N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

Complaint to TGA – N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

Acknowledgements: This complaint was worked up by 2019 Monash BMS3052 students; then checked and submitted by Assoc Prof Ken Harvey. Product and Sponsor Product name: WYLD MAN & WYLD WOMEN Sponsor: N-Hance Pty Ltd Address: PO Box 8303, BAULKHAM HILLS, NSW, 2153 Australia WYLD MAN - ARTG no: 264894, Product Ingredients: Epimedium sagittatum 150 mg Ginkgo biloba 60 mg Panax ginseng 50 mg Paullinia cupana 89.3 mg Schisandra chinensis 187.5 mg Tribulus terrestris 50 mg Zinc amino acid chelate 30 mg WYLD WOMEN - ARTG no: 264912 Product Ingredients: Calcium carbonate 250 mg Calcium pantothenate 13.64 mg Chromium picolinate 201.13 microgram Cyanocobalamin .025 mg Eleutherococcus senticosus 66.67 mg Equivalent: Eleutherococcus senticosus (Dry) 1000 mg Folic acid 50 microgram Ginkgo biloba 60 mg Equivalent: Ginkgo biloba (Dry) 3 g Heavy magnesium oxide 86.37 mg Nicotinamide 12.5 mg Paullinia cupana 83.33 mg Equivalent: Paullinia cupana (Dry) 416.67 mg Pyridoxine hydrochloride 25 mg Riboflavine 12.5 mg Thiamine nitrate 12.5 mg Tribulus terrestris 8.33 mg Equivalent: Tribulus terrestris (Dry) 500 mg Turnera diffusa 100 mg, Equivalent: Turnera diffusa (Dry) 1000 mg Advertisement type: Internet – Web site Accessed on: 08/01/2020 URL(s) listed (screen shots accessed 08/01/2020 appended) https://wyld.com.au/ https://wyld.com.au/wyld-products/wyld-man-natural-aphrodisiac https://www.chemistwarehouse.com.au/buy/56896/Wyld-For-Men-60-Tablets https://shop.coles.com.au/a/a-nsw-metro-alexandria/product/wyld-man-tablets https://wyld.com.au/wyld-blog/benefits-of-wyld-man-and-wyld-woman https://www.pharmacy4less.com.au/wyld-for-men-tabs-60-4.html https://www.ebay.com.au/itm/WYLD-MAN-VITALITY-SEX-DRIVE-ENHANCE-SEXUAL-DESIRE-MEN- HORNY-GOAT-WEED-TRIBULUS/162432779317 Etc.

Page 1 of 11 Complaint to TGA – N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

Complaint Summary These products prey on vulnerable consumers concerned about their sexual performance. Many complaints about similar products have been upheld by the TGCRP. Because of this, it is suggested this complaint should be given a medium priority. Both WYLD MAN and WYLD WOMEN contain a complex mix of herbal ingredients, vitamins and minerals. Some claims &/or ingredients are said to be supported by traditional evidence, but many other claims appear to be scientifically based. Herbal ingredients have varied active constituents and clinical trial results are only valid for specific identified extracts). In addition, combinations of herbs with other ingredients are not necessarily additive or synergistic, they can also be antagonistic and adverse effects are more likely the greater the number of ingredients combined. No scientific evidence was found supporting the claims made for this combination product, or its individual ingredients. In addition, many claims made were inconsistent with the ARTG entries, while some, such as ‘no known side effects' are untrue and unacceptable. It is alleged the claims documented breach the Therapeutic Goods Advertising Code (No.2) 2018, s.9(b), 9(d), s.10(a)(ii), 10(d)(ii), 12(3)(f) & 13(7), s.17(2). The ARTG Public Summary also contains many unsupported claims This product and similar exploitative ones such as ‘Horny Goat Weed for Him’ and ‘Horny Goat Weed for Her’ should be removed from the ARTG. Introduction These products prey on vulnerable consumers concerned about their sexual performance. Numerous complaints about similar products have been upheld by the TGCRP.1 Because of this it is suggested this complaint should be given a medium priority. Both WYLD MAN and WYLD WOMEN make numerous claims and contain a complex mix of herbal ingredients, vitamins and minerals. Some ingredients are said to have traditional evidence of use, but other claims appear to be scientifically based. Herbal ingredients have varied active constituents and clinical trial results are only valid for specific identified extracts). In addition, combinations of herbs with other ingredients are not necessarily additive or synergistic, they can also be antagonistic and adverse effects are more likely the greater the ingredients combined. No good scientific evidence was found supporting the numerous claims made for this combination product or for its individual ingredients. Claims disputed • 'Ignite your WYLD side'. 'WYLD MAN GIVES YOU THE ENDURANCE AND STAMINA YOU NEED TO PERFORM AT YOUR PEAK WHEN IT COUNTS. CREATED FOR OPTIMAL PERFORMANCE, WYLD HELPS YOU GET THE MOST OUT OF YOUR BODY WHEN IT COUNTS'! These claims, together with the illustrations, and others unqualified by "traditionally used" implies scientific evidence for the products claim as an aphrodisiac which is unsupported. • 'HELPS TO SUPPORT HEALTHY SEXUAL FUNCTION Due to maintenance of healthy circulation with Ginkgo biloba leaf'. 'Maintain blood flow to the extremities'. Also lacks evidence. • 'Most people experience an increase in their sex drive within two weeks', 'Recharge sex drive', 'Maintain a healthy sperm count'. Lacks evidence and not on the ARTG.

1 https://www.tgacrp.com.au/complaint-register/?_search=horny

Page 2 of 11 Complaint to TGA – N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

