Efficacy and putative mechanisms of action of nutraceuticals in the management of erectile dysfunction: a narrative review

4.1 Ginseng (Panax ginseng)

Among the most extensively studied nutraceuticals, Ginseng occupies a prominent place for the treatment of ED due to its pronounced endothelial vasodilation properties as well as the reduction of oxidative stress produced by ginsenosides, the main bioactive metabolites of Ginseng [40]. In fact, ginsenosides, due to the production of NO in the vascular endothelium, improve penile blood flow and modulate neurotransmitter release, further supporting erectile function [21]. In addition, due to their anti-inflammatory and antioxidant effects they protect endothelial cells from oxidative damage [21]. About 20 clinical and preclinical studies have been conducted on mild-to-moderate ED patients treated with ginsenosides, and in these studies, an average improvement of 3–5 points in the International Index of Erectile Function (IIEF) was reported [41]. In particular, a randomized trial of patients with mild-to-moderate ED showed significant benefits with respect to erectile stiffness, duration of erection and libido [42]. Of particular interest, in a systematic review, Lee et al. [43] found that Ginseng had a trivial effect on ED when compared to a placebo, based on the Erectile Function Domain of the IIEF-15, i.e., (mean difference of about 3 points compared to a placebo) with little or no side effects [43]. Nevertheless, standardization of dosages and confirmation of long-term efficacy require further studies.

4.2 Tribulus terrestris

Tribulus terrestris is a compound that has traditionally been used as an aphrodisiac. In fact, this plant modulates hormone levels, specifically increasing testosterone production and androgen receptor sensitivity through its active compound, namely protodioscin [44]. Tribulus terrestris has been analyzed in several studies reporting improvements of 2–4 points at IIEF, with effects more pronounced in men with ED related to hormonal imbalances than in those with ED of vascular origin [45]. In particular, Kamenov et al. [45] evaluated the efficacy and safety of a standardized extract (Tribestan®, Sopharma AD-coated tablets containing 250 mg of dry extract equivalent to furostanol saponins not less than 112.5 mg) for the treatment of men with mild to moderate ED and with or without hypoactive sexual desire disorder in a prospective, phase IV, randomized, double-blind, placebo controlled clinical trial in parallel groups. The authors showed a significant improvement in erection, libido and orgasmic function in the treated group, in the absence of any difference in the profile of side effects as compared with the placebo [45]. On the other hand, Santos et al. [46] in a prospective, randomized, double-blind study of patients with ED found that patients treated with 400 mg of Tribulus terrestris extract reported no significant benefit compared to the placebo group [46]. While one case of nephrotoxicity and another of increase in serum bilirubin levels have been described, no clinical trial in which Tribulus terrestris-based products were administered, have reported these side effects.

4.3 Maca (lepidium meyenii)

Maca is a Peruvian root known for its aphrodisiac properties [47, 48]. Several clinical trials have been performed on healthy men and patients with ED, showing significant improvements in libido and sexual satisfaction in both patient groups [48]. In particular, Maca has important potential as an adjuvant therapy to improve overall sexual health [48]. Maca has been shown to exert a modest impact on IIEF scores, with improvements of 1–2 points, the more significant effects being on libido and sexual satisfaction [49]. The safety profile is favorable with only mild gastrointestinal disturbances reported by few patients [49]. The properties of Maca are mainly due to its bioactive compounds, including alkaloids and flavonoids, which influence hormonal balance and improve mitochondrial energy production [50]. Its efficacy in patients with comorbidities such as obesity or diabetes and its potential for synergistic effects with other interventions are yet to be determined.

4.4 Epimedium (horny goat weed)

Epimedium, otherwise known as Horny Goat Weed, is a compound particularly well known for its use in ED. Its bioactive components, flavonoids and prenylhydroquinones are potent PDE5i, similar to sildenafil, one of the main drugs used to treat ED [51, 52]. Epimedium has been analyzed in several clinical studies showing modest improvements of 2–3 points at IIEF, particularly in combination with antioxidants that synergistically enhance the vasodilating capability of Horny Goat Weed [53, 54]. However, further research is needed to address issues such as long-term outcomes and potential anti-inflammatory properties, as well as combination strategies with other nutraceuticals to enhance its efficacy.

4.5 Yohimbine (extracted from pausinystalia yohimbe)

Pausinystalia yohimbe extract, Yohimbine, is an alkaloid that behaves as an antagonist of pre-synaptic alpha-2-adrenergic receptors, thereby promoting blood vessel relaxation and increasing blood flow in the penis. Moreover, Yohimbine, is able to enhance sexual arousal through central nervous system (CNS) stimulation thus proving efficacy in the treatment of psychogenic ED [55]. Controlled clinical trials have shown significant 2–3 point improvements in IIEF score in patients treated with Yohimbine compared with placebos, although side effects (e.g., hypertension and anxiety) may limit its use [56, 57, 58]. Future research directions should be aimed at optimizing dosing regimens to mitigate adverse effects and explore its use in combination with anxiolytics.

