Skip to main content Skip to main navigation menu Skip to site footer

Efficacy of tadalafil and l-arginine combination therapy compared with tadalafil-only for the treatment of erectile dysfunction: A systematic review and meta-analysis

  • Donny Austine Wibisono ,
  • Furqan Hidayatullah ,
  • Fikri Rizaldi ,
  • Tarmono Djojodimedjo ,


Introduction: Phosphodiesterase type 5 inhibitors (PDE5-I) has known to be the treatment for erectile dysfunction (ED), whereas tadalafil is a PDE5-I that has a rapid onset of action with a long duration of action and is not affected by dietary intake. L-arginine is a supplement that can improve erectile function by increasing the endogenous amino acids required for ideal nitric oxide (NO) synthesis and production. The combination of tadalafil and L-arginine can improve erectile function and testosterone levels. Thus, we conducted a meta-analysis to determine the efficacy and safety of the tadalafil and L-arginine combination therapy compared to tadalafil monotherapy for ED.

Methods: This meta-analysis study is consistent with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A total of four included studies were found by performing a systematic search thoroughly on Embase, MEDLINE, and Scopus databases. This study’s protocol is registered on PROSPERO (CRD42022343590).

Result: The study analysis revealed that the The International Index of Erectile Dysfunction 5 (IIEF-5) scores in the tadalafil and L-arginine combination therapy significantly increased the IIEF-5 scores (p < 0.00001; MD 1.64; 95% CI: 1.13-2.15) compared to tadalafil monotherapy. Testosterone levels were also observed to increase in the tadalafil and L-arginine combination therapy group (p < 0.00001; MD 3.05; 95% CI: 2.05-4.04).

Conclusion: A significant increase in IIEF-5 score and testosterone level is observed in patients with ED who received combination therapy of tadalafil and L-arginine compared to tadalafil monotherapy.


