Overview of the Evidence

There were 45 RCTs lasting at least 4 weeks that tested the effects of garlic on cardiovascular-related endpoints (Evidence Table 1). All but three RCTs reported intermediate physiological outcomes rather than clinical outcomes such as cardiovascular events or mortality. ^{69 70 71} Reported trial protocols included lipid measurements (n=44), blood pressure measurements (n=30), serum glucose concentration (n=12), antithrombotic activity (n=10), walking distance (n=2), myocardial infarctions and deaths (n=1), and regression of atherosclerotic plaques (n=1). Placebo comparisons were used in 39 trials, a "no garlic" comparison in 2, an active antilipidemic or antihypertensive agent in 3, and a head-to-head comparison of two garlic preparations in 1.

Trials were conducted in Germany (n=13), North America (n=14), India (n=5), United Kingdom (n=4), Thailand (n=2), Poland (n=2), Switzerland (n=1), Italy (n=1), Europe (n=1), and Australia (n=2). Industry sponsorship and free provision of commercially developed garlic products were stated in 35 trials and were unclear in 3. Seven trials stated no commercial sponsorship. ^{34 35 40 71 72 73 74} Four trials were published in symposia or meeting proceedings, ^{39 71 75 76} one in a book, ⁷⁷ one as a thesis, ⁷⁸ and the remainder in journals. We did not review the peer-review processes that were used by the journals.

Twenty-two studies used dehydrated garlic preparations that were standardized to an alliin content of 0.52 percent of the total tablet mass (Table 5). ^{24 37 38 39 47 69 75 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93} Such standardization is reportedly equivalent to a potential 0.6 percent allicin release. One study standardized to a guaranteed minimum release of 3,000 per million (0.3 percent) allicin. ⁷⁶ Another study standardized to produce 2.4 mg allicin per tablet. ⁷⁸

Table

Table 5. Characteristics of trials that evaluated standardized dehydrated garlic powder preparations.

Twenty-two trials used nonstandardized preparations or preparations in which standardization was unclear (Evidence Table 2). ^{30 34 35 36 40 64 70 71 72 73 74 77 83 94 95 96 97 98 99 100} Three trials used garlic ether extracts; ^{34 71 72} four used "aged garlic extract^TM" ^{30 77 94} one used cold-pressed garlic oil; ³⁶ two used raw or fried garlic; ^{35 74} one used "a garlic oil;" ⁸³ one used a steam-distilled, enteric-coated, beta-cyclodextrin-bound garlic oil preparation; ⁹⁵ two used "dried garlic tablets;" ⁹⁶ two used a "spray-dried garlic" preparation; ^{40 73} and five used combination products of garlic with other substances such as fish oil, ginkgo, soya, and hawthorn. ^{70 97 98 99 100} Although some authors equated different garlic preparations to equivalencies of whole or "fresh garlic," processes such as alcohol extraction, steam distillation, and aging may liberate constituents not present in fresh or whole garlic, making such comparisons meaningless. Thus, dosages in Evidence Table 2 are given only in terms of individual preparations that were used in each study.

Quality of the Trials

Numbers of participants in studies were fewer than 100 except for six studies that had sample sizes ranging from 100 to 432. ^{47 70 71 88 89 100} Descriptions of randomization processes were scant; two studies clearly defined methods that were used to assure concealed allocation. ^{47 78} It was unclear if two trials were actually randomized. ^{71 72} Attempts to clarify randomization processes with the author were unsuccessful. In 12 trials, there was no mention of baseline equivalency between groups for lipids or other important parameters, ^{30 34 35 36 37 39 70 71 72 74 82 84} while 7 reported minor differences in baseline lipids, ^{24 38 40 75 76 86 90} 2 in gender ratios, ^{81 83} 1 in systolic blood pressure, ⁸³ and 1 in alcohol consumption and activity level. ⁹¹ Five trials specifically conducted intention-to-treat analyses or had no dropouts. ^{47 85 96 97 98}