• 'A Low libido in men can also be addressed via supplementation. This supplementation revolves around addressing the more physical nature of a low libido. WYLD Man is a perfect solution to increase libido naturally. The men’s formula has been created for increased performance and sex drive with 3000mg of Tribulus making it one of the most potent formulas on the market'. Lacks evidence • 'WYLD WOMAN FIRES UP YOUR BODY AND MIND GIVING YOU INCREASED SEXUAL DESIRE' & 'HELPS TO SUPPORT HEALTHY SEXUAL FUNCTION Due to maintenance of healthy circulation with Ginkgo Biloba leaf'. Lacks evidence and not on ARTG. • 'There are no known side effects' Untrue and completely unacceptable. • Pharmacy4less and ebay.com.au web sites lack required information. • Also, dubious testimonials, unlikely to be typical, need verification by statuary declarations. Evidence reviewed ‘A Urologist’s Guide to Ingredients Found in Top-Selling Nutraceuticals for Men’s Sexual Health’ (2015) is appended.2 According to the authors, the top-selling nutraceuticals marked for men’s sexual health in the U.S. contain a blend of multiple supplements (up to 33 in one formulation identified), the most common being ginseng, tribulus, zinc, horny goat weed, B complex vitamins / trace minerals, fenugreek, L-arginine, maca, DHEA, ginkgo, and yohimbine. The currently available medical literature evaluating the efficacy of these substances is generally of low quality. Also, given the decreased oversight relative to prescription medication, there is limited study of toxicity in the setting of monotherapy, combination with prescribed medications or other supplements. In conclusion, they were not recommended. See also, ‘Rise of herbal and traditional medicine in erectile dysfunction management’.3 Some additional notes on specific ingredients contained in the WYLKD product follow. Ginkgo biloba – ‘'HELPS TO SUPPORT HEALTHY SEXUAL FUNCTION’, healthy circulation, 'Maintain blood flow to the extremities', 'WYLD WOMAN FIRES UP YOUR BODY AND MIND GIVING YOU INCREASED SEXUAL DESIRE' & 'HELPS TO SUPPORT HEALTHY SEXUAL FUNCTION Due to maintenance of healthy circulation with Ginkgo Biloba leaf' According to the U.S. National Center for Complementary and Integrative Health (NCCIH) there is no conclusive evidence that Ginkgo biloba is helpful for any health condition including memory enhancement and intermittent claudication (poor blood supply to the legs).4 In addition, NCCIH notes the side effects of ginkgo may include headache, stomach upset, and allergic skin reactions. The only relevant vaguely study found was by Wu et al. which investigated the effects of IV ginkgo biloba extract on the blood flow of healthy elderly individuals. 5 However, given the product was administered intravenously, not orally, it provided no support for the above claim. Tribulus terrestris – ‘The men’s formula has been created for increased performance and sex drive with 3000mg of Tribulus making it one of the most potent formulas on the market'. This is a common ingredient in products purporting to improve sexual functions, believed by some as a precursor of testosterone. While some studies in humans have shown mixed results, most find

2 https://www.ncbi.nlm.nih.gov/pubmed/26531010 3 https://www.ncbi.nlm.nih.gov/pubmed/21948222 4 https://nccih.nih.gov/health/ginkgo/ataglance.htm 5 https://www.sciencedirect.com/science/article/abs/pii/S0944711307003157

Page 3 of 11 Complaint to TGA – N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

tribulus no more effective than a placebo on improving symptoms of erectile dysfunction or serum total testosterone.6 Epimedium sagittatum -Also known as Horny Goat weed, this extract contains a substance called icariin which is shown to have the effect of dilating blood vessels through PDE5 inhibitory action in smooth muscle. While animal studies have exhibited positive results, particularly with reference to the improvement of blood flow in the corpus cavernosum of rats.7 However, none of this research has been replicated in humans. Panax Ginseng –Wyld Men claims the product helps a healthy sperm count. The only study found showed improved sperm count and motility in rats, not humans.8 Alleged regulatory breaches: Therapeutic Good Advertising Code (No. 2) 2018 s. s.9(a), s.9(b), 9(d), s.10(a)(ii), 10(d)(ii), 12(3)(f) & 13(7), s.17(2). The ARTG Public Summary also contains many unsupported claims This product and other similar exploitative ones such as ‘Horny Goat Weed for Him’ and ‘Horny Goat Weed for Her’ should be removed from the ARTG. Signed and dated Dr Ken Harvey MB BS, FRCPA, AM Associate Professor Public Health and Preventive Medicine Monash University 13 January 2020

6 https://www.ncbi.nlm.nih.gov/pubmed/24630840 7 https://www.ncbi.nlm.nih.gov/pubmed/21729132 8 https://www.ncbi.nlm.nih.gov/pubmed/29076302

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Appendix (Screen shots with offending claims arrowed)

https://wyld.com.au/

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https://wyld.com.au/wyld-products/wyld-man-natural-aphrodisiac

https://wyld.com.au/

https://wyld.com.au/wyld-products/wyld-woman-natural-aphrodisiac

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https://wyld.com.au/wyld-products/wyld-man-natural-aphrodisiac

Page 7 of 11 Complaint to TGA – N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

https://wyld.com.au/wyld-blog/benefits-of-wyld-man-and-wyld-woman

https://wyld.com.au/about-wyld-natural-aphrodisiac

Page 8 of 11 Complaint to TGA – N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

https://wyld.com.au/wyld-blog/a-wyld-mans-testimonial

Page 9 of 11 Complaint to TGA – N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

https://www.chemistwarehouse.com.au/buy/56896/wyld-for-men-60-tablets

Page 10 of 11 Complaint to TGA – N-Hance Pty Ltd, WYLD MAN, WYLD WOMEN

Missing required information

https://www.pharmacy4less.com.au/wyld-for-men-tabs-60-4.html

https://www.ebay.com.au/itm/Wyld-For-Man-Tablets-60-Increase-Sex-Drive-Enhance-Stamina- Endurance-Aphrodisiac/223130263461

Page 11 of 11 2105 REVIEW ARTICLE

A Urologist’s Guide to Ingredients Found in Top-Selling Nutraceuticals for Men’s Sexual Health

Tao Cui, MD, Robert C. Kovell, MD, David C. Brooks, MD, PhD, and Ryan P. Terlecki, MD Department of Urology, Wake Forest School of Medicine, Winston Salem, NC, USA

