Mucuna pruriens: A Dietary Supplement with Balancing Properties That Can Limit Neurological Disorders and Associated Depressive States

Abstract

Mucuna pruriens (M. pruriens) is a legume that attracts researchers for its benefits and has been used for centuries in Ayurvedic medicine. While its effectiveness has long been recognized, in-depth studies have shown that its activity is mainly due to its high levodopa (L-Dopa) content, but not exclusively. It also contains other structures that can improve its effectiveness and reduce the side effects encountered when using synthetic L-Dopa. Similarly, other molecules that selectively inhibit certain enzymes are present. Various methods of varying effectiveness have been used to extract the active ingredients, and recently, progress has been made in extraction methods. Clinical studies already exist demonstrating its therapeutic benefits, similar to those of synthetic L-Dopa, for several conditions, and showing the limitations of certain side effects such as dyskinesias. Further studies and clinical trials are still needed, but this plant could be a very good alternative in countries that do not have or no longer have access to certain drugs. This legume can be grown without difficulty in these countries, as it has the advantage of being resistant to drastic climatic conditions.

1. Introduction

In this review, we examine the health benefits of Mucuna pruriens. The genus Mucuna comprises approximately 150 species of climbing plants belonging to the Fabaceae family. M. pruriens is a tropical legume that has been used for centuries in Ayurvedic medicine, particularly for the treatment of neurological disorders such as Parkinson’s disease [1,2,3]. This self-pollinating climbing plant is easy to grow. It also adapts easily to harsh environmental conditions such as poor soil or drought [4]. Its flowers have a purple, butterfly-shaped corolla [5], and its fruits are pods covered with hairs that can sting [6,7]. Each pod contains three to eight brown or even black seeds, rich in bioactive compounds with therapeutic properties (Figure 1).

M. pruriens is also traditionally recommended to help regulate mood. It contains many beneficial molecules such as antioxidants, alkaloids, and amino acids that support the central nervous system (CNS) and overall health. Its beneficial effects on the CNS are likely attributable to a high L-Dopa (L-3,4-dihydroxyphenylalanine) content, a precursor to dopamine, typically ranging from 1.5 to 6%, depending on location and growing conditions [8,9]. Many CNS diseases, psychiatric disorders, and psychoses result from multifactorial psychopathological mechanisms characterized by dysregulation, deficiency, or excess of neurotransmitters such as dopamine (Scheme 1) or serotonin (Scheme 2) [10].

It is best to treat these symptoms together for better management. Dopamine is involved in many biological functions, and its deficiency can lead to cognitive, mood, and behavioral disorders, including decreased motivation that can potentially lead to depression [11]. Dopamine is synthesized in neurons from L-tyrosine in fairly limited areas of the brain, which can predispose some people to local neurotransmitter deficiencies. Tyrosine hydroxylase oxidizes the aromatic ring of L-tyrosine to generate L-Dopa, which is then undergoing decarboxylation to produce dopamine (Scheme 1). L-tyrosine itself is synthesized from phenylalanine, which is oxidized by phenylalanine hydroxylase to L-tyrosine.

Dopamine can also be secreted by the hypothalamus; in this case, it is considered a neurohormone rather than a neurotransmitter. Its involvement in the neurodegenerative Parkinson’s disease stems from its demonstrated role not only in psychiatric disorders but also in motor dysfunction, and from the fact that its deficiency has also been associated with attention-deficit/hyperactivity disorders (ADHD) [12,13,14]. Among psychiatric disorders, schizophrenia is a notable example, as there is currently no definitive treatment. This multifactorial psychiatric disorder, classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM) [15], manifests itself through disabling symptoms such as delusions, hallucinations, and lack of insight [16], associated with disorganized movements that can be violent due to loss of affect [17]. In this case, excessive dopaminergic activity is involved, which can cause certain “positive” symptoms such as hallucinations and delusions. The serotonergic pathway involves 5-HT receptors, particularly 5-HT2C, which are difficult to target selectively. However, specific modulation of this receptor could reduce involuntary movements or hyperactivity [18]. Given the prevalence and severity of psychiatric disorders, any therapeutic pathway that improves symptoms through selective action on receptors should be studied in depth.