Eleven trials were either not designed as double-blind studies or failed to state clearly whether blinding was attempted. ^{30 35 38 71 72 74 76 83 84 97} Three trials specifically used a placebo with a garlic odor. ^{36 64 95} Of 28 trials with reported dropout rates, 4 were equal to or greater than 20 percent. ^{69 73 88 94} Compliance with prescribed therapy was reportedly assessed in 18 trials; ^{24 30 47 64 69 70 78 79 82 83 86 88 90 93 94 95 96} results of this assessment were not given in 4. ^{24 70 82 88} In one trial, 20 percent of participants were excluded from the statistical analysis due to "insufficient" compliance. ⁶⁹ Compliance that was less than 80 percent during the intervention period was reported in three trials (i.e., 72 percent, 51 percent of garlic recipients less than 75 percent compliant, and 53 percent of garlic recipients less than 80 percent compliant). ^{47 90 94} Some trials only reported within-group differences or reported statistically significant differences between groups that we were not able to replicate or verify. ^{69 71 87 94} The authenticity of one trial has been challenged because of concerns about the ultrasound pictures accompanying the published text, the randomization process, and the high dropout rate without intention-to-treat analyses. ^{88 101}

Dietary or activity recommendations were included in several trial protocols. Seven reported no changes in diet during the trial, ^{64 77 79 80 90 93 95} 1 reported decreases in fat intake in the garlic group compared with the placebo group, ⁷⁸ 12 reported no changes in body mass or weight, ^{24 34 64 77 79 80 82 86 92 93 95 99} and 2 reported that activity did not change. ^{64 90} Dissolution standards of the garlic preparations and lots that were used in the trials were rarely reported. ⁷⁸

Clinical Outcomes

Trial Results

One multicenter trial involving 98 adults with hyperlipidemia found no differences in lipid outcomes at 3 months between persons given an antilipidemic agent (bezafibrate) and persons given a standardized dehydrated garlic preparation (Kwai^®). ⁸⁵ The trial that compared a garlic fish oil combination with placebo reported decreases in total cholesterol with active therapy that were of greater magnitude than reductions of most other trials and that were statistically significant. ⁹⁷ The single head-to-head comparison of a standardized dehydrated preparation (Kwai^®) with garlic oil (Hoefels Original Garlic Oil^®) was an open trial that did not attempt blinding. ⁸³ This trial found no significant differences between the two preparations in total cholesterol or HDL measurements at 1, 2, 3, and 4 months. A statistically significant reduction in low density lipoprotein cholesterol (LDL-C) favoring Kwai^®over Original Garlic Oil was found at 4-month, but not 2-month, followup observations.

Meta-analyses of other trials that were placebo controlled and that reported total cholesterol outcomes at 4 to 6 weeks, 8 to 12 weeks, and 20 to 24 weeks were conducted. (Of note, the study by Kandziora that compared garlic plus an antihypertensive agent with antihypertensive therapy alone is included in some of the analyses.) Prior to conducting meta-analyses, examination of Galbraith and funnel plots as well as statistical testing for heterogeneity identified some trials with outlier results (Figures 3-8). Review of the design and protocol characteristics of such trials did not elucidate obvious systematic differences that could explain their outlier status. Quantitative analyses were performed with and without outliers. Results are described below for analyses without the outlier studies. (Including the outliers yielded slightly different effect sizes that were in the same direction and usually of the same statistical significance as the results that excluded the outliers.)

Figure

Figure 3. Galbraith plot of studies with total cholesterol results at 4 to 6 weeks.

Figure

Figure 4. Funnel plot of studies with total cholesterol results at 4 to 6 weeks.

Figure

Figure 5. Galbraith plot of studies with total cholesterol results at 8 to 12 weeks.

Figure

Figure 6. Funnel plot of studies with total cholesterol results at 8 to 12 weeks.

Figure

Figure 7. Galbraith plot of studies with total cholesterol results at 20 to 24 weeks.

Figure

Figure 8. Funnel plot of studies with total cholesterol results at 20 to 24 weeks.

