The rosemary plant, Rosmarinus officinalis L (family Lamiaceae), is an aromatic evergreen shrub originating in the Mediterranean region and now growing widely in Europe, Asia, and Africa (Figure 1). The genus name Rosmarinus is derived from the Latin “Dew of the Sea” and has traditionally been associated with remembrance, love, and fidelity.1,2 This plant has been used extensively as a culinary spice in a variety of contexts. In Mexico, it is used in preparation of tea, and it seasons meats in the cuisines of Europe and the Middle East. Another use of rosemary is as part of a marinade for lamb, pork, and chicken dishes. Rosemary leaves flavor soups and beverages in India. Finely minced leaves can enhance stews, casseroles, fish, potatoes, salads, pasta, and breads such as focaccia. Rosemary and its extracts also are used as food preservatives and enhancers of sensory and functional properties.1–3 In the European Union, rosemary extracts are approved as an additive in a variety of products.4 Furthermore, rosemary and its constituents have been incorporated into cosmetics and cosmeceuticals in the hope of enhancing the health of skin and hair.5–8 For centuries, this plant has been an ingredient in folk medicines with associated claims for relief of such diverse symptoms and conditions as dysmenorrhea, mental decline, epilepsy, pain relief, and infertility, to name a few.1,2 It also has been promoted as a treatment for hair loss, dyspepsia, dermatitis, anxiety, cognitive improvement, constipation, joint and muscle pain, and improvement of circulation.1,2,9 Today, research attention is focusing more closely on whether this herb may have potential to alleviate complications of obesity and diabetes, inflammation-associated conditions, and neurological deficits.
Rosemary and its constituents have been the subject of considerable research interest because of their potential antioxidant, anti-inflammatory, and neurological activities,1,2,8,10 some of which are discussed in this article. In this overview, reports from in vitro and in vivo studies are discussed separately. Similarly when considering each health effect of rosemary, data from experiments examining the essential oil and extracts, as well as individual rosemary phytochemicals, are presented separately. Data from animal studies in which different delivery systems are used (topical, oral, injectable) may be included together in a section but are not necessarily directly comparable. For the sake of brevity, some cell culture and experimental animal studies are contained in the Appendix (Supplemental Digital Content 1, https://links.lww.com/NT/A15). Figure 2 provides chemical structures of several major rosemary constituents.
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FIGURE 1: Sketch of rosemary plant.
COMPOSITION AND BIOAVAILABILITY
The referenced studies evaluate the effects of diverse rosemary samples, including its dried powder, essential oil, and water and organic solvent extracts. Although the composition of these oils and extracts can vary widely depending on the specific preparation protocols used, the growth conditions of the plant, and the specific portion of the plant selected, some general descriptions of content can be noted. For example, the essential oil of rosemary may contain 6% to 41% 1,8-cineole, 18–28% camphor, 9% to 14% α-pinene, and 4% to 10% borneol. Several different essential oil chemotypes of indigenous and cultivated plants exist. Each essential oil from these has a different composition and thus potentially different biological activity.11–13 An ethanol extract of rosemary was reported14 to contain (mg/g dry extract) rosmarinic acid (RA; 11.6), rosmanol (34), carnosol (22), and CA (177). An acetone extract contained as major constituents RA, carnosol, carnosic acid (CA), methyl carnosate, and 12-methyl CA.15 A water extract has been reported to contain 1,8-cineole, camphor, borneol, and 2-carene as major ingredients.16 A methanolic extract consisted of carnosol and CA as major diterpenes, hesperidin and genkwanin as major flavonoids, and RA and gallic acids as major phenolic acids.17 The variety of extract compositions reported underscores the need to characterize the phytochemical profile of rosemary samples used in preclinical and clinical studies in order to better compare studies and to more fully determine the role of bioactive constituents contributing to a biological action.
Rosemary and other spices in the Lamiaceae family are well-known sources of diverse natural antioxidants.18,19 Several extracts of rosemary have been prepared for commercial use as food flavorings and antioxidant preservatives. The European Food Safety Authority (EFSA) has published detailed comparative profiles of these extracts.20 The principal antioxidant components of these extracts and the most widely studied of rosemary constituents are the phenolic diterpenes CA21 and its main breakdown product carnosol and the caffeoyl derivative RA (Figure 2).1,22–28 Seasonal variations, storage conditions, drying processes, and extraction procedures can substantially impact the balance of rosemary bioactive chemicals in a final product. Choice of solvent, culture medium, temperature of biological experiments, and exposure to light will modify effective concentrations of active rosemary constituents in studies of its health benefits.3,29–32
FIGURE 2: Chemical structures of several major rosemary constituents.
