Glycosaponin

Glycosaponin: A Comprehensive Reference

1. Identity, Botanical Source, and Common Names

Glycosaponin is not a single discrete chemical compound but rather a class designation for saponin-type glycosides — naturally occurring surface-active phytochemicals consisting of a non-polar aglycone (sapogenin) core linked to one or more hydrophilic sugar chains. Saponins are naturally occurring surface-active glycosides that possess an amphiphilic character originating from a lipophilic aglycone (sapogenin) and hydrophilic sugar moieties. Two major classes of saponins are distinguished based on their type of aglycone: steroid (or steroidal) saponins and triterpene (or triterpenoid) saponins.

In the context of commercial dietary supplements, "glycosaponin" almost exclusively refers to the saponin fraction of standardized aqueous root extracts of Eurycoma longifolia Jack — the plant more widely known as Tongkat Ali or Malaysian Ginseng. The standardized water extract of Eurycoma longifolia is a powder mainly containing polysaccharides (30–55%) and glycosaponins (40–65%).

Botanical Classification

• Binomial name: Eurycoma longifolia Jack
• Family: Simaroubaceae
• Common names: The plant is commonly known in Malaysia as Tongkat Ali, meaning "walking stick" and denoting the presence of long twisted roots. Other synonyms include Ali's Umbrella or Malaysia Ginseng (Malaysia), Ian-don (Thailand), Cay ba benh (Vietnam), Pasak Bumi or Bedara Pahit (Indonesia), and tho nan (Laotian).
• Geographic origin: Eurycoma longifolia Jack is a well-known tropical herb belonging to the Simaroubaceae family, indigenous to Southeast Asia including Indonesia, Malaysia, and Vietnam, with some species also found in regions of Myanmar, Cambodia, and Thailand.

Plant Description and Parts Used

Eurycoma longifolia is a slow-growing tree with pinnate, spiral leaves and panicle flowers. Tongkat Ali is an evergreen slow-growing herbal plant that completely matures after 25 years and can be harvested only after 5 years of cultivation. The root is the primary part of the plant from which glycosaponin-containing extracts are derived. The roots of E. longifolia are largely responsible for its biological activity due to the presence of peptides, alkaloids, quassinoids, diterpenoids, eurycomacoside, eurycolactone, laurylcolactone, and eurycomalactone.

Standardized Forms and Preparations

The commercially dominant form of glycosaponin-containing supplement is a standardized hot-water root extract. The water extract of E. longifolia, trademarked Physta® and LJ100 in the US, was produced by Biotropics Malaysia Berhad and standardized to 0.8%–1.5% eurycomanone, not less than 22% total protein, 30.0% total polysaccharide, and 40.0% glycosaponin.

Reflux method is used for the extraction of E. longifolia components, especially glycosaponin and eurycomanone. The aqueous extract produces more glycosaponin and eurycomanone compounds than methanolic extract, showing that water is the best solvent for both compound extraction.

The majority of human supplementation trials have been conducted on specific hot-water-extracts of Eurycoma longifolia (which is the traditional Malaysian preparation) produced using a patented extraction process to isolate and concentrate the bioactive compounds.

2. Traditional and Historical Use

In Malaysia, Eurycoma longifolia Jack is considered a national treasure and is called "Tongkat Ali," while other countries refer to it as Malaysian Ginseng. It is a Southeast Asian plant that has been used in traditional medicine for centuries. Since ancient times, people have relied on the medicinal properties of this plant's aqueous decoction. Traditional uses of the plant parts include antimicrobial, antimalarial, antidiabetic, aphrodisiac, antibacterial, and antipyretic properties.

Several publications describe the history of the consumption of E. longifolia as a herbal remedy (Oxley, 1850; Burkill, 1935; Gimlette, 1939; Elliott and Brimacombe, 1987; Bhat and Karim, 2010; Ong et al., 2012) prevalent in South-East Asian countries such as Malaysia, Indonesia, and Vietnam. Most of the parts of the plant have a history of consumption and particularly the root extract has been used for different, putative health benefits.

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, root extracts 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.

Tongkat Ali has been used for centuries in traditional medicine systems of Southeast Asia for treating lethargy, low libido, depression, and fatigue. It has been used as a traditional medicine for its aphrodisiac effects and treatment of intermittent fever (malaria).

