Family

Liliaceae.

Related Species

Allium cepa L. (onion), Allium schoenoprasum L. (chives).

Habitat and Cultivation

Originally native to central Asia; commercially cultivated for 5000 years as a food and medicinal herb worldwide.

Parts Used

Fresh or dried bulb.

Common Forms

• Fresh bulb.
• Dried bulb.
• Dried powder (allicin-stabilized).
• Aged garlic extract (AGE).
• Garlic oil (steam-distilled).
• Garlic oil (macerated).

Overview

Garlic dietary supplements consistently occupy second or third place of the top-selling botanical products in the United States, quite apart from the widespread availability and use of garlic cloves as a dietary/culinary herbal ingredient. Scientific studies and numerous clinical trials support the following three primary areas of use in modern practice:

1. For cardiovascular disease prevention and treatment as a hypolipidemic, antiatherosclerotic, hypotensive, antiplatelet, and fibrinolytic agent.
3. For infectious conditions as a broad-spectrum antibiotic, antifungal, antiviral, and anthelmintic agent.
4. As a chemopreventive and anticancer agent; antioxidant and immunostimulant properties impact each of these areas.

   The pharmacology of the herb derives from its organosulfur constituents (OSCs), although the chemistry of these is extremely complex and has not been fully characterized. Importantly, different garlic preparations may have significantly different constituent profiles; the principal compounds in the intact bulb are gamma-glutamyl cysteine peptides and the cysteine sulfoxide alliin. The enzyme allinase (released by damage to intact cells) converts alliin to the thiosulfinate allicin. Allicin is unstable and degrades to various volatile sulfide congeners, depending on the conditions applied. Steam distillation converts water-soluble thiosulfinates to oil-soluble diallyl sulfides, whereas oil maceration produces ajoenes and vinyldithins.

   Similarly, pharmacokinetic differences exist among the various preparations and their components. Metabolic transformation of various sulfides leads to the formation of compounds that have modulating effects on the cytochrome P450 (CYP450) system. Enteric-coated preparations have been shown to release only a fraction of their active allicin content.

   These differences complicate attempts to compare data from various experimental and clinical trials using different garlic preparations. More than 45 randomized clinical trials have been conducted with garlic preparations. Metastudies have concluded that these trials show positive, although limited, short-term benefits of garlic on serum cholesterol and some coagulation parameters, but no significant effect on hypertension or blood glucose levels. ^1-4Some authors have criticized the meta-analyses, noting the lack of equivalence between preparations and inadequate definition or characterization of active principles in the trials, which seriously limits the clinical conclusions that can be drawn from the majority of trials to date. ^5,6Epidemiological studies of the cancer-protective effects of garlic consumption have also been subject to meta-analysis, and positive effects were found for stomach and colon cancers from raw and cooked garlic consumption. ^7,8

   Garlic has not been official in the U.S. Pharmacopoeia since 1900, but it is listed in the 2002 edition of the National Formulary as “fresh or dried compound bulbs containing not less than 0.5% alliin.” The German Commission E approved the use of “fresh or carefully dried bulbs” as “supportive to dietary measures at elevated levels of lipids in the blood” and as a “preventative for age-dependent vascular changes.” ⁹ The European Scientific Cooperative on Phytotherapy (ESCOP) monograph indicates garlic for “treatment of elevated blood lipid levels insufficiently influenced by diet” and mentions the traditional indication for upper respiratory tract infections and catarrhal conditions while also noting that these lack trial support. ¹⁰ The World Health Organization (WHO) also includes mild hypertension as an indication. ¹¹ Both ESCOP and McKenna et al. ¹² provide comprehensive reviews of the recent scientific literature.

   Historical/Ethnomedicine Precedent

   In Europe, garlic has been used for millenia. It was a staple of the Roman army, Pliny recorded more than 60 uses for garlic, and Galen first recorded its use as a disinfectant before and after surgery. More recent folk use centers on respiratory conditions, including coughs, colds, flus, sinus and bronchial infections, pneumonia and tuberculosis, and the elimination of worms and other parasites. As an external treatment, garlic has been used as a “counterirritant” for rheumatic and arthritic conditions, as well as for earache, skin infections, and snakebites. Topical applications are also used in respiratory conditions. Garlic has been employed in all major world systems of medicine for many years. In China, garlic use was recorded in texts from the fifth centuryCE, principally as an antidote for poisons as well as a treatment for infectious and parasitical intestinal conditions such as diarrhea, dysentery, and diphtheria.

   Known or Potential Therapeutic Uses

   Antimicrobial, antifungal, atherosclerosis, bronchial and upper respiratory conditions, catarrh, colds, coughs, flu, gastric and colon carcinomas (prevention), hyperlipidemia, hypertension, hyperviscosity, immunostimulation, peripheral arterial occlusive disease, rhinitis, sinusitis, thrombosis.

