This method has inconsistent data in terms of efficacy in ED. One meta-analysis found minimal data to support the use of this technique based on methodology issues of past clinical trials [11]. Still, it would seem plausible that acupuncture does have a potential role for some forms of ED such as one with a psychogenic etiology [12–14]. Preliminary studies have suggested a high placebo response rate but an even higher response with acupuncture treatment for psychogenic ED. Acupuncture does not have adequate research in the area of FSD to make a recommendation.

On January 20, 2005 it became illegal to sell androstenedione dietary supplements in the United States [15, 16]. Androstenedione was considered a “prohormone” supplement that some men used in an attempt to build muscle. It was utilized by several notable US professional athletes before being banned, and it created much controversy. It was a potentially dangerous supplement because it had been associated with a reduction in “good cholesterol” or HDL and it had potentially other health consequences such as significantly increasing estrogen (estrone and estradiol) in healthy young men (ages 26–32 years) taking 100 mg or 300 mg per day for 7 days and significantly increasing testosterone levels at 300 mg per day (from 526 to 872 ng/dL on average in one study) [17]. Other studies of young men demonstrated just increases in estrogen with these dosages [18], which is why it would not been surprising that some individual reports of ED from these supplements can also occur arguably because of the suppression of the pituitary and gonadal axis [19]. The individual variability in the response is also what is striking about androstenedione (or DHEA) in men and women, except for the estrogen increases in young and older primarily eugonadal men. Men ages 35–65 years taking 200 mg of androstenedione had significant increases in estrogen but not testosterone over 12 weeks [20]. In postmenopausal women, a significant increase in estrone occurred, but the individual variability in the response was always notable, which is again part of the problem [21]. Regardless of the population, studied variability or unpredictability of the physiologic response should be mentioned to patients. It has also been my experience that men and women without overt hormone deficiencies have variable results and men experience dramatic increases in estrogen and potentially a small increase in testosterone the more testosterone deficient the male [22].

Therefore, there were so many concerns with these supplements that eventually the FDA and the US government decided to remove almost all of them, including androstenedione, from the market [15]. Other so-called “prohormone” supplements like DHEA were not banned but are still being allowed for sale. Now, if DHEA is similar to androstenedione in that it has similar effects, then why is this supplement still allowed to be for sale over the counter? This is part of the strange circumstances surrounding some dietary supplements and the inconsistency in the policies that are applied. DHEA supplements enjoy a unique exemption under federal law, because of a bill approved by Congress in late 2004. How did DHEA survive when other similar to identical supplements did not? Sports officials were in favor of an overall ban on steroids and related products, including DHEA. DHEA has been banned by the Olympics, the World Anti-Doping Agency, the National Collegiate Athletics Association, the National Football League, the National Basketball Association, and minor league baseball. The 2005 law that impacts prohormone supplements, passed without objection, also gave the Drug Enforcement Administration more authority to ban new or novel steroids, with one exemption: DHEA. The term “anabolic steroid” is defined now as any drug or hormonal substance chemically and pharmacologically related to testosterone (other than estrogens, progestins, corticosteroids, and DHEA). In my opinion, since such a large percentage of Congressional men and women use dietary supplements and some perceived DHEA as unique, the proposal to ban all over-the-counter prohormone supplements in the USA would have not passed Congress if DHEA were included in the proposal. Now, with this pertinent history, what about any new data to support DHEA for men’s health or sexual health?

Population studies such as the Massachusetts Male Aging Study have suggested a higher risk of ED with lower blood levels of DHEA-S [23]. Yet, what gets missed in referencing these studies is that there were also inverse associations of HDL with ED and a higher risk of ED in those with heart disease, hypertension, smoking, and diabetes, for example, which is a more tangible and productive conversation. It should be kept in mind that DHEA levels decrease substantially with aging, and this has been utilized in deceptive advertising in my opinion to encourage men and women to purchase this supplement. Other studies suggest that a lower level of DHEA and an increase risk of ED is only a weak association [24]. DHEA is produced primarily by the adrenal cortex and in smaller amounts by the testes and the ovaries, and then it is quickly sulfated by sulfotransferases into DHEA-S, which is more stable with a longer half-life and its concentrations stay stable most of the day [25]. DHEA is arguably the most abundant steroid in the human body (more than testosterone); thus, for this and many other reasons there will always be sufficient physiologic facts to give it some advertising cache. Yet, it does not appear to have a role for androgen-deficient or androgen-insufficient men because it is not predictable.

So, does DHEA appear to be of benefit in men with ED and low DHEA levels? Small studies of men utilizing 50 mg for 6 months (DHEA-S level<1.5 μmol/L) showed some improvements in function in those with hypertension and ED or those without organic etiology, but not in those with diabetes or neurologic issues [26, 27]. These men were all generally tested with prostaglandin E1 first to ensure that they were capable of having a full erection with pharmacologic intervention.

The problem with DHEA is a lack of large studies with good methodology and no really novel findings with DHEA and ED or in the area of male sexual health. DHEA-S levels are also not easy to acutely or chronically predict with lifestyle interventions; for example, in some studies there are minimal or large changes in this hormonal marker for men and women after large reduction in weight [28–30]. Perhaps this is due to the fact that DHEA levels need to be monitored over many years. Obesity appears to attenuate the association or correlation between higher DHEA and lower morbidity [31].

