Rosmarinic acid

Rosmarinic Acid: A Comprehensive Reference

1. Identity

Chemical Names and Structure

Rosmarinic acid (α-o-caffeoyl-3,4-dihydroxyphenyllactic acid; RA) is a naturally occurring hydroxylated compound. Designated by the molecular formula C₁₈H₁₆O₈, it is a naturally occurring phenolic acid considered to be the esterification product of caffeic acid and 3,4-dihydroxyphenyllactic acid. Its chemical structure contains two phenolic rings: one derived from phenylalanine via caffeic acid, and the other from tyrosine via dihydroxyphenyllactic acid. It has a molecular mass of 360 daltons.

The chemical structure includes two catechol groups that confer high antioxidant capacity by donating hydrogen atoms to free radicals and chelating metal ions involved in oxidative reactions.

Rosmarinic acid was first isolated and characterized in 1958 by the Italian chemists Scarpatti and Oriente from rosemary (Salvia rosmarinus), after which the acid is named. RA and related compounds were initially considered tannins of the Labiate plants; they were later discovered as a pure compound from Rosmarinus officinalis by the two Italian chemists in 1958.

Botanical Sources

Rosmarinic acid is present in over 160 species belonging to many families, especially the Lamiaceae. Rosmarinic acid accumulation is shown in hornworts, in the fern family Blechnaceae, and in species of several orders of mono- and dicotyledonous angiosperms; it is found most notably in many Lamiaceae (dicotyledons in the order Lamiales), especially in the subfamily Nepetoideae.

It is found in species used commonly as culinary herbs such as Ocimum basilicum (basil), Ocimum tenuiflorum (holy basil), Melissa officinalis (lemon balm), Salvia rosmarinus (rosemary), Origanum majorana (marjoram), Salvia officinalis (sage), thyme, and peppermint. It is also found in species of the family Boraginaceae, including Rosmarinus officinalis, Salvia officinalis, and Perilla frutescens.

Although it is commonly found among members of the plants from the Lamiaceae (mints) and Boraginaceae (borages) families, only certain plant species produce a comparatively high concentration of RA. From its first isolation, RA has been successively found in more than 160 plants belonging to Lamiaceae, Boraginaceae, Apiaceae, and others.

Biosynthesis

RA is biosynthesized from the amino acids L-phenylalanine and L-tyrosine by eight enzymes that include phenylalanine ammonia lyase and cinnamic acid 4-hydroxylase. Chemically, rosmarinic acid is an ester of caffeic acid with 3,4-dihydroxyphenyllactic acid; biologically, it is formed from 4-coumaroyl-4′-hydroxyphenyllactate. Rosmarinate synthase is an enzyme that uses caffeoyl-CoA and 3,4-dihydroxyphenyllactic acid to produce CoA and rosmarinate.

Common Forms and Preparations

As it is difficult to obtain high quantities of RA from natural sources, and since chemical manufacturing is costly and challenging, various biotechnological methods have been investigated to boost RA production. Plant cell tissue culture has been used to promote RA production in various plant species, particularly medicinal ones, with elicitation being the most commonly used technique. Its large-scale production is also obtained from plant cell cultures of Coleus blumei Benth.

RA can also be chemically produced by the esterification of caffeic acid and 3,4-dihydroxyphenyllactic acid. In commerce, rosmarinic acid is available as standardized plant extracts (particularly from rosemary, perilla, and lemon balm), as isolated powder for use in food-grade antioxidant applications, and in encapsulated dietary supplement formulations. RA-enriched dietary supplements have become popular products in the health industry. It is readily absorbed through the gastrointestinal tract as well as the skin.

RA and its numerous derivatives containing one or two RA units with other aromatic moieties are well known and include lithospermic acid, yunnaneic acid, salvianolic acid, and melitric acid.

2. Traditional and Historical Use

Mediterranean and European Traditions

Rosemary (Rosmarinus officinalis L.) and lemon balm (Melissa officinalis L.) are perennial plants from the Lamiaceae family, naturally occurring in the Mediterranean Sea and West Asia, as well as being commonly cultivated in Europe and North America. Rosemary has been a cornerstone of Mediterranean materia medica for centuries. It has been used in traditional medicine for many centuries, for respiratory disorders, depression, renal colic, and hair loss. Culpepper's Herbal recommends rosemary especially for conditions affecting the mind, for maladies of the eye, stomach, and joints due to effects of cold, and for coughs.

