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Review on a Traditional Herbal Medicine, Eurycoma longifolia Jack (Tongkat Ali): Its Traditional Uses, Chemistry, Evidence-Based Pharmacology and Toxicology
Eurycoma longifolia Jack (known as tongkat ali), a popular traditional herbal medicine, is a flowering plant of the family Simaroubaceae, native to Indonesia, Malaysia, Vietnam and also Cambodia, Myanmar, Laos and Thailand. E. longifolia , is one of the well-known folk medicines for aphrodisiac effects as well as intermittent fever (malaria) in Asia. Decoctions of E. longifolia leaves are used for washing itches, while its fruits are used in curing dysentery. Its bark is mostly used as a vermifuge, while the taproots are used to treat high blood pressure, and the root bark is used for the treatment of diarrhea and fever. Mostly, the roots extract of E. longifolia are used as folk medicine for sexual dysfunction, aging, malaria, cancer, diabetes, anxiety, aches, constipation, exercise recovery, fever, increased energy, increased strength, leukemia, osteoporosis, stress, syphilis and glandular swelling. The roots are also used as an aphrodisiac, antibiotic, appetite stimulant and health supplement. The plant is reported to be rich in various classes of bioactive compounds such as quassinoids, canthin-6-one alkaloids, β-carboline alkaloids, triterpene tirucallane type, squalene derivatives and biphenyl neolignan, eurycolactone, laurycolactone, and eurycomalactone, and bioactive steroids. Among these phytoconstituents, quassinoids account for a major portion of the E . longifolia root phytochemicals. An acute toxicity study has found that the oral Lethal Dose 50 (LD 50 ) of the alcoholic extract of E. longifolia in mice is between 1500–2000 mg/kg, while the oral LD 50 of the aqueous extract form is more than 3000 mg/kg. Liver and renal function tests showed no adverse changes at normal daily dose and chronic use of E. longifolia . Based on established literature on health benefits of E. longifolia , it is important to focus attention on its more active constituents and the constituents’ identification, determination, further development and most importantly, the standardization. Besides the available data, more evidence is required regarding its therapeutic efficacy and safety, so it can be considered a rich herbal source of new drug candidates. It is very important to conserve this valuable medicinal plant for the health benefit of future generations.
1.1. traditional, complementary/alternative and herbal medicine, 1.1.1. traditional medicine.
This is also well known as indigenous or folk medicine. According to the World Health Organization (WHO), traditional medicine is defined as “the sum total of the knowledge, skills, and practices based on the theories, beliefs, and experiences indigenous to different cultures, whether explicable or not, used in the maintenance of health as well as in the prevention, diagnosis, improvement or treatment of physical and mental illness” [ 1 ].
1.1.2. Complementary/Alternative Medicine
The terms “complementary medicine” and/or “alternative medicine” (and sometimes also “non-conventional”) are used interchangeably with “traditional medicine” in some countries. Complementary/alternative medicine refers to a broad set of health care and health-related practices that are not part of that specific country's own tradition, and are not considered the dominant health care system [ 2 ].
1.1.3. Herbal Medicine
According to the WHO, it includes herbs, herbal preparations, herbal materials, and all finished herbal products, that contain plants, other plant materials, or combinations, as an active ingredient [ 2 ].
1.1.4. Traditional Use of Herbal Medicines
This refers to the long historic or traditional use of herbal based medicines. The uses of these medicines are well-established and widely acknowledged their safety and efficacy, as well as accepted by national health authorities [ 2 ]. Traditionally employed, indigenous herbal or herb-derived medicines have been very popular from time immemorial; and today, these medicines have commanded much attention worldwide, due to their natural origin and nutraceutical potential [ 2 , 3 ]. The World Health Organization has estimated that 80% of people worldwide rely on herbal medicines for some part of their primary health care needs [ 4 ]. When adopted outside of its traditional culture, traditional medicine is often called complementary and alternative medicine [ 1 ].
Worldwide, many traditional medicine systems (TMS) are used, including Chinese Traditional Medicine, Indian Ayurvedic Medicine, and the popular Unani Medicine of Arab cultures. Many other indigenous traditional medicine systems have also been developed in past history by African, Asian, Arabic, Pacific, American, and also some other cultures. The theory and application of these traditional medicine systems, differ significantly from those of well-developed allopathic medicines [ 3 ]. Today, the increasing demands of use of traditional herbal therapies, more likely based on the good past experiences of the effectiveness as well as safety of these herbal medicines, still require positive research evidence, so recent developments in the biological and analytical sciences, along with innovations in proteomics and genomics surely can play a dominant role in the validation of traditionally based herbal medicines, to further improve their quality, safety and efficacy with clinic-based evidence [ 5 , 6 ].
1.2. Eurycoma longifolia Jack—A Promising Herbal Medicine
This is a well justified fact that the traditional medicines as well as complementary and alternative medicines have the well-established role in our health. E. longifolia Jack (Tongkat Ali) is one of the most well-known herbal folk medicines in Southeast Asia. Its roots are traditionally used for many disorders and diseases, in many countries Asia. Besides this, recently E. longifolia has contributed good role as a complementary and alternative medicine in herbal therapies, in the West.
Tongkat Ali, Ali’s Umbrella or Malaysia ginseng (Malaysia), Pasak Bumi or Bedara Pahit (Indonesia), Ian-don (Thailand), and Cay ba benh (Vietnam), tho nan (Laotian).
Indigenous to South-East Asian countries like Malaysia, Indonesia, and Vietnam, some of the plant species are also found in certain patches in regions of Cambodia, Myanmar, Laos and in Thailand [ 5 , 7 , 8 , 9 , 10 , 11 ]. It is planted mainly in Malaysia for its medicinal value in order to conserve the wild plants [ 12 , 13 , 14 , 15 ].
Besides Eurycoma longifolia Jack, there are three other plant species also known locally as Tongkat Ali, which literally means “Ali’s walking stick,” which refers to its aphrodisiac property. Some authors claim it gets its name “stick” from the long twisted roots that are harvested for their medicinal value. The three plant species are Entomophthora apiculata, Polyathia bullata, and Goniothalamus sp. [ 16 ].
“Malaysian ginseng” as it is known in Malaysia, is also regarded as an adaptogen [ 17 ], an herb or herbal compound that assists in combating stress and disease and improves physical strength without adverse effects.
E. longifolia is a tall, slender, shrubby tree, which grows in sandy soil. It belongs to the Simaroubaceae family. It has compound leaves on branches that can grow up to 1 m long. The leaves are pinnate in shape and green in colour. The numerous leaflets are opposite or subopposite, lanceolate to ovate-lanceolate, 5–20 cm by 1.5–6 cm, with smooth margins. Flowers are tiny, reddish, unisexual and are densely arranged. The drupes are ovoid with a distinct ridge, 1–2 cm by 0.5–1.2 cm and they turn dark reddish brown when ripe [ 18 , 19 , 20 ].
1.3. Genetic Diversity
The genetic diversity of E. longifolia is decreasing due to widespread harvesting; thus, single nucleotide polymorphisms have been used to study the remaining diversity [ 21 ], and microsatellite markers have been studied as tools for DNA profiling and genetic diversity studies [ 22 ]. Razi et al. , showed that in an uncontrolled cultivated area, the E. longifolia samples could be characterized based on their cultivar’s origins. They proved that identification of E. longifolia from various cultivars can be obtained using PCR-RAPD, with the help of some analytical software. The method yielded high quality and quantity of DNA. Six random primers (OPA-3, OPA-4, OPA-13, OPA-18, OPC-5 and OPC-6) were found to give good amplifications of E. longifolia DNA samples [ 23 ]. Some scientists are interested in the in vitro production of the E. longifolia plantlets or plant tissues for sustainable production of active ingredients [ 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. Ling et al. developed a protocol to optimize protoplast isolation from callus of E. longifolia [ 32 ]. Most recently, Lulu et al. , optimized the conditions for the production of adventitious roots from E. longifolia , in balloon-type bubble bioreactor cultures, suitable for the large-scale commercial production of its roots containing high yield of bioactive compounds [ 33 ].
2. Historical or Traditional Uses
E. longifolia is used to cure lumbago and indigestion. It is used as a power tonic after delivery, and use for treatment of fever, jaundice, cachexia, and dropsy [ 12 , 34 ]. E. longifolia is one of the most popular folk medicines for its aphrodisiac effects and treatment of intermittent fever (malaria) [ 35 ]. Decoctions of E. longifolia leaves are used for washing itches, while its fruits are used in curing dysentery [ 12 ]. Its bark is mostly used as a vermifuge [ 12 ], while the taproots are used to treat high blood pressure, and the root bark is used for the treatment of diarrhea and fever [ 36 ]. Mostly the roots extract of E. longifolia are used as folk medicine for sexual dysfunction, aging, malaria, cancer, diabetes, anxiety, aches, constipation, exercise recovery, fever, increased energy, increased strength, leukemia, osteoporosis, stress, syphilis and glandular swelling, as well as it is used as an aphrodisiac, antibiotic, appetite stimulant and health supplement [ 36 , 37 , 38 , 39 , 40 , 41 , 42 ].
Traditionally, the water decoction of E. longifolia root is consumed. Nowadays, more convenient formulas are available, primarily additives mixed with teas and coffees, and over 200 products are available either in the form of raw crude root powder or as capsules mixed with other herbs in the health-food market [ 7 ]. Due to the many traditional and scientific benefits, there has been a demand for E. longifolia products with over 200 E. longifolia products registered with the National Pharmaceutical Control Bureau of Malaysia (NPCB, 2016). It is now currently sold as a Traditional Herbal Medicine in Malaysia. Approximately 21,000 kg of E. longifolia are harvested by collectors per year, with a demand of approximately >54,000 kg per year.
3. Chemical Constituents
The wide spectrum of pharmacological effects was closely associated with various biologically active compounds of E. longifolia roots, stem, leaves and even bark. Kuo et al. , reported the isolation of sixty five phenolic compounds from the E. longifolia root [ 36 ]. E. longifolia is a rich source of various classes of bioactive compounds, which includes quassinoids, β-carboline alkaloids, canthin-6-one alkaloids, triterpene-type tirucallane, squalene derivatives, and eurycolactone, eurycomalactone, laurycolactone, biphenyl neolignan and bioactive steroids [ 7 , 36 , 42 , 43 , 44 , 45 ]. Among these, bitter tasting quassinoid phytoconstituents account for a major portion in the E . longifolia root contents. The quassinoids are a group of nortriterpenoids with dynamic pharmacological properties [ 40 ]. Quassinoids, are even effective at inhibiting cell growth in nanomolar and subnanomolar concentrations [ 41 ]. The presence of tirucallane and squalene-type triterpenes might be the quassinoids’ biological precursors. β-Carboline and Canthin-6-one alkaloids formed as metabolic by-products are natural amine compounds that repel herbivores and insects [ 46 ]. The metabolite type and concentration in E . longifolia plant extracts, depend on the processing temperature as well as geographical factors. For standardization, it is crucial to ensure the consistency of the chemical bioactive components, particularly for the efficacy of herbal medicines [ 47 ]. Summarized here are some major constituents of E . longifolia with their secondary metabolites:
Quassinoids, including various types of eurycomanone (pasakbumin-A), eurycomanols, pasakbumin-B, hydroxyklaineanones, eurycomalactones, eurycomadilactones, eurylactones, laurycolactones, longilactones, and hydroxyglaucarubol have been isolated from the roots of E. longifolia [ 38 , 39 , 48 , 49 , 50 , 51 , 52 ].
The squalene derivatives include teurilene, eurylene; 14-deacetyleurylene; and longilene peroxide [ 53 , 54 ].
The biphenyl neolignans class includes; 2-hydroxy-3,2,6-trimethoxy-4-(2,3-epoxy-1-hydroxypropyl)-5-(3-hydroxy-1-propenyl)-biphenyl; two isomeric 2,2-dimethoxy-4-(3-hydroxy-1-propenyl)-4-(1,2,3-trihydroxypropyl) diphenyl ethers; and 2-hydroxy-3,2-dimethoxy-4-(2,3-epoxy-1-hydroxypropyl)-5-(3-hydroxy-1-propenyl)biphenyl [ 55 ].