Figure 9 shows results of meta-analyses for trials reporting total cholesterol outcomes at 4 to 6 weeks. Combining all studies, regardless of preparation type, statistically showed that garlic preparations compared with placebo significantly reduced total cholesterol levels on average by 7.2 mg/dL (95 percent confidence interval [CI] 1.2 to 13.2 mg/dL). Combining only studies that used standardized dehydrated garlic preparations showed average reductions of 10.2 mg/dL (95 percent CI 3.1 to 17.3 mg/dL). A few studies that reported outcomes at 4 to 6 weeks could not be included in the figure or meta-analyses. Two studies reported that garlic significantly decreased cholesterol. ^{36 82}

Figure

Figure 9. Forest plot of studies with total cholesterol results at 4 to 6 weeks.

Figure 10 gives total cholesterol results at 8 to 12 weeks. Combining all studies, regardless of preparation type, statistically showed that garlic preparations compared with placebo significantly reduced total cholesterol levels on average by 17.1 mg/dL (95 percent CI 12.4 to 21.9 mg/dL). Combining only studies that used standardized dehydrated garlic preparations showed average reductions of 19.2 mg/dL (95 percent CI 13.0 to 25.4 mg/dL). Of note, one 12-week study that is not shown in the figure stated that "garlic tablets (Kwai^®) led to a marginal fall in total cholesterol at 6 weeks that was not sustained at 12 weeks." ⁸⁴

Figure

Figure 10. Forest plot of studies with total cholesterol results at 8 to 12 weeks.

Figure 11 shows results of the eight trials that reported total cholesterol outcomes at 20 to 24 weeks. Average reductions with garlic preparations compared with placebo at this time point were not significant (1.2 mg/dL, 95 percent CI --8.2 to 10.7 mg/dL). Limiting this analysis to the three 6-month studies that compared standardized dehydrated garlic preparations with placebo also was not significant (2.8 mg/dL, 95 percent CI -8.7 to 14.4 mg/dL) (Figure 11). Removing Koscielny's study from these analyses because of its questioned authenticity yields a larger but still nonsignificant effect. The statistical significance of these analyses should be interpreted cautiously because of few studies and low power. One additional trial that was not shown in the figure reported that total cholesterol decreased significantly after 3 years of followup in postinfarction patients who were given 6 to 10 g of garlic ether extract compared with patients given placebo (reported total cholesterol changes: 6.85 to 6.21 mmol with garlic and "no change" with placebo). ⁷¹

Figure

Figure 11. Forest plot of studies with total cholesterol results at 20 to 24 weeks.

Figure 12 shows the total cholesterol summary results for the different time periods. Observed reductions at 4 to 6 weeks appear smaller than observed reductions at 8 to 12 weeks, but not smaller than reductions at 20 to 24 weeks. It is not clear whether these observations are due to systematic differences among studies that have longer and shorter followup durations or are due to time-dependent effects of garlic. For example, there were few long-term studies; longer studies had higher dropout rates, and longer studies may have used preparations of Kwai^® that had lower allicin-release properties. Observations depicted in Figure 12 also suggest, but do not prove, that standardized dehydrated preparations may result in greater short-term (4- to 12-week) total cholesterol reductions than other preparations.

Figure

Figure 12. Forest plot of pooled results of total cholesterol findings at different time periods.

LDL reductions at 8 to 12 weeks for "all studies regardless of preparation type compared with placebo (n=13)" and for "dehydrated preparation studies only compared with placebo (n=10)" were 6.2 mg/dL (95 percent CI 0.8 to 11.7 mg/dL) and 6.7 mg/dL (95 percent CI 0 to 13.5 mg/dL), respectively. Triglyceride reductions at 8 to 12 weeks for "all studies regardless of preparation type compared with placebo (n=17)" and for "dehydrated preparation studies only compared with placebo (n=13)" were 19.1 mg/dL (95 percent CI 7.6 to 30.4 mg/dL) and 21.1 mg/dL (95 percent CI 8.3 to 34.0 mg/dL), respectively. None of the analyses regarding HDL values were statistically significant, possibly because few studies reported HDL. At 8 to 12 weeks, the average HDL reduction for "all garlic preparations compared with placebo (n=14)" was 0.9 mg/dL (95 percent CI --1.0 to 2.8 mg/dL), and for "standardized dehydrated preparations only compared with placebo (n=10)" was 0.2 mg/dL (95 percent CI --2.1 to 2.4 mg/dL). LDL, triglyceride, and HDL analyses are given in Appendix A.