4.6 Saffron (crocus sativus)

The main active compounds in Saffron, crocin and safranal, exert neuroprotective and antioxidant effects, improving both psychological and physiological factors involved in ED [59]. Saffron seems particularly useful in ED associated with stress or depression, by improving penile rigidity and sexual satisfaction [60]. Saffron has been evaluated in several clinical studies and results consistently show an average IIEF improvement of 3 to 4 points after four weeks of treatment [61, 62]. Also, Saffron has shown a favorable safety profile without major adverse events [59] Future research should assess its potential therapeutic role in combination therapies for patients with psychological comorbidities.

4.7 L-arginine

L-arginine is an essential amino acid that acts as a precursor of NO, a key mediator of vasodilation and physiologic endothelial function [63]. Supplementation with L-arginine increases the bioavailability of NO, and numerous clinical studies have shown that combining L-arginine with antioxidants (e.g., Pycnogenol) consistently improves erectile function in patients with vascular ED, with an improvement in IIEF of about 3–6 points [64, 65]. It should be specified, however, that L-arginine monotherapy produces less consistent results, compared with combination therapy depending on the dose and duration of administration [66, 67, 68]. Best results were obtained by administering 6–8 g/day for periods of time ranging from 3 to 6 months [67, 68]. Overall, L-arginine is safe and well-tolerated, suggesting that it might be an alternative treatment in mild-moderate vasculogenic ED patients with adverse effects or contraindications for chronic treatment with PDE5i. It should be used with caution in patients on nitrate therapy.

4.8 Pycnogenol (maritime pine bark extract)

Pycnogenol, a derivative of Maritime pine bark, is a potent antioxidant that improves endothelial function and reduces oxidative stress [69]. It is normally used in synergy with L-arginine, increasing NO production, enhancing vasodilation and consequently promoting erectile activity [64, 65]. Clinical studies involving patients with moderate ED demonstrated that the combination of L-arginine and Pycnogenol significantly improved the quality of erection within three months of therapy and with no significant side effects, leading to an increase in IIEF scores of 3–6 points [64, 65]. Future research should focus on evaluating its long-term safety profile and efficacy in diverse patient populations.

4.9 Ashwagandha (withania somnifera)

Ashwagandha is an adaptogenic compound known for its ability to improve stress response and promote hormonal balance [70]. These effects may have a positive impact on libido and erectile function, particularly in men with psychogenic ED. Furthermore, it has been shown to increase testosterone levels, further supporting libido and erectile function [70, 71]. Several studies have explored the role of Ashwagandha in ED, particularly in psychogenic cases [70, 71], whereby showing improvements in IIEF scores of 1–3 points. In particular, in an 8-week randomized, double-blind, placebo-controlled study Ashwagandha root extract at a dose of 300 mg twice daily in adult males with psychogenic ED was shown to exert significant improvement of sexual desire without any significant side effect [71]. Furthermore, Ashwagandha helps reducing cortisol levels, thereby alleviating stress, a key contributing factor to psychogenic ED, and improves sperm quality, testosterone, levels and libido [72]. However, its specific effects on erectile function require further research. In particular, its long-term clinical impact should be better clarified as well as whether combinations with anxiolytics or PDE5i may offer a more complete solution for patients with complex cases of ED with relevant psychological components [72].

4.10 Ginkgo biloba

Ginkgo biloba, a compound known to improve blood circulation due to its vasodilatory effects, acts as a modulator of NO thus ensuring greater blood flow to the corpora cavernosa of the penis [73, 74]. Moreover, the antioxidant properties of Ginkgo biloba help reduce oxidative stress, a common factor in ED of vascular origin [74]. Ginkgo biloba seems particularly useful in cases of ED caused by circulatory disorders or by the use of antidepressants. In fact, Gingko biloba has shown particular efficacy in cases of ED induced by the use of selective serotonin reuptake inhibitors (SSRIs), with patients reporting an improvement in erectile rigidity and overall sexual satisfaction with IIEF improvements ranging from 2 to 4 points [75, 76]. Despite these benefits, more extensive and standardized studies are needed to establish its long-term safety and optimal dosage, and whether it can be integrated with conventional therapies such as PDE5i. In this regard, a recent study has shown that a nutraceutical combination of Gingko biloba with alpha lipoic acid and Vitis vinifera L given for three months in association with Avanafil significantly increased sexual performance in 123 males with type 2 DM-associated ED, without any significant adverse event [77].

