administration Schedule
  • Ejaculation / drug effects*
  • Half-Life
  • Humans
  • Male
  • Models, Neurological
  • Rats
  • Receptors, Serotonin / drug effects
  • Receptors, Serotonin / physiology
  • Serotonin Uptake Inhibitors / administration & dosage
  • Serotonin Uptake Inhibitors / pharmacokinetics
  • Serotonin Uptake Inhibitors / pharmacology*
  • Sexual Dysfunction, Physiological / drug therapy*


  • Receptors, Serotonin
  • Serotonin Uptake Inhibitors