Salvia rosmarinus (formerly known as Rosmarinus officinalis L.), a perennial herb native to the Mediterranean region, plays a significant role in both traditional and contemporary medicinal practices, serving diverse purposes as an antibacterial, antiepileptic, antirheumatic, antispasmodic, carminative, diuretic, expectorant, renal colic, and wound-healing agent.

Lemon balm (Melissa officinalis), another major source of RA, also has extensive documentation of traditional use. Lemon balm is a perennial, bushy plant, native to West Asia and the Eastern Mediterranean regions, usually growing in clusters along roadsides. Melissa officinalis is a perennial, hardy herbaceous plant that belongs to the Lamiaceae family; numerous plants of the Lamiaceae family, used in traditional medicine, have biological activities tied mainly to their polyphenol content and especially their rosmarinic acid content.

Rosemary leaves were used internally for dyspepsia, and externally as supportive therapy for rheumatic diseases and circulatory problems (Commission E), to improve liver and gallbladder function, and for dyspeptic complaints; externally also as supportive therapy for rheumatic diseases and circulatory disorders as well as a mild antiseptic to promote healing of wounds (ESCOP). The HMPC (Committee on Herbal Medicinal Products of the EMA) has classified rosemary leaves and rosemary oil as a traditional herbal medicinal product.

Traditional Use of Perilla in East Asia

Plants of the genus Perilla and related Lamiaceae have been traditionally used to treat upper respiratory and allergic symptoms. In East Asian traditional medicine systems, particularly in Japan and China, Perilla frutescens has a long history of use as a culinary and medicinal herb. Traditional herbal prescriptions, such as FZHY, WHW, and Guanxinning injections, commonly include Lamiaceae plants, including Salvia miltiorrhiza and Perilla frutescens.

Summer Savory and Folk Medicine

Summer savory (Satureja hortensis L.) is an herb of the Lamiaceae family used in cooking and folk medicine in several regions of the world. In Georgia, dried and ground summer savory (local name kondari) is one of the most popular spices, used either on its own or as an ingredient in spice blends. From ancient times, it has been known locally as an antimicrobial folk remedy for gastrointestinal problems.

Both Melissa leaf and herb are used as herbal drugs in Slovak and Czech Republics; western pharmacopoeias prefer the leaf as the main source of therapeutic principles. Gradually, the pharmacopoeias also reflected the results of phytochemical research on lemon balm, and the main criterion of drug quality was changed from traditional total essential oil content to total hydroxycinnamic derivatives content.

3. Key Constituents, Related Compounds, and Mechanisms of Action

Chemical Context and Co-occurring Compounds

Rosmarinic acid is typically found alongside other bioactive phenolics in its source plants. Rosemary leaves contain essential oil with its aromatic scent made of 1,8-cineole, camphor, pinene, and other monoterpenes, plus bitter terpenphenolics and Lamiaceae tannins (mainly rosmarinic acid). In Melissa officinalis, major components include caffeic acid, rosmarinic acid, ferulic acid, and methyl carnosoate, as well as other flavonoids.

Antioxidant Mechanisms

Rosmarinic acid is one of the most important and well-known natural antioxidant compounds, which possesses neuroprotective effects in different models of neuroinflammation, neurodegeneration, as well as chemically induced neurotoxicity and oxidative stress. The two catechol groups in its structure enable direct free-radical scavenging and metal ion chelation. Rosmarinic acid is well known for its capacity to induce antioxidant, anti-inflammatory, pro-apoptotic, neuroprotective, and antitumor effects.

Anti-inflammatory Mechanisms

RA deciphers its anti-inflammatory and antioxidant properties by inhibiting NF-κB activity and reducing the production of prostaglandin E2 (PGE2), nitric oxide (NO), and cyclooxygenase-2 (COX-2) in RAW 264.7 cells. This mechanism helps to prevent inflammation and oxidative stress.

In a diabetic rat model treated with RA, anti-inflammatory activity has been reported. This activity is achieved through the inhibition of the expression of various proinflammatory factors, including interleukin-6 (IL-6), interleukin-1β (IL-1β), tumour necrosis factor-alpha (TNF-α), and endothelin-converting enzyme-1 (ECE-1).

The cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways, metabolized by arachidonic acid, produce highly pro-inflammatory lipid mediators involved in the classic signs of inflammation, including redness, fever, pain, swelling, and loss of function. RA has been demonstrated to modulate these pathways.

