Carnosic Acid: A Comprehensive Encyclopedic Reference
1. Identity: Chemical, Botanical, and Structural Profile
Carnosic acid is formally classified as a natural benzenediol abietane diterpene found in rosemary (Salvia rosmarinus) and common sage (Salvia officinalis). It is also known in older literature by the synonym salvin. Its molecular formula is C20H28O4, and it is a phenolic diterpene found in rosemary (Rosmarinus officinalis L.). Its PubChem CID is 65126, and its molecular weight is 332.43 g/mol. Carnosic acid is widely present in Lamiaceae plants such as rosemary (Rosmarinus officinalis L.).
Carnosic acid is a phenolic (catecholic) diterpene, endowed with antioxidative and antimicrobial properties. It is the only phenolic diterpene present in the native state in rosemary and sage and, accordingly, has the sole right to be called a natural product — related compounds such as carnosol, isorosmanol, rosmanol, and epirosmanol are largely artifacts of its oxidative degradation during processing or storage. Carnosic acid is a phenolic diterpene which corresponds to the empirical formula C20H28O4 and is a constituent of the species Salvia and Rosmarinus, where it is mainly to be found in the leaves.
1.1 Natural Sources and Plant Distribution
The primary commercial sources of carnosic acid are the leaves of Salvia rosmarinus (rosemary) and Salvia officinalis (common sage). It has been positively identified in various other species of sage, such as Salvia canariensis, Salvia willeana, Salvia triloba, and Salvia sclarea. Dried leaves of rosemary and sage contain 1.5 to 2.5% carnosic acid. The highest amounts of CA are found during winter, probably due to higher precipitations, while their concentration is lower in summer. Within the plant, carnosic acid is principally concentrated in the leaves and is associated with photoprotective functions in the chloroplast and related compartments.
1.2 Discovery and Chemical History
Well before its chemical structure was elucidated, carnosic acid (salvin) and similar compounds of the ferruginol type were extracted from sage Salvia carnosa Dougl. as a "bitter principle" (White and Jenkins, 1942). At that time, probably due to oxidation processes, only a derivative of carnosic acid could be isolated and named carnosol (pikrosalvin). Since its first extraction from a Salvia species (~70 years ago) and its identification (~50 years ago), numerous articles and patents (~400) have been published on specific food and medicinal applications of Rosmarinus and Salvia plant extracts abundant in carnosic acid. Formal chemical characterization was achieved in the 1960s: it was discovered first by Linde in Salvia officinalis [Helv. Chim Acta 47, 1234 (1962)] and by Wenkert et al. in Rosmarinus officinalis [J. Org. Chem. 30, 2931 (1965)].
1.3 Common Forms and Preparations
Carnosic acid is commercially available and used in several forms:
- Standardized rosemary leaf extracts: EU legislation specifies that acetone extracts of rosemary should contain more than 10% w/w of carnosol plus carnosic acid; supercritical extracts should contain more than 13% w/w; deodorized ethanolic extracts should contain more than 5% w/w; and decolorized and deodorized hexane and ethanol extracts should contain more than 5% w/w.
- Rosemary oleoresin (ROE): An oil-soluble extract used as a natural food preservative and in cosmetics. It contains carnosic acid together with co-occurring diterpenes including carnosol, rosmanol, and rosmaridiphenol.
- Dietary supplement capsules/tablets: Isolated or concentrated carnosic acid fractions are sold in encapsulated form. The effective dose in humans has not been established.
- Food additive (E392): Rosemary extract, specifically the type mainly consisting of carnosic acid and carnosol, is approved as a food preservative in several countries, having E number E392.
- Topical formulations: Carnosic acid and its esters are oil-soluble and have been incorporated into sunscreen preparations, creams, and lotions for skin protection.
2. Traditional and Historical Use
Isolated carnosic acid as a chemical entity has no documented traditional use; it was not identified until the twentieth century. Its historical significance is entirely as a major bioactive constituent of rosemary and sage, two plants with centuries-long medicinal traditions. The following reflects the traditional use of these plants, from which carnosic acid is now known to be a principal active component.
2.1 Rosemary in Mediterranean and European Medicine
For centuries, rosemary was valued in folk medicine as a plant that supports digestion, circulation and concentration. In ancient times it was also attributed symbolic significance — it was associated with memory, vitality and protection. Dioscorides discussed the plant in De materia medica, one of the most influential herbal books in history. Rosemary was widely used throughout Mediterranean Europe for its culinary and medicinal properties. Hungary water, dating to the 14th century, was one of the first alcohol-based perfumes in Europe and is primarily made from distilled rosemary.