4.11 L-citrulline

L-citrulline is a precursor to NO similar to L-arginine. However, while the latter’s efficacy can be limited by rapid metabolism, L-citrulline has better bioavailability and is rapidly converted into L-arginine [78, 79]. Studies show significant improvements in erection rigidity with L-arginine and L-citrulline administration, especially when combined with other compounds like Pycnogenol [65, 79], with an increase in IIEF score of 3 to 5 points. In a single-blind study involving patients with mild ED, L-citrulline supplementation significantly increased erection hardness and number of intercourses per month [78]. Because of its superior bioavailability when compared with L-arginine, L-citrulline offers a more effective option for sustained NO production [80].

4.12 Anti-oxidants

Oxidative stress plays a major role in causing vascular endothelial dysfunction which may in turn lead to ED. Therefore, natural compounds with anti-oxidant properties have been regarded to as possible therapeutic agents in this clinical setting. Resveratrol, a nonflavonoid polyphenol, improves endothelial function and reduces oxidative stress [81]. Significant benefits have been observed in cardiovascular health, indirectly linked to ED [81, 82]. It has been shown that resveratrol may provide modest benefits in ED management [82, 83], with IIEF score improvements averaging 2 to 3 points [82, 83]. Resveratrol’s cardiovascular benefits also suggest its potential as a preventive strategy for ED linked to metabolic syndrome or other vascular conditions [81]. While resveratrol can be regarded to as a safe agent without major adverse events linked to its use, the optimal dosage, long-term effects, and potential interactions with medications still need to be investigated through well-designed randomized controlled trials (RCTs). Flavonoids, found in abundance in cocoa and green tea, have also demonstrated significant promise in the treatment of ED by improving endothelial function and reducing oxidative stress [84, 85]. The use of these compounds has been associated with moderate increases in IIEF score, typically ranging from 2 to 4 points. By enhancing NO bioavailability and promoting vasodilation, flavonoids offer a natural and potentially preventive approach to managing ED, particularly in vascular-related cases [85, 86].

4.13 Vitamins C and E

Vitamins C and E are antioxidants capable of counteracting ROS, thereby improving vascular health [87]. These compounds have been the subject of numerous studies showing improvements of varying degrees in erectile function [88]. In particular, vitamins C and E have been shown to yeild modest improvements in IIEF scores of approximately 1–2 points. However, although their efficacy as monotherapy is limited, they have demonstrated synergistic effects when combined with other nutraceuticals, such as L-arginine or Pycnogenol [89]. Future research for the treatment of ED should focus on optimizing these combinations to increase their therapeutic potential.

4.14 Omega-3 fatty acid

Omega-3 fatty acids reduce systemic inflammation and improve the fluidity of cell membranes, thus enhancing vascular signaling and consequently increasing the endothelial compliance of the cavernous sinusoids [90]. Observational studies indicate a positive association between omega-3 consumption and a reduced incidence of ED [91]. Omega-3 fatty acids, known for their anti-inflammatory and vascular benefits, have been the focus a number of studies which have shown only modest improvements in penile rigidity [92]. They are particularly beneficial in ED cases linked to metabolic syndrome or chronic inflammation [91]. More robust clinical trials are needed to establish their efficacy and explore potential synergies with other nutraceuticals.

4.15 Zinc and other micronutrients

Zinc, a vital micronutrient, has also been explored in ED research [93]. Zinc is essential for testosterone synthesis and testicular function maintenance [93] and its deficiency has been correlated with an increased risk of ED [93]. Other micronutrients, such as magnesium and vitamin D, have been found to be essential in hormonal and vascular regulation [94]. Zinc supplementation has shown slight improvements in IIEF scores (1–2 points), mainly in individuals with underlying zinc deficiencies. Zinc supplementation has also been shown to improve hormonal balance and libido, although its effects on erectile function appear to be more pronounced in combination with other therapies [95]. Future research should be focused on zinc-deficient populations and investigate its interactions with other micronutrients, such as magnesium and vitamin D.

4.16 Probiotics and gut microbiota

Recently, much attention has been paid at the connection between gastrointestinal and genitourinary tracts. In particular conditions which alter the composition of gastrointestinal microbiota may affect the lower urinary tract through the mechanism of the pelvic cross-organ sensitization by which an altered gastrointestinal barrier potentially driven by intestinal dysbiosis may negatively affect adjacent organs through the passage of bacteria or bacterial products [96, 97, 98, 99]. While current evidence is preliminary, this area holds great promise for future exploration, particularly in metabolic and vascular-related ED.