DOI: 10.1111/jsm.13013

ABSTRACT

Introduction. Use of supplements is common among men seeking urologic evaluation for sexual health matters. With a dizzying array of formulations available and little regulation on the dosage, purity, or ingredients found in these products, the health effects of nutraceuticals are often confusing to patients and medical practitioners alike. Aim. In this review, we set out to concisely summarize the data on ingredients found within the top-selling nutraceutical agents marketed for men’s sexual health in order to provide a clinical guide for urologists. Methods. We used sales data from the most popular retail provider of men’s health supplements to identify the top-selling products marketed toward improvement of men’s sexual health. We summarized the available information related to the ingredients, dosage, cost, and mechanism of action for these substances and performed an extensive literature search to identify and review the current evidence available for each of the most common ingredients found in these nutraceuticals. Results. The top-selling nutraceuticals marked for men’s sexual health contain a blend of multiple supplements (up to 33 in one formulation identiﬁed), the most common being ginseng, tribulus, zinc, horny goat weed, B complex vitamins/trace minerals, fenugreek, L-arginine, maca, DHEA, ginkgo, and yohimbine. The currently available medical literature evaluating the efﬁcacy of these substances is generally of low quality. Conclusions. Despite the dearth of evidence supporting nutraceutical agents in the men’s health arena, these substances are still commonly used by patients. As these products can affect the health and well-being of men presenting to a urology clinic, a familiarity with commonly used agents can help the urologist appropriately counsel their patients. Cui T, Kovell RC, Brooks DC, and Terlecki RP. A urologist’s guide to ingredients found in top-selling nutraceuticals for men’s sexual health. J Sex Med 2015;12:2105–2117. Key Words. Neutraceutical; Dietary Supplement; Men’s Sexual Health; Erectile Dysfunction, Decreased Libido

Introduction products because they can be purchased without physician prescriptions, recommendations, or ntimate health concerns among male patients oversight, thus allowing patients to avoid surveil- I are not uncommon, with an estimated 40–70% lance or documentation. The use of natural (possi- of men experiencing some form of sexual dysfunc- bly a misnomer in some instances) products and tion [1]. Frequently, conversations concerning herbal remedies to improve men’s sexual health is sexual health topics such as libido, erectile function, widely accepted in many cultures across the world and sexual activity are hindered by feelings of and is increasing in popularity in the United States embarrassment, concerns over drug cost or side [2]. The annual sales of dietary supplements have effects, and the stigma of a sexual dysfunction diag- doubled between 1999 and 2007, and a recent nosis. Oftentimes, patients will turn to off-the-shelf nationwide survey showed that over 50% of

© 2015 International Society for Sexual Medicine J Sex Med 2015;12:2105–2117 2106 Cui et al. respondents reported using these products [2]. It is of over $2.6 billion. We identified the most estimated that over $30 billion a year is spent out of popular agents marketed to improve men’s sexual pocket on complementary or alternative medicine health by evaluating the 30 top-selling products [3]. according to GNC’s website (Table 1). There was The Dietary Supplement Health and Education considerable variability in the amount of informa- Act of 1994 reclassified dietary supplements as tion provided for individual products regarding foods, rather than drugs, and significantly reduced package contents. Most products listed multiple the Food and Drug Administration’s (FDA) role in active ingredients with some listing over 20. While testing the safety and efficacy of these products [4]. there were no obvious themes or trends in the As a result, manufacturers are largely responsible content of individual products, we identified the for ensuring the safety, purity, and efficacy of their substances most commonly named as active ingre- own products. With reduced medical and FDA dients (Table 2). oversight, there are few resources for consumers to A comprehensive search of Medline and verify the ability of these products to deliver on Natural Medicines (formerly Natural Standard their advertised effects or to investigate potential and Natural Medicines Comprehensive Database) side effects. Physicians should be aware of the was performed for the names of the top products information regarding efficacy and toxicity for and their most common active ingredients. Both those substances commonly used by their patients. name brands and generic names were utilized for For example, products interfering with the query. Studies were evaluated for relevance to hypothalamic–pituitary–testicular axis could affect men’s sexual health (erectile function, libido, and hormone balance, fertility, sexual performance, sexual performance) and reviewed for level of evi- and virility. Furthermore, the prevalence of sexual dence. A summary of the currently available evi- dysfunction secondary to comorbid conditions or dence pertaining to the most common ingredients to the use of prescription medication(s) renders it of top-selling supplements was compiled and sum- vital for providers to be aware of interactions rel- marized. It should be noted, therefore, that this is evant to commonly used supplements. not a review of only those nutraceuticals with Of particular importance to urologists, many high-level evidence. Given that the practicing products advertised for male sexual enhancement urologist is likely to encounter patients taking the are adulterated with undisclosed amounts of pre- products most commonly sold, we used sales data scription pharmaceuticals. Specifically, phosphodi- to define inclusion criteria. esterase type 5 inhibitors (PDE5I) have been found frequently in so-called “natural” products Evidence for Efficacy claiming to improve sexual function. One study analyzing over-the-counter products purchased in Red Ginseng (Panax Ginseng or Korean Ginseng) United States and Asia found either PDE5I or Ginseng is the most common ingredient among PDE5I analogs in 81% of the samples tested [5]. top-selling supplements for men’s sexual health. It In fact, 20% of samples contained >110% the was present in 13 (43%) of the top 30 products, highest approved dosage for the given drug. A with reported doses ranging from 10 to 150 mg. second study analyzing seized sexual enhancement The highest doses of ginseng are found in Now® products found a similar rate of adulteration, Testo Jack 200 and MAGNA RX+—BOGO as 70% of samples contained sildenafil [6]. In supplements. addition to commonly prescribed agents, Red ginseng exerts its mechanism by increasing aminotadalafil, a non-FDA approved PDE5I has production of nitric oxide (NO) through stimula- also been found as an adulterant [7]. The market tory effects on NO synthase, resulting in increased penetration for these adulterated products is sub- production of NO and blood flow into the corpora stantial, with one manufacturer producing over 1 cavernosa. Its active ingredients, ginsenosides and million capsules per month of a product laced with ginseng saponins, have been shown to cause dose- a PDE5I [8]. dependent relaxation of smooth muscle within the corpora cavernosa in rabbit models, with increased intracavernosal pressure noted in a dose/duration Commonly Sold Products related fashion [9]. These active ingredients, General Nutrition Corporation (GNC) is the however, are distributed unevenly throughout the largest specialty retailer of dietary supplements in ginseng plant, and the concentrations in individual the United States with estimated annual revenue supplements can vary.