The problem with DHEA in women is that longer randomized trials in postmenopausal women (26+ weeks) have not shown results better than placebo on sexual desire, for example, at 50 mg per day [32]. Also, more women experienced acne and increased hair growth in the DHEA arm. Overall the results are so mixed that reviews of past data tend to discourage the use of oral DHEA for sexual health improvements in women with FSD [33]. The good news is that overall the safety of 50 mg of DHEA tends to be excellent in 1-year studies, but I still am concerned about reductions in HDL over time with this and higher dosages [34]. Although, some of the criticism with DHEA studies is that the dosages utilized are not high enough for efficacy. Older studies of higher DHEA dosages (300 mg and more) in small groups of postmenopausal women have suggested a benefit over placebo that could have an impact on mental and physical sexual health and arousal within 60 min of visual sexual stimuli [35]. Yet, these are acute dosage studies and the positives and negatives of several days/months of high-dose DHEA ingestion have not received adequate attention. For example, a DHEA supplementation study (1,600 mg/day for 28 days) was published that showed profound reductions in HDL and significant increases in testosterone in postmenopausal women (no changes in estrogen) [36].

DHEA is not a promising or predictable option for those that need TRT or postmenopausal FSD, but perhaps those with adrenal or androgen insufficiency might benefit? Replacement with DHEA in those with androgen or especially “adrenal insufficiency” (e.g., adrenal adenectomy, autoimmune, or secondary from pituitary issues) appears practical and has some preliminary older data in women [37, 38], but the decision of whether or not it has consistent benefits is still very subjective. For example, a retrospective review (non-placebo) of over 100 women with androgen insufficiency and sexual dysfunction ingesting 50 mg of DHEA on average for 4 months reported a significant reduction in sexual distress and increases in desire, arousal, lubrication, satisfaction, and orgasm [38]. Women in this study (mean age of 43 years) had testosterone and DHEA-S levels that were in the lower range of normal. Increased facial hair (11 %), weight gain (7 %), acne (5 %), temporary breast tenderness, loss of head hair, and skin rash (1 % each) were the most commonly reported side effects. Thus, there is fairly general agreement that women with androgen or especially adrenal insufficiency are the best potential candidates for DHEA, especially if there is a need to increase mood and/or libido [39]. This is not tantamount to a solid recommendation. Small studies against placebo of women with adrenal insufficiency for 4 months suggest some benefit of DHEA supplementation of 50 mg per day on general sexual health [40]. Still, these data in patients with adrenal insufficiency are controversial, and there is always concern about long-term toxicity in these individuals [41]. Additionally, there have been several studies showing no impact on sexual health, which is arguably why one of the only meta-analyses performed on randomized trials for DHEA and quality of life in women with adrenal insufficiency did not recommend it [42]. This is a classic example of a mixed-data situation where the decision to add small amounts of DHEA for women who are androgen- or adrenal-insufficient should be left to the patient and clinician.

What about DHEA for specific and general antiaging health purposes? In one of the longest-duration clinical trials in the history of DHEA [43], the supplement was given for 2 years at a dose of 75 mg per day in men and 50 mg per day in women, and these researchers decided to look at the impact of this hormone on the body, physical performance, insulin, and other factors compared to a placebo. There were a total of 87 men (29 received DHEA, 27 received testosterone, and 31 received placebo) in this study and 57 women (27 received DHEA and 30 received placebo), and the average age of the participants ranged from 66 to 70 years. Men and women in this study were just slightly overweight, with a body mass index (BMI) of 26–27. Women who had low levels of DHEA (median value of 0.4 mcg/mL or 1.1 mmol/L), and men with low levels of DHEA (median value of 0.7 mcg/mL or 1.9 mmol/L) had their levels increased by approximately 3.5 mcg/mL or 9.5 mmol/L after taking DHEA. This is a 500 % increase in blood levels of this hormone in some of the patients. This current study showed that quality of life did not change on DHEA, but perhaps a larger study would have provided more clarity in this area. There were no changes in oxygen intake (a measure of metabolism change), muscle strength, or insulin. The DHEA group experienced an unhealthy drop in HDL or “good” cholesterol, which was a significant five-point reduction in women and an almost significant three-point reduction in men during the study (US units). No such HDL drop occurred in the testosterone-receiving group of men during the study. Men receiving testosterone had a slight reduction in fat tissue, and bone mineral density increased at the hip area in men on DHEA and testosterone. In women, DHEA increased bone mineral density only in the area of the wrist, but not at other sites. So, again this study leaves open the possibility of testing higher doses of DHEA and testosterone, but safety will ultimately also be an issue. Higher doses of DHEA need to be studied, but in the meantime, reversing the signs of aging with hormones has little to no evidence and may do harm.

Why not just give TRT to the men who truly require or qualify for testosterone or smaller amounts (10 % or less) to women deficient in androgen? This seems to make more sense as opposed to playing a guessing game with a dietary supplement for general antiaging purposes that also seems to possess safety and quality-control issues [15, 16, 44]. This is also a concern because just because someone purchases DHEA does not necessarily guarantee that DHEA is found in the bottle at the reported concentrations [41]. Finally, other areas of men’s health, such as muscle strength and physical function, have shown minimal impact with this supplement from short and long-term studies [45]. Other long-term (2 years) studies of women’s health suggest that a significant improvement in spinal bone mineral density (BMD) with 50 mg per day of DHEA in women (ages 65–75) also receiving 650 IU per day of vitamin D and 700 mg per day of calcium versus vitamin D and calcium alone suggests that this may be an area worth pursuing [46].

What does the future hold for DHEA? Vaginally administered DHEA (e.g., Prasterone, 0.25–1 % DHEA) appears to provide sexual health benefits (desire, arousal, lubrication, orgasm, and reduced dryness) for women with vaginal atrophy and estrogen deficiency in menopause [33, 47], but I would not consider this a CAM. It is applied intravaginally with an applicator at bedtime. Vaginal DHEA requires daily application, whereas other steroids (estradiol or estriol) require dosing two to three times a week and safety has been well established with vaginal estrogen [48]. So, how popular this will be in the future is a matter of opinion.