Unfortunately, the systematic characterization of major rosemary constituents’ bioavailability in animals and humans is incomplete. The oral bioavailability of rosemary bioactive constituents can affect systemic exposure and biological outcomes and is an important factor in determining their potential health effects.
In humans, it was reported that, following acute oral dosing with an extract of Perilla frutescens leaves containing 200 mg RA, a plasma RA concentration of 1.15 μM was achieved.33 A placebo-controlled trial was conducted with 11 healthy individuals receiving 100, 250, or 500 mg RA administered in an extract of Melissa officinalis.34 Participants were evaluated in both fasting and fed states. Maximum serum concentration of RA for those fasting and given 250 and 500 mg RA was 72.2 and 162.2 nmol/L, respectively. Food intake increased the exposure of RA and delayed absorption. In another study, normal subjects were fed 2.8 g/d of rosemary powder for 7 days, and blood subsequently drawn.35 Although levels of rosemary constituents were not measured in the blood, some rosemary components were sufficiently bioavailable so that, compared with controls, serum markers of inflammation were significantly suppressed. It is evident from these findings that in order to better understand the potential human health benefits of these rosemary constituents the impact of various oral doses, length of exposure, and presence of other dietary factors on the bioavailability and metabolism of CA, RA, and other prominent rosemary phytochemicals need to be more thoroughly assessed in humans. Additional bioavailability information from experimental animal studies is presented in the Appendix (Supplemental Digital Content 1, https://links.lww.com/NT/A15).
SCIENTIFIC EVIDENCE FOR SELECT POTENTIAL BENEFITS
Neurological Actions
Neuroprotective Effects
Rosemary Extracts and Essential Oil
Rosemary has been identified as a source of nutraceutical phytochemicals for potential use as neuroprotective agents.36 Compared with that for individual rosemary constituents (see Appendix, Supplemental Digital Content 1, https://links.lww.com/NT/A15), fewer studies have evaluated rosemary oil or extracts for neuroprotective actions. Some reported effects are inconsistent. For example, in an in vitro study, an undefined methanol extract protected human neuronal cells from the oxidative stress and apoptosis accompanying H2O2-induced injury.37 On the other hand, rosemary oil (2.5–10 mM) was ineffective in protecting cultures of PC12 cells from neurotoxicity induced by l-glutamate and N-methyl-4-phenylpyridinium ion.38
In a mouse model of pentylenetetrazol-induced seizures, rosemary essential oil (1.61 mL/kg, intraperitoneally) produced a small but significant increase in seizure latency and improved survival.39 This oil was analyzed to contain 45% 1,8-cineole, 14% α-pinene, and 9% borneol. In a rat model of neuronal cell death and brain damage, animals were fed diets supplemented with ground rosemary (1% and 2% wt/wt) for 6 weeks prior to dosing with CCl4.40 Feeding rosemary resulted in a significant 22% and 33% reduction in CCl4-induced tissue-type plasminogen activator levels in brain homogenates for rats fed the 1% and 2% diets, respectively, compared with controls. The authors suggested that rosemary lessened tissue-type plasminogen activator–associated extracellular proteolytic activity linked to the chemically induced brain damage.
Antinociceptive Actions
Rosemary Essential Oil
In a human randomized, crossover study (26 subjects), inhalation treatment with rosemary essential oil was evaluated for improvement of sensory ratings for several types of pain (contact heat, pressure, and ischemic pain). Compared with controls, rosemary inhalation did not affect quantitative pain sensitivity ratings, but did retrospectively reduce subjects’ global impressions of pain intensity and unpleasantness, although only marginally. The authors concluded that this aromatherapy produced a benefit not through direct analgesic effects but rather “by providing a competing pleasant sensory and affective experience that can alter retrospective pain evaluation.”41 The practical significance of this response is unclear.
Rosemary Extracts
A human open-label, 8-week observational trial investigated the pain-diminishing efficacy of a proprietary natural product formulation (Meta050) at doses varying from 440 mg (3 times per day) to 880 mg (twice per day) in 54 patients with arthritis or fibromyalgia. This Meta050 formulation was composed of iso-α acids from hops, a rosemary extract, and oleanolic acid. There was evidence that Meta050 alleviated indices of pain for arthritis patients, but not for those with fibromyalgia.42 The basis for this differential benefit was not determined. The contribution of rosemary extract individually to this effect cannot be determined. However, evaluating the separate action of rosemary in alleviating symptoms of these 2 patient groups is worth pursuing.
