IngredientsIridoids belong to the monoterpenoids, which are acetal derivatives of iridodial. Based on structure, these compounds can be divided into four groups: iridoid glycosides, secoiridoid glycosides, non-glycosidic iridoids, and bis-iridoids. Iridoids have hemiacetal hydroxyl groups and are active in nature; they are mostly in the form of glycosides combined with glucose at the C-1 hydroxyl group.
Because of the unstable nature of its C1-OH group, iridoids often react with sugar to form glycosides. According to the integrity of the cyclopentane unit, they can be divided into iridoid glycosides (including geniposide, loganin, acetylbarlerin, deacetylasperulosidic acid, and brasoside) and secoiridoid glycosides (including swertiamarine, gentiopicroside, sweroside, and oleuropein). In addition, dimers of iridoids called bis-iridoids (including cantleyoside, laciniatoside IāII, and sylvestroside I) and unglycosylated iridoids called non-glycosidic iridoids (including acevaltrate and valtrate) are also found in nature.
The iridoid glycosides at C-1 are polyhydroxyl-linked and polyglycoside-formed, and most of them are Ī²-d-glucosides. Among isolated iridoid glycosides, some rare new structures have been found, such as asperuloside, which has a ketone functional group at C-6. Structureāactivity relationship analysis suggests that glycosyl, ester, and epoxy groups are essential pharmacophores for their bioactivity.
So far, approximately 3,000 plant iridoid glycosides have been identified, most of which have been found in the green parts of plants, namely leaves and tender stems, and some in fruits and shoots.
Iridoids are secondary metabolites present in various plants, especially in species belonging to the Apocynaceae, Lamiaceae, Loganiaceae, Rubiaceae, Scrophulariaceae, and Verbenaceae families. Currently, around 60 plant families have been reported to produce iridoids, with plant orders such as the Dipsacales, Gentianales, and Lamiales having significantly high concentrations of iridoids.
Prominent plant sources include Morinda citrifolia (noni), Cornus officinalis (cornelian cherry), Gentiana lutea (gentian), and Lonicera caerulea (haskap berry or blue honeysuckle). These plants have been traditionally used in folk medicine, and their iridoid content is attributed to their therapeutic efficacy. Commonly utilized plant parts include fruits, leaves, and roots, with iridoid profiles varying significantly depending on species and cultivars.
The following are among the most studied individual sources and their signature iridoid glycosides:
Devil's claw, as one widely used example, is used for a wide variety of health conditions in the form of infusions, decoctions, tinctures, powders, and extracts. More broadly, iridoid glycosides are commercially available as standardized dried root or tuber powders, aqueous and ethanolic extracts, concentrated liquid extracts, and encapsulated standardized preparations. Standardization is typically expressed by harpagoside content (for devil's claw), catalpol content (for Rehmannia), or total iridoid glycoside percentage. Medicinal uses of Plantago lanceolata leaves are described in the European Pharmacopoeia.
Harpagophytum procumbens (Pedaliaceae) is an important traditional medicine growing in the Kalahari region of southern Africa where it is consumed as a general health tonic and for treating diverse ailments including arthritis, pain, fever, ulcers, and boils. In addition to the common local use for arthritis and pain, other ethnomedicinal uses include dyspepsia, fever, blood diseases, urinary tract infections, postpartum pain, sprains, sores, ulcers, and boils.
As one of the active components used in natural medicine and traditional Chinese medicine, iridoid compounds have many biological effects such as liver protection, anti-inflammatory, and anti-tumor effects. Rehmannia glutinosa is a common traditional herbal medicine used for the treatment of aging-related diseases in Korea and China, extensively used under the name Di-Huang in Chinese traditional medicine for treating diabetes mellitus.
The fruit of Gardenia jasminoides Ellis from Rubiaceae is a famous traditional Chinese medicine used in China. Catalpol and geniposide, as two kinds of iridoid glycosides with high activities, are the main bioactive components in Rehmannia glutinosa and Gardenia jasminoides Ellis, respectively.
Plants from the genus Patrinia, such as P. scabiosaefolia, P. villosa, and P. heterophylla, have a long history of use as a traditional Chinese medicine for detoxification, swelling, empyema, liver protection, and cholagogue.
In the Ayurvedic tradition, iridoid glycosides such as asperuloside and paederoside are significant due to their presence in Picrorhiza kurroa. These compounds exhibit antioxidant and anti-inflammatory properties and are crucial components in anti-diabetic drugs.