  1. McCabe MP, Sharlip ID, Lewis R, et al. Incidence and Prevalence of Sexual Dysfunction in Women and Men: A Consensus Statement from the Fourth International Consultation on Sexual Medicine 2015. Journal of Sexual Medicine 2016;13:144–152.
  2. Beutel ME, Weidner W, Brähler E. Epidemiology of sexual dysfunction in the male population. Andrologia. 2006;38(4):115-21.
  3. Gratzke C, Angulo J, Chitaley K, et al. Anatomy, physiology, and pathophysiology of erectile dysfunction. Journal of Sexual Medicine 2010;7:445–475.
  4. Hatzimouratidis K, Salonia A, Adaikan G, et al. Pharmacotherapy for Erectile Dysfunction: Recommendations From the Fourth International Consultation for Sexual Medicine (ICSM 2015). Journal of Sexual Medicine 2016;13:465–488.
  5. Fazio L, Brock G. Erectile Dysfunction: Management Update. Can Med Assoc J 2004;170: 1429–37.
  6. Forgue ST, Patterson BE, Bedding AW, et al. Tadalafil pharmacokinetics in healthy subjects. Br J Clin Pharmacol 2006;61:280-288.
  7. Gur S, Kadowitz PJ, Trost L, et al. Optimizing Nitric Oxide Production by Time Dependent L-Arginine Administration in Isolated Human Corpus Cavernosum. Journal of Urology 2007; 178: 1543–1548.
  8. Chen J, Wollman Y, Chernichovsky T, Iaina A, Sofer M, Matzkin H. Effect of oral administration of high-dose nitric oxide donor L-arginine in men with organic erectile dysfunction: results of a double-blind, randomized, placebo-controlled study. BJU Int. 1999;83(3):269-73.
  9. Abu El-Hamd M, Hegazy EM. Comparison of the clinical efficacy of daily use of L-arginine, tadalafil and combined L-arginine with tadalafil in the treatment of elderly patients with erectile dysfunction. Andrologia. 2020;52(7):e13640.
  10. El Taieb M, Hegazy E, Ibrahim A. Daily Oral l-Arginine Plus Tadalafil in Diabetic Patients with Erectile Dysfunction: A Double-Blinded, Randomized, Controlled Clinical Trial. J Sex Med. 2019;16(9):1390-1397.
  11. Ledda A, Belcaro G, Cesarone MR, et al. Investigation of a complex plant extract for mild to moderate erectile dysfunction in a randomized, double-blind, placebo-controlled, parallel-arm study. BJU Int. 2010;106:1030–1033.
  12. Mozaffari-Khosravi H, Fallahi M, Afkhami-Ardekani M. Effect of Oral Supplementation of L-arginine on Sexual Function in Men with Type 2 Diabetes: A Double-blind Clinical Trial. Journal of Nutrition and Food Security. 2017;2(2):165-172.
  13. Huang YP, Zheng FF, Yao FJ, et al. Daily medication of low dose tadalafil improves endothelial function and erectile hardness of ED patients. Zhonghua Nan Ke Xue 2010;16:1052–1055.
  14. Li JP, Li F, Guo WB, Zhou QZ, Liu CD, Mao XM, Tan WL, Zheng SB. [Efficacy of low-dose tadalafil on ED assessed by Self-Esteem and Relationship Questionnaire]. Zhonghua Nan Ke Xue. 2010;16(12):1147-9.
  15. Ozcan L, Polat EC, Kocaaslan R, Onen E, Otunctemur A, Ozbek E. Effects of taking tadalafil 5 mg once daily on erectile function and total testosterone levels in patients with metabolic syndrome. Andrologia. 2017;49(9):1-5.
  16. Cormio L, de Siati M, Lorusso F, et al. Oral L-citrulline supplementation improves erection hardness in men with mild erectile dysfunction. Urology 2011;77:119–122.
  17. Sansone A, Cignarelli A, Sansone M, Romanelli F, Corona G, Gianfrilli D, Isidori A, Giorgino F, Lenzi A. Serum Homocysteine Levels in Men with and without Erectile Dysfunction: A Systematic Review and Meta-Analysis. Int J Endocrinol. 2018;2018:7424792.
  18. Jones RW, Jeremy JY, Koupparis A, Persad R, Shukla N. Cavernosal dysfunction in a rabbit model of hyperhomocysteinaemia. BJU Int. 2005;95(1):125-30.
  19. Stühlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation. 2001;104(21):2569-75.
  20. Rizzo A, Trisolini C, Spedicato M, et al. In vitro effects of L-arginine on spontaneous and Homocysteine-induced contractility of pregnant canine uteri. Theriogenology. 2011;76:715–720.
  21. Rasic-Markovic A, Hrncic D, Krstic D, et al. The effect of subchronic supplementation with folic acid and L-arginine on homocysteine-induced seizures. Can J Physiol Pharmacol. 2016; 94:1083–1089.
  22. Lamm S. Prelox® for Improvement of Erectile Quality. Eur Endocrinol 2009;5:70-4.
  23. El-Wakeel LM, Fouad FA, Saleem MD, et al. Efficacy and tolerability of sildenafil/l-arginine combination relative to sildenafil alone in patients with organic erectile dysfunction. Andrology 2020;8:143–147.
  24. Gentile V, Antonini G, Bertozzi MA, et al. Effect of propionyl-L-carnitine, L-arginine and nicotinic acid on the efficacy of vardenafil in the treatment of erectile dysfunction in diabetes. Curr Med Res Opin. 2009;25:2223–2228.
  25. Chang Rhim H, Kim MS, Park YJ, et al. The Potential Role of Arginine Supplements on Erectile Dysfunction: A Systemic Review and Meta-Analysis. Journal of Sexual Medicine 2019;16: 223–234.
  26. Satriyasa BK. Tadalafil as New Treatment in Erectile Dysfunction: A Review. Bali Medical Journal. 2017;6(1):56–59.

How to Cite

Wibisono, D. A., Hidayatullah, F. ., Rizaldi, F. ., & Djojodimedjo, T. . (2023). Efficacy of tadalafil and l-arginine combination therapy compared with tadalafil-only for the treatment of erectile dysfunction: A systematic review and meta-analysis. Bali Medical Journal, 12(1), 312–318.




Search Panel

Donny Austine Wibisono
Google Scholar
BMJ Journal

Furqan Hidayatullah
Google Scholar
BMJ Journal

Fikri Rizaldi
Google Scholar
BMJ Journal

Tarmono Djojodimedjo
Google Scholar
BMJ Journal