3. Key Constituents and Active Compounds

Standardized E. longifolia root extracts contain multiple classes of bioactive phytochemicals. Glycosaponins constitute the largest fraction by dry weight in standardized extracts. The standardized powder contains total polysaccharide (30–55%), total protein (22–45%), total glycosaponin (40–65%), and eurycomanone (0.8–1.5%), consistent with the specifications established in the Malaysian Standard for this extract (Department of Standards Malaysia, 2011).

Eurycomanone (a quassinoid, CAS number 84633-29-4) was proposed as the major marker compound for the specification of the extract. Besides quassinoids (a group of nortriterpenoids), which account for a major portion of the E. longifolia root phytochemicals, the plant is reported to contain also canthin-6-one alkaloids, β-carboline alkaloids, and other bioactives.

The effects of E. longifolia are mediated by a myriad of bioactive compounds belonging to quassinoids, canthin-6-one alkaloids, tirucallane triterpenes, squalene derivatives, and bioactive steroids. Among these phytoconstituents, quassinoids account for a large portion of E. longifolia root phytochemicals.

Regulatory scientific bodies noted that the glycosaponin component, which makes up 40–65% of the material in standardized extracts, lacked comprehensive analytical characterization in early applications for novel food status. In subsequent analyses, the applicant provided LC-MS/MS analysis of the saponins obtained by precipitation, in which eight peaks were tentatively identified by molecular weight, peak fragmentation, and matching with data from the literature.

The saponin constituents of E. longifolia belong structurally to the broader category of triterpenoid glycosides. Triterpenoid glycosides are natural glycosides present in various plants, herbs, and sea cucumbers that possess 30 carbon atoms. These compounds consist of a triterpenoid aglycone attached to one or more sugar molecules. Triterpenoid glycosides exhibit a wide range of biological activities and pharmacological properties, making them valuable in traditional medicine and modern drug discovery. The triterpenoid aglycone is frequently subdivided into oleanane, ursolic acid, and dammarane subtypes.

Co-occurring Bioactive Compounds

• Eurycomanone: A quassinoid and the principal marker compound of standardized extracts (0.8–1.5%).
• Eurypeptides: A group of small peptides known to have effects on improving energy status and sex drive in studies of rodents.
• Canthin-6-one alkaloids and isoscopoletin (coumarin): Additional identified constituents present in the standardized water extract.
• Polysaccharides: Constitute 30–55% of dry weight in standardized preparations.

4. Established Mechanisms of Action

4.1 Amphiphilic and Membrane-Interacting Properties

The fundamental biochemical behavior of glycosaponins derives from their amphiphilic molecular architecture. This activity is strongly related to the amphiphilic character of saponins that allows them to aggregate in aqueous solution and interact with membrane components. Monodesmosides exhibit strong membrane activities which are due to their amphiphilic molecular structure with a lipophilic aglycone and a hydrophilic sugar side chain.

Saponins are a diverse family of naturally occurring plant triterpene or steroid glycosides with a wide range of biological activities. They have been shown to permeabilize membranes, and in some cases membrane disruption has been hypothesized to involve saponin/cholesterol complexes.

The formation of saponin-cholesterol complexes would occupy more space in the membrane than an individual cholesterol molecule, causing the membrane to become porous and permeable to smaller ions but causing it to lose its fluidic character so that the integration of amphiphilic molecules like cholesterol is hindered.

4.2 Hormonal and Endocrine Mechanisms

Previous studies have determined that Eurycoma longifolia contains a group of small peptides referred to as "eurypeptides" that are known to have effects on improving energy status and sex drive in studies of rodents. The precise mechanism by which eurypeptides or tongkat ali root extract restores normal testosterone levels is unknown, but has been suggested as influencing the release rate of "free" testosterone from its binding proteins.

Supplementation of E. longifolia increases the restoration of testosterone levels gradually in humans as it enhances the natural biological synthesis of testosterone.