Alkaloids included 5,9-dimethoxycanthin-6-one; 9,10-dimethoxycanthin-6-one, 11-hydroxy-10-methoxycanthin-6-one; 10-hydroxy-9-methoxycanthin-6-one; and 9-methoxy-3-methylcanthin-5,6-dione [ 45 , 56 , 57 ].
Major isolated chemical constituents with metabolites from E. longifolia Jack and their pharmacological effects, are listed in Table 1 , while their chemical structures are presented in Figure 1 .
Chemical structures of various biological active constituents from E. longifolia; ( A ) 7-Methoxy-beta-carboline-1-propionic acid (C15); ( B ) 9-methoxycanthin-6-one (C15); ( C ) Laurycolactone (C17); ( D ) Eurycolactone B (C18); ( E ) Eurycomalide A (C19); ( F ) Eurylactone (C19); ( G ) Longilactone (C19); ( H ) Eurycomalactone (C19); ( I ) Eurycomanone (C20); ( J ) Eurycomanol (C20); ( K ) Pasakbumin B (C20); ( L ) Hydroxyklaineanone (C20); ( M ) Biphenyl-neolignan (C21); ( N ) Quassin (C22, basic ring of quassinoids); ( O ) Niloticin (C30); and ( P ) Eurylene (C34).
Major isolated chemical constituents with metabolites from Eurycoma longifolia Jack and their pharmacological effects.
Note: ENR = Evidence Not Reported (much of the available evidence about the pharmacological effects of Eurycoma Longifolia , is related to its extracts (mixtures), so these effects cannot be correlated with specific chemical constituents or groups).
4. Analytical Methods
Besides the major constituents, secondary metabolites are usually present in a small amount. That’s why, high sensitivity and high mass accuracy is required to produce reliable data. Mostly, data from IR, UV, MS and X-ray analysis was evaluated further for 1 H- and 13 C-NMR spectral analysis. These procedures for identification of unknown entity, require high purity as well as high concentration of extracted compounds.
Today, mass spectrometry is the most specific and versatile method of detection in liquid chromatography, especially perfect for the analysis of some multiple components pharmaceutical and herbal products [ 93 , 94 ]. Liquid chromatography with mass spectrometry (LC-MS) is recognized as a most suitable and powerful tool for identification as well as quantification of various herbal product and their constituents [ 95 , 96 , 97 ]. From the plant kingdom, quassinoids are bitter constituents found exclusively in various species of the Simarouboidaea (a subfamily of the Simaroubaceae) and are biogenetically degraded triterpenes displaying a wide range of physiological properties in vitro and/or in vivo [ 98 , 99 ]. Numerous research reports are available on liquid chromatography methods for the analysis of quassinoid E. longifolia bio-constituents, using photodiode array or fluorescence and UV detection. However, none of these methods are sensitive enough to detect nonchromophoric bioactive constituents, such as eurycomanol present in E. longifolia [ 57 , 58 , 100 ], so mass spectrometry is the best option for analysis of all constituents and secondary metabolites from E. longifolia . Chua et al. , used a number of three liquid chromatography mass spectrometry hybrid systems (QTof, QTrap and TripleTof), to scan for small metabolites and also to detect the targeted metabolites, such as alkaloids, quassinoids, triterpene and biphenylneolignans from E. longifolia extracts [ 47 ]. Teh et al. , developed and optimized a LC-MS method using ESI in a positive ion mode for bioactive compounds simultaneous determination, from E. longifolia [ 101 ]. Recently, liquid chromatography-tandem mass spectrometry method for the simultaneous determination of six major quassinoids of E. longifolia i.e. , eurycomanone, 13α(21)-epoxyeurycomanone, 13,21-dihydroeurycomanone, 14,15β-dihydroxy-klaineanone, longilactone and eurycomalactone was developed. By using a LC-MS method, the content of these quassinoids was measured in in dietary supplement tablets and capsules, to confirm the purity of E. longifolia in commercial products [ 102 ]. For quick screening of sildenafil analogues in E. longifolia products, a two-tier screening method using a near infrared (NIR) spectral database was developed. This method has allowed rapid screening on the test samples to verify their content as labelled despite not having the spectra of those products in the database. It could be used for product identification, drug screening for mixed adulteration as well as drug quality surveillance, particularly in cases where reference samples are difficult to obtain [ 103 ].
5. Evidenced-Based Pharmacology
5.1. male fertility enhancement effect.
Infertility is a major clinical problem, which affects the people medically, economically and psychosocially. Almost, 15% of all couples in the U.S. are infertile, and it is predicted that the male factor is responsible in many of such cases [ 104 ]. Male infertility refers to a male’s inability to achieve a pregnancy in a fertile female. In humans, this accounts for 40%–50% of infertility cases [ 105 , 106 ]. Infertility in males is a multifactorial disease, based on numerous factors including reduced spermatogenesis and also production of dysfunctional sperm, which are the major prevalent underlying characteristic in idiopathic male infertility cases [ 107 , 108 ]. One meta-analysis of sixty-one studies worldwide reported s downward trend in the sperm count and semen volume over the past fifty years [ 109 , 110 ].
Mostly, the water-soluble E. longifolia extracts were reported to be able to enhance male fertility (with regards to higher semen volumes, spermatozoa count, and motility) in rodents [ 111 , 112 ] and in human trials [ 86 , 113 , 114 ].
The standardized extract F2 of E. longifolia (25mg/kg p.o ) and its major quassinoids, especially eurycomanone (250 mg/kg p.o ) improved rat spermatogenesis by affecting the hypothalamic-pituitary-gonadal axis and the potential efficacy may be worthy of further investigation [ 111 ].
Eurycomanone, the major quassinoid in the E. longifolia root extract, significantly increased testosterone production on a dose-dependent manner at 0.1, 1.0 and 10.0 μM ( p < 0.05). It enhanced testosterone steroidogenesis at the rat testicular Leydig’s cells by inhibiting aromatase conversion of testosterone to oestrogen, and may also involve in phosphodiesterase inhibition at a high concentration, so authors have suggested that quassinoids from E. longifolia may be worthy for further development as new phytomedicines for the treatment of testosterone-deficient idiopathic male infertility and sterility [ 112 ]. Also, standardized extracts of E. longifolia Jack containing a high concentration of quassinoids (20% eurycomanone and 4% of 13α,21-dihydroeurycomanone) may have potential anti-estrogenic effects [ 86 ].
The quassinoid-containing E. longifolia extract affects male infertility by suppressing α-2-HS glycoprotein expression, which indirectly increases the testosterone levels and insulin sensitivity. They indicated that serum α-2-HS glycoprotein was reduced in rats treated with standardized E. longifolia extract, which will provide rational for further investigation in animal models of infertility with diabetes [ 113 ].
A randomized, double-blind, placebo-controlled, parallel group study was conducted to investigate the aphrodisiac clinical evidence of E. longifolia extract in men. The total twelve weeks’ study in 109-men between 30- and 55- years of age, divided in a group of 300 mg of water extract of E. longifoli a (Physta ® )-treated and placebo. The E. longifoli a group showed higher scores in the overall erectile-function-domain (IIEF, p < 0.001), the sexual libido (14% by week 12), Seminal Fluid Analysis (SFA)-with sperm motility at 44.4%, and semen-volume at 18.2% after treatment [ 114 ].
Chan et al. , statistically analyzed the spermatozoa count, morphology, motility, plasma testosterone level and Leydig cell count of the animals by ANOVA. Their results showed that the sperm counts of rats given the standardized methanol extract alone at doses of 50, 100 and 200 mg/kg were increased by 78.9%, 94.3% and 99.2%, respectively, when compared with that of control ( p < 0.01) [ 115 ].
Ang and Ngai showed that the fractions of E. longifolia Jack (0.5 g/kg) decreased the hesitation time. Furthermore, they caused a transient increase in the percentage of the male rats responding to the right choice; more than 50% of the male rats scored “right choice”; using the electrical copulation cage [ 116 ].
E. longifolia has been shown to elevate serum testosterone and increased muscle strength in humans. Chen et al. , investigated the effects of standardized water extract of E. longifolia (Physta ® ) at a dose of 400 mg/day for 6 weeks on testosterone: epitestosterone (T:E) ratio, liver and renal functions in male recreational athletes found no significant difference between the results of supplementation results and placebo [ 117 ].
Study on the sexual qualities of middle-aged male rats after dosing with 0.5 g/kg of various fractions of E. longifolia , showed that it enhanced the sexual qualities of the middle-aged male rats by decreasing their hesitation time as compared to controls [ 118 ].
A randomized, double-blind, study with placebo-controlled was conducted for proprietary freeze-dried water extract of E. longifolia (Physta ® ) effects on sexual performance and well-being in men. For this study, men aged 40–65 years were screened for 12-week. Results showed the significant improvements in scores for the sexual intercourse attempt diary, erection hardness scale, sexual health inventory of men, and aging male symptom scale ( p < 0.05 for all), concluded that Physta ® was well tolerated and more effective than placebo in enhancing sexual performance in healthy volunteers [ 59 ].
E. longifolia extract acts as a potential agent to increase spermatogenesis and sperm counts, and for reversing the effects of estrogen in rats, after fourteen consecutive days of treatment [ 119 ].
In other study, Ang et al. , showed that E. longifolia produced a dose-dependent, recurrent and significant increase in the episodes of penile reflexes as evidenced by increases in quick flips, long flips and erections of the treated male rats during 30 min observation period [ 17 ].
According to Tambi and Imran’s investigations, 350 patients were given 200 mg of the E. longifolia extract daily, and follow-up semen analyses were performed every 3 months up to 9 months. These patients showed significant improvement in all semen parameters, allowing for 11 (14.7%) spontaneous pregnancies [ 120 ].
Erasmus et al. , treated semen samples with E. longifolia extract ( in vitro condition), found a significant dose-dependent trends for vitality, total motility, acrosome reaction and reactive oxygen species-positive spermatozoa; but no deleterious effects on sperm functions at therapeutically used concentrations (<2.5 µg mL −1 ) [ 121 ].
An increase in sperm count, motility and viability in rats, when treated with aqueous E. longifolia extract. Noor et al. , investigated that E. longifolia can increase sexual behavior of male rats and the sperm quality; which were found to be dose dependent [ 122 ]. One study indicates that E. longifolia exerts proandrogenic effects that enhance the testosterone level [ 123 ].
The in vivo effect of aqueous extract of E. longifolia was investigated on body and organ weight as well as functional sperm parameters in terms of safety and efficacy in the management of male infertility, in male rats. Testosterone concentration increased by 30.2%, total sperm concentration, progressive motility and vitality significantly increased, MMP improved markedly by 25.1%, with increased in muscle weight, non-significantly, so it appears that E. longifolia use is safe for possible treatment of male infertility and ageing male problems [ 124 ].
In human studies, Tambi et al. , treated a group of patients suffering from late-onset hypogonadism (LOH) with Tongkat ali extract, which showed significantly ( p < 0.0001) improved the Ageing Males’ Symptoms (AMS) score as well as the serum testosterone concentration. Thus, Tongkat ali extract appears to be useful as a supplement in overcoming the symptoms of LOH and for the management of hypogonadism [ 125 ].
The testosterone deficiency syndrome (TDS), can be characterised by numerous symptoms, including low libido, fatigue, increased fat mass, osteoporosis or erectile dysfunction, and up-to 80% of men have experience some sort of ageing male symptoms. Conventionally, TDS is treated with testosterone replacement therapy (TRT). With the beneficial effects of this therapy, significant adverse effects have been indicated, including prostate cancer. E. longifolia is the herbal alternative to TRT, which has been shown to successfully restore serum testosterone levels, and significantly improve the physical condition and sexual health of patients. Therefore, E. longifolia might be considered a safe alternative to TRT [ 126 ].
