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Sage

Scientific Name(s): Salvia officinalis L.
Common Name(s): Broadleaf sage, Common sage, Culinary sage, Dalmatian sage, Garden sage, Golden sage, Kitchen sage, Meadow sage, Sage, True sage

Clinical Overview

Use

Sage has been used in traditional medicine for its antimicrobial, antidiabetic, and antioxidant effects. It has been investigated for its potential in treating cognitive impairment and Alzheimer disease, vasomotor symptoms, cancer, inflammation, and hyperlipidemia. However, no quality clinical trials are available to support these uses.

Dosing

Doses of 300 and 600 mg of dried sage leaf have been investigated in mood and cognitive performance studies. A standardized S. officinalis ethanolic extract at a dose of 333 mg was used in a study evaluating its effects on memory and attention in healthy older volunteers. A typical dosage has been described as 4 to 6 g/day of the sage leaf.

Contraindications

Contraindications have not been identified.

Pregnancy/Lactation

S. officinalis is generally recognized as safe (GRAS) by the US Food and Drug Administration (FDA). Information regarding safety and efficacy in pregnancy and lactation is lacking. One study in pregnant Palestinian women found infrequent use of herbs, including sage, during pregnancy to be safe. Animal data suggest potential lactiferous effects. Until further information is available, sage should not be routinely recommended during pregnancy and lactation.

Interactions

None well documented.

Adverse Reactions

In 2 clinical trials of healthy volunteers, no clinically significant adverse reactions were reported; however, in a study in patients with Alzheimer disease, adverse effects were similar to those reported with cholinesterase inhibitors. Cheilitis, stomatitis, dry mouth, and local irritation have been reported. Seizures have been reported in children, and contact dermatitis resulting from a topical preparation is noted in the literature.

Toxicology

No data.

Botany

Approximately 900 species and many varieties belong to the sage genus Salvia, including Salvia hispanica L. and Salvia miltiorrhiza. S. officinalis is a small, evergreen, perennial plant that is native to the Mediterranean region but grows throughout much of the world. The plant can grow up to 1 m in height and has grayish leaves, short woody stems that branch extensively, and violet-blue flowers that bloom from June through September. S. officinalis should not be confused with red sage or desert brush sage, which are unrelated.Blumenthal 2000, Chevalier 1996, Leung 1980, Modabbernia 2013, Salvia 2009

History

The name Salvia derives from the Latin "salvere," meaning "to cure." Traditionally, sage and its oil have been used to treat a wide range of conditions. Ethanolic tinctures and decoctions have been used to treat inflammation of the oral cavity and GI tract, and sage has also been used as a tonic and antispasmodic.

Use of sage as a cognitive enhancer and treatment for cognitive decline dates back to the ancient Greeks.Kennedy 2011

The plant has been used topically as an antiseptic and astringent, as well as to manage excessive sweating. Sage tea has been ingested for the treatment of dysmenorrhea, diarrhea, gastritis, tonsillitis, and sore throat. The dried leaves have been smoked to treat asthma.

Dried sage leaf is used as a culinary spice and as a source of sage oil, which is obtained via steam distillation. Sage oil is used as a fragrance in soaps and perfumes. Sage is used as a food flavoring, and its aroma is said to suppress the odor of fish. Sage oleoresin is also widely used in the culinary industry.Chevalier 1996, Duke 1985, Leung 1980

Chemistry

Twenty-eight components have been identified from S. officinalis, with the primary components being 1,8-cineole, camphor, alpha-thujone, beta-thujone, borneol, and viridiflorol.Hamidpour 2014

Monoterpenes have been identified using gas chromatography and other techniques; alpha- and beta-thujones account for about one-half of the oil's composition.Bozin 2007, Loizzo 2008, Raal 2007 Capillary electrophoresis has been used to identify the polyphenols,Ben Hameda 2006, Fecka 2007 while high performance liquid chromatography and nuclear magnetic resonance techniques have been applied to cold water extracts to identify polysaccharides.Capek 2004, Capek 2008