Historically, iridoid-containing plants have played an important role in herbal remedies, particularly in European, Asian, and Native American herbal traditions. The traditional use of extracts of Euphrasia rostkoviana to relieve ocular inflammation or infections is well documented and supported by clinical studies.
Morinda citrifolia (noni) is a Polynesian medicinal plant with over 2,000 years of traditional use. The iridoid-containing plant Teucrium parviflorum is mainly used in Kurdish traditional medicine to treat jaundice, liver disorders, and stomachache.
Within the broad category of iridoid glycosides, several individual compounds have been extensively characterized:
Iridoid glycosides modulate critical signaling pathways, including NF-ĪŗB, NLRP3 inflammasome, MAPK, and JAK-STAT, thereby suppressing key inflammatory cytokines such as TNF-Ī±, IL-1Ī², and IL-6, while also activating antioxidant defenses.
Studies involving iridoid glycosides reinforce the hypothesis that these compounds act as neuroprotective agents through the regulation of MAPK (p-38, ERK 1/2, JNK-p), Nrf2 (a transcription factor linked to the coding of genes of antioxidant enzymes), and NF-ĪŗB (a transcription factor responsible for providing modulation of COX-2 and cytokines).
Research on the iridoids monotropein and deacetyl asperulosidic acid, extracted from Morinda officinalis, has demonstrated their ability to inhibit the activation of nuclear factor-kappa B (NF-ĪŗB).
Iridoid glycosides such as harpagoside, harpagide, and procumbide stop certain pathways and enzymes (including COX-2) from increasing inflammation.
Loganic acid, the most abundant iridoid of Lonicera caerulea, scavenges free radicals and amplifies the function of endogenous antioxidant enzymes such as superoxide dismutase (SOD) and catalase (CAT). The antioxidant properties of iridoids such as catalpol, swertiamarin, geniposide, loganin, and oleuropein have been established in various in vitro and in vivo experimental models, revealing their capacity to diminish oxidative damage associated with chronic diseases such as cardiovascular diseases and type 2 diabetes.
The hepatoprotective effect of iridoids is mainly attributed to their antioxidant activity. This action is both indirect, through the stimulation of the antioxidant defense system, and direct, through the removal of reactive oxygen species (ROS).
Pharmacological studies in vivo and in vitro have indicated that both catalpol and geniposide are neuroprotective agents through multiple targets and multiple pathways, including TNF-Ī±, IL-1Ī², Bcl-2, COX-2, iNOS, MMP, LDH, GSH-Px, MDA, PKC, SOD, BDNF, ChAT, and ERK1/2, MAPK, IkB/NF-kB, and other pathways.
Elevated serotonin and BDNF levels by catalpol significantly protect against depression and neurodegeneration. Catalpol demonstrated increased mitochondrial biogenesis and activation of the PI3K/Akt pathway for insulin-sensitizing effect. Its cardiovascular protective effect was linked to the PI3K/Akt, apelin/APJ, and Jak-Stat pathways.
Preclinical evidence suggests that iridoid glycosides, including geniposide, shanzhiside methylester, 8-OaS, morroniside, and catalpol, may act as small molecule GLP-1 receptor agonists, indicating their broad therapeutic potential for diabetes and associated conditions including obesity, fatty liver, hypertension, and cardiovascular diseases.
In an in vivo model of non-alcoholic fatty liver disease (NAFLD), aucubin ameliorated tyloxapol-induced hyperlipidemia, oxidative stress, and inflammation by improving lipid profiles (TC, TG, LDL, VLDL) and activating Nrf2, PPARĪ±/Ī³, HO-1, and AMPK pathways.
In general, glycosides do not work directly in the blood, but undergo changes in the digestive system via enzymes, stomach acid, intestinal bacteria, and intestinal membrane enzymes into another structure, and then play a role. In vivo and in vitro studies using the intestinal perfusion and Caco-2 model demonstrated that geniposide absorbed by passive diffusion had better absorption in the duodenum and jejunum.
Verapamil influenced the transportation of geniposide, while EDTA did not, indicating that the absorption of geniposide in vivo may involve the active efflux mechanism mediated by P-glycoprotein. The discovery of gardenoside in the brain suggests that it can pass through the blood-brain barrier for therapeutic purposes.
Studies have found that intestinal bacteria can convert geniposide to genipin. After sulfatase hydrolysis of plasma samples, many genipins appeared, indicating that genipin sulfate is the main metabolite of genipin.
Regarding catalpol specifically: Research found that catalpol is rapidly absorbed in patients, with an absolute bioavailability of 66.9%. The compound demonstrates a quick onset, rapid and complete excretion, no accumulation in the body, and no damage to major organs. These properties make it suitable for long-term use without significant drug interactions, positioning it as a TCM hypoglycemic agent with minimal toxicity and side effects.