For the copulatory activity of sexually sluggish rats, with acute (500, and 1000 mg/kg) and also subacute treatments with E. longifolia root powder, significantly reduced ejaculation latencies, and increased the percentage of mounting and ejaculating animals; while the subacute administration reduced post-ejaculatory interval. In case of impotent rats, both treatments increased the percentage of mounting and ejaculating rats. Serum testosterone levels were increased in rats that were treated subacutely, in comparison with control [ 127 ].
One experiment by Ang and Sim showed that E. Iongifolia Jack continued to enhance and also maintain a high level of both the total number of successful crossovers, mountings, intromissions and ejaculations during the 9–12th week observation period [ 128 ].
In animal research, an herbal combination containing Panax quinquefolius , Eurycoma longifolia , Epimedium grandiflorum , Centella asiatica , and flower pollen extracts enhanced erectile function [ 129 ]. Improvements were noted in the penile erection index (PEI). In boars, an herbal preparation containing Eurycoma longifolia , Tribulus terrestris , and Leuzea carthamoides increased libido (by 20%) and semen quality (volume, concentration, etc. ) [ 130 ].
Randomized controlled trials investigating E. longifolia compared to placebo were included by Kotirum et al. and suggests that E. longifolia root extract may have a clinical benefit on improving erectile dysfunction performance. Based on current evidence, the herbal extract of E. longifolia may have clinical effect on erectile function, but needs further clinical evidence of efficacy trials to make any firm recommendation [ 131 ].
In a pilot study, Henkel et al. investigated the ergogenic effect of E. longifolia in elderly people and found that it is a potential herbal supplement for physically active aged male and female (age 57–72 years). Treatment resulted in significant increases in total and free testosterone concentrations and muscular force in men and women, when E. longifolia extract 400 mg/day was used for 5 weeks [ 132 ].
5.2. Antimalarial Effect
The WHO estimates that in 2013, there were 207 million annual cases of malaria, resulting in 627,000 deaths, from Plasmodium falciparum [ 133 , 134 ]. There are about 10,000 malaria cases per year in Western Europe, and 1300–1500 in the United States [ 135 ]. E. longifolia extract is traditionally used for malarial fevers and has good anti-malarial effect against P. falciparum.
Chan et al. , tested the extracts of E. longifolia for antiplasmodial activity against a multi-drug resistant Thailand’s strain (K-1) of P. falciparum under in vitro conditions. They isolated 10-hydroxycanthin-6-one, eurycomalactone, eurycomanone and eurycomanol from the plant, which showed antimalarial activities [ 60 ].
According to Kardono et al. , two compounds, eurycomanone and 7-methoxy-β-carboline-1-propionic acid showed significant antimalarial activity against P. falciparum strains [ 61 ]. Low et al. , concluded that the administration of the bioactive standardized extract Fr2 (200 mg/kg) showed a good antimalarial effect. 13α(21)-epoxyeurycomanone and eurycomanone may be the only quassinoids contributing to the overall antimalarial activity of E. longifolia [ 62 ].
In study, conducted during 2008 in Mae Sot, Tailand, a standardized extract of E. longifolia containing three major quassinoids, eurycomanone ( 1 ), 13,21-dihydroeurycomanone ( 2 ) and 13α(21)-epoxyeurycomanone ( 3 ) was evaluated for antiplasmodial activity against Plasmodium falciparum . Activity was compared with that of artemisinin, using thirty-eight fresh parasite isolates and assessment of inhibition of schizont maturation. The IC 50 , IC 90 and IC 99 values for artemisinin were 4.30, 45.48 and 310.97 μg/L, and those for the root extract from E. longifolia 14.72, 139.65 and 874.15 μg/L respectively. The inhibitory activity of the E. longifolia extract was higher than that expected from the three quassinoids isolated from the plant, suggesting synergism between the quassinoids or the presence of other unidentified compounds [ 63 ].
Ang et al. , tested E longifolia extract activity in vitro on Malaysian chloroquine-resistant Plasmodium falciparum culture. They showed that the antimalarial activity of E. longifolia Jack was dose-dependent and reached a maximum of <50% at 0.07−5.00 μg·mL −1 after 1-day post-treatment. However, complete inhibitions were observed at 1.25–5.00 μg·mL −1 extract after 3 days’ post-treatment and 0.62 and 0.31 μg·mL −1 after 4 and 6 days’ post-treatment, respectively [ 64 ].
E. longifolia methanol extract (TA164) decreased the glutathione (GSH) content of both infected and healthy erythrocytes at a certain dosage and incubation period. Both effects of TA164 to GSH content of host or parasite can be the cause of P. falciparum growth inhibition in vitro and screening the activity of GSH synthesis can be one of the procedures in evaluating the antimalarial properties of herbal products [ 136 ].
5.3. Cytotoxic and Anti-Proliferative Effect
Cytotoxic effects of novel drug entities and traditional medicines are very essential to be investigated before testing their further pharmacological activity. After establishment of positive cytotoxic effects, anti-proliferative effects (rate of cytotoxicity) are also investigated to check and confirm their further anti-cancer effectiveness, using in vitro as well as in vivo models. Various constituents from E. longifolia have been tested for cytotoxic effects, and some of these also showed positive anti-proliferative effects.
Cancer, medically known as a malignant neoplasm, is a broad group of diseases involving unregulated cells. In malignant neoplasm (cancer), cells divide and grow uncontrollably, forming malignant tumors, and invading nearby parts of the body. It may also spread to more distant parts of the body through the lymphatic system or bloodstream. Over 200 different known cancers that can affect humans; and there are over sixty different organs in the body where a cancer can develop. A statistical report in 2012 showed that total 338,623 people were diagnosed with cancer in the UK, while 161,823 deaths from cancer ocurred (survival rate was 50%) [ 137 ].
E. longifolia has cytotoxicity and antiproliferative effects on various human cancer cell lines, as well as various solid tumors, including lung, breast and cervical cancers. Kuo et al. , [ 36 ] isolated and identified nearly 65 compounds from the roots of E. longifolia and screened them for the potential cytotoxicity and anti-HIV activities by in vitro assays. Among the compounds evaluated, 13β,21-dihydroxyeurycomanol [ 60 ], 6-dehydroxylongilactone [ 72 ], 9-methoxycanthin-6-one [ 75 ], canthin-6-one [ 76 ], eurylene [ 53 ], 9-hydroxycanthin-6-one [ 76 ], longilactone [ 75 ], 9-methoxycanthin-6-one 3 N -oxide [ 76 ], 14,15β-dihydroxyklaineanone [ 75 ], pasakbumin C [ 50 ], canthin-6-one 9- O -β-glucopyranoside [ 76 ], were screened for in vitro cytotoxicity against A-549 and MCF-7 tumor cell lines [ 138 ] and no inhibition of HIV replication in H9 lymphocytes except for eurylene and pasakbumin B [ 139 ]. Compounds longilactone, 6-dehydroxylongilactone, 9-methoxycanthin-6-one, canthin-6-one, longilactone, 9-methoxycanthin-6-one, 14,15β-dihydroxyklaineanone, pasakbumin C, and canthin-6-one 9- O -β-glucopyranoside demonstrated strong cytotoxicity toward A-549 cell lines, however, longilactone, 6-dehydroxylongilactone, 9-methoxycanthin-6-one, eurycomanone, pasakbumin B, and 9-methoxycanthin-6-one displayed strong cytoxicity toward the MCF-7 cell line.
According to Park et al. , [ 51 ] the compounds eurycomalactone [ 49 ], longilactone [ 140 ], and 14,15β-dihydroxyklaineanone [ 140 ] showed significant cytotoxicity in both A549 and MCF-7, while 13,21-dihydroeurycomanone [ 140 ] was more selective against A549 and eurycomanone [ 140 ] showed cytotoxic effects only against MCF-7. In the HeLa cell line, compounds eurycomalactone, 13,21-dihydroeurycomanone, eurycomanone, 13α(21)-epoxyeurycomanone, longilactone, and 14,15β-dihydroxyklaineanone displayed significant cytotoxicity showing the relative cell viability ranging from 21.01% ± 2.46% to 66.9% ± 6.67% at the concentration of 100 μM.
Three new [ n -pentyl β-carboline-1-propionate, 5-hydroxymethyl-9-methoxycanthin-6-one, and 1-hydroxy-9-methoxycanthin-6-one] and 19 known β-carboline alkaloids were isolated from the roots of E. longifolia . These compounds were screened for in vitro cytotoxic activities; in which 9-methoxycanthin-6-one and canthin-6-one demonstrated significant cytotoxicity against human lung cancer (A-549) and human breast cancer (MCF-7) cell lines [ 76 ].
Kardono et al. , isolated and characterized five cytotoxic constituents from the roots of E. longifolia . Four of the canthin-6-one alkaloids, namely, 9-methoxycanthin-6-one, 9-methoxycanthin-6-one- N -oxide, 9-hydroxycanthin-6-one, and 9-hydroxycanthin-6-one- N -oxide and one quassinoid, eurycomanone, were found to possess cytotoxic effects against a panel of cell lines like: human cancer cell types (breast, colon, fibrosarcoma, lung, melanoma, KB, and KB-V1) and murine lymphocytic leukemia (P-388) [ 61 ].
Eurycomanone is a cytotoxic bioactive ingredient found in E. longifolia Jack, that has a cytotoxic response against many epithelial cell types. The antiproliferative activity of eurycomanone was investigated on cancerous cell lines (Caov-3, HeLa, Hep G2, HM3KO and MCF-7) and it was found to be relatively nontoxic on noncancerous cell lines (MDBK, Vero). Eurycomanone proved to be cytotoxic towards HeLa cells by triggering apoptotic cell death [ 141 ].
Tong et al. investigated the in vitro and in vivo anti-cancer activities of a standardized quassinoid mixture (SQ40) from E. longifolia on LNCaP human prostate cancer cells, and showed that it induced selective cytotoxicity on human prostate cancer cells and inhibited the growth of LNCaP cells. SQ40 down-regulated the expression levels of G 1 -to-S phase transition regulatory proteins, cyclin D1, CDK4 and CDK2 and up-regulated cyclin inhibitor protein, p21 Waf1/Cip1 which subsequently led to cell cycle arrest in G 0 /G 1 phase. The anti-tumorigenic activity of SQ40 was successfully demonstrated in the mouse xenograft model [ 142 ].
Recently, Hajjouli et al. concluded that E. longifolia constituents, eurycomanone and eurycomanol are the regulators of signaling pathways involved in proliferation, cell death and inflammation. Both eurycomanone and eurycomanol inhibited Jurkat and K562 cell viability and proliferation without affecting healthy cells. Furthermore, eurycomanone inhibited NF-κB signaling pathway through inhibition of IκBα phosphorylation and upstream MAPK (mitogen activated protein kinase) signaling. Eurycomanone and eurycomanol present differential toxicity towards leukemia cells, and eurycomanone having the α,β-unsaturated ketone could be prerequisite for the NF-κB inhibition [ 143 ].
Wnt signaling regulates various processes such as cell proliferation, differentiation, and embryo development. 9-hydroxycanthin-6-one, decreased the expression of Wnt signal target genes, mitf and zic2a, through the activation of GSK3β independent of CK1α [ 144 ].
The quassinoids isolated from E. longifolia have been studied for thir in vitro cytotoxicities against KB cells derived from human epidermoid carcinoma of the nasopharynx [ 140 ]. Itokawa et al. , isolated a new squalene-type triterpene, named eurylene, from E. longifolia which were found to be cytotoxic [ 53 ]. Chan et al. , isolated a new C19 quassinoid 6α-hydroxyeurycomalactone from the roots of E. longifolia and have reported that the cytotoxic activity of these quassinoids was not mediated through DNA cleaving properties [ 49 ].
Chronic myelocytic leukemia (CML) is a malignant disease of the human hematopoietic stem cell which is characterized by a marked increase in granulocytes bone marrow hyperplasia and splenomegaly [ 145 ]. CML accounts for 15–20 percent of all leukemias [ 145 , 146 ] with a worldwide incidence of 1–2/100,000 [ 147 , 148 , 149 ]. The various isolates and purified eurycomane, an active compound from the roots of E. longifolia , were examined for their cytotoxic effect in K-562 cells isolated from patients with chronic myelocytic leukaemia (CML).