In allergic inflammatory contexts, after treatment with RosA, the level of histamine in the serum was significantly reduced. RosA suppressed the protein and mRNA expressions of IL-1β, IL-6, and TNF-α in nasal mucosa or spleen. The increase in mast cell and eosinophil infiltration caused by allergen sensitization was reduced in the drug-administered group. Furthermore, COX-2 expression and caspase-1 activity were prevented by administering RosA in nasal mucosa tissue. In activated human mast cells, RosA suppressed the activation of NF-κB and caspase-1.

Neuroprotective Mechanisms

Rosmarinic acid, along with phenolic diterpenoids, inhibits tau fibrillization. Since rosmarinic acid was the most active compound in this comparison, morphological changes in atomic force microscopy images were observed after treatment. Rosmarinic acid leads to a decrease in amide regions I and III, indicating that it prevents β-sheet assembly. Molecular docking studies suggest that rosmarinic acid binds to the steric zipper of the tau hexapeptide 306VQIVYK311 involved in fibrillization and β-sheet formation, with similar chemical interactions to those of orange G, a known pharmacophore for amyloid.

Rosmarinic acid exhibits antioxidant and anti-inflammatory effects and has been shown to protect neurons in vitro against oxygen-glucose deprivation. Treatment of rats one to five hours after ischemia-reperfusion reduces brain infarction and blood-brain barrier breakdown via inhibition of NF-κB activation and decreased expression of the proinflammatory cytokine high-mobility group protein B1 (HMGB1).

PPARγ Activation

In a rat model of cardiac ischemia/reperfusion injury, RosA pretreatment restored decreased cardiac hemodynamic parameters, decreased infarct size, and reduced cardiomyocyte apoptosis. Furthermore, RosA pre-treatment inhibited the levels of inflammatory cytokines (IL-6, TNF-α, and CRP), up-regulated PPARγ expression, and down-regulated NF-κB expression in myocardial tissue.

Antiviral Mechanisms

Rosmarinic acid demonstrates promising antiviral activity both in vitro and in vivo. It effectively inhibits viral entry and replication, significantly enhances the survival rate of infected mice, and mitigates virus-induced damage across multiple organs. Further mechanistic investigation indicates that rosmarinic acid functions by activating the Nrf2 pathway, a crucial endogenous antioxidant defense system.

4. Scientific Evidence by Area of Use

4.1 Allergic Rhinitis and Allergic Disease

This is the area with the most direct human clinical evidence for rosmarinic acid. The present study determined whether oral supplementation with rosmarinic acid is an effective intervention for patients with seasonal allergic rhinoconjunctivitis (SAR). In this 21-day, randomized, double-blind, age-matched, placebo-controlled parallel group study, patients with mild SAR were treated daily with extract of Perilla frutescens enriched for rosmarinic acid (200 mg [n=10] or 50 mg [n=9]) or placebo (n=10). Profiles of infiltrating cells and concentrations of eotaxin, IL-1beta, IL-8, and histamine were measured in nasal lavage fluid.

As compared with placebo supplementation, supplementation with extract of Perilla frutescens enriched for rosmarinic acid resulted in a significant increase in responder rates for itchy nose, watery eyes, itchy eyes, and total symptoms (P<0.05). Active treatment significantly decreased the numbers of neutrophils and eosinophils in nasal lavage fluid (P<0.05 vs. placebo). Patients reported no adverse events, and no significant abnormalities were detected in routine blood tests.

In conclusion, extract of Perilla frutescens enriched for rosmarinic acid can be an effective intervention for mild SAR at least partly through inhibition of PMNL infiltration into the nostrils.

Evidence assessment: This randomized, double-blind, placebo-controlled trial is a meaningful proof-of-concept, but was limited in scale (n=29 total), duration (21 days), and disease severity (mild SAR only). These findings require replication in larger, longer trials before definitive conclusions can be drawn.

In activated human mast cells, NF-κB/RelA and caspase-1 activation increased, whereas NF-κB/RelA and caspase-1 activation was inhibited after treatment with Perilla extract or RA. These results indicate that RA ameliorates allergic inflammatory reactions such as allergic rhinitis and allergic rhinoconjunctivitis.