4.3 Signaling Pathway Interactions

Saponins as a broader class have been shown to interact with key cellular signaling pathways. Saponins are a class of glycosides comprising nonpolar triterpenes or sterols attached to hydrophilic oligosaccharide groups that exert antitumor effects by targeting the NF-κB, PI3Ks-Akt-mTOR, MAPK, Wnt-β-catenin, JAK-STAT3, AMPK, p53, and EGFR signaling pathways. It should be noted that this characterization applies to saponins from Chinese herbal medicines broadly, and specific pathway involvement for E. longifolia glycosaponins specifically has not been as thoroughly delineated in clinical research.

4.4 Antimalarial Mechanism

Extracts of E. longifolia have been tested for antiplasmodial activity against a multi-drug resistant Thailand strain (K-1) of P. falciparum under in vitro conditions. Researchers isolated 10-hydroxycanthin-6-one, eurycomalactone, eurycomanone, and eurycomanol from the plant, which showed antimalarial activities. These studies tested whole or fractionated extracts rather than isolated glycosaponins specifically.

5. Scientific Evidence by Area of Use

5.1 Testosterone and Male Hormonal Health

Strength of evidence: Moderate — multiple RCTs with favorable results, supported by a meta-analysis, though study heterogeneity, small sample sizes, and industry sponsorship remain limitations.

After literature screening, a total of nine studies was included in a systematic review. Five RCTs were included in the meta-analysis. A significant improvement in total testosterone levels after E. longifolia treatment was mostly reported in both healthy volunteers and hypogonadal men. The random model effect revealed a significant increase (SMD = 1.352, 95% CI 0.565 to 2.138, p = 0.001) in total testosterone levels in men receiving E. longifolia supplementation, which was confirmed in the hypogonadism subgroup.

A specific double-blind, placebo-controlled multicentre RCT investigated two doses of the standardized Physta® extract in older men. The objective of this study was to investigate the effect of two different doses of Physta®, that is, 100 and 200 mg of the standardized aqueous extract of E. longifolia root on total and free testosterone, and the quality of life (QoL) in older male subjects aged 50–70 years. Physta® supplementation at 100 and 200 mg was able to improve total testosterone levels, reduce ageing symptoms, and reduce fatigue as early as 4 and 2 weeks of supplementation, respectively.

Cortisol levels significantly decreased (P < 0.01) in the Physta® 200 mg group, while muscle strength significantly increased (P < 0.001) in both Physta® groups at week 12 in the within-group comparison. No safety-related clinically relevant changes were observed in that study.

A six-month randomized, double-blind, placebo-controlled trial examined E. longifolia combined with concurrent training. A 200 mg supplement of Eurycoma longifolia and the practice of concurrent training for 6 months significantly improved the erectile function of men with androgen deficiency of aging males (ADAM). Eurycoma longifolia increased testosterone levels in almost 50% of study participants.

5.2 Sexual Health, Libido, and Erectile Function

Strength of evidence: Preliminary to moderate — positive signals in RCTs but small populations and study heterogeneity limit firm conclusions.

A randomized, double-blind, placebo-controlled, parallel group study was carried out to investigate the clinical evidence of E. longifolia in men. The 12-week study in 109 men between 30 and 55 years of age consisted of either treatment with 300 mg of water extract of E. longifolia (Physta) or placebo. Primary endpoints included Quality of Life investigated by SF-36 questionnaire and Sexual Well-Being investigated by the International Index of Erectile Function (IIEF) and Sexual Health Questionnaires. Comparison of the two treatment groups resulted in a significant increase in total IIEF score in subjects who took the herbal product from baseline to end of trial after 12 weeks, compared to placebo. Selected IIEF items on erection during sexual activity or frequency of penetration during intercourse increased significantly during the 12-week intake of E. longifolia. Using the Sexual Health Questionnaire, significant increases were found for interest towards sexual relationship, more frequent sexual dreams, and satisfaction improvement, all in favor of the herbal treatment.

Clinical research with tongkat ali preparations has focused on male fertility enhancement, ergogenic (performance-enhancing) effects, and reducing stress, but at present there is no definitive evidence for efficacy in these conditions. A meta-analysis included two randomised controlled trials of tongkat ali extracts for 12 weeks on erectile function improvement in 139 healthy men aged 30–65 years.

Randomized controlled trials investigating E. longifolia compared to placebo were included in a review that suggested 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 a clinical effect on erectile function, but needs further clinical evidence of efficacy trials to make any firm recommendation.