Cognition and Mood Benefits
It is not surprising that rosemary would have cognitive benefits in light of its ancient use for memory enhancement by Greek and Roman students prior to examinations by rubbing its oil into their temples and foreheads.43
Rosemary Essential Oil
Rosemary essential oil has been shown to elicit physiological responses and changes in mood in several human aromatherapy studies. For example, 22 healthy volunteers sniffed rosemary oil aroma for 5 minutes. Saliva subsequently was collected, and free radical–scavenging activity and the levels of the stress hormone cortisol were measured. Inhaling the rosemary aroma increased scavenging activity values and decreased cortisol levels. A significant inverse correlation was observed between scavenging values and cortisol levels at each rosemary concentration tested.44 In another investigation, a quasi-experimental design with pretest and posttest measures was used to determine the effect of rosemary essential oil inhalation on test-taking anxiety among graduate nursing students. Test-taking stress was reduced by exposure to rosemary oil sachets, and it was determined that pulse rate also decreased significantly among students compared with controls.45 In contrast, in another student study, exposure to rosemary scent prior to an anxiety-provoking task actually was associated with higher tension-anxiety scores and higher confusion-bewilderment ratings among participants, compared with controls. The authors suggested that, in this context, the magnitude of the rosemary scent may have overstimulated the subjects.46 Several additional reports evaluated the impact of rosemary aromatherapy on cognition and mood. For example, individuals exposed to rosemary aroma showed increased alertness and a decrease in frontal α power as measured by electroencephalography (EEG), a result consistent with a higher level of alertness. Participants inhaling rosemary aroma also reported being less anxious and more relaxed and were noted to perform math computations faster but without better accuracy.47 In another study using EEG monitoring, the effect of exposure to rosemary scent was measured by determining the relative left frontal EEG activation, an indication of composed mood, in contrast to that for right frontal activation. For both adults and infants as subjects, those with greater relative right frontal EEG activation at baseline (higher anxiety and depression) benefited the most from exposure to rosemary.48 In a similar manner, another investigation evaluated the effect of rosemary oil inhalation on subjective feelings and nervous system activities.49 Healthy subjects (n = 20) were administered 10% vol/vol rosemary oil using an oxygen pump connected to a respiratory mask for 20 minutes. After rosemary oil inhalation, there were significant increases in blood pressure, heart rate, and respiratory rate. Moreover, based on EEG and autonomic nervous system recordings, there was a reduction in the power of α1 and α2 waves and increased β activity in the anterior region of the brain. The oil consisted of 19.4% α-pinene, 20% 1,8-cineole, and 21.3% camphor. These results suggest that stimulatory effects occur following rosemary oil inhalation. The olfactory property of rosemary essential oil on cognitive performance and mood was also evaluated in 48 participants performing a computerized cognitive assessment battery. Rosemary produced a significant improvement in memory performance, compared with controls, although there was decreased memory speed. Rosemary also was reported to enhance alertness and contentment in those participating.50 A mechanism for this rosemary-associated memory benefit was not determined. In a more recent report, 23 students participated in a study to investigate the relationship between ambient odor and memory. It was found that rosemary was effective as a memory cue in retrieval of information. However, its benefit may not have been due to any specific component but to a nonspecific cue related to its perception as unpleasant and distinctive.51
Lastly, a benefit of aromatherapy was tested in 28 elderly patients with dementia. A crossover method was used to measure the effect of exposure to several essential oils. Odors of oil-impregnated gauze diffused with an electric fan were evaluated for effects on multiple functional assessment tests for Alzheimer disease and dementia. In 1 protocol, patients were exposed for 28 days to lemon and rosemary oils for 3 hours in the morning and to lavender and orange oils for 1.5 hours in the evening. This aromatherapy regimen significantly improved cognitive function, although the magnitude of any individual contribution from rosemary oil cannot be assessed.52
Collectively considering these human inhalation studies, it would be helpful for future studies not only to better quantitate doses of oil inhaled, but also to measure internal levels of absorbed rosemary oil chemical constituents that could be used as markers of exposure among subjects. For example, blood levels of myrcene, 1,8-cineole, or α-pinene might be considered for this purpose.
