Garlic

Allium sativum L.

[Fam. Liliaceae]

Overview

In the United States and Western Europe, garlic is one of the most popular substances used to reduce various risks associated with cardiovascular disease. Most of garlic’s popularity is based on the extensive traditional use of this herb and on scientific research suggesting that cardiovascular benefits are associated with ingesting garlic as both a conventional food and dietary supplement (Blumenthal et al., 2000). Garlic preparations have been one of the top-selling herbal supplements on the U.S. market for many years (Brevoort, 1998), ranking third in retail sales in the mainstream market in 2000, and generating revenues over $61 million (Blumenthal, 2001). To date more than 3,000 scientific papers have been published investigating the activities of garlic and garlic compounds, including chemical, toxicological, pharmacological, clinical, and epidemiological studies (Amagase et al., 2001). Garlic preparations with uniquely different chemical compositions, including powdered dried garlic products standardized to allicin yield and aged garlic extract (AGE™) products that are standardized to S-allylcysteine (SAC), have been the subject of numerous clinical studies. Determining which forms are the most effective remains controversial and is an ongoing subject of study and debate. Medical literature includes positive outcomes in clinical studies involving several types of garlic preparations.

Description

Garlic preparations consist of the fresh or dried bulbs (main bulb and secondary bulbs or cloves) of Allium sativum L. [Fam. Lilaceae], and various dosage forms (Blumenthal et al., 1998). Garlic oil is not present in fresh or dried garlic bulbs; instead, the oil is produced by converting water-soluble thiosulfinates to oil-soluble sulfides via steam distillation. Aged garlic involves long-term extraction in dilute ethanol for up to 20 months, then drying; pickling garlic involves immersion in vinegar (5% acetic acid) (Amagase et al., 2001; Lawson, 1998a).

Primary Uses

Cardiovascular

Hyperlipidemia (Isaacsohn et al., 1998; Lash et al., 1998; McCrindle et al., 1998; Steiner et al.,1996a, 1996b; Yeh et al., 1995; De A Santos and Johns, 1995; Steiner and Lin, 1994; Jain et al., 1993; Grünwald et al., 1992; Holzgartner et al., 1992; Mader, 1990; Vorberg et al., 1990; Lau et al., 1987; Bordia, 1981)

Atherosclerosis (Koscielny et al., 1999)

Other Potential Uses

Cardiovascular

Hypertension, mild (Steiner et al., 1996; Auer et al., 1990)

Peripheral arterial occlusive disease (PAOD) (Koscielny et al., 1999; ESCOP, 1997; Kiesewetter et al., 1993b)

Hematology

Decreased platelet function (Rahman and Billington, 2000; Steiner et al., 2001; Steiner et al., 1996; Kiesewetter et al., 1991; Kiesewetter et al., 1993a)

Chemopreventative

Colon cancer preventative (Steinmetz et al, 1994; Witte et al., 1996)

Stomach cancer preventative (You et al., 1989)

Miscellaneous

Garlic has traditionally been used to relieve cough, colds, catarrh, and rhinitis, although clinical trials do not support such uses (ESCOP, 1997)

Dosage

Internal

Crude Preparations

Fresh herb: 4 g daily (1 clove) minced bulb or equivalent preparations (Blumenthal et al., 1998). [Note: Some authors have suggested that this dosage level should be revised downward to approximately 2,700 mg of fresh garlic, equivalent to the 900 mg of garlic powder used in some clinical trials that studied the ability of garlic to prevent and/or reverse atherosclerotic plaque build-up (Schulz et al., 2001).]

Infusion: 4 g in 150 ml of hot water (Blumenthal et al., 2000).

Fluid extract: 1:1 (g/ml), 4 ml (Blumenthal et al., 2000).

Tincture: 1:5 (g/ml), 20 ml (Blumenthal et al., 2000).

Standardized Preparations

Garlic powder (Kwai^®): 200–300 mg, 3 times daily (Warshafsky et al., 1993).

AGE ™ (Kyolic^®) aged garlic extract: 300–800 mg, 3 times daily or 1–5 ml daily (Steiner 2001; Steiner et al., 1996; Rahman and Billington, 2000; USP, 2002; Lau et al., 1987).

Duration of Administration

Long-term treatment is generally advised in the prevention of atherosclerosis (Koscielny et al., 1999), and the prophylaxis and treatment of peripheral arterial vascular diseases (ESCOP, 1997). Epidemiological observations support the long-term consistent use for prevention of cancer in the stomach and intestines (You et al., 1989).

Chemistry

Crude Preparations

Fresh garlic bulbs contain about 65% water, 28% carbohydrates (fructans), 2.3% organosulfur compounds (OSC), 2% protein, and 1.2% free amino acids. The main OSC in whole garlic are the cysteine sulfoxides (1% alliin and 0.1% cycloalliin) and the g-glutamylcysteines (0.6% g-glutamyl-S-trans-1-propenylcysteine and 0.4% g-glutamyl-S-allylcysteine). When the bulb is bruised, crushed, chewed, or minced, the alliin, in the presence of the enzyme alliinase, is converted to allicin (ESCOP, 1997). One mg of alliin produces 0.458 mg of allicin, which is considered to be responsible for some of garlic’s biological activity and is a precursor to some thiosulfinates, which also have been shown to be active (Lawson 1998a; Block, 1985; Bradley, 1992; Budavari, 1996; ESCOP, 1997). However, allicin is unstable and decomposes to other volatile sulfur compounds (the half-life of allicin is not more than 24 hours), so the extent of allicin’s activity has been questioned. Intact garlic cloves (the sections that comprise the garlic bulb) also contain S-allylcysteine (SAC), but no allicin. SAC is formed from gamma-glutamyl cysteine catabolism and has been reported to contribute to the health benefits of some garlic preparations (Amagase et al., 2001). Fresh and aged garlic extract (AGE, see below) also contain steroidal saponins (Matsuura, 2001).