Nitric oxide (NO) is produced from l-arginine by nitric oxide synthase (NOS) [22]; thus, the idea of utilizing l-arginine supplements to enhance the treatment of ED appears logical and is an option for some patients. In fact, l-arginine, with its ability to increase NO and lower blood pressure, makes it a potential preventive or treatment option in other areas of medicine such as hypertension and preeclampsia [49–51].

Still, over the years of clinical research there appear to be multiple questionable areas with l-arginine supplements that needed to be answered, in my opinion. These are:

l-carnitine is an amino acid that transports fatty acids from the cytosol to the mitochondria for energy production in each cell of the body [75]. Humans can produce carnitine de novo in the liver from lysine and methionine (25 %), but dietary intake is the primary source of carnitine (75 %). Foods high in carnitine include dairy and meat and a plant-based diet is in general a poor source of carnitine. Excretion of carnitine occurs from the kidneys, but reabsorption is also efficient, so that vegans are still able to maintain close to normal blood levels of this amino acid despite only 10 % of less the consumption of carnitine compared to omnivores.

There are several minimally different forms of l-carnitine available for purchase that have been used in clinical trials, including l-carnitine, acetyl-l-carnitine (ALC), and propionyl-l-carnitine (PLC). These other types of l-carnitine have been tested because l-carnitine itself tends to be unstable. Yet, these other forms of l-carnitine do not necessarily have better data in other areas of urology such as male subfertility, especially when compared to each other at higher dosages such 3,000 mg per day [76], and are more costly for the patient. Still, the potential minimal to moderate impact of l-carnitine on male subfertility has become better known because of multiple clinical trials in this area of medicine [77–82] (see fertility chapter 4).

There are a few serious potential issues with utilizing l-carnitine for ED and FSD. Most of the efficacy data stems from its use in combination products, such as l-arginine and niacin with or without a PDE-5 inhibitor, and the small number of participants in some studies [83–86].

In my opinion, one clinical trial of carnitine from Italy clearly stands out among the rest and should be discussed [87]. This was a trial of 120 men with symptoms of androgen reduction and a free testosterone lower than 6 pg/mL. Participants were randomized to one of three groups: testosterone undecanoate 160 mg/day, propionyl-l-carnitine 2,000 mg/day + acetyl-l-carnitine 2,000 mg per day, or placebo for 6 months (mean age 66 years). Carnitine and testosterone significantly improved the mean IIEF score. The only real issue with this trial is the 4,000 mg per day of total carnitine needed for efficacy, which can be costly and the number of pills needed per day can be as high as eight because most carnitine large tablets or pills are 500 mg each. Additionally, oral testosterone is not standard of care in many areas where other delivery systems appear to be more efficacious and safer [22]. Still, it was notable in this trial that the duration was 6 months and IIEF-15 erectile function, orgasm, sexual desire, and general well-being domain scores significantly increased at 3 months (p < 0.01). Erectile function and orgasm increased significantly at 6 months (p < 0.01), but sexual desire and general well-being did not. Sexual intercourse satisfaction had significantly increased at 6 months (p < 0.01), but not at the 3-month evaluation period. Nocturnal penile tumescence (NPT) also increased significantly with this supplement at 3 months. Carnitine was more efficacious compared to placebo but in terms of NPT, IIEF, and improving mood, it was more effective than oral testosterone. The authors noted that propionyl-l-carnitine was registered in Italy for intermittent claudication, which suggests an improvement in circulation with carnitine, and increases in peak systolic and diastolic velocity in this trial suggest a benefit. Improvement in mood were also noted, but not testosterone levels, so whether or not this could be an option for men needing symptomatic improvement that do not qualify for prescription TRT is controversial at this time because other trials with this supplement have not been published specifically in this area. Still, it is worthy of mentioning it to patients with a strong need for symptomatic changes because of low testosterone without actually wanting or qualifying for TRT. Still, l-carnitine is a controversial supplement in terms of true efficacy and heart health [22], so it would be nice to have another clinical trial support or refute the original 4,000-mg positive trial in men with low levels of free testosterone. l-carnitine has received little to no attention in the area of FSD.

Penile erection is initiated by the relaxation of smooth muscle in the corpus cavernosum and its arterioles [88, 89]. During sexual stimulation, NO is released from nerve endings of parasympathetic nonadrenergic, noncholinergic neurons, and endothelial cells in the corpus cavernosum. NO causes a molecular cascade that results in the relaxation of smooth-muscle cells in the corpus cavernosum. NO accomplishes this by activating the enzyme guanylate cyclase, resulting in increased synthesis of cyclic guanosine monophosphate (cGMP) in these cells. The available cGMP in turn triggers the smooth-muscle relaxation, which permits increased blood flow into the penis and an erection. Citrulline could function as a better precursor to arginine and NO production compared to arginine itself [89].

As mentioned earlier in the section of this chapter on “l-arginine”, oral l-arginine is extensively metabolized by arginase in the gut wall and liver [56–58] and is converted to ornithine and proline or used as a substrate in the liver for ureagenesis. Therefore, trials of l-arginine in the treatment of ED have found that large doses are necessary to have an effect. Another problem with l-arginine has been the questionable safety in some studies [52, 53] and the possibility that ADMA (endogenous inhibitor of nitric oxide production) levels can increase in time on l-arginine [59, 60, 90], which may be another reason that larger dosages of arginine might be needed over time to overcome this negative-feedback mechanism (tachyphylaxis effects).

