Castalagin

Castalagin at a Glance

Castalagin is a C-glycosidic ellagitannin — a large hydrolysable tannin (MW ~934) built from an open-chain glucose triply esterified by a nonahydroxytriphenoyl (NHTP) unit that is also bonded to the sugar’s C-1 by a carbon–carbon bond. That last bond is the whole story of this molecule: it cannot be hydrolysed, so castalagin does not behave like the ester-linked ellagitannins it is usually grouped with.

It has two almost completely separate literatures. In wood and beverage chemistry — where nearly all the quantitative work lives — castalagin and its epimer vescalagin are the two dominant tannins of oak and sweet chestnut heartwood, and the principal ellagitannins extracted into barrel-aged wine and spirits ^{3,8Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →Reference 8Stark T et al. · 2010Matrix-calibrated LC-MS/MS quantitation and sensory evaluation of oak ellagitannins and their transformation products in red winesView study →}. In immuno-oncology, a 2022 Cancer Discovery paper identified castalagin as the active compound in camu-camu berry that remodels the gut microbiota and restores response to anti-PD-1 checkpoint blockade in mice ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. Those two bodies of work barely cite each other.

The unifying fact is that castalagin is not absorbed. In the mouse study the authors could not detect it in serum or faeces by HPLC even at twenty times the effective dose, and its antitumour effect disappeared entirely in germ-free and antibiotic-treated animals ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. Whatever this molecule does in a body, it does in the gut lumen, to bacteria — not in plasma, to human cells. Every micromolar in-vitro result here should be read against that.

Castalagin vs. Vescalagin

Castalagin and vescalagin are C-1 epimers: identical molecules that differ only in whether the hydroxyl at the glucose C-1 position points up or down. They are almost always reported together, and in oak they occur in a fairly stable ratio (vescalagin/castalagin ≈ 0.69 in Quercus robur, ≈ 0.53 in Q. petraea) ^{3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →}.

The difference is not cosmetic. Conformational analysis shows vescalagin is the more polar, more oxidisable and more thermally fragile of the two, and its C-1 hydroxyl sits in an orientation that makes it reactive toward nucleophilic substitution — in wine it captures ethanol, catechin, anthocyanins and glutathione to form condensation products, while castalagin does not ^{7Reference 7Vivas N et al. · 2004Conformational interpretation of vescalagin and castalagin physicochemical propertiesView study →}. Castalagin is the stable, unreactive epimer. That is why castalagin, not vescalagin, is the ellagitannin that survives to predominate in oak-matured red wine ^{8Reference 8Stark T et al. · 2010Matrix-calibrated LC-MS/MS quantitation and sensory evaluation of oak ellagitannins and their transformation products in red winesView study →}, and why toasting and ageing shift the pair’s ratio.

The epimers also diverge biologically. Vescalagin is the better inhibitor of DNA topoisomerase IIα and the better protector against amyloid-β42 oligomer toxicity, in both cases because of that C-1 geometry ^{22Reference 22Araújo AR et al. · 2020Vescalagin and castalagin reduce the toxicity of amyloid-beta42 oligomers through the remodelling of its secondary structureView study →}. Castalagin is the stronger PARP1 inhibitor of the two — IC50 0.86 µM versus vescalagin’s 2.67 µM in a purified-enzyme assay ^{16Reference 16Kamada Y et al. · 2018Castalagin and vescalagin purified from leaves of Syzygium samarangense (Blume) Merrill & L.MView study →}. And the anti-PD-1 microbiota effect was tracked specifically to castalagin ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. Findings do not transfer between the two, and a paper reporting “vescalagin and castalagin” as a pair rarely resolves which one carried the activity.

The C-Glycosidic Bond and Why It Matters

Most ellagitannins — punicalagin, corilagin, geraniin — hang their galloyl and hexahydroxydiphenoyl units on a normal pyranose glucose by ester bonds. Gut bacteria and tannases hydrolyse those esters readily, liberating ellagic acid, which colonic microbiota then convert through a sequence of dehydroxylations into the urolithins (A, B, C, D) that are the only ellagitannin-derived metabolites to reach human plasma in any quantity — and only in people whose microbiome carries the right enzymes, which is the basis of the urolithin metabotype A/B/0 split ^{9Reference 9García-Villalba R et al. · 2022ReviewUrolithins: a comprehensive update on their metabolism, bioactivity, and associated gut microbiotaView study →}.