Standardized Preparations

Processed garlic preparations contain a variety of sulfur-containing compounds other than those found naturally in intact garlic cloves, depending on the conditions applied (Lawson, 1998a; Fenwick and Henley, 1985). Sulfur-containing compounds in commercial garlic preparations vary, depending on their manufacturing process. Powdered preparations of dried garlic contain alliin and compounds derived from its subsequent transformation, but no allicin. Enteric coatings protect these powdered preparations from conversion while in the stomach. Garlic oil yields neither alliin, nor allicin as the converting enzyme is destroyed by heat. It does contain diallyl disulfide, diallyl trisulfide, and allyl methyl trisulfide. Macerated garlic-derived oil contains vinyldithiins, ajoene, and diallyl trisulfides (Lawson, 1998a). Garlic extract and odorless AGE are listed in the United States Pharmacopeia/National Formulary (USP, 2002). The most abundant sulfur compound in AGE is SAC; it is standardized to not less than 0.05% SAC (USP, 2002).

Pharmacological Actions

Human

Garlic reduces total cholesterol (TC) and serum triglycerides (TG) and elevates high density lipoproteins (HDL) (Auer et al., 1990; Barrie et al., 1987; Lau et al., 1987; Bordia, 1981; De A Santos and Johns, 1995; Silagy and Neil, 1994a); prevents platelet aggregation and thrombus formation (Rahman and Billington, 2000; Barrie et al., 1987; Kiesewetter et al., 1993a; Kiesewetter et al., 1993b; Legnani et al., 1993); stimulates fibrinolysis, prolongs clotting time (Chutani and Bordia, 1981; Gadkari and Joshi, 1991; Harenberg et al., 1988; Legnani et al., 1993); reduces low-density lipoprotein (LDL) oxidation (Ide and Lau, 2001; Lau, 2001; Munday, 1999; Steiner and Lin, 1994; Harris et al., 1995; Phelps and Harris, 1993); reduces systolic blood pressure, diastolic blood pressure, and mean blood pressure from baseline (Steiner et al., 1996a, 1996b; De A Santos and Johns, 1995; Silagy and Neil, 1994b; Grünwald et al., 1992; Auer et al., 1990;); attenuates age- and blood pressure-related increases in aortic stiffness (Breithaupt-Grögler et al.,1997); stimulates peripheral microcirculation (Okuhara, 1994); is antifungal and fungistatic against Cryptococcus neoformans, the organism that causes cryptococcal meningitis (Anon., 1980; Davis et al., 1990); may decrease the risk of gastrointestinal cancers (Gail et al., 1998; You et al., 1991, 1989, 1988; Reuter et al., 1996; Buiatti et al., 1989; Lau, 1989); modulates immune system activity (Brosche and Platt, 1993; Kandil et al., 1988; Lawson, 1998a; Reuter et al., 1996); reduces blood glucose levels (Kiesewetter et al., 1991). Garlic does not inhibit H. pylori bacteria in the stomach (Graham et al., 1999). Although one study concluded that garlic extracts had no statistically significant impact on how far patients with peripheral vascular disease (PVD) can walk (Kiesewetter et al., 1993b), AGE has been reported to exhibit stimulation of peripheral circulation in human subjects (Okuhara, 1994; Kikuchi et al., 1994). One pilot clinical trial (Ohnishi et al., 2000) indicated an effect of AGE and other antioxidants in the potential treatment of sickle cell anemia patients.

Animal

Garlic lowers elevated levels of serum homocysteine (Yeh, 1999); lowers serum cholesterol and lipids (Bordia et al., 1975; Kamanna and Chandrasekhara, 1982; Chi et al., 1982); is antithrombotic (Bordia et al., 1975); increases fibrinolysis and clotting time (Bordia et al., 1975; Reuter et al., 1996); reduces blood pressure (Sial and Ahmad, 1982; Ruffin and Hunter, 1983); is antioxidant (Han et al., 1992; Lawson, 1998a); modulates immune system (Kyo et al., 1999, 1998; Lawson, 1998a; Reuter et al., 1996); reduces blood glucose levels and increases insulin levels (Augusti, 1975; Chang and Johnson, 1980); is anti-allergenic (Kyo et al., 1997); exhibits antitumor activity against transitional cell carcinoma of the bladder with AGE (Lau et al., 1986; Riggs et al., 1997); reduces breast cancer incidence (Amagase and Milner, 1993; Liu et al., 1992; Kröning, 1964); decreases incidence of hepatic tumors in the Bufo regularis toad (El-Mofty et al., 1994).

In vitro

Antithrombotic

The rational clinical application of garlic necessitates demonstrating the association between garlic consumption and important clinical outcomes such as atherosclerosis. In vivo and in vitro studies suggest garlic extracts and several garlic constituents have a significant antithrombotic effect (Ariga et al., 1981; Boullin, 1981; Srivastava, 1986; Mohammed and Woodward, 1986). Garlic has been shown to increase fibrinolysis and prolong clotting time (Reuter et al., 1996). Adenosine in AGE and its constituents are the most potent antiplatelet constituents of garlic. Allicin was thought an active compound in garlic due to its highly reactive and oxidative characteristics, but it is rapidly metabolized in human blood (in in vitro culture) and therefore might not contribute to the in vivo antithrombotic effect of garlic (Freeman and Kodera, 1995; Koch and Lawson, 1996).