Rosemary Extracts
One short-term clinical study (randomized, placebo-controlled, double-blind, repeated-measures, crossover study design) evaluated the effect of powdered rosemary-containing tomato juice on cognitive function in an elderly population.53 This rosemary sample consisted of the volatile oil constituents 1,8-cineole (0.57%) and borneol (0.14%) and α-pinene (0.13%), as well as the nonvolatile components RA (1.5%), CA (1.7%), and ursolic acid (2.9%). Tomato juices containing 4 rosemary doses (750–6000 mg) were given acutely to 27 older adults 1 to 6 hours prior to testing with the Cognitive Drug Research computerized assessment system. Doses were counterbalanced, and there was a 7-day washout between visits. A significant biphasic effect on speed of memory was apparent, with the 750-mg dose yielding a beneficial response and the 6000-mg dose a detrimental effect. A similar biphasic effect was noted for self-reported alertness, compared with controls. Two measures were not affected by treatment (power of attention and quality of episodic memory), whereas 2 other measures (continuity of attention and quality of working memory) were impaired by rosemary treatment, although for these latter 2 measures dose-specific effects were not evident.53 The authors noted that the dose nearest to culinary consumption (750 mg) benefited speed of memory, which indicates that longer-term studies measuring cognitive functions would be very worthwhile to conduct. In contrast, capsules containing a total of 6.8 g rosemary were ingested by young adults (n = 40) 1 hour prior to administration of cognitive, motivation, and mood tests.54 The rosemary sample was analyzed to contain 20 mg RA/g. It was determined that rosemary did not induce consistent short-term improvements in attention, cognitive motivation, or feelings of mental energy or fatigue in these young adults with low energy. Additional neurological actions of rosemary and its constituents are detailed in the Appendix (Supplemental Digital Content 1, https://links.lww.com/NT/A15).
Anti-inflammatory Actions
Rosemary Powder
Rosmarinus officinalis L (crushed and encapsulated) was given orally (2.8 g/d) to 12 subjects for 7 days.35 Human serum isolated from these subjects was added ex vivo to cultures of oxidized low density lipoprotein (oxLDL)-stimulated THP-1 human monocytes. Serum from those fed rosemary showed significantly lower expression of inflammatory markers interleukin 6 (IL-6) and tumor necrosis factor α, compared with controls. These findings suggest that the rosemary constituents were sufficiently bioavailable so that subjects’ serum samples had a significant impact on THP-1 inflammatory markers. No adverse effects were noted.
Rosemary Essential Oil
Several studies have shown anti-inflammatory effects of rosemary essential oil. Compared with controls, oral treatment of rats with the oil (250–750 mg/kg [unless otherwise indicated, mg/kg refers to mg sample/kg body weight]) 30 minutes prior to injection of paws with carrageenan significantly inhibited paw edema at a rate similar to that of the drug indomethacin given at a dose of 5 mg/kg. In contrast to indomethacin, which inhibited only edema, the essential oil (500 mg/kg) also reduced the volume of pleural inflammatory exudate and suppressed the number of migrated cells.55 This oil’s major constituents were 25% myrcene, 20% 1,8-cineole, and an unidentified terpene (20%). In a study using essential oil containing α-pinene (17%), 1,8-cineole (16%), camphor (28%), and β-myrcene (10%), an in vivo leukocyte migration assay was used to evaluate the anti-inflammatory effects of the essential oil.56 This oil was administered to mice (125–500 mg/kg, orally) prior to carrageenan injection into the scrotal chamber. For those given the oil, there was a significant reduction in the number of leukocytes that rolled, adhered, and migrated to the scrotal endothelium, compared with controls. In addition, cultures of leukocytes were obtained from the carrageenan-treated mice and were exposed in vitro to the essential oil (10−4 to 10−2 μL/mL). The oil caused a significant reduction of leukocyte migration toward a casein stimuli, compared with controls. The authors suggested that rosemary essential oil’s anti-inflammatory action is due to its inhibition of leukocyte chemotaxis and leukocyte-endothelial cell interactions in the microcirculatory network. In another mouse study, a mixture of rosemary volatile constituents (43% 1,8-cineole, 41% camphor, 14% limonene, 2.5% borneol, 0.5% α-pinene) was administered intratracheally (4.6 μg) to mice 3 hours before intratracheal instillation of 500 μg of suspended diesel exhaust particles.57 Compared with particle-treated controls, after 24 hours, the oil extract significantly inhibited particle-induced lung inflammation and suppressed the expression of macrophage inflammatory protein 1α, macrophage chemoattractant protein 1, and keratinocyte chemoattractant. Interleukin 1β expression was not suppressed. Moreover, the beneficial effect of the rosemary oil–derived mixture appeared not to be mediated by suppression of 8-hydroxyguanosine- and nitrotyrosine-mediated oxidative stress. In a second study,58 using this oil mixture, mice were treated with 1 μg of house dust mites by intratracheal cannula 4 times weekly. The rosemary oil preparation at 2 doses (9.6 and 46 μg/mouse) was administered 7 times weekly for 6 weeks. Treatment of mice with this oil preparation inhibited house dust mite–induced pulmonary eosinophilic inflammation and IL-13 expression, a critical mediator of airway inflammation. In light of these findings, the authors suggested that this extract could be considered for supportive therapies of airway diseases such as asthma.