Today, neurotransmitters are generally the main targets of pharmacological treatments. Psychotic disorders affect between 0.5 and 2% of the general population, with schizophrenia alone accounting for 1%. This condition exerts a major socioeconomic impact and requires ongoing medical supervision to mitigate the serious disruptions it can cause, both for patients and for their families during violent episodes [19]. The etiology of psychiatric disorders reflects genetic factors, biochemical disturbances, and influences. The role of increasing psychotropic substances use in the onset or worsening of symptoms remains unclear, although it has been proven [20,21,22]. Cannabis is the most commonly used substance among young people and socially vulnerable groups due to its accessibility. However, cocaine may also be used and cause the same effects. The growing use of these substances and their deleterious effects on mental health, particularly their role in triggering schizophrenia, as in our previous example, are now well established [23]. The release of dopamine during the use of various psychotropic drugs leads to dependence and addiction. Conversely, maintaining a moderate but constant level of dopamine may help mitigate the growing prevalence of depression, loss of motivation, or dependence. This highlights the potential value of M. pruriens as a natural source of L-Dopamine, which could limit psychiatric or neurodegenerative diseases.

Given its high L-Dopa content and associated benefits, increased dietary consumption of M. pruriens could be a natural complementary approach for people suffering from insufficient dopamine production. Rather than relying exclusively on pharmacological administration of levodopa (a dopamine precursor), to patients with Parkinson’s disease, incorporating moderate amounts of this legume into the diet could offer an alternative strategy. Indeed, current recommendations already encouraged the consumption of nuts (e.g., almonds, walnuts), bananas, and other fruits and vegetables rich in L-tyrosine, which promote dopamine synthesis in the brain. It is therefore important to document the biological results associated with M. pruriens, whether they are attributable to its high L-Dopa content or to other compounds present that could explain its long history of effective traditional use [24,25]. In addition to L-Dopa, this plant contains quercetin, nicotine, oxitriptan, N,N-dimethyltryptamine (N,N-DMT), serotonin (5-hydroxytryptamine), and bufotenin or 5-hydroxy-N,N-dimethyltryptamine (5-OH-DMT) (Figure 2), as well as numerous alkaloids, all of which may have interesting effects on the human central nervous system [26,27].

Extracts from the leaves of M. pruriens have been relatively less studied, but they contain heterocyclic compounds with potential antioxidant and cytotoxic activities [28,29]. These include ferulic acid, which is also present in various citrus fruits and is known for its antioxidant proprieties [30], as well as 2-(5-methoxy-1-benzofuran-3-yl)-N-ethylthanamine and stizolamine (Figure 3) [31].

There is an urgent and pressing need to develop effective solutions for treating psychiatric disorders, addictions, and attention disorders involving these neurotransmitters, which are becoming increasingly common among younger generations. It should be noted that M. pruriens seed powder is already commercially available in capsule form as a dietary supplement.

2. Discussion

As mentioned in the introduction, M. pruriens is frequently recommended in Ayurvedic medicine to relieve stress and apathetic depressive states, as well as to treat anemia and certain infections. It is mainly used in the form of a standardized plant extract (SPE). This legume produces seeds enclosed in pods, and these seeds are the focus of phototherapy research. They have additional properties that demonstrate their therapeutic value. As recently reported by L. Navaro et al. [32], these properties include antioxidant [33], antimicrobial [34], anti-inflammatory activities [35], which may be related to the plant’s primary antidepressant effect. Antitumor activities have also been reported [36]. In the following sections, we review the main uses of M. pruriens (also called purple bean) and its potential applications.