Ajoene is found in small amounts in garlic oil-macerates, but not in commercial garlic preparations and garlic powders. Bioavailability of ajoene has not yet been established. Antithrombotic and vasodilatory actions of garlic might be due to adenosine deaminase and cyclic AMP phosphodiesterase, which can be found in garlic extracts. The decrease of thromboxane B2 (TXB2) levels is another possible explanation for garlic’s antithrombotic effects. Most of the above explanations are based on in vitro and in vivo experiments (Berthold and Sudhop, 1998; Rahman and Billington, 2000; Bordia et al., 1996; Agarwal 1996).

Koscielny et al. (1999) reported a slowing and reversal of atherosclerotic plaque formation. AGE has been shown to protect vascular endothelial cells against hydrogen peroxide-induced lipid peroxidation and biomembrane damage (Yamasaki et al., 1994); prevent oxidized LDL-induced membrane damage, loss of cell viability, and lipid peroxidation (Ide and Lau, 1997b); and demonstrate antihypertensive activity (Lawson, 1998a; Steiner et al., 1996; Koch et al., 1992a; Sendl et al., 1992).

Anticancer

Garlic inhibits the induction and growth of cancer (Milner, 1996; Lea, 1996). The effect on tumor initiation and promotion has been documented, and both the oil-soluble and water-soluble OSCs such as methyl propyl disulfide and propylene sulfide, SAC, S-allylmercaptocysteine (SAMC), and allicin reduce the proliferation of neoplasms and inhibit the development of liver glutathione S-transferase placental (GST-P) positive tumor foci and other indications of cancer in different organs. In contrast, OSCs such as diallyl sulfide, diallyl trisulfide, and allyl methyl trisulfide enhance the formation of liver tumor foci.

However, in rats, diallyl disulfide shows the following activities: inhibits the potential for colon and renal tumor development (Fukushima et al., 1997); inhibits the growth of human prostate cancer cells (Pinto et al., 1997a); demonstrates cytotoxic activity against MBT2 bladder tumor cells (Riggs et al., 1997); is antiallergenic (Kyo et al., 1997); stimulates macrophage activity, natural killer cells, and LAK cells. It may also increase production of interleukin (IL-2), tumor necrosis factor (TNF) and interferon gamma, which are cytokines associated with beneficial antitumor responses. AGE protects against the immunosuppression induced by chemo- and radiation therapy (Lamm and Riggs, 2000; Lau, 1989) and UV light (Reeve et al., 1993a, 1993b).

Antimicrobial effects

Antibacterial activity against Escherichia, Salmonella, Staphylococcus, Streptococcus, Klebsiella, Proteus, Bacillus, Mycobacterium, Clostridium, and resistant strains (Adetumbi and Lau, 1983; Farbman et al., 1993; Hughes and Lawson, 1991; Lawson 1998a; Reuter et al., 1996); antifungal activity against Candida and Cryptococcus (Anon., 1980; Caporaso et al., 1983; Hughes and Lawson, 1991; Lawson, 1998a); antiulcer/antibacterial against Helicobacter pylori (Sivam, 2001; Sivam et al., 1997); antifungal, antiparasitic (Ankri and Mirelman, 1999). The main antimicrobial effect of allicin is limited when in direct exposure to the microorganisms due to its chemical reaction with enzymes (e.g., alcohol dehydrogenase, thioredoxin reductase) and RNA polymerase. This reaction can affect the essential metabolism of cysteine proteinase activity involved in the virulence of Entamoeba histolytica. An aqueous extract of garlic cloves, standardized for its thiosulfinate concentration tested positively for its antimicrobial activity against H. pylori (Sivam et al., 1997). Minimum inhibitory concentration was 40 mcg thiosulfinate per ml. It is possible that the sensitivity of H. pylori to garlic extract at such low concentrations may be related to the reported low risk of stomach cancer in those populations with high allium vegetable intake. However, an uncontrolled trial involving 20 patients with positive urea breath tests, taking 300 mg tablets of dried garlic powder, three times daily for eight weeks, did not eradicate H. pylori (Fennerty et al., 1999).

Hematology effects

In vitro studies (and a pilot clinical trial) have indicated an effect of AGE and other antioxidants in the potential treatment of sickle cell anemia patients (Ohnishi et al., 2000, 2001; Ohnishi and Ohnishi, 2001).

Mechanism of Action

Lipid-lowering

One possible mechanism is thought to be attributed to allicin/thiosulfinates (Lawson, 1998a; Reuter et al., 1996) but a recent study revealed water-soluble OSC, e.g., SAC and SPC, may be the active compounds inhibiting cholesterol synthesis (Liu and Yeh, 2001). However, oil-soluble OSC, e.g., diallyl disulfide (DADS) and others, decomposed from thiosulfinates including allicin, actually killed the cells, thus indirectly inhibiting cholesterol synthesis (Liu and Yeh, 2001).

Increases catabolism of fatty acid-containing lipids, especially triglycerides (Yeh et al., 1995; Yeh and Yeh, 1994; Lawson, 1998a).

Inhibits cholesterol biosynthesis at the level of b-hydroxy-b-methylglutaryl-CoA (HMG-CoA) reductase (Yeh et al., 1995; Yeh and Yeh, 1994; Gebhardt et al., 1994; Gebhardt, 1993).

Inhibits cholesterol biosynthesis at later steps, as evidenced by accumulation of the cholesterol precursors, lanosterol and 7-dehydrocholesterol, although this latter effect may be of minor therapeutic significance (Gebhardt et al., 1994; Gebhardt, 1993).

Enhances palmitate-induced inhibition of cholesterol biosynthesis (Gebhardt, 1995).

Inhibits cholesterol biosynthesis by targeting squalene monooxygenase, an enzyme that catalyzes the downstream pathway in cholesterol synthesis (in vitro study on fresh garlic extract) (Gupta and Porter, 2001).

