Apart from the registered synthetic drugs such as sildenafil and tadalafil, there is one natural product, yohimbine, which has been approved by the Food and Drug Administration (FDA) for management of sexual dysfunction, specifically male erectile dysfunction (ED). Yohimbine is an alkaloid, derived from the bark of the Central African tree, Corynanthe yohimbe. The compound has high affinity for alpha-2a and alpha-2c receptors in the central nervous system (CNS). It also functions as a presynaptic alpha-2-adrenergic antagonist. Yohimbine is thought to act by dampening contraction induced by blockade of post-junctional alpha-2 receptors, and perhaps by relative antagonism of alpha-1 receptors. It is proposed to facilitate sexual arousal by acting directly on alpha-2 adrenoreceptors in the CNS and blocking adrenergic influences at the peripheral level (10).

Yohimbine has been used for more than a century in the treatment of ED, and is generally supported by animal and human studies, though most contain significant flaws in their design. Surprisingly, no systematic dose-response studies have been performed, or have any comparisons of different administration routes or of standing versus “as-needed” dosing. Likewise, there has been little investigation on yohimbine’s synergy with other drugs, comparisons against other sexual enhancers, and efficacy in women. One proposed reason for the limited number of clinical trials is that yohimbine is a very old drug without patent protection or commercial viability (11,12).

At least a dozen placebo-controlled, randomized clinical trials (RCTs) and two open trials with yohimbine for sexual dysfunction have been published, primarily with all-male samples. The two open studies were encouraging, with response rates in the neighborhood of 50% for ED (13) and nonorgasmic dysfunction (14). Among the RCTs with yohimbine, five may be considered positive, with response rates in the range of 30% to 70% that were significantly better than for placebo (15, 16, 17, 18, 19). The other studies were essentially negative, failing to demonstrate significant differences between active treatment and placebo (20, 21, 22, 23, 24, 25, 26), though Kunelius et al. (24) did obtain fairly strong response rates for both yohimbine (44%) and placebo (48%) that did not separate from each other. Sample sizes in these studies ranged from less than 10 subjects to more than 80, and impotence from various causes was examined. Eight of these studies used crossover designs (15, 16, 17,19,21,23,24,26) and five used some sort of combined regimen consisting of yohimbine plus other agents such as isoxsuprine (21), apomorphine (20), trazodone (17), and arginine (19,26). The two studies with all-female samples were negative (25,26).

With regard to sexual dysfunction secondary to antidepressants, two open trials and one RCT examining yohimbine’s efficacy have been published. Jacobsen (27) treated 9 men with fluoxetine-induced sexual dysfunction, administering 5.4 mg yohimbine thrice daily. Eight
subjects responded, and five had side effects that led to discontinuation. Hollander and McCarley (28) treated six subjects with various mood or anxiety disorders who reported SSRI-induced sexual dysfunction. Yohimbine was administered on an as-needed basis at various doses, with improvement seen in five of the six patients, and good tolerability. Michelson et al. (29) carried out a lone RCT on 148 premenopausal women with sexual dysfunction secondary to fluoxetine. Yohimbine was compared against mirtazepine, olanzapine, or placebo for 6 weeks. None of these drugs separated from placebo with regard to efficacy.

Carey and Johnson (30) reported four convergent meta-analyses that included RCTs and uncontrolled trials of yohimbine monotherapy or combined therapy with yohimbine plus another agent. The authors concluded that the data as a whole suggest a “consistent tendency for yohimbine … to enhance erectile functioning relative to placebo.” A meta-analysis of seven double-blind RCTs (31) suggested that yohimbine 5 to 10 mg thrice daily was superior to placebo with an odds ratio of 3.85 (confidence interval [CI] 2.22 to 6.67).

The clinical studies reviewed here have dosed yohimbine between 6 and 50 mg per day, usually divided into thrice daily dosing. The typical dose used for sexual dysfunction in clinical practice is 5.4 mg three times a day. Animal data, however, suggest that response to yohimbine declines with chronic administration (32), and human studies have shown that yohimbine has a short half-life of about 35 minutes (33). Given these observations, some have suggested that “as-needed” (p.r.n.) dosing may be the optimal way to administer this drug (28).

