Oleanolic acid

Pharmacology & Research

Oleanolic acid is a pentacyclic oleanane triterpenoid with an unusual profile among plant compounds: it has been sold and used in China as an over-the-counter oral drug for hepatitis since the 1970s ^{4Reference 4Liu J · 1995Pharmacology of oleanolic acid and ursolic acidView study →}. Yet three facts complicate that reputation. First, it is a BCS-Class-IV molecule with ~0.7% oral bioavailability — barely absorbed, which limits every systemic claim ^{10Reference 10Jeong DW et al. · 2007AnimalDose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in ratsView study →}. Second — the honest surprise — its marketed liver indication is its weakest by controlled-trial quality, while its best human evidence is actually diabetes prevention ^{1Reference 1Santos-Lozano JM et al. · 2019RCTPrevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid — the PREDIABOLE study, a randomised controlled trialView study →}. Third, at high or prolonged doses the liver protector becomes cholestatic-hepatotoxic ^{13,15Reference 13Lu YF et al. · 2013AnimalRepeated oral administration of oleanolic acid produces cholestatic liver injury in miceView study →Reference 15Xu Y et al. · 2025AnimalHepatotoxicity from long-term administration of hepatoprotective low doses of oleanolic acid in miceView study →}. Throughout, keep it distinct from its isomer ursolic acid, from the oleanane saponins it is the aglycone of, and from the synthetic derivative bardoxolone methyl (whose trial data are not natural oleanolic acid’s).

1. Diabetes prevention & glucose

Oleanolic acid’s strongest human signal — and, surprisingly, not its marketed use. The PREDIABOLE RCT randomised 176 prediabetic adults to oleanolic-acid-enriched olive oil (~30 mg/day) versus non-enriched olive oil for a median ~2 years; progression to type 2 diabetes was roughly halved (17 vs 31 cases; adjusted HR 0.45, 95% CI 0.24–0.83) with no reported adverse effects ^{1Reference 1Santos-Lozano JM et al. · 2019RCTPrevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid — the PREDIABOLE study, a randomised controlled trialView study →}. Human PK and a companion olive-oil study confirm oleanolic acid is absorbed and bioactive from that matrix ^{2,3Reference 2Biel S et al. · 2016RCTThe NUTRAOLEOUM study — a randomised controlled trial for achieving nutritional added value for olive oilsView study →Reference 3García-González N et al. · 2023Bioavailability and systemic transport of oleanolic acid in humans, formulated as a functional olive oilView study →}, and the mechanism is coherent (AMPK/insulin-sensitising, α-glucosidase inhibition).

Gap: one modestly-sized single-centre trial delivering oleanolic acid inside olive oil — maslinic acid, polyphenols and monounsaturated fat all confound, so the effect cannot be cleanly attributed to oleanolic acid alone. No large multicentre replication and no hard glycaemic endpoint with a pure-OA formulation ^{1Reference 1Santos-Lozano JM et al. · 2019RCTPrevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid — the PREDIABOLE study, a randomised controlled trialView study →}.

2. Liver & hepatoprotection

The flagship indication by usage, the weakest by evidence quality. Oleanolic acid has been an over-the-counter oral treatment for acute and chronic viral hepatitis in China since the 1970s ^{4Reference 4Liu J · 1995Pharmacology of oleanolic acid and ursolic acidView study →}, and its preclinical hepatoprotection is robust — it “reprograms” the liver via Nrf2 to resist diverse hepatotoxicants ^{5Reference 5Liu J et al. · 2019Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high dosesView study →}.

Gap — the key honesty point: despite being the marketed use, there is no rigorous, indexed, English-language RCT of pure oleanolic acid for hepatitis. The clinical basis is old, largely Chinese-language practice/case-series grade, and predates modern trial standards; its ~0.7% bioavailability further undercuts plausibility for the free molecule at conventional doses. A widely-used drug on thin controlled evidence ^{4,5Reference 4Liu J · 1995Pharmacology of oleanolic acid and ursolic acidView study →Reference 5Liu J et al. · 2019Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high dosesView study →}.

3. Cardiovascular & endothelial

A randomised dose-response crossover in healthy adults showed maslinic and oleanolic acids from olive oil rise dose-dependently in biofluids, and their consumption was associated with improved endothelial function ^{6Reference 6de la Torre R et al. · 2020RCTPharmacokinetics of maslinic and oleanolic acids from olive oil — effects on endothelial function in healthy adults, a randomised controlled dose-response studyView study →}; preclinical work adds an eNOS/antioxidant vascular mechanism.