Lipid-lowering activity may be due to the presence of steroid saponins in fresh garlic and AGE, which may interfere with the absorption of total and LDL cholesterol from the intestine lumen, thereby reducing plasma levels (40–57% in test animals), without adversely affecting HDL levels. Saponins are known to inhibit intestinal absorption of cholesterol, suggesting possible hypocholesterolemic effect (Matsuura, 2001).

Antithrombotic

Garlic inhibits platelet aggregation and stimulates fibrinolysis; this may be attributed to allicin/thiosulfinates at lower garlic doses and cycloalliin at higher garlic doses (in vitro) (Lawson, 1998a; Reuter et al., 1996). However, since it is argued that allicin/thiosulfinates may not be bioavailable, other compounds may be responsible (Amagase et al., 2001).

Inhibits normal arachidonate metabolism (Ariga et al., 1981; Makheja et al., 1980; Makheja et al., 1981; Reuter et al., 1996).

Inhibits the lipoxygenase and cyclo-oxygenase pathways of the arachidonic acid cascade, thereby inhibiting the synthesis of prostaglandins and thromboxanes (PGE2, PGD2, PGI2, TXB2) (Rahman and Billington, 2000; Reuter et al., 1996; Ariga et al., 1981; Makheja et al., 1981, 1980).

Inhibits fatty acid lipoxygenase (Liu and Yeh, 2001; Reuter et al., 1996; Ariga et al., 1981; Makheja et al., 1981, 1980).

Ajoene affects fibrinogen-induced human platelet aggregation and inhibits binding of fibrinogen to adenosine diphosphate (ADP) stimulated platelets in vitro (Reuter et al., 1996).

Antihypertensive

Action is thought to be attributed to g-glutamylcysteines and fructans; allicin is not involved (Lawson, 1998a; Reuter et al., 1996).

g-glutamylcysteines can inhibit angiotensin-converting enzyme (ACE), thus inhibiting angiotensin II (a hormone that increases vasoconstriction) (Lawson, 1998a; Sendl et al., 1992).

Fructans can inhibit adenosine deaminase in isolated cells, thus increasing adenosine and its associated blood vessel dilatory activity (Lawson 1998a; Koch et al., 1992).

Increases nitric oxide through activation of nitric oxide synthase activity (Das et al., 1995).

Antimicrobial

Action is in vitro or externally thought to be attributed to allicin/thiosulfinates (Lawson, 1998a; Reuter et al., 1996).

Allicin disrupts cellular metabolic processes in vitro through inactivation of proteins by oxidation of essential thiols to disulfide, competitive inhibition of enzymes containing cysteine in their active sites by reacting with the sulfhydryl (-SH) group, and noncompetitive inhibition of enzymes by reacting with -SH groups at allosteric sites (Adetumbi and Lau, 1983; Cavallito et al., 1944; Lawson, 1998a).

Garlic extract inhibits H. pylori bacterial in vitro at moderate concentrations, thereby suggesting mechanism for antigastric ulcer effect (Sivam, 2001; Sivam et al., 1997).

Anticancer

Action is thought to be attributed to any number of garlic compounds: SAC, SAMC, thiosulfinates, g-glutamylcysteines, and other unknown compounds (Lawson, 1998a; Pinto et al., 1997b; Reuter et al., 1996, Amagase and Milner, 1993; Liu et al., 1992) although the thiosulfinates (e.g., allicin) are questioned due to their instability.

Decreases the amount of nitrate-reducing bacteria in the stomach, thus reducing the formation of carcinogenic nitrosamines (Dion and Milner, 1996; Mei et al., 1985, 1982).

Inhibits the induction and growth of cancer, which may be mediated by modulation of carcinogen metabolism (Lea, 1996).

Stimulates macrophage activity, natural killer cells, and LAK cells, and might increase the production of IL-2, TNF, and interferon gamma, which are cytokines associated with beneficial antitumor response (Lamm and Riggs, 2000; Lau et al., 1991; Lau, 1989; Abdullah et al., 1989).

Antiallergenic

Inhibits antigen-specific histamine release from mast cells in vitro (Kyo et al., 1997); decreases antigen-specific IgE mediated skin reactions in vivo (Kyo et al., 1997); and reduces antigen-specific, late-phase reaction by modulating the production and release of cytokines from activated T-lymphocytes in vivo (Kyo et al., 1997).

Antioxidant

Action is thought to be attributed to primarily water-soluble OSC (e.g., SAC and SAMC) in addition to fructosyl-arginine, other Maillard reaction compounds in AGE, and other compounds (Ryu, 2001; Imai, 1994); some authors suggest action may be due to the allicin/thiosulfinates (Lawson, 1998a; Reuter et al., 1996).

Decreases oxidation of LDL cholesterol in humans (Ide and Lau, 2001; Lau, 2001; Munday, 1999; Steiner and Lin, 1994; Harris et al., 1995; Phelps and Harris, 1993).

Increases the activity of several enzymes (including glutathione peroxidase and catalase) involved in antioxidative processes and decreases the concentration of lipid peroxides in the blood (Ide and Lau, 1999; Steiner and Lin, 1994; Geng and Lau, 1997; Han et al., 1992).

Increases intracellular glutathione (GSH) (a potent intracellular antioxidant and detoxifier), modulates the activity of the GSH redox cycle, and increases activity of superoxide dismutase (SOD, a potent intracellular antioxidant) activity (Ide and Lau, 2001; Wang et al., 1999; Hatono et al., 1996; Geng and Lau, 1997).

Immunomodulatory

Action thought to be attributed to protein fraction of garlic (Moraika et al., 1993; Lau et al., 1991; Hirao et al., 1987).

•nhibits activation of nuclear factor kappa B (NF-kB) in human T-cells that are involved in immune and inflammatory reactions (Geng et al., 1997).

Increases phagocytosis, natural killer cell activity, antibody titer, and lymphocyte counts (Brosche and Platt, 1993; Kandil et al., 1988; Lawson, 1998a; Reuter et al., 1996).