Yohimbine has been successfully combined with agents, such as L-arginine (reviewed later in this chapter), that stimulate release and action of nitric oxide (NO) in the corpus cavernosum, and this has been considered a particularly effective way to use yohimbine (34). Yohimbine is generally well tolerated, though at higher doses, reversible side effects may occur, including elevation of blood pressure, anxiety and panic attacks, and urinary disturbances (35). Other side effects that have been associated with yohimbine include agitation, dizziness, increased heart rate, sweating, headaches, gastrointestinal upset, bronchospasm, and lupus-like reactions (35). While yohimbine is generally safe to combine with most drugs, there is a theoretic risk of interactions with tricyclic antidepressants and phenothiazines (35,36).

To conclude, yohimbine monotherapy appears to have modest benefits for ED, and remains the lone natural remedy sanctioned by the FDA for this indication. The concern over precipitation of anxiety, panic attacks, and cardiovascular side effects has limited yohimbine’s use in psychiatric populations and patients with cardiovascular disease. Further research is needed on yohimbine’s efficacy in female populations, as well as in antidepressant-induced sexual dysfunction.

NO has been shown to play an important role in cholinergically induced relaxation of cavernous smooth muscle in rabbit and human corpus cavernosum tissue, and is proposed to be a nonadrenergic, noncholinergic neurotransmitter of penile erection (37,38). Because NO is synthesized from L-arginine by NO synthase (NOS), arginine has been examined as a possible treatment for impotence.

Klotz et al. (39) treated 32 males with mixed-type impotence in a double-blind, crossover RCT comparing L-arginine 1,500 mg per day versus placebo. Patients were treated for 17 days with each treatment (including a 7-day washout period), and the KEED questionnaire (39) served as the outcome measure. Among the 30 completers, 17% reported significant improvement in erectile function with L-arginine compared to 20% of the placebo group, but 56% of arginine recipients and 43% of placebo recipients reported little improvement, and 27% of the arginine group reported no change or slight worsening. None of these comparisons reached statistical significance, suggesting no advantage for L-arginine over placebo.
In another RCT (40), 50 men with ED were randomized after a 2-week placebo run-in to high-dose L-arginine (5 g per day) or placebo. In this case, L-arginine was found to be significantly more effective than placebo. The investigators also noted that all responders had initial low-urinary NO that doubled by the end of the study.

A number of studies have examined the combinations of L-arginine and other purported sexual enhancing agents. Ito et al. (41) performed an open study with ArginMax, a supplement containing a blend of L-arginine, ginseng, ginkgo, damiana, multivitamins, and minerals, marketed for enhancement of sexual function. Among the 25 participating men with mild-to-moderate ED, 88.9% reported improvement in ability to maintain an erection and 75% reported improvement in sex life overall, but this study was limited by its lack of a placebo-control arm (41).

These investigators then carried out an RCT of ArginMax (42) to follow up on their open study (41). They recruited 77 healthy women of age 21 and older who wished to improve their sexual function. Thirty-four subjects received ArginMax for 4 weeks, and 43 received placebo. 73.5% of the ArginMax recipients reported improved sexual satisfaction, as opposed to 37.2% of the placebo group (P<0.01). Improvements were observed in sexual desire, vaginal dryness, frequency of sexual intercourse and orgasm, and clitoral sensation. The treatment was well tolerated, with no side effects reported.

In another follow-up RCT of the same supplement, Ito et al. (43) recruited 108 women, ages 22 to 73 years, with loss of libido. Fifty-nine women were premenopausal, 20 perimenopausal, and 29 postmenopausal. Fifty-five participants received ArginMax for 4 weeks and the other 53 received placebo. Outcome was measured by the Female Sexual Function Index (FSFI) scales (44). Premenopausal women on ArginMax reported statistically significant improvement in level of sexual desire (72%), satisfaction with overall sex life (68%), frequency of sexual desire (60%), and frequency of intercourse (56%) compared to the women on placebo (P<0.05). Among perimenopausal women, significant improvement was reported for frequency of intercourse (86%), satisfaction with sexual relationship (79%), and vaginal dryness (64%) compared to placebo (P<0.05). Postmenopausal women showed a significant increase in sexual desire (51%) compared to the placebo group (8%) (P<0.05). The authors suggested that ArginMax’s lack of estrogenic activity (45) may make it a particularly good alternative to hormone therapy for sexual dysfunction.

