Betulinic acid

Pharmacology & Research

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 152024ReviewPhytochemical, 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 122024Advancements 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.

1. Anticancer

The marquee application. Bioassay-guided fractionation identified betulinic acid as a melanoma-selective cytotoxin that kills by inducing apoptosis, with complete tumour-growth inhibition in athymic-mouse melanoma xenografts and no gross toxicity ^{1Reference 1Pisha E et al. · 1995Discovery of betulinic acid as a selective inhibitor of human melanoma that functions by induction of apoptosisView study →}. The mechanism is direct and mitochondrial — loss of mitochondrial transmembrane potential and release of apoptogenic factors, largely independent of p53/CD95 ^{2,3,4Reference 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 4Mullauer FB et al. · 2009ReviewBetulinic acid, a natural compound with potent anticancer effectsView study →} — and later work extended the selective activity to prostate and colon cancer via degradation of specificity-protein (Sp1/3/4) transcription factors ^{9,10Reference 9Chintharlapalli S et al. · 2007Betulinic acid inhibits prostate cancer growth through inhibition of specificity-protein transcription factorsView study →Reference 102011Betulinic acid inhibits colon cancer cell and tumour growth and induces downregulation of specificity-protein (Sp) transcription factorsView study →}.

Gap: entirely cell-line and rodent for the isolated parent, with no controlled human efficacy data, and poor solubility stalled its NCI development ^{11Reference 11Saneja A et al. · 2018Therapeutic applications of betulinic acid nanoformulationsView study →}.

2. Antiviral (derivative)

The parent betulinic acid has only modest anti-HIV activity in vitro ^{5Reference 5Cichewicz RH · 2004Chemistry, biological activity and chemotherapeutic potential of betulinic acid for the prevention and treatment of cancer and HIV infectionView study →}. The important development is the C-3 semisynthetic derivative bevirimat (PA-457), a first-in-class HIV-1 maturation inhibitor that blocks cleavage of SP1 from the capsid ^{6Reference 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 →} and progressed to human safety and pharmacokinetic trials ^{7Reference 7Smith PF et al. · 2007Safety and pharmacokinetics of bevirimat (PA-457) in healthy volunteersView study →}.

Gap: bevirimat is not the parent molecule, its own development ultimately stalled (Gag-polymorphism-linked variable response), and the parent has no clinical antiviral status ^{6,7Reference 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 →}.

3. Anti-inflammatory

Isolated from camu-camu seed (not pulp), betulinic acid suppressed carrageenan-induced paw oedema and macrophage nitric-oxide release ^{13Reference 13Yazawa K et al. · 2011Anti-inflammatory effects of seeds of the tropical fruit camu-camu (Myrciaria dubia)View study →}, mechanistically downregulating the NF-κB p65 subunit among Sp-regulated genes ^{10Reference 102011Betulinic acid inhibits colon cancer cell and tumour growth and induces downregulation of specificity-protein (Sp) transcription factorsView study →}.

Gap: rodent and cell only, with no human anti-inflammatory data and oral relevance limited by absorption ^{13Reference 13Yazawa K et al. · 2011Anti-inflammatory effects of seeds of the tropical fruit camu-camu (Myrciaria dubia)View study →}.

4. Antimalarial

Betulinic acid showed antiplasmodial activity against chloroquine-sensitive and -resistant Plasmodium falciparum and activity in P. berghei-infected mice — with the clean structure-activity note that betulin was inactive where betulinic acid was active ^{8Reference 8Steele JCP et al. · 1999In-vitro and in-vivo evaluation of betulinic acid as an antimalarialView study →}.

Gap: weak potency relative to standard antimalarials, and preclinical only ^{8Reference 8Steele JCP et al. · 1999In-vitro and in-vivo evaluation of betulinic acid as an antimalarialView study →}.

Mechanisms

Target / pathway	Effect	Relevant to
Mitochondrial permeability transition (↓ ΔΨm, apoptogenic-factor release)	intrinsic apoptosis, largely p53/CD95-independent	anticancer (marquee)
Specificity proteins Sp1/Sp3/Sp4 (degradation)	↓ survivin, VEGF, cyclin D1, NF-κB p65	prostate & colon cancer
NF-κB (p65 downregulation)	anti-inflammatory; anti-survival	inflammation, anticancer
iNOS / macrophage NO (↓)	anti-inflammatory	rodent oedema
HIV-1 Gag processing (SP1–capsid cleavage) — via derivative bevirimat	maturation inhibition → non-infectious virions	anti-HIV (derivative)

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 122024Advancements 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 122024Advancements 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 randomised 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’s low, selective toxicity is a genuine point in its favour: in the founding melanoma-xenograft work it inhibited tumour growth with no observable systemic toxicity in mice, and it is repeatedly reported as favourable 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.

Pregnancy & lactation

Avoid. There is no human or reproductive-toxicity data for isolated betulinic acid, and its pro-apoptotic, mitochondria-targeting mechanism makes concentrated supplemental use inadvisable in pregnancy or lactation — dietary or whole-herb exposure (jujube, Bacopa) is a separate matter from isolated-compound dosing.

Dosage

There is no human dose for betulinic acid, and the following are research doses, not recommendations. Antitumour mouse xenograft work used parenteral/high dosing with a favourable 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 122024Advancements in betulinic-acid-loaded nanoformulations for enhanced anti-tumour therapyView study →}, so any oral figure has unpredictable exposure — which is why dosing work now centres on nanoformulations rather than the plain compound.

References