J Sex Med 2015;12:2105–2117 Guide to Nutraceuticals for Men’s Sexual Health 2107

Table 1 Top 30 best-selling products targeted at improving men’s sexual health according to GNC. Product cost is broken down by day for daily supplements and by serving for on demand supplements. The number of ingredients were identiﬁed using product nutrition lables

Cost per No. of Product name serving/day ingredients Biotab Nutraceuticals Inc. Extenze® $1.83 10* BioXgenic BIO-HARD $1.33 13* BioXgenic High Test Male Performance $4.00 1† CAVALIER™ Daily Sexual Health Support $3.00 4* CAVALIER™ Daily Testosterone Support $2.00 3* Daily Wellness Company® FertilityBlend® for Men $1.33 10* EPIQ™ TEST $1.33 3* Force Factor® Test X180 ALPHA™ $3.50 8† Force Factor® Test X180™ $2.33 5* Forta $5.00 5 GNC ArginMax® $1.23 17 GNC Horny Goat Weed $0.87 3 GNC Maca Man® $1.40 5 GNC Preventive Nutrition® Healthy Testosterone Formula $2.33 18 GNC Staminol™ $0.83 13* GNC Staminol™ Ultra $1.33 18 HighT® Black Caffeine Free $1.83 9* Irwin Naturals Steel-Libido™ $1.61 13* MAGNA RX+—BOGO $0.67 20 Maximum Human Performance T-Bomb™ II $1.79 24* Now® Testo Jack 200 $3.00 7 Nugenix™ Testosterone Booster $2.33 5* PERFORMIX™ SUPER T $5.77 8* PharmaFreak Test Freak™ $1.93 17† Progene® Daily Complex $1.25 33* Prolongz™ $4.60 3 Sera-Pharma Amidren™ $2.33 17* Vitalast® NewVigor® $2.50 4 Vitalast® NewVigor® Boost™ $1.20 2 vitaliKoR® $3.00 5

*Product lists ingredients without specifying amount per dose†Product lists a proprietary blend containing unnamed ingredients

A 2008 meta-analysis by Jang et al. reviewed seven randomized clinical trials (RCTs) investigat- ing the effects of red ginseng on men’s sexual health [10]. Collectively, methodological quality Table 2 Top 20 most commonly identified ingredients was low, and methods, patient populations, follow- based on product nutrition labels up, and evaluation methods were highly heterog- Number of products enous but did suggest a significant improvement in Ingredient name containing ingredient erectile function. Variable dosing schedules of the Ginseng 13 supplement were used, including 600 mg tid in Tribulus spp. 13 four trials, 900 mg tid in one trial, and 1,000 mg Zinc 13 Epimedium spp. (Horny goat weed) 11 tid in another trial. Side effects observed in the Vitamin B6 10 overall analysis were few and generally mild, con- Fenugreek 10 sisting of headaches/insomnia, gastric upset, rash, L-Arginine 10 Vitamin B12 9 and constipation. There was some concern for Maca 9 hypoglycemia, and red ginseng should be used Vitamin B3 (also as Niacin) 6 with caution in diabetic men. Positive effects were Saw Palmetto 6 Vitamin B9 (also as Folate) 5 noted in each trial, suggesting the possibility of a Dehydroepiandosterone (DHEA) 5 negative publication bias [10]. Vitamin E 5 In an updated 2013 meta-analysis of the Korean Ginkgo Biloba 5 Magnesium 5 literature, Choi et al. evaluated Korean red gin- Yohimbine 5 seng’s role in overall health [11]. The supplement is Vitamin B1 (also as Thiamin) 4 used for a wide variety of conditions in Korea. Vitamin B2 (also as Riboflavin) 4 Selenium 4 Thirty RCTs were evaluated for multiple

J Sex Med 2015;12:2105–2117 2108 Cui et al. conditions, including six on erectile dysfunction men’s health supplements, the majority contain at (ED). Once again, the methodological quality was least one trace element, most commonly zinc (13 of generally quite poor, but no serious adverse effects 30). The reported zinc levels among these products were reported from use of red ginseng in any of the range from 1 to 30 mg. For reference, the recom- trials [11]. mended daily intake of zinc for a healthy adult male Based on two small studies showing improve- is 11 mg. The highest doses of zinc are found ment in the International Index of Erectile Func- in BioXgenic High Test Male Performance, tion (IIEF) scores of approximately 60% of PharmaFreak TestFreak™, and Maximum Human participants, the Journal of Family Practice recom- Performance T-Bomb™ II supplements. Magne- mended consideration of red ginseng for patients sium was found in five of 30 products with levels with ED on the basis of its positive safety profile ranging from 11 to 90 mg. The recommended daily and low associated costs. While ginseng appears to intake of magnesium is 400–420 mg. The highest be well tolerated, affordable, and reasonably safe, dose of magnesium was found in the PharmaFreak there is presently not enough quality evidence of Test Freak™ supplement. Selenium was found in efficacy to recommend it as first-line therapy for four of 30 products with levels ranging from 50 to ED. 70 mcg. The recommended daily intake for selenium is 55 mcg. The highest doses of selenium Tribulis terrestris were found in Daily Wellness Company®, T. terrestris is a common weed found in 13 (43%) FertilityBlend® for Men and GNC ArginMax® of our 30 products, with reported doses ranging supplements. from 100 to 1,000 mg. Most (10 of 13) of these supplements did not specify the amount of Zinc T. terrestris contained in each dose; the highest The association of zinc deficiency with hypogonad- documented dose was found in PharmaFreak Test ism was described as early as 1960 by Prasad et al. Freak™ (SAGA Sciences International Inc., Van- [17]. Prasad also went on to show that zinc supple- couver, BC, Canada). T. terrestris is a low growing mentation could reverse the effects associated with vine that advertisers claim improves sexual and hypogonadism [18]. One study of healthy young sports performance by increasing testosterone men placed on zinc-restricted diets showed that production. Some animal experiments have even marginal zinc deficiencies resulted in signifi- shown that T. terrestris can increase serum testos- cantly decreased testosterone production [19]. terone levels; however, these results have not Zinc, however, is plentiful in the western diet, and been replicated in humans [12]. Two recent lit- the World Health Organization estimates the erature reviews did not find any studies linking prevalence of zinc deficiency in North America to T. terrestris supplementation to improved sports be 6.3% [20]. There is no evidence that zinc supple- performance, improved sexual performance, or mentation in normal individuals causes increased increased serum testosterone [12,13]. A recent serum testosterone. double-blind RCT showed no difference in erec- In addition, it is unclear if increased testosterone tile function or serum testosterone following due to zinc repletion results in improved sexual T. terrestris administration [14]. performance or libido. A review of treatment While no studies of T. terrestris toxicity have options for sexual dysfunction in patients with been performed in humans, there are two accounts chronic kidney disease found several RCTs where of hepatonephrotoxicity following high dose zinc repletion failed to correct hypogonadism, and ingestion in young healthy men [15,16]. One one trial where zinc supplementation was associ- patient presented with hyperbilirubinemia and ated with decreased frequency of sexual activity progressed to acute renal failure, whereas the [21]. other patient presented with seizures and elevated liver enzymes. Therefore, in the absence of Magnesium benefit, and given reports of severe toxicity, Magnesium is another trace mineral plentiful in patients should be cautioned regarding supple- the Western diet. Hypomagnesemia is usually sec- mentation with T. terrestris. ondary to poor gastrointestinal absorption (e.g., diarrhea), malnutrition, alcoholism, or increased Trace Minerals renal excretion from diuretic use, diabetes, or renal Trace minerals are common ingredients for many disease [22]. Hypomagnesemia has not been health products and supplements. Of the top 30 directly linked to any sexual disorders, and no