5.3 Stress, Mood, and Cortisol

Strength of evidence: Preliminary — one published randomized trial in 63 subjects, results require replication in larger studies.

Stress hormones and mood state were assessed in 63 subjects (32 men and 31 women) screened for moderate stress and supplemented with a standardized hot-water extract of TA root or placebo for 4 weeks. Significant improvements were found in the TA group for Tension (−11%), Anger (−12%), and Confusion (−15%). Stress hormone profile (salivary cortisol and testosterone) was significantly improved by TA supplementation, with reduced cortisol exposure (−16%). The study found that daily supplementation with tongkat ali root extract (200 mg/day) improves stress hormone profile (lower cortisol; higher testosterone) and certain mood state parameters.

5.4 Ergogenic and Physical Performance Effects

Strength of evidence: Preliminary — small pilot studies only; larger confirmatory trials are lacking.

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 males and females (age 57–72 years). Treatment resulted in significant increases in total and free testosterone concentrations and muscular force in men and women.

A significant within-group improvement in muscle tone in both treatment groups compared to baseline confirms the observation of a previous study that proved E. longifolia, particularly Physta®, to be ergogenic by enhancing muscle strength in elderly people supplemented with 400 mg Physta® daily for 5 weeks.

An endurance exercise study using the same standardized extract investigated anabolic parameters. Thirty healthy male subjects of ages between 26 to 52 were recruited for a 24-hour mountain biking event.

5.5 Antimalarial and Antiparasitic Activity

Strength of evidence: Preclinical only (in vitro and animal); no robust human clinical trials for this indication.

Preclinical studies have provided some evidence for male fertility enhancement, anti-malarial, cytotoxic and anti-proliferative, antimicrobial, anti-inflammatory, anti-anxiety, anti-diabetic, and osteoporosis-preventive effects of Eurycoma longifolia.

Eurycomanone and 7-methoxy-β-carboline-1-propionic acid showed significant antimalarial activity against P. falciparum strains in laboratory conditions. These findings are from in vitro work and are not specific to the glycosaponin fraction.

5.6 Anti-inflammatory Activity

Strength of evidence: Preclinical in vitro; human evidence is absent for this specific indication.

The nitric oxide (NO) inhibitory activities of isolated E. longifolia compounds were examined in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Piscidinol A, 24-epi-piscidinol A, bourjotinolone A, and scopoletin were found to play an important role in suppressing NO levels without cytotoxicity.

E. longifolia is reported to have anti-inflammatory and immune-regulating properties, as well as having anti-malarial, anti-anxiolytic, cytotoxic, and anti-proliferative functions in malignancy. These properties are primarily based on preclinical data.

5.7 Bone Health

Strength of evidence: Preclinical only.

E. longifolia may lead to increased osteoblast proliferation and apoptosis of osteoclasts. This reduces bone loss in osteoporosis, and thus it can be considered as an alternative to testosterone replacement therapy (TRT) in these patients. This claim derives from preclinical studies; human clinical evidence is not available.

6. Body Systems and Health Areas

Based on the available peer-reviewed evidence, glycosaponins from E. longifolia are associated with the following body systems and health domains:

• Endocrine system: Modulation of testosterone synthesis and release; influence on cortisol and the hypothalamic-pituitary-gonadal (HPG) axis.
• Reproductive system (male): Aphrodisiac effects, erectile function, libido, spermatogenesis, and male fertility.
• Musculoskeletal system: Potential ergogenic effect on muscle strength; preclinical evidence for osteoprotective effects via osteoblast/osteoclast modulation.
• Nervous system / psychological: Mood modulation, reduction of tension, anger, and confusion in stressed subjects.
• Immune and anti-infective: Traditional use and in vitro evidence for antimalarial, antimicrobial, and anti-inflammatory activity.
• Metabolic: Traditional use for diabetes management; limited preclinical evidence.

Supplementation with Eurycoma longifolia has been shown to be efficacious for alleviating stress, as well as many other ailments including fever, arthritis, high blood pressure, diabetes, low energy or libido, bacterial infections, and cancer, based on traditional use and early research.

7. Dosage Forms and Dosages Reported in Studies

All dosages below are reported exactly as found in peer-reviewed clinical studies; no extrapolation or recommendation is made.