Extracts of Rosemary
Limited human data are available regarding use of rosemary extract. A proprietary formulation containing reduced iso-α acids from hops, a rosemary extract, and oleanolic acid was given (1320-1760 mg/d) to patients (open-label, observational 8-week study) with rheumatic disease. A trend toward decreasing levels of C-reactive protein in blood was observed for those subjects initially presenting with elevated C-reactive protein.42 The individual contribution of rosemary cannot be determined. In another study of 56 osteoarthritis patients, a similar phytochemical combination, when given orally for 4 weeks (600 mg/d), decreased reports of disease symptoms in patients with osteoarthritis.59 A randomized double-blind study of 62 individuals with medically diagnosed knee osteoarthritis was conducted to evaluate the effects of a high RA spearmint tea.60 For 16 weeks, participants in the treatment group consumed 2 cups of tea/d, which contained 130 to 150 mg RA/cup, and controls consumed 13 mg RA/cup of tea. Pain scores significantly decreased for the high-RA group, compared with controls, and there was improvement in physical function as measured in the 6-minute walk test.
Individual Constituents
Rosmarinic Acid
In a human study of subjects with mild atopic dermatitis, topical application of RA (0.3% cream emulsion) twice a day for 8 weeks to elbow flexures significantly reduced erythema and transepidermal water loss on the antecubital fossa, compared with cream controls.61 Treated subjects also self-reported noticeable improvements in dryness and pruritus. A randomized, double-blind, age-matched, placebo-controlled clinical trial was conducted with patients with seasonal allergic rhinoconjunctivitis who were treated orally with RA (50 mg/d or 200 mg/d) for 21 days.62 Based on patients’ daily records, compared with controls, those treated with 50 mg RA exhibited significantly improved symptoms for itchy nose, watery eyes, and itchy eyes. Rosmarinic acid also significantly reduced the numbers of neutrophils and eosinophils in nasal lavage fluid. Neither adverse events nor significant abnormalities in blood tests were detected. These results were similar to those reported by the same authors when patients with seasonal allergic rhinoconjunctivitis were treated orally with an extract of P frutescens enriched for RA (50 or 200 mg RA) daily for 21 days.63
1,8-Cineole
In a recent double-blind, placebo-controlled study, 242 patients with chronic obstructive pulmonary disease were randomly assigned to receive 200 mg 1,8-cineole or placebo, orally 3 times per day for 6 months.64 Compared with controls, those treated with 1,8-cineole showed a significant drop in frequency, severity, and duration of respiratory problems, and, secondarily, lung function and quality of life were significantly improved. Adverse events were comparable in both groups. In another double-blind, placebo-controlled trial, 32 patients with steroid-dependent bronchial asthma were randomly allocated to take small capsules containing 200 mg 1,8-cineole 3 times a day or placebo for 12 weeks.65 For those receiving 1,8-cineole, there was a significant reduction in oral steroid doses needed to maintain clinical stability. No serious adverse events were reported. Two earlier studies by the same researchers suggested that the effects of 1,8-cineole may be mediated by suppression of cytokine production and arachidonic acid metabolism.66,67 The appendix contains more findings on anti-inflammatory actions of rosemary68 (see Appendix, Supplemental Digital Content 1, https://links.lww.com/NT/A15).