Traditional uses of rosemary include helping alleviate muscle pain, improving memory, boosting the immune and circulatory system, and promoting hair growth. One of the traditional uses of rosemary is as a mild analgesic or pain reliever.
2.2 Sage in Traditional Medicine
Sage and rosemary are both widely used in traditional medicine. Common sage (Salvia officinalis) has been employed in European herbal traditions for its antiseptic, anti-inflammatory, and memory-supporting properties, uses documented in numerous classical herbals. In 1997, the European Scientific Cooperative on Phytotherapy (ESCOP) recommended the internal use of rosemary leaf to improve hepatic and biliary function and the external use as adjuvant therapy for rheumatism, peripheral circulatory disorders, and as an antiseptic to promote wound healing.
2.3 Antimicrobial Use (Salvine in Russian Literature)
Carnosic acid is a powerful antioxidant and, according to a number of Russian works where it bears the name salvine, an antibiotic against Staphylococcus aureus and against certain microorganisms responsible for dental caries and bad breath. In connection with this latter property, it is mentioned in prior art for the production of dentifrices and mouthwashes. This use thus bridges traditional ethnobotanical practice and mid-twentieth-century applied pharmacognosy.
3. Key Constituents and Phytochemical Context
Rosemary leaves are rich in diverse bioactive compounds. Rosmarinus officinalis contains monoterpenes, sesquiterpene chemical composition, diterpenes, triterpenoids, flavonoids, fatty acids, amino acids and branched alkanes. Carnosic acid co-occurs with a family of structurally related phenolic diterpenes. These include carnosic acid (1), carnosol (2), isorosmanol (3), 11,12-di-O-methylisorosmanol (4), rosmanol (5), 12-O-methylcarnosic acid (6), rosmanol-9-ethyl ether (7), epirosmanol (8), and 7-methyl-epirosmanol (9).
Among these, carnosic acid and carnosol are quantitatively and pharmacologically the most significant. CA and carnosol are the main phenolic diterpene antioxidant constituents of sage and rosemary. Other prominent phytochemicals in rosemary include rosmarinic acid (a hydroxycinnamic acid derivative), ursolic acid, caffeic acid, betulinic acid, and a range of volatile monoterpenes (camphor, 1,8-cineole, α-pinene). Rosemary essential oil contains about 150 phytochemicals, including rosmarinic acid, camphor, α-pinene, caffeic acid, ursolic acid, betulinic acid, carnosic acid, and carnosol.
4. Mechanisms of Action
4.1 Pro-Electrophilic Antioxidant: The Keap1/Nrf2/ARE Pathway
The most thoroughly characterized mechanism of carnosic acid is its activation of the Keap1/Nrf2/ARE (antioxidant response element) transcriptional pathway. This mechanism is unusual and distinguishes carnosic acid from simple radical-scavenging antioxidants. CA and carnosol are compounds found in rosemary. Importantly, CA and CS themselves are not electrophilic, but in response to oxidation, become electrophilic, and then activate the Keap1/Nrf2/ARE transcription pathway to synthesize endogenous antioxidant "phase 2" enzymes.
The molecular sequence is well-characterized: Keap1 is an adapter protein that facilitates ubiquitination of Nrf2 and thus drives constitutive degradation of this transcription factor. When electrophiles react with critical cysteine residues on the Keap1 protein to form an adduct, they perturb this system, thereby stabilizing Nrf2 and allowing it to be translocated from the cytoplasm into the nucleus, where it binds to AREs and stimulates the transcription of phase 2 genes.
Activation of the neuroprotective Keap1/Nrf2 transcriptional pathway by CA involves the conversion of CA from an electrophilic precursor to an electrophilic form through a mechanism involving the release of Nrf2 from the Keap1/Nrf2 complex, which results in the transcription of antioxidant enzymes that protect neurons from oxidative stress and excitotoxicity. It has also been shown that the hydrophilicity of CA is critical for its neuroprotective effects, which require both free carboxylic acid and catechol hydroxyl moieties.
The mechanism of neuroprotection of CA involves a sequence of events whereby the activation of the Keap1/Nrf2 pathway is followed by the transcription and induction of enzymes involved in glutathione (GSH) metabolism (glutathione S-transferase, alpha 4; glutathione S-transferase, alpha 2).