In pediatric populations, a multicentric, randomized, double-blind, parallel-group, placebo-controlled study evaluated the efficacy and safety of Lertal (a mixture of Perilla extract, quercetin, and Vitamin D3) as an add-on treatment in 146 children with allergic rhinoconjunctivitis, demonstrating that this treatment was able to significantly prevent the occurrence of clinical events. However, because Lertal is a combination product, the specific contribution of rosmarinic acid alone cannot be isolated from these results.

4.2 Neurological and Neurodegenerative Disease

Investigations into the therapeutic potential of rosmarinic acid in an amyloid beta1–42 (Aβ1–42)-induced model of Alzheimer's disease have been conducted. RA and ursolic acid are major bioactive constituents of Rosmarinus officinalis, which is a medicinal herb belonging to family Lamiaceae and exhibiting significant biological properties including neuroprotection. RA and UA substantially improve the deficits in cognition as well as synaptic dysregulation and the associated neurodegeneration in an AD model of Aβ1–42-induced neurotoxicity, suggesting their therapeutic significance against AD.

RA has been identified in therapeutic strategies for the prevention of neurodegenerative diseases, most importantly Alzheimer's disease. In vitro, rosmarinic acid leads to a decrease in amide regions I and III, indicating that it prevents β-sheet assembly, a key pathological feature of tauopathies.

Evidence assessment: The neuroprotective evidence for rosmarinic acid is predominantly preclinical — animal models and cell culture studies. In vivo rosmarinic acid-based behavioral/neuroprotective studies used very high oral doses whose results are difficult to extrapolate to humans; several groups used intraperitoneal exposures that resulted in quantities of rosmarinic acid that were largely unachievable via oral exposures, creating very unrealistic human exposure scenarios. The bioavailability in the rat exceeds that of humans by about 5 to 6-fold, diminishing, to some extent, the practical relevance of animal studies for human application. No large-scale human clinical trials in neurodegenerative disease have been completed.

4.3 Inflammation and Inflammatory Diseases

The anti-inflammatory effects of rosmarinic acid have been revealed through in vitro and in vivo studies of various inflammatory diseases like arthritis, colitis, and atopic dermatitis.

In macrophage cell studies (RAW264.7), water and ethanol extracts of Prunella vulgaris, which is rich in RA, applied to mouse macrophages significantly inhibited lipopolysaccharide-stimulated PGE2 and NO production at 30 µg/mL without affecting cell viability. Extracts from different accessions were screened for anti-inflammatory activity. The inhibition of PGE2 and NO production was dose-dependent, with significant effects seen at concentrations as low as 10 µg/mL. Although this provides evidence for anti-inflammatory activity, additional research is required to demonstrate that these observations are relevant to human health and that these compounds impact macrophages in vivo.

For inflammatory bowel conditions, animal research shows that RosA treatment reduced the levels of IL-6, TNF-α, and PGE2 in the liver and the activity of COX-2. RosA significantly inhibited the expression of IL-1β, IL-6, IL-8, CCL20, and TNF-α and down-regulated the NF-κB pathway. In the aspect of reducing the levels of NLRP3 and ASC and the secretion of activated IL-1β and caspase-1, RosA inhibited poly (I:C)-induced activation of inflammatory bodies.

Evidence assessment: Anti-inflammatory data for RA in these disease areas is almost entirely from animal and cell studies. Large-scale human clinical trials for arthritis or colitis are lacking.

4.4 Diabetes and Metabolic Function

Through anti-inflammatory and antioxidant properties, including inhibiting NF-κB activity and reducing production of PGE2, NO, and COX-2 in RAW 264.7 cells, RA is an abundant phytochemical with various therapeutic implications for human health, including metabolic conditions.

In an animal study using diabetic mice, mice were divided into three groups: diabetic mice with 0, low dose RA (25 mg/mL), and high dose RA (50 mg/mL). Results from this and similar studies suggest RA modulates diabetic inflammation in the liver. A large number of pharmacological studies have demonstrated various biological activities of RA such as anti-inflammation, anti-oxidation, anti-diabetes, anti-virus, anti-tumor, neuroprotection, and hepatoprotection.

Evidence assessment: Antidiabetic evidence for RA in humans is absent. Studies are animal-based and are generally preliminary in nature.

4.5 Anticancer Activity

Rosmarinic acid, a polyphenolic compound found in herbs such as rosemary, basil, and mint, has garnered significant attention due to its potent antioxidant and anticancer properties. A systematic review examined the molecular mechanisms underlying these properties and their potential application in cancer prevention and therapy, focusing specifically on RA's role in modulating cancer-related pathways.

