Hydrangea

This is the deepest and most consistent signal, and it rests substantially on hydrangenol, the dihydroisocoumarin that H. arborescens shares with the Asian species. A whole water extract of processed H. macrophylla leaf suppressed nitric oxide, PGE₂ and TNF-α in LPS-stimulated macrophages by inhibiting Akt-mediated NF-κB activation ^{1Reference 1Dilshara MG et al. · 2013In vitroWater extract of processed Hydrangea macrophylla leaf attenuates the expression of pro-inflammatory mediators by suppressing Akt-mediated NF-κB activation — in vitroView study →}, and the isolated constituent reproduces this: in LPS-stimulated macrophages and BV2 microglia, hydrangenol suppresses nitric oxide, iNOS and COX-2 by blocking NF-κB nuclear translocation while activating the Nrf2/HO-1 axis ^{2,6Reference 2Kim HJ et al. · 2016In vitroHydrangenol inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-mediated HO-1 pathway — in vitroView study →Reference 6Yoo HS et al. · 2025In vitroAnti-inflammatory and antinociceptive activities of a synthetic hydrangenol derivative — in vitro and in vivoView study →}. In vivo, oral hydrangenol reduced intestinal inflammation in an LPS endotoxemia model ^{3Reference 3Jang SY et al. · 2023AnimalProtective effect of hydrangenol on lipopolysaccharide-induced endotoxemia by suppressing intestinal inflammation — mouse in vivoView study →} and ameliorated dextran-sulfate colitis by curbing macrophage infiltration and protecting the epithelial tight junction ^{4Reference 4Kim SY et al. · 2023AnimalHydrangenol, an active constituent of Hydrangea serrata, ameliorates colitis by suppressing macrophage-mediated inflammation in DSS-treated mice — mouse in vivoView study →}. A 2025 study of standardised H. serrata hot-water extract showed anti-inflammatory and chondroprotective effects in macrophages, chondrocytes and two rodent arthritis models via NF-κB/MAPK, with hydrangenol named as the major active metabolite ^{5Reference 5Heo HS et al. · 2025In vitroIn vitro and in vivo anti-inflammatory and chondroprotective effects of standardised hot-water extract from Hydrangea serrata via NF-κB and MAPK pathways — animal modelView study →}; a synthetic hydrangenol derivative extended the same anti-inflammatory/antinociceptive profile ^{6Reference 6Yoo HS et al. · 2025In vitroAnti-inflammatory and antinociceptive activities of a synthetic hydrangenol derivative — in vitro and in vivoView study →}. Doses are typically 20–40 mg/kg orally in mice.

Gap: no human anti-inflammatory data, and every positive study used leaf extract or isolated hydrangenol — not an H. arborescens root decoction or tincture at a realistic human intake.

The classic Hydrangea pharmacology, from the Yoshikawa/Matsuda group, concerns mast-cell stabilisation by isocoumarins of Hydrangeae Dulcis Folium. Thunberginol A, B and F inhibit antigen- and calcium-ionophore-induced degranulation and the release of TNF-α and IL-4 in RBL-2H3 mast cells, and suppress the AP-1/ERK signalling that drives cytokine transcription — with a transcriptional profile resembling that of the anti-allergic flavone luteolin ^{10,11Reference 10Wang Q et al. · 2007In vitroInhibitory effects of thunberginols A, B and F on degranulation and release of TNF-α and IL-4 in RBL-2H3 cells — in vitroView study →Reference 11Matsuda H et al. · 2008In vitroInhibitory effects of thunberginols A and B on cytokine mRNA expression and AP-1 activation in RBL-2H3 cells — in vitroView study →}. Structure–activity work identified the 3,4-double bond and specific hydroxyls as essential, making the fully aromatic thunberginols more potent than dihydro forms such as hydrangenol ^{9Reference 9Matsuda H et al. · 1999In vitroStructure requirements of isocoumarins, phthalides and stilbenes from Hydrangeae Dulcis Folium for inhibition of histamine release from rat peritoneal mast cells — in vitroView study →}. In the rat passive cutaneous anaphylaxis model, these constituents (excepting phyllodulcin) significantly inhibited the reaction; the authors judged hydrangenol the principal antiallergic component of the processed leaf once abundance is accounted for ^{8Reference 8Matsuda H et al. · 1999AnimalEffects of phyllodulcin, hydrangenol, their 8-O-glucosides, and thunberginols A and F on passive cutaneous anaphylaxis reaction in rats — rat in vivoView study →}. Thunberginols A, B and F were first isolated as combined antiallergic/antimicrobial principles ^{7Reference 7Yoshikawa M et al. · 1992In vitroThunberginols A, B, and F, new antiallergic and antimicrobial principles from Hydrangeae Dulcis Folium — in vitroView study →}.

Gap: the potent actives (thunberginols) are documented in the Asian fermented leaf and have not been confirmed in H. arborescens; the constituent that is shared, hydrangenol, is the weaker antiallergic. All data are in vitro or in rats.