The major source of l-arginine within the endothelial cell is from l-citrulline, and both l-arginine and l-citrulline raise vascular NO levels [73]. Yet, it appears that in some individuals l-citrulline may be at least twice as efficient at increasing NO levels compared to l-arginine, which could solve some of the dosage and other issues mentioned with l-arginine. In a double-blind, randomized, placebo-controlled crossover study, 20 (mean age 57 years) healthy volunteers received six different dosing regimens of placebo, citrulline, and arginine. l-citrulline was significantly more effective at increasing l-arginine plasma levels compared to l-arginine itself (p < 0.01). At a dosage of only 1.5 g per day of oral l-citrulline, l-arginine blood levels were raised to a similar degree as 3.2 g per day of oral l-arginine. l-citrulline raised the ratio of l-arginine to ADMA, and the arginine/ADMA ratio is again thought to determine substrate availability of arginine to the endothelium. The correlation observed in this study between increases in the arginine/ADMA ratio and forearm flow-mediated vasodilatation indicated a dose–response relationship with NO production. The highest dose of l-citrulline (3 g twice a day or 6 g total) was the most effective at raising NO levels compared to l-arginine (p < 0.01). Urinary nitrate (a marker of NO) and cGMP (another potential indicator of systemic NO production and bioactivity) were significantly (p = 0.01, p = 0.04) increased over arginine. Neither blood urea nitrogen (BUN) nor serum creatinine was changed, and there were no safety issues over placebo.

It is interesting that the 1.5 g of l-citrulline used as one dosage in the previously mentioned study was the same daily dosage found to be effective in 1-month crossover trial of men with mild to moderate ED [74]. A total of 24 men (mean age is 56.5 years ±9.8 years) took 1.5 g of l-citrulline a day or placebo for 1 month. An improvement in erection hardness score (a validated ED instrument) was found after 1 month in the l-citrulline group compared to placebo (p < 0.01). No adverse events occurred over placebo, and 37.5 % of participants had hypertension, 21 % had high cholesterol, 12.5 % had BPH, and 12.5 % had diabetes. This is preliminary but potentially exciting research, suggesting that l-citrulline could be one of the best CAM options for ED and should also be researched as ancillary supplementation to conventional ED options. l-citrulline should also be tested in women with FSD.

Still, the question of short- and long-term safety with l-citrulline needs to be addressed. High dosages of l-citrulline have been utilized in some short-term clinical trials with good safety. For example, a total of ten healthy volunteers were given 0.18 g/kg body weight of oral l-citrulline at one time [91]. The average age was 24 years, and BMI was 22.5. This dosage equates to a 70-kg man receiving 12.6 g of l-citrulline. Plasma and urine were evaluated every 3 h from 11 a.m. to 8 p.m. Significant increases in plasma (fivefold or 490 %), urine, and red blood cell citrulline (p of at least 0.001) occurred and doubling of the plasma arginine level without changes in blood urea or urinary urea excretion. The authors concluded that oral citrulline could be used to enhance systemic citrulline and arginine availability, because citrulline is bioavailable and very little citrulline is lost in urine. This may also explain the safety of l-citrulline, because these authors note that past research suggested that “citrulline may be a better candidate than arginine for supplementation, because extensive uptake and metabolism of arginine by the liver may cause excessive ureagenesis.” Citrulline was efficiently absorbed in the gut and reabsorbed by the kidney. In addition, the authors concluded that this study is one of the first to suggest that oral citrulline can be used to increase arginine availability without affecting urea excretion and may enhance nitrogen balance. It does appear that adequate renal function is needed for maximum citrulline conversion into arginine, and this should be kept in mind.

Another 1-day study of eight fasting, healthy males undergoing four separate (2, 5, 10, and 15 g) oral loading doses of citrulline in random order was published [92]. Blood was drawn ten times over an 8-h period for measurement of biomarkers, and urine samples were collected at baseline and after 24 h. No adverse events occurred at any dosage. Even at the highest dosages, there was very little urine excretion of citrulline. Plasma insulin and growth hormone were not impacted. Citrulline increased in the plasma at higher dosages, while plasma arginine levels increased less than expected. This may be due to saturation of the renal conversion of citrulline into arginine. Citrulline administration had no impact on total nitrogen or calcium excretion, and no effect on hematologic or other biochemical markers or blood pressure. No side effects were observed, and again this study confirmed that acutely citrulline bypasses splanchnic extract. Still, a limitation that one could derive (not mentioned) from this and other studies is that in individuals without adequate kidney function, there could be inadequate conversion of citrulline into arginine because again this is where the primary reaction appears to occur. Additionally, this study suggested that the 15-g daily dose of citrulline is when saturation occurs, so that 10 g a day should be the maximum amount used in clinical practice. It is also interesting that another form of l-citrulline, citrulline malate, has a good safety record and has been given in large dosages (e.g., 8 g) to reduce muscle fatigue [93], but this form of citrulline has not gone through an ample number of nitric oxide generating studies nor a single ED study compared to just the free form of l-citrulline [74]. It is also of interest that citrulline from synthetic or watermelon extract supplements have not been known to cause acute side effects and is another source of citrulline and arginine, but blood pressure reductions could occur, especially in prehypertensive and hypertensive patients, and this has to be noted to anyone before starting citrulline supplementation [94].

