Approximately one in three older adults suffer from diabetes, however, obesity, physical inactivity, and poor eating habits have led to an increase in the incidence of diabetes in children, adolescents, and young adults [1]. There are complications associated with diabetes that affect the brain, such as cerebrovascular disease (CVA), and Parkinson’s disease (PD). The disability and death rates in patients with PD are greater than those in patients with any other neurological disorder. An estimated 5.8 million disability-adjusted life years were lost in 2019 due to PD; an increase of 81% since 2000, and 329,000 deaths occurred due to the disease [2]. Numerous epidemiological studies have linked type 2 diabetes (T2D) with PD progression risk [3, 4]. There is promising evidence that antidiabetic medications may be used as treatments for PD, suggesting that T2D could be modified in terms of its pathogenesis. PD patients with T2D may benefit from personalized antidiabetic treatments that also provide neuroprotection due to their high prevalence. Therefore, understanding how T2D affects specific molecular pathways in the brain and how these pathways interact mechanistically is important. The pathogenesis of PD and diabetes involves insulin signaling, mitochondrial function, autophagy, and inflammation [5, 6]. A strong correlation exists between diseases of the body and diseases of the mind [7]. PD impairs physiological responses to sexual stimulation. It is common among patients with erectile dysfunction (ED). PD also impairs a patient’s ability to have an erection when sexually stimulated [8]. Many medicinal plants contain antioxidants that help control blood sugar levels in human bodies, and scientists are keen to learn more about the process. It has been demonstrated that Mucuna pruriens, also known as velvet bean, may be effective in treating diabetes, PD, and ED [9]. Leva-dopa (LD) is present in Mucuna pruriens at a mean concentration of 5.3%. Due to the absence of alkaloids, it is a sustainable therapeutic option for PD patients in the long term [10]. Studies also suggest that Mucuna pruriens is effective in the treatment of ED [11]. The antioxidant properties of Mucuna pruriens seeds naturally restore erectile function and reduce diabetic-induced sperm damage caused by oxidative stress [12]. A significant and common medical problem, the ED is characterized by extreme or complete erections. There are more than 150 million men worldwide who suffer from ED in some form or another. It is estimated that by 2025, 322 million men will suffer from ED. The incidence of ED in the United States is 25.9 cases/1,000 people, and it increases with age, with more than 70% of men over 70 having ED [13]. Phosphodiesterase-5 (PDE5) is an enzyme involved in preventing the breakdown of cyclic guanosine monophosphate (cGMP) in the cGMP signaling pathway, and is directly associated with penile erections. A penile erection is regulated primarily by the signaling pathways nitric oxide (NO) and cGMP. As a result of the downstream effect of cGMP caused by NO, PDE5 inhibitors can improve the erectile response and help treat ED [14]. In T2D patients, the incidence of severe ED increases with age. Age, duration of diabetes, and cholesterol are positively associated with ED [15]. Preclinical studies and clinical trials were reviewed to update the knowledge of the potential therapeutic effects of Mucuna pruriens on diabetes, PD, and ED. Research on reactive oxygen species (ROS) is gaining popularity in medical science due to their involvement in metabolic related disorders like T2D, PD, and ED. As a notable source of hypoglycemic compounds, Mucuna pruriens activates the antioxidant defense mechanism, helping to prevent diabetes, PD, and ED [16]. Despite the multipurpose healing capabilities of Mucuna pruriens, there is still a lack of scientific evidence and clinical trials to support the efficacy of the herb.

This is the first study to investigate the potential benefits of Mucuna pruriens for PD, diabetes prevention, and most importantly ED. There is no standard method for diagnosing PD, and ED. All of these metabolic disorders are directly affected by glucose and insulin metabolism. Scientific advancements have made it easier for us to understand inflammation and endocrine pathways, which affect brain functions [17, 18].

A literature search was carried out using the PubMed, MEDLINE, and Mendeley databases. For the database searches, terms related to Mucuna pruriens and/or Diabetes, PD, and ED were used. The following data were evaluated for eligibility in each study: first author’s surname, publication year, country of study, study design, sample size, follow-up duration, characteristics of participants, disease targeted, and major results.

This study considered the following: (1) clinical studies; (2) prospective observational studies conducted with participants at least 18 years of age; (3) prospective observational studies (animal model); (4) studies published in English; (5) studies that included the following end-points: Mucuna pruriens, diabetes, PD, and ED; and (6) a study protocol, case report, comment, letter, editorial, duplicate study, and narrative or systematic review were excluded.

A total of 557 records were found in the initial search, and 453 reports were removed based on the title and abstract, leaving 104 for full-text consideration (Figure 1). Out of 104 reports, 78 reports were excluded for the different reasons outlined in Figure 1, and 26 studies were considered eligible for inclusion. Among these studies, five included clinical trials [19–23], and 21 included studies using animal models [9, 11, 24–42].

