Aegeline: A Comprehensive Reference Article
1. Identity
Chemical and Botanical Classification
Aegeline is a naturally occurring alkaloid isolated from Aegle marmelos. Chemically, aegeline is classified as a secondary metabolite and is categorized under the group of alkaloids. It is specifically identified as an N-acylated amino alcohol. Its full systematic (IUPAC) name is N-[2-hydroxy-2-(4-methoxyphenyl)ethyl]-3-phenyl-2-propenamide, reflecting a cinnamoyl group linked via an amide bond to an aminoalcohol bearing a para-methoxyphenyl substituent.
The plant belongs to the Rutaceae family and has been recognized for its diverse pharmacological activities, including anti-diabetic, anti-hyperlipidemic, and anti-inflammatory effects.
Physical and Chemical Properties
Aegle marmelos extract containing aegeline carries the CAS number 456-12-2, a molecular formula of C19H17NO2, and a molecular weight of 291.35 g/mol. The compound typically appears as a yellowish crystalline powder, and it is sourced from the fruits, leaves, or bark of the sacred bael tree native to India and Southeast Asia. Some supplier databases alternatively list the molecular formula as C18H19NO3 with a molecular weight of 297.35 g/mol — a discrepancy in the literature that likely reflects the different stereoisomeric and enantiomeric forms of the molecule. Aegeline is naturally available in racemic form.
Other Natural Sources
While Aegle marmelos is the primary and most widely studied source, aegeline was also found in the methanolic extract of Sarcorhachis naranjoana as an active compound after bioassay-guided fractionation. Additionally, total synthesis chemists have reported X-ray structures of the naturally occurring (R)-(−)-aegeline, also isolated from Fagara hyemalis.
Commercial and Supplement Forms
In the dietary supplement industry, aegeline has been sold both as an extract of Aegle marmelos leaves and as a synthetic product produced in China, which may have included contaminants, synthetic precursors, metabolic derivatives, or racemic forms of the chemical. It has appeared in formulations marketed as weight-loss aids and "thermogenic" products. The extraction of aegeline from plant material begins with the collection of Aegle marmelos leaves, which are dried and powdered. The extraction process typically involves Soxhlet extraction using 75% methanol at 70 °C.
2. Botanical Source: Aegle marmelos (Bael)
Taxonomy and Distribution
Aegle marmelos (L.) Correa, commonly known as bael, belongs to the family Rutaceae. Commonly known as bael in northern India, the plant has been used in traditional medicinal practices for more than 5,000 years. It is native to India, Bangladesh, Nepal, and Pakistan, but is also found in Thailand, Malaysia, Sri Lanka, Cambodia, the Philippines, Myanmar, Java, and other Southeast Asian countries.
Bael has various names in different Indian languages, such as Bilva and Shivaphala in Sanskrit; Bel, Beli, and Belgiri in Hindi; and Vilva marum in Tamil. Other names include Be Li in Sinhalese, Matoom in Thai, and Bela in Spanish.
Aegle marmelos is a subtropical, usually medium to large-sized deciduous tree growing well in dry forests of plain and hilly areas, up to a height of about 1,200 m above sea level, and can adapt to a wide range of habitats.
Plant Parts Bearing Aegeline
Each part of the tree — root, bark, fruit, leaf, and flower — has therapeutic significance in Ayurvedic as well as other traditional medicinal systems. Aegeline itself is most concentrated in the leaves. Alkaloids, including aegeline, marmesin, and marmelosin, are found in roots and leaves of Aegle marmelos. Phytochemical investigations have additionally revealed that in previous phytochemical investigations on the leaves, alkaloids, coumarins, flavonoids, steroids, triterpenes, and essential oils were isolated.