2.1. M. pruriens Has Great Potential in Animal Feed

Sandoval-Castro et al. [37] analyzed the chemical composition of M. pruriens, focusing on seed proteins and their digestibility. The seeds were soaked in water with or without added sodium bicarbonate for varying lengths of time, then cooked in a pressure cooker. Digestibility was improved in all cases, in vitro. It should be noted that in M. pruriens, L-Dopa is found mainly inside the seed, in the cotyledons, and since it is water-soluble, it is partially eliminated during soaking and heat treatment (boiling or autoclaving) [38]. In the same year, G. Shanmugavel and G. Krishnamoorthy [39] studied the nutritional and phytochemical profile of uncooked M. pruriens seeds. M. pruriens seed flour has a high energy value, high carbohydrate content, and contains classes of therapeutically relevant compounds, including alkaloids, flavonoids, polyphenols, saponins, steroids, terpenoids, and L-Dopa [26,27,40]. Fourier Transform Infrared (FTIR) and Gas Chromatography coupled with Mass Spectrometry (GCMS) analysis revealed the presence of several groups and putative constituents, although individual compounds were not isolated. P. Kwankhao et al. [27] quantified L-Dopa in an aqueous extract of M. pruriens seeds using high-performance liquid chromatography (HPLC). For this analysis, 10 kg of M. pruriens seeds were roasted for 30 min at 180 °C, ground into flour, and mixed with water at 100 °C. The filtrate obtained after extraction was then lyophilized. Quantification by HPLC revealed that L-Dopa was present at 7.05 +/− 0.02% in the lyophilized aqueous extract, while the levels of phenolic derivatives and flavonoids were considerably lower. Given that prolonged use of synthetic L-dopa can cause serious side effects, such as dyskinesia, it is essential to determine whether natural sources have similar drawbacks. In this study, aqueous extracts of M. pruriens seeds demonstrated significant neuroprotective properties at concentrations as low as 10 ng/mL. This brings us to the therapeutic interest for which the molecules contained in M. pruriens are being researched. It is also in this context that M. pruriens is being tested to understand its supposed action in depressive disorders and other degenerative diseases. S. Nishad et al. [3] compiled natural compounds derived from plants and reported that treatment with M. pruriens improved Parkinson’s symptoms in monkeys, which is consistent with its traditional use in Ayurvedic for this disease.

2.2. Neuropsychiatric Potential Uses

2.2.1. Dopamine Receptors and Their Molecular Targets

Experimentally, it has been demonstrated that extracts of M. pruriens modulate the dopaminergic, serotonergic, and noradrenergic systems and can activate mechanisms that do not induce dyskinesias [41]. Furthermore, treatment with M. pruriens reduced the neuroinflammation pathway, and NF-kB mediated neurotoxicity was reduced in murine models of the disease [42,43]. Dopamine binds to five G protein coupled receptors (D1–D5), each characterized by seven transmembrane domains. These receptors subtypes are differentially expressed in tissues and brain regions, and their activation or inhibition modulates intracellular signaling cascades [44]. Within the central nervous system, dopaminergic receptors are involved in motor control, learning, memory, and reward mechanisms underlying addictive behaviors. Outside the CNS, they contribute to the regulation of renal and cardiovascular functions [45]. In vitro studies have shown that this compound exhibits catechol-O-methyltransferase (COMT) inhibitory activity similar to that obtained with tolcapone, a commercially available COMT inhibitor (Figure 4) [46]. COMT converts dopamine to 3-methoxytyramine (3-MT). The compound showed negligible effects on amino acid decarboxylase (AADC), which, as already mentioned, converts L-Dopa to dopamine and monoamine oxidase B (MAO-B), which oxidizes the amine function of dopamine to aldehyde. Similarly, it showed minimal agonist activity at dopamine receptors (D1 and D2L), confirming its selectivity as a COMT inhibitor. An in vivo evaluation in two animal models (the C. elegans model and rat model) confirmed its effectiveness in inhibiting COMT binding to dopaminergic receptors. It is important to note that this tetrahydroisoquinoline does not appear to cross the blood–brain barrier and acts solely as a peripheral COMT inhibitor. These results highlight the potential of M. pruriens as a valuable source of bioactive compounds for Parkinson’s disease and other neurological disorders.