A systematic review of PubMed, Scopus, and Web of Science databases was conducted in accordance with PRISMA guidelines, focusing on studies published between 2019 and 2024. A total of 25 articles providing evidence from in vitro, in vivo, and in silico studies were selected. These findings elucidate the role of RA in inhibiting tumor cell proliferation, inducing apoptosis, and preventing metastasis in various types of cancer through diverse mechanisms, including its antioxidant properties.

Recent findings indicate that RA could be an alternative in chemoprotection due to its antioxidant and anti-inflammatory capabilities through regulation of the NF-κB pathway.

Evidence assessment: Despite promising results, RA's bioavailability challenges limit its therapeutic efficacy, underscoring the necessity for improved delivery methods. All meaningful anticancer data derives from in vitro or animal studies; no human clinical oncology trials testing isolated RA have been published.

4.6 Antiviral Activity

Rosmarinic acid is a phenolic compound with antiviral properties, often encountered in dietary supplements and herbal drugs. In vivo, it effectively inhibits viral entry and replication, significantly enhances the survival rate of infected mice, and mitigates virus-induced damage across multiple organs. Further mechanistic investigation indicates that rosmarinic acid functions by activating the Nrf2 pathway, a crucial endogenous antioxidant defense system.

RA is a phenolic compound with antiviral properties often encountered in dietary supplements and herbal drugs. One study investigated the plasma levels of RA after 12 weeks of use and the potential interactions of RA with selected antiretroviral drugs; patients infected with human immunodeficiency virus took a supplement containing RA for 12 weeks, after which RA concentrations in the plasma samples were analyzed.

Evidence assessment: Antiviral activity is supported by in vitro and animal data. The study in HIV patients was primarily a pharmacokinetic investigation rather than an efficacy trial. Direct antiviral efficacy in human subjects remains unstudied in controlled trials.

4.7 Antifibrotic Effects

All plants whose single extract was reported to contain RA and to show antifibrotic activity belong to the family Lamiaceae. These include Glechoma hederacea, Melissa officinalis, Elsholtzia ciliata, Lycopus lucidus, Ocimum basilicum, Prunella vulgaris, Salvia rosmarinus (Rosmarinus officinalis), and Salvia miltiorrhiza. This suggests that RA is the active ingredient for the antifibrotic effect of Lamiaceae plants, and these plants are a valuable source of RA. Evidence is from preclinical models; human clinical data are absent.

5. Body Systems and Health Areas

• Immune and Allergic System: Rosmarinic acid has antioxidant and anti-inflammatory effects and is associated with use for asthma and reactive airway diseases, allergic disorders such as allergic rhinitis, otitis media, chemical sensitivity, and multiple allergen reactivity.
• Nervous System: RA is widely investigated for its biological properties and protective efficacies in neuroprotective and anti-Alzheimer's activities.
• Cardiovascular System: RA has been investigated for the treatment of cardiovascular disease; it has been validated to restore decreased cardiac hemodynamic parameters and decrease infarct size and cardiomyocyte apoptosis in a rat model of cardiac ischemia/reperfusion injury.
• Hepatic System: Pharmacological studies have demonstrated hepatoprotective activity of RA.
• Musculoskeletal System: Osteoclast differentiation is inhibited by rosmarinic acid through quenching of reactive oxygen species.
• Metabolic and Endocrine: Several studies have ascertained multiple therapeutic benefits of RA in various diseases, including cancer, diabetes, inflammatory disorders, neurodegenerative disorders, and liver diseases.
• Skin: In a clinical study of 50–60-year-old adult females (n=21), application of an NHE1 activator-containing cream significantly improved skin barrier functions by reducing skin surface pH and transepidermal water loss and increasing skin hydration. Creams containing NHE1 activators, such as rosmarinic acid, could help maintain or recover skin barrier functions.
• Connective Tissue: In osteogenesis imperfecta patients' fibroblasts, exposure to extracts (0.1–100 µg/mL) and RA (0.1–100 µM) significantly increased collagen type I, with best results obtained with 0.1–10 µM RA.

6. Dosage Forms and Reported Dosages

The landmark SAR clinical trial used Perilla frutescens extract enriched for rosmarinic acid at 200 mg (n=10) or 50 mg (n=9) daily for 21 days in patients with mild seasonal allergic rhinoconjunctivitis.