Emerging evidence suggests that a “healthy” gut microbiota strongly contributes to normal sexual functioning [100, 101]. In the context of ED, dysbiosis (i.e., an imbalance within gut microbiota community), may lead to systemic inflammation, endothelial dysfunction and hormonal imbalances, all key factors in ED pathogenesis. A decrease in short chain fatty acids production, such as butyrate, may alter gut barrier integrity, and impair endothelial function by promoting inflammation and reducing NO availability [101]. Moreover, the modulation of bile acid metabolism by gut microbiota influences energy balance and immune homeostasis through the interaction with bile acid receptors [101]. Finally, dysbiosis can lead to alterations in neurotransmitter production, immune activation and hypothalamic–pituitary–adrenal axis regulation, potentially affecting mood and stress levels, which are known to influence erectile function. All of these processes are critical in the maintenance of vascular health and in the regulation of sex hormones, both essential for erectile function. Therefore, intestinal dysbiosis may contribute to ED by the alteration of hormone levels, by dysruption of the gut-brain axis leading to stress/anxiety-mediated (i.e., psychogenic) ED, or by influencing the development of altered metabolic conditions such as obesity and diabetes mellitus or hypertension [102]. Therefore, it has been suggested that improving gut health might positively influence endothelial function and reduce systemic inflammation, indirectly benefiting erectile performance [102]. Moreover, it has been demonstrated that in ED there is a decrease in beneficial bacteria such as Alistipes and Bifidobacterium and an increase in harmful bacteria such as Actinomyces and Bacteroides [101]. Based on this, treatment strategies for ED through the modulation of gut microbiota by using specifically designed probiotic/symbiotic formulations or even fecal microbiota transplantation (FMT) represent a promising area of research [101]. It would therefore be crucial to identify specific bacterial strains or microbial metabolites that exert a beneficial effect on erectile function. In this regard, it has been suggested that taxa like Ruminococcaceae and Lactobacillus, as well as metabolites like butyrate may reduce systemic inflammation and improve vascular health, thus positively affecting male sexual function [101]. However, the association between specific gut microbial taxa and ED is derived from cross-sectional studies which do not account for potential confounders such as nutritional status, the use of medication such as antibiotics or gastric acid secretion inhibitors, and comorbidities like obesity, diabetes and hypertension, all of which can affect the gut microbiota composition. Moreover, only a limited number of observational and pilot studies have explored gut microbiota-targeted strategies in ED, and, therefore, well-designed randomized clinical trials are warranted to assess the real efficacy of gut microbiota manipulation in specific types of ED.

4.17 Muira puama

Muira puama (i.e., Ptychopetalum olacoides) is a plant native to the Amazonian regions of Brazil, particularly in rainforest areas. It is traditionally used by Brazilian indigenous populations, and is known for its aphrodisiac and stimulating properties [103]. The name “Muira puama” originates from the local language, with “muira” meaning “strength” or “energy” and “puama” referring to the plant itself [104]. The bark and roots are the parts of the plant primarily used for medicinal purposes, containing a range of bioactive compounds, such as alkaloids, sterols and flavonoids, believed to be responsible for the stimulating effects on sexual function [103, 104]. Muira puama has shown positive effects on libido and quality of erections [105], particularly in cases of psychogenic ED [105]. A few studies have shown improvements in IIEF score of approximately 3–4 points after 8 weeks of treatment with Muira puama, with a significant increase in erectile rigidity and sexual satisfaction [105, 106]. Muira puama primarily acts as a central nervous system stimulant, enhancing sensitivity and sexual response [103]. Its effects are linked to hormonal modulation, which can reduce psychological stress, a key factor in ED [104].

4.18 Cocoa polyphenols

Cocoa polyphenols, especially flavonoids, are known for their positive effects on cardiovascular health and consequently on erectile function, thanks to their ability to increase the bioavailability of NO [107]. There are numerous studies suggesting that the consumption of flavonoid-rich cocoa can improve blood flow and erectile function in patients with ED associated with endothelial dysfunction [108]. In particular, patients with mild ED have been reported to achieve significant improvements in penile rigidity after 4 weeks of treatment with high-flavonoid cocoa [108, 109].

4.19 Reishi (ganoderma lucidum)

Reishi, otherwise known as Ganoderma lucidum, is a medicinal mushroom known for its adaptogenic and antioxidant properties, with beneficial effects on vascular health and consequently on erectile function [110]. Although research on its efficacy in ED is still limited, some clinical studies suggest that Reishi may improve erectile function, especially in cases of vascular or stress-related dysfunction. In fact, the use of Reishi for 12 weeks has been shown to lead to improvements in penile rigidity [111]. The mushroom acts on various fronts in the treatment of ED: on the one hand, by regulating fibrosis and the Nitric Oxide Synthase/Extracellular signal-Regulated Kinase/Janus Kinase (NOS/ERK/JNK) pathway [111], on the other hand, by reducting oxidative stress, thus preserving endothelial health of the penile corpora cavernosa [112].