Castalagin’s glucose is different in two ways. It is open-chain rather than a closed pyranose ring, and it is joined to the NHTP unit at C-1 through a carbon–carbon bond that no tannase can cleave. Complete hydrolysis of castalagin therefore cannot yield the same clean crop of free ellagic acid a comparable ester-linked tannin would — one part of the NHTP unit stays covalently stapled to the sugar as an ellagic acid C-glycoside.

The practical consequences run through the whole page:

• It survives further down the gut than an ester-linked tannin of the same size, arriving at the colonic microbiota largely intact.
• It is a poorer urolithin precursor, so the urolithin literature — which is where most of the human pharmacology of ellagitannins actually sits — transfers to castalagin only partly.
• Its own molecule-level activity has to be a luminal activity, which is exactly what the anti-PD-1 work found: castalagin binds the surface of gut bacteria and never enters the bloodstream ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}.

The Anti-PD-1 Adjuvant Story

This is the finding that made castalagin interesting outside enology, and it deserves stating precisely because it is easy to over-read.

Messaoudene and colleagues fed mice a polyphenol-rich camu-camu (Myrciaria dubia) preparation at 200 mg/kg and saw the gut microbiome shift, tumours shrink, and anti-PD-1 responses strengthen. Fractionating the berry, they identified castalagin as the active compound — and then reproduced the whole effect with the isolated molecule at 0.85 mg/kg/day, a dose-response run out to 2.55 mg/kg ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. Oral castalagin enriched bacterial taxa associated with checkpoint-inhibitor response (Ruminococcaceae, Alistipes), raised the intratumoural CD8⁺/FOXP3⁺CD4⁺ T-cell ratio, increased taurine-conjugated bile acids, and — the strongest result — restored anti-PD-1 activity in mice colonised by faecal transplant from checkpoint-refractory patients ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}.

Three details matter more than the headline:

It is a prebiotic, not a drug. Castalagin binds the cell envelope of Ruminococcus bromii — 79% of cells were labelled by a fluorescent castalagin probe — without being internalised, in a specific but non-energy-dependent interaction the authors suggest may involve radical scavenging or iron chelation at the bacterial surface ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. It was undetectable in serum and faeces by HPLC at up to 17 mg/kg/day, and had no antitumour effect at all in germ-free mice or in mice on antibiotics ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. The molecule does not touch the tumour.

The castalagin actually tested was oak-derived. Because camu-camu is a poor source in absolute terms, the group developed an extraction and purification protocol from oak wood to obtain material for the mouse experiments ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. So the marquee experiment is an oak-wood molecule validating an Amazonian berry — a striking inversion of the usual isolate-vs-plant caveat.

The human evidence is two case reports and an unpublished phase 1. Two patients with checkpoint-refractory metastatic melanoma achieved deep, durable responses after camu-camu was added to nivolumab, both maintained beyond a year with minimal immune-related adverse events ^{2Reference 2Pang SA et al. · 2023Case reportTwo cases of durable and deep responses to immune checkpoint inhibition-refractory metastatic melanoma after addition of camu camu prebioticView study →}. That is a case series of two, on whole camu-camu, not on castalagin. A phase 1 trial of camu-camu prebiotic with checkpoint inhibition in non-small-cell lung cancer and melanoma (NCT05303493, n = 45) has completed without a published readout, and a phase 1 renal-cell-carcinoma trial of nivolumab/ipilimumab ± camu-camu (NCT06049576, n = 31) is active. No human trial has yet dosed isolated castalagin.

What It's Used For

Beyond the microbiota work, castalagin’s pharmacology is a set of clean in-vitro and small-animal findings on the isolated molecule, plus a large body of whole-extract work in which it is one tannin among many. The recurring caveat is exposure: the concentrations that produce these effects are reachable in the gut lumen or on skin, essentially never in plasma.