Salvia lavandulaefolia (Spanish sage) and S. officinalis have similar compositions; however, S. officinalis has a much higher concentration of thujone, which is toxic in large doses.Kennedy 2006 S. lavandulaefolia also contains variable amounts of camphor, cineol, limonene, camphene, and pinene. Sage oil is often adulterated by the addition of thujone derived from the leaves of Juniperus virginiana (red cedar).Leung 1980, Raal 2007, Savelev 2003, Tildesley 2003

Uses and Pharmacology

Anti-inflammatory effects

Animal/In vitro data

Proinflammatory cytokines were suppressed in in vitro experiments with human leukocytes,Poeckel 2008 as well as in induced colitis in mice.Perry 2003 No histological changes were apparent.Juhás 2008 Chloroform extracts of S. officinalis leaves, in particular ursolic acid, have shown strong anti-inflammatory properties after topical application. In one study, ursolic acid exhibited dose-dependent inhibition of croton oil-induced ear edema in mice; the anti-inflammatory effect of ursolic acid was 2-fold more potent than that of indomethacin.Baricevic 2001, Imanshahidi 2006 In another study, a hydroalcoholic extract of S. officinalis exerted anti-inflammatory and antinociceptive effects on chemical behavioral models of nociception in mice.Rodrigues 2012

Antimicrobial/Antifungal activity

Animal/In vitro data

Numerous in vitro studies investigating sage's antimicrobial effects have been conducted, using various formulations and components. In general, a wide antimicrobial spectrum has been suggested.Bozin 2007, Hayouni el 2008, Khedher 2017, Kozlowska 2015, Pozzatti 2008, Snowden 2014, Sokovic 2010, Weckesser 2007 Interest centers on activity against vancomycin-resistant enterococci,Horiuchi 2007 herpes simplex and corona viruses,Loizzo 2008, Schnitzler 2008 and HIV.Bailly 2005, Geuenich 2008 However, data from one study suggest that sage did not exert significant antimicrobial activity against Escherichia coli, Klebsiella oxytoca, or Klebsiella pneumoniae strains.Fournomiti 2015

The antifungal effects of S. officinalis have also been studied, with mixed results. In some studies, S. officinalis exerted effects against strains of Candida albicans.Cutillas 2017, Sookto 2013 One study showed the essential oil of S. officinalis to be effective against Colletotrichum acutatum and Botrytis cinerea.Elshafie 2016 In another study, sage did not demonstrate antifungal activity against Candida glabrata strains.Soares 2015

Antileishmanial effects of sage have been demonstrated. A methanolic extract of S. officinalis leaves was associated with antileishmanial effects against Lesihmania major. Specifically, it significantly reduced the number of amastigotes in macrophages compared with the control group (P<0.001).Nikmehr 2014 In another study, a hydroalcoholic extract of S. officinalis was associated with total inhibition of L. major growth.Serakta 2013

Clinical data

In a study of 70 girls aged 11 to 14 years, sage mouthwash used twice daily for 21 days was associated with a significantly reduced colony count of Streptococcus mutans in dental plaque (P=0.001).Behesthti-Rouy 2015

Antioxidant activity

The antioxidant effects of sage are believed to be attributable to rosmarinic acid and carnosic acid, which are polyphenolic components of sage.Hamidpour 2014

Animal/In vitro data

Aqueous extracts of sage, sage tea, essential oils of S. officinalis, and volatile and phenolic sage compounds have been used in experiments demonstrating the antioxidant potential of sage and other related species. Oxygen radical absorbance capacity assay and electron spin resonance techniques have been used in assay and in vitro experiments. In vivo markers, such as glutathione levels, have been used in rats. Inhibition of lipid peroxidation and increased food oil stability have been demonstrated, but clinical application data are lacking.Aherne 2007, Bozin 2007, Capek 2009, Celik 2008, Cutillas 2017, Lima 2004, Lima 2005, Lima 2007, Oboh 2009, Orhan 2009, Poeckel 2008 In a study of rats receiving sage in their drinking water, sage was associated with increased resistance in liver cells against oxidative stress.Horvathova 2016

Clinical data

In a small study of 6 healthy female volunteers, consumption of 300 mL of a sage tea twice daily for 4 weeks was associated with an increase in lymphocyte Hsp70 expression as well as in erythrocyte superoxide dismutase and catalase activity, indicating potential beneficial antioxidant effects for patients with diabetes.Sa 2009

