eurycomaona

Eurycomanone: A Comprehensive Reference Article

1. Identity and Chemical Characterization

1.1 Nomenclature

Eurycomanone is a quassinoid diterpenoid compound primarily isolated from the roots of Eurycoma longifolia Jack, a medicinal plant native to the tropical rainforests of Southeast Asia and commonly known as Tongkat Ali. The compound is also known in the literature by the synonym pasakbumin-A. Its CAS registry number is 84633-29-4.

As the most abundant bioactive quassinoid in the plant's root extracts, it features the molecular formula C₂₀H₂₄O₉. The quassinoids are a group of nortriterpenoids with dynamic pharmacological properties. Eurycomanone is a highly oxygenated, bitter-tasting natural product characteristic of the Simaroubaceae family.

1.2 Botanical Source

Eurycoma longifolia (commonly called tongkat ali, Malaysian ginseng, or long jack) is a flowering plant in the family Simaroubaceae. It is native to Indochina (Cambodia, Laos, Malaysia, Myanmar, Thailand, and Vietnam) and Indonesia (the islands of Borneo and Sumatra), but has also been found in the Philippines. The plant is a medium-sized slender shrub that can reach 10 m (33 ft) in height, and is often unbranched.

Eurycomanone is distributed throughout the plant, with the highest concentration in leaves. Researchers measured 6.0568 μg/mL in leaves, and only 0.3533 μg/mL in roots. However, a separate study using UPLC analysis found variable concentrations depending on geographic provenance. Findings showed that the highest percentage of eurycomanone present in the root extract was from Terengganu (Malaysia) at 1.46%, while the lowest was from Melaka at 0.17%. The stem part of the plant showed eurycomanone in relatively small percentages, except for Terengganu.

Eurycomanone is the major quassinoid in E. longifolia and is used as a marker compound in quality control of commercial products derived from this plant. The metabolite type and concentration in E. longifolia plant extracts depend on the processing temperature as well as geographical factors.

1.3 Related Compounds in the Plant

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. Other quassinoid compounds closely related to eurycomanone include 13α,21-dihydroeurycomanone, 13α(21)-epoxyeurycomanone, and eurycomanol. In a standardized extract (Fr 2), concentrations were characterized as 4.0% 13α(21)-epoxyeurycomanone (EP), 18.5% eurycomanone (EN), 0.7% 13α,21-dihydroeurycomanone (ED), and 9.5% eurycomanol (EL).

1.4 Common Forms and Preparations

E. longifolia is prepared as a water decoction or as a commercial extract in the form of capsules. Today, the consumption of E. longifolia is popular through the incorporation of its extract in food items, most frequently in drinks such as tea and coffee. In commercial supplement products, eurycomanone content in standardized extracts is specified. The standardized novel food water extract proposed for supplementation is prepared from the dried ground root chips of Tongkat Ali and is proposed for use as a food supplement in amounts up to 200 mg/day, targeting the adult population, except pregnant and lactating women. The characteristic components are glycosaponins (40–65%) and eurycomanone (0.8–1.5%).

Out of 41 products containing E. longifolia as a single or compound formulation from Malaysia, 24 products contained eurycomanone: 11/24 reached the recommended levels, while 9 were above the recommended levels (1.6–8.48% w/v). Some products did not contain any eurycomanone. This highlights significant variability in commercial product standardization.

2. Traditional and Historical Use

2.1 Cultural and Geographic Traditions

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. The root has been used in traditional medicine in Southeast Asia over centuries.

According to traditional medicine of the Southeast Asian region, the root of E. longifolia is the most valuable component, and its extract is used in traditional medicine for the treatment of diseases such as persistent fever, malaria, aches, dysentery, sexual insufficiency, restoring energy and vitality, enhancing blood flow, and as a herbal ingredient for women after childbirth.

2.2 Specific Plant Parts and Their Traditional Uses

Different parts of the plant were employed in traditional medicine for different purposes. Decoctions of E. longifolia leaves were used for washing itches, while its fruits were used in curing dysentery. Its bark was mostly used as a vermifuge, while the taproots were used to treat high blood pressure, and the root bark was used for the treatment of diarrhea and fever.

Mostly, the root extracts of E. longifolia were 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 were also used as an aphrodisiac, antibiotic, appetite stimulant, and health supplement.