Al-Salahi et al. , assessed the in vitro and in vivo anti-proliferative and apoptotic potentials of E. longifolia on K-562 leukemic cell line. Intraperitoneal administration of TAF273 ( E. longifolia fraction, 50 mg/kg) resulted in a significant growth inhibition of subcutaneous tumor. TAF273 showed potent anti-proliferative activity in vitro and in vivo models of Chronic Myelogenous Leukemia (CML) and therefore, justifies further efforts to define more clearly the potential benefits of using TAF273 as a novel therapeutic strategy for CML management [ 150 ]. The cytotoxic activity of quassinoids was not found to be mediated through DNA cleaving properties [ 49 ]. In vitro , the anticancer effects of a fraction of E. longifolia were due to apoptosis via a caspase-9 and p53-independent manner [ 151 ] that perhaps involved Bcl-2 protein [ 152 ].
Angiogenesis, a process of formation of new branches of blood vessels, is strongly implicated in several important physiological situations [ 153 , 154 ]. Dysregulation of angiogenesis is involved in several pathological conditions, including atherosclerosis, proliferative retinopathies, rheumatoid arthritis, psoriasis, tumor growth and metastasis [ 155 ]. It is well recognized that angiogenesis is essential for the growth and metastasis of most solid malignancies, an increased body of evidence supports the enhancement of angiogenesis in hematologic malignancies as well [ 156 ]. Therefore, angiogenesis is currently becoming an important target for chemotherapeutic approaches in cancer therapy [ 157 ].
Antiangiogenic potential of partially purified quassinoid-rich fraction (TAF273) of E. longifolia root extract was evaluated using ex vivo and in vivo angiogenesis models and the anti-angiogenic efficacy of TAF273 were investigated in human umbilical vein endothelial cells (HUVEC). In vivo , it causes significant suppression in sprouting of microvessels in the rat aorta (IC 50 , 11.5 μg/mL), and shows a remarkable inhibition (63.13%) of neovascularization in chorioallantoic membrane of the chick embryo (IC 50 , 50 μg/mL). In vitro , TAF273 significantly inhibited the major angiogenesis steps such as proliferation, migration and differentiation of HUVECs. Thus, E . longifolia could be the potential source of promising therapeutic agents to treat angiogenesis-related disorders [ 158 ].
Fractions of E. longifolia extract have also been reported to induce apoptosis in breast cancer cells [ 152 ]. Further, Tee et al. , elucidated the mode of action of F16 (a plant-derived pharmacologically active fraction) and observed that the intrinsic apoptotic pathway was invoked, with the reduction of Bcl-2 protein. It was concluded that the F16 from E. longifolia exerts anti-proliferative action and growth inhibition on MCF-7 cells through apoptosis induction, and that it may have anticancer properties [ 151 ].
The anti-proliferative, apoptotic and differentiating activities of partially purified sub-fractions (F1–F3) of E. longifolia root extracts were investigated on HL-60 leukemic cells. F1 showed unremarkable growth inhibition rate while F2 and F3 showed growth inhibitory effects with median inhibitory concentration (IC 50 ) values of 15.2 and 28.6 µg/mL, respectively. E. longifolia extract (F2) showed promising anti-leukemic activity and can be a candidate for the development of a drug for the treatment of acute promyelocytic leukemia (APL) [ 159 ].
Nurhanan et al. , evaluated the methanol, n -butanol, chloroform and water extracts obtained from the root of E. longifolia for its possible cytotoxic effect against KB, DU-145, RD, MCF-7, CaOV-3, and MDBK cell lines. Their results indicated that except for the water extract, all the other extracts produced significant cytotoxic effecte on these cell lines with no significant cytotoxic effect on MDBK (kidney) normal cell line. An alkaloid, 9-methoxycanthin-6-one was detected in each extract with different intensities, and was envisaged to be responsible for the observed activities [ 160 ].
Razak et al. , reported that the extract of E. longifolia is found to be cytotoxic with IC 50 of 11 μg/mL and 13 μg/mL on Hep2 and HFL1 cell lines respectively and that the combined extracts of E. longifolia and Hunteria zeylanica are more cytotoxic than the single extract on Hep2 cell lines [ 161 ].
5.4. Antimicrobial Effects
Farouk et al. , showed that the alcoholic and acetone extracts of the leaves and stem were active on both the Gram-positive and Gram-negative bacteria Escherichia coli and Salmonella typhi . The root extracts had no antibacterial activity against the Gram-positive and Gram-negative bacteria tested. Aqueous leaves extract showed antibacterial activity against Staphylococcus aureus and Serratia marscesens [ 162 ].
Extracts from E. longifolia and L. pumila leaves were evaluated and analyzed for their antibacterial activity against human pathogenic Gram positive ( Staphylococcus aureus ) and Gram negative ( Pseudomonas aeruginosa ) bacteria. The extracts were prepared in different solvents (acetone, methanol, ethanol, and phosphate buffer) and at various concentrations ranging from 5 to 100 mg/mL. Most of the extracts showed relatively high antibacterial activity against the tested bacteria with inhibition zone diameters ranging between 7 and 25 mm. The minimum concentration of E. longifolia and L. pumila extracts which inhibited the growth of S. aureus and P. aeruginosa was 75 mg/mL in ethanol and 25 mg/mL in a phosphate buffer, respectively [ 163 ].
Kong et al. screened natural extracts from six plants, including E. longifolia , that improved the survival of S. aureus -infected worms by at least 2.8-fold, suggesting that these extracts could possibly activate host immunity to eliminate the bacteria or possibly interfere with the factor/s that prevent pathogen accumulation [ 164 ].
5.5. Anti-Inflammatory Effects
It was demonstrated that the β-carboline alkaloid 7-MCPA (7-methoxy-(9 H -β-carbolin-1-yl)-( E )-1-propenoic acid) isolated from E. longifolia hairy-root cultures activated Nrf2 via a ROS-dependent p38 MAPK pathway and 7-MCPA anti-inflammatory effects was associated with 7-MCPA-induced activation of the Nrf2/HO-1 pathway. This study clarified the molecular mechanisms underlying the anti-inflammatory activities of β-carboline alkaloids of E. longifolia , which may be useful to prevent or treat inflammatory diseases [ 165 ].
Eurycomalactone, 14,15β-dihydroklaieanone, and 13,21-dehydroeurycomanone were identified as potent NF-κB inhibitors with IC50 values of <1 μM [ 45 ]. Varghese et al , studied hydroalcoholic extract of E. longifolia Jack for its antioxidant and in vitro anti-inflammatory properties. The antioxidant activity (free radical scavenging) was evaluated to determine the total antioxidant capacity of extract E. longifolia . The DPHH assay showed significant antioxidant activity in all concentrations used ( i.e., 10, 25, 50, 100 and 250 µg/mL). The human RBC (HRBC) stabilization method was utilized to evaluate the in vitro anti-inflammatory activity of the extract, and it was found that this anti-inflammatory activity increased in a concentration dependent manner [ 82 ].
5.6. Anti-Anxiolytic Effect
The anti-anxiety effect of various fractions of E. longifolia was investigated in mice using various behavioral tests, including the open field (emotional state), elevated plus-maze (anxiolytic and anxiogenic drug effects), and anti-fighting test. The E. longifolia anxiolytic effect was similar to that of the positive control diazepam [ 166 ].
In human, effects of E. longifolia hot-water extract was screened for stress hormones and mood state in 63 subjects (32 men and 31 women) for moderate stress, with placebo for 4 weeks, and indicates that daily supplementation with E. longifolia extract improves stress hormone profile and certain mood state parameters [ 167 ].
5.7. Antidiabetic Effect
Blood glucose decreased in streptozotocin-induced hyperglycemic adult rats after treatment of 150 mg/kg body weight using aqueous extracts of E. longifolia . Blood-glucose levels decreased 38% ( p < 0.05) and 47% ( p < 0.001) for two different E. longifolia extracts. In normoglycaemic rats, no significant reduction was noted when the same extracts were used [ 168 ].
E . longifolia root extract increased insulin sensitivity through the enhancement of glucose uptake by more than 200% at 50 μg/mL and suppressed lipid accumulation in a concentration-dependent manner, suggesting the ability of E. longifolia to suppress lipid production would provide additional benefits in the treatment of diabetes [ 169 ].
5.8. Osteoporosis Preventive Effect
Osteoporosis in men is attracting more interest as it is becoming one of the main causes of morbidity and mortality in older men. Approximately 2 million men in the United States suffer from osteoporosis [ 170 ]. Worldwide, 1 in 3 women over 50 will experience osteoporotic fractures, as will 1 in 5 men [ 171 , 172 , 173 ]. According to Tambi and Kamarul, E. longifolia contains high concentrations of superoxide dismutase (SOD), an antioxidant that plays an important role in counteracting oxidative stress [ 120 ]. Other components of E. longifolia , such as alkaloids and triterpenes, can also act as antioxidants that may reduce bone loss and maintain the bone formation rate [ 123 ].
Recently, it was established that E. longifolia may be used in the prevention and treatment of osteoporosis, or more specifically, male osteoporosis. Shuid et al. , showed that both testosterone replacement and E. longifolia supplementation to orchidectomised rats were able to maintain the bone calcium levels, with the former showing better effects, so E. longifolia prevented bone calcium loss in orchidectomised rats and therefore, has the potential to be used as an alternative treatment for androgen deficient osteoporosis [ 174 ]. The bioactive complex polypeptides from the E. longifolia root extract, labelled as eurypeptides, can exert and enhance their effects on the biosynthesis of various androgens [ 175 ]. Eurypeptides work by stimulating dihydroepiandosterone (DHEA). DHEA in turn will act on androgen receptors to initiate the conversion of androstenedione and androstenediol to testosterone and estrogen, respectively [ 125 ]. These eurypeptides may also alleviate SHBG and subsequently increase the free testosterone level [ 176 ]. Due to these proandrogen properties of E. longifolia , it is able to stimulate osteoblast proliferation and differentiation, resulting in increased bone formation rate. High levels of testosterone and estrogen may also exert proapoptotic effects on osteoclasts, reducing the bone resorptive activity. As testosterone levels decrease with age, it has been suggested that men can consume E. longifolia (at suitable dosages) as a supplement [ 177 ]. Other than its proandrogenic properties, E. longifolia contains high levels of nitric oxide (NO) [ 178 ] that have effects on bone.
Male osteoporosis can also be explained in terms of an oxidative stress mechanism. Free radicals, mainly reactive oxygen species (ROS), are efficiently scavenged in the body. However, oxidative stress will occur when there is an imbalance between increased ROS levels and inadequate antioxidant activity [ 179 ]. Orchidectomy (a model of androgen-deficient osteoporosis), can promote up-regulation of ROS which leads to oxidative stress. Oxidative stress plays a role in osteoblast apoptosis and osteoclast differentiation [ 180 ]. There are several mechanisms proposed for its antiosteoporotic effects. The main mechanism is via its testosterone-enhancing effects for the prevention and treatment of androgen-deficient osteoporosis. Other mechanisms involved are through its nitric oxide generation and antioxidative properties. Due to E. longifolia ’s safety profile and potential as an alternative antiosteoporotic agent, further studies are warranted to document a better and conclusive mechanism for its therapeutic action [ 123 ].