J Sex Med 2015;12:2105–2117 Guide to Nutraceuticals for Men’s Sexual Health 2109

Table 3 B vitamin information found in popular men’s sexual health supplements

Number of Recommended products Dosage range DV Highest dosage containing products B1—Thiamine 4 out of 30 1.5 mg–2 mg 1 mg Force Factor® Test X180 Alpha™ GNC Preventive Nutrition® Healthy Testosterone Formula GNC Staminol™ Ultra B2—Riboﬂavin 4 out of 30 1.7 mg–2 mg 1.1 mg Force Factor® Test X180 Alpha™ GNC Preventive Nutrition® Healthy Testosterone Formula GNC Staminol™ Ultra B3—Niacin 6 out of 30 3 mg–50 mg 12 mg GNC Maca Man® B6 10 out of 30 2 mg–10 mg 1 mg GNC Preventive Nutrition® Healthy Testosterone Formula PharmaFreak Test Freak™ Progene® Daily Complex B9—Folate 5 out of 30 400 mcg–600 mcg 320 mcg GNC Staminol™ Ultra B12 9 out of 30 4 mcg–50 mcg 2 mcg GNC Preventive Nutrition® Healthy Testosterone Formula Nugenix™ Testosterone Booster HighT® Black Caffeine Free

studies have associated magnesium supplementa- In addition, icariin has been shown to have tion with improved sexual function. neuroprotective [25] and anti-inflammatory [26] effects. Despite these favorable effects in animal Selenium experiments, no human trials have been conducted Although selenium has been studied for prostate with either HGW or purified icariin. Although cancer prevention, there are no studies on its use toxicity from HGW is rare and generally mild, for improving sexual health. There are a few there is one account of tachyarrhythmia and hypo- underpowered studies suggesting selenium supple- mania reported in the literature [27]. mentation may have a role in management of male Despite promising animal studies showing infertility, however, these studies do not address icariin improves erectile function in rodents, there erectile function or libido [23]. is no evidence of improvement in sexual health Thus, while trace minerals are common within among humans. At this time, until future human most top-selling supplements, there is limited data studies demonstrate a benefit of using HGW in to support their value in management of condi- men with ED, recommendations for patient use tions such as ED, decreased libido, or infertility. should likely be withheld. However, data suggest that in the setting of zinc deficiency due to dietary malnutrition and hypogonadism, zinc repletion may improve testoster- B Vitamins one production. B vitamins are a heterogeneous group of enzyme cofactors found in numerous dietary supplements. Horny Goat Weed (Epimedium spp.) We found 13 out of 30 products contained at least Horny goat weed (HGW) is an extract of the one B vitamin, most commonly B6 (10 out of 13). Epimedium plant, which is a flowering perennial Dosages, recommended daily value, and products found throughout Asia and parts of the Mediter- containing the highest dosages are detailed in ranean. HGW is found in 11 of the top 30 supple- Table 3. ments with doses ranging from 50 to 600 mg. HGW is heavily promoted in supplements such B6 as GNC Horny Goat Weed and Vitalast® Vitamin B6 is a group of compounds that act as NewVigor® Boost™. Of note, HGW has been cofactors in enzymatic metabolism of glucose, found to contain low levels of icariin, a flavonol lipid, and amino acids. Vitamin B6 is usually plen- glycoside that has been shown to have a PDE5I tiful in the western diet and can be found in meats, effect. grains, and nuts. Vitamin B6, in combination with A study where rats were fed 1, 5, and 10 mg/kg vitamin B9 and B12, also serves to regulate homo- doses of icariin for 4 weeks following cavernous cysteine levels in the body. High levels of homo- nerve injury noted improved penile hemodynamic cysteine have been associated with decreased NO parameters when compared with controls or synthesis and poor erectile function [28]. A study groups receiving a single injection of icariin [24]. of diabetic patients demonstrated better reported

