AUA2022: REFLECTIONS: The Safety and Efficacy of Sexual Supplements

By: Lawrence C. Jenkins, MD, MBA; Nicolas M. Ortiz, MD; Nelson E. Bennett, MD | Posted on: 01 Aug 2022

There is an increasing number of patients looking for natural options to aid in their sexual functioning. This has become a growing industry and the global market for sexual enhancement supplements is estimated at $300 million in the year 2020 and is projected to reach $608 million by 2030, based on a compound annual growth rate >9%. This has attracted many companies to distribute products with many sometimes false claims. These products are also of varying quality and sometimes with contaminants like prescription drugs. Generally, manufacturers do not need U.S. Food and Drug Administration (FDA) approval before producing or selling but must ensure safety and good manufacturing practice. The FDA acts against unsafe products after they reach the market under the Dietary Supplement Health and Education Act of 1994. There have been reports of erectile dysfunction (ED) supplements containing prescription drugs such as sildenafil and tadalafil.1 The FDA maintains a website for “Tainted Sexual Enhancement Products” at https://www.fda.gov/drugs/medication-health-fraud/tainted-sexual-enhancement-products.

“Most herbal supplements provide minimal harm; however, there are limited efficacy data.”

Most herbal supplements provide minimal harm; however, there are limited efficacy data. Verification by the United States Pharmacopeia, an independent nonprofit organization, ensures the product contains the ingredients on the label in the declared potency and amount, does not contain harmful contaminants and has been made using good manufacturing practices. Unfortunately, most of the sexual supplements available do not utilize any independent testing like that done by the United States Pharmacopeia to assure product quality. Thus, quality is the main concerning feature in this product market, which limits any recommendation for use. As providers, we should warn our patients that although there may be low safety risks, they may not be getting exactly what they are paying for.

The following section is a breakdown of some of the most common ingredients found on the market today.2

Ashwagandha

Withania somnifera, commonly used in Ayurvedic medicine since ancient times as an anti-stress agent, aphrodisiac, for impotence and infertility treatment. Active components include alkaloids, steroidal lactones, saponins and withanolides.

Mechanism of action (MOA): Anti-inflammatory and neuroprotective effects, possible influence on hypothalamic-pituitary-gonadal axis.

Adverse effects (AEs): Mild/moderate drowsiness, upper gastrointestinal discomfort, loose stools.

Research: Three randomized controlled trials (RCTs) and 1 RCT/crossover showed an effect on testosterone concentrations in men.3 All were small with only 45-60 patients. Three studies showed a benefit and averaged a 14% increase in testosterone vs placebo; 1 study showed no benefit.

Ginseng

There are several different types: Korean, Asian, Chinese or red ginseng, American ginseng and Siberian ginseng. Ginsenosides are the principal molecular ingredients of ginseng.

MOA: Activates endothelial NOS to release nitric oxide (NO) and inhibit calcium accumulation. Also, it can activate large-conductance K calcium channels in smooth muscles. Has antioxidant properties.

AEs: Headache, nausea, constipation, insomnia.

Research: In an article by Choi et al, 8 weeks of ginseng tablets vs placebo resulted in a statistically significant increase in International Index of Erectile Function (IIEF-15): from mean ± SD 40.95 ± 7.05 to 46.19 ± 12.69.4

“As providers, we should warn our patients that although there may be low safety risks, they may not be getting exactly what they are paying for.”

maca (Lepidium meyenii)

Used for centuries by native Andean populations as an aphrodisiac, energizer and enhancer of fertility and sexual function.

MOA: Unknown.

AEs: Gastritis and insomnia.

Research: Only 1 RCT, which examined 50 men with mild ED.2,5 The authors concluded that the data were insufficient to draw conclusions on the efficacy of maca relative to sexual function.

Tribulus terrestris

Used in medicinal herbs by Ayurvedic medicine for various ailments, in Western medicine it is used to improve sexual function.

MOA: The ingredient protodioscin may lead to an aphrodisiac-like effect via an increase in some sex hormones. Erectogenic effects are via conversion of protodioscin to dehydroepiandrosterone. Concentration-dependent relaxation of the corpus cavernosum via NO/NO synthase pathway.

AEs: Elevation of transaminases leading to hepatic toxicity, nephrotoxicity.

Research: A prospective RCT included 180 males 18–65 years old with mild to moderate ED.6 Exclusion of hypertension, diabetes mellitus (DM) and metabolic syndrome. Results showed that IIEF increased 2.7 points in the Tribulus group (p <0.0001). However, there was no change in serum testosterone levels.

Horny Goat Weed (Yin Yang Huo)

Epimedium species, usually E. grandiflorum; leaves or roots are used. Commonly used in Chinese medicine.

MOA: Active ingredient = icariin (a flavonol glycoside) with phosphodiesterase type 5 inhibitor activity.

AEs: Generally mild. One report of hypomania and tachyarrhythmia.