• 200 mg/day: The standardized water extract of Eurycoma longifolia was proposed to be used as a food supplement in amounts up to 200 mg/day in an EFSA novel food evaluation. This dose was used in the 4-week stress hormone trial (63 subjects) and in the multicentre testosterone/QoL RCT in men aged 50–70.
• 100 mg and 200 mg/day (comparative doses): The multicentre RCT investigated the effect of 100 and 200 mg of the standardized aqueous extract of E. longifolia root on testosterone and quality of life in older male subjects aged 50–70 years.
• 300 mg/day: The 12-week study in 109 men between 30 and 55 years of age consisted of either treatment with 300 mg of water extract of E. longifolia (Physta) or placebo.
• 400 mg/day (5 weeks): A study proved E. longifolia, particularly Physta®, to be ergogenic by enhancing muscle strength in elderly people supplemented with 400 mg Physta® daily for 5 weeks.
• Range across reviewed clinical trials: Research protocols across nine studies spanned dosages from 100–600 mg daily with treatment durations ranging from two weeks to six months.

The extract is most commonly available as oral capsules or tablets of the standardized hot-water root extract powder. The preparation designated Physta® has been used in the largest number of human clinical trials and is standardized to defined minimum levels of glycosaponin (≥40%), polysaccharides, protein, and eurycomanone.

8. Safety Considerations and Regulatory Status

8.1 Regulatory Evaluation

Following a request from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver an opinion on Eurycoma longifolia (Tongkat Ali) root extract as a novel food pursuant to Regulation (EU) 2015/2283. The NF is a standardized water extract prepared from the dried ground root chips and was proposed to be used as a food supplement in amounts up to 200 mg/day. The target population is the adult population, except pregnant and lactating women.

8.2 Genotoxicity Signal

A critical safety finding was identified during EFSA's novel food assessment. The EFSA Panel notes positive results from the submitted in vitro chromosome aberration test, which indicates clastogenic properties of the NF. The EFSA Panel on Nutrition, Novel Foods and Food Allergens concludes that the NF has the potential to induce DNA damage, which is of concern, particularly locally for tissues that represent first sites of contact. This is a formally documented regulatory concern of scientific significance.

8.3 Analytical Gaps Regarding the Glycosaponin Fraction Specifically

The EFSA's Advisory Committee on Novel Foods and Processes (ACNFP) raised concerns, noting that analytical data on the glycosaponin content — which makes up 40–60% of the total weight of the NF — was considered to be important given the potential pharmacological nature of the product. The identity and full chemical characterization of the glycosaponin fraction therefore remains an active area of scientific scrutiny.

8.4 Chronic Toxicity (Animal Studies)

A 12-month chronic toxicity study in rats at 250, 500, and 1000 mg/kg bodyweight per day revealed no toxicity for E. longifolia extract.

8.5 Human Clinical Safety Observations

In the multicentre RCT using Physta® (100 mg and 200 mg), no safety-related clinically relevant changes were observed. However, the scope and duration of existing human safety data remains limited, and longer-term human studies are lacking.

8.6 Special Populations

The standardized extract has been proposed to be used as a food supplement in amounts up to 200 mg/day and the target population is the adult population, except pregnant and lactating women.

8.7 Potential Drug Interactions

No formal human pharmacokinetic interaction studies specific to the glycosaponin fraction of E. longifolia were identified in peer-reviewed sources. The extract can also contain canthin-6-one alkaloids and isoscopoletin (coumarin), components that have known pharmacological activity and may be relevant to interactions with anticoagulants or other metabolized drugs, though this has not been formally studied in clinical trials.

8.8 Evidence Quality Limitations

Most clinical trials and reviews have involved a specific tongkat ali product, although it is unclear if the products tested across studies were identical. Large, robust, long-term studies using well-defined extracts of Eurycoma longifolia that meet accepted standards for pharmaceutical quality are required.

It is important to note that the majority of studies, and all of the human supplementation trials, have been conducted on specific hot-water-extracts of Eurycoma longifolia (which is the traditional Malaysian preparation) produced using a patented extraction process. Findings from these studies may not be generalizable to other commercial preparations or extraction methods.

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