Hematological (AGE)

Inhibits anion transport and sickle cell dehydration (Ohnishi et al., 2001), restricts dense cell formation (Ohnishi and Ohnishi, 2001) and 4.0 mg/mL was shown to inhibit dense cell formation by 50% (Ohnishi et al., 2000). A U.S. patent has been granted to Wakunaga of America, Mission Viejo, CA for the “Therapeutic Uses of Specially Processed Garlic for Sickle Cell Disease” (Ohnishi and Tsuyoshi, 2001).

Increased natural killer cell activity and improved helper suppressor T-cell ratios in AIDS patients (Abdullah et al., 1989).

Contraindications

None known according to the German Commission E and other leading European scientific bodies (Blumenthal et al., 1998; ESCOP, 1997). The World Health Organization (WHO) cautions against the use of garlic by patients with a known allergy to garlic, and those taking warfarin (and presumably other anticoagulants) (WHO, 1999). However, AGE has been tested in a placebo-controlled, double-blind clinical trial in patients taking Coumadin^® (warfarin); there was no demonstrated interaction with Coumadin^® and no prolonged bleeding (Rozenfeld et al., 2000). Several case reports of increased clotting time suggest that patients should discontinue use prior to surgery (Brinker, 2001), usually by at least one week.

Pregnancy and Lactation: None known (Blumenthal et al., 1998; ESCOP, 1997). A controlled trial showed that major sulfur-containing volatiles from garlic are transmitted to breast milk, leading to improved drinking habits of infants (ESCOP, 1997; Mennella and Beauchamp, 1991). In Japan, AGE is an ingredient in pharmaceutical products that are used in nutritional nourishment for pregnant and lactating women.

Adverse Effects

The most commonly reported adverse effect of garlic is that its odor may pervade the breath and skin (Blumenthal et al., 1998). Raw garlic has a stronger odor and higher levels of high molecular weight sulfur compounds than cooked garlic, but malodorous breath tested in humans who ingested raw garlic showed higher levels of low molecular weight sulfur compounds and different constituents than those associated with common halitosis (Tamaki and Sonoki, 1999). Differences in the frequency of other adverse effects caused by various garlic preparations have not been completely determined (Mulrow et al., 2000), such adverse effects being dependent upon the method of preparation. Gastrointestinal symptoms and changes to the intestinal flora or allergic reactions are rare but are occasionally reported (Lembo et al., 1991). In separate, single-case reports, garlic was associated with postoperative bleeding (Burnham, 1995), spontaneous spinal epidural hematoma, and platelet dysfunction from excessive ingestion (Rose et al., 1990). Occupational exposure to crushed garlic products and the topical application of garlic to treat wounds or skin infections may cause allergic contact dermatitis (Lee and Lam, 1991; Bojs and Svensson, 1998). Allergic reactions including burns (Roberge et al., 1997), zosteriform dermatitis (Farrell and Staughton, 1996), induction of pemphigus (blisters) (Brenner and Wolf, 1994), allergic asthma and rhinitis, contact urticaria, and protein contact dermatitis have been reported for garlic and various generic garlic preparations (WHO, 1999; DeSmet, 1992), but no adverse effects were reported for AGE according to toxicological and clinical studies (Miyoshi et al., 1984; Nakagawa et al., 1984, 1980; Sumiyoshi et al., 1984). Cross-sensitivity may occur with onions and tulips (Siegers, 1992; WHO, 1999). Garlic preparations can increase clotting time (Chutani and Bordia, 1981; Gadkari and Joshi, 1991; Harenberg et al., 1988; Legnani et al., 1993), which is sometimes beneficial, but in some cases, can contribute to an adverse event.

Drug Interactions

Concurrent use of garlic and antiplatelet agents (e.g., aspirin) and anticoagulants (e.g., warfarin) might increase the potential for prolonged bleeding. One report showed that clotting time (International Normalization Ratio) doubled for two patients taking warfarin and garlic simultaneously (Sunter, 1991); how-ever, this report lacks adequate data to assess causality (Rotblatt and Ziment, 2001). Further, a controlled clinical trial on AGE showed no interactions with warfarin (Rozenfeld, 2000). Another trial on nine HIV-negative individuals produced significant decreases in serum levels of the anti-HIV drug saquinavir (Piscitelli et al., 2002); however, this study has design problems rendering the results uninterpretable.

American Herbal Products Association (AHPA) Safety Rating

Class 2c: Not to be used while nursing (McGuffin et al., 1997). However, a controlled trial indicated a positive therapeutic use during lactation (ESCOP, 1997; Mennella and Beauchamp, 1991).

Regulatory Status

Canada: Drug or possibly “New Drug” if claims made. Food in absence of claims (HPB, 1993). Schedule OTC “Herbal and Natural Products” and “Homoeopathic Products” have marketing authorization with Drug Identification Numbers (DIN) assigned (Health Canada, 2001).

European Union: Powder, freeze-dried, or low temperature dried (<65°C), containing not less than 0.45% allicin, official in European Pharmacopoeia 3rd ed. Suppl. 2001 (Ph.Eur., 2001).

France: Traditional Herbal Medicine (THM) permitted for treatment of minor circulatory disorders (Bradley, 1992). Essential oil is dispensed as an aromatherapy drug (Goetz, 1999).

Germany: Fresh or carefully dried bulb is approved by Commission E as non-prescription drug (Blumenthal et al., 1998). Fresh bulb for preparation of mother tincture official in the German Homoeopathic Pharmacopoeia (GHP, 1993).

Ghana: Monograph for fresh whole bulb occurs in Ghana Herbal Pharmacopoeia (GHP, 1992).

India: Bulb and oil are approved single drugs dispensed in Unani system of medicine (CCRUM, 1997).