RNA interference (RNAi) of Nrf2 completely abrogated the neuroprotective effect of CA, implicating this pathway as the primary cytoprotective mechanism.
4.2 Concomitant ATF4 Activation
Research has identified a second, complementary transcriptional mechanism. By comparative transcriptome analysis, CA activates activating transcription factor 4 (ATF4) in addition to Nrf2 at high doses. CA activated ATF4 in phospho-eIF2α- and heme-regulated inhibitor kinase (HRI)-dependent manners, indicating that CA activates ATF4 through the integrated stress response (ISR) pathway. CA activated Nrf2 and ATF4 cooperatively to enhance the expression of NGF (nerve growth factor) and many antioxidant genes while acting independently to certain client genes. These results represent a novel mechanism of CA-mediated gene regulation evoked by Nrf2 and ATF4 cooperation.
4.3 Anti-Inflammatory Signaling
Although the molecular target of CA has not been fully identified, its antioxidative activity, activation of peroxisome proliferator-activated receptor gamma (PPARγ), and 5-lipoxygenase inhibition are regarded as major mechanisms of its multifunctional pharmacology. In adipose tissue, LPS-stimulated adipocytes showed elevated mRNA expression of tumor necrosis factor (TNF)-α, interleukin-6, and monocyte chemoattractant protein-1, and CA significantly inhibited the expression of these adipokine genes. LPS-induced up-regulation of TLR4, myeloid differentiation factor 88, TNF receptor-associated factor 6, and nuclear factor-κB was inhibited by CA.
CA has been shown to mediate the activation of the PI3K/Akt/NF-κB pathway, leading to the upregulation of GSTP (Glutathione S-transferase pi), one of the seven classes of GSTs and one that is highly expressed in glial cells of the nervous system.
4.4 Anticancer Signaling Pathways
The potential mechanisms involved by CA in cancer include inhibiting cell proliferation, inhibiting metastasis, inducing cell apoptosis, stimulating autophagy, regulating the immune system, reducing inflammation, regulating the gut microbiota, and enhancing the effects of other anti-cancer drugs. At the molecular level, CA induces apoptosis by reducing anti-apoptotic Bcl-2 expression and increasing pro-apoptotic Bax and Caspase-3 levels. CA reduces cell growth and migration by suppressing key signaling pathways like Akt/mTOR, PI3K, and MAPK, while also inhibiting the cell cycle.
4.5 Metabolic Mechanisms
CA is reported to possess potent antioxidant, anti-inflammatory, and anti-hyperglycemic properties. The limited evidence available indicates that CA activates AMPK and may have anti-obesity and antidiabetic potential. AMP-activated protein kinase (AMPK) activation is associated with improved insulin signaling, fatty acid oxidation, and reduced lipogenesis, making this a mechanistically plausible target for metabolic conditions.
5. Scientific Evidence by Area of Application
A critical caveat applies to all sections below: using the database from ClinicalTrials.gov with keywords related to rosemary compounds, there were found two clinical trials for rosmarinic acid and oleanolic acid, three studies for ursolic acid and none for carnosic acid or carnosol. No clinical trials have tested carnosic acid specifically. The body of evidence is almost entirely composed of cell-culture (in vitro) and animal (in vivo) studies. Where human evidence exists, it is for rosemary preparations (extracts or essential oils) rather than isolated carnosic acid. Accordingly, the evidence strength for most applications must be characterized as preliminary, preclinical, or indirect.
5.1 Antioxidant Activity
Evidence level: In vitro and in vivo (preclinical); mechanisms well-characterized.
Carnosic acid is best known as an antioxidant. Carnosic acid induces the antioxidant defense system through its di-phenolic catechol moiety, which can scavenge free radicals, making it an electron-donating antioxidant. The dual mechanism — direct radical scavenging plus indirect Nrf2-mediated induction of endogenous antioxidant enzymes — distinguishes carnosic acid from purely chain-breaking antioxidants like vitamin E or ascorbic acid. The diverse biological properties of carnosic acid that include antioxidant, anti-inflammatory, and anticarcinogenic activities have instigated studies on its mechanistic role, providing further insights into its potential as a therapeutic agent. The antioxidant function in food systems is well-established and forms the basis for its regulatory approval as a food additive.