Several 1-week studies of l-citrulline have supported the potential for short-term use in healthy individuals with adequate safety. For example, a double-blind, randomized, placebo-controlled parallel-group trial of 15 healthy male subjects (mean of 58 years old) were given 5.6 g of l-citrulline per day or placebo for 7 days and a variety of measurement were conducted including arterial stiffness [95]. No differences in blood pressure were found, and the serum nitrogen oxide (NOx, the sum of nitrite plus nitrate) and NO metabolic products were significantly increased only in the l-citrulline group (p < 0.05). This study also suggested that l-citrulline could improve arterial stiffness, independent of blood pressure and without short-term adverse effects. Another 1-week study of a mean of 11.7 g of citrulline per day or placebo in young adults with a mean age of 22 years was conducted [96]. There was no impact on insulin or IGF-1 concentrations and no impact on nitrogen balance. Arginine is known to be a stimulus of insulin secretion, which could be another favorable reason to use citrulline in some individuals over arginine. No side effects were observed. Additionally, no side effects were noted in a citrulline compared to placebo crossover study of 6 g a day for 4 weeks each [97] or an 8-week study of 3 g of citrulline malate or 8 g of l-arginine per day for those with heart failure [98]. Some experts now believe that citrulline is the ideal amino acid to deliver arginine to endothelial and immune cells and appears to have the ability to prevent abnormally excessive uncontrolled NO production, thus having a better potential safety profile compared to l-arginine [99]. Still, other interesting questions remain unanswered but look encouraging at this time, such as can citrulline really also act in other favorable ways in the body such as an accelerator of injury repair or protein synthesis [100, 101]? And, since NO production inhibits platelet aggregation as demonstrated from l-arginine infusion studies [102], it should be expected that l-citrulline can do the same but needs more research. More short- and long-term studies are needed in the area of ED, FSD, and potentially with TRT to determine the best potential use of this interesting amino acid from watermelon. Since citrulline has the potential to be heart healthy, this also makes it a potential ideal candidate in the area of ED and hopefully FSD in the future [22].

L. meyenii or “maca” is an Andean plant that is a part of the Brassica family and has been used for centuries in the Andes to enhance fertility and sexual health in humans and animals [103, 104]. Maca may also slightly improve sexual function from a series of recent and past preliminary clinical trials in men, and it does not appear to alter testosterone levels [105, 106]. The data points toward good preliminary safety and a potential enhancement in fertility that should receive attention in the future as much as its potential impact on ED.

The potential issues with maca are threefold: this product has not been tested beyond preliminary studies with small numbers of individuals, high dosages are required in some studies to observe an impact (2,400–3,000 mg), and there is a question of what to look for when standardizing the ingredients of maca. This is also the case in FSD, where maca appeared to significantly increase libido in nine women with SSRI-induced FSD when taking 3 g per day compared to seven individuals taking 1.5 g per day, but there was no placebo arm [107]. However, one older clinical trial appeared to find an improvement in libido at 1,500 mg per day after 8 and 12 weeks that was as good as 3,000 mg [105]. A past systematic review also agrees that although interesting it is difficult to comment with more certainty whether or not this product can be a stand-alone or ancillary option for ED or FSD [108]. My biggest concern is standardization of maca during a clinical trial because it appears that dried maca roots need to be standardized to a specific amount of the “macamide” and “macaene” (polyunsaturated fatty acids and their amides) amount from a lipidic extract of this herb because these are the proposed potential active ingredients, and macamides, for example, are a unique class of secondary metabolites not found in another plant species [109, 110]. Therefore, they would be useful markers of not only efficacy but also quality control. It appears that a product with at least 0.6 % macamides and macaenes should be the minimum quality-control marker of standardization [111]. Maca also contains diverse amino acids, including almost 100 mg of arginine per gram of maca [112]. It is concerning that a large study to determine if maca really improves sexual desire and other parameters of sexual health in men and women has not been conducted based on the preliminary results with this herbal product.

Niacin used to be a logical choice to study as a potential ED treatment, in my opinion, because of its past success of improving heart-healthy parameters (increase HDL, reduce triglycerides, lower LDL, etc.) [113]. However, niacin is immersed in ongoing controversy because of its recent lack of efficacy beyond intense statin therapy and because the newer prescription form of niacin has not performed any better and there may be toxicity concerns [114, 115]. It is for these and other reasons that I believe the future of this supplement and drug in medicine is very questionable. It is also difficult to purchase and tolerate niacin as a dietary supplement, even in dosages of 100 mg (immediate release niacin) because of the cutaneous flushing that can occur, liver toxicity, exacerbation of gout, hyperglycemia, peptic ulcer disease, and perhaps other issues such as increasing the risk of dry eye [116, 117]. Prescription niacin (extended release) may be easier to tolerate even at higher dosages of 500–2,000 mg, and fewer pills are needed, but similar side effects of over-the-counter niacin and new concerns of a lack of efficacy in heart disease only fuel the ongoing controversy of using this drug or supplement. Yet, for those that believe that niacin still has a future in cardiovascular or sexual medicine, there was one notable trial in men with ED using the prescription form (Niaspan) that deserves some attention [118]. This was a single-center prospective randomized, placebo-controlled parallel-group trial of 160 men (mean age 58 years) with ED and dyslipidemia. Men were randomized to receive 1,500 mg of oral niacin daily or placebo for 12 weeks.

No significant differences overall were found between groups. However, when men were stratified and analyzed based on ED severity, men with mild ED also showed no improvement, but men with moderate and severe ED (50 % or more of men) on niacin showed a significant improvement on IIEF-3 and -4 (maintenance of erection questions) compared to baseline values. A significant improvement for niacin compared to baseline values was also found for IIEF-3 in men not on statins. Flushing (36 vs. 3 %) and itchiness (33 vs. 9 %) were significantly greater side effects with niacin compared to placebo. A total of 12 patients from the niacin group and six from the placebo group dropped out of the study. Using niacin in combination dietary supplements for ED does have some minimal clinical research [83, 84]. Still, the near future will determine the fate of prescription niacin in cardiovascular medicine, which should determine the fate of niacin as a dietary supplement; for reasons already outlined, I am not optimistic, but I hope I am incorrect.

