Betulinic acid

Other Names

(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-Hydroxy-1-isopropenyl-5a,5b,8,8,11a-pentamethylicosahydro-3aH-cyclopenta[a]chrysene-3a-carboxylic acid(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid(1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-prop-1-en-2-yl-1,2,3,4,5,6,7,7a,9,10,11,11b,12,13,13a,13b-hexadecahydrocyclopenta[a]chrysene-3a-carboxylic acid(3b)-3-hydroxylup-20(29)-en-28-oic acid(3β)-3-Hydroxylup-20(29)-en-28-oic acid3-Hydroxylup-20(29)-en-28-oic acid3beta-Hydroxy-20(29)-lupaene-28-oic acid3beta-Hydroxy-20(29)-lupene-28-oic acid3β-Hydroxy-20(29)-lupaene-28-oic acid3β-Hydroxy-20(29)-lupene-28-oic acidALS-357BetABeta-betulinic acidBetulic acidCCRIS 6748GratioloneLup-20(29)-en-28-oic acid, 3-hydroxy-, (3β)-Lup-20(29)-en-28-oic acid, 3β-hydroxy-Lupatic acidMairinMelaleucinNSC 113090NSC 677578PlatanolPlatanolic acid

Synopsis

Betulinic Acid: A Comprehensive Reference

1. Identity

1.1 Chemical Names and Classification

Betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid, BA) is a pentacyclic lupane-type triterpene, widely distributed in the plant kingdom. Its systematic IUPAC name is 3β-hydroxy-lup-20(29)-en-28-oic acid, also rendered as lup-20(29)-en-28-oic acid, 3β-hydroxy-. Betulinic acid is a pentacyclic triterpenoid with a double bond at position 20(29), as well as 3β-hydroxy and 28-carboxy substituents; it is a hydroxy monocarboxylic acid derived from a hydride of a lupane. Its molecular formula is C₃₀H₄₈O₃, with a molecular weight of 456.7 g/mol. The CAS registry number is 472-15-1. Common synonyms include betulic acid, Mairin, Lupatic acid, and NSC 113090.

Pentacyclic triterpenoids represent a significant class of phytochemicals, categorized into oleanane, ursane, friedelane, and lupane types. Betulinic acid is a lupane-type pentacyclic triterpenoid. Its five-ring carbocyclic skeleton — four six-membered rings and one five-membered ring — is characteristic of the lupane series.

1.2 Natural Sources

Betulinic acid is a pentacyclic triterpene compound that can be obtained by separation, chemical synthesis, and biotransformation from birch tree bark. Betulinic acid and betulin come from a variety of botanical sources such as bark from Betula alba, Platanus orientalis, Corylus avellana, Carpinus betulus, Alnus glutinosa, as well as from Ziziphus spp. Betulinic acid is found in many plant species, although in low concentration compared to betulin. A rare exception is the rich content of betulinic acid in Menyanthes trifoliata, a bog plant.

Betulinic acid has also been isolated from Ziziphus spp., Syzygium spp., Diospyros spp., Triphyophyllum peltatum, Ancistrocladus heyneanus, Tovomita krukovii, Ipomoea pes-caprae, Rosa canina, and Rosmarinus officinalis. Betulinic acid is a chemotaxonomic agent found in the roots, stems, bark, leaves, and fruits of the Dilleniaceae, Ebenaceae, and Rhamnaceae families. Among secondary plant sources, the leaves of Syzygium aromaticum (clove) have been found to contain high levels of betulinic acid — particularly leaf extract at approximately 17% wt/wt.

Betulin and betulinic acid are pentacyclic triterpenes present in the bark of the birch tree and other vegetal sources. Quantitatively, in birch bark betulin is more significant than betulinic acid; therefore, birch can serve as a large and feasible source. Analysis of birch bark extract reveals a high amount of betulin (up to 50%) and an important quantity of betulinic acid exceeding 3%.

1.3 Preparation and Common Forms

Though birch bark is the major plant source for extracting betulinic acid, the minute amount present in its tissues limits large-scale production for the market, making the development of additional preparative methods a major research area. Because of its various bioactivities, betulinic acid is in great demand; however, extracting it from botanical materials is time-consuming, not environmentally friendly, and produces a low yield, making direct extraction unsuitable for large-scale manufacturing. Chemical synthesis is another method to obtain it.