J Sex Med 2015;12:2105–2117 2110 Cui et al. erectile function scores when treated with vitamin such as diosgenin, an important precursor in the B6 in combination with PDE5 than with a PDE5 synthesis of numerous sex hormones as well as alone [29]. components that bind to estrogen receptors induc- ing estrogen responsive genes [34]. It also contains B12 numerous other compounds including amino acids Vitamin B12 is essential in regulating metabolism (such as arginine), essential oils, vitamins (such as and DNA synthesis. Even mild B12 deficiencies vitamin D), lipids, and alkaloids. Fenugreek is a can result in fatigue and depression [30]. Correct- relatively common ingredient in general men’s ing underlying B12 deficiencies may improve health supplements and is found in 10 of the top 30 sexual function by improving psychological selling GNC men’s health supplements, with aspects such as mood, arousal, libido, and energy. reported doses ranging from 600 to 1,100 mg. Most products (seven out of 10) do not list the B9—Folate amount of fenugreek per dose, but the highest Folate is essential to DNA synthesis and cell divi- reported dose was found in PharmaFreak Test sion, but it also plays a key role in homocysteine Freak™. and iron metabolism. Folate deficiency can result Tothis point, there has only been one published in symptoms of low energy, similar to B12 defi- trial evaluating fenugreek’s effects on male sexual ciency [30], and hyperhomocysteinemia [28], as health. In a double-blind, placebo-controlled RCT, seen in B6 deficiency. Steels et al. studied the impact of a standardized formulation of Trigonella foenum-graecum extract B3—Niacin (Testogen)on the male libido [35]. Sixty males aged Niacin has traditionally been used for treatment of 25–52 and without evidence of ED, were given hyperlipidemia; however, it can cause significant either oral fenugreek (600 mg) or placebo daily for vasodilation and flushing. Literature regarding 6 weeks. They noted significant increases in the niacin treatment for sexual dysfunction is limited. sexual arousal and orgasm domains on the However, there are isolated studies showing Derogatis Interview for Sexual Functioning—Self patients with concomitant sexual dysfunction and Report scale. Men in the fenugreek group also diabetes [31] or hyperlipidemia [32] may benefit noted increased quality of life related to muscle from niacin therapy. strength, energy, and well-being. Serum testosterone and prolactin levels were measured and B1—Thiamine remained within normal range. No adverse events Thiamine and its phosphorylated products play a were noted, consistent with the safety profile noted key role in energy metabolism. Thiamine defi- in numerous other studies. ciency, occasionally seen in alcoholics, results in a Further human clinical trials certainly seem number of neurologic dysfunctions, including worthwhile to evaluate the efficacy and safety of neurogenic impotence. In these select populations, fenugreek before recommending it for men for there is some evidence that thiamine replacement improvement in sexual function. may improve sexual function [33]. B Vitamins are essential to a healthy metabo- L-Arginine lism. Dietary deficiency in one or more of these L-Arginine is the most common amino acid cofactors can result in conditions such as hyperlip- among men’s health supplements. Based on our idemia, hyperhomocysteinemia, and degenerative investigation, L-arginine was found in 10 of the neuropathy that may be associated with sexual dys- top 30 supplements with reported doses ranging function. B vitamin supplementation to reverse between 118 mg and 3 g. The highest reported these underlying metabolic derangements may dose of L-arginine was seen in GNC ArginMax® help restore sexual health toward baseline. and Vitalast® NewVigor® supplements. L-arginine is the immediate precursor of NO, Fenugreek (Trigonella foenum-graecum) resulting in increased production of NO when Fenugreek (Trigonella foenum-graecum), also consumed in supraphysiologic doses (usually >3g/ known as “methi,” is thought to assist hormonal d). NO is a vital component of the male erectile regulation, with potential implications for male response, and impaired NO activity is associated sexual health, lactation, circadian rhythms, and with ED. As such, L-arginine has been an area of control of serum glucose and cholesterol levels. interest for medical management of ED. At times, Fenugreek contains numerous steroidal saponins, L-arginine has been combined with other supple-

J Sex Med 2015;12:2105–2117 Guide to Nutraceuticals for Men’s Sexual Health 2111 ments capable of stimulating NO synthase, such as ily in Peru [41]. Traditional medicine of the pygnogenol (a derivative of pine bark), to further region has relied on maca for centuries to treat a boost NO levels. One small study claimed an variety of maladies. It has been used for male improvement in the erectile function of 92% of sexual health for decades and is a very common men taking this combination therapy [36]. ingredient among commercially available supple- In one placebo-controlled RCT, Chen et al. ments [42]. It purportedly enhances all areas of randomized 50 men with organic ED to treatment male sexuality including libido, erections, energy, with either 5 g per day of oral L-arginine or and urinary symptoms. The mechanism of action placebo [37]. At the end of a 2-week period, 9/29 for maca is currently unknown, and animal (31%) men receiving L-arginine reported subjec- studies regarding physiologic effects are limited. tive improvements in their erectile function com- In one study, intake of maca extract was associ- pared with 2/17 (12%) in the placebo group. ated with increased sexual behavior among male Interestingly, although objective serum parameters mice [43]. Another study, also in mice, noted were unchanged between the two groups, the improved semen parameters following maca responders in the L-arginine group were noted to administration [44]. have doubled their urinary NO production at the There is limited human evidence in the peer- end of the study period. The hemodynamics of the reviewed literature to support utilization of maca corpora cavernosa were also not affected by in management of male sexual health. A meta- L-arginine at the doses prescribed in the study. No analysis examining maca’s effect on sexual function significant side effects were noted except for an revealed only four relevant studies [42]. Of those, approximately 10% drop in both systolic and dia- one was on postmenopausal women [45], a second stolic blood pressure without significant changes looked at healthy men [46], and a third was on a in heart rate [37]. However, a small crossover very small cohort of endurance athletes [47]. study, in which 32 patients were given 1,500 mg of There was only one RCT that examined 50 men L-arginine for 17 days and then placebo for 17 with mild ED [48]. The authors of the meta- days, showed no significant improvement in erec- analysis concluded that the data were insufficient tile parameters [38]. to draw conclusions on the efficacy of maca rela- One of the challenges with oral administration tive to sexual function. Use of this agent appears to of L-arginine is first pass hepatic metabolism, be relatively safe, with rare reports of toxicity such resulting in increased formation of ornithine and as mild AST elevation and increased diastolic urea. Several studies have examined L-citrulline as blood pressure in healthy volunteers [49]. an alternative, as it escapes first pass metabolism Despite the amount of historical anecdotal evi- and is instead converted to L-arginine in the dence of maca being used to improve male virility, kidney [39]. A study by Cormio et al. demon- there is limited hard evidence that it improves strated that oral L-citrulline increased erectile erectile function, libido, or any other element of function and number of intercourse sessions per male sexual health. Even though maca seems to month [40]. have a favorable safety profile, the lack of evidence In theory, L-arginine supplementation may be does not support routine use for male sexual valuable for patients with known endothelial dys- health. function or disorders resulting in deficient NO production. Further clinical studies would be Dehydroepiandosterone (DHEA) needed for corroboration. At present, there is DHEA is produced in the adrenal glands as a insufficient evidence to support widespread use of prohormone in the androgen synthetic pathway. It L-arginine for treatment of ED. is the most abundant steroid in the body and is mildly androgenic in nature. DHEA is converted Maca to testosterone and estrogen in the peripheral Maca is the most common vegetable found in our tissues. While most studies fail to demonstrate an list of men’s health supplements, identified in nine association between DHEA supplementation and of the top 30. The reported doses among products increased serum testosterone or estrogen, other ranged from 100 to 2,000 mg. Maca was the pre- reports advise caution in hypogonadal men on dominant component in GNC Maca Man® and androgen deprivation [50–52]. Vitalast® NewVigor®. Among the 30 top-selling GNC men’s health Also known as Lepidium meyenii, maca is a root supplements, DHEA is found in five, making it vegetable native to the Andes Mountains, primar- one of the less common ingredients among major