Anxiolytic effects

Clinical data

In a study of 30 healthy volunteers, an acute anxiolytic effect (lasting up to 20 minutes) was noted following administration of 300 mg of sage.Kennedy 2006, Sarris 2013

Bronchodilatory/Respiratory effects

Animal data

In a study of rats, an aqueous methanolic extract of S. officinalis inhibited carbachol-induced bronchospasms in a dose-dependent manner. The bronchodilatory effects were mediated through the activation of voltage-dependent potassium channels as well as through phosphodiesterase inhibition.Gilani 2015

Cognitive effects

S. officinalis has been associated with inhibition of acetylcholinesterase, and rosmarinic acid has been shown to exert neuroprotective, antioxidant, and antiapoptotic effects against amyloid beta fibrils, mechanisms of action suggesting potential benefit for use in Alzheimer disease.Hamidpour 2014

Animal/In vitro data

Improved memory retention has been demonstrated in animal studies.Eidi 2006 In vitro data demonstrate the ability of S. officinalis essential oils to inhibit acetylcholinesterase activity.Cutillas 2017, Lopresti 2017, Modabbernia 2013 In a review of studies evaluating effects of widely used herbal medicines on mental health, S. officinalis was associated with improvements in mood and cognition as well as with protective effects against cellular damage.Modabbernia 2013 In a model of rats, S. officinalis 600 mg/kg and 800 mg/kg doses reversed learning and memory deficits associated with diabetes in a group with streptozocin-induced diabetes, and also improved cognition in nondiabetic rats.Hasanein 2016

Clinical data

In one study, mood and cognitive performance were improved in young healthy volunteers given 300 and 600 mg of dried S. officinalis leaf.Kennedy 2006 In another study in older healthy volunteers (mean age, 72.95 years), ethanolic leaf extract increased memory and attention at lower doses (333 mg extract), but had no effect at higher doses.Scholey 2008

Limited studies have evaluated the efficacy of sage extracts in Alzheimer disease.Akhondzadeh 2003, Akhondzadeh 2006, Kennedy 2006 While results are promising, some methodological issues remain, and larger, long-term trials are needed to determine a definitive role for sage in the management of Alzheimer disease.Kennedy 2006 Similar results were demonstrated in studies using other Salvia species, including S. lavandulaefolia and Salvia miltiorrhiza, as well as rosmarinic acid alone.Imanshahidi 2006, Kennedy 2006, Orhan 2009, Pereira 2005, Perry 2003, Tildesley 2003, Tildesley 2005 The latter was associated with delaying the formation and aggregation of amyloid beta fibrils, a mechanism of action that suggests a potential role in Alzheimer disease.Wu 2011

A systematic review of the literature concluded that both S. officinalis and S. lavandulaefolia were associated with improvements in cognitive performance in healthy patients as well as in those with dementia or cognitive impairment.Miroddi 2014 In a trial of patients with mild to moderate Alzheimer disease, adverse reactions were similar to those reported with cholinesterase inhibitors.Akhondzadeh 2006

Cytotoxic effects

Cytotoxic and antiangiogenic effects have been reported with S. officinalis.Hamidpour 2014

Animal/In vitro data

In bacterial studies, sage essential oil and its monoterpenes were effective in protecting against ultraviolet-induced mutations.Vukovic-Gacic 2006

An ethanolic extract of S. officinalis exerted antiangiogenic effects on cultures of rat aorta and human umbilical vein endothelial cells. A dose-dependent inhibition of endothelial cell proliferation was also noted.Keshavarz 2010

In a study evaluating effects on colon cancer prevention, S. officinalis reduced the proliferation marker Ki67 as well as hydrogen peroxide-induced and azoxymethane-induced damage to colonocytes and lymphocytes. The investigators also found sage to be associated with a chemopreventive effect on colorectal cancer, as noted by a reduction in aberrant crypt foci formation.Pedro 2016