Japan: OTC drug for fatigue (Okada and Miyagaki, 1983). AGE approved for nourishment of pregnant and lactating women.

Sweden: Classified as ‘Natural Remedy’ for self-medication requiring pre-marketing authorization from Medical Products Agency (MPA). One product (e.g. Bio-Garlic Pharma Nord) is listed in the “Authorised Natural Remedies” with the approved indication “Traditionally used for the relief of cold symptoms” (MPA, 2001a; Tunón, 1999). Homoeopathic dilutions (e.g., Radiotron AB) are also registered drugs (MPA, 2001b).

Switzerland: Powdered garlic in tablets, standardized powdered extract in tablets, oily macerate in capsules, and multiple-herb preparations containing standardized garlic extract have positive classification (List D) by the Interkantonale Konstrollstelle für Heilmittel (IKS) and corresponding sales category D, with sales limited to pharmacies and drugstores, without prescription (Morant and Ruppanner, 2001). Twenty-eight garlic phytomedicines and two homoeopathic medicines are listed in the Swiss Codex 2000/01 (Ruppanner and Schaefer, 2000).

U.K: Herbal medicine on the General Sale List (GSL), Table A (internal or external use), Schedule 1 (requires full product license) (GSL, 1989).

U.S.: Dietary Supplement (USC, 1994). Fresh or dried compound bulbs, powdered garlic, fluidextract and extract are official in the U.S. National Formulary 19th edition (USP, 2002). Tincture of mature bulb, 1:10 (w/v) in 55% alcohol (v/v), is a Class C OTC drug of the Homoeopathic Pharmacopoeia of the United States (HPUS, 1989).

Clinical Review

Thirty-two studies, including 45,694 participants, are outlined in the following table, “Clinical Studies on Garlic.” All but four of the studies (Berthold et al., 1998; Isaacsohn et al., 1998; McCrindle et al., 1998; Simons et al., 1995) demonstrated positive effects on conditions including cardiovascular and arterial health, cancer, immunity, and circulation. Studies from the table are categorized and discussed in the following six sections. In addition to the studies in the table, this Clinical Review discusses numerous reviews and meta-analyses that are not listed in the table.

Based on the Agency for Healthcare Research and Quality’s (AHRQ) review and summary of clinical studies on garlic (Mulrow et al., 2000), researchers concluded that garlic preparations may have small, positive, short-term effects (less than three months) on lipids, and promising antithrombic effects. However, the data was insufficient to draw conclusions about certain clinical cardiovascular outcomes (e.g., myocardial infarction), antithrombic activity, or cancer prevention. No effects on glucose or insulin sensitivity, or consistent decreases in blood pressure were found. Case-control studies suggest that consuming large amounts of garlic in the diet may reduce the risks of laryngeal, gastric, colorectal, and endometrial cancers, and adenomatous colorectal polyps (Mulrow, et al., 2000). A subsequent review of 45 randomized trials by some of the same researchers concluded that the trials suggest possible small short-term benefits of garlic preparations on some lipid and antiplatelet factors, insignificant effects on blood pressure, and no effect on glucose levels (Ackermann et al., 2001). Conclusions regarding clinical significance are limited due to the marginal quality and short duration of many trials, as well as the unpredictable release and inadequate definition of active constituents in many of the garlic preparations used in the studies.

Lipid-lowering effect

Thirteen trials involving a total of 795 participants demonstrated a positive correlation between garlic oil, powder, or capsule intake and lipid-lowering effects. Six randomized, double-blind, placebo-controlled (R, DB, PC) studies (Yeh et al., 1995; Jain et al., 1993; Rotzsch et al., 1992; Auer et al., 1990; Mader et al., 1990; Vorberg et al., 1990), as well as two DB, multi-center studies (Grünwald et al., 1992; Holzgartner et al., 1992) supported the use of garlic in treating elevated lipid conditions including hyperlipidemia and hypercholesterolemia. Three studies showed the positive impact of taking Kyolic^® capsules specifically for improving hypercholesterolemia conditions (Steiner et al., 1996; Steiner and Lin, 1994; Lau et al., 1987). One R, open, parallel group, comparison (O, PG, Cm) found garlic powder to have a significant impact over garlic oil on lowering blood lipid counts and blood pressure, as well as increasing the overall sense of well-being in 70 subjects (De A Santos and Johns, 1995). An R, PC study involving 35 renal transplant patients found the garlic product, Pure-Gar^®, to have positive effects on hyperlipidemia (Lash et al., 1998). One O study involving 82 subjects (Bordia, 1981) found garlic to have, in conjunction with the lipid-lowering effects, a positive impact on patients with coronary heart disease.

A meta-analysis on the effect of garlic on total serum cholesterol levels found a statistically significant reduction in total cholesterol levels (Warshafsky et al., 1993). Another analysis assessed clinical data from 952 patients and 16 trials, indicating a decrease in total cholesterol levels (Silagy and Neil, 1994b). A subsequent reanalysis of all data still demonstrated a significant reduction of total cholesterol compared to placebo (Warshafsky et al., 1993). Three studies on the allicin-standardized garlic powder tablets (Kwai^®) failed to show a significant reduction in elevated serum cholesterol (Isaacsohn et al., 1998; McCrindle et al., 1998; Simons et al., 1995). It was later determined that the allicin release from the tablets varied significantly, and that negative studies were possibly due to the lack of expected allicin release (Lawson et al., 2001). A study of 24 brands of enteric-coated tablets found that 83% of the brands released less than 15% of their allicin potential (Lawson and Wang, 2001). Therefore, the researchers recommend that manufacturers standardize supplements to dissolution of allicin release, not to allicin potential. (For non-allicin releasing products, e.g., AGE, the standardization is to other compounds, e.g., SAC.) In a recent, comprehensive meta-analysis of 13 R, DB, PC trials researchers demonstrated a significant difference (p<0.01) in the reduction of total cholesterol levels between baseline and placebo, equivalent to a 5.8% reduction in total cholesterol levels. The authors concluded that current evidence indicates that any specific lipid-lowering effect is small, and the clinical outcome may not be meaningful (Stevinson et al., 2000). However, there were several problems identified with the meta-analysis, indicating that the conclusions can only be attributed to the specific brands tested and not the effectiveness of garlic in general. In particular, the brand used in 10 of the trials did not protect allinase from exposure to gastric acid. Another tested supplement was spray-dried, resulting in the loss of alliin. The study on the garlic oil that showed no effect utilized a form that has demonstrated low bioavailability; therefore the conclusions of the meta-analysis need to be considered within this context (Lawson, 2001). Several of these products are not standardized to a bioavailable marker compound. Clinical studies with positive outcomes using AGE standardized with bioavailable SAC have shown significant levels of SAC in human blood during the study period (Steiner and Li, 2001).