This indication carries the only human trial. A randomised, double-blind, placebo-controlled study (n=151, once-daily oral H. serrata leaf extract “WHS” 300 or 600 mg for 12 weeks) reported significant reductions in skin wrinkles and improvements in hydration, elasticity, texture and roughness versus placebo, with no extract-related adverse events ^{14Reference 14Myung DB et al. · 2020RCTOral intake of Hydrangea serrata leaves extract improves wrinkles, hydration, elasticity, texture and roughness in human skin: a randomised, double-blind, placebo-controlled study — randomised controlled trialView study →}. It is supported mechanistically: in UVB-irradiated human fibroblasts, hydrangenol preserved procollagen and boosted hyaluronic-acid production while downregulating MMP-1/-3 and COX-2 ^{12Reference 12Shin JS et al. · 2019In vitroChemical constituents from leaves of Hydrangea serrata and their anti-photoaging effects on UVB-irradiated human fibroblasts — in vitroView study →}, and in UVB-exposed hairless mice it reduced wrinkling and collagen loss via MAPK/AP-1 suppression and Nrf2/HO-1 induction ^{13Reference 13Myung DB et al. · 2019AnimalHydrangenol isolated from the leaves of Hydrangea serrata attenuates wrinkle formation and repairs skin moisture in UVB-irradiated hairless mice — mouse in vivoView study →}.

Gap: genuinely strong evidence — but for a different species (H. serrata leaf), a different preparation (standardised oral leaf extract), and a cosmetic endpoint with no bearing on the traditional urinary/antilithic use of H. arborescens root. The score is capped to reflect that mismatch, not the trial’s quality.

Antioxidant activity is best read as a mechanism running underneath the anti-inflammatory and photoaging findings rather than a standalone therapeutic claim. Hydrangenol activates nuclear factor erythroid-2-related factor 2 (Nrf2), driving heme oxygenase-1 (HO-1) and related cytoprotective genes in microglia and skin models ^{2,13Reference 2Kim HJ et al. · 2016In vitroHydrangenol inhibits lipopolysaccharide-induced nitric oxide production in BV2 microglial cells by suppressing the NF-κB pathway and activating the Nrf2-mediated HO-1 pathway — in vitroView study →Reference 13Myung DB et al. · 2019AnimalHydrangenol isolated from the leaves of Hydrangea serrata attenuates wrinkle formation and repairs skin moisture in UVB-irradiated hairless mice — mouse in vivoView study →}. In Caenorhabditis elegans, a phyllodulcin-rich H. macrophylla fraction raised catalase activity and lowered reactive-oxygen species and lipid accumulation under oxidative and thermal stress ^{15Reference 15Cho M et al. · 2024AnimalPhyllodulcin from the hexane fraction of Hydrangea macrophylla inhibits glucose-induced lipid accumulation and ROS generation in Caenorhabditis elegans — in vivo (invertebrate)View study →}. The dihydroisocoumarin/coumarin scaffold is a recognised Keap1/Nrf2/ARE modulator class.

Gap: entirely mechanistic and preclinical; no clinical antioxidant biomarker data, and the effect is inferred at the constituent level rather than demonstrated for the whole arborescens root.

A coherent preclinical metabolic story sits on the Asian leaf constituents. Hydrangenol, phyllodulcin and hydrangeic acid promote adipocyte differentiation and adiponectin release with a PPARγ-agonist-like profile — without directly binding the receptor, unlike thiazolidinediones ^{16,18Reference 16Zhang H et al. · 2007In vitroNew type of anti-diabetic compounds from the processed leaves of Hydrangea macrophylla var. thunbergii — in vitro and mouseView study →Reference 18Matsuda H et al. · 2014ReviewSearch for a new type of PPARγ agonist-like anti-diabetic compounds from medicinal plants — reviewView study →}. Hydrangeic acid (200 mg/kg/day) lowered blood glucose, triglycerides and free fatty acids in diabetic KK-Aʸ mice ^{17Reference 17Zhang H et al. · 2009AnimalHydrangeic acid from the processed leaves of Hydrangea macrophylla var. thunbergii as a new type of anti-diabetic compound — KK-Aʸ mouse in vivoView study →}. On the obesity side, phyllodulcin reduced fat mass and induced fat-browning genes (UCP1, PRDM16, PGC-1α) in high-fat-diet mice ^{19Reference 19Kim E et al. · 2017AnimalPhyllodulcin regulates obesity-related metabolic changes and fat-browning genes in high-fat-diet-induced obese mice — mouse in vivoView study →}, and a 2026 study found hydrangenol disrupts adipogenesis (AMPKα up; Akt/mTOR down) and shifts gut microbiota toward a leaner profile in obese mice ^{20Reference 20Han HS et al. · 2026AnimalHydrangenol exerts anti-obesity effects by disturbing adipogenesis via mitotic clonal expansion and gut-microbiota dysbiosis — mouse in vivoView study →}.

Gap: promising but rodent/cell-only; the principal actives (phyllodulcin, hydrangeic acid) are leaf/species-specific and not documented in H. arborescens, so the bridge to this monograph’s herb is weak.