Gap: a surrogate endpoint (endothelial function) in healthy volunteers, again in an olive-oil matrix, with no blood-pressure outcome trial and no cardiovascular-event data for oleanolic acid specifically. (Note olive-leaf blood-pressure data belong to oleuropein, not oleanolic acid — do not conflate) ^{6Reference 6de la Torre R et al. · 2020RCTPharmacokinetics of maslinic and oleanolic acids from olive oil — effects on endothelial function in healthy adults, a randomised controlled dose-response studyView study →}.

4. Anticancer & anti-inflammatory

A systematic review and meta-analysis found oleanolic acid inhibits tumour growth and reduces tumour weight across animal models ^{7Reference 7Zeng Y et al. · 2024Meta-analysisAntitumour activity of oleanolic acid — a systematic review and meta-analysisView study →}, consistent with reproducible preclinical anti-inflammatory (NF-κB inhibition) and pro-apoptotic signals ^{8Reference 8Ayeleso TB et al. · 2017Oleanolic acid and its derivatives — biological activities and therapeutic potential in chronic diseasesView study →}.

Gap: entirely preclinical — no human oncology efficacy trials of natural oleanolic acid, and the reviewers themselves flag poor solubility/bioavailability as the barrier to translation. Mechanistically interesting, clinically unproven ^{7Reference 7Zeng Y et al. · 2024Meta-analysisAntitumour activity of oleanolic acid — a systematic review and meta-analysisView study →}.

Mechanisms

Target / pathway	Effect	Relevant to	Evidence
Nrf2 / antioxidant activation	induces phase-II & antioxidant genes; “reprograms” liver	hepatoprotection, CV antioxidant, chemoprevention	preclinical (the axis bardoxolone also exploits) 5,9Reference 5Liu J et al. · 2019Oleanolic acid reprograms the liver to protect against hepatotoxicants, but is hepatotoxic at high dosesView study →Reference 9Reisman SA et al. · 2009Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processesView study →
AMPK / metabolic signalling	↑ insulin sensitivity, modulates glucose/lipid handling	diabetes prevention, glucose	preclinical + PREDIABOLE human outcome 1Reference 1Santos-Lozano JM et al. · 2019RCTPrevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid — the PREDIABOLE study, a randomised controlled trialView study →
NF-κB inhibition	↓ pro-inflammatory cytokines	anti-inflammatory, anticancer	preclinical
TGR5 / bile-acid signalling	agonism (benefit) but disrupts bile-acid transport at high dose (harm)	metabolic; cholestatic injury	preclinical, double-edged 13,14Reference 13Lu YF et al. · 2013AnimalRepeated oral administration of oleanolic acid produces cholestatic liver injury in miceView study →Reference 14Liu J et al. · 2013AnimalOleanolic acid alters bile acid metabolism and produces cholestatic liver injury in miceView study →

Pharmacokinetics

Oleanolic acid’s defining pharmacological fact is that almost none of it gets in. It is highly lipophilic (logP ≈ 6.3), nearly insoluble in water, a poor passive permeant, and heavily first-pass metabolised — a BCS-Class-IV combination that yields ~0.7% absolute oral bioavailability in rats and only nanogram-per-millilitre serum concentrations in humans even when formulated for absorption in a functional olive oil, where it rides on albumin and lipoproteins rather than circulating freely ^{3,10Reference 3García-González N et al. · 2023Bioavailability and systemic transport of oleanolic acid in humans, formulated as a functional olive oilView study →Reference 10Jeong DW et al. · 2007AnimalDose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in ratsView study →}. This is the load-bearing caveat on every systemic claim: dietary and supplemental intakes deliver very little intact molecule to the blood, and effects shown with injected or high-concentration in-vitro exposures cannot be assumed to occur after eating it. Because the limiter is so well understood, most translational effort has gone into formulation — self-microemulsifying and nanoparticle systems raise exposure several-fold (a SMEDDS reported ~500% relative bioavailability versus a conventional tablet) ^{11,12Reference 11Yang R et al. · 2013Self-microemulsifying drug delivery system for improved oral bioavailability of oleanolic acid — design and evaluationView study →Reference 12Feng A et al. · 2020Development and evaluation of oleanolic acid dosage forms and its derivativesView study →} — but these start from a very low base and none has established a validated human therapeutic exposure.

Clinical trials

Oleanolic acid’s human record is split between a real diabetes-prevention RCT (in an olive-oil matrix) and decades of Chinese OTC hepatitis use on thin controlled evidence; everything else is preclinical or formulation work.

Diabetes (RCT)	Liver (OTC use)	Vascular	Anticancer
1 (PREDIABOLE) + 1 ongoing	Marketed drug, case-series grade	1 crossover (surrogate)	Preclinical only

Last checked: July 2026.