2.3 Traditional Preparation Methods

The primary traditional preparation involved water-based decoctions of the root material. Eurycoma longifolia Jack, known locally as "Tongkat Ali" by the ethnic population, is popularly taken as a traditional remedy to improve the male libido, sexual prowess, and fertility. Many tea, coffee, and carbonated beverages pre-mixed with the root extract are available commercially for the improvement of general health and libido.

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.

3. Phytochemistry: Key Constituents and Compound Class

3.1 Quassinoid Class

The major compounds found in the roots of E. longifolia belonging to quassinoids (degraded triterpenes) are among the compounds known to contribute to various medicinal effects based on in vitro and/or in vivo studies, including anticancer properties. Quassinoids are even effective at inhibiting cell growth at nanomolar and subnanomolar concentrations.

From the roots, several classes of compounds have been identified and they include quassinoids, canthin-6-one alkaloids, β-carboline alkaloids, tirucallane-type triterpenes, squalene derivatives, and biphenylneolignans. Beside 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, coumarins, squalenes, triterpenes and biphenylneolignans.

3.2 Eurycomanone as a Marker Compound

Eurycomanone, as the dominant quassinoid, is universally used as the chemical marker for quality standardization of commercial E. longifolia products. Eurycomanone (a quassinoid, CAS number 84633-29-4) was proposed as the major marker compound for the specification of the novel food. More than 85 compounds have been reported from aqueous extracts of E. longifolia and characterized by liquid chromatography with tandem mass spectrometry (LC-MS/MS).

4. Mechanisms of Action

4.1 Steroidogenesis: Aromatase Inhibition

Eurycomanone is thought to be central to the sex-hormone increasing effects of Eurycoma longifolia supplementation. In vitro, eurycomanone has been shown to enhance testosterone steroidogenesis through its inhibitory effects on aromatase, presumably causing testosterone production to increase to restore downstream estrogen homeostasis.

Eurycomanone enhanced testosterone steroidogenesis at the Leydig cells by inhibiting aromatase conversion of testosterone to oestrogen, and at a high concentration may also involve phosphodiesterase inhibition. The quassinoid was non-responsive to the inhibition of oestrogen receptor by tamoxifen, but displayed improved formestane inhibition of aromatase in reducing oestrogen production. The molecular docking studies further supported that eurycomanone and formestane bound to aromatase with similar orientations and free energy binding values.

4.2 Phosphodiesterase (PDE) Inhibition

Eurycomanone significantly increased testosterone production dose-dependently at 0.1, 1.0 and 10.0 μM (P<0.05), but the two lower doses combined with 3-isobutyl-1-methylxanthine (IBMX), the phosphodiesterase inhibitor, were not significantly higher than eurycomanone or IBMX alone, except at a higher concentration. The molecular docking studies indicated eurycomanone and IBMX were binding at different sites of the enzyme.

4.3 Hypothalamic-Pituitary-Gonadal (HPG) Axis Modulation

E. longifolia root extract induced testosterone synthesis along with an increase in LH and FSH but decreased the oestrogen level. This provided evidence that E. longifolia root extract may potentially down-regulate the oestrogen-mediated feedback effect on LH and FSH secretion in the HPG axis.

4.4 Apoptosis and Anticancer Signaling

The prime mode of cytotoxicity of Eurycoma longifolia and its medicinal compounds is the induction of apoptosis (programmed cell death) via the up-regulation of the expression of p53 (tumor suppressor protein) and pro-apoptotic protein (Bax) and downregulation of the expression of anti-apoptotic protein (Bcl-2). A remarkable alleviation in the mRNA expression of various cancer-associated biomarkers including heterogeneous nuclear ribonucleoprotein (hnRNP), prohibitin (PHB), annexin-1 (ANX1) and endoplasmic reticulum protein-28 (ERp28) has also been evidenced.

4.5 Anti-inflammatory Mechanisms

In RAW 264.7 cells stimulated with poly(I:C), a viral mimic, eurycomanone inhibited pro-inflammatory cytokines IL-6 (IC50 = 5.14 ± 0.60 µM) and TNF-α (IC50 = 2.32 ± 0.40 µM), while also suppressing the anti-inflammatory cytokine IL-10 (IC50 = 14.60 ± 0.32 µM), indicating a regulatory role in inflammatory responses. This suppression reduced overall cytokine-mediated inflammation without completely abolishing macrophage function.