Sensitivity analyses that were limited to trials that specifically included only participants with hyperlipidemia did not vary significantly from those presented above. (Few trials had normal mean values of total cholesterol at baseline; thus, few were excluded in this sensitivity analyses.) Finally, sensitivity analyses that excluded studies that were not designed as double blind were not different than the analyses presented above.

Laryngeal Cancer

A single, population-based, case-control study from Shanghai, China evaluated associations between garlic consumption and laryngeal cancer. ¹¹⁶ Of the 263 participants with laryngeal cancer who were identified from a population-based cancer registry, 201 (76 percent) were interviewed; 92 percent of these had histologically proven disease. Age- and gender-matched control participants were randomly selected from the general population. Of 414 interviewed control participants, 48 (12 percent) were chosen as "second controls" because initially selected controls had died or could not be located. Garlic exposure was assessed with a structured questionnaire that asked about the usual frequency and amount of consumption in the previous 10-year period, ignoring any recent changes. Whether interviewers were aware of participants' disease status was not stated. The odds ratios were adjusted for age, education, and smoking and used the lowest tertile of garlic consumption as the referent point. The odds ratio was 0.6 for the middle tertile of garlic consumption and 0.5 for the highest tertile. No CIs were given, but the test for trend was statistically significant (p=0.02).

Breast Cancer

A large prospective cohort study, which began in 1986, on diet and cancer in The Netherlands assessed associations between the use of garlic supplements and breast cancer. ^{106 109} The cohort of 120,852 men and women, age 55 to 69 years, originated from 204 population registries. Cancer followup was linked to pathology and cancer registries. Completeness of cancer followup for the first 3.3 years of the study was estimated to be 95 percent. Dietary history regarding the consumption of 150 food items in the year prior to the start of the study was assessed with a self-administered semiquantitative food-frequency questionnaire. Consumption of fresh garlic was not assessed in the baseline questionnaire; a later version of the questionnaire completed by a sample of the cohort in 1990 suggests that less than 2 percent of the participants consumed fresh garlic daily, while 13 percent consumed up to one clove per week.

Garlic supplement users were defined as persons who self-reported daily use of any garlic supplement for at least 1 year in the 5-year period before baseline. Recall was estimated to be 78 percent accurate. Types and brands of garlic supplements were not reported. (Of note, Lawson analyzed 23 brands and 4 types [powder tablets, gel-suspended powder capsules, steam-distilled oil capsules, and oil macerate capsules] of European supplements that were available in the late 1980s. Marked variation in allicin yields, allyl sulfide content, and sulfur compounds were found.) ¹³¹

After 3.3 years of followup, a case-cohort analysis was performed that assessed whether garlic consumption was associated with incident primary breast cancer that had been microscopically confirmed in 469 women. The comparison group, consisting of 1,716 women, was a randomly selected subcohort from the original cohort sample. Persons with prevalent cancer other than skin cancer, in situ breast cancer, or breast cancer other than carcinoma (sarcoma, lymphoma, or unspecified morphology) were excluded from analyses.

Multivariable analyses were adjusted for age, parity, age at menarche, age at first birth, age at menopause, artificially induced menopause, oral contraceptive use, history of benign breast disease, breast cancer in the mother, breast cancer in sisters, alcohol consumption, Quetelet index, highest level of personal education, smoking status, and dietary intake of vitamin C and β-carotene. Using persons who denied any supplement use as the reference, the following adjusted rate ratios were found: garlic supplement use with or without use of other supplements was 0.87 (95 percent CI 0.58 to 1.31) and garlic supplement use only without any other supplement use was 0.75 (95 percent CI 0.41 to 1.38).