Ginseng actually refers to the root of several species in the genus Panax, of which P. ginseng is one of the most widely utilized species and is native to Asian countries such as China and Korea [119–122]. P. ginseng has a medical history stretching over thousands of years. The word is derived from the Greek words pan, meaning all, and axos, meaning cure. The species name is derived from the Chinese word rensheng, which means “human,” because ginseng roots have some resemblance to the human body. In China and Korea, ginseng roots are usually harvested after 3–6 years. In Korea, fresh ginseng is less than 4 years old, white ginseng is 4–6 years old and dried after peeling, and red ginseng is harvested when it is 6 years old and then steamed and dried (red ginseng is not skinned before it is steamed). These different processes appear to increase the concentration and number of active ingredients (ginsenosides) in ginseng, especially Korean red ginseng.

Ginsenosides, which are also known as ginseng saponins or glycosylated steroidal saponins, are unique to the Panax species and are the primary active ingredients in ginseng [119–122]. More than 30 different ginsenosides have been isolated from the root of P. ginseng, and although ginseng contains other miscellaneous compounds, the individual and collective ginsenosides appear to be the generally agreed upon active ingredients whose clinical effects are supported by basic science [119–126].

Ginsenosides have multiple mechanisms of action, and each ginsenoside may have tissue-specific impacts [123–126]. The backbone of each ginsenoside is similar and consists of a common four-ring steroid-like structure that includes multiple carbon atoms with attached sugar moieties. Each ginsenoside has a different type, position, and number of sugar moieties attached by a glycosidic bond at C-3 and C-6. Each type of ginsenoside also has at least three side chains at the C-3, C-6, or C-20 position. These side chains are free or are attached to monomers, dimers, or trimers of sugars. It is these sugar compounds that may provide the cellular-specific or receptor effects of each ginsenoside. The ginseng species, age, part of the plant, harvest season, preservation, and extraction method can all impact the compounds found in ginseng and even alter somewhat the ginsenoside content.

Over several decades, the content of ginsenoside standardized extracts utilized in clinical trials has varied, from approximately 4 % ginsenosides in the 1990s to 4–7 % ginsenosides in the mid-2000s, and higher standardized extracts are offered today (e.g., >8 %) [127, 128]. The ginsenoside content should be considered when comparing different efficacy doses from clinical trials. When the ginsenoside concentration is isolated, it appears to elicit the same or better results than the sum of the total ginseng components [128], which again supports the accepted general philosophy that ginsenosides are the active medical components of P. ginseng [119–128]. In other words, the more concentrated the specific ginsenosides, the greater the potential impact and the lower the dosage needed for that impact. Yet, as ginseng becomes more concentrated, in my opinion, the overall cost can become quite high for the consumer and adverse effects have less research at these concentrations, so patients need to be aware of this issue.

One of the more influential evidence-based endorsements for ginseng and male sexual function was a clinical evidence guideline of conventional and alternative medicines [129]. The authors used P. ginseng data from six randomized trials conducted over a period of approximately 15 years that included a total of 349 men. The investigators found that ginseng significantly (p < 0.00001) improved erectile function compared with placebo over 4–12 weeks. Approximately 58 % of men experienced an improvement in some aspect of sexual function compared with 20 % of men who received the placebo. No other dietary or truly CAM supplement was recommended. Ginseng was found to have “moderate-quality evidence” and the investigators concluded that ginseng is “likely to be beneficial” in men with erectile dysfunction of any etiology (organic and psychogenic causes). The final clinical evidence-based guideline provided in this review stated “Ginseng is a traditional Asian remedy with rare adverse effects in the recommended dose of 0.5–2.0 g daily.” What was not mentioned in this review and any others to date to my knowledge, and should be kept in mind, is that these dosages recommended were for the older, less concentrated form of ginseng (4–7 % ginsenosides).

In this same systematic review [129], the authors mentioned that they still needed to evaluate a more concentrated ginsenoside randomized trial by Park and colleagues that was published in Korean in the Korean Journal of Urology [130] but that the article was being translated. Interestingly, I had this study by Park and colleagues translated into English, and it arguably provides some of the best preliminary clinical data to date for a dietary supplement compared with placebo over 8 weeks for men with ED. This was a multicenter, randomized, double-blind, placebo-controlled study of 69 participants that used a highly concentrated ginsenoside product (800 mg/day) [130]. The primary endpoint was the response to the erectile function domain of the International Index of Erectile Function (IIEF) questionnaire at baseline and 8 weeks. The other domains of the IIEF were secondary endpoints, and safety was monitored. Every single sexual health domain from the IIEF-15 was significantly improved by Korean ginseng compared with placebo: erectile function (primary endpoint), sexual desire, orgasmic function, intercourse satisfaction, and overall satisfaction. Additionally, every question on the IIEF (15 out of 15) was improved significantly in this specific clinical trial. The sexual desire domain, frequency, and degree of sexual desire were all also significantly increased (p < 0.001). In other words, both the primary and the secondary endpoints significantly favored ginseng over placebo.

Additionally, there were no significant differences in adverse events reported for ginseng compared with placebo [130]. The results of this trial will strengthen the clinical evidence for P. ginseng and the evidence that highly concentrated ginsenosides are the active or effective ingredients in ginseng. The product used was from a Korean Ginseng Company (BT Gin) that I have had discussions with in terms of their unique ability to concentrate ginsenosides, and they are conducting multiple clinical trials in other areas of medicine, including as cardiovascular health product. Still, the current and future cost of this and other products need to be discussed, because again they can be quite high depending on the source and time of year.

Another prominent review of systematic reviews of alternative medicines for sexual function [131] arrived at a similar conclusion as the previous review [129]. The qualitative methods utilized from past clinical trials were evaluated by two independent experts, and the only dietary supplement that received a cautiously positive conclusion with no safety issues was P. ginseng. Another older systematic review of all randomized data from P. ginseng trials up to that time period also deserves to be mentioned [132]. This meta-analysis emphasized the significant (p < 0.00001) effect of ginseng on erectile function. Subgroup analyses also found a significant (p = 0.001) impact of ginseng on the psychogenic etiology of sexual dysfunction. The authors stated that adverse events or side effects were “scarce and those that were reported were mild.” No significant side effects compared with placebo were reported. According to this review, the methodology of future trials must be improved, but still numerous randomized trials met the inclusion criteria set by these investigators.