Betulinic acid is a naturally occurring compound that can be obtained through methanolic or ethanolic extraction from plant sources, as well as through chemical synthesis or microbial biotransformation. Methods such as chemical synthesis and microbial biotransformation have been employed to prepare betulinic acid, and with the development of synthetic biology and genetic engineering — along with elucidation of biosynthetic pathways of terpenoids — biosynthesis of betulinic acid has been extensively researched. In research settings, betulinic acid is available as a pure reference powder. Commercial formulations investigated in studies include topical ointments (notably at 20% concentration), liposomal preparations, nanoparticle-based delivery systems, and spray-dried preparations developed to overcome the compound's poor water solubility.

Betulinic acid has very low water solubility, which causes low bioavailability. This physicochemical constraint has driven investigation into encapsulation strategies — including liposomes, oleogels, and nanoparticles — to facilitate delivery.

2. Traditional and Historical Use

2.1 Birch Bark in Northern and Eastern European Folk Medicine

Although over a hundred Betula species are found globally, about seven different species have been documented for traditional uses. Phytochemical research on Betula species has led to the isolation of triterpenoids, diarylheptanoids, phenylbutanoids, lignans, phenolics, and flavonoids; crude extracts and phytochemical constituents showed a wide spectrum of pharmacological activities including immunomodulatory, anti-inflammatory, antimicrobial, antiviral, antioxidant, antidiabetic, dermatological, gastroprotective, and hepatoprotective effects. Antiarthritic and anticancer are two major areas of research conducted on these species. The anti-carcinogenic effects of Betula bark, betulin, and betulinic acid have been extensively studied. Several species belonging to the genus Betula are widely used in traditional medicine.

Johann Tobias Lowitz isolated the reduced form of betulinic acid from plants in 1788 and found it to be a prominent outer-bark constituent of white-barked birch trees. The formal structural characterization of betulinic acid itself followed considerably later with advanced spectroscopic methods.

2.2 African Traditional Medicine

The stem bark of betulinic acid-containing plants has been traditionally employed to treat diarrhoea, dysentery, sore throat, wounds, HIV/AIDS, venereal diseases, and infertility. Isolated betulinic acid from the ethyl acetate fraction of Berlina grandiflora at 100 and 500 ppm showed strong anthelmintic activities comparable to piperazine, confirming the traditional use of that plant as an anthelmintic and indicating betulinic acid as the active component.

2.3 South Asian and Ayurvedic Contexts

Dillenia indica Linn. (Dilleniaceae) is traditionally used to treat skin inflammation. Folk preparations of D. indica in oral or topical form have been used to treat abdominal and joint pain, cough, diarrhoea, fever, tumours, diabetes, toning up the nervous system, and removing fatigue. Most traditional uses of D. indica in folk medicine are associated with anti-inflammatory purposes, and popular traditions in Brazil corroborate this use, particularly the fruits, which are used in preparations for skin applications to treat inflammation.

2.4 Central American Ethnobotany

Betulinic acid has been identified as the key active component accounting for the antianxiety activity of the leaves and bark of Souroubea sympetala, and Souroubea gilgii, a neotropical vine native to Costa Rica and other Central American countries. The use of these plants by local communities to alleviate anxiety and stress states precedes modern isolation of the active compound.

3. Chemistry: Key Constituents and Structural Features

Betulinic acid is the principal bioactive constituent of interest in birch bark and related botanical sources. It is the oxidation product of betulin — the more abundant lupane-type triterpene in birch bark. Betulin is a multitarget compound mainly found in the Betulaceae family, especially in the birch bark. Betulinic acid differs from betulin in having a carboxylic acid group at C-28 instead of a hydroxymethyl group. Betulonic acid is similar to betulinic acid in chemical structure, with the hydroxyl group at C-3 replaced by a ketone.

Structurally relevant related compounds isolated from the same botanical sources include:

Betulin (betulinol): Betulin is a multitarget compound existing primarily in the Betulaceae family; ample evidence indicates it has protective effects on cardiovascular and liver diseases, cancer, and diabetes, potentially due to anti-inflammatory properties.
Lupeol: A related lupane triterpene found alongside betulinic acid in many of the same plant species.
Betulinaldehyde: An intermediate in the biosynthetic pathway between betulin and betulinic acid.
Ursolic acid and oleanolic acid: Pentacyclic triterpenoids of the ursane and oleanane series, respectively, frequently co-occurring in source plants.