The main characteristics of the 26 selected articles are summarized in Table 1 [19–23] and Table 2 [9, 11, 24–42]. Five studies (n = 5) reported PD clinical trials in humans [19–23], thirteen studies reported PD in animal models [24–36], two (n = 2) studies reported diabetes in animal models [9, 37], and six (n = 6) reported ED [11, 38–42]. Diabetes and ED have not been studied in humans. Twenty-six of these studies (n = 26) were published in English in the last twenty years (2002–2022), with the exception of [23]. Human trials have been conducted in Bolivia [19, 20], Italy [21], and the UK [22], while one was multicenter [23]. The majority of animal trials have been conducted in India [27, 30, 31, 37, 39–41], and the USA [26, 32–36]. The remaining studies were carried out in Italy [24, 25, 28], Thailand [11, 38], and Nigeria [8]. There were 13 preclinical trials conducted on animal models of PD, of which (n = 5) were conducted on the Drosophila melanogaster fruit fly model [24–26, 28, 29], (n = 4) on the Sprague-Dawley rat model [33–36], (n = 3) on the Swiss albino rat model [27, 30, 31], and one (n = 1) was conducted on the monkey [32].

The tropical legume Mucuna pruriens is indigenous to Africa and tropical Asia, but has become widely naturalized and cultivated throughout the world. The most common names for these plants are cowage, cowitch, Florida velvet bean, lacuna bean, Lyon bean, Mauritius velvet bean, monkey tamarind, velvet beans, and Yokohama velvet bean [43]. Mucuna pruriens seed extract contains alkaloids, flavonoids, glycosides, saponins, steroids, tannins, terpenoids, and other plant secondary metabolites, as well as other secondary metabolites, which are responsible for its medicinal properties [44] or their health disorders. The use of Mucuna pruriens-based therapeutics as a source of LD medication could have a positive impact on the market. It is widely available in local markets at an affordable price in many countries. It is well tolerated and beneficial for brain function and well-being. There is clinical evidence that it has a positive effect on libido and testosterone levels. It also has a positive effect on ED and diabetes [16]. Researchers can learn how to prevent, treat, and cure human diseases through animal testing in clinical research since humans and animals are biologically similar. The Missouri Medicine Institute reported that rats, mice, and humans all have approximately 30,000 genes in common, approximately 95% of which are shared by all three [45]. This review therefore reviewed clinical and preclinical studies to obtain more accurate results. A major disadvantage of using Drosophila to investigate human diseases is the difference between the brain anatomy of flies and that of humans. However in flies expressing mutant α-synuclein, inclusions of the protein were also found in non dopaminergic neuronal cells, as in human brains affected by PD [46]. It is pertinent to note, however, that mice and rats are not suitable models for humans in many significant areas, for example, in brain function, and reproduction, where human biology is remarkably different from that of rodents [47]. Research on monkeys led to the development of life-changing PD treatments, such as dopaminergic therapies, deep brain stimulation for tremor reduction, and constraint-induced movement therapy. ED is well understood in animal models. While human sexual function cannot be reproduced perfectly, these animal models provide a reproducible paradigm for investigating and evaluating ED. While there is some scientific research investigating the potential benefits of Mucuna pruriens for these conditions, it is important to note that the evidence is limited, and further studies are needed to establish its efficacy.

To determine the link between EDs and PD, researchers conducted a study on 32,616 health professionals from 1986 to 2000. They observed that ED was associated with a higher risk of developing PD [48]. Diabetes inhibits the firing of SN dopaminergic neurons, leading to PD. Insulin receptors are relatively abundant in SN neurons. The toxicity of MPTP, which causes parkinsonism in many patients, has also been linked to mitochondrial dysfunction. A key component of diabetes pathophysiology is mitochondrial dysfunction, a key regulator of glucose-stimulated insulin secretion in pancreatic epithelial cells [49, 50]. Several studies have confirmed that men with EDs are more likely to have diabetes mellitus than men without EDs [51, 52].

In diabetes mellitus, oxidative stress is increased and ROS are produced at an elevated rate, resulting in a cascade of events: reduced NO increased prothrombotic factors including tissue factor, and plasminogen activator inhibitor-1 increased endothelin-1, resulting in thrombosis and vasoconstriction, and increased nuclear factor kappaB and activation protein 1, which leads to ED [52]. Diabetes-related ED is closely associated with adenosine triphosphate (ATP) levels in the mitochondria. Specifically, long-term hyperglycemia impairs the function of smooth muscles in the corpus cavernosum by reducing mitochondrial biogenesis, increasing adenosine diphosphate (ADP)/ATP ratios, altering ultra structural changes, and triggering ROS [53]. It is important to note that the relationship between these conditions is complex. The exact mechanisms linking PD and ED are not fully understood, but several factors may contribute to these findings (Figure 2). Not all people with diabetes or PD experience ED.