J Sex Med 2015;12:2105–2117 2112 Cui et al. nutraceuticals. It is found in reported doses tion with DHEA does not seem to affect overall ranging from 25 to 50 mg, with the highest doses hormonal levels but should be considered with found in GNC Preventive Nutrition® Healthy caution. Testosterone Formula, and Nugenix™ Testoster- one Booster. Ginkgo biloba DHEA has been marketed for improvement of Not only has G. biloba extract been advertised to sexual function, and as an anti-aging, wellness treat ED, but it has also been promoted to treat supplement due to its perceived effects on cogni- numerous other conditions ranging from hyper- tion, cardiovascular health, body composition, tension to Alzheimer’s dementia. We found skin health, and immune function [53]. In the G. biloba extract listed in five of 30 products with liver, it is converted to DHEAS, which circulates reported doses ranging from 25 to 120 mg. The in relatively large quantities, peaking around the highest listed dose of G. biloba extract was found in age of 20 and decreasing by about 2/3 of peak the supplement Irwin Naturals Steel-Libido™. levels by the age of 60 [54,55]. Both DHEA and G. biloba tree extracts have been used to treat DHEAS levels have been correlated positively peripheral vascular diseases for nearly two decades with erectile function. Multiple uncontrolled [59]. There is some evidence to support the use of trials have noted increased DHEA levels to be G. biloba extract for a variety of circulatory impair- associated with improvement in erectile function ments, including cutaneous ulcers and claudica- when ED had been attributed to hypertension tion. Furthermore, it is thought to offer cognitive and other non-organic causes. In 1994, the Mas- improvement via an effect on cerebral vasculature sachusetts Male Aging Study noted lower levels [60]. The beneficial circulatory effects make of ED in participants with higher serum DHEA G. biloba an attractive therapeutic option for levels [56]. vasogenic ED. The proposed mechanism of action Reither et al. [57] performed a double-blind, involves induction of NO in endothelial cells and prospective, placebo-controlled RCT in which relaxation of vascular smooth muscle cells. In vitro men with low serum DHEA and otherwise data highlights G. biloba-mediated relaxation of normal hormonal parameters and who demon- rabbit corpus cavernosal smooth muscle cells [61]. strated normal responses to cavernosal prosta- In an uncontrolled study of 60 men follow- glandin E1 (PGE1) injections received either ing prostatectomy, researchers demonstrated 50 mg of DHEA or placebo daily for 6 months. improved penile perfusion by ultrasound after 2 The patients receiving DHEA demonstrated sig- months of G. biloba supplementation [62]. In a well- nificantly higher IIEF scores in all five domains recognized study evaluating selective serotonin by the end of the study. Mean serum PSA, tes- reuptake inhibitor (SSRI)-related ED, authors tosterone, and prolactin levels, as well as mean demonstrated improvement in sexual function fol- prostate volume and post-void residual, were lowing G. biloba therapy [63]. There were, however, unaffected by treatment [57]. many problems with this study, including lack In another study, however, Morales et al. ran- of a placebo control, unclear criteria linking domized 86 men with decreased serum testoster- SSRI use with ED, no report of SSRI efficacy in one and/or DHEA levels to receive 80 mg of oral treating depression, possible miscalculation/ testosterone twice daily, 50 mg of oral DHEA misrepresentation of the data, and no report of side twice daily, or placebo. No significant differences effects [64]. Since then, two different placebo- were seen between groups on multiple question- controlled, blinded studies have shown no naires including IIEF, Androgen Deficiency in the improvement in ED in patients with documented Aging Male (ADAM), Aging Males’ Symptoms SSRI-induced sexual dysfunction [65,66]. The (AMS), and Geneva Appraisal Questionnaire reported toxicities of G. biloba include headaches, (GAQ), suggesting no clinical benefit. There was a major bleeding (especially in patients taking warfa- significant increase in DHEA levels between the rin), and seizures with reported fatality [67–71]. beginning and end of the trial for men in the Despite earlier reports that G. biloba may hold DHEA group but no change in testosterone levels promise for management of ED in men using in men receiving testosterone supplementation SSRIs, more recent studies of better design have [58]. failed to show a benefit. Although benefit has been While DHEA has shown promise in some shown with conditions with physiologic similari- studies, data on efficacy for treating sexual health ties to ED, at present there is no convincing clini- problems is still lacking. In general, supplementa- cal data to support its routine use in men with ED.

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Yohimbine L-Carnitine Yohimbine is an indole alkaloid derived from the The amino acid derivative carnitine is involved in bark of the African yohimbe tree [72]. There have the transport mechanism for fatty acid metabo- been claims that yohimbine can treat fatigue, lism and has been implicated in the development depression, diabetes, and sexual dysfunction. of atherosclerosis [82]. However, L-carnitine, the Yohimbine was identified in five of 30 products active isomer, has also been shown to act as a with reported doses ranging from 50 to 63 mg. vasodilator in subcutaneous arterioles by stimu- The highest reported doses of yohimbine were lating prostaglandin synthesis [83]. Cavallini et al. found in the GNC Maca Man® and GNC compared carnitine with androgen supplementa- Staminol™ supplements. The proposed mecha- tion and found that carnitine increased nocturnal nism of action for yohimbine is through inhibition penile tumescence and IIEF scores more than of central alpha-2-adrenergic receptors, decreas- androgen supplementation [84]. Unfortunately, ing central inhibition of arousal, and increasing this is the only study showing that carnitine penile nerve stimulation resulting in increased NO can independently improve erectile function. [73]. However, a number of studies, including a RCT Yohimbine is one of the more heavily researched by Morano et al., demonstrate that carnitine can natural products in urology. A meta-analysis in potentiate the effect of PDE5I, particularly in 1998 reviewed seven placebo-controlled trials [74– diabetics [85]. 79] and determined yohimbine was superior to placebo for treatment of ED [80]. The meta- Antioxidants analysis also demonstrated that adverse events were Antioxidants have long been touted to improve rare and concluded that yohimbine was a reason- erectile function due to the amelioration of oxida- able therapeutic option for ED. Since 1998, there tive stress and improved NO-mediated vasodila- has been a study looking at a combined regimen of tion within the corpora cavernosa. Several of the yohimbine and L-arginine that demonstrated aforementioned substances, including HGW, improvement in ED compared with placebo [81]. L-arginine, L-carnitine, and ginkgo biloba, are The most common side effects are due to alpha-2- reported antioxidants. In addition, numerous adrenergic blockage and include headache, sweat- other substances, including lycopene, vitamin E, ing, agitation, hypertension, and insomnia. It has and plant phenols have all been suggested to also been associated with anxiety and panic attacks. improve men’s sexual function through antioxi- Yohimbine is contraindicated in patients taking tri- dant effects. A number of animal studies [86] dem- cyclic antidepressants, antihypertensives, and onstrated improved erectile function following central nervous system (CNS) stimulants. administration of various antioxidants; however, Yohimbine is one of the more promising natural we were unable to identify any human studies products for treatment of ED. The conclusion of a showing a similar effect. While oxidative stress meta-analysis comparing yohimbine with placebo clearly plays a role in the development of ED, it is showed improved erectile function with a low inci- unclear if supplementing with antioxidants post dence of adverse reactions. However, at this time, hoc improves erectile function. there is no direct comparison of yohimbine to first-line pharmaceutical treatments such as PDE5. Without such evidence, yohimbine would Conclusion not be considered a first-line therapeutic choice for male sexual health. We identified the most common active ingredients among top-selling men’s health supplements. It seems probable that a considerable Other Notable Nutraceuticals number of men seen in urologic consultation for Although a number of other natural products sexual health may have initiated use of some of were found in our literature search, they were these agents. Thus, it seems imperative for urolo- not well represented among the top-selling gists to be aware of both the physiologic and supplements. While it is unclear why these prod- pathologic effects of these compounds. In this ucts are presently unpopular with either manu- review, we have summarized the available evi- facturers or consumers, they are summarized dence for improvement in male sexual health as here with references to the highest level of avail- well as the most common side effects associated able evidence. with these supplements. Most of these products