A hospital-based, case-control study examined 107 incident, histologically confirmed cases of breast cancer. ¹¹⁵ Case participants were women younger than 76 years old who were admitted or referred to a hospital in Lausanne, Switzerland. Cases were linked to incidence data from the Vaud Cancer Registry. The hospital control participants were 318 women with admission diagnoses unrelated to known or suspected risk factors for breast cancer. Specifically, women with breast, gynecological, hormonal, metabolic, or neoplastic disease were excluded. Most case participants were admitted for trauma (30 percent) or surgical conditions (30 percent). Less than 15 percent of the persons who were approached for interview refused. Garlic exposure was assessed with a self-reported subjective score that assessed the general weekly level of intake. Serving size was not reported. The odds ratios given for garlic were adjusted for age and used the lowest tertile of garlic consumption as the referent point. The odds ratio was 0.7 for the middle tertile of use and 0.6 for the highest tertile. CIs were not given, and the chi-square test for trend was negative.

Lung Cancer

The Netherlands cohort study, previously described, also examined associations between garlic supplement use and lung cancer after 3.3 years of followup. ¹¹³ This case-cohort analysis involved 484 cases of microscopically confirmed incident lung carcinoma and 3,123 randomly sampled subcohort members. No participants had other prevalent cancers (except for skin cancer), in situ lung carcinoma, or lung cancer other than carcinoma.

Multivariable analyses were adjusted for gender, age, pack years of past smoking, pack years of current smoking, highest educational level, history of obstructive lung disease, onion and leek consumption, and dietary intake of vitamin C and β-carotene. Using persons who denied any supplement use as the reference, the following adjusted rate ratios were found: garlic supplement use with or without use of other supplements was 1.22 (95 percent CI 0.81 to 1.86) and garlic supplement use exclusive of other supplements was 1.78 (95 percent CI 1.08 to 2.92). Using any other supplement use as the reference, adjusted rate ratios for garlic with or without other supplements was 0.92 (95 percent CI 0.46 to 1.86).

Esophageal and Stomach/Gastric Cancer

Two case-control studies examined associations with esophageal cancer. ^{117 118} One case-cohort study and three case-control studies examined associations with gastric carcinoma. ^{56 111 112 118}

Colorectal Cancer

Two case-cohort studies and one case-control study assessed associations between garlic and colorectal cancer. ^{59 60 108} The first case-cohort study was from the first 3.3 years of followup in The Netherlands cohort study. ¹⁰⁸ It involved 293 microscopically proven incident colon carcinoma cases, 150 microscopically proven incident rectal carcinoma cases, and 3,123 randomly sampled subcohort members. Risk ratios were adjusted for age, gender, smoking status, education, family history of intestinal cancer, previous history of chronic intestinal disease, cholecystectomy, and dietary intake of vitamin C and β-carotene. Using persons who denied any garlic supplement use as the reference, the following adjusted rate ratios for colon carcinoma were found: garlic supplement use with or without use of other supplements was 1.26 (95 percent CI 0.84 to 1.91) and garlic supplement use exclusive of other supplements was 1.36 (95 percent CI 0.79 to 2.35). Using any other supplement use as the reference, the adjusted rate ratio for garlic with or without other supplements was 0.93 (95 percent CI 0.51 to 1.71). Using persons who denied any supplement use as the reference, the following adjusted rate ratios for rectal carcinoma were found: garlic supplement use with or without use of other supplements was 0.77 (95 percent CI 0.41 to 1.46) and garlic supplement use exclusive of other supplements was 1.28 (95 percent CI 0.63 to 2.60).