Thus, the three most recent comprehensive reviews of conventional or alternative medicine in the treatment of sexual dysfunction all arrived at a similar conclusion, which is that ginseng is a potential option for men at diverse dosages and ginsenoside concentrations [129, 131, 132]. The onset of action or efficacy of ginseng could arguably occur within days to months [130, 132]. The time period is variable and requires further elucidation, but at least 4–8 weeks should be attempted on a P. ginseng supplement before deciding upon efficacy. The onset of action will not be as rapid on average as PDE-5 inhibitors, but the impact on libido, lower cost in some cases, and safety afford ginseng its own set of advantages for certain patients. In addition, the potential for combining ginseng with conventional ED treatments should be explored.

Interestingly, a more natural (wild form) and older P. ginseng known as “tissue-cultured mountain ginseng extract” that was approved by the Korean Food and Drug Administration in 2003 also has preliminary clinical data as a treatment for ED [133]. This form of ginseng has a structure similar to that of P. ginseng, and collectively these trials included over 100 participants with fairly adequate overall methodology [133, 134], especially the most recent clinical trial [133]. Significantly greater improvements were observed over placebo in terms of erectile function, intercourse satisfaction, overall satisfaction, and total IIEF score [133]. This form of ginseng apparently contains higher concentrations of ginsenoside Rb [135] but could arguably be potentially less efficacious owing to its lack of ginsenoside standardization, scarcity, and costs. This mountain ginseng extract was still shown to be clinically effective and should be considered in future meta-analysis or systematic reviews in terms of the overall quality and quantity of the evidence and safety analysis for P. ginseng.

Both P. ginseng and P. quinquefolius (American ginseng) have been shown in the past in laboratory studies to positively impact male sexual behavior [136, 137]. Since 1995, however, favorable clinical trial results in men with ED of diverse etiologies have been published only for P. ginseng. Yet, it is unfortunate that research has not continued for American ginseng in the area of ED or FSD. In terms of P. ginseng, the laboratory data for ginsenosides suggest multiple mechanisms of action. In cultured bovine endothelial cells, ginsenosides were shown to stimulate the conversion of [14C]l-arginine to [14C]l-citrulline and to promote vasorelaxation [138]. More specific studies in rabbit corpus cavernosum tissue continue to support the potential of increasing endogenous NO concentrations via the addition of ginsenosides [139]. Other basic laboratory investigations and reviews support this thought and mechanism whereby the stimulation of NO synthase may produce higher quantities of NO and peripheral neurophysiologic enhancement may also occur [140–143]. Other laboratory investigations of a primary ginsenoside (Rg1) from P. ginseng showed significantly increased mounting and pelvic thrusting frequency and intromission numbers with male mice [144]. Ginseng components also increased testosterone (not observed in clinical trials), cyclic GMP accumulation, and NO release. Thus, the potential to isolate and concentrate one particular ginsenoside for nutraceutical or pharmaceutical investigation will hopefully be of interest in the near future because at least seven or more ginsenosides appear to have some mechanism of action in P. ginseng.

A past human interventional mechanistic study of 12 males demonstrated that a single oral administration of P. ginseng water extract (500 mg/50 kg) significantly (p < 0.05) increased NO levels for about a 2-h period 45 min after ingestion [145]. Ginseng increased NO in exhaled breath and reduced blood pressure and heart rate. The correlation between NO levels and heart rate was significant (p < 0.01). The active components of ginseng may enhance the release of NO from endothelial cells, and ginseng components may act synergistically with other vasoactive substances and specific nerves in the corpus cavernosum. Via this central mechanism of action, these endothelial and neurogenic impacts of ginseng in causing relaxation of the corpus cavernosum may also be responsible for the aphrodisiac effect of P. ginseng. For example, the central and not just peripheral mechanism of action with ginseng deserves more research. Ginsenosides compete with agonists for binding to GABA-A and GABA-B receptors [146, 147], which could also explain a central mechanism of action impacting desire or arousal. Anxiolytic effects have also been demonstrated in mice and maze models. Ginseng and ginsenosides have been shown to positively impact striatal dopaminergic activity and dopamine receptors [148]. Ginseng may exert a direct effect on the hypothalamus or pituitary to also suppress prolactin secretion, but I believe these hormonal changes are minor at best because past clinical trials measuring hormonal changes in men did not find significant or consistent increases in prolactin or testosterone [149]. The neurotransmitter or centrally acting effects of ginsenosides require further investigation, because animal models continue to demonstrate central or neurotransmitter effects [150, 151].

Heart-healthy changes could occur with ginseng, which theoretically could explain the improvement in sexual function. A randomized, controlled, double-blind, crossover trial of 17 healthy, fasted individuals examined the effects of P. ginseng on arterial stiffness [128]. On separate occasions, 3 g of placebo, P. ginseng root, or a bioequivalent dose of P. ginseng root ginsenoside or polysaccharide fractions was used. Blood pressure and arterial health as measured by the augmentation index were recorded 1, 2, and 3 h after treatment. Three grams of ginseng significantly lowered the radial augmentation index by 4.6 % compared with placebo (p = 0.05), and the ginsenoside fraction reduced it by 4.8 %; no significant effect was found with the polysaccharide fraction. No significant difference in blood pressure was found, but this was one of the first recent investigations to demonstrate a potential improvement in arterial stiffness. The researchers concluded, “…it appears that ginsenosides may be the principal pharmacologically active component of the root, rather than the polysaccharide fraction.” The potential improvement in multiple potential cardiovascular parameters, including glucose, lipids, and blood pressure, should also be of interest [152, 153].