An emerging cluster of single studies. Oral H. macrophylla extract protected cortical neurons against corticosterone toxicity and reduced restraint-stress anxiety in mice, with thunberginol C identified as an active ingredient ^{21Reference 21Lee J et al. · 2022AnimalHydrangea macrophylla and thunberginol C attenuate stress-induced anxiety in mice — mouse in vivoView study →}. Phyllodulcin inhibited amyloid-β aggregation, reduced hippocampal Aβ deposition and improved synaptic plasticity in 5XFAD Alzheimer’s-model mice ^{22Reference 22Cho E et al. · 2023AnimalPhyllodulcin improves hippocampal long-term potentiation in 5XFAD mice — mouse in vivoView study →}. Separately, thunberginol C and a hydrangenol glucoside were identified in vitro as natural cholinesterase inhibitors ^{23Reference 23Hwang J et al. · 2021In vitroDiscovery of natural inhibitors of cholinesterases from hydrangea (thunberginol C, hydrangenol 8-O-glucoside) — in vitroView study →}.

Gap: each mechanism rests on one study; all preclinical; and the actives are again the Asian-leaf constituents rather than anything confirmed in H. arborescens.

The anticancer evidence is narrow. Hydrangenol inhibited proliferation, migration and invasion of EJ bladder-cancer cells via p21ᵂᴬᶠ¹-mediated G1 arrest, p38 MAPK activation and suppression of Sp-1-driven MMP-9 — but at an IC50 of about 100 µM, a high concentration ^{24Reference 24Shin SS et al. · 2018In vitroHydrangenol inhibits proliferation, migration and invasion of EJ bladder cancer cells via p21ᵂᴬᶠ¹-mediated G1 arrest and p38 MAPK — in vitroView study →}. A follow-up reported antiangiogenic activity (VEGFR-2 signalling, MMP-2, G1 arrest) in vitro ^{25Reference 25Gho Y et al. · 2019In vitroHydrangenol suppresses VEGF-stimulated angiogenesis by targeting p27ᴷᴵᴾ¹-dependent G1 arrest and VEGFR-2 signalling — in vitroView study →}.

Gap: a single cancer cell line at high micromolar doses plus one in vitro angiogenesis study; no animal tumour models and no selectivity or pharmacokinetic data.

The original 1990s isolations described thunberginol A, B and F as combined antiallergic and antimicrobial principles, with activity against oral bacteria ^{7Reference 7Yoshikawa M et al. · 1992In vitroThunberginols A, B, and F, new antiallergic and antimicrobial principles from Hydrangeae Dulcis Folium — in vitroView study →}. A more recent food-chemistry screen found leaf dihydroisocoumarins (hydrangenol, phyllodulcin) bind ACE2 and inhibit SARS-CoV-2 spike–ACE2 interaction in vitro, framed as a rationale for the traditional sweet-tea ^{26Reference 26Yano A et al. · 2023In vitroDihydroisocoumarins of Hydrangea macrophylla var. thunbergii inhibit binding of the SARS-CoV-2 spike protein to ACE2 — in vitroView study →}.

Gap: in vitro and constituent-level only, with no MICs against clinically relevant pathogens, no in vivo infection models, and — as elsewhere — reliance on Asian-leaf compounds not confirmed in H. arborescens.

Hydrangea arborescens root has a long record of traditional use with low reported toxicity, but two genuine cautions apply. It is a documented contact allergen: occupational allergic contact dermatitis to Hydrangea has been reported in a florist ^{28Reference 28Romita P et al. · 2020Case reportOccupational allergic contact dermatitis to Hydrangea spp. in an Italian florist — case reportView study →}. Traditional sources warn that excessive doses may cause dizziness, a feeling of chest tightness and gastroenteritis; these effects are dose-related and not well characterised in the modern literature. The often-repeated claim that the plant’s “hydrangin” is a cyanogenic glycoside appears to be an error — hydrangin is a coumarin (an umbelliferone glycoside), not a cyanogen, and releases no cyanide. A true cyanogenic glycoside, taxiphyllin, has been quantified in the leaves of the Asian species H. macrophylla var. thunbergii, but it was found to be largely hydrolysed during processing and was judged unlikely to have caused the reported food-poisoning cases ^{27Reference 27Tsukioka J et al. · 2023Quantitative analysis of taxiphyllin, a cyanogenic glycoside, in the leaves of Hydrangea macrophylla var. thunbergii — analyticalView study →}; it has not been characterised in H. arborescens root. Separately, a folkloric reputation for the root as a psychoactive or “cannabinoid-mimic” is not supported by any evidence and should be disregarded.

No formal herb–drug interaction studies exist for H. arborescens, so interactions have not been assessed; the mouse glucose-lowering data for leaf constituents (hydrangeic acid, phyllodulcin) raise a theoretical additive-hypoglycaemic consideration, but this is untested and those constituents are not confirmed in this species. The absence of reported problems should not be read as evidence of safety.