The second case-cohort study involved 41,837 women from Iowa, age 55 to 69 years. ⁶⁰ Participants had completed a self-administered 127-item food-frequency questionnaire in 1986 and were monitored for cancer incidence for 5 years. Garlic consumption that was queried included fresh cloves or powdered preparations (shakes). A "serving" was defined as a commonly used portion size. Participants in the cohort were randomly selected from licensed drivers; 43 percent returned questionnaires. Pathologically confirmed incident colon cancer cases were identified from state and national registries. Persons with prevalent cancer other than skin cancer, calculated daily energy intakes of less than 600 kilocalories, and more than 30 missing items on questionnaires were excluded from all analyses. After applying these exclusion criteria, 80 percent of cases and 84 percent of noncases remained. Relative risks were adjusted for age and energy intake. (Relative risks that were adjusted for other factors, such as body mass index, physical activity, smoking, alcohol intake, and history of colitis or polyps, were reportedly similar to those adjusted only for age and energy intake.) Using persons denying any garlic intake as the reference, persons who reported consuming a half-serving per week had relative risks for proximal colon cancer of 1.32 (95 percent CI 0.79 to 2.22) and those consuming one or more servings per week had risks of 1.00 (95 percent CI 0.56 to 1.79). Using persons denying any garlic intake as the reference, persons who reported consuming a half-serving per week had relative risks for distal colon cancer of 0.85 (95 percent CI 0.53 to 1.36) and those consuming one or more servings per week had risks of 0.52 (95 percent CI 0.30 to 0.93). The chi-square test for trend for the protective association with distal colon cancer data was significant (p<0.05) for unadjusted, but not adjusted, analyses.

The case-control study involved 223 persons with histologically confirmed colon (n=119) or rectal (n=104) cancer who had been admitted to a Swiss hospital. ⁵⁹ Controls were 491 patients who had been admitted to the same university hospital for a "wide spectrum of acute nonneoplastic conditions unrelated to long-term modifications of diet." Acute conditions included traumatic and nontraumatic orthopedic conditions (49 percent); surgical conditions (32 percent); and miscellaneous medical, ear, nose, and throat and skin diseases (19 percent). Numbers of eligible participants were not stated, but fewer than 15 percent of the persons who were approached for interview refused. Garlic exposure was assessed using a food-frequency questionnaire that assessed average weekly consumption during the 2 years before cancer diagnosis or hospital admission. Whether interviewers were aware of participants' disease status was not stated. Odds ratios were adjusted for age, sex, education, smoking, alcohol, body mass index, physical activity, and meat and vegetable intake. Using the lowest tertile of garlic consumers as the reference, the adjusted odds ratio for the middle tertile of garlic consumers was 0.50 (95 percent CI 0.34 to 0.74). The adjusted odds ratio for the highest tertile was 0.39 (95 percent CI 0.21 to 0.70). The chi-square test for trend was significant (p<0.01).

Endometrial Cancer

A single case-control study examined 274 incident, histologically confirmed cases of endometrial cancer. ¹¹⁴ Case participants were recruited using a population-based cancer registry in Switzerland and hospital records in Northern Italy. Control participants were women who had been admitted to the same networks of hospitals in which cases had been identified. They had primary diagnoses unrelated to known or suspected risk factors for endometrial cancer or to any long-term modification in diet. Specifically, women with gynecological, hormonal, metabolic, or neoplastic disease or who had undergone hysterectomy were excluded. Most case participants were admitted for trauma (32 percent) or surgical conditions (26 percent). Less than 10 percent of the persons approached for interview refused. Garlic exposure was assessed with a self-reported subjective score that assessed general weekly level of intake; serving size was not reported. The odds ratios given for garlic were adjusted for age and study center and used the lowest tertile of garlic consumption as the reference. The odds ratio was 0.67 for the middle tertile of use and 0.71 for the highest tertile. CIs were not given, but the chi-square test for trend was positive (p<0.05).