   Key Constituents

   Organosulfur compounds (OSCs), principally alliin [(+)- S-allyl-L-cysteine sulfoxide] and gamma-L-glutamyl peptides. Alliin is transformed into allicin by allinase, and depending on physicochemical conditions, various derivatives may be formed. Flavonoids and saponins are also present.

   Therapeutic Dosing Range

   • Fresh Garlic: 2.7 to 4.0 g daily.
   • Dried Powder: 0.4 to 1.2 g daily.
   • Tincture (1:5): 20 mL daily.
   • Oil: 2 to 5 mg daily.
   • Standardized Extracts:
     • Garlic powder (Kwai): 200 to 300 mg three times daily.
     • Aged garlic extract (AGE, Kyolic): 300 to 800 mg three times daily.
     • Other preparations: Corresponding to 4 to 12 mg alliin, or 2 to 5 mg allicin-equivalent daily.

Strategic Considerations

The German Commission E did not list any known interactions for garlic in its 1998 monograph. ⁹ However, the later monographs by WHO and ESCOP both list a possible interaction between garlic and warfarin. ^10,11Although garlic consumption is usually assumed to be a risk to anticoagulated patients, reliable reports of such interactions are not available. ¹³

As with ginkgo, garlic and several of its constituents have established antiplatelet activity in vitro. Using aggregometry in response to platelet-stimulating factors such as collagen and adenosine diphosphate (ADP), three clinical trials have demonstrated modest effects on platelet aggregation in vivo by AGE extracts ^14,15and garlic powder. ^16,17Bleed times and international normalized ratio (INR) were not measured, and the clinical significance of the antiaggregatory effects of garlic remains to be established. Three reports associate garlic alone with spontaneous bleeding, but none of these allows causality to be attributed to the herb ^18-20(see later discussion on garlic and antiplatelet thromboprophylactics). Cessation of high levels of garlic consumption before elective surgery may be prudent, but on the basis of currently available evidence, the risk of garlic-induced bleeding and interactions with drugs affecting hemostasis appears to be very low. ²¹

On the other hand, inclusion of garlic in protocols for patients at risk of thrombosis, particularly those with history of atherosclerotic disease, offers multiple “collateral” benefits due to the pleiotropic actions of the herb on several cardiac risk factors. ^22-27The lipid-lowering effect of garlic extracts operates by several mechanisms, including the inactivation of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase. This has led at least one author to suggest the potential value of combining garlic with pharmaceutical HMG-CoA reductase inhibitors for hyperlipidemia to reduce the risk of adverse effects such as rhabdomyolysis in sensitive populations, such as renal transplant patients. ²⁸ This potentially beneficial interaction is proposed later, although previously undefined in the literature.

Effects on Drug Metabolism and Bioavailability

Experimental, animal, in vitro, and ex vivo human data suggest that garlic OSCs may be substrates, inducers, and/or inhibitors of various CYP450 enzymes. As with the pharmacodynamic effects of garlic, there are differences in effect among the different OSCs, different dose/duration regimens, and different species (mouse, rat, rabbit, human). The full spectrum of effects of OSCs on drug metabolism in humans is not well understood, but in vivo evidence is compelling for an inhibition of CYP450 2E1 by OSCs.

Diallyl sulfide (DAS) is converted by CYP2E1 to diallyl sulfoxide (DASO) and sequentially to diallyl sulfone (DASO2). ²⁹ These derivatives are competitive inhibitors of 2E1, and DASO2is also an irreversible (suicide) inhibitor of 2E1. ^30,31This is a typical example of 2E1 activity, which shares with CYP450 1A1 and 1A2 the role of metabolizing potentially carcinogenic aromatic hydrocarbons, and which may also bioactivate certain substrates to toxic or reactive intermediates (e.g., acetaminophen; see later discussion). ^32,33Loizou and Cocker ³⁴ found that both DAS and garlic oil extract showed significant inhibition of 2E1 in eight healthy human volunteers with the 2E1 probe chlorzoxazone. Gurley et al. ³⁵ also found significant inhibition of 2E1 after 28 days of garlic oil administration in healthy human volunteers using the same chlorzoxazone probe methodology. Davenport and Wargovich ³⁶ found that single-dose in vivo OSCs in a rodent model decreased 2E1 protein but not its messenger ribonucleic acid (mRNA) levels. They also noted a slight increase in 1A1 and 1A2 levels.