Evidence supports the hypothesis that Mucuna pruriens seed extract containing LDs and antioxidants can enhance sperm quality and essential testicular proteins under cesarean section (CS) conditions by enhancing testosterone levels while reducing caspase proteins involved in apoptosis [54, 55]. It improves sperm count, motility and alleviates psychological stress and seminal plasma lipid peroxide levels. Additionally, treatment restored the amount of SOD, catalase, GSH, and ascorbic acid in the seminal plasma of infertile men [56]. In PD, the ethanolic Mucuna pruriens extract improves immunoreactivity and protects dopaminergic neurons from NO injury. It has been shown that the ethanolic extract from Mucuna pruriens seeds naturally restores erectile tissue from oxidative stress, and reduces diabetes-induced sperm damage [16]. As “first-line” drugs for treating ED, PDE inhibitors prevent PDE5 enzymes from neutralizing cGMP in a way that prolongs penile erection. PDE5 inhibitors can cause major side effects, so researchers are investigating natural bioactive compounds that can alleviate and cure ED [57]. The extract of pruriens free of LDs contained catechols and polyphenols, which upregulated the expression of NO-producing genes. This extract improved sexual behavior and prevented diabetes-induced penile tissue deterioration. By inhibiting ROCK-II, Mucuna pruriens relaxes erectile tissue, improving sexual function. ROCK-II is responsible for contracting penile smooth muscle and impairing erections [40]. The PDE5 inhibitory constituents of medicinal plant extracts include alkaloids, phenolics, and polycyclic aromatic hydrocarbons. Isoflavones and biflavones are the major active constituents of isoflavones, and the prenyl groups in isoflavones and the methoxy groups at the C-5 position in flavones are considered essential for their inhibitory action [58]. Mucuna pruriens contains polyphenolic compounds that are pharmacological precursors and contribute to antioxidant activity. Mucuna pruriens has a high phenolic content (3,730.1 ± 15.52 mg gallic acid equivalent/g; flavonoids = 63.03 ± 1.95 mg quercetin equivalent/g), which may be responsible for its antioxidant activity and therapeutic properties [59]. Mucuna pruriens contains isoflavanones, isoflavones, and pterocarpans that inhibit α-glucosidase [60]. There is preliminary evidence that Mucuna pruriens may improve erectile function and sexual desire in men with ED. However, additional well-designated studies are needed to verify the efficacy and safety of these herbs.

Diabetes complications may develop due to the production of ROS in mitochondria by hyperglycemia. AMP-activated protein kinase (AMPK) works through peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) to promote mitochondrial biogenesis. However, the mechanism by which AMPK upregulates PGC-1α activity remains unclear [61]. Blockade of mitochondrial ROS production through the induction of AMPK or PGC-1α could be useful in the design and development of drugs to prevent diabetic complications [62]. Diabetes patients could benefit from Mucuna pruriens because it has an antihyperglycemic effect [63]. However, further research is needed to determine efficacy, optimal dosage, and safety of Mucuna pruriens in humans.

A rich source of LD, a precursor to dopamine in PD, Mucuna pruriens could ease symptomatic symptoms with fewer side effects. In PD, dopamine deficiency results in motor symptoms and Mucuna pruriens may alleviate these symptoms by increasing dopamine levels. Protein aggregation, oxidative stress, excitotoxicity, neuroinflammation, and genetic mutations all contribute to the development of PD [64, 65]. Additional neuroprotective effects of Mucuna pruriens beyond LD supplementation have been suggested [36, 66]. A number of antioxidant compounds as well as bioactive substances may protect neurons from inflammation and oxidative stress. A key mediator of neurodegeneration in PD is synuclein overexpression, inflammation, mitochondrial dysfunction, and apoptosis, which are protected from Mucuna pruriens and its constituent compound, ursolic acid. A recent study revealed that the possible mechanism involved the regulation of glycogen synthase kinase 3β (GSK-3β)/α-synuclein/Ca2⁺ signaling [67]. A recent study indicated that neurons with mutations in glucosylceramidase beta 1 (GBA1) exhibit extended mitochondria-lysosome connections [68]. A recent study demonstrated that seed extract and LD can potentially alleviate neuronal apoptosis by regulating the PI3K/Akt signaling pathway and affecting both forkhead box transcription factor and GSK-3β [69]. These studies support the protective effects of Mucuna pruriens in PD. However, additional clinical trials are necessary to prove its effectiveness.

Various clinical and preclinical studies confirm that Mucuna pruriens powder has similar clinical outcomes to commercial LD/CD powders. However, some patients reported gastrointestinal side effects. Long-term treatment of PD with Mucuna pruriens seed powder is more effective than treatment with conventional LD. Mucuna pruriens has been shown to alleviate PD symptoms by increasing dopamine levels in the brain. There are several antioxidant compounds as well as bioactive compounds in Mucuna pruriens that may prevent inflammation and oxidative stress in neurons. Clinical evidence suggests that Mucuna pruriens enhances libido and testosterone levels. It also reduces blood sugar levels and improves glucose tolerance. The results of numerous clinical trials (human) and preclinical trials (animal) suggest that Mucuna pruriens may be effective at treating ED, PD, and diabetes, although additional clinical evidence is still needed. However, more rigorous clinical trials are needed to establish the efficacy, optimal dosage, and long-term safety of Mucuna pruriens for the treatment of diabetes, ED, and PD.