Co-occurring Compounds
Aegeline is only one of a rich array of bioactive compounds found in Aegle marmelos. The plant's ethnomedicinal properties are partly attributable to its ability to synthesize alkaloids, cardiac glycosides, anthocyanins, flavonoids, steroids, saponins, terpenoids, tannins, lignins, quinones, and coumarins, among other chemical classes. Key identified compounds include aegeline, auroptene, umbelliferone, psoralene, marmin, imperatorin, and skimmianine. The fruit portion contains flavonoids and phenolic acids known for their antioxidant and cardioprotective effects, including kaempferol, chlorogenic acid, protocatechuic acid, gallic acid, ferulic acid, quercetin, and ellagic acid.
3. Traditional and Historical Use
Ancient Textual Record
Mention of Aegle marmelos has been found in writings dating back to 800 B.C. It is cultivated throughout India, mainly in temple gardens because of its status as a sacred tree, and also in Pakistan and Northern India. Aegle marmelos is widely recognized from prehistoric times for its therapeutic characteristics.
Religious and Cultural Significance
Bael (Aegle marmelos Corrêa) is considered a sacred tree by Hindus and is offered to Lord Shiva in worship. It grows in the Indian subcontinent and Southeast Asia and is called by various names in different regions. The tree is also sacred to the Jains; the 23rd Tirthankara, Bhagwan Parasnathji, is said to have attained enlightenment under a bael tree.
Traditional Medical Systems
For centuries, the bael tree has held a significant place in Ayurveda, Siddha, and Unani systems of healing, where its extracts — including aegeline — have been valued for a range of therapeutic applications. Aegle marmelos (bael) has a long history of use in traditional medicine across Southeast Asia, with roots in the ancient Indian traditional medicinal system, Ayurveda.
Conditions Treated
Bael has been used as a traditional medicine in India and other Southeast Asian countries to treat various ailments, including diarrhea, chronic dysentery, constipation, gonorrhea, catarrh, diabetes, deafness, inflammations, ulcerated intestinal mucosa, intermittent fever, melancholia, heart palpitation, and also to control fertility. Traditionally used preparations addressed jaundice, constipation, chronic diarrhea, dysentery, stomach-ache, fever, asthma, inflammations, febrile delirium, acute bronchitis, and snakebite.
Traditionally, aegeline-rich bael leaf infusions have been used to support healthy digestion, manage diabetes, and promote cardiac wellness. Folk remedies often recommend bael leaf preparations for their gentle laxative effect and to help alleviate respiratory conditions such as asthma and bronchitis.
Traditional Preparations
Many parts of the bael tree, including stem, bark, root, leaves, fruits, and seeds, find usage in traditional medicine. Various parts have been used from prehistoric times in traditional systems of medicine for wound healing; curing digestive disorders, ulcers, hypertension, and respiratory infections; and relieving dysentery, diarrhea, and constipation, among numerous other ailments.
4. Key Constituents and Chemical Relationships
Biosynthetic Precursor
A rare alkaloid, shahidine, which contains an unstable oxazoline ring, has been found to be the parent compound of aegeline and related amides. This discovery illuminated part of the biosynthetic pathway through which the plant produces the alkaloidal amide.
Structure–Activity Relationships and Enantiomeric Considerations
Aegeline is naturally available in racemic form. Most studies have been done on the isolated aegeline from the plant. Synthetic derivatives or analogues that have been studied for biological activity are also not specified for their chirality. Further studies can be done to explore the therapeutic potential of its individual enantiomers along with the safety profile.
Synthetic chemistry work has produced optically pure forms: optically active β-aminoalcohols are important structural elements in chiral drugs, such as α- or β-adrenergic blockers and agonists in the treatment of cardiovascular disease, cardiac failure, asthma, antidepressants, and glaucoma.
5. Mechanisms of Action
β3-Adrenergic Receptor Agonism (Proposed)
Earlier research reported that aegeline, an N-acylated-1-amino-2-alcohol isolated from the leaves of Aegle marmelos, showed anti-hyperlipidemic activity, for which QSAR studies predicted the compound to be a β3-adrenergic receptor (β3-AR) agonist, but the mechanism of its action was not elucidated. This receptor subtype is involved in fatty acid oxidation and thermogenesis in adipose tissue, linking the proposed mechanism to potential metabolic effects.