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 row here is capped by the same ceiling: castalagin is not systemically absorbed, so read each entry for where the effect happens.

01Cancer immunotherapy adjuvant (microbiota)Promising48%Isolated-molecule mouse mechanism + faecal-transplant rescue; human data = 2 case reports on whole berry ^{1,2Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →Reference 2Pang SA et al. · 2023Case reportTwo cases of durable and deep responses to immune checkpoint inhibition-refractory metastatic melanoma after addition of camu camu prebioticView study →}

02Antiviral (herpes simplex)Shaky38%Isolated castalagin in vitro + a newborn-mouse HSV-1 model; acyclovir synergy ^{14,15Reference 14Vilhelmova-Ilieva N et al. · 2014Ellagitannins as synergists of ACV on the replication of ACV-resistant strains of HSV 1 and 2View study →Reference 15Stoyanova A et al. · 2023AnimalEffect of castalagin against HSV-1 infection in newborn miceView study →}

03Anti-infective & anti-inflammatory (mucosa, skin)Shaky34%Pure castalagin vs. H. pylori and C. acnes in human cell models, extract-matched ^{12,13Reference 12Piazza S et al. · 2023Ellagitannins from Castanea sativa Mill. leaf extracts impair H. pylori viability and infection-induced inflammation in human gastric epithelial cellsView study →Reference 13Piazza S et al. · 2024Investigation into the anti-acne effects of Castanea sativa Mill leaf and its pure ellagitannin castalagin in HaCaT cells infected with Cutibacterium acnesView study →}

04Antioxidant (tannin fraction)Shaky28%In-vitro, as the dominant phenolic of camu-camu/jabuticaba seed extracts ^{11,24Reference 11Fidelis M et al. · 2020Camu-camu seed (Myrciaria dubia) — from side stream to an antioxidant, antihyperglycemic, antiproliferative, antimicrobial, antihemolytic, anti-inflammatory, and antihypertensive ingredientView study →Reference 24Fidelis M et al. · 2020Response surface optimization of phenolic compounds from jabuticaba (Myrciaria cauliflora [Mart.] O.Berg) seeds: antioxidant, antimicrobial, antihyperglycemic, antihypertensive and cytotoxic assessmentsView study →}

05Direct anticancer cytotoxicityShaky22%Enzyme-level PARP1/topoisomerase-II inhibition + class-level cell screens; no in-vivo isolate data ^{16,17Reference 16Kamada Y et al. · 2018Castalagin and vescalagin purified from leaves of Syzygium samarangense (Blume) Merrill & L.MView study →Reference 17Kashiwada Y et al. · 1992Antitumor agents, 129View study →}

06Glycaemic / metabolicShaky18%One isolated-castalagin hepatocyte study; α-glucosidase inhibition is a class result ^{19,26Reference 19Chang WC et al. · 2013AnimalEffect of water extracts from edible Myrtaceae plants on uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose in TNF-α-treated FL83B mouse hepatocytesView study →Reference 26Cardullo N et al. · 2020C-glucosidic ellagitannins and galloylated glucoses as potential functional food ingredients with anti-diabetic properties: a study of α-glucosidase and α-amylase inhibitionView study →}

Mechanisms

The mechanism table is misleading unless read with the exposure column in mind. Only the top three rows and the α-glucosidase row describe things that can happen in a person who swallows castalagin; the enzyme-level and antiviral rows describe what the molecule does when you put it in a tube with a target it will never meet in vivo.

Pharmacokinetics

The defining pharmacokinetic fact about castalagin is that there is almost no pharmacokinetics. In the mouse immunotherapy work the authors ran HPLC on serum and faeces from animals given up to 20× the effective dose (17 mg/kg/day) and could not detect the parent molecule in either ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →} — it is neither absorbed nor excreted intact in recoverable amounts. Consistent with that, its antitumour effect vanished in germ-free and antibiotic-treated mice, i.e. the entire in-vivo effect is microbially mediated ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}.