This is the area with the strongest and most extensive clinical evidence base for iridoid glycosides in humans, primarily from studies on Harpagophytum procumbens.
Devil's claw exhibits cellular signalling modulating activities that down-regulate inflammatory markers. Five randomized clinical trials (RCTs) have reported on the effects of devil's claw in the treatment of osteoarthritis (OA). Three trials demonstrated significant positive results, while two studies that employed less than 30 mg harpagoside recorded results that were less significant. An aqueous extract of devil's claw consisting of 60 mg harpagoside was found to be as effective as 12.5 mg of rofecoxib for the treatment of acute non-specific lower-back pain in a double-blind pilot RCT.
A randomized double-blind study evaluating the therapeutic effect of devil's claw on lower back pain was carried out over four weeks. A characterized Harpagophytum extract (WS 1351) was administered bidaily as a 600 mg (Group 1) or 1200 mg dose (Group 2) containing 50 and 100 mg of harpagoside, respectively, to 197 subjects with chronic back pain and current exacerbations. Six of Group 1 and 10 of Group 2 were pain-free by the end of the trial; analysis indicated that patients in the lower dose group with less severe pain and without radiation or neurological deficit benefitted more.
One definitive study was designed with 90% power to detect a small difference (10 mm on a 100-mm visual analogue scale) between freeze-dried Harpagophytum and the weak NSAID diacerrhein for hip or knee pain. After 4 months, no statistically significant difference was found between the two treatments. The study showed that freeze-dried root tubers of Harpagophytum at a dose containing 60 mg harpagoside per day was as effective as, and had fewer side effects than, diacerrhein.
Preparations made from the secondary tubers of devil's claw are used in patients with rheumatic diseases (arthrosis and low back pain). An uncontrolled multicenter drug surveillance study for about 12 weeks was conducted in 75 patients with arthrosis of the hip or knee using an aqueous extract (Doloteffin; 2,400 mg extract daily, corresponding to 50 mg harpagoside). The results of the study revealed a strong reduction of pain and the symptoms of osteoarthritis.
An open trial that enrolled patients with arthrosis of the hip, knees, fingers, or spine (n=630) showed significant improvements in pain after six months of treatment with devil's claw extract (3,000ā9,000 mg/day). Additionally, a clinical trial on devil's claw extract (4,500 mg/day containing 30 mg harpagoside) for tendonitis of the shoulder, neck, and/or back showed significantly less pain in the treatment group compared with the placebo group.
Evidence assessment: Twelve trials were included in a systematic review, with six investigating osteoarthritis. There is limited evidence for an ethanolic Harpagophytum extract containing less than 30 mg harpagoside per day in the treatment of knee and hip osteoarthritis. Reviews of clinical trials have focused primarily on arthritic conditions (hip and knee) and low back pain. A meta-analysis of available data has not been conducted, possibly because of diverse methodologies; however, there is general support for evidence of effect in pain reduction. Overall, the evidence for harpagoside-standardized devil's claw in musculoskeletal pain is the most developed of any iridoid glycoside application in humans, though trial quality is mixed and methodological heterogeneity limits definitive conclusions.
Over the past few decades, catalpol and geniposide have been widely studied for their therapeutic effects. Preclinical experiments demonstrated that they possessed significant neuroprotective activities against Alzheimer's disease, Parkinson's disease, stroke, and depression.
Catalpol, an iridoid glycoside compound, is one of the main active components of Rehmannia glutinosa. A large number of experimental studies in vivo and in vitro have confirmed that catalpol has antioxidant, anti-inflammatory, antiapoptotic, and other neuroprotective effects, and it plays a significant role in the prevention and treatment of AD.
In a study using a lymphoblastoid cell line from patients with late-onset Alzheimer's disease, catalpol activates the Keap1/Nrf2/ARE signaling pathway, providing antioxidant and anti-apoptotic effects. In both in vitro (human neuroblastoma SH-SY5Y cells) and in vivo (double transgenic mice expressing chimeric mouse/human amyloid precursor protein and mutant human presenilin 1), catalpol alleviates Alzheimer's disease progression.
Catalpol, geniposide, and harpagoside, in Parkinson's disease models, improved the expressions of GDNF and Bcl-2 proteins and TH-positive neurons by increasing the levels of antioxidant enzymes SOD and GSH-PX and down-regulating insulin/IGF signaling via activation of MEK protein. Furthermore, geniposide increased the expression of autophagy-related LAMP-2A protein for clearance of Lewy bodies from dopaminergic neurons in PD brain via improving lysosomal autophagy process.