Meston and Worcel (26) compared single doses of L-arginine 6 g plus yohimbine 6 mg versus yohimbine 6 mg alone versus placebo in a three-way crossover trial in 24 postmenopausal women with sexual arousal disorder. Subjects were tested by exposure to erotic stimuli at 30, 60, and 90 minutes following medication administration. Sexual arousal was increased in all groups, but did not differ significantly between groups.

Other combination treatments that have been studied include L-arginine plus sildenafil (46), with the rationale that arginine could improve sildenafil activity in the presence of NO. A total of 116 patients (64 status post-prostatectomies and 52 status post-cystectomies) were recruited. One group received sildenafil 50 to 100 mg alone and the other received sildenafil with L-arginine. The outcome measure was the Buckling test (a measure of pressure threshold of cavernous flexation). Buckling test scores of greater than 500 were obtained in both groups, with more notable improvement in the combined treatment group, suggesting the combination of L-arginine and sildenafil is effective, though in vitro studies with rabbit tissue have not consistently demonstrated synergy between sildenafil and arginine (47,48).

Lebret et al. (19) compared 6 g L-arginine glutamate plus 6 mg yohimbine versus 6 mg yohimbine alone versus placebo in a double-blind, randomized, placebo-controlled, three-way crossover trial in 45 men with ED. During each of the 2-week treatment periods, the drug was administered 1 to 2 hours before sexual intercourse. Results were measured by the Erectile Function Domain of the International Index of Erectile Function (IIEF). Significant
improvement over placebo was found with the combined arginine-yohimbine regimen, with most robust improvement in patients with mild-to-moderate ED. Results suggested possible synergy between yohimbine and arginine.

Stanislavov and Nikolova (49) tested a combination of L-arginine and pycnogenol, a compound that increases NO production via NOS, in 40 men with ED. In the first of 3 months, subjects received the equivalent of 1.7 g per day of L-arginine. In the second month, pycnogenol 40 mg b.i.d. was added; and in the third month, pycnogenol was increased to 40 mg t.i.d. Based on a sexual function questionnaire and a sexual activity diary, only two patients experienced a normal erection following the first month of treatment. The combination restored sexual function in 80% after the second month; and after the third month, 92.5% reported normal erections, suggesting a synergistic effect between pycnogenol and arginine.

A number of concerns have been raised about L-arginine, and arguments against its use center on the resulting increased production of NO, which may have potentially toxic effects. Adverse effects associated with arginine include diarrhea, elevated blood urea nitrogen and creatinine levels, flushing, hypotension, gastrointestinal upset, numbness, headaches, phlebitis, and hyperkalemia in patients with liver and kidney disease (50). Arginine may increase the release of a number of hormones, including growth hormone, insulin, glucagon, and prolactin (PRL), though the clinical significance of this is unclear (50).

These studies, though difficult to interpret in the context of mixed results and frequent combination treatments, are nonetheless encouraging as a whole. Arginine appears safe by itself and in combination with various other sexual enhancing agents, with the evidence thus far supporting synergistic effects. Only three studies so far (26,42,43) have examined efficacy of L-arginine in women, with collectively mixed results. No studies have emerged yet examining whether arginine is effective for antidepressant-induced sexual dysfunction. Judicious use as a second or third-line agent is likely the best niche for arginine at this time.

Ginkgo (reviewed in Chapter 10) has long been thought to contain sexual enhancing properties, and has been used by itself and in combination with other agents for this indication. For example, the ginkgo-containing supplement ArginMax, discussed earlier in this chapter, has been studied in at least two RCTs and one open study, all of which have suggested some efficacy for both men and women (41, 42, 43).

Waynberg and Brewer (51) performed a month-long open study of Herbal vX, a combination of Ginkgo biloba and Muira puama (Ptychopetalum, a flowering plant from the Amazon rainforest) examining libido and sexual activity in 202 healthy premenopausal and postmenopausal women with low sex drive. Treatment was well tolerated, and 65% of subjects reported significant improvement, particularly in frequency of sexual desire, sexual intercourse, sexual fantasies, satisfaction with sex life, intensity of sexual desires, excitement from fantasies, ability to reach orgasm, and intensity of orgasm.