Androgen-deficient osteoporosis in men is treated with testosterone therapy, which is associated with many side effects. E. longifolia is known to possess androgenic properties and has been reported to protect bone from androgen-deficient osteoporosis in experimental animal models [ 181 ]. The combination therapy of E. longifolia and low-dose testosterone has potential for treatment of androgen-deficient osteoporosis. The lower testosterone dose is beneficial in reducing the side effects of testosterone therapy [ 181 ]. E. longifolia exerts proandrogenic effects that enhance testosterone levels, as well as stimulate osteoblast proliferation and osteoclast apoptosis [ 123 ]. E. longifolia has been shown recently to protect against bone calcium loss in orchidectomised rats, the model for androgen-deficient osteoporosis. Supplementation with it extract elevated the testosterone levels, reduced the bone resorption marker and upregulated OPG gene expression of the orchidectomised rats. These actions may be responsible for the protective effects of E. longifolia extract against bone resorption due to androgen deficiency [ 182 ]. Further studies on the regulation of OPG production by E. longifolia may provide insight into this novel mechanism. E. longifolia exerts proandrogenic effects that enhance the testosterone level, as well as stimulate osteoblast proliferation and osteoclast apoptosis. This will maintain bone remodelling activity and reduce bone loss. Phytochemical components of E. longifolia may also prevent osteoporosis via its antioxidative property. Hence, E. longifolia has the potential as a complementary treatment for male osteoporosis [ 123 ].
5.9. Miscellaneous Effects
5.9.1. hormonal effects.
A standardized extract of E. longifolia Jack containing a high concentration of quassinoids (20% eurycomanone and 4% 13α,21-dihydroeurycomanone) had antiestrogenic effects against 17α-ethynylestradiol (EE)-induced uterotrophy of immature rats [ 86 ]. Another study showed that the E. longifolia plant extract normalized irregular estrous cycles and reduced the follicular morphological damage caused by chronic testosterone administration in the female rats. The reversal effect derived from the anti-estrogenic properties of the plant quassinoids. Further work is required to identify the exact mechanism behind the ameliorative effects of E. longifolia [ 183 ].
5.9.2. Ergogenic Effects
The ergogenic effects of E. longifolia were discussed in a review [ 184 ]. The authors reviewed its medicinal properties and studies investigating physiological responses and endurance exercise performance. Increased testosterone, as shown in animal models [ 115 ], has been suggested in anecdotal reports as being responsible for E. longifolia -induced increases in muscle mass and strength in humans. According to secondary sources, E. longifolia enhances testosterone production by the Leydig cells and frees bound testosterone for use by muscles [ 185 ].
5.9.3. Insecticidal Effects
E. longifolia -containing smoke from mosquito coils resulted in increased knock-down activities of mosquitos, but not increased mortality [ 186 ]. One study showed that E. longifolia exhibits the highest anti-protozoal activity at 1.0 mg/mL. The ethyl acetate fraction exhibited a slightly higher percentage of anti-protozoal activity and demonstrated the highest anti-protozoal activity against Blastocystis sp. isolates and showed a sizeable reduction in the cell count in comparison to the allopathic drugs [ 187 ].
5.9.4. Muscular Effects
In animal research, E. longifolia extracts increased weight of the levator ani muscle (involved in tail wagging) in castrated animals, but not testosterone-treated animals and uncastrated animals [ 188 ].
5.9.5. Antiulcer Effect
A bioassay study of Pasak bumi (E. longifolia) led to the isolation of four quassinoids, pasakbumin-A, -B, -C, and -D. Both pasakbumin-A (eurycomanone) and pasakbumin-B exhibited potent antiulcer activity [ 50 ]. In one other study, Qodriyah et al. , investigation showed that E. longifolia in Radix is as effective as ranitidine in the treatment of ethanol-induced gastric lesions in rats [ 189 ].
5.9.6. Anti-Rheumatism Effect
Studies showed that decoction, and an alcoholic extract of E. longifolia roots are used to treat rheumatism [ 45 , 190 ].
The bioavailability of the constituent eurycomanone was investigated in animal research [ 65 ]. Following intravenous injection, eurycomanone was detected in the plasma, declining to zero within 8 h. Following oral administration, C max and T max values were 0.33 ± 0.03 mcg/mL and 4.40 ± 0.98 h, respectively. The plasma concentration was lower following oral administration vs. intravenous administration, even at a much higher oral dose (five times the dose). The authors concluded that eurycomanone is poorly bioavailable orally (10.5%).
In animal research, less than 1% of the constituent 9-methoxycanthin-6-one was found to be absorbed orally [ 100 ].
Following oral administration of a standardized extract (Fr 2) of E. longifolia , 13 α(21)-epoxy-eurycomanone had a higher C max than eurycomanone (1.61 ± 0.41 mcg/mL vs. 0.53 ± 0.10 mcg/mL) [ 62 , 86 , 191 ]. The absolute bioavailability was also higher due to increased membrane permeability (higher log Kow value of −0.43 vs. −1.46 at pH 1). Following oral administration of a standardized extract (Fr 2) of E. longifolia , eurycomanol and 13α,21-dihydroeurycomanone were not detected in plasma [ 62 ].
In animal research, the volume of distribution ( V d ) of eurycomanone was relatively high (0.68 ± 0.30 L/kg), suggesting that it is well distributed in the extravascular fluids [ 65 ].
Following intravenous injection, the mean elimination rate constant ( k e ) and clearance ( CL ) for eurycomanone were 0.88 ± 0.19 h −1 and 0.39 ± 0.08 L/h/kg, respectively [ 65 ].
6.4 CYP Inhibition
In vitro evaluation of the modulatory effects of eurycomanone, an active constituent of E. longifolia on cytochrome P450 (CYP) isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 were conducted by Pan et al. They indicated that eurycomanone did not potently inhibit any of the investigated CYP isoforms, with IC50 values greater than 250 μg/mL, hence appears to be little likelihood of drug-herb interaction via CYP inhibition [ 192 ].
Recent, CYP inhibition study of E. longifolia by Han et al. , showed that E. logifolia has a weak, concentration-dependent inhibitory effect on CYP1A2, CYP2A6, and CYP2C19 isozymes, showing IC 50 values of 324.9, 797.1, and 562.9 μg/mL, respectively. It needs careful attention in taking E. longifolia extracts products with conventional drugs [ 193 ].
Following intravenous administration of a standardized extract (Fr. 2) of E. longifolia , 13α(21)-epoxyeurycomanone had a longer biological half-life than eurycomanone (0.75 ± 0.25 h vs. 0.35 ± 0.04 h), due to a lower elimination rate constant [ 62 ]. Conversely, another study reported the biological half-life (t 1/2 ) of eurycomanone to be 1.00 ± 0.26 h [ 65 ].
7. Evidence-Based Toxicology
7.1. safety and toxicity.
Although E. longifolia has been used in traditional medicine for generations in Malaysia, it was only in the late 1990s that researchers started to pay more attention to its safe dosage and toxicity profile. Safety studies carried out thus far showed that Tongkat Ali ( E. longifolia ) concentrations used therapeutically (2.5 µg·mL −1 ) appear not to have any detrimental effects on human spermatozoa in vitro [ 194 ]. However, at concentrations higher than 100 µg·mL −1 , cytotoxic effects might occur [ 36 , 160 ] supporting in vivo data by Tambi and Kadir, that the extract is not toxic [ 9 ]. In animal studies, no negative effect on the offspring could be found, either in terms of malformations or of any effect on body weight or the number of the offspring [ 124 ]; yet an acute toxicity study done by Satayavivad et al. has found that the oral Lethal Dose 50 (LD 50 ) of the alcoholic extract of E. longifolia in mice is between 1500–2000 mg/kg, while the oral LD 50 of the aqueous extract form is more than 3000 mg/kg [ 194 ]. These authors further showed that dosages of 200 mg·kg −1 body weight of the ethanolic extract and 300 mg·kg −1 of the aqueous extract daily were not toxic. Only at dosages above 1200 mg·kg −1 body weight, were significant hepatotoxic effects shown in the rat [ 195 ]. The acute toxicity studies in mice found that the n-butanol fraction of E. longifolia was the most toxic, mainly due to eurycomanone [ 191 ].
It simply means that as the composition of ethanolic, n-butanolic- and aqueous-based fractions of E. longifolia differs, therefore, LD 50 as well daily effective doses are also varied among fractions. The water-based fraction of E. longifolia is considered the safest among others, as its LD 50 value is comparatively high (>3000 mg/kg) than other fractions, so this needs attention when using different fractions of E. longifolia and proper reference of the corresponding range of LD 50 .
Choudhary et al. , investigated the acute, subacute and subchronic toxicity of the standardized aqueous E. longifolia extract (Physta ® ) in a rat model. Male and female Wistar rats were treated for 90 days with E. longifolia concentrations from 250 mg·kg −1 body weight to 2000 mg·kg −1 body weight. Results clearly show no significant changes in blood chemistry and haematological parameters. There were also no histopathological changes and even in acute toxicity tests, no changes in mortality or in the behaviour of the animals was seen [ 196 ].
With reference to the prostate, the Endocrine Society recommends that prostate cancer (PCa) has to be regarded as a contraindication for any testosterone treatment [ 197 ]. Considering that E. longifolia extract increases the serum testosterone concentrations, there might be a potential risk from its treatment in elderly men, which might cause prostatic problems. On other hands, a randomized double-blind, placebo-controlled clinical trial by Ismail et al. , revealed no difference between the placebo and the verum group for serum prostate-specific antigen (PSA) levels [ 114 ]. Li et al. showed that neither mutagenicity nor clastogenicity was noted, and the acute oral LD 50 was more than 6 g/kg b.w for E. longifolia extract. After 4-week subacute and 13-week subchronic exposure paradigms (0, 0.6, 1.2, and 2 g/kg b.w. per day), adverse effects attributable to test compound was not observed with respect to body weight, hematology, serum biochemistry, urinalysis, macropathology, or histopathology. However, the treatment significantly reduced prothrombin time, partial thromboplastin time, blood urea nitrogen, creatinine, aspartate aminotransferase, creatine phosphate kinase, lactate dehydrogenase, and cholesterol levels, especially in males ( p < 0.05). Calculated acceptable daily intake (ADI) for E. longifolia extract, was up to 1.2 g/adult/day. The investigated intension of E. longifolia extract intake by Li et al. was to calculate its safety profile in health supplements. This information is useful for product development and safety management [ 198 ].
From Hamoud and Qamar’s findings, it is strongly suggested that E. longifolia Jack has no evidence of side effects or any deleterious effect on the pancreatic tissues when used orally in small quantities for more than a month. Regular E. longifolia use at low doses does not appear to cause any toxic effect on the pancreas and could be considered a safe herbal supplement as far as the safety of the pancreas in human beings is concerned [ 199 ].
No toxic symptoms were observed in TAF273-treated pregnant female rats, and their pregnancies were normal with no fetus abnormalities. After administration of a 100 mg/kg daily dose of TAF273, which is almost >10-fold lower than the LD 50 value, no adverse effect was observed in reproductive toxicity and teratology studies in rats. The authors concluded that any human dose derived from converting the rat doses of 100 mg/kg/day or below, may be considered safe for further clinical studies [ 200 ].
Chen et al. , investigated the effects of standardized water extract of E. longifolia the Physta ® at dose of 400 mg/day for 6 weeks, showed no significant changes in both the liver and renal functions tests, so supplementation of E. longifolia at this dosage and duration was non-toxic to the liver and renal functions [ 117 ].
The Food and Drug Administration has suggested that the extrapolation of animal doses to human doses is correctly performed only through normalization to BSA, which often is represented in mg/m 2 . The human dose equivalent can be more appropriately calculated by using the formula as HED (mg/kg) = Animal dose (mg/kg) [Animal Km /Human Km ] [ 201 ].
E. longifolia is considered safe as long as it is not taken in a high dose. Based on the results of previous toxicity studies, E. longifolia is normally recommended to be administered to men at the dose of 200–400 mg daily and should be used with caution, especially in the elderly. Currently, E. longifolia is commercially sold worldwide following this established dosage in the form of tablets for easier daily consumption [ 195 ].
Based on studies in animals suggesting that E. longifolia reduced blood glucose in hyperglycemic animals [ 168 ] and unpublished studies in humans suggesting the possibility for increased blood glucose, it should be used cautiously in patients using hypoglycemic agents. Also use with in individuals using propranolol, as in healthy males, a water-based extract of E. longifolia decreased the bioavailability of propranolol [ 202 ].