Phytochemical research on Betula species has led to the isolation of triterpenoids, diarylheptanoids, phenylbutanoids, lignans, phenolics, and flavonoids — all contributing to the overall bioactivity of whole-bark preparations, though betulinic acid is the most extensively studied single entity.

4. Mechanisms of Action

4.1 Apoptosis via the Mitochondrial Pathway

Betulinic acid is a plant-derived pentacyclic triterpenoid with potent anticancer activity that targets the mitochondrial pathway of apoptosis. The main mechanism of anti-cancer action of betulinic acid is the induction of apoptosis in cells independent of their p53 status. Mechanistically, betulinic acid induces apoptosis in a p53- and CD95-independent manner in cancer cells.

Betulinic acid leads to a decrease in mitochondrial outer membrane potential (MOMP) and the production of reactive oxygen species (ROS); it inhibits antiapoptotic proteins and increases the level of proapoptotic proteins. Betulin and betulinic acid exhibit anticancer properties through mechanisms including the induction of autophagy, promotion of apoptosis, and anti-inflammatory effects; these compounds enhance autophagy, facilitating cellular degradation and recycling processes, while selectively inducing apoptosis in cancer cells.

4.2 NF-κB and Signaling Pathway Modulation

The transcription factor NF-κB is a key mediator of the cellular stress response and inflammation; in cells exposed to anticancer therapy, NF-κB typically activates survival pathways. It has been demonstrated that inhibition of NF-κB activity in cancer cell lines could reduce cell proliferation and metastatic capabilities in vivo. Compelling evidence highlights betulinic acid's therapeutic action in suppressing the Akt/NF-κB-p65 signaling cascade. Betulinic acid exerts cardioprotective effects via multiple signaling pathways, including NRF2, NF-κB, MAPK, and NFAT.

4.3 Topoisomerase I Inhibition

Betulinic acid was recently shown to be a potential anticancer agent by inhibition of topoisomerase I (Top1). Betulinic acid acts as a eukaryotic topoisomerase I inhibitor, with an IC₅₀ of 5 μM.

4.4 Additional Anticancer Mechanisms

The generation of reactive oxygen species, inhibition of topoisomerase I, activation of the MAP kinase cascade, inhibition of angiogenesis, and modulation of pro-growth transcriptional activators and aminopeptidase N activity may play a role in betulinic acid-induced apoptosis. These potential mechanisms of action may enable betulinic acid to be effective in cells resistant to other chemotherapeutic agents.

Betulinic acid significantly inhibits cell proliferation in hepatocellular carcinoma cells (HepG2 and SMMC-7721), but with little cytotoxicity in normal liver cells (l-02). This differential toxicity toward malignant versus normal cells is a consistent feature noted across multiple studies.

4.5 Anti-HIV Mechanism (Maturation Inhibition)

Bevirimat [3-O-(3′,3′-dimethylsuccinyl)betulinic acid] is the first in a new class of anti-HIV drugs that inhibit viral maturation by specifically blocking cleavage of the Gag capsid (CA) precursor, CA-SP1, to mature CA protein, resulting in defective core condensation and release of immature noninfectious virions. Betulinic acid is a lupane-structured pentacyclic triterpene recognized as effective against HIV through inhibition of replication; its derivative bevirimat prevents HIV-1 virus maturation and virus release from infected cells.

4.6 Anti-Inflammatory Mechanisms

Betulinic acid, a lupane-type pentacyclic triterpene, is a potential lead compound for the development of new anti-inflammatory treatments, and a large number of derivatives have been produced and tested. Betulinic acid has been shown to reduce proinflammatory cytokines and cyclooxygenase enzymes (COX-1 and COX-2) with IC₅₀ values ranging from 11.5 to 46.9 μM.

4.7 AMPK Activation and Metabolic Modulation

Betulinic acid stimulates AMPK in a fashion similar to known AMPK activators such as 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside and metformin. The level of glucose uptake by betulinic acid was not altered by wortmannin, suggesting this activation does not depend on phosphoinositide 3-kinase. Betulinic acid also stimulated mRNA expression of glucose transporter 4, which could partly explain increased glucose uptake.

4.8 Anxiolytic Mechanism

The mode of action of betulinic acid has been shown to involve the GABA_A-BZD (benzodiazepine) receptor. When animals were pretreated with the antagonist flumazenil, the antianxiety effect of both Souroubea leaf extracts and the pure, more soluble derivative methyl ester of betulinic acid was extinguished.