Alleviation of Metabolic Disorders (Obesity and Diabetes)
Rosemary Extracts
Several studies show consistent effects of rosemary extracts on signs of diabetes and the metabolic syndrome. In normoglycemic mice provided a water extract of rosemary (10 g/L) in place of tap water, plasma glucose levels decreased a significant 12% after 3 months, compared with controls. For alloxan-treated hyperglycemic mice consuming the same water extract for 1 month, plasma glucose levels significantly decreased by 45%.69 No toxic effects during chronic application were noted, and no mechanisms for this hypoglycemic effect were identified. Two experiments with rosemary were reported for normal and alloxan-induced rabbits. An undefined ethanol extract of rosemary administered orally to fasting normal rabbits (100–200 mg/kg) produced a significant drop in blood glucose levels of up to 21% within 6 hours, without changing insulin levels. In alloxan-treated rabbits, dosing with this extract (100–200 mg/kg, orally) for 8 days produced a significant decrease in blood glucose and an increase in serum insulin levels, compared with controls, an effect determined in part to be due to the extract’s potent antioxidant activity.70 The authors speculated that the elevation of circulating insulin levels in the rosemary-treated alloxan-diabetic rabbits could be due to components that either protect functional β cells from additional damage or stimulate regeneration of β cells. These possibilities need to be further examined. A recent study found that combining treatment of streptozotocin-induced diabetic rats with an aqueous extract of rosemary (200 mg/kg per day, intragastrically) with a regimen of endurance exercise for 8 weeks resulted in lowered blood indices of oxidative stress by enhancing antioxidant enzyme activates and decreasing lipid peroxidation levels approaching normal levels seen in healthy controls.71 In 2 rodent experiments, a rosemary extract rich in CA was evaluated. Mice were provided for 16 weeks a high-fat diet supplemented (500-mg/kg diet) with a rosemary extract standardized to 20% CA. Diet supplementation with the extract decreased fasting blood glucose and plasma cholesterol levels, compared with controls.72 Moreover, body and epididymal fat weights for mice fed the rosemary supplemented high-fat diets were less than those for mice fed the control high-fat diet. The authors suggested that this effect may partly be associated with activation of peroxisome proliferator-activated receptor γ. In a second investigation, an ethanol extract of rosemary containing 39% CA, 6.5% carnosol, and 6.9% methyl carnosate was added to diets (0.5% wt/wt) of lean and obese Zucker rats for 64 days.73 Compared with controls, the rosemary-supplemented diet moderated the weight gain of both groups of rats without affecting food intake. Moreover, primarily in the lean rats, the plasma lipid profile was improved. This diet significantly inhibited gastric lipase and thus was hypothesized to reduce fat absorption. Of note is that animals consuming rosemary extract exhibited increased liver weights and enzymatic activities, a response to rosemary extract reported by others.74,75 The authors suggested that long-term consumption of rosemary extracts rich in CA may be beneficial for weight maintenance and normalization of lipid profiles. However, the consequences of increased liver weight and liver enzyme induction would need to be better characterized. This report led to a subsequent opinion article suggesting that CA should be considered for the treatment of nonalcoholic liver disease or the metabolic syndrome.76 Of additional interest, an ethanol extract of rosemary (39% CA, 7% carnosol) was supplemented to diets (0.5% wt/wt) for 64 days to both lean and obese Zucker rats.77 Compared with controls, feeding of the extract to lean rats led to an increase in circulating adiponectin in contrast to that seen for obese rats in which feeding of the extract resulted in decreased circulating adiponectin. In lean rats, consumption of the rosemary extract led to a significant decrease in circulating IL-1β and tumor necrosis factor α, compared with controls, in contrast to that for obese rats in which no changes were noted. Activated AMP-activated protein kinase in perivisceral adipose tissue of rosemary fed rats was significantly decrease in obese rats, whereas no effect of dietary supplementation was seen for lean rats. Based on the observation that AMP-activated protein kinase may mediate the metabolic effects of leptin and adiponectin, the authors speculated that a functioning leptin signaling pathway is required for the rosemary extract to exert metabolic regulatory effects on obese Zucker rats. A recent study using cultures of human primary omental preadipocytes and adipocytes found exposure to rosemary extract modulated adipocyte differentiation and interfered with adipogenesis and lipid metabolism.78 In a similar feeding study by the same authors,79 dietary supplementation with rosemary extract decreased cecal Lactobacillus/Leuconostoc/Pediococcus groups and increased Blautia coccoides and Bacteroides/Prevotella groups, compared with controls, for both lean and obese Zucker rats. The metabolic consequences of these microbial population changes in the gut are not clear. Furthermore, extract supplementation increased short-chain fatty acid excretion in the feces of obese rats but decreased excretion in lean rats, compared with their controls, which, according to the authors likely reflects differential uptake and metabolism of short-chain fatty acid between the lean and obese animals. In another study,80 mice were fed for 50 days an ethanol extract of rosemary that was added to high-fat diets at 0.025% wt/wt (20 mg/kg body weight) and 0.25% wt/wt (200 mg/kg body weight). This extract contained 5.6% carnosol, 2.5%, CA, and 4% RA. The animals fed the higher dose of rosemary extract gained less weight and had a 57% reduction in fat mass accrual, compared with