4.20 Cordyceps sinensis

Cordyceps sinensis is another medicinal mushroom that has positive effects on sexual function due to its ability to improve cellular energy and blood circulation. In particular, its benefits are due to the stimulation of Adenosine Triphosphate (ATP) production, which increases the energy efficiency of cells and promotes vasodilation to improve penile blood flow, and increased synthesis of NO [113]. In different clinical studies conducted on patients with ED of vascular origin, supplementation with Cordyceps for 8 weeks led to a significant improvement in penile rigidity. Also, in patients with chronic fatigue, Cordyceps increased erectile rigidity, sexual desire and the overall sensation of a firm and sustained erection leading to improvement in sexual performance and confidence [114, 115]. When taken in high doses, Cordyceps sinensis may have a few side effects such as epigastric pain and diarrhea. Therefore, it is important to choose the safe dose and duration of treatment prior to considering it as a possible ergogenic aid in ED patients.

4.21 Capsicum frutescens

Capsicum frutescens is a bioactive compound found in hot chili peppers, known for its stimulating effects on metabolism and blood flow [116]. Specifically, Capsicum frutescens acts as a vasodilator, through a positive effect on the release of NO [116, 117]. Several clinical studies suggest that Capsicum frutescens may be beneficial in the treatment of ED, particularly in cases of mild to moderate ED [116]. Capsicum frutescens supplementation has been demonstrated to lead to a significant improvement in penile hardness, possibly mediated by boosted production of NO in endothelial cells of the corpora cavernosa [117]. Because of its capacity of improving circulation and reducing oxidative stress, Capsicum frutescens might be useful in patients with heart failure-related ED [118].

4.22 Quercetin

Quercetin is a flavonoid found in foods such as apples, onions, red grapes and citrus fruits, known for its potent antioxidant and anti-inflammatory properties [119]. Quercetin has been considered as a potential treatment for ED due to its ability to reduce oxidative stress [119]. Specifically, Quercetin can improve vascular health and promote vasodilation, thereby enhancing blood flow to the penis and improving erectile function [120]. In different studies conducted in patients with mild ED, Quercetin supplementation for 12 weeks showed significant improvements in IIEF scores, with an average increase of 3–4 points [121]. The benefits were primarily attributed to Quercetin-induced reduction in ROS-related alteration of endothelial function [121]. Moreover, Quercetin has been shown to modulate NO production [120].

4.23 Schisandra (schisandra chinensis)

Schisandra is an adaptogenic plant also known for its ability to reduce stress, improve physical resistance and stimulate vital energy, especially used in Chinese medicine for its tonic effects and its ability to balance vital energy, known as “Qi” [122]. Schisandra is mainly used as a tonic, but its therapeutic applications also include the promotion of cardiovascular and sexual health. In addition, this plant seems to have positive effects on blood circulation and production of NO, and is especially appreciated for its antioxidant properties [122, 123, 124]. In different studies conducted in men suffering from stress- or fatigue-related mild ED, Schisandra led to an improvement in erectile rigidity, sexual desire and the overall sensation of a firm and sustained erection leading to improved sexual performance and confidence.

4.24 Astragalus (astragalus membranaceus)

Astragalus is a plant that has been used for thousands of years in traditional Chinese medicine, where it is mainly recognized for its tonic properties and its ability to strengthen the immune system. This plant is used in the treatment of many conditions, but numerous studies underline its beneficial effects on blood circulation and cardiovascular health [125]. Astragalus shows important antioxidant properties, being capable of reducing oxidative stress and protecting the endothelial cells that line the blood vessels, thus preserving the good functioning of the cardiovascular system. Astragalus appears to improve blood flow to the penis by increasing intracellular levels of cyclic adenosine 3′-5′-monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which are both signaling molecules involved in penile erection. Moreover, this plant has has been shown to have anti-inflammatory properties that can be useful in cases of ED caused by vascular inflammation or damage to the vessels [126]. In a clinical study involving 122 patients with ED, Hongjing I granules, a herbal Chinese medicine containing Astragalus, was significantly superior to a placebo after 8 weeks of treatment, and this was particularly evident in patients with ED related to chronic stress or vascular inflammation [127]. Astragalus might be regarded as a useful supportive treatment for ED, especially for patients with comorbidities such as diabetes or hypertension, in which inflammation and poor blood circulation are predominant factors. Furthermore, its ability to tone the body and improve circulation could contribute to the general improvement of sexual health [128]. Astragalus use is associated to a limited number of side effects such as skin eruption, headache and diarrhea, whose occurrence is however very rare.