A decade ago, Ellison and DeLuca (52) reported that ginkgo could reverse fluoxetine-induced penile anesthesia, and Cohen and Bartlik (53) proposed that ginkgo might be effective for treating antidepressant-induced sexual dysfunction. In his open study with 63 subjects (33 women and 30 men), ginkgo at doses of 60 to 240 mg per day (mean dose 209 mg per day) was found to produce an 84% response rate overall for antidepressant-induced sexual dysfunction caused by SSRIs, serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and tricyclic antidepressants (TCAs). Ginkgo had a positive effect on all four phases of the sexual response cycle: desire, excitement (erection and lubrication), orgasm, and resolution. Female subjects responded better, at rates of 91% compared to 76% in males. Side effects reported included gastrointestinal disturbances, headache, and general CNS activation.

Ashton et al. (54) reported a 1-month open trial of 300 mg thrice daily of G. biloba for 22 outpatients (9 men and 13 women) who presented with SSRI-induced sexual dysfunction, including 40 specific complaints. Based on clinical interviews, three (13.6%) patients reported partial improvement in overall sexual function. Improved sexual response was reported in three (23.1%) of the 13 women and in none of the nine men. Four (12.9%) of the 31 specific complaints of the women improved, but none of the nine complaints of the men. No side effects were reported. The overall results were not considered encouraging, though the authors noted several limitations, such as lack of a placebo arm, potential variation in product potency, selection bias, and lack of a standardized outcome measure.

Placebo-controlled, RCTs of ginkgo for antidepressant-induced sexual dysfunction have not been particularly encouraging thus far. Kang et al. (55) carried out an RCT of ginkgo for antidepressant-induced sexual dysfunction in 37 adults, 19 of which were randomized to ginkgo and 18 to placebo for 2 months. The authors found no significant difference between treatments at weeks 2, 4, and 8 of the study. Both treatment groups, however, showed improvement in some areas of sexual function, and the authors interpreted this finding as a placebo effect.

Wheatley (56) performed a triple-blind (regarding investigator, patient, and statistician), placebo-controlled trial of G. biloba for antidepressant-induced sexual dysfunction. After a 1-week control period, 24 patients were randomized to ginkgo 240 mg daily or placebo for 12 weeks. Three subjects dropped out after 6 weeks. A validated gender-oriented questionnaire was administered approximately every 3 weeks, and a nonblind follow-up on ginkgo was carried out for 6 additional weeks. Hamilton anxiety and depression ratings as well as global assessments of alertness and memory were obtained at weeks 0, 6, and 12. The authors described some “spectacular individual responses” in both groups, but overall there were no statistically significant differences, and no differences in side effects between ginkgo and placebo.

Among the proposed mechanisms of action for ginkgo with regard to sexual function are effects on platelet-activating factor (PAF), prostaglandins, peripheral vasodilatation, central serotonin and norepinephrine receptor factor modulation (53,57), MAO effects (58), acetylcholinergic effects (59), and improved penile endothelial L-arginine-NO activity (60,61). Despite the mixed results reported thus far, ginkgo may be a worthwhile second- or third-line agent for patients who are experiencing antidepressant-induced sexual dysfunction and have not been helped by more conventional medications, such as sildenafil, tadalafil, or yohimbine. One of ginkgo’s appeals is that, apart from the risk of hemorrhage in people who take anticoagulants (62), it appears to be safe to combine with most medications, and has relatively mild side effects. The full extent of ginkgo’s role in the management of sexual dysfunction requires further investigation.

Maca (Lepidium meyenii) is a root vegetable (tuber) that grows in the mountains of Peru at altitudes ranging from 11,000 to 14,500 ft (63,64). The origins of maca (also called Peruvian ginseng) are not fully understood, but native Peruvians have been known to use maca as a food and for medicinal purposes since before the time of the Incas (63). The historic uses of maca include nutritional supplementation for life in a harsh environment, as well as enhancing fertility and sexual potency. When the Spanish arrived in Peru in 1526, they were advised by locals to feed maca to their horses to keep them well nourished and to maintain their fertility (65). Impressed by the results, the Spaniards reasoned that maca might also promote sexual function in humans.

Maca’s fertility-enhancing properties were first reported in the literature in 1961, when it was shown that maca administration increased the fertility of rats (66). Today, maca is growing
in popularity due to claims of energizing effects, fertility enhancement, and particularly its aphrodisiac qualities. Other documented uses for maca include the alleviation of menstrual irregularities and female hormonal imbalances, including menopausal symptoms and chronic fatigue syndrome (63,67). In traditional Peruvian herbal medicine, maca is also used as an immunostimulant, as a memory enhancer, and for treating various medical conditions, such as anemia, tuberculosis, and stomach cancer (63,67,68).