Its chemistry explains why the usual ellagitannin escape route is partly closed. Ester-linked ellagitannins are hydrolysed by gut tannases to free ellagic acid, which colonic bacteria dehydroxylate stepwise to the urolithins — the only ellagitannin metabolites that reach human plasma at meaningful concentrations, and then only in people carrying the right microbial enzymes (the urolithin A/B/0 metabotypes) ^{9Reference 9García-Villalba R et al. · 2022ReviewUrolithins: a comprehensive update on their metabolism, bioactivity, and associated gut microbiotaView study →}. Castalagin’s C-1 carbon–carbon bond to the NHTP unit cannot be hydrolysed, so full breakdown to free ellagic acid is only partial — part of the aromatic unit remains covalently attached to the sugar. In-vitro colonic fermentation of a castalagin-containing fruit powder does show the molecule being released and further transformed alongside gallic acid and other metabolites over 48 h ^{20Reference 20Adiamo OQ et al. · 2024In-vitro colonic fermentation of Kakadu plum (Terminalia ferdinandiana) fruit powder: microbial biotransformation of phenolic compounds and cytotoxicityView study →}, but no quantitative human absorption, metabotype or urinary-recovery study exists for castalagin specifically.

Practically: assume plasma concentrations of intact castalagin are effectively zero, treat any in-vitro IC50 above the nanomolar range as unreachable systemically, and read the molecule as acting on the gut lumen and its bacteria.

Clinical Trials

No completed trial has administered isolated castalagin to humans. The clinical programme built on this molecule doses whole camu-camu powder: a completed phase 1 study of camu-camu prebiotic with immune-checkpoint inhibition in non-small-cell lung cancer and melanoma (NCT05303493, n = 45, no published readout), an active phase 1 study of nivolumab and ipilimumab ± camu-camu in metastatic renal-cell carcinoma (NCT06049576, n = 31), and an earlier completed phase 1 in ART-treated people living with HIV (NCT04058392, n = 22) whose preliminary faecal analysis showed a trend toward R. bromii enrichment ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. Published human evidence is limited to two melanoma case reports ^{2Reference 2Pang SA et al. · 2023Case reportTwo cases of durable and deep responses to immune checkpoint inhibition-refractory metastatic melanoma after addition of camu camu prebioticView study →}.

Last checked: August 2026.

Isolate vs. Plant Studies

Castalagin sits unusually well on this axis in one respect and badly in another.

The good half. The signature finding is a genuine isolate result: the camu-camu extract was fractionated, castalagin was identified as the active compound, and the pure molecule reproduced the microbiota shift, the T-cell change and the anti-PD-1 rescue on its own ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. The chestnut-leaf infection studies likewise ran extract and purified castalagin side by side and reported both potencies ^{12,13Reference 12Piazza S et al. · 2023Ellagitannins from Castanea sativa Mill. leaf extracts impair H. pylori viability and infection-induced inflammation in human gastric epithelial cellsView study →Reference 13Piazza S et al. · 2024Investigation into the anti-acne effects of Castanea sativa Mill leaf and its pure ellagitannin castalagin in HaCaT cells infected with Cutibacterium acnesView study →}, and the antiviral, PARP1 and hepatocyte glucose-uptake work all used purified compound ^{14,15,16,19Reference 14Vilhelmova-Ilieva N et al. · 2014Ellagitannins as synergists of ACV on the replication of ACV-resistant strains of HSV 1 and 2View study →Reference 15Stoyanova A et al. · 2023AnimalEffect of castalagin against HSV-1 infection in newborn miceView study →Reference 16Kamada Y et al. · 2018Castalagin and vescalagin purified from leaves of Syzygium samarangense (Blume) Merrill & L.MView study →Reference 19Chang WC et al. · 2013AnimalEffect of water extracts from edible Myrtaceae plants on uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose in TNF-α-treated FL83B mouse hepatocytesView study →}.

