Betulinic acid

Betulinic acid at a Glance

Betulinic acid is a lupane-type pentacyclic triterpenoid from birch bark, jujube and many other plants — the oxidised C-28 carboxylic acid derived from betulin, and a close relative of lupeol.

Its large preclinical anticancer literature has an unusual feature: the cytotoxicity is reported as selective for tumour cells, acting through the mitochondrial apoptosis pathway rather than by damaging DNA. Selectivity of that kind is rare and is what sustained decades of interest.

It is also poorly water-soluble, which is the practical obstacle every development attempt has run into.

What It's Used For

Betulinic acid is a pentacyclic triterpenoid of the lupane class, found in birch bark, jujube, camu-camu seed ^{13Reference 13Yazawa K et al. · 2011Anti-inflammatory effects of seeds of the tropical fruit camu-camu (Myrciaria dubia)View study →}, Bacopa ^{14Reference 14Valotto Neto LJ et al. · 2024Investigating the neuroprotective and cognitive-enhancing effects of Bacopa monnieriView study →} and many other plants ^{15Reference 15Liu MH et al. · 2024ReviewPhytochemical, pharmacological, pharmacokinetic and toxicological characteristics of Ziziphi Spinosae Semen: a reviewView study →} — usually as a minor part of the triterpene fraction, and often as the C-28 carboxylic-acid oxidation product of betulin (the diol precursor). It is a close structural relative of lupeol, differing by that C-28 oxidation. Its literature has a clear shape: a large, mechanistically coherent preclinical anticancer body — it was once an NCI development lead — and no proven human efficacy. The defining limitation is pharmacokinetic: very poor water solubility (~21 µg/mL) and oral bioavailability under ~1% ^{11,12Reference 11Saneja A et al. · 2018Therapeutic applications of betulinic acid nanoformulationsView study →Reference 12Wang K et al. · 2024Advancements in betulinic-acid-loaded nanoformulations for enhanced anti-tumour therapyView study →}, which is why it never advanced despite strong in-vitro potency. One important attribution caveat runs through the page: the anti-HIV reputation belongs to a semisynthetic derivative (bevirimat), not to the parent molecule.

Evidence by IndicationStrength of support · Beta

Support is an experimental score — weighted by study type (human > animal > in vitro) and volume. A beta, not a validated metric. Every application here is preclinical for the isolated parent, so scores stay low by design. Each application links to its write-up.

01AnticancerShaky44%Large in-vitro panel + mouse xenograft; once an NCI lead ^{1,2,3,9,10Reference 1Pisha E et al. · 1995Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosisView study →Reference 2Fulda S et al. · 1998Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acidView study →Reference 3Fulda S · 2000Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumoursView study →Reference 9Chintharlapalli S et al. · 2007Betulinic acid inhibits prostate cancer growth through inhibition of specificity-protein transcription factorsView study →Reference 10Chintharlapalli S et al. · 2011Betulinic acid inhibits colon cancer cell and tumour growth and induces downregulation of specificity-protein (Sp) transcription factorsView study →}

02Antiviral (derivative)Shaky28%Modest parent; the signal is the derivative bevirimat ^{5,6,7Reference 5Cichewicz RH · 2004Chemistry, biological activity and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infectionView study →Reference 6Li F et al. · 2003PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing (bevirimat)View study →Reference 7Smith PF et al. · 2007Safety and pharmacokinetics of bevirimat (PA-457) in healthy volunteersView study →}

03Anti-inflammatoryShaky28%Rodent edema + macrophage assays ^{13,10Reference 13Yazawa K et al. · 2011Anti-inflammatory effects of seeds of the tropical fruit camu-camu (Myrciaria dubia)View study →Reference 10Chintharlapalli S et al. · 2011Betulinic acid inhibits colon cancer cell and tumour growth and induces downregulation of specificity-protein (Sp) transcription factorsView study →}

04AntimalarialShaky24%In-vitro + mouse, modest potency ^{8Reference 8Steele JCP et al. · 1999In-vitro and in-vivo evaluation of betulinic acid as an antimalarialView study →}