5.2 Neuroprotection and Neurodegeneration
Evidence level: In vitro and animal models; no completed human clinical trials for carnosic acid specifically.
Accumulating evidence has established the relevance of carnosic acid as a neuroprotective agent exhibiting therapeutic efficacy in combatting neuronal-injury-induced disorders. The physiological importance of carnosic acid in the mitigation of neurodegenerative disorders is just beginning to be understood.
In an Alzheimer's disease rat model, animals received carnosic acid (10 mg/kg) intraperitoneally one hour before surgery, again 3–4 hours after surgery (3 mg/kg), and repeated each afternoon for 12 days. A lesion was made by bilateral intra-hippocampal injection of beta-amyloid protein. The study reported histological protection of neurons in the CA1 region of the hippocampus. In cellular models, CA pretreatment at 1 µM for 12 hours suppressed mitochondria-related pro-oxidant and mitochondria-dependent pro-apoptotic effects. CA prevented mitochondrial membrane potential disruption and decreased the levels of oxidative stress markers in mitochondrial membranes. CA also inhibited cytochrome c release and activation of caspases-9 and -3, as well as decreased DNA fragmentation.
A 2019 preclinical study demonstrated that pro-electrophilic drugs like CA provide anti-inflammatory responses and neuroprotection by activating the Keap1/Nrf2 transcriptional pathway and subsequently increasing the levels of anti-inflammatory and antioxidant phase 2 enzymes. Research into a modified prodrug of carnosic acid (diAcCA) designed for improved bioavailability is ongoing in transgenic Alzheimer's disease mouse models. In traumatic brain injury models, pharmacological Nrf2-ARE induction by carnosic acid is capable of neuroprotective efficacy when administered after TBI.
Limitation: All findings cited above are from cell lines or animal models. No randomized controlled trials exist for carnosic acid in any neurological condition in humans.
5.3 Oncology (Anticancer Properties)
Evidence level: Predominantly in vitro (cell lines); some animal studies; no human clinical trials.
Carnosic acid is widely present in Lamiaceae plants such as rosemary. In recent years, there has been increasing evidence that CA has significant anti-cancer activity, such as in leukaemia, colorectal cancer, breast cancer, lung cancer, liver cancer, pancreatic cancer, stomach cancer, lymphoma, prostate cancer, oral cancer, etc.
In human gastric cancer cell lines (AGS and MKN-45), CA treatment decreased cell viability in both cell lines in a dose-dependent manner. In AGS cells, the IC50 values were 19.90, 18.93, and 16.57 µg/mL after 24, 48, and 72 h incubation respectively.
In lung cancer (NSCLC) models, carnosic acid induced apoptosis in these cells along with initiating DNA fragmentation. It also inhibited cell migration and invasion along with decreasing the expression levels of MMP-9. Carnosic acid inhibits cell growth and induces cell cycle arrest in B16F10 melanoma cells along with enhancing p21 expression. Carnosic acid has also been reported to inhibit the growth of estrogen receptor (ER)-negative human breast cancer cells along with inducing G1 cell cycle arrest.
In glioma, CA enhanced the cytotoxic effect of temozolomide (TMZ) in glioma cancer cells. CA enhanced TMZ-induced inhibition of colony formation and cell migration and enhanced TMZ-induced cell cycle arrest and cellular apoptosis.
In breast cancer, carnosic acid has been shown to cooperate with tamoxifen: in combination with cisplatin and tamoxifen, carnosic acid promoted apoptosis in lung and breast cancer cells.
Across cancer types, common pathways identified include: downregulation of cyclin A1 in both leukemia and colon cancer cells; induction of apoptosis in human prostate cancer, neuroblastoma, and hepatocellular carcinoma cell lines; and inhibition of cell growth via targeting the Akt/mTOR pathway leading to autophagy induction in hepatoma cells.
Limitation: Every finding cited above originates from in vitro cell culture studies or animal xenograft models. No completed human clinical trials for carnosic acid in oncology have been identified in the literature. The relevance of in vitro IC50 values to achievable human plasma concentrations is unknown.
5.4 Metabolic Health: Obesity, Insulin Resistance, and NAFLD
Evidence level: Animal models; in vitro; no human clinical trials for carnosic acid specifically.