Evidence assessment: The entirety of the current neuroprotection evidence base for iridoid glycosides derives from preclinical (in vitro and animal) models. Although the clinical features of Alzheimer's and Parkinson's disease have been reported for a long time, what can currently be done is to alleviate severity of symptoms; these diseases cannot be completely cured. One promising field worthy of attention is iridoid glycosides in traditional Chinese medicine. No adequately powered human clinical trials have been completed in this domain, and conclusions about clinical benefit remain premature.
Iridoid glycosides have a variety of biological activities including anti-inflammatory and analgesic, hepatoprotective and cholagogic, bacteriostatic, sedative, antihypertensive, and antitumor properties.
One study tested vegetable oilā and carbon tetrachlorideāinduced liver fibrosis rat models to evaluate the hepatoprotective effects of iridoid glycosides from Boschniakia rossica. Rats were continuously treated with iridoid glycosides (200 mg/kg) for 10 days. Compared to normal controls, serum ALT, AST, and TBIL levels were significantly increased in the model group, and hepatocytes exhibited degeneration, necrosis, and hepatic fibrosis. The rats treated with Boschniakia rossica iridoid glycosides showed significantly lower levels of serum ALT, AST, and TBIL, with markedly reduced liver fibrosis compared with the model control group. The expression of Ī±-SMA in the treated group was significantly lower, suggesting that the iridoid glycosides could inhibit liver fibrosis by inhibiting the activation of hepatic stellate cells.
Researchers focused on six popular iridoid compounds ā gentiopicroside, sweroside, swertiamarin, loganic acid, 6-O-Ī²-d-glucosyl-gentiopicroside, and amarogentin ā for their effects on CYP3A4. In particular, amarogentin showed a significant inductive effect on CYP3A4 mRNA levels in HepG2 cells.
Evidence assessment: Hepatoprotective evidence for iridoid glycosides is predominantly from animal models and in vitro systems. Human clinical data are very limited. Picroliv (from Picrorhiza kurroa) has been studied to a modest degree in humans with liver disease, but large, well-controlled trials are absent.
Iridoid glycosides are active natural products with extensive pharmacological and physiological effects. Iridoid glycosides extracted from various traditional Chinese medicines have significant curative effects in the treatment of diabetes, cardiovascular diseases, neurological diseases, and cancer.
The pharmacokinetics of geniposide in type 2 diabetic rats showed higher Cmax, larger area under the curve (AUC), longer Tmax, lower clearance rate (CL), and shorter mean residence time (MRT) compared to healthy rats. These variable results are attributed to geniposide being hydrolyzed to aglycone by Ī²-glucosidase produced by intestinal epithelial cells and absorbed into blood circulation differently in type 2 diabetic rats.
Evidence suggests that oleuropein targets skeletal muscle and enhances glucose uptake and its related protein signaling cascades, improving glucose tolerance and insulin sensitivity. Despite this evidence of oleuropein's anti-inflammatory and anti-diabetic potential, more animal and clinical studies are needed to proceed towards clinical/therapeutic use for metabolic diseases.
In 2017, the new hypoglycemic drug "Catalpol Tablets" received approval for clinical trials by the China State Food and Drug Administration.
Evidence assessment: Evidence for anti-diabetic activity is robust at the preclinical level, encompassing multiple mechanisms (GLP-1 receptor agonism, insulin sensitization, antioxidant reduction of glucotoxicity). Human clinical trial data remain sparse and preliminary. Catalpol's entry into clinical trial evaluation in China represents an early-stage but significant development.
In mice with constriction of the transverse aorta, a functional decline in the heart was observed with decreases in ejection fraction and fractional shortening. All these morphological changes could be attenuated by geniposide treatment. In vivo, the iridoid glycoside (25 and 50 mg/kg) activated AMPKĪ± and inhibited mTOR, ERK, and ER stress in hypertrophic heart and in H9c2 cardiomyocytes, with the protection mediated via the GLP-1 receptor.
The cardiovascular protective effect of catalpol was linked to the PI3K/Akt, apelin/APJ, and Jak-Stat pathways.
Evidence assessment: Cardiovascular evidence is entirely preclinical (animal and cell studies). No human cardiovascular trials specifically examining iridoid glycosides as a class have been identified in the peer-reviewed literature.
