Erectile dysfunction (ED) is a complex disorder influenced by both physiological and psychological components. Although phosphodiesterase type 5 inhibitors (PDE5i) remain the mainstay of treatment, prior meta-analyses have highlighted a notable placebo response, typically yielding small to moderate effect sizes. With increasing attention toward regenerative therapies for ED, recent randomized controlled trials (RCTs) have included placebo interventions such as intracavernosal saline injections or sham low-intensity shockwave therapy. This systematic review and meta-analysis aimed to assess the extent of the placebo effect in RCTs involving regenerative treatments for ED.

We conducted a comprehensive search of PubMed and Scopus databases through March 2025. Eligible studies included RCTs comparing regenerative therapies, namely platelet-rich plasma (PRP), extracorporeal shockwave therapy (ESWT), stem cell therapy, and electrical stimulation, with placebo groups, assessing erectile function outcomes before and after intervention. Studies involving concurrent treatments or medications were excluded.

Of 527 identified records, 19 RCTs met inclusion criteria: 1 involving electrical stimulation, 4 evaluating PRP, and 15 investigating ESWT. No stem cell trials with a standalone placebo group were identified. Pooled analyses revealed significant improvements in International Index of Erectile Function (IIEF) scores within placebo arms at both 1-month (mean difference: 0.9; 95% CI: 0.21–1.59; p < 0.0001) and 3-month (mean difference: 1.01; 95% CI: 0.60–1.42; p < 0.0001) follow-ups. No significant changes were observed at 6 months or beyond. Subgroup analyses indicated a greater placebo response in ESWT trials compared to PRP. Overall, 14.3% of placebo recipients reached the minimal clinically important difference in IIEF by study end. A significant increase in Erectile Hardness Score (EHS) was also seen at 1 month (mean difference: 0.47; 95% CI: 0.19–0.76; p = 0.001), though no objective improvements, such as peak systolic velocity on penile Doppler, were detected.

These findings suggest that placebo interventions in regenerative ED trials can lead to short-term subjective improvements, particularly in ESWT studies. Awareness of this placebo impact is crucial when interpreting the effectiveness of novel regenerative treatments for ED.