CA has been reported to reduce body weight and the adipose tissue accumulation in overweight and obese mice. In high-fat diet mouse models, CA treatment significantly decreased HFD-induced metabolic syndrome by decreasing the serum levels of triglycerides, total cholesterol, insulin and glucose. CA significantly decreased the protein expression levels of various pro-inflammatory cytokines in serum and brain tissues, including interleukin-1β, IL-6 and tumor necrosis factor-α, regulated by the NF-κB signaling pathway.
In a NAFLD mouse model, the production of pro-inflammatory cytokines and lipid accumulation were suppressed by CA. MARCKS was reduced in mice fed the high-fat diet; CA treatment upregulated MARCKS expression compared to the HF group. Treatment with 10 µM CA for 24 h attenuated palmitate-induced insulin resistance in muscle and fat (3T3-L1) cells — a result accompanied by an increase in AMPK activation.
Anti-adipogenic mechanisms in cell studies include inhibition of TLR4-MyD88-dependent inflammatory pathways: results suggest that CA directly inhibits TLR4-MyD88-dependent signaling pathways and decreases the inflammatory response in adipocytes.
Limitation: All obesity and metabolic data are from cell culture or rodent studies. Translational validity to humans is unproven.
5.5 Anti-Inflammatory Activity
Evidence level: In vitro; animal models; no clinical trials for isolated carnosic acid.
Research over the past decade indicates that carnosic acid has multiple bioactive properties including antioxidant, anti-inflammatory and anticancer activities among others. In a skin inflammation model, CA was found to inhibit Syk/Src signaling pathways, which regulate inflammatory responses in immune and epithelial cells. Carnosic acid has been reported to possess antioxidative, anti-cancer, anti-angiogenic, anti-inflammatory, anti-metabolic disorder, photoprotective, and hepatoprotective and neuroprotective activities.
5.6 Skin Health and Photoprotection
Evidence level: In vitro and early mechanistic studies; limited clinical data on rosemary preparations in skincare.
Studies have found that rosemary has anti-aging effects on the skin due to it containing carnosic acid. Carnosic acid may help protect the skin from damage caused by UV rays, which may support graceful aging. Carnosic acid's oil-soluble nature makes it suitable for topical formulations. The composition provides a temporary prophylactic effect against the production of peroxides in skin tissues to which it has been applied. Preferred phenolic diterpenes for use in such compositions are carnosic acid, C1–5 alkyl esters of carnosic acid, carnosol, and carnosic acid alkali metal salts.
5.7 Antimicrobial Activity
Evidence level: In vitro; well-documented antibacterial activity against specific pathogens.
Potent antibacterial activities against Propionibacterium acnes (ATCC 6919) and methicillin-resistant Staphylococcus aureus (ATCC 33592) of carnosic acid and carnosol have been reported. The compound's antimicrobial activity against S. aureus was documented in Soviet-era literature under the name "salvine," where it was explored as a topical antibiotic. These properties underpin its use in natural food preservation.
5.8 Mood, Depression, and Neuropsychiatric Research
Evidence level: Animal studies only.
In an ovariectomized mouse model of post-menopausal depression, the current study provides insights into the potential neuroprotective, antioxidant, and anti-inflammatory effects of CA and its ability to attenuate depressive-like behavior in OVX mice. Nrf2/HO-1 signaling suppression and the associated proinflammatory state are key mechanisms in post-OVX depression. CA exerts multifaceted neuroprotection in OVX mice and represents a promising candidate for clinical evaluation as an antidepressant. No human data exist.
5.9 Hair Loss (Alopecia)
Evidence level: Mechanistic and in vitro data on carnosic acid specifically; human trials exist for rosemary preparations but not isolated carnosic acid.
In recent years, natural compounds have garnered attention as potential alternatives, with carnosic acid emerging as a promising candidate due to its multifaceted biological activities. Carnosic acid exhibits potent antioxidant, anti-inflammatory, anti-androgenic, neuroprotective, and hair follicle-regenerative properties. Despite its therapeutic potential, its poor solubility and stability in conventional formulations limit its clinical application.
6. Regulatory Status and Food Safety
Since 2008, the European Food Safety Authority (EFSA) has recognised rosemary extract as a food additive. Directive 2010/67/EU of 2010 approved the use of rosemary extracts as a new food additive, attributing the label E392. Rosemary extracts are authorised to be added to food and beverages at levels of up to 400 mg/kg, considering the sum of carnosic acid and carnosol, which are the most abundant antioxidants present in the rosemary extract.