GLUT4 Translocation and Glucose Transport
Aegeline is an alkaloidal-amide isolated from the leaves of Aegle marmelos and has shown antihyperglycemic as well as antidyslipidemic activities in validated animal models of type 2 diabetes mellitus. Research has shown that aegeline enhanced GLUT4 translocation-mediated 2-deoxy-glucose uptake in both a time- and concentration-dependent manner, and this uptake was completely blocked by transport inhibitors (wortmannin and genistein) in C2C12 myotubes. Pharmacological inhibition of Akt (protein kinase B) and Rac1 suggested that both Akt and Rac1 operate aegeline-stimulated glucose transport via distinct parallel pathways.
Moreover, aegeline activates p21 protein-activated kinase 1 (PAK1) and cofilin (an actin polymerization regulator). Rac1 inhibitor and PAK1 inhibitor completely blocked aegeline-induced phosphorylation of cofilin and PAK1.
Aegeline has been depicted to enhance GLUT4 translocation and 2-deoxy-glucose uptake in C2C12 myotubes at a concentration range of 1–10 μM. The aegeline-mediated glucose transport was observed through the Akt pathway.
LOX-1 / Oxidized LDL Pathway
This study explored the binding affinity of aegeline to LOX-1 for the first time. Targeting LOX-1 may provide a novel therapeutic strategy for hypercholesterolemia and vascular diseases. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL (Ox-LDL) in the aorta. LOX-1 has been identified first in endothelial cells as the major Ox-LDL receptor; macrophages and smooth muscle cells also express LOX-1, altogether contributing to the induction of endothelial dysfunction.
Anti-inflammatory Mechanisms
Aegeline inhibited histamine release from RBL-2H3 cells induced by DNP(24)-BSA. Aegeline showed strong inhibition when RBL-2H3 cells were induced by Ca²⁺ stimulants such as thapsigargin and ionomycin. The inhibitory effects of aegeline on histamine release from mast cells involved mechanisms related to intracellular Ca²⁺ signaling events via the same target as thapsigargin or a downstream process of intracellular Ca²⁺ signaling in mast cells.
Metabolic Activation and Toxicological Pathway
Research has identified reactive metabolites related to aegeline's metabolic pathways. A demethylation metabolite (M1) and a glutathione (GSH) conjugate (M2) were detected in rat liver microsomal incubations containing aegeline and GSH. Both metabolites were found in the bile of rats and rat primary hepatocytes after aegeline administration. Recombinant P450 enzyme incubations showed that CYP2C19 was the principal enzyme catalyzing this metabolic activation. Ticlopidine, a selective inhibitor of CYP2C19, decreased the formation of M1 and M2 in hepatocytes and attenuated the susceptibility of hepatocytes to cytotoxicity. The results suggest that aegeline was metabolized to a p-quinone methide intermediate which could in part participate in aegeline-induced cytotoxicity.
6. Scientific Evidence by Area of Use
6.1 Blood Glucose Regulation and Type 2 Diabetes
Evidence Type: Animal and in vitro (preclinical only; no human clinical trials identified in the peer-reviewed literature).
Aegeline has shown antihyperglycemic as well as antidyslipidemic activities in validated animal models of type 2 diabetes mellitus. In rat studies, treatment with aegeline lowered blood glucose by 12.9% at 5 hours and 16.9% at 24 hours at 100 mg/kg body weight. In hamster models, aegeline was administered orally at a dose of 50 mg/kg body weight for seven consecutive days.
At the cellular level, aegeline enhanced basal glucose uptake at a minimum concentration of 5.0 μM (1.39-fold, P<0.05 vs. control). Maximum increase in basal glucose uptake was found in C2C12 myotubes treated with aegeline at a 10 μM concentration in the medium (1.71-fold, P<0.01 vs. control) for 24 hours of incubation.
Regarding synthetic analogues inspired by aegeline, analogues of aegeline have shown promise in reducing insulin resistance in adipocytes, with similar effects observed in high-fat diet-fed mice, where a 50 mg/kg dose improved insulin sensitivity and glucose tolerance.