controls, effects coinciding with increased fecal lipid excretion and lower pancreatic lipase activity. Hepatic triglyceride levels were decreased by 39% in the rosemary-treated mice. In contrast to other reports, rosemary supplementation had no significant effect on the intraperitoneal glucose tolerance test and fasting insulin levels in this study. The authors suggested that rosemary extract may have potential use in strategies to limit weight gain and liver disease associated with obesity. In another study, a rosemary extract enriched for CA was given to C57BL/6J mice as part of either a high-fat diet or a high-fat diet supplemented with either 0.14% or 0.28% (wt/wt) CA-enriched extract for 16 weeks.81 Supplementation of diets with rosemary extract significantly reduced body weight gain, percent body fat composition, plasma transaminases, glucose and insulin levels, and liver triglycerides, compared with the high-fat controls. Moreover, in similar comparisons among groups, liver peroxidation and lipid accumulation were decreased for the mice fed the rosemary supplemented diets, and fecal lipid excretion was elevated, compared with controls. The authors concluded that the CA-enriched rosemary extract dose-dependently suppressed obesity and metabolic syndrome induced by a high-fat diet in mice. These results are similar to those reported Park and Sung82 in these mice. A recent review highlighted the potential benefits of rosemary in preventing obesity and the metabolic syndrome.83
The effect of a natural product mixture containing 0.02% rosemary extract on urine metabolite profiles of diabetic humans was reported.84,85 Although some treatment-related effects were observed, interpretation of the urine patterns was not entirely straightforward, and further exploration of these profiles and the metabolic changes they reflect is needed. The authors subsequently provided a detailed strategy for obtaining urine fingerprints from metabolomics data.86 In another trial, a high antioxidant spice blend in which rosemary was 1 of 9 spices attenuated postprandial insulin and triglyceride responses when fed to overweight men (randomized controlled, 2-period crossover study). The individual contribution of rosemary to this benefit, however, cannot be determined but deserves further study.87 Additional reports about effects of rosemary on metabolic disorders are described in the Appendix (Supplemental Digital Content 1, https://links.lww.com/NT/A15).
CONCLUSIONS
Several actions of rosemary are evident that warrant further confirmation. First, neurological benefits do occur when rosemary extracts and individual constituents are administered orally in animal models. Oral administration of RA and CA in animal models is associated with neuroprotective effects and actions in the brain. Oral dosing with rosemary oil and rosemary extracts in several animal models of pain leads to antinociceptive responses, although it is unclear which individual constituents contribute to these actions. Aromatherapy with rosemary oil in humans is associated with changes in mood and physiological measures of anxiety and alertness. Oral RA improved cognitive performance in animal models, whereas oral rosemary oil and rosemary extract produced antidepressant-like activities in several in vivo models. Multiple constituents of rosemary likely contributed to these latter effects, although oral RA elicited antidepressant-like responses when given alone. Individual rosemary phytochemicals do not always exhibit similar responses when different neurological end points are measured. For example, RA may be active in an amyotrophic lateral sclerosis (ALS) transgenic mouse, but have no effect in a rodent pain model. This suggests that, although identifying specific rosemary phytochemicals that are biologically active is important for mechanistic characterizations, the mix of constituents in rosemary is likely to have a broader impact on health end points than 1 component alone. Moreover, examining rosemary’s effects on neurological end points at lower doses approximating dietary exposures in humans would certainly be worthwhile. Comparisons of findings between animal studies are often difficult not only because of dosing and sample identity disparities, but also because recognized markers of rosemary bioavailability are not reported. Future rosemary feeding studies in animals evaluating neurological benefits need to identify and measure chemical profiles in the blood and brain associated with rosemary exposure and bioavailability. For example, 1,8-cineole could be measured when essential oils are administered, or, similarly, total CA and CA-glucuronides could be measured when water or alcohol extracts of rosemary are used.
Reports of rosemary’s anti-inflammatory actions, particularly following oral exposure in animals, provide emerging evidence that rosemary essential oil, rosemary extracts, and individual constituents can improve diverse respiratory, vascular, and dermatological conditions. Rosmarinic acid and 1,8-cineole in particular have demonstrated potential benefits in human studies evaluating skin and respiratory responses, respectively.
Evaluation of different rosemary samples provided mixed evidence of efficacy in improving symptoms of metabolic disorders. For example, oral rosemary oil elicited inconsistent effects on blood glucose levels in several animal models. In contrast, water and alcohol extracts of rosemary provided orally to normal and diabetic animals resulted in hypoglycemic responses, improved blood lipid profiles, and lower weight gains. Oral CA in particular was associated with hypoglycemic and antiadipogenic responses. Besides further confirmation of the extracts’ effects on these end points and identification of the active constituents, an assessment of rosemary’s effects on satiety, energy balance, and body weight regulation also would be worthwhile, especially when provided at levels consistent with amounts typically consumed by humans.