4.9 Antiplatelet Activity

A common pharmacophore was defined between the NMR-derived structure of betulinic acid and prostacyclin agonists (PGI₂), and the importance of its carboxylate group in antiplatelet activity was determined. Results indicate that betulinic acid has potential use as an antithrombotic compound, and suggest that the mechanism underlying its antiplatelet effects is similar to that of PGI₂ receptor agonists.

5. Scientific Evidence by Area of Use

5.1 Oncology: Melanoma

In 1995, betulinic acid was reported as a selective inhibitor of human melanoma. It was subsequently demonstrated to induce apoptosis in human neuroblastoma in vitro and in vivo in model systems, and at one time it was undergoing drug development with assistance from the Rapid Access to Intervention Development program of the National Cancer Institute.

The significant qualities of betulinic acid attracted interest for clinical trials. The compound aroused interest of the National Cancer Institute's (NCI) Rapid Access to Intervention Development (RAID) program. A phase I/II clinical trial between 2006 and 2013 was performed with 28 patients for the evaluation of the safety and effectiveness of an ointment containing 20% betulinic acid as a treatment for dysplastic nevi — lesions with transformation potential into melanoma (NCT00346502, ClinicalTrials.gov database). The study planned daily application for 4 weeks followed by surgical removal and histological comparison with untreated lesions; however, this trial was suspended in 2013 due to funding issues, and results were never published.

In laboratory studies of A375 human melanoma cells, betulinic acid demonstrated a dose-dependent inhibitory effect in both mitochondrial respiration and glycolysis, and at sub-toxic concentrations (10 μM) induced mitochondrial dysfunction by eliciting a decrease in the mitochondrial membrane potential and changes in mitochondria morphology and localization.

Evidence strength (melanoma): Extensive in vitro data and in vivo animal model data exist. One phase I/II clinical trial was initiated in humans (NCT00346502) but was suspended before publication of results. No completed, published randomized controlled trials (RCTs) in humans exist for this indication. The evidence base remains primarily preclinical.

5.2 Oncology: Broad-Spectrum Anticancer Activity

Betulinic acid was found active in vitro against neuroectodermal tumors (neuroblastoma, medulloblastoma, Ewing's sarcoma) and malignant brain tumors, ovarian carcinoma, human leukemia HL-60 cells, and malignant head and neck squamous cell carcinoma SCC25 and SCC9 cell lines.

Betulinic acid exhibits anticancer functions in human cancer cells; it is highly effective against the human cervical cancer cell line HeLa by inducing dose- and time-dependent apoptosis. Betulinic acid demonstrates selective antitumor activity against glioblastoma cells by inhibiting proliferation and inducing apoptosis, consistent with observations in other cancer types.

Notably, betulinic acid's ability to cross the blood–brain barrier addresses a significant challenge in treating neurological pathologies. Betulinic acid can cross the blood–brain barrier, suppressing one of the primary obstacles to treating glioblastoma and other neurological disorders.

Clinical trials using betulinic acid reached phase I/II, and almost none have progressed to phase III.

Evidence strength (anticancer, general): Very broad in vitro evidence across numerous cancer cell lines, supported by preclinical in vivo animal model data. Human clinical evidence is very limited — no completed phase III trials. The oncology evidence is promising but remains at an early clinical stage.

5.3 Antiviral Activity: HIV

Bevirimat (BVM), derived from betulinic acid, was the first HIV maturation inhibitor. It exhibits potency against virus strains resistant to integrase inhibitors, protease inhibitors, nucleoside reverse transcriptase inhibitors (NRTIs), and non-nucleoside reverse transcriptase inhibitors (NNRTIs). Novel C-28 modified bevirimat analogues, developed as maturation inhibitors, have succeeded in phase I and IIa clinical trials. These analogues block the last step of the HIV life cycle, inhibiting the virus and producing non-infectious immature HIV-1 particles.

In a phase I/II human study, bevirimat [3-O-(3′,3′-dimethylsuccinyl)betulinic acid] was administered to four cohorts of six HIV-infected adults (with CD4 counts >200 and plasma viral loads of 5,000 to 250,000 transcripts/mL, not currently receiving antiretroviral therapy), randomized to receive a single oral dose of placebo, 75, 150, or 250 mg of bevirimat.