Inhibition of CYP450 2E1 is considered one of the major mechanisms by which garlic consumption reduces mutagenesis and carcinogenesis and exerts hepatoprotective effects. ^37,38Other mechanisms may be involved, including OSC induction of glutathione transferases as well as scavenging of carcinogenic free-radical species. ^39,40Recent studies suggest that a number of complex effects on signal-transduction pathways may be involved in the chemopreventive effects of garlic OSCs. ⁴¹ Garlic-drug interactions with 2E1 substrates caused by inhibition by garlic OSCs have not yet appeared to be a clinically significant issue, and case reports are lacking. Drug substrates that theoretically may be affected by inhibition of 2E1 are verapamil, the halogenated anesthetics, and (a minor pathway) theophylline. In a clinical study restricted to older volunteers (mean age, 67 years), Gurley et al. ⁴² found a 22% inhibition of 2E1 by garlic oil administered for 28 days. The authors suggested that age-related changes in CYP450 activity are significant and should be factored into drug dose and potential interactions calculations.

Garlic is not the only dietary substance to modulate 2E1 expression. Inducers include ethanol, lettuce, and above all, increased body weight or obesity, whereas inhibitors include watercress and elements of Camellia sinensis (both green tea and black tea), especially epigallocatechin-3-gallate. If polymorphisms are taken into account, the total contribution of these variables to individual response variation in 2E1-mediated clearance of the probe substrate chlorzoxazone is 73%, with body weight alone accounting for 43% of the phenotypical variability in 2E1 activity. ^43,44

The effect of garlic on CYP450 enzymes other than 2E1 is less clear. A “before and after” probe study with healthy volunteers examined the effect of Kwai (aged) garlic consumption (600 mg three times daily for 14 days) on probe drugs for CYP3A4 (alprazolam) and CYP2D6 (dextromethorphan) pharmacokinetics and found no significant effects after garlic administration. ⁴⁵ The authors concluded that aged (Kwai) garlic is unlikely to cause 3A4-modulated or 2D6-modulated drug interactions. Gurley et al. ³⁵ found no effect of garlic oil on 3A4, 2D6, or 1A2 in healthy volunteers using a midazolam, debrisoquin, and caffeine cocktail in the study previously mentioned that demonstrated 2E1 inhibition.

Foster et al. ⁴⁶ conducted an in vitro study using recombinant human CYP450 enzymes that investigated the effects of 10 different garlic products (including aged, odorless, oil, freeze-dried, and three fresh forms: common, Chinese, and elephant) on enzyme activity. The authors found that 2D6 was unaffected, but that 2C9^*1, 2C19, 3A4, 3A5, and 3A7 were all inhibited by fresh garlic, whereas 2C9^*2 was actively stimulated by fresh garlic. These authors concluded that pharmacokinetic interactions with narrow-therapeutic-range drugs may result from garlic consumption, affecting metabolism of drug substrates mediated by 2C9, 2D6, and 3A4. The same extracts were tested against an in vitro model of P-glycoprotein (P-gp) based on an adenosinetriphosphatase (ATPase) colorimetric assay, using verapamil as a positive control. (Stimulation of the ATPase assay is correlated with increased inhibitory activity of P-gps.) Aqueous extracts of aged garlic preparations exerted a very low to moderate inhibition of P-gp in the assay used. ⁴⁶ In another in vitro model based on human KB-C2 cells, Nabekura et al. ⁴⁷ found no effect of OSCs on the P-gp–mediated transport of daunorubicin and rhodamine 123. Greenblatt et al. ⁴⁸ used an in vitro human hepatocyte model to test possible activity of different water-soluble compounds in garlic for CYP inhibitory activity and found negligible effect, except for high concentrations (100 µmol/L) of S-methyl-L-cysteine and S-allyl-L-cysteine, both of which produced modest inhibition of CYP3A. The authors concluded that CYP3A interactions with garlic and prescription drugs were unlikely.

Pharmacokinetic data for garlic (other than those related to drug-metabolizing systems) are minimal. However, one rodent study examined the effect of the saponin constituents of garlic and concluded that these compounds may contribute to the lipid-lowering activity of garlic by reducing lipid absorption levels at the intestinal wall. ⁴⁹ Studies are required to delineate human pharmacokinetics of garlic and OSC preparations in order to determine the extent to which many of the important effects of OSCs described in vitro in animal models can be replicated in vivo at micromolar concentrations that correspond to those employed in the experimental models. Further research is also required to establish the full spectrum of effects of different forms of garlic and OSCs on drug metabolism and potential pharmacokinetic interactions. Inconclusive data are available relating to garlic and the human immunodeficiency virus type 1 (HIV-1) protease inhibitors, saquinavir and ritonavir (discussed later). Patients with HIV infection are likely to take garlic products or preparations, and physicians specializing in this patient population are usually aware of the complexities of managing polypharmaceutical regimens and empirically monitoring possible interactions. Other than this clinically circumscribed area, currently no compelling data exist on adverse pharmacokinetic interactions between pharmaceuticals and garlic preparations. The established inhibition of CYP450 2E1 underlies a major part of the hepatoprotective and chemoprotective benefits of garlic consumption.

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