It has been established that the dopaminergic system regulates a wide range of biological processes and that its dysfunction can lead to numerous pathologies whose prevalence is constantly increasing, such as neurodegenerative diseases like Parkinson or Alzheimer [47]. Current treatments do not cure neurodegenerative diseases; they mainly compensate for dopaminergic deficits and improve patients’ quality of life. Current therapeutic strategies for Parkinson’s disease remain largely limited to compensating for dopamine deficits, either through the administration of levodopa or by stimulating dopaminergic receptors. This highlights the importance of continuing in-depth study of the plant M. pruriens. S.B. Zaigham and D.-G Paeng [48] studied the effect of M. pruriens in vivo compared to synthetic L-Dopa in a model using male C57BL/6 mice exposed to rotenone (Figure 5). The protocol consisted of a daily intraperitoneal injection of rotenone (30 mg/kg body weight) for 28 days. Rotenone, which readily crosses the blood–brain barrier, is known to increase oxidative stress and neuroinflammation. In this study, twelve mice were used to evaluate the therapeutic effects of M. pruriens by measuring changes in neuroinflammatory cytokines. The selected serum biomarkers included IL-6, TGF-β1, and IL-12p40, which represent both pro-inflammatory and anti-inflammatory mediators. The results indicated that M. pruriens appeared to alleviate certain disease-related disorders in this model, significantly reducing levels of IL-6, IL-12p40, and TGF-β1 cytokines. In addition, M. pruriens improved disease symptoms by activating dopaminergic neurons, which is consistent with its high L-Dopa content. It should be noted that the improvements observed in mice treated with M. pruriens or synthetic L-Dopa confirm the therapeutic efficacy of this plant. These results are consistent with other previous findings [49].

Determining the bioavailability of L-Dopa contained in M. pruriens depending on the type of consumption and exploring potential synergies with other compounds present in smaller quantities remains to be studied. Further studies are needed to assess whether incorporating it into the diet or taking it as a dietary supplement could prevent, or at least slow down, the onset of these neurodegenerative conditions, thereby enabling future patients to live longer and healthier lives. Unlike dopamine, L-Dopa is able to cross the blood–brain barrier, which is currently essential for the treatment of Parkinson’s disease as a prodrug. However, many factors need to be studied, as it has been shown that the effectiveness of dopaminergic treatment decreases over time, leading to a form of dependence. Moreover, harmful side effects such as hypotension, motor disorders, and hallucinations may occur. Further, Vimolmangkang et al. [50] attempted to optimize the extraction process in order to improve the stability of the extraction. To do this, they adjusted the acidification conditions and used fruit juice as a solvent to mimic stomach acidity. Previous work had already shown that citric acid in an aqueous solution increased the efficiency of L-Dopa extraction from M. pruriens seeds [51]. On this basis, Vimolmangkang et al. [50] demonstrated that juice or water from Phyllanthus emblica (Amla) significantly improved L-Dopa preservation compared to conventional solvents. The fruit P. emblica or Amla, rich in vitamin C, and other natural acids, has therefore been considered a promising source of natural acidified water for the M. pruriens seeds extraction. In addition, some constituents, particularly gallic acid and ascorbic acid, may help limit oxidative stress in the CNS, offering potential benefits for Parkinson’s and Alzheimer’s diseases. The phenolic compounds present in M. pruriens have similar protective effects. Consequently, M. pruriens seed extraction was therefore carried out in P. emblica juice (acidic water) and compared with conventional acidic solvents. Quantification of L-Dopa by HPLC revealed that extraction with 2% Amla juice was as effective as with a 2% hydrochloric acid solution. However, contact with ascorbic acid during heating can ultimately degrade L-Dopa, while conditioning and storage at low temperatures allow for its preservation [52]. In 2022, A Maciuk et al. [53] identified a tetrahydroisoquinoline in M. pruriens and subsequently synthesized it to evaluate its pharmacological profile, both in vitro and in vivo. The compound (1R,3S)-6,7-dihydroxy-1-methyl-1,2,3,4-tetrahydroisoquinoline-1,3-dicarboxylic acid is extracted from M. pruriens powder using a water-ethanol mixture and purified by reverse-phase silica gel chromatography. It was also easily synthesized L-Dopa, pyruvic acid, and trifluoroacetic acid at 70 °C (Schema 3), yielding a mixture of diastereoisomers in a 2:1 ratio. Recrystallization of this mixture in isopropanol allowed the isolation of mainly the cis isomer in 28% yield and a diastereomeric purity of 94:6 (Scheme 3).