Prostate Cancer

One British case-control study involved 328 white men with prostate cancer who were diagnosed before age 75 years, and 328 age-matched population controls. ⁶¹ Of 425 eligible participants, 77 percent of those identified through histopathology or other laboratory records and cancer registries participated in dietary interviews. The response rate in the first selected controls was 81 percent. Garlic use was ascertained by a food-frequency questionnaire and by asking participants if they had regularly taken nutritional supplements during the last 5 years. The food-frequency questionnaire queried the usual frequency of consumption of standard portion sizes. Whether interviewers were aware of participants' disease status was not clear. Odds ratios were adjusted for social class. Using no consumption of garlic in the last 5 years as the reference, adjusted odds ratios were: 0.94 (95 percent CI 0.51 to 1.73) for consuming garlic less than once monthly; 0.77 (95 percent CI 0.49 to 1.20) for consuming garlic one to four times monthly; and 0.64 (95 percent CI 0.38 to 1.09) for consuming garlic at least twice weekly. The p value for trend was 0.13. Adjusted odds ratios examining garlic exposure from food plus supplements were similar to those examining exposure from food (within 0.05).

Precancerous Lesions

One survey from a village of garlic farmers in China examined gastroscopy-proven precancerous lesions in 197 villagers who consumed various quantities of garlic. ¹⁰⁴ Participating villagers represented 30 percent of the eligible population. Reasons for refusing participation were not given. Garlic consumption over an unspecified time period (presumably 1 year) was assessed by questionnaire; whether garlic intake referred mainly to raw garlic or various home preparations was not stated. Dietary interviews appeared to have occurred prior to knowledge of gastroscopy results. The small study found a statistically significant positive association between helicobacter pylori with histologically proven chronic atrophic gastritis and gastric metaplasia or dysplasia. Higher garlic consumption was not associated with statistically significant lower prevalence of helicobacter . Garlic consumption of 5 to 15 kg annually compared with 0 to 5 kg annually was associated with decreased, but not statistically significant, odds of chronic atrophic gastritis (odds ratio 0.70, 95 percent CI 0.21 to 2.30) and metaplasia/dysplasia (odds ratio 0.55, 95 percent CI 0.08 to 3.71).

A large age- and gender-matched case-control study from two Southern California Kaiser Permanente Medical Centers examined the associations between multiple vegetables, including garlic, and colorectal polyps. ¹⁰⁵ All 976 study participants had screening sigmoidoscopies between 1991 and 1993; none had known invasive cancer, inflammatory bowel disease, or severe gastrointestinal symptoms. Approximately 80 percent of all eligible persons participated. Cases were defined as persons who had histologically confirmed adenomatous polyps, whereas controls were defined as persons who had no polyps at sigmoidoscopy and no history of polyps. Food consumption was assessed by a 126-item, semiquantitative, food-frequency questionnaire covering diet in the year before sigmoidoscopy. Serving size was not reported. The food interview was administered approximately 5 months after sigmoidoscopy; interviewers were unaware of the participants' disease status for 70 percent of the cases and 87 percent of the controls. Odds ratios were adjusted for race; body mass index; physical activity; smoking; calories; saturated fat; vitamin c, β-carotene, and folate intake; and dietary fiber. The adjusted odds ratio for colorectal polyps in persons reporting 0.5 "servings" of garlic per week compared with no garlic consumption was 0.92 (95 percent CI 0.64 to 1.34). Comparisons with persons reporting 1.0 to 2.5 servings per week and more than 3.0 servings per week were 0.98 (95 percent CI 0.61 to 1.56) and 0.66 (95 percent CI 0.43 to 1.01), respectively. A linear model assessing trend was statistically significant (p=0.01).

Garlic Breath or Body Odor

Five trials reported that statistically significant greater numbers of persons who were given standardized dehydrated tablets (Kwai^® or noncommercial enteric-coated preparation) had breath or body odor (as perceived by themselves or others) compared with persons given placebo. ^{47 78 88 89 93} Other trials reported that persons receiving dehydrated tablets (Kwai^®) had smelly breath or body odor, but the trials had too few numbers to compare differences between garlic and placebo groups. ^{24 39 64 69 86 90 93} In one trial, some persons taking "aged garlic extract ^TM" as well as some taking placebo reportedly perceived unusual body odor. ⁹⁴ In another trial, participants taking steam distilled garlic and those taking placebos with coatings tasting like garlic reported garlic odor. ⁹⁵ Neither of the latter studies reported numbers of participants with these adverse effects.