4.25 Damiana (turnera diffusa)

Damiana (Turnera diffusa), a plant native to Central and South America, has traditionally been used to increase libido and improve sexual function. This plant is known primarily for its aphrodisiac properties, but its application also extends to the treatment of digestive and respiratory disorders [129]. As for ED, Damiana is often used as a tonic to increase energy and promote sexual well-being by stimulating the central nervous system and hormonal production [130]. Damiana has also been shown to increase the production of dopamine, a neurotransmitter essential in sexual stimulation and desire [129]. Furthermore, Damiana appears to have positive effects on blood circulation by improving blood flow to the penis, which explains its potential use in the treatment of mild to moderate ED [130]. While not a primary treatment for ED, Damiana, due to its aphrodisiac and sexual tonic effects, may be considered a natural option to be used in combination with other treatments, especially in patients with psychogenic or aging-related ED experiencing loss of libido or sexual fatigue [129, 131, 132]. Although research on Damiana for ED is limited, some studies have found significant improvements in IIEF scores. In particular, in one study conducted in men with mild to moderate ED, the use of this herb for six weeks showed an average increase of 2 points in IIEF, with significant benefits regarding erectile strength and sexual satisfaction [132].

4.26 Catuaba (erythroxylum catuaba)

Catuaba (Erythroxylum catuaba) is an aphrodisiac plant native to Brazil that indigenous populations of the Amazon used to increase sexual desire and sexual performance [133]. Although there is currently no impressive clinical evidence in this regard, the plant is used and appreciated for its positive effects on blood circulation and for its stimulating action on the central nervous system (CNS). Catuaba is believed to act as a tonic for the body, also improving resistance and sexual vitality. These properties are due to the alkaloids contained in the plant such as flavonoids and tannins that have an aphrodisiac action [134]. Catuaba is also known for its neuroprotective properties and the ability to increase the production of dopamine, a key neurotransmitter linked to sexual desire and pleasure [134]. Also, it may act as a PDE5i [134]. Although research on Catuaba for ED is limited, some studies indicate that this plant may improve erection quality and stimulate sexual desire in the presence of factors such as stress and fatigue [135]. In fact, in a study conducted in men with mild ED, the supplementation of this compound for eight weeks showed a significant improvement of about 2–3 points in IIEF scores. In addition, treated patients also reported improvements in erection rigidity, duration and sexual satisfaction [136].

4.27 Bacopa monnieri (Brahmi)

Bacopa monnieri, also known as Brahmi, is an adaptogenic herb widely used in Ayurvedic medicine to improve memory, concentration and reduce stress that has recently attracted attention for its potential positive effects on male sexual function. In particular, this herb acts as a tonic for the CNS, helping reduce anxiety and improve the body’s response to stress, which is often responsible of sexual problems [137]. Although research is still limited, there is some evidence that Bacopa monnieri may improve erectile function, particularly in men with psychogenic or stress-induced ED. Furthermore, it has been shown that one of the main mechanisms through which Bacopa monnieri exerts its effects on erectile dysfunction is through the stimulation of NO production [138]. In a study conducted on men with mild ED, administering Bacopa for six weeks led to an average increase of 2 points in IIEF scores, showing improvements in erection and sexual satisfaction [139]. Although the efficacy of Bacopa Monnieri is not yet well established, its positive effects on stress reduction, increased blood circulation and NO production could make it useful in combination with other therapies for ED, especially for those patients suffering from psychogenic ED.

4.28 Suma (pfaffia paniculata)

Suma, also known as “Brazilian ginseng”, is a plant that primarily grows in the Amazon and is traditionally used to boost energy, vitality and improves sexual health [140]. Although scientific research on Suma is still in the preliminary stages, there is evidence to suggest that this plant may have an important action on sexual activation especially for those who suffer from ED due to fatigue or stress. Suma has been shown to increase the production of testosterone, thus counteracting the decrease in libido associated with low hormone levels typically found in a number of patients with ED [141]. Although studies on Suma and ED are limited, some suggest that this herb helps significantly in counteracting poor sexual stamina and low energy levels [142].