Evidence strength: Preliminary. All available data are from animal or cell-based studies. No controlled human clinical trials on aegeline's antidiabetic effects have been identified in the peer-reviewed literature.
6.2 Lipid Metabolism and Anti-atherosclerotic Effects
Evidence Type: Animal in vivo and cell-based studies only.
In an animal study, the pathology group rats were fed a high-cholesterol diet (HCD) for 45 days, and the treatment group rats were fed HCD with aegeline or atorvastatin for the last 30 days. In vivo and in vitro experiments were carried out to assay markers of atherosclerosis such as Ox-LDL and LOX-1 levels. Histopathological examination was performed, and Oil Red O staining was carried out in the IC-21 cell line. Docking studies were also performed.
Aegeline administration effectively reduced lipid levels induced by HCD. Lowered levels of Ox-LDL and LOX-1 in aegeline-administered rats indicated it to be a potent antihypercholesterolemic agent. Compared to atorvastatin, aegeline had a pronounced effect in downregulating lipid expression evidenced by Oil Red O staining. Aegeline binds with LOX-1 at a higher affinity validated by docking.
Both aegeline and atorvastatin were found to decrease atherogenic risk, affording cardioprotection. Moreover, the efficacy of aegeline in combating hypercholesterolemia was described as more or less similar to that of atorvastatin in the studied animal model.
Evidence strength: Preliminary animal and in vitro data only. No human studies. Caution is required in extrapolating these findings to clinical use.
6.3 Adipogenesis Inhibition and Body Weight
Evidence Type: In vitro cell-based studies only.
Aegeline was screened for adipogenesis inhibition at 50 and 100 μM concentrations. Aegeline showed 16.29 ± 0.85% lipid content at 100 μM. Despite these in vitro observations, aegeline has been used as an ingredient in weight-loss products, but there is no evidence that it is effective for weight loss in humans.
Evidence strength: Very weak — cell-based only. No animal weight-loss studies with aegeline alone and no human data.
6.4 Anti-inflammatory and Antihistamine Activity
Evidence Type: In vitro cell-based studies.
Aegeline inhibited histamine release from RBL-2H3 cells induced by DNP(24)-BSA. Aegeline showed strong inhibition when RBL-2H3 cells were induced by Ca²⁺ stimulants such as thapsigargin and ionomycin. The inhibitory effects of aegeline on the histamine release from mast cells depended on the type of mast cell and also involved some mechanisms related to intracellular Ca²⁺ signaling events.
Aegeline has also been shown to possess both anti-inflammatory and antihyperlipidemic activity, as observed in studies in fatty liver conditions.
Evidence strength: Preliminary, in vitro only. No human clinical trials on aegeline as an anti-inflammatory agent have been identified.
6.5 Gastrointestinal / Antidiarrheal Activity
Evidence Type: Preclinical in vitro study (whole plant extract rather than isolated aegeline); strong traditional evidence.
A decoction of the unripe fruit pulp of A. marmelos, despite having limited antimicrobial activity, affected the bacterial colonization of gut epithelium and the production and action of certain enterotoxins. These observations suggest varied possible modes of action of A. marmelos in infectious forms of diarrhea, validating its mention in ancient Indian texts and continued use by local communities for diarrheal diseases. These studies were conducted on whole plant extracts rather than purified aegeline, so aegeline's individual contribution to antidiarrheal activity cannot be isolated from these results.
Evidence strength: Traditional use well-documented; preclinical validation for whole extracts is supportive, but clinical trials specifically attributing effects to aegeline are absent.
6.6 Hepatoprotective Activity
Evidence Type: Traditional claim; contradicted by safety data for synthetic preparations (see Section 7).
The plant has been used for treating jaundice, diarrhea, fever, diabetes, and hepatoprotection. However, research into the safety of supplemental aegeline has raised serious concerns about its hepatotoxic potential under certain conditions, particularly in synthetic form (see Safety section).