Bevirimat went up to phase 2 clinical trials; however, in clinic despite optimal plasma concentrations, not all patients given bevirimat had a robust viral load reduction. Non-respondent patients had more frequent baseline Gag polymorphisms near the capsid SP1 cleavage site than responders. Bevirimat was developed by chemical modification of betulinic acid as a first-in-class HIV-1 maturation inhibitor; in clinical trials, however, bevirimat showed less activity than expected because of a natural mutation in the Gag protein that conferred resistance in a high proportion of HIV-1 strains.

Two derivatives of betulinic acid, bevirimat and BMS-955176, were undergoing clinical trials for the treatment of HIV.

Evidence strength (HIV): Phase I/II human clinical data exist for the betulinic acid derivative bevirimat, establishing pharmacokinetic profiles and demonstrating proof-of-concept antiviral activity. Development stalled due to baseline Gag polymorphisms causing resistance in a subset of patients. No approved therapy has emerged from betulinic acid itself; research continues with next-generation derivatives.

5.4 Antiviral Activity: Influenza

The antiviral activity of betulinic acid was investigated in influenza A/PR/8 virus-infected A549 human lung adenocarcinoma epithelial cells and C57BL/6 mice. Betulinic acid showed anti-influenza viral activity at a concentration of 50 μM without significant cytotoxicity in influenza A/PR/8 virus-infected A549 cells. Betulinic acid significantly attenuated pulmonary pathology — including increased necrosis, numbers of inflammatory cells, and pulmonary edema induced by influenza A/PR/8 virus infection — compared with vehicle- or oseltamivir-treated mice in a vivo model. Downregulation of IFN-γ level after betulinic acid treatment in mouse lung suggested that its anti-influenza effect may be mediated via anti-inflammatory activity.

Evidence strength (influenza): Preliminary, based on in vitro cell-line and mouse model data. No human clinical data.

5.5 Anti-Inflammatory Activity

Betulinic acid shows a wide spectrum of biological and pharmacological properties, including anti-inflammatory effects; among them, the antitumor activity of betulinic acid has been extensively studied. Betulinic acid has anti-inflammatory, antioxidant, and anticancer properties and modulates key metabolic pathways such as NF-κB and AMPK signaling; the compound improves insulin sensitivity, reduces hepatic steatosis, mitigates the progression of atherosclerosis and fibrosis, and suppresses inflammatory responses.

In an animal model, a study evaluated the healing effect of Dillenia indica fruit extracts standardized to betulinic acid on induced psoriasis-like wounds in Wistar rats, using topical treatments applied once daily for 7 days at 1 mL of aqueous ethanolic extract or ethyl acetate extract at 5 or 50 mg/mL.

Evidence strength (anti-inflammatory): Extensive in vitro and preclinical animal data. No completed human RCTs specifically testing betulinic acid for inflammatory conditions.

5.6 Antimicrobial Activity

A study investigated the activity of betulinic acid against different strains of bacteria and fungi by determining the minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and minimum fungicidal concentration (MFC). The results showed that betulinic acid inhibited the growth of microbial species; among the 12 species investigated — including Staphylococcus aureus, S. epidermidis, Pseudomonas aeruginosa, Escherichia coli, Mycobacterium tuberculosis, Candida albicans, C. tropicalis, C. glabrata, Aspergillus flavus, Penicillium citrinum, Trichophyton rubrum, and Microsporum canis — 9 (75%) inhibited growth at a concentration of 561 μM and 1 at a concentration of 100 μM.

Evidence strength (antimicrobial): In vitro data only. Modest potency observed against a range of bacterial and fungal species in laboratory models. No human clinical data.

5.7 Antimalarial Activity

Betulinic acid has a wide range of biological and medicinal properties, including antimalarial activity. Betulinic acid presents a diverse mode of biological actions, including antimalarial activities. The compound has shown activity against Plasmodium species in laboratory models; this activity was among the early drivers of research interest in the 1990s.

Evidence strength (antimalarial): Preclinical/in vitro and limited in vivo animal model data. No human clinical trials.

5.8 Antidiabetic and Metabolic Effects

Betulinic acid was intragastrically administered to diabetic Sprague–Dawley rats, which significantly reduced blood glucose and insulin levels, suggesting its protective role in managing diabetes. An in vitro study showed that betulinic acid inhibited the activity of α-amylase and α-glucosidase. Betulinic acid attenuates hyperglycemia by inhibiting hepatic glucose production through modulation of the CAMKK-AMPK-CREB pathway; in vitro, it significantly reduced hepatic glucose production, activated AMPK, and inhibited the expression of phosphorylated CREB; in vivo, betulinic acid decreased plasma glucose, triglyceride, and insulin resistance index in high-fat diet-fed ICR mice.