4.29 Paeonia lactiflora (Peony)

Paeonia lactiflora or Peony, is a plant used in traditional Chinese medicine to treat various disorders, including those related to sexuality. This plant is known for its anti-inflammatory and antioxidant properties, which can help improve cardiovascular health and blood circulation, therefore it may have a role in the treatment of ED, often linked to circulatory problems [143, 144]. Furthermore, Peony is known for its calming effects, which may help reduce performance anxiety, a common psychological factor that may sometimes play a particularly impactful role in psychogenic ED [144, 145]. It should be noted that although the data at our disposal are still scarce, some small clinical studies have shown that the use of Paeonia supplements leads to improvements in erectile rigidity, sexual desire and the overall sensation of a firm and sustained erection, leading to improved sexual performance and confidence [144, 145]. Furthermore, it has been noted that its anti-inflammatory action may reduce oxidative damage to endothelial cells, improving vascular function and, consequently, supporting erectile function.

4.30 Longjack (eurycoma longifolia)

Longjack or Eurycoma longifolia, is a plant from Southeast Asia that has been used for centuries as a natural aphrodisiac. This plant, also known as Tongkat Ali, is known for its ability to stimulate the production of testosterone, a hormone of vital importance for male sexual health [146]. Longjack has been studied extensively for its positive effects on libido, fertility and sexual function and has also been used to treat hypogonadism, a condition characterized by low testosterone production that is one of the most common causes of ED [147]. The effectiveness of this herb has been analyzed in several clinical studies. In particular, in a study involving 109 men with ED and low testosterone levels, taking Longjack for 12 weeks showed significant improvements in IIEF scores, with an average increase of 3–4 points. In addition, the study participants reported significant improvements from a qualitative point of view in terms of erection hardness, erection duration and sexual satisfaction [148, 149]. The herb seems to act mainly by stimulating testosterone production, but it also improves blood circulation, thereby increasing the supply of oxygen and nutrients to the penile corpora cavernosa. This might be particularly useful for men with vascular-based ED [149]. Longjack has also been shown to have positive effects on fertility, as it appears to improve sperm quality and quantity, making it a very interesting therapeutic option not only for men seeking to improve erectile function, but also for those who have difficulty conceiving [149]. While Longjack is very promising as a natural therapeutic agent for altered sexual function, it is important to note that its effectiveness may vary between individuals and that further research is certainly needed to determine its long-term benefits and the optimal dose for therapy. In summary, Longjack represents a very promising treatment for patients with ED associated with low testosterone levels and may be particularly useful as a complement to hormonal therapies to help improve male sexual health.

4.31 Hypoxis hemerocallidea (African potato)

Hypoxis hemerocallidea, also known as African potato, is a plant from southern Africa traditionally used to treat a variety of disorders, first of all, ED. In fact, the extracts of Hypoxis are rich in phytosterols, saponins and flavonoids, known for their antioxidant and anti-inflammatory properties [150]. Also, the plant acts by increasing testosterone levels and improving blood circulation, two fundamental factors to ensure the sexual health of men [150]. Several clinical studies have shown that Hypoxis extracts lead to an improvement in sexual function, mainly in patients with ED associated with low testosterone levels or vascular problems. In particular, daily intake of Hypoxis extracts resulted in an increase of approximately 2–3 points in IIEF scores, with clear and significant improvements in erection quality and libido [151, 152]. In addition, positive effects have been shown on prostate health, which also is a crucial factor for sexual function [152].

4.32 Sclerocarya birrea (Marula)

Sclerocarya birrea, commonly known as Marula, is a plant native to sub-Saharan Africa, whose fruits and seeds are rich in unsaturated fatty acids, vitamins and antioxidants, which contribute to the improvement of cardiovascular health and, consequently, of erectile function [153]. Traditionally, Marula infusions have been used as a tonic to increase libido and sexual stamina. The plant, in fact, improves blood flow, thus reducing the likelihood of ED related to circulatory problems. Furthermore, Marula is also known for its anti-inflammatory and antioxidant properties, which can help counteract oxidative cell injury and damage to blood vessels [154, 155]. Although evidence-based efficacy of Marula on ED is still limited, because of its beneficial effects on vascular health one may hypothesize that this plant may serve as a therapeutic alternative to treat ED of vascular origin.

4.33 Cissus quadrangularis (veldt grape)

Cissus quadrangularis, commonly known as Veldt grape, is a climbing plant native to Africa, which has traditionally been used to treat a variety of conditions, including ED. Cissus extracts contain antioxidants, flavonoids and phenolic compounds that improve blood circulation and vascular function, especially at the penile cavernous level [156]. The plant is also known for its anti-inflammatory properties and for supporting bone and muscle health, but it is its positive effects on vascular health that make it promising for the treatment of ED [157]. Clinical studies on men with mild ED have shown improvements in IIEF scores, with increases of 2–3 points [158]. Although further research is needed to confirm these results, the plant seems to have a very important potential for the treatment of ED of vascular origin both alone or in combination.