It should be used cautiously in people with weakened immune systems, as some evidence suggests that it may further weaken immune function, according to secondary sources [ 185 ]. Use is to be avoided in individuals with diseases like breast cancer, prostate cancer, heart disease, kidney disease, liver disease, or sleep apnea, according to secondary sources [ 185 , 203 ].
Use in patients with known allergy or hypersensitivity to E. longifolia , its constituents, or hypersensitivity to other members of the Simaroubaceae family is also to be avoided [ 185 , 203 ]. Use during pregnancy and lactation and in children is not suggested due to a lack of sufficient data [ 185 ]. Information on E. longifolia’s effects on lactation is lacking in the National Institute of Health’s Lactation and Toxicology Database (LactMed) [ 203 ].
One in vivo study indicates that in animals, no negative effect on the offspring could be found, neither in terms of malformations nor of any effect on body weight or the number of the offspring [ 195 ]. Low et al. , investigated reproductive toxicity, up-&-down acute toxicity, and two generations of fetus teratology in orally TAF273 (quassinoid-rich E. longifolia extract)-treated rats. The results showed that the lethal dose (LD 50 ) of TAF273 for male and female rats was >2000 and 1293 mg/kg, respectively. Fertility index and litter size of the treated rats were significantly increased, compared to non-treated rats [ 200 ].
Novel molecular diversity (abbreviate as NMD) poses a formidable challenge for a rational drug design. Bioassay-guided fractionation of natural products is one high-throughput screening (HTS) approach to identify potent bioactive molecules. Today natural products continue to play a major role as active substances and model molecules for the discovery and validation of drug targets. Herbal medicines have been used for thousands of years in almost all developing countries and recently, the World Health Organization estimated that 80% of people worldwide rely on herbal medicines for some part of their primary health care. A multidisciplinary approach in new drug discovery, mostly involving the generation of truly novel molecular diversity from natural herbal sources, combined with combinatorial synthetic methodologies, provides the best solution to increase the novelty and productivity in novel drug discovery and further development. Screening for new drugs in plant sources implies the screening of extracts for the presence of novel compounds as well as investigation of their biological activities.
Whereas over 100,000 secondary metabolites are already known, only a small percentage of all species have been studied for the presence of secondary metabolites. It is currently estimated that approximately 420,000 plant species exist in Nature [ 204 ], and less than 5% of known plants have been screened for one or more biological activities [ 205 ].
The advances in the phytochemical analysis, especially the impact of high-performance liquid chromatography (HPLC)-coupled spectroscopy on natural product research, have been tremendous in the rapid characterization of natural product extracts. The concerted use of photodiode-array UV-Vis absorbance detection (DAD), MS and even NMR spectroscopy, LC-DAD, -MS and -NMR has opened entirely new possibilities to characterize the profiles of the metabolites in the biological extracts [ 206 ]. MS-guided isolation has taken great progress in drug discovery. Rapid processes are required for post-HTS “hit” characterization, at which point milligram or more quantities of the compound of interest must typically be isolated for further biological evaluation, as well as complete structure elucidation that illustrates the complementary nature of NMR and MS data for phytochemical analysis. Several in vitro tests that illuminate the property of interest are available for screening plants and their constituents in order to find the most effective materials and components for further investigations [ 207 ].
E. longifolia Jack is reported to be rich in various classes of bioactive compounds such as quassinoids, canthin-6-one alkaloids, β-carboline alkaloids, triterpene tirucallane type, squalene derivatives and biphenyl neolignans, eurycolactone, laurycolactone, and eurycomalactone, and bioactive steroids. LC-MS is also recognized as a powerful tool for identification and quantification of various major and minor constituents from E. longifolia , which is used as a folk medicine for sexual dysfunction, aging, malaria, cancer, diabetes, anxiety, aches, constipation, exercise recovery, fever, increased energy, increased strength, leukemia, osteoporosis, stress, syphilis and glandular swelling; it is also used as an aphrodisiac, antibacterial, appetite stimulant and health supplement.
It is suggested that the integration of natural chemistry, medicinal chemistry, biology, pharmacology, toxicology and other associated disciplines could be the most promising way to discovering drugs and to ensure a greater chance of advancing natural products and natural-based products into therapeutically useful drugs.
E. longifolia is one of the most useful and safe traditional herbal medicines. Based on established literature on the health benefits of E. longifolia , it is important to focus more attention on its more active constituents and these constituents’ identification, determination, further development and most importantly, standardization. Besides the available data, more evidence regarding its therapeutic efficacy and safety is required, to establish proper clinical recommendations for E. longifolia ’s safe use. By doing so, it is not hard to imagine that not far into the future E. longifolia will be considered a rich source for new drug candidates. It is also very important to conserve this valuable medicinal plant for the health benefit of future generations.
This work was supported by the research grant through the National Research Foundation (NRF) funded by the Korea government (NRF-2014R1A1A1A05002840).
For research articles with several authors, a short paragraph specifying their individual contributions must be provided. The following statements should be used “H.H.Y. and K.C. conceived and designed the paper; S.U.R. wrote the paper.”
Conflicts of Interest
The authors declare no conflict of interest.
LongJack XXXL: The Best Man Power Booster Long Jack XXXL?
If you’re curious about the effectiveness of Long Jack XXXL and its claimed benefits, you’ve landed on the right resource. This article aims to investigate whether LongJack XXXL truly lives up to its claims and to explore any potential side effects associated with its use. Stay tuned to uncover the truth about this product.
So, let’s dive into this comprehensive review to learn more about the product before you start to consume it.
Which Penis Enlargement Techniques Are Most Effective?
When seeking methods for penile enlargement, it is important to navigate through the available choices carefully. While numerous options exist, it is crucial to be aware that many of these procedures can be harmful or fail to deliver the promised results.
When penis extenders were initially introduced, they generated significant interest. However, upon usage, they proved to be ineffective and, in some cases, caused harm to the genital area, making the product more hazardous than beneficial. Despite these concerns, some companies persist in manufacturing and promoting penis extenders with misleading claims.
Similarly, the market is flooded with various penis enhancement pills and capsules. Due to less stringent regulations, manufacturers are not obligated to disclose the exact ingredients of their products on the packaging. This lack of transparency enables unscrupulous producers to deceive consumers by falsely claiming their products contain natural components, when in reality, they may contain dangerous and toxic chemical compounds.
In the thriving male enhancement market, it is essential to approach product selection with caution. Given that male enhancement can significantly impact your sexual life in the long run, it is crucial to make informed decisions and prioritize your well-being.
What Is LongJack XXXL and Why Is it Popular?
LongJack XXXL has garnered recognition as a reliable solution for enhancing stamina and maintaining testosterone levels during sexual activity. Through its consistent usage, this product has been shown to contribute to penis enlargement, improve erection quality, and provide essential support for a satisfying sexual experience. As a result, it has gained immense popularity among individuals in Kenya and Nigeria.
Low testosterone levels in the body are often a primary factor contributing to sexual dysfunction, particularly in men. As men age, typically after reaching 30, testosterone levels naturally decline. Long Jack XXXL serves as a solution to combat this issue by promoting increased testosterone levels and enhancing libido, thereby addressing the underlying causes of sexual dysfunction.
The active ingredients that are present in LongJack pills boost men’s reproductive system. So, they will be able to get rid of problems, such as,
- Premature Ejaculation
The mechanism of action of the man power drug revolves around facilitating improved blood flow to the penis. This powerful medicine contains beneficial active substances specifically designed to combat sexual dysfunction. By increasing blood flow to the penis, it effectively addresses erectile dysfunction and supports longer-lasting intercourse. Furthermore, the supplement incorporates mood-enhancing elements, which can help reduce stress levels. Meticulously developed and clinically tested, this product aims to deliver intense orgasms and maximize enjoyment during intimate encounters.
Who Should Use Long Jack Capsules?
LongJack XXXL is specifically formulated for men aiming to enhance their sexual performance and libido. When considering this supplement, it is essential to prioritize your well-being by consulting with a healthcare professional. It’s important to note that dietary supplements are not regulated by the FDA. By involving a healthcare professional, they can assess your health status and medical history to determine the suitability of LongJack XXXL for your specific needs. Make informed decisions about your sexual health and embrace a cautious approach.
What Is the Importance of Male Performance?
Male sexual performance and libido hold significant importance in men’s lives. They play a vital role in overall well-being, enhancing quality of life, and fostering stronger emotional bonds with partners. By prioritizing and maintaining good sexual health , men can experience heightened satisfaction, increased intimacy, and a deeper connection with their loved ones.
It’s important to acknowledge that individual priorities vary, and what holds significance for one person may not hold the same weight for another. Sexual performance is influenced by other factors, too, including,
- Mental health
- Physical health
- Relationship dynamics
But some of these sexual problems can be solved by taking the LongJack XXXL capsule.
Why Is Long Jack XXXL the Best and Natural Option to Boost?
LongJack XXXL is a food supplement, which increases your erection power and can easily solve all types of erectile problems, such as premature ejaculation and erectile dysfunction. The best thing about Long Jack XXXL is that it is made up of all-natural ingredients. Hence, it can effectively improve energy levels and stamina in a sexual encounter.
It is the ideal choice for men who want to increase their penis size and improve their sexual confidence to give their partners ultimate satisfaction.
Does Long Jack XXXL Really Work?
LongJack XXXL works by enhancing blood circulation in the penis, resulting in the enlargement of blood vessels and overall size. With regular use, it promotes longer, harder, and thicker erections by improving blood flow. This natural supplement facilitates the growth of your penis, allowing you to achieve peak performance and excel in the bedroom.
If you are wondering what Long Jack enlargement pills are, you need to look into the outcomes of the clinical trials and the users’ feedback. According to the clinical trial, the effectiveness of the product is more than 96% on the subjects who were tested. The product has active ingredients that will help in eliminating sexual problems. It works to improve blood flow in the penis for solving erectile issues and ensure long-lasting sex.
What Are the Ingredients of LongJack Capsules?
The Men Power Booster LongJack XXL features a proprietary blend of all-natural ingredients. With a patented composition, it has been proven effective in Ghana, Kenya, and Nigeria. Clinical trials reveal that over 96% of men witness significant improvements in size, both in length and girth. Experience the power of LongJack XXL and unleash your potential.
The ingredients of Jack enlargement pills are discussed below:
It helps in improving blood circulation in the penis. This, in turn, helps in increasing the size of the penis.
This will help in improving testosterone levels and enhances sexual performance. Moreover, it helps in increasing sexual desires in men.
It can provide stamina and improve stamina for long-lasting sex. It’s proven by many users.
This can manage stress levels, enhances immune function, improves mood, and control ejaculation.
Horny Goat Weed
It is an ingredient that can increase sperm count and intensity of orgasm. Thus, it can help men last longer.
What Are the LongJack Side Effects?
LongJack results have shown that it doesn’t have any known contraindications or side effects. The clinical trial has shown that this product works in Kenya and Ghana. It doesn’t lead to digestive problems, allergies, or unpleasant side effects.
User reviews have shown any complaints about problems or side effects of taking the pills.
How to Use LongJack XXL?
Customers should keep in mind that LongJack XXL capsules exhibit rapid results. Strict adherence to the comprehensive usage instructions provided in the extensive guidance manual is crucial. Store the container bottle in a cool, dry location, shielded from direct sunlight. Experience the power of Long Jack XXL and embrace its effective performance-boosting benefits.
To use LongJack capsules, here are the steps you have to follow,
- Take two capsules twice every day. It is better to consume one capsule in the morning and another in the evening.
- Then you can get ready to have some fun with your partner.
- Continue taking the pills for 30 consecutive days, while staying hydrated.
However, remember that you can keep taking this pill even after 30 days if you would like to improve your performance. Nonetheless, take a break of 7 days before continue taking a pill.
Manufacturer, Support, and Certificates
- Company: VIP VITAMINS
- Launch Year: 2022
- Address: 148 E STREET RD # 166, FEASTERVILLE TREVOSE, PA 19053-7604 US1
- Email: [email protected]
Is LongJack XXXL Certified?