4.6 Lipid Metabolism and Lipolysis

Results from in vitro and in vivo combination studies showed that eurycomanone (and other quassinoids) decreased fat, cholesterol, and triglyceride accumulation and also promoted lipolysis (fat breakdown). Additionally, the treatment reduced fat accumulation in the liver, improved glucose tolerance, and enhanced metabolism. These findings, however, are preclinical and have not been confirmed in clinical human trials specifically for eurycomanone.

5. Scientific Evidence by Area of Use

5.1 Male Reproductive Health and Testosterone

Systematic Review and Meta-Analysis Evidence

After literature screening, a total of nine studies was included in a systematic review of E. longifolia's effect on testosterone. 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. This systematic review and meta-analysis, conducted according to PRISMA guidelines, represents the most methodologically robust clinical evidence to date.

Randomized Controlled Trial: Sexual Well-Being (2012)

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 were Quality of Life investigated by SF-36 questionnaire and Sexual Well-Being investigated by IIEF and Sexual Health Questionnaires, Seminal Fluid Analysis, fat mass, and safety profiles. The E. longifolia group significantly improved in the domain of Physical Functioning of SF-36, from baseline to week 12 compared to placebo (P = 0.006) and between groups at week 12 (P = 0.028).

Randomized Controlled Trial: ADAM (2020)

A 6-month, randomized, double-blind, placebo-controlled four-arm clinical trial enrolled 45 men (47.38 ± 5.03 years) randomized into 4 groups (G1: control + placebo; G2: control + Eurycoma longifolia; G3: concurrent training + placebo; G4: concurrent training + E. longifolia). Twenty-two received a 200 mg supplement of E. longifolia and 23 underwent the intervention with concurrent training, 3 times a week for 60 minutes at progressive intensity. Eurycoma longifolia increased testosterone levels in almost 50% of study participants. Erectile function demonstrated improvements in both interventions; however, the most significant results were obtained by men allocated to concurrent training plus E. longifolia. A 200 mg supplement of E. longifolia and the practice of concurrent training for 6 months significantly improved the erectile function of men with ADAM. A notable limitation noted by the authors is that the main limitation is the study not having groups that used only Eurycoma longifolia and only concurrent training, making it difficult to isolate the compound's independent contribution.

Evidence Limitations

Clinical trials to date have been conducted predominantly on standardized E. longifolia root extracts rather than on isolated eurycomanone itself. The testosterone-related evidence, while showing a positive direction, is largely based on small sample sizes. It is also a widely used dietary supplement by bodybuilders, who believe that it increases testosterone levels and athletic performance, although there is no clinical evidence for its effectiveness on health or any disease per a rigorous clinical standard. Any increases in testosterone levels appear to be small and do not seem to help improve physical performance.

5.2 Antimalarial Activity

In Vitro Evidence

Eurycomanone was one of the quassinoids which exhibited high antiplasmodial activity compared to chloroquine treatment against chloroquine-resistant or multidrug-resistant Plasmodium falciparum. The findings revealed that eurycomanone was found to be 8.66 times more potent than chloroquine diphosphate against the isolate. The presence of an α,β-unsaturated ketone at C-2 in ring A of eurycomanone was reported to confer the strong antiplasmodial activity of eurycomanone.

Eurycomanone exhibits activity against Plasmodium falciparum, aligning with traditional uses of its source plant. In vitro assays against the parasite showed an IC50 of 3.96 µg/mL, with stage-specific inhibition observed across the erythrocytic cycle, particularly targeting ring and trophozoite stages. Other eurycomanone derivatives such as 13,21-dihydroeurycomanone and 13,21-epoxyeurycomanone were also more potent than chloroquine diphosphate against the Gombak A isolate of P. falciparum, whereas eurycomanol was found to be less potent in antimalaria.

Evidence Strength

All antimalarial evidence for eurycomanone remains at the in vitro level. No clinical trials in human malaria patients have been published to date. The evidence is therefore considered preliminary and hypothesis-generating.