In 2016, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) evaluated this food additive and established a temporary acceptable daily intake (ADI) of 0–0.3 mg/kg body weight per day for rosemary extract, expressed as carnosic acid plus carnosol.
In the United States, rosemary extract appears in the FDA's substances-added-to-food database as a GRAS flavouring agent or adjuvant under 21 CFR 182.20. FSANZ in 2024 reported no public health and safety concern with extending additional rosemary extract food-additive uses in Australia and New Zealand.
The highest mean refined exposure estimate (non-brand loyal scenario) was 0.09 mg/kg bw per day in children (3–9 years) and the highest 95th percentile of exposure was 0.20 mg/kg bw per day in children. These figures remain well within the established temporary ADI.
7. Dosage Forms and Doses Reported in Research
The dose has not been established in humans. The following doses appear only in preclinical (animal or in vitro) studies:
- Alzheimer's disease rat model (intraperitoneal): CA 10 mg/kg intraperitoneally one hour before surgery, then 3 mg/kg at 3–4 hours after surgery, repeated each afternoon for 12 days.
- Doxorubicin-induced cardiotoxicity rat model (intraperitoneal): Carnosic acid was used at 10, 20, or 40 mg/kg per day (IP, 16 days) alongside doxorubicin (2 mg/kg, every 48 hours, IP, 12 days).
- Cell culture (in vitro) — metabolic studies: Treatment with 10 µM CA for 24 h attenuated palmitate-induced insulin resistance in muscle and fat cells.
- Cell culture (in vitro) — TLR4 anti-inflammatory studies: 3T3-L1 adipocytes were treated with CA (0–20 µM) for 1 hour.
- Cell culture (in vitro) — neuroprotection: CA pretreatment at 1 µM for 12 hours suppressed the mitochondria-related pro-oxidant effects of chlorpyrifos in human neuroblastoma SH-SY5Y cells.
- Gastric cancer cells (in vitro): CA treatment used increasing concentrations of 0, 1, 10, 25, 50, 100, and 200 µg/mL for 24, 48, and 72 hours.
- Ovariectomized mice (obesity, dietary supplementation): Mice were fed a normal diet (ND), HFD, ND and 0.02% CA, or HFD and 0.02% CA for 12 weeks.
- Topical skin preparations (patent range): An antioxidant effective amount of preferred phenolic diterpene for use in skin compositions may be as low as 1 ppm by weight and as high as 100,000 ppm, with 10–10,000 ppm being the preferred range.
- Food additive exposure (dietary, calculated): Intake of carnosic acid and carnosol from natural diet (herbs) was estimated at a maximum of 1.66 mg/kg bw per day at the 95th percentile.
8. Safety Considerations and Drug Interactions
8.1 Human Safety Data
No studies have specifically examined the long-term safety of carnosic acid in humans. No clinical trials have tested the safety of carnosic acid specifically. Carnosic acid as a therapy for human disease and weight loss poses many challenges. To date, there are no publicly available, adequate, and well-controlled data on safety and efficacy of carnosic acid to treat any human disease.
Rosemary is generally recognized as safe (GRAS) when used in food. Safety is unproven for dosages above those found in food.
8.2 Preclinical Toxicology
The acute oral toxicity study in Kunming mice was designed following OECD guidelines 423, and a 30-day chronic oral toxicity study in Wistar rats was performed based on the enhanced OECD test guideline 407. The oral lethal dose (LD50) for mice was 7100 mg/kg of body weight in the acute toxicity study. Histopathological changes were observed in the heart, liver and kidney for the survival mice treated with a single dose CA.
For the sub-chronic toxicity study, CA administered for 30 days produced slight reductions in weight gain pattern, which did not reach the significant level when compared with control values. With respect to serum biochemistry, decreased total serum protein levels but conversely increased aspartate aminotransferase (AST) levels were detected in the high-dose groups.
The regulatory toxicology reference value (NOAEL) for systemic toxicity is a subchronic systemic toxicity NOAEL of 64 mg/kg bw/day (expressed as carnosic acid and carnosol) determined from 90-day studies referenced in the derivation of the ADI for rosemary extract. Rosemary extract (D74) was non-mutagenic in the Ames test.
8.3 In Vitro Hepatotoxicity
An in vitro study using primary human hepatocytes found that carnosic acid showed a dose-dependent increase in hepatotoxicity with an EC50 value of 94.8 ± 36.7 µM in three human hepatocyte donors without a concurrent increase in the apoptosis markers caspase-3/7. This finding indicates necrotic rather than apoptotic hepatocellular injury at high concentrations in vitro. The relevance to oral doses in humans is uncertain, but this finding warrants caution at high supplemental doses.