The bad half. All the human evidence points the other way. The two melanoma case reports used whole camu-camu ^{2Reference 2Pang SA et al. · 2023Case reportTwo cases of durable and deep responses to immune checkpoint inhibition-refractory metastatic melanoma after addition of camu camu prebioticView study →}; the registered trials dose whole camu-camu powder; and every antioxidant, antiproliferative and antihypertensive claim attached to camu-camu, jabuticaba or Kakadu plum rests on whole seed or fruit extracts in which castalagin is merely the largest identified peak ^{11,20,24Reference 11Fidelis M et al. · 2020Camu-camu seed (Myrciaria dubia) — from side stream to an antioxidant, antihyperglycemic, antiproliferative, antimicrobial, antihemolytic, anti-inflammatory, and antihypertensive ingredientView study →Reference 20Adiamo OQ et al. · 2024In-vitro colonic fermentation of Kakadu plum (Terminalia ferdinandiana) fruit powder: microbial biotransformation of phenolic compounds and cytotoxicityView study →Reference 24Fidelis M et al. · 2020Response surface optimization of phenolic compounds from jabuticaba (Myrciaria cauliflora [Mart.] O.Berg) seeds: antioxidant, antimicrobial, antihyperglycemic, antihypertensive and cytotoxic assessmentsView study →}. Naming the dominant phenolic in an extract is not the same as showing it did the work.

There is also a source inversion worth holding onto. The castalagin used in the decisive mouse experiments was extracted from oak wood, not from camu-camu, because oak heartwood is roughly a hundredfold richer ^{1,3Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →}. So the molecule’s marquee result belongs to neither plant cleanly: an oak-derived compound, validating an Amazonian berry, working through bacteria.

Its Role in Plants

Castalagin is a heartwood defence tannin. In oak and sweet chestnut it accumulates as the tree converts sapwood to heartwood, where — with vescalagin — it constitutes 40–60% of the total ellagitannin load and helps make the dead central wood resistant to fungal and insect attack ^{3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →}. Its concentration is under strong genetic and species control: pedunculate oak is consistently richer than sessile oak, and the difference between them is a botanical marker rather than a site effect ^{3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →}.

In fruit-bearing Myrtaceae — camu-camu, jabuticaba, wax apple — castalagin is concentrated in seed and seed coat rather than pulp, the tissue the plant most needs to protect and the tissue humans discard ^{11,24Reference 11Fidelis M et al. · 2020Camu-camu seed (Myrciaria dubia) — from side stream to an antioxidant, antihyperglycemic, antiproliferative, antimicrobial, antihemolytic, anti-inflammatory, and antihypertensive ingredientView study →Reference 24Fidelis M et al. · 2020Response surface optimization of phenolic compounds from jabuticaba (Myrciaria cauliflora [Mart.] O.Berg) seeds: antioxidant, antimicrobial, antihyperglycemic, antihypertensive and cytotoxic assessmentsView study →}. Its ellagitannin relatives are also implicated in metal handling: recent work characterises ellagitannins as aluminium(III) chelators, plausibly part of how these plants tolerate acid soils ^{30Reference 30Frešer F et al. · 2026Ellagitannins as Al(III) chelators: determined binding sites with a predictive modelView study →}.

Two chemical behaviours that look like enological trivia are really plant chemistry. Castalagin is oxidatively labile, degrading through a regioselectively generated quinone intermediate ^{31Reference 31Liu ZB et al. · 2023Identification of unstable ellagitannin metabolites in the leaves of Quercus dentata by chemical derivatizationView study →}, and it is thermally degraded — which is why toasting a barrel roughly halves its content ^{3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →}. Both are the reactions a defensive polyphenol is built to undergo.

Prevalence in Nature

Castalagin is, overwhelmingly, a wood compound. Its documented range centres on the Fagaceae — Quercus (oak) and Castanea (sweet chestnut) — where it is quantified in milligrams per gram of dry heartwood, and extends thinly into the Myrtaceae fruits, Lythraceae (henna) and a few others, where it is a minor constituent measured in the noise of a phenolic profile.