Isolate vs. Plant Studies

Oleanolic acid needs three separations kept clear. The best human evidence is a food matrix, not the molecule: PREDIABOLE delivered oleanolic acid inside enriched olive oil, alongside maslinic acid, polyphenols and monounsaturated fat, so its diabetes-prevention effect is a fortified-olive-oil result more than a pure-oleanolic-acid one ^{1Reference 1Santos-Lozano JM et al. · 2019RCTPrevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid — the PREDIABOLE study, a randomised controlled trialView study →}. In plants it is often the aglycone of oleanane saponins: within this database the demulcent/expectorant action of chickweed and the gastroprotective calendasaponins of calendula belong to the glycosides, with “oleanolic acid” naming the shared skeleton, not the free acid. And it co-occurs and is co-studied with its isomer ursolic acid — repeatedly paired in holy basil, melissa (where both inhibit GABA-transaminase), guamura and bearberry — so a “triterpene-acid” finding is often really about the pair. One trap on the current herb notes: holy basil’s ~2.5–5% standardisation figure is for ursolic acid, not oleanolic. Finally, the synthetic derivative bardoxolone methyl shares this scaffold but is a different, far more potent drug — its trial data are firewalled below.

Prevalence in Nature

Oleanolic acid is one of the most widely distributed pentacyclic triterpenoids in the plant kingdom, occurring free and as the aglycone of oleanane saponins. It is fundamentally a cuticular-wax and defence triterpenoid — plants deposit it (with its isomer ursolic acid) in the waxy outer surfaces of leaves, fruit skins and bark, so the richest sources are surface tissues rather than whole foods ^{20Reference 20Jäger S et al. · 2009Pentacyclic triterpene distribution in various plants — rich sources for a new group of multi-potent plant extractsView study →}. The flagship is the olive (Olea europaea): oleanolic acid reaches ~3–3.5% of dry weight in the leaf (the single highest common source) and concentrates in the fruit-skin/epicarp wax (~100 mg/100 g, though maslinic acid dominates there), making olive pomace and mill by-products triterpene-rich waste streams from which it is commercially recovered ^{21Reference 21Guinda Á et al. · 2010Pentacyclic triterpenoids from olive fruit and leafView study →}. Beyond olive it is abundant across Lamiaceae herbs (rosemary, thyme, sage, oregano, holy basil), clove buds, mistletoe, and appears in grape/raisin, apple peel, cranberry and legumes — always alongside ursolic acid, at a species-specific ratio (olive is oleanolic-dominant; many Lamiaceae leaves are ursolic-dominant) ^{20,22Reference 20Jäger S et al. · 2009Pentacyclic triterpene distribution in various plants — rich sources for a new group of multi-potent plant extractsView study →Reference 22Zhang F et al. · 2013Oleanolic acid and ursolic acid in commercial dried fruitsView study →}. See the Content-by-Source chart (two tiers: dried wax-bearing tissue, and much lower dried whole fruit).

Biosynthetically, oleanolic acid comes from the isoprenoid/triterpenoid pathway: the C₃₀ precursor 2,3-oxidosqualene is cyclised by β-amyrin synthase to β-amyrin, which CYP716A enzymes oxidise in three steps at C-28 (via erythrodiol and oleanolic aldehyde) to oleanolic acid; a parallel α-amyrin → ursolic acid route explains their constant co-occurrence ^{20Reference 20Jäger S et al. · 2009Pentacyclic triterpene distribution in various plants — rich sources for a new group of multi-potent plant extractsView study →}. There is essentially no non-plant source — it is a plant (and some fungal/lichen) metabolite, absent from animal tissue except via plant foods.

Discovery & Synthesis

Oleanolic acid takes its name directly from the olive, Olea europaea, the plant in which it is abundant — in the leaves, the fruit skin/waxy cuticle, and olive pomace (the pressing by-product). The naming after Olea is well established, but a specific first-isolation date and chemist could not be reliably confirmed, so none is asserted here. Chemically it is a pentacyclic oleanane triterpenoid, 3β-hydroxyolean-12-en-28-oic acid (C₃₀H₄₈O₃) — a 12-ene with a 3β-hydroxyl and a C-28 carboxylic acid. It is the positional isomer of ursolic acid, which sits on the ursane skeleton and differs only in the placement of a methyl group on the E-ring; that near-identity is why the two co-occur and are routinely reported and analytically resolved together, and a page on one should keep it distinct from the other. Oleanolic acid also occurs widely as the aglycone of oleanane-type saponins, freed on hydrolysis. Commercially it is obtained by extraction — from olive leaf and olive pomace (valorising an oil-industry waste stream) and many other botanicals — not by synthesis; synthetic chemistry on this scaffold is instead directed at derivatives such as the bardoxolone series.