6.7 Overall State of Clinical Evidence
This body of research concludes that various parts of A. marmelos have been evaluated in preclinical studies for different activities. Many chemical compounds have been isolated, but fewer studies have been conducted. In the future, clinical trials are needed for those activities. As of current sources, there are no published randomized controlled trials (RCTs) in humans specifically examining the effects of isolated aegeline on any health outcome.
7. Body Systems and Health Areas Associated with Aegeline
- Endocrine / Metabolic System: Proposed antihyperglycemic activity via GLUT4 translocation and Akt/Rac1 signaling; proposed β3-AR-mediated antidyslipidemic effects. All evidence is preclinical.
- Cardiovascular System: Proposed antihypercholesterolemic action via LOX-1 receptor modulation and reduction of oxidized LDL. Preclinical animal evidence only.
- Gastrointestinal System: Longstanding traditional use for diarrhea, dysentery, constipation, and gastrointestinal infections; supported by preclinical studies of whole plant extracts.
- Immune / Inflammatory System: In vitro evidence of mast cell histamine-release inhibition via intracellular Ca²⁺ signaling pathways.
- Hepatic System (Safety Concern): Synthetic or high-dose formulations have been implicated in acute liver injury; CYP2C19-mediated formation of reactive metabolites provides a mechanistic hypothesis for hepatotoxicity.
- Adipose / Body Composition: In vitro adipogenesis inhibition at micromolar concentrations; no verified in vivo weight-loss effect in humans.
8. Dosages Reported in Studies
The following dosages are reported in primary research sources only. These figures are descriptive of what was studied, not recommendations.
- In rat studies, aegeline was used at 100 mg/kg body weight, resulting in blood glucose reductions of 12.9% at 5 hours and 16.9% at 24 hours.
- In hamster models, aegeline was administered orally at 50 mg/kg body weight for seven consecutive days.
- In high-fat diet-fed mice, aegeline analogues at a dose of 50 mg/kg improved insulin sensitivity and glucose tolerance.
- In C2C12 myotube cell culture, aegeline enhanced basal glucose uptake at a minimum concentration of 5.0 μM (1.39-fold) with maximum increase at 10 μM for 24 hours (1.71-fold).
- For adipogenesis inhibition, aegeline was screened at 50 and 100 μM concentrations, showing 16.29 ± 0.85% lipid content at 100 μM.
No human clinical dosing data for aegeline has been identified in peer-reviewed sources.
9. Safety Considerations
The OxyELITE Pro Outbreak (2013) — The Critical Safety Event
The most significant safety concern associated with aegeline arose in 2013. OxyELITE Pro is the commercial name for a variety of multi-ingredient dietary supplements marketed for weight loss and bodybuilding. In 2013, one of the OxyELITE Pro products called "Super Thermogenic" was withdrawn from use in the United States after it was implicated in more than 50 cases of acute hepatitis, including several instances of fatal, acute liver failure.
Over 40 cases of severe acute hepatitis and liver failure were linked to the use of the "Super Thermo" formulation of OxyELITE Pro, primarily among individuals residing in Hawaii. The etiology and risk factors remained under investigation; however, the outbreak followed shortly after a major modification of the product's components with the addition of aegeline, a constituent of the native Ayurvedic herbal product made from the bark of the bael tree (Aegle marmelos).
The cause of acute liver injury associated with OxyELITE Pro has been attributed to aegeline, which was added to the commercial product in early 2013. Aegeline is a derivative of the fruit and other components of the bael tree and is a commonly used herbal agent in Southeast Asia, employed in Ayurvedic medicine for digestive complaints.
At least 24 people reported using OxyELITE Pro before developing liver damage, including 2 people who required liver transplants and one woman who died. The FDA reviewed medical records on 20 people who became ill, of whom 14 (70%) reported using OxyELITE Pro. OxyELITE Pro was the only common risk factor among the victims.
At that time, dietary supplements with synthetic aegeline had been associated with 90+ cases of acute liver injury, some even leading to death.