Major Natural Sources

Source	Part	Castalagin	Note
Sweet chestnut (Castanea sativa)	heartwood (seasoned 24 mo)	~17.4 mg/g	The richest single figure reported 3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →
Pedunculate oak (Quercus robur)	heartwood (green)	9.4–13.0 mg/g	Consistently richer than sessile oak 3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →
Pyrenean oak (Q. pyrenaica)	heartwood (green)	10.6–12.6 mg/g	Alternative cooperage wood 3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →
Portuguese oak (Q. faginea)	heartwood (green)	~10.0 mg/g	3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →
Sessile oak (Q. petraea)	heartwood (green)	3.9–9.1 mg/g	The classic French cooperage oak 3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →
American white oak (Q. alba)	heartwood (green)	~1.2 mg/g	~10× lower than European oak — part of why bourbon barrels taste different 3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →
Colombian oak (Q. humboldtii)	heartwood (green)	~0.6 mg/g	Lowest oak reported 3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →
Camu-camu (Myrciaria dubia)	whole fruit / seed	not quantified	Total ellagitannins ~16 mg/100 g in dried pulp powder 10Reference 10Fracassetti D et al. · 2013Ellagic acid derivatives, ellagitannins, proanthocyanidins and other phenolics, vitamin C and antioxidant capacity of two powder products from camu-camu fruit (Myrciaria dubia)View study →; castalagin is a fraction of that

Seasoning and toasting move these numbers substantially. Twenty-four months of natural seasoning concentrates castalagin (Q. robur rising to ~30 mg/g), while toasting degrades it — a chestnut sample toasted at 165 °C for 35 min fell to 6.6 mg/g ^{3Reference 3Martínez-Gil A et al. · 2020ReviewAlternative woods in enology: characterization of tannin and low molecular weight phenol compounds with respect to traditional oak woodsView study →}. In finished beverages, castalagin is the predominant ellagitannin of oak-matured red wine, present at concentrations straddling its own sensory threshold for smooth astringency, 0.9–2.8 µmol/L ^{8Reference 8Stark T et al. · 2010Matrix-calibrated LC-MS/MS quantitation and sensory evaluation of oak ellagitannins and their transformation products in red winesView study →}; validated LC-MS/MS methods now track it through cognac ageing in barrel ^{23Reference 23Gadrat M et al. · 2021Validation of a mass spectrometry method to identify and quantify ellagitannins in oak wood and cognac during aging in oak barrelsView study →}.

Other Reported Sources

• Camu-camu (Myrciaria dubia) — seed and whole fruit; with vescalagin the main phenolics of the seed extract ^{1,11Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →Reference 11Fidelis M et al. · 2020Camu-camu seed (Myrciaria dubia) — from side stream to an antioxidant, antihyperglycemic, antiproliferative, antimicrobial, antihemolytic, anti-inflammatory, and antihypertensive ingredientView study →}
• Jabuticaba (Plinia cauliflora) — seed, leaf and branch extracts ^{24Reference 24Fidelis M et al. · 2020Response surface optimization of phenolic compounds from jabuticaba (Myrciaria cauliflora [Mart.] O.Berg) seeds: antioxidant, antimicrobial, antihyperglycemic, antihypertensive and cytotoxic assessmentsView study →}
• Kakadu plum (Terminalia ferdinandiana) — fruit powder, released during colonic fermentation ^{20Reference 20Adiamo OQ et al. · 2024In-vitro colonic fermentation of Kakadu plum (Terminalia ferdinandiana) fruit powder: microbial biotransformation of phenolic compounds and cytotoxicityView study →}
• Wax apple (Syzygium samarangense) — leaf and fruit ^{16,19Reference 16Kamada Y et al. · 2018Castalagin and vescalagin purified from leaves of Syzygium samarangense (Blume) Merrill & L.MView study →Reference 19Chang WC et al. · 2013AnimalEffect of water extracts from edible Myrtaceae plants on uptake of 2-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)-2-deoxyglucose in TNF-α-treated FL83B mouse hepatocytesView study →}
• Henna (Lawsonia inermis) — leaf, alongside two novel C-glycosidic ellagitannins ^{21Reference 21Orabi MAA et al. · 2021Two new C-glycosidic ellagitannins and accompanying tannins from Lawsonia inermis leaves and their cytotoxic effectsView study →}
• Allspice (Pimenta dioica) — leaf, among eighteen isolated tannins ^{32Reference 32Marzouk MS et al. · 2007Anticancer and antioxidant tannins from Pimenta dioica leavesView study →}
• Black raspberry (Rubus occidentalis) — seed ^{25Reference 25Kim RH et al. · 2023Anti-inflammatory activities of black raspberry seed ellagitannins and their structural effects on the stimulation of glucagon-like peptide-1 secretion and intestinal bitter taste receptorsView study →}
• Rose apple (Eugenia jambos) — as the derivative 1-O-galloylcastalagin ^{18Reference 18Yang LL et al. · 2000Induction of apoptosis by hydrolyzable tannins from Eugenia jambos L. on human leukemia cellsView study →}