Antihypertensive effect

Two R, DB, PC studies and one R, O, PG, Cm study (159 total participants) demonstrated the antihypertensive effects of garlic (De A Santos and Johns, 1995; Jain et al., 1993; Auer et al., 1990). A systematic review and meta-analysis of randomized controlled trials was conducted to determine the effect of garlic on blood pressure. Eight trials, including 415 participants, were identified. Of the seven trials that compared the effect of garlic with a placebo, three demonstrated a significant reduction in systolic blood pressure (SBP), and 4 in diastolic blood pressure (DBP). The authors concluded that more rigorously designed trials can provide evidence to recommend the clinical application of garlic in the treatment of hypertension (Silagy and Neil, 1994b).

Antiplatelet effects

One R, DB, PC, crossover (CO) study and 2 DB, PC studies involving a total of 214 subjects indicate the potential use of garlic as a coronary disease preventative due to its positive impact on platelet functions (Steiner and Li, 2001; Kiesewetter et al., 1991; 1993a).

Anti-atherosclerotic effect

In the longest clinical trial on garlic to date, garlic’s ability to prevent and possibly reverse atherosclerosis was tested in a R, DB, PC, four-year study in which 152 men and women were given 900 mg garlic powder as tablets (Kwai^®) per day (Koscielny et al., 1999). The subjects possessed significant plaque buildup and at least one additional cardiovascular risk factor (e.g., high LDL levels, hypertension, diabetes, and/or history of smoking). After the four years, garlic subjects had an average 2.6% reduction in plaque volume while the placebo group’s plaque increased 15.6%. Researchers concluded that garlic has a preventive and possibly curative role in arteriosclerosis therapy. In one epidemiological, cross-sectional, observational (E, CS, OB) study with 202 participants, standardized garlic powered was found to have positive effects on arterial activities including elastic vascular resistance, pulse wave velocity, and systolic blood pressure (Breithaupt-Grogler, 1997).

Anticancer/Chemoprevention

Anti-cancer and chemopreventative qualities of garlic were demonstrated in five studies involving a total of 44,044 subjects. One E study spanning over a period of 15 years, demonstrated that raw and cooked garlic use had a significant impact on decreasing stomach cancer incidents (You et al., 1989). Two other E studies found that garlic intake significantly decreased the risk of colon cancer in 42,325 participants (Witte et al., 1996; Steinmetz et al., 1994). Garlic’s chemopreventative potential was demonstrated in two OB studies through the improvement of arachidonic acid and acetaminophen metabolism (Dimitrov and Bennink, 1997; Gwilt et al., 1994). Case-control studies suggest that consuming large amounts of garlic in the diet may reduce the risks of laryngeal, gastric, colorectal, and endometrial cancers and adenomatous colorectal polyps (Mulrow, et al., 2000).

Several reviews of E studies have examined the cancer-preventive effect of garlic, including garlic ingested as a food (Dorant et al., 1993; Fleischauer et al., 2000). A meta-analysis of the epidemiological evidence on the association between garlic consumption and risk of stomach, colon, head and neck, lung, breast, and prostate cancers concluded that raw and cooked garlic consumption might have a protective effect against stomach and colorectal cancers (Fleischauer et al., 2000). An earlier review of in vitro, in vivo, epidemiologic, and case-control studies suggested that the evidence is not conclusive to support chemoprevention in humans, but further research is warranted (Dorant et al., 1993); however, this review preceded much of the salient research in this area.

Other

One pilot study involving 7 HIV+ patients demonstrated a positive impact on natural killer cell activity as well as improvement in conditions such as diarrhea, genital herpes, and candidiasis (Abdullah et al., 1989). One R, DB, PC study showed that garlic did not negatively impact bleeding potential in patients undergoing warfarin therapy (Rozenfeld, et al., 2000). Two studies involving 92 subjects demonstrated garlic’s positive impact on peripheral circulation: one R, CO, Cm study showed an immediate improvement in hand and foot circulation (Okuhara, 1994); and one DB, PC study involving 80 subjects with peripheral arterial occlusive disease (PAOD) showed a significant increase in walking distance (Kiesewetter et al., 1993b). This last study was the only study to meet the inclusion criteria established by the Cochrane Library for its review on the use of garlic for PAOD. The Cochrane Review concluded that further trials on garlic’s effectiveness on PAOD are warranted because the one study reviewed was small, of short duration (12 weeks), and found no significant overall improvement in patients with PAOD. The discrepancy between the conclusions of the study and those of the review is a result of the study’s analysis of the mean difference between the garlic and placebo groups instead of analyzing the mean change within the groups’ pre- and post-treatment.