8.4 Cytochrome P450 Drug Interactions
A significant safety concern identified by in vitro research involves the modulation of drug-metabolizing enzymes. In human liver microsomes, carnosic acid did not exhibit significant time-dependent inhibition for any of the cytochrome P450 enzymes investigated, although it did inhibit CYP2C9- and CYP3A4-catalyzed reactions with Ki values of 9.2 and 4.3 µM, respectively. Carnosic acid also induced CYP2B6 and CYP3A4 mRNA and enzyme activity in a dose-dependent manner.
At 10 µM, carnosic acid increased CYP2B6 enzyme activity 61.6 and 49.3% in two donors compared with phenobarbital, and it increased CYP3A enzyme activity 82.6 and 142% compared with rifampicin. These results indicate the potential for drug interactions with carnosic acid and illustrate the need for an appropriate safety assessment before being used as a weight loss supplement.
CYP3A4 is the enzyme responsible for metabolizing a large proportion of prescription drugs, including immunosuppressants (cyclosporine, tacrolimus), statins, benzodiazepines, and many antiretrovirals. CYP2C9 metabolizes warfarin and several NSAIDs. Induction of these enzymes could reduce plasma concentrations of co-administered drugs, while competitive inhibition could increase them. These interactions are established only in vitro; their in vivo significance at dietary or supplement doses in humans remains to be determined.
8.5 Other Safety Considerations
In excess levels, rosemary may increase menstrual flow or cause miscarriages. Ingestion of large amounts of rosemary essential oils can be toxic and have antigonadotrophic activity, based on a study in mice. Dermatitis and allergy to rosemary have also been reported. These observations apply to rosemary preparations broadly; they have not been attributed specifically to isolated carnosic acid.
Because carnosic acid is categorized as a dietary supplement, relevant safety and efficacy studies at therapeutic doses probably will not be performed as would be for new drug entities developed by the pharmaceutical industry. Carnosic acid is also readily available without prescription and will probably not be administered under the supervision of a healthcare provider. Therefore, individuals are free to self-dose with little guidance.
9. Body Systems and Health Areas Associated with Carnosic Acid
- Central Nervous System: Neuroprotection, Alzheimer's disease models, Parkinson's disease models, traumatic brain injury, mood/depression (all preclinical)
- Oncology: Multiple cancer cell line studies across colorectal, breast, lung, prostate, gastric, liver, leukemia, glioma, and melanoma (all in vitro / animal)
- Metabolic System: Obesity, insulin resistance, type 2 diabetes models, non-alcoholic fatty liver disease (all preclinical)
- Cardiovascular System: Cardioprotection against chemotherapy-induced toxicity in animal models; lipid profile improvement in rodent studies
- Integumentary System (Skin): UV photoprotection, anti-aging, anti-inflammatory dermatology applications (mechanistic and in vitro); E392 food preservative use (regulatory)
- Immune / Inflammatory System: Inhibition of NF-κB, TLR4-MyD88, and pro-inflammatory cytokine pathways (in vitro and animal)
- Microbiology: Antibacterial activity against S. aureus and P. acnes (in vitro)
- Dermatology / Hair: Hair follicle regeneration and anti-androgenic properties under investigation (mechanistic); broader rosemary research includes a human trial for rosemary oil against minoxidil in androgenetic alopecia
10. Summary of Evidence Strength
A review of in vitro and in vivo data summarizes the current evidence on the efficacy of carnosic acid in the prevention or treatment of various experimental health disorders. The antioxidant mechanism through the Keap1/Nrf2/ARE pathway is among the most well-characterized and widely replicated findings at the molecular level. The food-preservative application (E392) is regulatory-grade established. However, for nearly all health claims — anticancer, neuroprotective, metabolic, anti-inflammatory — the entire human evidence base consists of indirect rosemary preparations studies, not isolated carnosic acid. From the available literature, R. officinalis has a promising future especially in the treatment and prevention of various diseases, such as cancers, infectious diseases and CNS disorders. However, no clinical trials for carnosic acid or carnosol were identified in the ClinicalTrials.gov database. To date, there are no publicly available, adequate, and well-controlled data on safety and efficacy of carnosic acid to treat any human disease.
References
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