Betulinic acid exerted antiobesity effects by influencing the absorption of lipids from the small intestine by inhibiting pancreatic lipase and accelerating lipolysis in adipose tissues.

Evidence strength (antidiabetic/metabolic): Primarily in vitro and rodent in vivo model data. Mechanistically plausible via AMPK activation. No human clinical trials for diabetes or obesity.

5.9 Anxiolytic Activity

Betulinic acid has been identified as the key active component accounting for the antianxiety activity of the leaves and bark of Souroubea sympetala and Souroubea gilgii. The antianxiety activity of S. sympetala plant extracts was demonstrated by in vivo studies in rats using accepted paradigms such as the elevated maze, fear-potentiated startle, and social interaction tests; these same tests were used to demonstrate the antianxiety activity of pure betulinic acid and a number of its derivatives.

Betulinic acid and its derivatives also significantly lower levels of the stress hormone cortisol in stressed rats, dogs, piglets, and trout. In dogs, the effect was shown in two efficacy trials involving a colony of more than 50 beagles exposed to simulated thunder; the onset of activity occurred within 1 hour of administration of the plant material at 1–2 mg/kg.

Evidence strength (anxiolytic): Preclinical rodent and canine model data showing GABA_A-BZD receptor involvement. No human clinical trial evidence.

5.10 Antiplatelet / Cardiovascular Effects

The potency of betulinic acid as an inhibitor of human platelet activation was evaluated, and its antiplatelet profile against in vitro platelet aggregation, induced by several platelet agonists (adenosine diphosphate, thrombin receptor activator peptide-14, and arachidonic acid), was explored; flow cytometric analysis was performed to examine the effect of betulinic acid on P-selectin membrane expression and PAC-1 binding to activated platelets. Treating diabetic apolipoprotein-E gene knockout mice with betulinic acid produced positive effects on early atherosclerosis.

Evidence strength (cardiovascular): In vitro platelet studies and animal model atherosclerosis data. Clinical trials directly evaluating betulinic acid in cardiovascular patients are lacking, so its safety profile in this context remains uncertain.

5.11 Dermatology / Skin Applications

Betulinic acid is a triterpene previously studied as an efficient treatment of skin ailments due to its innate pharmacological properties; nonetheless, due to its lipophilic nature and low bioavailability, topical delivery systems are necessary for its proper administration. There has been great emphasis on the use of betulinic acid as an antioxidative additive; creams containing betulinic acid have been shown to help against highly reactive radicals that might cause skin DNA damage.

Evidence strength (dermatology): Topical use is the area closest to clinical application; the phase I/II trial in dysplastic nevi was initiated but suspended (NCT00346502). Otherwise, evidence remains preclinical or experimental.

6. Body Systems Associated with Betulinic Acid

Oncological / Cell biology: Induction of apoptosis in multiple cancer lineages via mitochondrial pathway; topoisomerase I inhibition; NF-κB suppression.
Immune / Inflammatory: Distributed in a variety of plants, betulinic acid shows a wide spectrum of biological and pharmacological properties, including anti-inflammatory and antibacterial effects.
Infectious disease / Antiviral: Betulinic acid has been extensively studied for anti-viral activity against certain viruses, including HIV and influenza viruses, as well as antimalarial and antioxidant activity.
Metabolic / Endocrine: AMPK activation with antidiabetic and antiobesity effects demonstrated in preclinical models; inhibition of α-amylase and α-glucosidase.
Cardiovascular: Betulinic acid exerts cardioprotective effects via multiple signaling pathways including NRF2, NF-κB, MAPK, and NFAT.
Neurological / Anxiolytic: GABA_A-BZD receptor modulation; ability to cross the blood–brain barrier.
Hematological: Antiplatelet activity mediated via PGI₂-like mechanism.
Dermatological: Topical antioxidant and anti-inflammatory properties; investigated for melanoma precursor lesions.

7. Dosage Forms and Dosages Reported in Studies

There is no established human therapeutic dose for betulinic acid as a dietary supplement. The following dosages are those reported in specific studies and should not be interpreted as recommended doses.