Mechanisms

Pharmacokinetics

Load-bearing and the central limitation — the reason betulinic acid never advanced despite strong in-vitro potency. It is highly lipophilic with very low aqueous solubility (~21 µg/mL) and correspondingly poor oral absorption (under ~1%), plus a short in-vivo half-life ^{11,12Reference 11Saneja A et al. · 2018Therapeutic applications of betulinic acid nanoformulationsView study →Reference 12Wang K et al. · 2024Advancements in betulinic-acid-loaded nanoformulations for enhanced anti-tumour therapyView study →}. This is precisely why the field has pivoted to prodrugs and nanoformulation engineering — nanoparticles, liposomes, micelles and self-nanoemulsifying systems to raise solubility, bioavailability and half-life ^{11,12Reference 11Saneja A et al. · 2018Therapeutic applications of betulinic acid nanoformulationsView study →Reference 12Wang K et al. · 2024Advancements in betulinic-acid-loaded nanoformulations for enhanced anti-tumour therapyView study →}. The practical implication: the impressive in-vitro concentrations are not obviously achievable from oral intake of unformulated betulinic acid, so preclinical potency should not be read as oral human efficacy.

Clinical trials

There are no completed randomized human efficacy trials of isolated betulinic acid for any indication. A topical 20% betulinic-acid ointment for dysplastic (melanocytic) nevi was registered as a Phase I/II trial but was suspended and never published — investigational only, not evidence of efficacy. The derivative bevirimat reached human safety/PK trials for HIV ^{7Reference 7Smith PF et al. · 2007Safety and pharmacokinetics of bevirimat (PA-457) in healthy volunteersView study →} before its development stalled.

Completed (efficacy)	Registered/suspended	Derivative in humans	Preclinical
— (none)	Topical dysplastic-nevi Phase I/II (suspended)	Bevirimat (HIV) 7Reference 7Smith PF et al. · 2007Safety and pharmacokinetics of bevirimat (PA-457) in healthy volunteersView study →	Extensive

Last checked: July 2026.

Toxicity & Safety

Betulinic acid looks unusually clean in animals — what stalled it was solubility, not toxicity — but the low-toxicity verdict is entirely preclinical, with no human safety record behind it.

Safety at a Glance

✅ Low / no toxicity

• Selective, low toxicity in animal work. Tumor-growth inhibition in mice with no observable systemic toxicity, and relative sparing of normal cells even at high doses.
• Avoid concentrated use in pregnancy and breastfeeding. No reproductive data, plus a pro-apoptotic mechanism.
• No regulatory-grade chronic toxicology or human safety profile. The verdict rests on aggregate preclinical observation.
• Theoretical overlap with oncologic and anti-inflammatory drugs. It modulates mitochondrial apoptosis, NF-κB and Sp-regulated survival genes; no human interaction data exist.

Full Safety & Interactions Detail

Betulinic acid’s low, selective toxicity is a genuine point in its favor: in the founding melanoma-xenograft work it inhibited tumor growth with no observable systemic toxicity in mice, and it is repeatedly reported as favorable even at high doses with relative sparing of normal cells ^{1,5Reference 1Pisha E et al. · 1995Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosisView study →Reference 5Cichewicz RH · 2004Chemistry, biological activity and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infectionView study →}.

That said, formal regulatory-grade chronic toxicology and a clean human safety profile are not established — the “low toxicity” verdict rests on aggregate preclinical observation, not human data, and it is best regarded as a research compound whose limiting factor has been poor solubility rather than toxicity. There is no human drug-interaction data; because it modulates mitochondrial apoptosis, NF-κB and Sp-regulated survival genes, theoretical additive or interfering effects with oncologic or anti-inflammatory agents cannot be excluded.