SAFETY
Rosemary consumed in usual culinary contexts or as an approved food additive is considered generally recognized as safe by the US Food and Drug Administration.9,20 Rosemary essential oil has been recognized by the US Food and Drug Administration as generally recognized as safe for its intended use as a food additive. Rosemary extracts have been used for more than 20 years by the food industry as a flavoring and preservative. Also, in 2010, the European Commission classified rosemary extracts as food additives to be produced by specific extraction processes with defined standards of purity. Japan and China also list rosemary extracts as approved food additives.20,21 Both acute and subchronic toxicity studies for rosemary extracts and select individual phytochemicals have been published.20,73,88,89 Of particular relevance is a summary of toxicology tests in rodents that was provided by the EFSA in which several types of rosemary extracts were evaluated at multiple doses.20 As summarized in this report, subchronic studies at the highest doses of rosemary extract tested (320 mg/kg body weight per day or 5000-mg/kg diet) showed that the only adverse effect was a slight increase in relative liver weights, which was reversible and assessed not to be of toxicological concern. Based on these studies, the EFSA determined that the NOAEL (no-observed-adverse-effects level) for intake of these rosemary extracts is 180 to 400 mg extract/kg body weight per day, which was estimated to correlate to approximately 20 to 60 mg total CA and carnosol/kg body weight per day. For purposes of comparison, it has been estimated that adult dietary exposure in the United Kingdom to total rosemary-derived CA and carnosol present in approved food additives is likely to be approximately 0.04 mg/kg body weight per day.20 This estimate did not include background culinary use, which was considered not to be regular or chronic. Consumption data for culinary use of rosemary are not available, although dried rosemary use in cooking in the United Kingdom is estimated to be 0.4 to 2.5 g/serving, which would translate for a 60-kg person to 5 to 40 mg rosemary/kg body weight or 0.1 to 0.8 mg/kg body weight of carnosol plus CA.20 These values can be used in considering amounts of rosemary to use in human studies. Based on these toxicity data and on the estimated large margins of safety, the EFSA considered that the expected dietary exposure to rosemary used as an additive does not pose a safety concern.
In animal studies discussed in this overview, the oral dosing protocols used for many of the experiments often approached the NOAEL determined by the EFSA. For example, in some cases, extracts of rosemary were administered orally at levels up to 200 to 300 mg/kg and CA doses up to 20 mg/kg. On the other hand, there were studies that found biological activity at less than or equal to 100 mg/kg rosemary extract orally and less than or equal to 10 mg/kg CA orally or when CA was supplemented to diets at less than or equal to 0.05% wt/wt. These latter studies suggest that measurable biological effects of rosemary or its individual constituents could likely occur at more modest levels of oral intake with less expectation of adverse consequences. Unfortunately, extrapolation of these animal findings to humans is not straightforward. Based on 1 suggested methodology, an approximation of human equivalent doses of rosemary using reported animal doses could be estimated through normalization to body surface area.90 Other guidance for determining human dosing strategies could come from the EFSA and from human studies35,53 in which rosemary powder was given to humans at acute doses of 0.75 to 6.0 g without apparent adverse effects.
Despite EFSA’s conclusions about the safety of rosemary, others have cautioned against the use of higher intakes of individual phytochemicals such as CA for weight loss strategies, because there is evidence that CA and other constituents in rosemary extracts can alter activities of cytochrome P450 enzymes, such as CYP3A4 and CYP2B6, and thus have the potential to affect the metabolism of their substrates.74,75,91–95
SUMMARY
Rosmarinus officinalis contains a cocktail of biologically active phytochemicals with diverse health benefits that have only begun to be elucidated. An emerging body of literature supports rosemary as having the potential to improve neurological deficits, inflammatory conditions, and some complications associated with obesity and diabetes. Animal and well-controlled human studies are needed to characterize dose-response relationships for those biological actions that follow dietary administration of rosemary samples at culinary-relevant levels. Specific phytochemicals responsible for any benefits need to be identified along with mechanisms of action and possible toxicities in vivo. In animal models of disease, interactions of dietary rosemary with drug efficacies should be clarified. The composition of rosemary samples used for in vivo investigations must be provided in more detail, and quantitation of blood and tissue markers of rosemary bioavailability would aid in comparisons among experiments.
It also would be valuable to determine whether dietary intake of culinary-relevant levels of rosemary leads to biologically relevant circulating levels of the major rosemary bioactive constituents and whether other dietary factors influence this bioavailability. Such progress in understanding rosemary’s biological activities and in defining dietary rosemary’s health benefits is possible, because preclinical disease models and clinical capabilities to monitor established biomarkers are available.
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