Topical (human, clinical trial): A phase I/II clinical trial evaluated an ointment containing 20% betulinic acid applied to dysplastic nevi in 28 patients (NCT00346502).
Oral (human, bevirimat derivative): In a phase I/II study of bevirimat, four cohorts of six HIV-infected adults received a single oral dose of placebo, 75, 150, or 250 mg of bevirimat.
Oral (animal model, anxiolytic): In dogs exposed to simulated thunder, onset of anxiolytic activity occurred within 1 hour of administration of plant material at 1–2 mg/kg.
Oral (animal model, immunological): In sheep red blood cell-immunized mice, orally administered 5 mg/kg betulinic acid five times in 24 hours increased the number of plaque-forming cells but inhibited the production of anti-SRBC antibodies on the fourth day after immunization.
In vitro (anticancer/antiviral reference doses): Betulinic acid showed anti-influenza viral activity at a concentration of 50 μM without significant cytotoxicity in A549 cells. As a topoisomerase I inhibitor, an IC₅₀ of 5 μM has been reported.

Betulinic acid has very low oral bioavailability, which, together with the scarcity of clinical trials in humans, leaves its efficacy and long-term safety in cardiovascular, metabolic, hepatic, or oncological contexts uncertain. Betulinic acid has very low oral bioavailability, with less than 1% of the administered dose absorbed into circulation, which limits its therapeutic effectiveness. Numerous formulation strategies — including liposomal encapsulation, spray-dried preparations, nanoparticles, and oleogels — have been developed in research settings to improve this.

8. Safety Considerations and Interactions

8.1 General Preclinical Safety Profile

Betulinic acid inhibited melanoma tumor development in mice without causing systemic toxicity. The toxicity of triterpenes is reportedly relatively low. In addition to subchronic toxicity, acute and subacute toxicity studies as well as skin sensitization, mutagenesis studies (Ames test, in vitro human lymphocyte test, in vivo micronucleus test) were performed as required for clinical investigations; birch bark triterpene extract showed no effect in all pharmacological safety studies at concentrations up to 540 mg/kg (intraperitoneal) and 300 mg/kg (subcutaneous).

Spray-dried formulations of betulinic acid caused no changes in body weight in animal models, and histopathology of the intestine, liver, lung, heart, spleen, and kidney showed no tissue damage.

8.2 Adverse Effects and Toxicity Concerns

Preclinical studies report dose-dependent cytotoxicity in non-target cells, temporary anaemia at high doses, and reproductive toxicity in diabetic mice. While betulinic acid has not been directly linked to cardiovascular toxicity, the absence of human studies and the possibility of adverse effects at higher doses raise important safety concerns for its use in cardiovascular therapy.

8.3 Clinical Evidence Gaps

Clinical trials using betulinic acid reached phase I/II, and almost none have progressed to phase III. Studies have often stalled at the animal model testing stage, caused mainly by the lack of evidence concerning the safety of these drugs and potential mid-to long-term toxicity.

8.4 Pharmacokinetics and Bioavailability Constraints

Numerous detailed experiments have been conducted to explore the dynamic effects of different administration routes on the metabolism of betulinic acid, examining changes in serum concentration, half-life, clearance rate, and tissue distribution following oral, topical, and intraperitoneal injection routes. The compound's highly lipophilic character and essentially negligible aqueous solubility are the primary physicochemical obstacles to its oral delivery. Due to its lipophilic nature and low bioavailability, topical delivery systems are considered necessary for its proper administration.

8.5 Potential Antiplatelet Interaction

A common pharmacophore was defined between the NMR-derived structure of betulinic acid and prostacyclin agonists (PGI₂), and betulinic acid's carboxylate group was identified as important for antiplatelet activity; the mechanism underlying these antiplatelet effects is similar to that of PGI₂ receptor agonists. This mechanistic finding suggests that betulinic acid could potentially interact with anticoagulant or antiplatelet medications, though no formal human drug-interaction studies have been published.

8.6 Safety Studies in Dogs

Two safety studies of plant material containing betulinic acid in dogs, where animals received as much as 5–10 times the recommended dosage of 1 mg/kg, demonstrated a very high degree of safety. With beagle dogs, daily dose levels up to 300 mg/kg were tolerated and there were no histopathological changes, though haematological and clinical-chemical parameters showed a dose-dependent inflammatory reaction due to triterpene particles.

References

Health Conditions

Health conditions that Betulinic acid may help support.

No conditions available.

Body Systems

Body systems that Betulinic acid may help support.

No body systems available.