Patents: not yet researched (future patent-loop pass).

Toxicity & Safety

At the levels found in food — olive oil, olive leaf, herbs — oleanolic acid has a benign safety record, and ordinary dietary exposure carries no established toxicity. The important, counter-intuitive signal is at the pharmacological/high-dose end: oleanolic acid is dose-dependently hepatotoxic, and the injury is specifically cholestatic — paradoxical for a compound used at low doses to protect the liver. In mice, repeated oral dosing raised ALT and bilirubin with hepatocellular apoptosis, necrosis and feathery (cholestatic) degeneration ^{13Reference 13Lu YF et al. · 2013AnimalRepeated oral administration of oleanolic acid produces cholestatic liver injury in miceView study →}, traced mechanistically to disrupted bile-acid uptake and down-regulated hepatic bile-acid transporters ^{14Reference 14Liu J et al. · 2013AnimalOleanolic acid alters bile acid metabolism and produces cholestatic liver injury in miceView study →}; even low, nominally hepatoprotective doses given long-term (14 weeks) produced hepatocyte degeneration and early fibrosis with oleanolic-acid accumulation in liver ^{15Reference 15Xu Y et al. · 2025AnimalHepatotoxicity from long-term administration of hepatoprotective low doses of oleanolic acid in miceView study →}. So the hepatotoxic ceiling is a function of cumulative exposure, not just single-dose size — a genuine dose-/duration-dependent liver-injury flag for a liver supplement. (The low-dose protective face is real too — low-dose oleanolic acid protected against lithocholic-acid cholestasis ^{16Reference 16Chen L et al. · 2014AnimalLow dose of oleanolic acid protects against lithocholic-acid-induced cholestasis in miceView study →} — hence the hormetic, dose-dependent framing.)

Do not attribute the bardoxolone story to natural oleanolic acid. Bardoxolone methyl (CDDO-Me) is a synthetic oleanane Nrf2 activator built on this scaffold but far more potent; its Phase-3 BEACON trial in diabetic stage-4 CKD was terminated early for excess heart-failure events from fluid retention ^{18,19Reference 18de Zeeuw D et al. · 2013Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease (BEACON)View study →Reference 19Chin MP et al. · 2014Clinical trialRisk factors for heart failure in patients with type 2 diabetes and stage 4 chronic kidney disease treated with bardoxolone methylView study →}. That is a cautionary note about engineering potency into this chemical class — relevant lineage context, not a property of dietary oleanolic acid. On interactions, oleanolic acid is an Nrf2 inducer ^{9Reference 9Reisman SA et al. · 2009Oleanolic acid activates Nrf2 and protects from acetaminophen hepatotoxicity via Nrf2-dependent and Nrf2-independent processesView study →} and an in-vitro inhibitor of CYP1A2/CYP3A4 (at high Kᵢ) ^{17Reference 17Kim KA et al. · 2004Inhibition of cytochrome P450 activities by oleanolic acid and ursolic acid in human liver microsomesView study →}, so a theoretical CYP3A4 interaction exists but is unlikely at the low plasma levels achievable orally; caution is nonetheless reasonable in hepatobiliary disease or with hepatotoxic/cholestatic co-medications.

Dosage

The one real efficacy trial used ~30 mg/day of oleanolic acid delivered as enriched olive oil (55 mL/day) over ~2 years ^{1Reference 1Santos-Lozano JM et al. · 2019RCTPrevention of type 2 diabetes in prediabetic patients by using functional olive oil enriched in oleanolic acid — the PREDIABOLE study, a randomised controlled trialView study →}. Historical Chinese hepatitis tablets used higher oral doses, but on thin controlled evidence and against the reality that only ~0.7% is absorbed ^{10Reference 10Jeong DW et al. · 2007AnimalDose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in ratsView study →}. Because bioavailability is the limiter, formulation (with-fat, or nanoparticle/SMEDDS delivery) affects exposure far more than the milligram figure ^{11Reference 11Yang R et al. · 2013Self-microemulsifying drug delivery system for improved oral bioavailability of oleanolic acid — design and evaluationView study →}.

These are descriptive research/practice figures, not a recommendation — the diabetes evidence is a single olive-oil-matrix trial, the liver use rests on weak controlled evidence, and high or prolonged dosing carries a documented cholestatic-liver-injury risk (see Safety).

References