Research: There have been no human studies. In animal studies, rats were fed icariin for 4 weeks following cavernosal nerve injury and showed improved penile hemodynamic parameters when compared with placebo.5

Yohimbe/Yohimbine

Yohimbe bark extract is traditionally used in Africa as an aphrodisiac. Modern-day marketing is for ED and delayed orgasm.

MOA: It is believed to block the alpha-2 adrenoceptors in the locus coeruleus in the brain. In the periphery, it’s suggested to inhibit alpha-1 and alpha-2 adrenoceptors as well as enhance the release of NO from cavernosal endothelial cells.

AEs: High blood pressure, increased heart rate, bronchospasm, palpitations, insomnia, anxiety, irritability, shivering, sweating, nausea, flushing and headaches, which all can be attributed to its central adrenergic activity.

Research: A meta-analysis (1998) reviewed 7 placebo-controlled trials and determined yohimbine was superior to placebo for the treatment of ED.2,5

Fenugreek

One of the oldest medicinal plants, it has been described as a panacea, a cure-all. A description of the plant was found in “Ebers Papyrus” circa 1550 BC.

MOA: The seeds contain several compounds: diosgenin’a precursor for hormone production, amino acids (arginine), vitamin D, essential oils and lipids.

AEs: None reported.

Research: One double-blind, placebo-controlled RTC in 60 males without ED: 600 mg fenugreek vs placebo for 6 weeks.7 It led to an increase in sexual arousal and orgasm domains on Derogatis Interview for Sexual Functioning-Self Report scale. It also increased muscle strength, energy and well-being. However, total testosterone and prolactin levels remained normal.

Arginine

It has a long history as a sexual supplement, especially before phosphodiesterase type 5 inhibitor was introduced.

MOA: It is an immediate precursor of NO. When using supraphysiological doses (usually >3 mg/day), increased production of NO ensues. The increased bioavailability of NO is thought to enhance erectile function.

AEs: 10% decrease in systolic blood pressure.

Research: In a placebo-controlled RCT by Chen et al, 50 men with ED were randomized to 5 gm/day or placebo.8 At followup of 2 weeks, 31% L-arginine group vs 12% placebo group showed an increase in erectile function. The L-arginine group also showed increased urinary NO production.

“In animal studies, rats were fed icariin for 4 weeks following cavernosal nerve injury and showed improved penile hemodynamic parameters when compared with placebo.5

Vitamin D

Sources: Sunlight, fatty fish, fortified milk. Deficiency is associated with cardiovascular disease, hypogonadism, depression and DM.

MOA: Increases endothelial NOS, affecting endothelial function.

AE: Weakness, dry mouth, nausea, vomiting.

Research: Tirabassi et al in 2018 showed a positive correlation with supplementation in bivariate analysis independent of testosterone levels, DM, hypertension or smoking status.9 Canguven et al in 2017 showed that 600 K IU/month for a year led to significant improvements in IIEF-5, from 13.88 to 20.25.10

  1. Chiang J, Yafi FA, Dorsey PJ et al: The dangers of sexual enhancement supplements and counterfeit drugs to “treat” erectile dysfunction. Transl Androl Urol 2017; 6: 12.
  2. Cui T, Kovell RC, Brooks DC et al: A urologist’s guide to ingredients found in top-selling nutraceuticals for men’s sexual health. J Sex Med 2015; 12: 2105.
  3. Smith SJ, Lopresti AL, Teo SYM et al: Examining the effects of herbs on testosterone concentrations in men: a systematic review. Adv Nutr 2021; 12: 744.
  4. Choi YD, Park CW, Jang J et al: Effects of Korean ginseng berry extract on sexual function in men with erectile dysfunction: a multicenter, placebo-controlled, double-blind clinical study. Int J Impot Res 2013; 25: 45.
  5. Corazza O, Martinotti G, Santacroce R et al: Sexual enhancement products for sale online: raising awareness of the psychoactive effects of yohimbine, maca, horny goat weed, and ginkgo biloba. Biomed Res Int 2014; 2014: 1.
  6. Kamenov Z, Fileva S, Kalinov K et al: Evaluation of the efficacy and safety of Tribulus terrestris in male sexual dysfunction’a prospective, randomized, double-blind, placebo-controlled clinical trial. Maturitas 2017; 99: 20.
  7. Steels E, Rao A and Vitetta L: Physiological aspects of male libido enhanced by standardized Trigonella foenum-graecum extract and mineral formulation. Phytother Res 2011; 25: 1294.
  8. Chen J, Wollman Y, Chernichovsky T et al: 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: 269.
  9. Tirabassi G, Sudano M, Salvio G et al: Vitamin D and male sexual function: a transversal and longitudinal study. Int J Endocrinol 2018; 2018: 1.
  10. Canguven O, Talib RA, El Ansari W et al: Vitamin D treatment improves levels of sexual hormones, metabolic parameters and erectile function in middle-aged vitamin D deficient men. Aging Male 2017; 20: 9.
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