For this reason and others, it should also be further tested in postmenopausal women with FSD. For example, a P. ginseng double-blind randomized parallel trial of 72 postmenopausal women over 12 weeks found a significant benefit for relieving menopausal symptoms and significant reductions in low-density lipoprotein and carotid intima-media thickness compared with placebo without significant changes in estradiol [154].

The antifatigue effect or improved energy levels with ginseng should also be considered another potential mechanism of action, whereby ED or FSD could theoretically be improved. A large (n = 290) Mayo Clinic trial of American ginseng found sufficient improvements in cancer-related fatigue over placebo to warrant further clinical study [155]. Interestingly, no side effects over placebo were found in the low (750 mg) or higher (1,000 or 2,000 mg) ginseng dose group. The mental or physical energy-enhancing effects of ginseng are of interest in both sexes [156, 157] and again could theoretically explain some of the sexual health improvements. It is interesting that 4–8 weeks were needed to improve energy levels over placebo.

In our opinion, one ancillary mechanism of action that appears most fascinating as of yet may be the neurologic improvement or protection via ginsenosides from degenerative or abnormal conditions in the central or peripheral nervous system [158–163]. Ginsenosides have demonstrated some anti-inflammatory, antioxidant, anti-apoptotic, neuronal growth factor enhancement, and other mechanisms of action. Therefore, the potential of ginsenosides to improve sexual function with prescription agents after prostate cancer treatment (e.g., surgery or radiation) should be investigated. An intervention that generates some excitement in the area of neuronal protection and regeneration outside of sexual health should be of interest within sexual health. High doses of ginseng have already been utilized in patients with neuronal degenerative diseases with at least a hint of some clinical efficacy, which should increase the interest in diverse neurological research with ginseng extracts [164, 165]. Ginseng’s potential impact on cognition is preliminary but notable from past clinical trials [166], and quality-of-life improvements in an aging population are also of interest [167].

Laboratory studies have consistently found no overt safety or toxicity issues of concern with unadulterated ginseng. P. ginseng was nominated by the US National Institutes of Health to the US National Toxicology Program for assessment of its carcinogenic potential because it is one of the most popular and widely used herbs in the world [168, 169]. Researchers examined chronic toxicity, tumorigenicity, and safety in multiple studies in male and female mice (B6C3F1) and rats (Fischer 344). Studies included a 2-week, repeated-dose toxicity study (0, 125, 250, 500, 1,000, or 2,000 mg/kg) for 5 days per week for 16 days. Another study was a 3-month ingestion study (0, 1,000, 2,000, 3,000, 4,000, or 5,000 mg/kg) in which P. ginseng was ingested 5 days per week for 14 weeks. In yet another study, male and female rats and mice were given 0, 1,250, 2,500, or 5,000 mg/kg 5 days per week for 104 weeks. Ginseng was also tested in two independent bacterial mutagenicity assays. No significant safety issues were found in animals in the 2-week, 3-month, or 2-year gavage studies. The results of the US National Toxicology Program acute and chronic toxicity and tumorigenic bioassays found P. ginseng to be neither toxic nor tumorigenic even when administered at doses of 5,000 mg/kg. Interestingly, the incidence of mammary gland fibroadenoma was significantly decreased in female rats administered 5,000 mg/ kg.

Past laboratory studies investigating the impact of P. ginseng on sexual function also noted no safety issues of concern. For example, in the most recent investigation, the researchers reported no animal (mouse) mortality even with doses up to 20 g/kg for 10 days [144]. In another ancillary study by this same group and noted in the same publication, no signs of toxicity were observed in beagle dogs that were treated with a primary ginsenoside (Rg1) at a dose of 500 mg/kg by mouth daily for 5 months.

The consistency of safety data from human studies is also notable and is derived from a variety of sources. One analysis included a systematic review from five electronic databases and all articles with original data on adverse events and drug interactions with P. ginseng [170]. Information was also requested from 12 manufacturers of preparations of ginseng, the spontaneous reporting of the World Health Organization, and national drug safety bodies. No language restrictions were imposed. The incidence of side effects of ginseng was found to be similar to that of placebo. More serious side effects were reported in isolated case reports and through spontaneous reporting and not in randomized trials. The authors concluded, “Collectively, these data suggest that P. ginseng monopreparations are rarely associated with adverse events or drug interactions. The ones that are documented are usually mild and transient. Combined preparations are more often associated with such events but causal attribution is usually not possible.” An update to this manuscript reached a similar conclusion and stated that the potential for drug-ginseng interactions is “low” and the concern over other medications is primarily based on isolated case reports [171].

A rare but still surprising concern with some herbal preparations, in my opinion, is the chance for them to be inappropriately and falsely labeled with an acute safety issue on the basis of isolated case reports or uncontrolled investigation without an examination of the of the majority of the objective laboratory and clinical evidence. One perpetuated example is a 1979 observational series in a notable medical journal that associated the self-reported utilization of ginseng products with hypertension in 14 individuals after 3 months of use [172]. Despite no control group, and other basic methodology quality-control issues, including a lack of correction for other confounders, such as high intakes of caffeine and potentially other stimulants, this investigation was used by multiple authors as cause and effect or evidence [173–175]. These hypertensive effects have not been replicated since 1979 in a controlled setting. Randomized trials of hypertensive and non-hypertensive individuals have demonstrated no impact or a partial reduction in blood pressure with Panax or American ginseng and isolated ginsenosides, regardless of dose utilized and time period (up to 3 months) [176–181].