The database entry to note here is that no castalagin-specific concentration has been published for camu-camu, the plant this molecule is best known for. The only camu-camu number available is for total ellagitannins (~16 mg/100 g dried pulp) ^{10Reference 10Fracassetti D et al. · 2013Ellagic acid derivatives, ellagitannins, proanthocyanidins and other phenolics, vitamin C and antioxidant capacity of two powder products from camu-camu fruit (Myrciaria dubia)View study →} — roughly a hundredfold below oak heartwood on a dry-weight basis, which is precisely why the immunotherapy group extracted their material from oak instead ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}.

Discovery & Synthesis

Castalagin was first reported in 1959 by Wilhelm Mayer’s group at Heidelberg, in a Naturwissenschaften note announcing castalagin and vescalagin as “two new crystalline ellagitannins from the wood of sweet chestnut and oak” ^{5Reference 5Mayer W et al. · 1959Castalagin und Vescalagin, zwei neue, kristallisierte Ellagengerbstoffe aus dem Holz der Edelkastanie und EicheView study →}. The full isolation procedure — which also yielded their smaller relatives castalin and vescalin — appeared in Liebigs Annalen in 1967 ^{4Reference 4Mayer W et al. · 1967Mayer W, Gabler W, Riester A, Korger H (1967). Über die Gerbstoffe aus dem Holz der Edelkastanie und der Eiche, II. Die Isolierung von Castalagin, Vescalagin, Castalin und Vescalin. Justus Liebigs Annalen der Chemie. https://doi.org/10.1002/jlac.19677070125View study →}. The names come straight from the botany: castalagin from Castanea (chestnut), vescalagin from Quercus vesca, an old name for the same Castanea sativa. The stereochemical assignment at C-1 that distinguishes the two epimers was later revisited and revised.

Total synthesis took another fifty-eight years. The molecule’s combination of an open-chain glucose, a doubly axially chiral NHTP unit and a C-arylglucosidic bond defeated repeated attempts; the first total synthesis of (−)-vescalagin was completed only in 2025 by Quideau’s group in Bordeaux, using a bioinspired route with atroposelective phenolic couplings and a methoxyamine-driven ring-opening of a glucopyranose intermediate followed by a phenolic aldol-type reaction to install the C-aryl bond. The minor C-1 epimer produced in that step gave the first total synthesis of (−)-castalagin ^{6Reference 6Larrieu R et al. · 2025Total synthesis of (−)-vescalagin, the iconic member of the C-glucosidic ellagitannin familyView study →}.

Manufacture today is entirely extractive. No synthetic route is remotely economic, so research-grade castalagin is purified from oak or chestnut wood; the immunotherapy group’s contribution included an efficient oak-wood extraction and purification protocol developed specifically to supply their mouse studies ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. Oak-wood extracts standardised for ellagitannins are also a commodity in enology and animal nutrition, though those are extracts, not the isolated molecule.

Patents: not yet researched.

Toxicity & Safety

Castalagin carries a low flag. It is a normal constituent of foods and beverages people have consumed for centuries — barrel-aged wine and spirits, chestnut, camu-camu, jabuticaba — and the mouse work found daily oral dosing to twenty times the effective dose (17 mg/kg/day) tolerable enough to run as a control condition ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. Its poor absorption is protective: whatever risks it carries are gut-luminal.

That said, no dedicated toxicology package exists for the isolated molecule — no repeat-dose study, no genotoxicity battery, no reproductive-toxicity data, no drug-interaction work identifying a CYP isoform or transporter. The safety picture below is inferred from the hydrolysable-tannin class and from the molecule’s own mechanism, and silence should not be read as safety.