Rosmarinic acid in the treatment of humans suffering from inflammatory diseases and disorders has been described as administered in daily doses ranging from 50 to 1000 mg, preferably from 100 to 500 mg.

Data on the pharmacokinetics of RA are lacking in cases of the chronic use of supplements containing this compound, and only limited data on the metabolism and distribution of RA are available. One study aimed to investigate plasma levels of RA after 12 weeks of use and to determine potential interactions of RA with selected antiretroviral drugs. Patients infected with human immunodeficiency virus took a supplement containing RA for 12 weeks.

In the skin barrier clinical study, a cream was applied to 50–60-year-old adult females (n=21), significantly improving skin barrier functions. Topical RA concentrations used were not specified in available summaries; full formulation details are in the primary literature.

Although many achievements have been made in various research aspects, there still exist some problems or issues to be answered, especially regarding RA's toxicity and bioavailability. Accordingly, a universally established optimal human dose has not been defined by current evidence.

7. Pharmacokinetics

Rosmarinic acid is easily absorbed through the gastrointestinal tract as well as the skin. After prolonged supplementation, RA can be detected in patients' plasma samples, mainly in the form of sulphoglucuronide. Potential interactions are suggested on the level of liver metabolizing enzymes and efflux P-glycoprotein, with RA competing with other drugs as a substrate in metabolism and distribution systems.

Intravenously injected rosmarinic acid showed bi-exponential decay, and unchanged rosmarinic acid was mainly eliminated by urinary excretion, suggesting the involvement of transporters in its renal excretion.

The bioavailability of rosmarinic acid in the rat exceeds that of humans by about 5 to 6-fold, diminishing the practical relevance of many animal studies for human application. RA's bioavailability challenges limit its therapeutic efficacy, underscoring the necessity for improved delivery methods.

8. Safety Considerations and Drug Interactions

General Safety

Rosmarinic acid has an excellent antiphlogistic (anti-inflammatory) activity at very low doses, has no ulcer-forming activity at all, and only a very low toxicity, based on early animal and experimental data. In the SAR clinical trial, patients reported no adverse events, and no significant abnormalities were detected in routine blood tests.

Considerable evidence indicates the pro-oxidant properties of natural polyphenols, which could lead to deleterious effects. A recent computational study suggested that the pro-oxidant risk of RA becomes remarkable when superoxide anions are present. This dual antioxidant/pro-oxidant potential at different concentrations is characteristic of many polyphenols.

Rosmarinic acid has been extensively studied at the cellular, whole animal, and molecular mechanism levels, presenting a complex array of multi-system biological effects. Rosmarinic acid-induced hormetic dose responses are widespread, occurring in numerous biological models and cell types for a broad range of endpoints. This dose-response complexity — in which the compound may show beneficial effects at lower doses but different effects at higher doses — is an important consideration when interpreting both safety and efficacy data.

Pharmacokinetic Drug Interactions

Rosmarinic acid showed organic anion transporter (OAT)1-mediated active transport with a Km of 26.5 μM and a Vmax of 69.0 pmol/min in HEK293 cells overexpressing OAT1. Importantly, rosmarinic acid inhibited the transport activities of OAT1, OAT3, OATP1B1, and OATP1B3, and the inhibitory effect on OAT3 transport activity caused an in vivo pharmacokinetic interaction with furosemide by inhibiting its renal excretion and by increasing its plasma concentration. OAT1 and OAT3 are the major transporters that may regulate the pharmacokinetic properties of rosmarinic acid and may cause herb-drug interactions, although their clinical relevance awaits further evaluation.

Potential interactions are suggested at the level of liver metabolizing enzymes and efflux P-glycoprotein, with RA competing with antiretroviral drugs as a substrate in metabolism and distribution systems. The simultaneous use of RA and antiretroviral therapy (containing efavirenz, darunavir, or raltegravir) may affect the plasma levels of RA after prolonged supplementation.

Scope of Evidence Limitations

Clinical trials have been performed to evaluate the effects of plant extracts containing RA on several diseases, but the direct isolation of RA's effects from complex herbal extracts is methodologically challenging. Additional research is required to demonstrate that observations from in vitro studies are relevant to human health. Studies of bioavailability and long-term low-dose effects in vivo are needed, especially since only relatively high concentrations of extracts showed significant activity.

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