2.2.2. Neuropsychiatric and Antidepressant Effects in Parkinson’s Disease

Avoiding states of confusion is particularly important in pathologies such as schizophrenia [54]. The peaks in plasma concentration observed after levodopa administration are often responsible for adverse effects. This raises the question of the consequences of L-Dopamine absorption when M. pruriens is consumed either as food dietary supplements or as extracts. A hydroalcoholic extract of M. pruriens was compared with imipramine (a tricyclic antidepressant, Figure 6) to evaluate its antidepressant effect on rats [55]. Imipramine acts by inhibiting the reuptake of norepinephrine and serotonin, thereby promoting synaptic transmission. The rats received high oral doses of M. pruriens extracts (100 and 200 mg/kg). After one week of treatment, immobility, considered a marker of depressive behavior in the forced swim test, was reduced by half compared to the control group demonstrating greater efficacy of imipramine (10 mg/kg). Additional tests confirmed that M. pruriens interacts with the dopaminergic system, particularly with D2 receptors.

This dietary supplement may be an attractive alternative for patients who cannot afford or do not have access to conventional medications prescribed to treat Parkinson’s disease. In 2017, a clinical study was conducted in patients with advanced stages of the disease to evaluate the effect of M. pruriens at different concentrations (high dose of 17.5 mg/kg and low dose of 12.5 mg/kg) compared to levodopa, which is usually prescribed in combination with a dopa decarboxylase inhibitor (DDCI) and with a placebo [56]. In this study, benserazide was used as the DDCI, which significantly improves dopamine levels [57]. However, the authors suggested that M. pruriens extracts may inherently contain a DDCI-like activity, since no additional inhibitor was required [58,59]. At higher doses, M. pruriens improved motor strength and reduced potential dyskinesias, while adverse effects were less pronounced than with standard levodopa, supporting its therapeutic potential in Parkinson’s disease [60]. The reduction in dyskinesias and its rapid absorption of M. pruriens favors its long-term use. Conversely, T. W. Pangestningsih et al. [61] reported that an extract of seeds boiled and fermented in n-propanol had a greater neuroprotective effect in Parkinson rats than fresh seeds. This finding contrasts with other results indicating that heat partially destroys L-Dopa and therefore reduces its content. Others clinical research have shown that, in the treatment of Parkinson’s disease, M. pruriens extracts generate fewer side effects than synthetic L-Dopa [62,63,64]. This may be explained by the presence of additional compounds in M. pruriens that exert beneficial effects on the central nervous system [65]. However, these extracts are prone to degradation [66,67]. In addition to visible changes in their appearance; a decrease in L-Dopa content has been observed. Therefore, extraction, purification and formulation must be optimized to preserve bioactive compounds. J. Novak et al. [68] developed an effective and gentle method for extracting L-Dopa. In contrast, methods involving prolonged extraction times at high temperatures should be avoided, as thermal procedure promotes oxidation [67]. Another approach involved ultrasonic extraction in the presence of acid, but this method required heating which is not optimal. Instead, J. Novak et al. [68] performed a double extraction of M. pruriens seeds at room temperature, using 0.2% acetic acid added to the extraction solvent. The protocol employed 25 mL of solvent per gram of dry seeds with two successive cycles of 20 min each. Depending on the seed origin, yields ranged from 3.6 to 9.1 g of L-Dopa per 100 g of dry seeds.