LongJack XXXL is accompanied by a quality certificate and guarantee, ensuring its reliability. However, it is strongly recommended to consult with a healthcare professional before incorporating any new supplement into your routine. By seeking professional guidance, you can make informed decisions regarding the suitability of LongJack XXXL for your health and well-being. Prioritize your safety and consult a healthcare professional for personalized advice.
What Is the LongJack Price in Nigeria?
Take advantage of the exclusive limited-time offer for LongJack XXL Nigeria, now available at a discounted price of 40,666.17 NGN. Don’t delay! Visit their official website and swiftly place your order to seize this amazing opportunity.
Discover all the necessary purchase and delivery details on the official LongJack XXL Ghana website. Ordering is simple and hassle-free, involving the submission of basic information through a concise order form on the homepage. Following confirmation by one of their agents, your package will be discreetly dispatched to you, ensuring privacy throughout the process. Visit the website now for a seamless experience.
Each bottle of this product contains 60 capsules, providing a sufficient supply. Furthermore, it’s worth noting that purchasing multiple bottles may entitle you to additional discounts, offering you even greater value for your investment.
What Is the LongJack Price in Kenya?
Purchasing LongJack XXL from a pharmacy, whether in Kenya or any other country, is not recommended. The manufacturer has withdrawn all original product quantities from pharmacies due to the emergence of negative online reviews. It has come to light that pharmacies were selling counterfeit imitations of the original product for personal gain. These fraudulent products proved ineffective, leading to customer dissatisfaction and complaints. To ensure your safety and satisfaction, obtaining LongJack XXL from trusted and authorized sources is advisable.
Exercise caution when encountering LongJack XXL in sex shops, as counterfeit copies of the product have been identified. It is crucial not to waste your hard-earned money on these fake items.
Presently, the price of Long Jack XXXL price in Kenya is KSh 5999. Take advantage of the discounted price offered for this product. When placing an online order, you can expect delivery within 7 working days. The convenience of this arrangement is that no advance payment is required. Simply pay the agent directly upon delivery to your specified location.
LongJack XXXL Pros and Cons
- Treats premature ejaculation.
- Increases libido.
- Increase penis size and ensures a better erection.
- Eliminates the problem of potency in men.
- Helps improving sleep.
- Enhances sexual performances.
- Increase sperm production and quality.
- Individual results might vary.
- Limited scientific evidence.
Questions and Answers
Is it safe to consume longjack xxxl.
LongJack XXXL is generally considered safe for consumption when taken as directed. Everyone’s body reacts differently to supplements. While many people tolerate LongJack XXXL well, some individuals may experience mild side effects such as digestive issues, headaches, or allergic reactions. If you have any underlying health conditions, it’s important to consult with a healthcare professional before taking LongJack XXXL. However, to ensure safety, it is important to purchase LongJack XXXL from reputable sources that provide genuine and quality products. Counterfeit or adulterated versions of the supplement may pose health risks.
How Much Time Does it Take for LongJack XXXL to Take Effect?
The time it takes for LongJack XXXL to take effect can vary from person to person. Some individuals may experience noticeable effects within a few days, while others may require several weeks of consistent use before experiencing any changes. It’s important to keep in mind that individual factors such as metabolism, body composition, and overall health can influence the timeframe for results. Moreover, the specific benefits sought from LongJack XXXL may also impact the time it takes to see desired effects. For example, improvements in energy levels or mood may be noticed sooner compared to changes in libido or physical performance. To optimize the potential benefits of LongJack XXXL, it’s recommended to follow the recommended dosage instructions provided by the manufacturer and maintain a consistent routine of usage.
What Does LongJack XXXL Do to the Body?
LongJack XXXL is marketed as a male enhancement supplement that aims to provide several potential benefits to the body. It has been promoted as a product that may enhance sexual performance by increasing libido, improving erectile function, and promoting longer-lasting erections. The supplement may help boost energy levels and stamina, which can contribute to improved physical performance, both in and out of the bedroom. Some claims suggest that LongJack XXXL may contribute to an increase in penis size by promoting improved blood circulation and expanding blood vessels.
Does LongJack XXXL Contain Herbal Ingredients?
LongJack XXL boasts an entirely organic formulation. Its primary extract is derived from the Tongkat Ali South Asian plant, renowned for its potential benefits. The supplement also incorporates additional plant and herb extracts known for enhancing libido. Included in the ingredients are Maca Root Extract, Fenugreek Extract, Tongkat Ali Extract, Siberian Ginseng Extract, and Horny Goat Weed Extract. By combining these natural elements, LongJack XXL aims to provide a comprehensive approach to supporting male sexual health. As with any supplement, it is important to review the product label and consult with healthcare professionals for personalized advice and information.
Where Can I Buy LongJack XXXL?
LongJack XXXL, a popular product, can be conveniently purchased from multiple online stores. Recsmedix is one such store where customers can acquire LongJack XXXL for $59.99. However, it is important to be cautious of online scams and fraudulent activities on platforms like Amazon. The manufacturer, VIP VITAMINS, advises customers to purchase the original product exclusively from its official website to ensure authenticity.
LongJack XXXL Customer Reviews
A customer of LongJack XXXL, Wayne, is absolutely happy. The product worked well for this man.
Another customer, Tina, bought LongJack XXXL for her husband. She wrote that it was great fun and great sex.
As by Yefim FIsher, LongJack XXXL works because of the right herbs and ingredients in it.
Unfortunately, LongJack XXXL didn’t work for this guy. However, we don’t know the exact reason.
LongJack XXXL is not only an affordable dietary supplement but also a reliable solution for male enhancement. Its specially formulated blend of natural ingredients and herbal extracts ensures both safety and effectiveness in promoting penis enlargement. With a multitude of positive reviews published online, this supplement has gained a reputation for delivering safe and natural results in increasing penis size. Available exclusively through the manufacturer’s official website, LongJack XXXL offers a convenient and trusted option for individuals seeking to boost their confidence, improve stamina, and optimize overall sexual health. Embrace this remarkable supplement and embark on a journey towards enhanced male vitality and satisfaction.
So, if you looking to improve your sexual stamina or enlarge your penis naturally, don’t wait. Get this supplement now and be BIG!
If you’re curious about the effectiveness of Long Jack XXXL and its claimed benefits, you’ve landed on the right resource. This article aims to investigate whether LongJack XXXL truly lives up to its claims and to explore any potential side effects associated with its use. Stay tuned to uncover the truth about this product. So,…
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Tongkat Ali (Eurycoma longifolia): Everything You Need to Know
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Taking a tongkat ali supplement may help with mood and hormone regulation, but research is still new.
Tongkat ali is an herbal remedy that has been a part of traditional Southeast Asian medicine for centuries.
It’s often used to treat a variety of ailments, including fevers, erectile dysfunction, and bacterial infections.
Studies suggest that tongkat ali may boost male fertility, relieve stress, and improve body composition, though research in these areas is limited ( 1 , 2 , 3 ).
The European Food Safety Authority issued a warning in 2021 that tongkat ali has the potential to induce DNA damage ( 4 ).
This article reviews tongkat ali, including its benefits, possible side effects, and dosage.
What is tongkat ali?
Tongkat ali, or longjack, is an herbal supplement that comes from the roots of the green shrub tree Eurycoma longifolia , which is native to Southeast Asia.
It’s used in traditional medicine in Malaysia, Indonesia, Vietnam, and other Asian countries to treat malaria, infections, fevers, male infertility, and erectile dysfunction ( 5 ).
The health benefits of tongkat ali likely stem from various compounds found in the plant.
Specifically, tongkat ali contains flavonoids, alkaloids, and other compounds that act as antioxidants . Antioxidants are compounds that fight cellular damage caused by molecules called free radicals. They may benefit your body in other ways as well ( 3 , 6 , 7 , 8 ).
Tongkat ali is typically consumed in pills that contain an extract of the herb or as part of herbal drinks ( 3 ).
Summary Tongkat ali is an herbal medicine derived from the Southeast Asian Eurycoma longifolia shrub. It contains several potentially beneficial compounds and is used to treat a variety of ailments, including male infertility and infections.
Potential health benefits
Most of the alleged health benefits of tongkat ali are not well researched, but some studies suggest that it may help treat male infertility, improve mood, and increase muscle mass.
May increase testosterone levels and improve male fertility
Tongkat ali’s potential to increase testosterone in men with low levels of this primary sex hormone is well known and well documented.
Low testosterone can result from aging, chemotherapy, radiation treatments, some medications, injury or infection of the testicles, and certain diseases, such as chronic alcoholism and obstructive sleep apnea ( 9 ).
Effects of inadequate testosterone levels include low libido, erectile dysfunction, and in some cases, infertility. Since compounds in tongkat ali may boost low testosterone, it could treat these issues ( 9 , 10 , 11 ).
A 1-month study in 76 older men with low testosterone found that taking 200 mg of tongkat ali extract per day significantly increased levels of this hormone to normal values in over 90% of participants ( 11 ).
What’s more, studies in both animals and humans show that taking tongkat ali stimulates sexual arousal and may improve erectile dysfunction in men ( 12 , 13 , 14 , 15 ).
Finally, tongkat ali may improve sperm motility and concentration, boosting male fertility ( 1 , 15 , 16 , 17 , 18 ).
One study in 75 male partners of couples with infertility found that taking 200 mg of tongkat ali extract per day significantly improved sperm concentration and motility after 3 months. The treatment helped over 14% of couples become pregnant ( 1 ).
Similarly, a 12-week study in 108 men ages 30–55 observed that taking 300 mg of tongkat ali extract daily increased sperm volume and motility by an average of 18% and 44%, respectively ( 15 ).
According to these studies, tongkat ali effectively treats low testosterone and infertility in some men, but more extensive research is needed.
May relieve stress
Tongkat ali may lower stress hormones in your body, decrease anxiety , and improve mood.
A 1999 study first identified the possible role of this remedy in treating mood issues and found that tongkat ali extract was comparable to a common anti-anxiety medication in reducing symptoms of anxiety in mice ( 19 ).
Similar effects have been seen in humans, but research is limited.
A 1-month study in 63 adults with moderate stress found that supplementing with 200 mg of tongkat ali extract per day reduced levels of the stress hormone cortisol in saliva by 16%, compared to those who received a placebo ( 2 ).
Participants also reported significantly less stress, anger, and tension after taking tongkat ali ( 2 ).
While these results are promising, more studies in humans are needed.
May improve body composition
Tongkat ali is often claimed to boost athletic performance and increase muscle mass .
This is because it contains compounds called quassinoids, including eurycomaoside, eurycolactone, and eurycomanone, which may help your body use energy more efficiently, reduce fatigue, and improve endurance ( 3 ).
In other words, the supplement may act as an ergogenic aid, which is a substance that can enhance physical performance and improve body composition ( 3 , 20 ).
A small, 5-week study in 14 men participating in a strength training program found that those who took 100 mg of tongkat ali extract per day experienced significantly greater increases in lean body mass than those taking a placebo ( 21 ).
They also lost more fat than participants in the placebo group ( 21 ).
What’s more, a 5-week study in 25 active older adults discovered that supplementing with 400 mg of tongkat ali extract daily significantly increased muscular strength, compared to a placebo ( 22 ).
However, a small study in cyclists observed that consuming a drink with tongkat ali during exercise did not improve performance or strength any more than plain water ( 23 ).
These conflicting results suggest that tongkat ali may exhibit some ergogenic effects, depending on the dose and length of treatment, but more research is needed.
Summary Studies show that tongkat ali may boost testosterone levels and help treat infertility in men, relieve stress, and possibly increase muscle mass. Still, more extensive research is needed.
Possible side effects and dosage
According to a 2021 report by the European Food Safety Authority (EFSA) Panel on Nutrition, Novel Foods and Food Allergens, a high dose (2,000 mg/kg body weight) of the water-based extract from dried ground tongkat ali may lead to DNA damage of stomach and duodenum tissues. ( 4 )
Because tongkat ali has the potential to cause DNA damage, the panel concluded that the safety of any condition of its use has not been established.
The few studies on the use of tongkat ali in humans, however, have not reported any side effects ( 1 , 2 , 21 ).