5.3 Anticancer Properties

In Vitro Cytotoxicity

Each compound was evaluated against a panel of cell lines comprising a number of human cancer cell types (breast, colon, fibrosarcoma, lung, melanoma, KB, and KB-V1, a multi-drug resistant cell line derived from KB) and murine lymphocytic leukemia (P-388). Eurycomanone was inactive against murine lymphocytic leukemia (P-388) but was significantly active against the human cell lines tested.

Eurycomanone was reported to have anticancer effects in breast, colon, fibrosarcoma, lung, and melanoma cancer cell lines, with IC50 values ranging from 0.49 to 35 µM.

The findings suggested that eurycomanone was cytotoxic on cancerous liver cells (HepG2) and less toxic on normal cells (Chang's liver and WLR-68). Furthermore, various methods proved that apoptosis was the mode of death in eurycomanone-treated HepG2 cells. The characteristics of apoptosis including chromatin condensation, DNA fragmentation and apoptotic bodies were found following eurycomanone treatment.

Quassinoids such as eurycomanone were reported to have in vitro anticancer effects against breast cancer, colon adenocarcinoma, fibrosarcoma, lung cancer cells and melanoma, whereas eurycomalactone was reported to have in vitro anticancer effects against murine lymphocytic leukemia, epidermoid, melanoma, breast, lung and colon cancer cells.

Evidence Strength

All anticancer evidence for eurycomanone remains at the in vitro and, to a lesser degree, in vivo (rodent) level. Eurycoma longifolia and its medicinal constituents exhibit promising anticancer efficacy and can be considered as a potential complementary therapy for the treatment of various types of human cancers, but no human clinical oncology trials have been reported. Translational significance from cell culture to clinical outcomes cannot be established without such trials.

5.4 Anti-inflammatory Activity

The anti-inflammatory evidence for eurycomanone is entirely preclinical. In vitro studies in macrophage cell lines (RAW 264.7) have documented inhibition of pro-inflammatory cytokines, as described above in the mechanisms section. No dedicated human clinical trials evaluating eurycomanone's anti-inflammatory effects as a primary endpoint have been published.

5.5 Antiulcer Activity

Two quassinoids, pasak bumi A (also known as eurycomanone) and pasak bumi B exhibited antiulcer activity in preclinical research. This evidence is limited to in vitro and animal model data.

5.6 Lipolytic and Anti-Obesity Activity

In an effort to discover anti-obesity agents from medicinal plants, research groups have uncovered the potential of Eurycoma longifolia Jack for reducing lipid accumulation. Eurycomanone has been identified as contributing to this lipolytic activity. These results are preclinical; no human clinical trials specifically for eurycomanone's anti-obesity potential have been reported.

6. Body Systems Associated with Eurycomanone

• Endocrine/Reproductive System: Eurycomanone enhanced testosterone steroidogenesis at the Leydig cells by inhibiting aromatase conversion of testosterone to oestrogen, and at a high concentration may also involve phosphodiesterase inhibition.
• Immune System: In vitro inhibition of pro-inflammatory cytokines (IL-6, TNF-α) in macrophage cell lines, as noted above.
• Hepatic System: Eurycomanone was cytotoxic on cancerous liver cells (HepG2) and less toxic on normal cells in vitro; however, hepatotoxic concerns also exist in vivo (see Safety section).
• Hematological/Parasitic: Antiplasmodial activity against P. falciparum demonstrated in vitro.
• Metabolic System: Preclinical evidence for effects on lipid accumulation, lipolysis, and glucose tolerance.

7. Dosage Forms and Reported Dosages

7.1 Forms of Administration

E. longifolia is prepared as a water decoction or commercial extract in the form of capsules. Because eurycomanone is rarely administered as a pure isolated compound, dosage information in clinical research is expressed in terms of the whole or standardized root extract. The novel food standardized water extract is proposed to be used as a food supplement in amounts up to 200 mg/day.

7.2 Dosages Reported in Clinical Studies

• A 12-week study in 109 men between 30 and 55 years of age used either 300 mg of water extract of E. longifolia (Physta) or placebo.
• In a 6-month ADAM trial, 22 men received a 200 mg supplement of Eurycoma longifolia.
• In in vitro mechanistic studies, eurycomanone at 0.1–10 µM significantly increased the testosterone level following a dose-dependent manner over that of the non-treated control.