Branded Products*

AGE™ (Aged Garlic Extract): Wakunaga of America Co., Ltd. / 23501 Madero / Mission Viego, CA 92691 / U.S.A. / Tel: (800) 421-2998 / www.kyolic.com. This refers to a proprietary garlic extract with stable sulfure compounds standardized to bioavailable components (e.g., SAC) in various types of formulations. See Kyolic^® below.

Höfel’s^® Garlic Pearles One-A-Day: Seven Seas Ltd., a division of the Merck Group / Hedon Road / Marfleet / Hull / England / HU9 5NJ / U.K. / Tel.: +44-1482-37-5234 / Fax: +44-1482-37-4345 / Email: info@hofels.com or Info@Seven-Seas.ltd.uk / www.hofels.com. A gelatin or glycerin capsule containing 2 mg garlic oil, and soybean oil.

Kwai^® forte 300 mg LI 111: 1. Lichtwer Pharma AG / Wallenroder Strasse 8-14 / 13435 Berlin / Germany / Tel: +49-30-40-3700 / Fax: +49-30-40-3704-49 / www.lichtwer.de. One sugar-coated tablet (dragée) contains: garlic bulb powder 300 mg. Other components: lactose monohydrate, cellulose, highly dispersive silicon dioxide, magnesium stearate, castor oil, Macrogol 6000, Hypromellose, saccharose, talcum, gelatin, Povidon K25, carnauba wax, bleached wax, yellow quinoline E104, indigo carmine E132.

Kwai^âN LI 111: Lichtwer Pharma AG. One tablet contains 100 mg dried powder from Allium sativum (garlic bulb) standardized to contain 1.3% allicin (yielding 0.6% allicin). Inactive ingredients: lactose, magnesium stearate, powdered cellulose, colloidal anhydrous silica, methylhydroxypropylcellulose, polyethylene glycol 6000, castor oil, talc, polyvinylpyrrolidone 25, sucrose, gelatin, quinoline yellow E 104, indigotine E 132, carnauba wax, cera alba.

Kyolic^® Liquid: Wakunaga of America Co., Ltd. Aged Garlic Extract™ in water and residual alcohol from extraction.

Kyolic^® Reserve: Wakunaga of America Co., Ltd. 600 mg Aged Garlic Extract™ per capsule.

Kyolic^® Super Formula 100: Wakunaga of America Co., Ltd. 300 mg Aged Garlic Extract™ per capsule plus whey.

Kyolic^® Super Formula 101: Wakunaga of America Co., Ltd. 270 mg Aged Garlic Extract™ per capsule, plus brewer’s yeast, kelp, and whey.

Kyolic^® Super Formula 102: Wakunaga of America Co., Ltd. 350 mg Aged Garlic Extract™ per capsule, plus food enzymes: amylase, protease, lipase, and cellulase (30 mg).

Kyolic^® Super Formula 103: Wakunaga of America Co., Ltd. 220 mg Aged Garlic Extract™ per capsule, plus Ester C^® (105 mg), Astragalus membranaceous (100 mg), and calcium (23 mg).

Kyolic^® Super Formula 104: Wakunaga of America Co., Ltd. 300 mg Aged Garlic Extract™ per capsule, plus 190 mg lecithin.

Kyolic^® Super Formula 105: Wakunaga of America Co., Ltd. 200 mg Aged Garlic Extract™ per capsule, plus beta-carotene (6 mg), vitamin C (120 mg), vitamin E (60 IU), selenium (25 mg), and green tea (45 mg).

Kyolic^® Super Formula 106: Wakunaga of America Co., Ltd. 300 mg Aged Garlic Extract™ per capsule, plus hawthorn berry (50 mg), cayenne pepper (10 mg), and vitamin E (100 IU).

Pure-Gar^® Garlic Powder A-2000: Essentially Pure Ingredients™, c/o Pure Gar L.P. / 21411 Prairie Street / Chatsworth, CA 91311 / U.S.A. / Tel: (800) 537-7695 / www.essentiallypure.com. Dried powder from Allium sativum (garlic bulb): allicin yield 2,000 ppm min.; total thiosulfinates yield 2,100 ppm minimum; allian 7,500 ppm minimum; gamma-glutamylcysteines 10,000 ppm minimum.

Pure-Gar^® Garlic Powder A-5000: Essentially Pure Ingredients™ / 21411 Prairie Street / Chatsworth, CA 91311 / U.S.A. / Tel: 818-739-6046 / www.essentiallypure.com. Dried powder from Allium sativum (garlic bulb): allicin yield 5,000 ppm minimum; total thiosulfinates yield 5,000 ppm minimum; allian 11,000 ppm minimum; gamma-glutamylcysteines 10,000 ppm minimum; total sulfur 6,500 ppm minimum.

Pure-Gar^® Garlic Powder A-8000: Essentially Pure Ingredients™. Dried powder from Allium sativum (garlic bulb): allicin yield 8,000 ppm minimum; total thiosulfinates yield 8,000 ppm minimum; allian 18,000 ppm minimum; gamma-glutamylcysteines 8,000 ppm minimum.

Pure-Gar^® Garlic Powder A-10000: Essentially Pure Ingredients™. Dried powder from Allium sativum (garlic bulb): allicin yield 10,000 ppm minimum; total thiosulfinates yield 10,000 ppm minimum; allian 23,000 ppm minimum; gamma-glutamylcysteines 8,000 ppm minimum.

Sapec^®: Lichtwer Pharma AG. 300 mg tablet of dried garlic powder standardized to contain 1.3% allicin (yielding 0.6% allicin).

Tegra^®: Hermes Fabrick Pharma / Georg-Kalb-Str. 5-8 / 82049 Grosshesselohe / Germany. Steam-distilled garlic oil (does not contain allicin, fructans, agrinine, or gamma-glutamylcysteines).

*American equivalents, if any, are found in the Product Table beginning on page 398.

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