Iridoids such as catalpol, aucubin, and oleuropein act as glycation inhibitors through mechanisms including NF-ĪŗB factor and aldose reductase inhibition, dicarbonyl trapping, and antioxidant effects.
Oral catalpol, aucubin, geniposide, harpagoside, loganin, and globularifolin can reduce stress and depression by diminishing anhedonia, enhancing corticosterone and BDNF, and decreasing COX-2 levels.
Evidence assessment: Antioxidant and anti-glycation activity is well-established in vitro but human clinical demonstration is lacking.
Iridoid glycosides including aucubin, scandoside methyl ester, geniposide, loganin, sweroside, gardenoside, and gentiopicroside were investigated for anticancer properties. All of the intact iridoid glycosides demonstrated no anticancer activity. However, the aglycones of the iridoids, especially aucubin and scandoside methyl ester, had significant anticancer activity against leukemia P388, with maximum T/C values of 162% and 160%, respectively, at 100 mg/kg.
Catalpol produced a significant reduction in cell proliferation and an increase in apoptosis in different cancer conditions.
Evidence assessment: Anticancer research on iridoid glycosides is at a very early, predominantly preclinical stage. The observation that aglycones (not intact glycosides) drive activity in some models highlights a complexity that must be resolved. No human clinical trials examining iridoids for cancer treatment have been identified.
Dosages vary substantially by plant source, preparation type, and the specific iridoid glycoside used as a marker. The following dosages are drawn directly from published studies and clinical trials:
Note: Animal and in vitro dosages cannot be directly extrapolated to human use. Human clinical dosages are based specifically on preparations standardized by harpagoside content for devil's claw; standardized human dosing guidelines for other individual iridoid glycosides such as catalpol or geniposide have not been established in Western clinical practice.
Devil's claw has been used safely in small clinical trials. It was found to be generally well tolerated when used orally for up to one year. Long-term safety is unknown. The most common side effect is diarrhea. Other stomach issues such as nausea, vomiting, gas, and abdominal pain have been reported. Other possible side effects include headache, ringing in the ears, loss of appetite or taste, and a single reported case of syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Harpagoside has been found to be of low acute toxicity, with a median lethal dose of more than 13.5 g/kg in mice.
Because of the bitterness of devil's claw preparations and consequent increase in gastric secretion, devil's claw is contraindicated in patients with gastric or duodenal ulcers.
A significant area of concern is the potential interaction of devil's claw with anticoagulant and antiplatelet medications such as warfarin, clopidogrel, and aspirin. Because devil's claw may possess mild antiplatelet activity, co-administration with these drugs could theoretically increase the risk of bleeding and bruising.
Devil's claw may interact with warfarin. This could increase the risk of bleeding. Purple/red discoloration of the skin (purpura) was seen in a patient taking these two drugs together.
Devil's claw should not be used with antiarrhythmic, chronotropic, or inotropic medicines.
Screening studies report that H. procumbens is unable to inhibit cytochrome P450 enzymes and is unlikely to have any clinically relevant effect on the cytochrome system. It is possible that devil's claw may affect multidrug P-glycoprotein (P-gp) drug transporter.
Verapamil influenced the transportation of geniposide, indicating that its absorption in vivo may involve the active efflux mechanism mediated by P-glycoprotein. This raises the theoretical possibility that co-administration of P-glycoprotein substrates or inhibitors could alter the pharmacokinetics of geniposide-containing preparations.
Among the gentian iridoids studied for their effects on hepatic metabolism, amarogentin in particular showed a significant inductive effect on CYP3A4 mRNA levels in HepG2 cells. CYP3A4 induction could theoretically reduce blood levels of drugs metabolized by this enzyme, but robust human interaction data are lacking.
Documented oxytocic adverse effects have been associated with devil's claw. Use during pregnancy should be avoided.
Histopathological analysis of tissues from the liver, spleen, kidney, lung, and heart in animal studies revealed no abnormalities, and biochemical assessments showed no signs of hepatorenal toxicity. The definitive toxicity, safety margin, and potential adverse reactions in humans have not been reported.
Evidence from large-scale, well-controlled human studies remains limited. The diversity of iridoid glycosides and variation in plant sources complicate definitive conclusions on efficacy and safety. Across iridoid glycosides as a broad class, individual compounds differ substantially in potency, bioavailability, source plant, preparation, and studied populations. Effects demonstrated for one iridoid glycoside (e.g., harpagoside in pain trials) should not be assumed to apply to structurally distinct members of the class (e.g., catalpol or geniposide) without specific evidence.
Health conditions that Iridoid glycosides may help support.
Body systems that Iridoid glycosides may help support.
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