Safety at a Glance

✅ Low / no toxicity

• Long dietary history at low doses. Present in oak-aged wine and spirits, chestnut, camu-camu and jabuticaba; not absorbed systemically.
• It deliberately remodels the gut microbiome. That is its mechanism, not a side effect — and it is the reason to avoid self-supplementing camu-camu or oak extracts while on immune-checkpoint inhibitors without oncology oversight.
• Tannin-class cautions apply. Astringency, protein and iron binding, and possible reduced non-haem iron absorption at high intakes; relevant if iron status is marginal.
• No isolate toxicology. No repeat-dose, genotoxicity, reproductive or drug-interaction data exist for pure castalagin; nothing here is a clearance.

Full Safety & Interactions Detail

Gut-microbiome modification is the intended effect. Castalagin’s documented action is to change which bacteria dominate the colon and to shift the bile-acid pool ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. In the oncology setting that is being pursued deliberately, but it is also why unsupervised use during immunotherapy is a bad idea: the checkpoint-inhibitor response is microbiome-sensitive in both directions, the effective dose in humans is unknown, and the trials that would answer this are ongoing rather than reported. The same caution transfers to the whole-plant sources — see the camu-camu monograph.

Tannin-class effects. As a large polyphenol that precipitates proteins, castalagin contributes to the astringency of the drinks and foods carrying it — detectable at 0.9–2.8 µmol/L in wine ^{8Reference 8Stark T et al. · 2010Matrix-calibrated LC-MS/MS quantitation and sensory evaluation of oak ellagitannins and their transformation products in red winesView study →} — and shares the hydrolysable-tannin tendency to bind dietary protein and chelate metals. Ellagitannins have been characterised as aluminium(III) chelators ^{30Reference 30Frešer F et al. · 2026Ellagitannins as Al(III) chelators: determined binding sites with a predictive modelView study →}, and iron chelation is one proposed explanation for how castalagin protects bacteria at the bacterial surface ^{1Reference 1Messaoudene M et al. · 2022A natural polyphenol exerts antitumor activity and circumvents anti-PD-1 resistance through effects on the gut microbiotaView study →}. High habitual tannin intake is a recognised, modest inhibitor of non-haem iron absorption; that is a class caution rather than a castalagin finding.

Reproductive and developmental (prose only). No reproductive or developmental toxicity study has been performed on isolated castalagin, and none of the plant sources’ pregnancy data are attributable to this molecule. Decisions about intake in pregnancy or lactation belong on the herb or product page where the intake is actually decided, not on a molecule page.

Interactions. No CYP or transporter interaction study exists for castalagin. The interaction that is real and mechanism-based is the immunotherapy one above. A theoretical second is with any orally active drug whose absorption is sensitive to tannin binding, though this has not been tested for castalagin specifically.

Selectivity signal. Where cytotoxicity has been measured, castalagin-rich extracts have tended to spare normal cells — a jabuticaba seed extract in which castalagin was a main compound was antiproliferative against A549 and HCT8 tumour lines with no cytotoxicity to normal IMR90 fibroblasts ^{24Reference 24Fidelis M et al. · 2020Response surface optimization of phenolic compounds from jabuticaba (Myrciaria cauliflora [Mart.] O.Berg) seeds: antioxidant, antimicrobial, antihyperglycemic, antihypertensive and cytotoxic assessmentsView study →} — and the newborn-mouse antiviral study reported a selectivity ratio ≥33 ^{15Reference 15Stoyanova A et al. · 2023AnimalEffect of castalagin against HSV-1 infection in newborn miceView study →}. Reassuring in direction, but these are extract and small-animal figures, not a toxicology dataset.

Dosage

There is no established human dose of castalagin, and no product supplies the isolated molecule. The figures below are what research has used, for orientation only.

Scaling the mouse dose to a person is not meaningful here, because the effect is a local action on gut bacteria rather than a systemic exposure — the relevant variable is luminal concentration and the composition of the individual’s microbiome, neither of which the animal work translates. These are doses studied in research and are not a personal recommendation.

References

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