Dosage

There is no human dose for betulinic acid, and the following are research doses, not recommendations. Antitumor mouse xenograft work used parenteral/high dosing with a favorable therapeutic index reported to ~500 mg/kg in animals ^{1,5Reference 1Pisha E et al. · 1995Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosisView study →Reference 5Cichewicz RH · 2004Chemistry, biological activity and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infectionView study →}, and antimalarial mouse studies used the isolated triterpene in P. berghei models ^{8Reference 8Steele JCP et al. · 1999In-vitro and in-vivo evaluation of betulinic acid as an antimalarialView study →}. Unformulated oral betulinic acid has under ~1% absorption ^{12Reference 12Wang K et al. · 2024Advancements in betulinic-acid-loaded nanoformulations for enhanced anti-tumour therapyView study →}, so any oral figure has unpredictable exposure — which is why dosing work now centers on nanoformulations rather than the plain compound.

References

1. Pisha E, Chai H, Lee IS, et al. (1995). Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosis. Nature Medicine. https://pubmed.ncbi.nlm.nih.gov/7489361/
2. Fulda S, et al. (1998). Activation of mitochondria and release of mitochondrial apoptogenic factors by betulinic acid. Journal of Biological Chemistry. https://pubmed.ncbi.nlm.nih.gov/9852046/
3. Fulda S, Debatin KM (2000). Betulinic acid induces apoptosis through a direct effect on mitochondria in neuroectodermal tumours. Medical and Pediatric Oncology. https://pubmed.ncbi.nlm.nih.gov/11107130/
4. Fulda S, Kroemer G, et al. (2009). Betulinic acid, a natural compound with potent anticancer effects. Drug Discovery Today / mitochondrial-apoptosis review. https://pubmed.ncbi.nlm.nih.gov/19520182/
5. Cichewicz RH, Kouzi SA (2004). Chemistry, biological activity and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infection. Medicinal Research Reviews. https://pubmed.ncbi.nlm.nih.gov/14595673/
6. Li F, et al. (2003). PA-457: a potent HIV inhibitor that disrupts core condensation by targeting a late step in Gag processing (bevirimat). PNAS. https://pubmed.ncbi.nlm.nih.gov/14573704/
7. Smith PF, et al. (2007). Safety and pharmacokinetics of bevirimat (PA-457) in healthy volunteers. Antimicrobial Agents and Chemotherapy. https://pubmed.ncbi.nlm.nih.gov/17576843/
8. Steele JCP, et al. (1999). In-vitro and in-vivo evaluation of betulinic acid as an antimalarial. Phytotherapy Research. https://pubmed.ncbi.nlm.nih.gov/10190183/
9. Chintharlapalli S, et al. (2007). Betulinic acid inhibits prostate cancer growth through inhibition of specificity-protein transcription factors. Cancer Research. https://pubmed.ncbi.nlm.nih.gov/17363604/
10. Chintharlapalli S, Papineni S, Lei P, et al. (2011). Betulinic acid inhibits colon cancer cell and tumour growth and induces downregulation of specificity-protein (Sp) transcription factors. BMC Cancer. https://pubmed.ncbi.nlm.nih.gov/21864401/
11. Saneja A, et al. (2018). Therapeutic applications of betulinic acid nanoformulations. Annals of the New York Academy of Sciences. https://pubmed.ncbi.nlm.nih.gov/29377164/
12. Wang K, Shang J, Tao C, et al. (2024). Advancements in betulinic-acid-loaded nanoformulations for enhanced anti-tumour therapy. International Journal of Nanomedicine. https://pubmed.ncbi.nlm.nih.gov/39748899/
13. Yazawa K, et al. (2011). Anti-inflammatory effects of seeds of the tropical fruit camu-camu (Myrciaria dubia). Journal of Nutritional Science and Vitaminology. https://pubmed.ncbi.nlm.nih.gov/21512298/
14. Valotto Neto LJ, et al. (2024). Investigating the neuroprotective and cognitive-enhancing effects of Bacopa monnieri. Antioxidants (Basel). https://pubmed.ncbi.nlm.nih.gov/38671841/
15. Liu MH, Jin HX, Song Z, et al. (2024). Phytochemical, pharmacological, pharmacokinetic and toxicological characteristics of Ziziphi Spinosae Semen: a review. Frontiers in Pharmacology. https://pubmed.ncbi.nlm.nih.gov/39679366/

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