J Sex Med 2015;12:2105–2117 2114 Cui et al. are lacking well-designed studies to determine Statement of Authorship efficacy. Also, given the decreased oversight rela- Category 1 tive to prescription medication, there is limited (a) Conception and Design study of toxicity in the setting of monotherapy, or Tao Cui; Robert C. Kovell; Ryan P. Terlecki in combination with prescribed medications or (b) Acquisition of Data other supplements. Tao Cui; Robert C. Kovell; David C. Brooks Based on our analysis of the available evidence (c) Analysis and Interpretation of Data for these top-selling products, we would be Tao Cui; Robert C. Kovell; David C. Brooks; Ryan unlikely to routinely recommend them to our P. Terlecki patients. While there is evidence that yohimbine might improve ED, there are no studies compar- Category 2 ing it to pharmaceutical interventions such as (a) Drafting the Article PDE5I. Similarly, although B-vitamin use in dia- Tao Cui; Robert C. Kovell; David C. Brooks betics or patients with hyperhomocysteinemia (b) Revising It for Intellectual Content shows promise, properly controlled studies are Tao Cui; Robert C. Kovell; David C. Brooks; Ryan still needed. L-arginine could potentially find a P. Terlecki niche for use in patients with endothelial dysfunction or dysregulation of NO synthesis; Category 3 however, efficacy remains lower than standard (a) Final Approval of the Completed Article therapy. While red ginseng has been recom- Tao Cui; Robert C. Kovell; David C. Brooks; Ryan mended by the Journal of Family Practice,wedo P. Terlecki not believe there is enough evidence at present to support its use as a first-line treatment for sexual References dysfunction. Furthermore, evidence of adulterated supple- 1 Braun M, Wassmer G, Klotz T, Reifenrath B, Mathers M, Engelmann U. Epidemiology of erectile dysfunction: Results ments containing unknown amounts of PDE5I of the “Cologne Male Survey”. Int J Impot Res 2000;12:305– raises concerns of potential side effects, especially 11. if full dose PDE5I are prescribed in combination 2 Regan KS, Wambogo EA, Haggans CJ. NIH and USDA with these products. Recently, the New York attor- funding of dietary supplement research, 1999-2007. J Nutr 2011;141:1–3. ney general targeted four major retailers, GNC, 3 Nahin RL, Barnes PM, Stussman BJ, Bloom B. Costs of Target, Walgreens, and Walmart, for selling mis- complementary and alternative medicine (CAM) and fre- leading or adulterated dietary supplements [87]. quency of visits to CAM practitioners: United States, 2007. The attorney general’s investigation revealed Nat Health Stat Rep 2009;18:1–14. 4 Questions and answers on dietary supplements. 2015. widespread discrepancies with a majority of prod- Available at: http://www.fda.gov/Food/DietarySupplements/ ucts either containing contaminants or not con- QADietarySupplements/default.htm (accessed May 15, 2015). taining substances listed on the nutritional label. 5 Campbell N, Clark JP, Stecher VJ, Thomas JW, Callanan AC, Donnelly BF, Goldstein I, Kaminetsky JC. Adulteration of Urologists should be observant to any potential purported herbal and natural sexual performance enhancement adverse reactions and report them to the FDA via dietary supplements with synthetic phosphodiesterase type 5 MedWatch [88]. inhibitors. J Sex Med 2013;10:1842–9. While certain natural supplements show great 6 Low MY, Zeng Y, Li L, et al. Safety and quality assessment of 175 illegal sexual enhancement products seized in red-light promise at improving mild sexual dysfunction, all districts in Singapore. Drug Saf 2009;32:1141–6. substances reviewed in this article lack robust 7 Ulloa J, Sambrotta L, Redko F, Mazza ON, Garrido G, Becher human evidence. In addition, concerns of con- EF, Muschietti L. Detection of a tadalafil analogue as an adul- tamination and adulteration are sufficiently worri- terant in a dietary supplement for erectile dysfunction. J Sex Med 2015;12:152–7. some that we would presently caution against 8 Cohen PA, Venhuis BJ. Adulterated sexual enhancement routinely recommending dietary supplements for supplements: More than mojo. JAMA Intern Med 2013;173: male sexual health. 1169–70. 9 Cho KS, Park CW, Kim CK, et al. Effects of Korean ginseng berry extract (GB0710) on penile erection: Evidence from in Corresponding Author: Tao Cui, MD, Department of vitro and in vivo studies. Asian J Androl 2013;15:503–7. Urology, Wake Forest School of Medicine, Winston 10 Jang DJ, Lee MS, Shin BC, Lee YC, Ernst E. Red ginseng for Salem, NC 27157, USA. Tel: 3367165690; Fax: treating erectile dysfunction: A systematic review. Br J Clin 3367165711; E-mail: [email protected] Pharmacol 2008;66:444–50. 11 Choi J, Kim TH, Choi TY, Lee MS. Ginseng for health care: Conflict of Interest: The author(s) report no conflicts of A systematic review of randomized controlled trials in Korean interest. literature. PLoS ONE 2013;8:e59978.

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