4.34 Kigelia africana (sausage tree)

Kigelia africana, commonly known as the Sausage tree, is a plant native to sub-Saharan Africa that is traditionally used to treat various disorders, including ED [159]. Kigelia extract is rich in flavonoids and phenolic compounds, which have antioxidant and anti-inflammatory properties which are beneficial to sexual health. Also, this plant has been shown to be able to improve blood circulation and stimulate libido [160]. Although data on the effects of Kigelia africana in ED are still limited, some preliminary studies have suggested that Kigelia extracts may have positive effects on erectile quality, with several studies showing that IIEF scores increased by approximately 2–3 points, especially in combination with other aphrodisiac remedies [161]. However, further research is needed to confirm the effectiveness of the plant, and additional clinical studies will certainly be needed to confirm its specific improvements in sexual function.

4.35 Mondia whitei (whitei)

Mondia whitei is a climbing plant from Central and West Africa that is traditionally used as an aphrodisiac, with its extract being used to stimulate testosterone production and help improve blood circulation, two essential factors for proper erectile function [162]. In addition, this plant is also used to treat digestive disorders and to improve physical endurance [163]. A number of preliminary studies have been performed, suggesting that Mondia whitei could also be useful in the treatment of ED, with improvements in erectile rigidity, sexual desire and the overall sensation of a firm and sustained erection, leading to improved sexual performance [164].

4.36 Astragali complanati semen

Semens of Astragali complanati are dried ripe seeds of Flatstem Milkvetch, which is mainly used in traditional Chinese medicine for the treatment of reproductive system diseases such as ED [165]. Among its components complanatoside, astragalin, complanatoside B, and kaempferol have recently been found to be responsible for its anti-ED effect [166]. Astragali complanati semen due to its content of flavonoids also positively affects oxidative stress and lipid metabolism, thus lowering serum lipids. Despite its traditional use for male health, efficacy in ED has never been tested in a systematic manner in clinical trials.

4.37 Detarium senegalense

Detarium senegalense J.F.Gmel. is a medicinal plant native to the west African region and is commonly known as the African star apple or tallow tree, rich in flavonoids, tannins, saponins, alkaloids and phenolic compounds [167]. A recent computational investigation on the therapeutic effects of Detarium senegalense has shown that among its flavonoid components, catechin, epicatechin and gallic acid have the capability of targeting six enzymes which are relevant to erectile function showing a significant binding affinity to PDE5, comparable to that exhibited by sildenafil [168]. Catechin in particular shows superior binding energies, favourable pharmacokinetic profile, and good binding conformation/interaction at the receptor site and might therefore be regarded as a multi-target inhibitor of key enzymes involved in the pathogenesis of ED. Therefore, the flavonoid-rich fraction of Detarium senegalense could lead to improved sexual performance and sustained erection for satisfactory sexual intercourse. Moreover, catechin could serve as a potential lead compound for development of a drug for the management of ED, due to its satisfactory pharmacokinetic profile, good binding affinity and good interaction at the receptor sites of the enzymes. Also, the flavonoid components of Detarium senegalense have shown high gastrointestinal absorption, good bioavailability and drug likeness [168]. Overall, this study supports the potential of Detarium senegalense phytochemicals as promising candidates for developing new, safer and more effective therapies for ED, offering an alternative to current treatments with fewer side effects. However, further research is needed to exactly quantify these compounds in Detarium senegalense and evaluate their efficacy in animal experimental models and, subsequently in clinical trials.

4.38 Fadogia agrestis

Fadogia agrestis, Schweinf. Ex Hiern, locally referred to by the Hausas of Northern Nigeria as gai gai and in English as Black aphrodisiac is a plant belonging to the Rubiaceae family. In ethnomedicine, it has been used to improve athletic performance, to increase sex drive and to treat ED. A recent study conducted in male Wistar rats has shown that aqueous extracts of Fadogia agrestis are capable of restoring the NO/cGMP pathway and ED-associated key enzymes in the penile and testicular tissues, which is attributed to its antioxidant activity [169]. This suggests that aqueous extracts of this medicinal plant should be tested in clinical trials to evaluate whether they may prove useful in the treatment of ED.

4.39 Kaempferia parviflora

Kaempferia parviflora Wall. ex Baker (KP), known in Thailand as Black Ginger or Krachai Dam, belongs to the family of the Zingiberaceae family and is widely distributed in Southeast Asia. It has traditionally been employed to ameliorate physical capacities. Ethnopharmacological evidence indicates that a rhizome of Kaempferia parviflora is able to increase libido and sexual function [170].