7.3 Eurycomanone Content of Standardized Products

The characteristic components of the EFSA-reviewed standardized novel food are glycosaponins (40–65%) and eurycomanone (0.8–1.5%). Therefore, a 200 mg dose of such an extract would contain approximately 1.6–3.0 mg of eurycomanone.

8. Pharmacokinetics and Bioavailability

8.1 Oral Bioavailability

Eurycomanone is poorly bioavailable when given orally. A comparison of the AUC(0→∞) obtained orally to that obtained after an intravenous administration (normalized for dose differences) revealed that the absolute bioavailability of the compound was low, at 10.5%. Following intravenous injection, plasma eurycomanone concentrations declined rapidly to zero after 8 hours. Following oral administration, its Cmax and Tmax values were detected as 0.33 ± 0.03 μg/mL and 4.40 ± 0.98 h, respectively.

8.2 Distribution and Elimination

The compound appeared to be well distributed in extravascular fluids because of its relatively high volume of distribution (Vd) value. However, once absorbed, the compound is not easily metabolized (is stable), hence retaining its bioactive properties, which may be responsible for the various reported biological activities.

8.3 Interspecies Differences

The bioavailability of eurycomanone in its pure form or as a compound of the novel food was characterized by a series of in vitro and in vivo studies in rats and mice. This study confirmed the similar bioavailability of eurycomanone in rats following oral administration in comparison to an earlier study. However, a higher bioavailability for mice suggested interspecies differences, and the pharmacokinetic values may not be directly extrapolated from rodents to humans, as concluded by the study authors.

8.4 Reason for Poor Oral Bioavailability

The poor oral bioavailability was not attributed to instability problems because eurycomanone has been shown to be stable under different pH conditions. Thus, its poor oral bioavailability may be due to poor membrane permeability in view of its low partition (P) value and/or high first-pass metabolism.

9. Safety Considerations

9.1 Acute Toxicity (Animal Data)

An acute toxicity study has found that the oral LD50 of the alcoholic extract of E. longifolia in mice is between 1500–2000 mg/kg, while the oral LD50 of the aqueous extract form is more than 3000 mg/kg. A 12-month chronic toxicity study in rats at 250, 500, and 1000 mg/kg body weight per day revealed no toxicity for E. longifolia extract.

9.2 Genotoxicity Concerns (EFSA Assessment)

The EFSA Panel on Nutrition, Novel Foods and Food Allergens concluded that the novel food has the potential to induce DNA damage, which is of concern, particularly locally for tissues that represent first sites of contact. Specifically, the Panel noted that the NF induced a dose-dependent increase in aberrant cells in an in vitro mammalian chromosome aberration test using cultured human lymphocytes, thus showing clastogenic properties. While the positive results observed at the highest dose (2,500 μg/mL) may have been caused by cytotoxicity, no signs of overt cytotoxicity were seen at the low- and mid-dose groups (500 and 1,000 μg/mL).

9.3 Hepatotoxicity

Rare cases of liver injury have occurred from its use, mostly in bodybuilders. In preclinical fish models, significant genotoxic effects (micronuclei and DNA damage) and elevation in biochemical parameters (AST, ALT, and LDH) were detected in the high-dose group. These findings suggest hepatic stress at supratherapeutic exposures.

9.4 Drug Interactions: Cytochrome P450

Eurycomanone was examined for modulatory effects on cytochrome P450 isoforms CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, and CYP3A4 using in vitro assays. The IC50 value was determined to assess the potencies of modulation for each CYP isoform. Results indicated that eurycomanone did not potently inhibit any of the CYP isoforms investigated, with IC50 values greater than 250 μg/mL. Hence there appears to be little likelihood of drug-herb interaction between eurycomanone or herbal products with high content of this compound and CYP drug substrates via CYP inhibition. This finding is qualified as applying to in vitro conditions only.

9.5 Allergenic Potential

Within the same family Simaroubaceae, the eventual allergenic potential is seen in two out of 19 plant genera only (Ailanthus and Alvaradoa), whereas no data are available on the genus Eurycoma and on the species E. longifolia. The EFSA Panel considered that the likelihood of allergenic reactions to the NF is low.

9.6 Populations of Concern

The standardized water extract is proposed to be used as a food supplement in amounts up to 200 mg/day, with the target population being the adult population, except pregnant and lactating women. The exclusion of pregnant and lactating women reflects the absence of safety data in these populations rather than established evidence of harm.

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