A 2016 review that included toxicology studies found that mice did not experience changes in their liver or kidney function when they were orally given 200 mg/kg body weight of tongkat ali in an alcohol-based extract or 300 mg/kg in a water-based extract. ( 23 )
The same study found the lethal oral dose for mice was from 1,500-2,000 mg/kg for alcohol-based tongkat ali extract, and over 3,000 mg/kg for the water-based extract.
One 2012 study of 109 men between the ages of 30 and 55 noted that taking 300 mg of tongkat ali extract daily over a 12-week period was as safe as taking a placebo. ( 14 ).
More recently, in Egypt, a 12-week randomized clinical trial was conducted on men with mild to moderate erectile dysfunction to determine the safety of tongkat ali when combined with maca root , a natural remedy for low sex drive. The results of this clinical trial have not yet been published. ( 27 )
Other studies suggest that taking up to 1.2 grams of tongkat ali extract per day is safe for adults, but this amount has not been used in research. Plus, no studies examine its long-term use, making it unclear whether the supplement is safe over longer periods ( 23 , 24 ).
What’s more, an older 2006 study examining the mercury content of 100 tongkat ali supplements from Malaysia found that 26% had levels of mercury higher than the recommended limit ( 25 ).
Consuming too much mercury can result in mercury poisoning, which is characterized by mood changes, memory problems, and motor skill issues ( 26 ).
Furthermore, the effects of tongkat ali in children or pregnant and breastfeeding women have not been researched. Therefore, it’s unknown whether the remedy is safe for these populations.
Summary Tongkat ali appears to be safe in doses of 200–400 mg per day for most healthy adults. However, high dosages have the potential of damaging gastrointestinal DNA. It’s unknown whether tongkat ali is safe for pregnant or breastfeeding women. Some supplements may also contain mercury.
Should you take tongkat ali?
Some studies suggest that tongkat ali may reduce anxiety and improve body composition , but research is limited.
It may also treat low testosterone, poor libido, and male infertility.
While tongkat ali does not appear to have adverse effects in doses up to 400 mg per day, research is limited, and available studies focus on short-term use.
It’s unclear whether taking the supplements over longer periods is beneficial and safe.
If you’re interested in taking tongkat ali, consult your healthcare provider to ensure proper safety.
Additionally, keep in mind that some supplements may be contaminated with mercury. Plus, they’re not well regulated and may contain more or less tongkat ali than listed on the label. Look for a reputable brand that has been tested by a third party.
Lastly, pregnant and breastfeeding women should not take tongkat ali, due to the lack of research in this area. Additionally, those with medical conditions or taking medications should speak to their healthcare provider before taking tongkat ali.
Summary Tongkat ali may boost low testosterone, combat anxiety, and improve body composition, but research is limited. Check with your healthcare provider before taking this supplement.
The bottom line
Tongkat ali, or longjack, is an herbal supplement suggested to improve low testosterone, male fertility, anxiety, athletic performance , and muscle mass.
Still, research is limited.
If you’re interested in trying tongkat ali, talk to your healthcare provider and look for a reputable brand in stores or online .
Last medically reviewed on December 9, 2022
How we reviewed this article:
Our experts continually monitor the health and wellness space, and we update our articles when new information becomes available.
May 19, 2023
Lizzie Streit, Laura Goldman
Copy Edited By
Dec 9, 2022
Medically Reviewed By
Kerry Boyle D.Ac., L.Ac., CYT
VIEW ALL HISTORY
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What are the benefits and side effects of tongkat ali?
There are various benefits of tongkat ali. These include improvement in male sexual performance, bone health, and stress reduction. It may cause side effects in people with certain cancers, heart disease, and those taking blood glucose medications.
There has been promising research into tongkat ali’s properties. However, people should be cautious about trying it if they have certain health conditions or are taking specific medications.
Keep reading to learn more about tongkat ali’s traditional uses and what the scientific evidence says about its potential benefits and side effects.
What is tongkat ali?
Eurycoma longifolia, or tongkat ali, is a shrubby tree native to Southeast Asia . The plant is indigenous to Malaysia, Indonesia, and Vietnam. Some species of the plant also grow in regions of Cambodia, Myanmar, and Thailand.
Tongkat ali literally means “Ali’s walking stick,” which makes reference to its aphrodisiac effects. Some people say that the “stick” refers to the plant’s long, twisted roots that some groups harvest for their medicinal value.
Other common names for E. longifolia are Long Jack, Malaysian ginseng, and Ali’s Umbrella.
There are, in fact, three other plant species that people may refer to as tongkat ali. These are Entomophthora apiculata, Polyalthia bullata, and Goniothalamus.
This article, however, will focus on E. longifolia.
In Asia, E. longifolia is a well-known aphrodisiac and malaria remedy. People tend to use the roots, bark, and fruits of the flowering plant to make remedies.
According to a 2016 review , in traditional medicine, people use E. longifolia to relieve the following conditions:
- sexual dysfunction
- high blood pressure
- intestinal worms
- exercise recovery
- aches and pains
The same review concluded that E. longifolia is a promising herbal remedy for some conditions. However, there is insufficient evidence regarding its safety and efficacy.
People also use the plant roots to stimulate appetite and increase strength and energy. Others use them as an antibiotic.
Traditionally, people drank a water decoction of the plant. Nowadays, though, there are many E. longifolia products available, including powders and capsules.
The plant contains many bioactive compounds, including alkaloids and steroids. Quassinoids are the major active compound in the roots.
Herbalists regard the plant as an adaptogen. An adaptogen is an herb that helps the body adapt to different kinds of stress, including physical, chemical, and biological stress.
Tongkat ali may have health benefits for certain conditions. The following sections will look at some of these conditions in more detail.
Male fertility and sexual performance
Some research indicates that E. longifolia may enhance male fertility and sexual performance.
According to a 2016 review , animal and human studies suggest that the beneficial effects may include:
- increased semen volumes, sperm count, sperm viability, and sperm motility
- increased production of testosterone
- enhanced erectile function and sexual performance
A 2019 study in rats suggested that the aphrodisiac effects of E. longifolia may be due to the elevation of testosterone levels and enhancement of dopamine in the brain.
Athletes sometimes use ergogenic aids to enhance their performance. E. longifolia may act as an ergogenic aid because it decreases stress and increases testosterone levels, according to one 2016 review .
The researchers concluded that with high dosages and long-term supplementation, E. longifolia might have some benefit in relation to endurance performance.
A 2014 pilot study in physically active people aged 57–72 years reported enhanced muscle strength and increases in testosterone following supplementation with E. longifolia extract for 5 weeks .
A 2018 review examined the evidence for E. longifolia on osteoporosis in rats . It concluded that E. longifolia seemed less effective than other traditional Malaysian herbs.
However, there could still be potential for its use in preventing bone loss, according to the review.
A study in the Journal of the International Society of Sports Nutrition assessed stress hormones in 63 people taking tongkat ali extract or a placebo for 4 weeks.
The researchers saw significant improvements in anger, tension, and confusion in people taking the extract. Testosterone levels increased, and levels of the stress hormone cortisol decreased.
They concluded that tongkat ali might be an effective remedy for modern-day chronic stress, sleep deprivation, and exercise training.
Another study from 2018 looked at the combined effects of E. longifolia and multivitamins in moderately stressed but otherwise healthy participants. The participants reported enhanced vigor and emotional well-being. Glucose concentrations also decreased, which may also have contributed to the participants’ well-being.
Scientists are discovering and identifying new quassinoids in E. longifolia that may help fight cancer. Laboratory studies in test tubes indicate that the compounds are toxic to lung and cervical cancer cells.
A review from 2018 identified 16 compounds in E. longifolia , isolated from various parts of the plant, that showed promising anticancer properties.
Another laboratory study indicated that quassinoids from E. longifolia were effective against human prostate cancer cells. However, the Endocrine Society contraindicate testosterone treatment in prostate cancer, so using the plant for this condition is not advisable.
Anti-inflammatory and antimicrobial effects
Some research indicates that E. longifolia is effective against bacteria, including Escherichia coli and Salmonella typhi.
In test tube studies, extracts of the plant showed anti-inflammatory and antioxidant properties.
Risks and side effects
A 2016 review on the safety and toxicity of E. longifolia reported that it does not seem to have detrimental effects on sperm in test tubes when the scientists used it in therapeutic doses. However, animal studies show that in higher concentrations, it may be toxic.
The same review concluded that scientists consider E. longifolia safe as long as people do not take it in high doses. The authors recommend taking 200–400 milligrams daily with caution, especially if the person is an older adult.
People who have hormonal cancers should be cautious of taking E. longifolia , as it may increase testosterone levels. Although laboratory studies have indicated beneficial effects, these effects may not be the same in the human body.
People taking medications to lower their blood glucose should speak to their doctor before taking E. longifolia , as it may increase the effects of these medications.
According to the review, some sources advise people with certain conditions to avoid E. longifolia . These conditions include cancer, heart disease, and kidney disease. People with weakened immune systems should also be cautious.
Tongkat ali seems to be a promising remedy for several health issues. Some research suggests that it is beneficial for male fertility, sexual performance, and stress. It might also be an effective ergogenic aid.
Some laboratory studies indicate the effectiveness of E. longifolia against cancer in test tubes. However, research also suggests that people with certain cancers should avoid using it.
There are some safety issues for people who have certain health conditions and those who are taking specific medications. Therefore, a person should check with their doctor before taking any herbal supplements.
Last medically reviewed on October 13, 2020
- Erectile Dysfunction / Premature Ejaculation
- Sexual Health / STDs
- Complementary Medicine / Alternative Medicine
How we reviewed this article:
- Bhasin, S., et al. (2010). Testosterone therapy in men with androgen deficiency syndromes: An Endocrine Society clinical practice guideline [Abstract]. https://pubmed.ncbi.nlm.nih.gov/20525905/
- Ezzat, S. M., et al . (2019). Brain cortical and hippocampal dopamine: A new mechanistic approach for Eurycoma longifolia well-known aphrodisiac activity and its chemical characterization. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6582863/
- George, A., et al . (2018). Efficacy and safety of Eurycoma longifolia (Physta) water extract plus multivitamins on quality of life, mood and stress: A randomized placebo-controlled and parallel study. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294837/
- Henkel R. R., et al. (2014). Tongkat ali as a potential herbal supplement for physically active male and female seniors--A pilot study [Abstract]. https://pubmed.ncbi.nlm.nih.gov/23754792/
- Khanijo, T., & Jiraungkoorskul, W. (2016). Review ergogenic effect of Long Jack, Eurycoma longifolia . https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5214558/
- Liao, L.-Y., et al . (2018). A preliminary review of studies on adaptogens: Comparison of their bioactivity in TCM with that of ginseng-like herbs used worldwide. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240259/
- Meng, D., et al . (2014). Four new quassinoids from the roots of Eurycoma longifolia Jack [Abstract]. https://pubmed.ncbi.nlm.nih.gov/24513570/
- Mohammad, N. A., et al . (2018). An evidence-based review: The effects of Malaysian traditional herbs on osteoporotic rat models. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422536/
- Park, S., et al. (2014). Five new quassinoids and cytotoxic constituents from the roots of Eurycoma longifolia [Abstract]. https://pubmed.ncbi.nlm.nih.gov/25066952/
- Rehman, S. U., et al. (2016). Review on a traditional herbal medicine, Eurycoma longifolia Jack (tongkat ali): Its traditional uses, chemistry, evidence-based pharmacology and toxicology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6274257/
- Talbott, S. M., et al . (2013). Effect of tongkat ali on stress hormones and psychological mood state in moderately stressed subjects. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669033/
- Thu, H. E., et al . (2018). Eurycoma longifolia , a potential phytomedicine for the treatment of cancer: Evidence of p53-mediated apoptosis in cancerous cells [Abstract]. https://pubmed.ncbi.nlm.nih.gov/28721818/
- Tong, K. L., et al. (2015). The in vitro and in vivo anti-cancer activities of a standardized quassinoids composition from Eurycoma longifolia on LNCaP human prostate cancer cells. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0121752
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