Synthetic vs. Natural Aegeline: An Unresolved Question
Cases of acute liver injury had not been previously reported with aegeline use from traditional sources. The aegeline used in OxyELITE Pro implicated in liver injury, however, was a synthetic product produced in China, and may have included contaminants, synthetic precursors, metabolic derivatives, or racemic forms of the chemical that are toxic or immunogenic.
Some researchers have contested the straightforward attribution of causality. Aegeline is a constituent of Aegle marmelos, which has a long history of consumption as a food and traditional medicine. Due to its inclusion in OxyELITE Pro, which was apparently associated with liver injury in the fall of 2013 with a suspected cluster in Hawaii, it became the subject of speculation regarding hepatotoxic potential. However, in vitro, animal model, and epidemiological data have been cited as demonstrating a lack of hepatotoxic effects with aegeline.
Furthermore, the concentration of aegeline in dietary supplements is likely higher than in nature, so aegeline's "long history of use" in traditional medicine is not sufficient evidence for safety at supplement doses.
Regulatory Action
The FDA issued an information update stating that the FDA along with the Centers for Disease Control and Prevention were investigating more than 50 cases of liver damage. The FDA also issued a warning letter to a company marketing a dietary supplement containing aegeline, because it is not currently recognized as a legitimate ingredient for dietary supplements.
USPLabs, the manufacturer of OxyELITE Pro and VERSA-1, had never submitted a notification for aegeline. This made the ingredient adulterated and illegal to use in dietary supplements. In October 2013, under pressure from the FDA, the sponsor of OxyELITE Pro withdrew it from the market and requested retrieval of products already in distribution.
Mechanism of Potential Hepatotoxicity
Aegeline is a natural alkaloidal amide mainly isolated from the leaves and fruits of Aegle marmelos, with multiple pharmacological activities. As one component of several dietary supplements, it caused a series of acute and chronic liver injuries. The mechanisms of aegeline-induced hepatotoxicity remained unclear; research identified a demethylation metabolite (M1) and a GSH conjugate (M2) in rat liver microsomal incubations. Ticlopidine, a selective inhibitor of CYP2C19, decreased the formation of M1 and M2 in hepatocytes and attenuated the susceptibility of hepatocytes to the cytotoxicity of aegeline. The results suggest that aegeline was metabolized to a p-quinone methide intermediate which could in part participate in aegeline-induced cytotoxicity.
Reported Clinical Symptoms in Cases
All 36 OxyELITE Pro-exposed cases reported having dark urine, and almost all (92%) reported yellowing of the eyes or skin, loss of appetite, and fatigue. Less severe reported side effects associated with the supplement cases included fatigue, nausea, and jaundice.
Outcome After Cessation
After discontinuing OxyELITE Pro, most patients recovered, implying that OxyELITE Pro was causing the problem. However, some cases were severe enough to require liver transplantation.
Drug Interaction Potential
The identification of CYP2C19 as the principal enzyme responsible for aegeline's metabolic activation has implications for drug interactions. Compounds that inhibit or are metabolized by CYP2C19 (including clopidogrel, proton pump inhibitors such as omeprazole, and certain antidepressants) could potentially interact with aegeline's metabolic pathways, though this has not been studied in human clinical settings. The existing mechanistic evidence is limited to in vitro and rat data.
10. Research Gaps and Future Directions
A 2025 review in a peer-reviewed journal provided a concise overview of aegeline's isolation and synthesis and highlighted its potential as a therapeutic agent for metabolic disorders. Despite this, the field remains substantially preclinical. Synthetic derivatives or analogues studied for biological activity are not specified for their chirality. Further studies can be done to explore the therapeutic potential of individual enantiomers along with the safety profile.
Preclinical studies on various parts of A. marmelos have been conducted, but fewer studies exist on isolated compounds. Clinical trials remain a future necessity. The serious hepatotoxic signal associated with synthetic formulations of aegeline represents an important barrier to clinical development that has not been resolved by definitive causal studies.
References
Go back