2.2.3. Post-Traumatic Depression

The recent work of L. Navarro et al. [69] highlights the benefits of M. pruriens in the treatment of central nervous system disorders and its potential to mitigate the effects of mild traumatic brain injury (mTBI). This type of injury is the most common form of head trauma, yet no specific treatment currently exists, although serotonin reuptake inhibitors are frequently prescribed [70,71,72,73,74,75]. Beyond its well-established role in relieving certain symptoms of Parkinson’s disease [76,77], M. pruriens may offer additional neuroprotective benefits. The onset of post-traumatic depression is thought to be linked to oxidative stress resulting from an imbalance between the production of reactive oxygen species (ROS) and the availability of antioxidants [78]. In this context, researchers investigated whether short-term administration of M. pruriens extracts after head trauma could prevent neurobehavioral and depressive disorders in a mouse model. Given the antioxidant and anti-inflammatory proprieties of M. pruriens [79], its administration could play a role in modulating oxidative stress. To investigate this, the authors measured lipid peroxidation levels in the brains of male Wistar rats. The ability of M. pruriens to prevent oxidative stress through the activation of antioxidant enzymes in the brain has already been mentioned in the literature on various animal models [80,81], as has its anti-inflammatory activity [82]. L. Navarro et al. [69] showed that administration of lyophilized M. pruriens extracts limited the onset of post-traumatic depression-related phenomena in rats with mild head trauma. This effect was associated with reduced production of ROS, which following trauma, can trigger extensive neuronal death and functional disorders [83,84]. Antidepressant effects were observed at a dose of 50 mg/kg of lyophilized M. pruriens extract via a decrease in lipid peroxidation in the midbrain. These finding represent an important starting point but further investigations, particularly clinical studies, are require to confirm the reported benefits of M. pruriens in Parkinson’s disease and also in depression resulting from various causes.

These CNS disorders, which can lead to various forms of addiction, particularly to psychotropic drugs, could therefore benefit from a natural solution capable of alleviating depressive states. These states are often involved in the onset of addictions, leading to vicious circles that are difficult to break out of.

2.2.4. Antiobesity Potential Properties

Depression is a multifactorial condition that can contribute to the development of comorbid disorders for which this plant could offer therapeutic potential. In 2020, J.S. Aquino et al. [35] evaluated the efficacy of M. pruriens in combating obesity, a condition closely linked to chronic systemic inflammation [85,86]. Since obesity predisposes individuals to numerous comorbidities, identifying natural therapeutic approaches that limit side effects is of particular importance [87]. Obesity is often linked to addictive behaviors and depressive states that alter neuroendocrine activity and metabolism [88,89]. This pioneering study on the use of M. pruriens against obesity was conducted in male Wistar rats divided into two groups: obese rats maintained on a high-fat diet and healthy rats fed a standard diet. A relatively high dose of M. pruriens (750 mg/kg body weight) was administrated. The treatment produced satietogenic effects and weight reduction, probably due to its anxiolytic and antidepressant properties, which limited food consumption. Moreover, the reduction in body mass was accompanied by a decrease in brain inflammation through downregulation of interleukin 6 (IL6), a pro-inflammatory cytokine, thereby attenuating neuroinflammation [90]. M. pruriens, through its anti-inflammatory proprieties combined with its activity on the dopaminergic pathway, may exert an antiobesity effect. In treated rats, both thoracic and abdominal circumferences decreased, a particularly relevant finding given that visceral adipose tissue is major contributor to the development of metabolic disorders [91].

3. Conclusions

The results obtained on this legume indicate that it is very effective in limiting the symptoms of certain diseases, such as Parkinson, but that it should be avoided in cases of schizophrenia as a precaution, as it can trigger delusions and hallucinations, thereby exerting harmful effect. Medical advances in recent decades have contributed to an increase in healthy life expectancy, but the curve is beginning to flatten and even decline. This is partly due to the gradual reduction in the diversity of our food resources and the decline in physical activity. It is therefore necessary to systematically evaluate the benefits and drawbacks for both human and animal health of edible terrestrial and marine plant and animal species. Ultimately, various diets could be recommended in medical circles to limit drug doses by taking advantage of potential synergistic effects. Compiling all the scientific data already available would be a considerable task, but could lead to medically prescribed diets tailored to specific disease.