In one study, extracts of S. officinalis exerted antiproliferative effects on liver hepatocellular carcinoma (HepG2) cells in both a time- and dose-dependent manner. Investigators noted an increase in lactate dehydrogenase leakage, a decrease in cellular adenosine triphosphate, changes in the morphology of the HepG2 cells, and induction of apoptosis, suggesting potential cytotoxic effects in hepatocellular carcinoma cells.Jiang 2017

In another study, the crude ethanolic extract of S. officinalis and a few of its food formulations were associated with varying concentration- and time-dependent cytotoxic and antiproliferative effects on leukemia L1210 cells; these effects were noted within the first 24 hours of treatment.Jantova 2014

In a study evaluating cytotoxic activities of crude methanolic extracts of S. officinalis, suppressed proliferation of KG-1A (human acute myelocytic leukemia), Raji (non-Hodgkin lymphoma), and U937 (human leukemic monocyte) cell lines by more than 80% (P<0.01) was observed in a dose- and time-dependent manner. No cytotoxic effects on human umbilical vein endothelial cells were noted with S. officinalis. The investigators suggested a cytotoxic effect via an apoptosis-dependent pathway.Zare Shahneh 2013

Isorosmanol, a phenolic diterpene of S. officinalis, was found to inhibit melanin in B16 melanoma cell lines.Sallam 2016 Another diterpene, manool, selectively inhibited HeLa (human cervical adenocarcinoma) and U343 (human glioblastoma) cell lines.de Oliveira 2016

Dermatological effects

Animal and in vitro data

In a murine model, an ethanolic extract of S. officinalis improved skin lesions associated with atopic dermatitis. S. officinalis also inhibited nerve growth factor-induced neuritic outgrowth in pheochromocytoma 12 cells.Takano 2011

GI effects

There is some evidence that sage oil may exert a centrally mediated, antisecretory action; the carminative effect is likely caused by the irritating effects of the volatile oil.Blumenthal 2000

Animal and in vitro data

The crude extract of sage was associated with antidiarrheal and antispasmodic activities in an in vitro study.Hamidpour 2014 A hydroethanolic extract was protective against ethanol-induced gastric lesions in rats.Mayer 2009

Hot flushes

Sage has been traditionally and anecdotally used to treat hot flashes in menopausal women.

Animal/In vitro data

In an in vitro study, an aqueous ethanolic subextract of S. officinalis exhibited estrogenic effects, suggesting a potential mechanism of action for its effects on hot flushes.Rahte 2013

Clinical data

In an open, multicenter clinical trial, menopausal women with at least 5 hot flushes per day were given a tablet of fresh sage leaves (3,400 mg) once daily for 8 weeks. The total score for mean number of intensity-rated hot flushes decreased by 50% at 4 weeks and by 64% at 8 weeks (P<0.0001). Over 8 weeks, mean number of mild flushes decreased by 46% (P>0.05), moderate flushes decreased by 62% (P=0.0001), severe flushes decreased by 79% (P=0.0001), and very severe flushes decreased by 100% (P<0.05).Bommer 2011

In a study of prostate cancer patients experiencing hot flashes due to androgen deprivation therapy, S. officinalis 150 mg given 3 times daily for 9 to 10 weeks significantly reduced the mean weekly hot flash score (P=0.002); however, there was no impact on patient quality of life.Vandecasteele 2012

Metabolic/Glycemic effects

Sage has traditionally been used for its hypoglycemic effects, which are attributed to its flavonoids. Inhibition of alpha-glucosidase and upregulation of various mRNA levels are two mechanisms also suggested to play a role in the hypoglycemic action of S. officinalis.Moradabadi 2013 Additionally, S. officinalis has been found to activate peroxisome proliferator-activated receptor gamma, which is involved in the regulation of glucose and lipid metabolism.Hamidpour 2014

Animal/In vitro data

Animal studies have shown effects of methanol leaf extracts and sage tea on fasting plasma glucose levelsEidi 2005, Lima 2006; the essential oil had no effect on serum glucose.Eidi 2005 In a study of diabetic rats, S. officinalis methanolic extract reduced postprandial glucose in a manner similar to acarbose; these results were also shown using the oral glucose tolerance test. S. officinalis also upregulated Insulin and Glut-4 gene expression as well as inhibited alpha-glucosidase.Moradabadi 2013

Clinical data

In a study of 50 patients with type 2 diabetes with glycosylated hemoglobin (HbA1c) levels less than 8% and low-density lipoprotein (LDL) levels between 100 and 130 mg/dL despite daily treatment with atorvastatin 10 mg, glyburide 15 mg, and metformin 2,000 mg, S. officinalis 500 mg given 3 times daily for 2 months reduced fasting plasma glucose levels, 2-hour postprandial glucose levels, HbA1c, total cholesterol, triglycerides, and LDL, and increased HDL.Kianbakht 2016 In a similar study, 80 patients with type 2 diabetes who received 150 mg of S. officinalis 3 times daily for 3 months experienced a reduction in postprandial glucose levels as well as in cholesterol; however, no changes were observed in fasting plasma glucose or HbA1c levels.Behradmanesh 2013 In a small study of 6 healthy female volunteers, consumption of 300 mL of a sage tea twice daily for 4 weeks did not impact glucose levels. However, total cholesterol and LDL levels decreased, and HDL levels were improved during treatment and for 2 weeks following discontinuation.Sa 2009

Morphine tolerance/dependence

Animal data

In a study of rats, a hydroalcoholic extract of S. officinalis, given at 600 mg/kg and 800 mg/kg doses, attenuated signs of withdrawal from morphine. These findings also suggest a protective effect against tolerance when morphine is given in combination with S. officinalis.Hasanein 2015

Dosing

Doses of 300 and 600 mg of dried sage leaf have been investigated in mood and cognitive performance studies.Kennedy 2006 A standardized S. officinalis ethanolic extract at a dose of 333 mg was used in a study evaluating its effects on memory and attention in healthy older volunteers.Scholey 2008 A typical dosage has been described as 4 to 6 g/day of the sage leaf.Duke 1985

Pregnancy / Lactation

Information regarding safety and efficacy in pregnancy and lactation is lacking. One study in pregnant Palestinian women found infrequent use of herbs, including sage, to be safe.Al-Ramahi 2013 In a study of rats, sage was associated with alveologenesis of the mammary glands, which suggests potential lactiferous activity.Monsefi 2015 Until further information is known, sage should not be routinely recommended during pregnancy and lactation.

Interactions

None well documented. Interactions with cholinergic drugs, such as pilocarpine and scopolamine, are expected based on studies evaluating the effect of sage extracts on Alzheimer disease.Akhondzadeh 2006, Eidi 2006

Adverse Reactions

Cheilitis, stomatitis, dry mouth, and local irritation have been reported following ingestion of sage.Duke 1985 In 2 clinical trials of healthy volunteers, no clinically significant adverse reactions were reported; however, in a study in patients with Alzheimer disease, adverse effects were similar to those reported with cholinesterase inhibitors. Increases in blood pressure were reported in a trial evaluating S. lavandulaefolia essential oil in 2 patients with preexisting hypertension.Perry 2003

Two case reports describe the occurrence of seizures following accidental ingestion/administration to a 5-year-old and a newborn.Halicioglu 2011 The convulsant activity is believed to be due to the direct effect of S. officinalis oil on the CNS.Ghorbani 2017

Another case report describes a patient who developed contact dermatitis after use of a lip balm containing sage that was intended for treating dry lips.Mayer 2011

Toxicology

S. officinalis has GRAS status.FDA 2017 In vitro, doses of more than 200 nL/mL of the essential oil were hepatotoxic,Lima 2004 and at concentrations of 120 mcg/mL, decreased cell viability was observed.Aherne 2007 In rats, the median lethal dose (LD50) of a methanolic extract of sage leaves was calculated to be 4,000 mg/kg when injected intraperitoneally.Eidi 2006, Ghorbani 2017 The LD50 of orally administered S. officinalis oil is reported to be 2.6 g/kg.Ghorbani 2017 The constituents thujone and camphor are recognized as neurotoxic,Lima 2004 while rosmarinic acid, carnosic acid, and carnosol were not genotoxic at dosages used in experiments.Pereira 2005, Poeckel 2008

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