Skin Manifestations

Allergic Manifestations

In addition to the skin manifestations described above, other reported allergic reactions to garlic include: asthma, rhinitis, conjunctivitis, urticaria, anaphylaxis, and angioedema. Several case reports and two case series reported respiratory symptoms such as asthma and rhinitis. ^{139 160 176 177 178 179 180 181 182 183 184 185} In almost all cases, the respiratory symptoms occurred after occupational chronic inhalation of garlic dust. Most patients had a delay of at least 5 years between the first exposure to garlic dust and the appearance of the symptoms. ^{139 182 183 184} In one person, the exposure interval was 3 months, ¹⁷⁸ and in another, respiratory symptoms were precedent to the chronic garlic exposure. ¹⁸¹

Diagnostic tests confirming the allergic etiology of respiratory symptoms, such as the prick test and bronchial challenge test, were usually positive for multiple allergens, including garlic. ^{139 160 176 177 178 181 182 183 184} In six of eight reports, symptoms were noted to improve once garlic exposure was discontinued, and to recur with rechallenge or new exposure. ^{139 178 179 180 181 184} One report did not comment on resolution of symptoms, ¹⁸³ and another noted symptoms improved after exposure to garlic was discontinued, but a bronchial challenge test was negative. ¹⁸² In this latter case, the prick test, radioallergosorbent test (RAST), and bronchial challenge test were positive for Tyrophagus putrescentiae , raising the possibility that asthma that is induced by garlic dust inhalation may be related to dust contaminants with other allergens such as storage mites.

Of the above reports addressing respiratory symptoms with chronic inhalation of garlic, three noted some persons complained of allergic symptoms after eating garlic. ^{139 183 184} Allergic symptoms included urticaria, asthma, angioedema, and anaphylaxis. A positive formal oral challenge test in one person with asthma and angioedema was reported. ¹⁸³

There were two reports of persons without occupational exposure to garlic dust who had allergic reactions to garlic ingestion; ^{186 187} the first person had recurrent episodes of systemic urticaria and angioedema following ingestion of foods containing both raw or cooked garlic. He also had a strong reaction on the skin prick test to commercial garlic extract and fresh garlic. The second person had nausea, diarrhea, dizziness, tachycardia, and Quicke's edema 4 hours after he ingested raw garlic. A scratch test was positive for lid edema.

We found three case series and a case report that included patients with suspected food allergy who were tested for garlic. ^{188 189 190 191} In the first case series, 12 of 219 persons with suspected food allergy complained of itching, urticaria, and/or gastrointestinal symptoms after eating garlic. Seven of the 12 persons had increased Immunoglobulin E (IgE) for garlic, while only one reacted positively to a commercial extract skin prick test. In the second case series, 1 of 142 children with suspected food allergy had a positive skin prick test, specific serum IgE, and labial food challenge test for garlic. ¹⁸⁹ The third case series described 580 persons who had been evaluated from 1984 to 1992 for food sensitization or allergy. The frequency of positive allergy tests for garlic in persons seen during different time periods was 13 percent from 1984 to 1986, 18 percent from 1987 to 1989, and 20 percent from 1984 to 1992. ¹⁹⁰

Coagulation Dysfunction

Four patients with bleeding following garlic ingestion have been described. ^{24 192 193 194} None had received medication known to cause bleeding disorders. Spontaneous spinal epidural hematoma causing paraplegia was reported in a patient who consumed an average of four garlic cloves per day. ¹⁹² This patient had a prolonged bleeding time and normal prothrombin time, partial thromboplastin time, and platelet count. The prolonged bleeding time corrected within 1 week of presentation. "Significant" bloody oozing during an augmentation mammoplasty and a 200-cubic-centimeter postoperative hematoma was reported in a patient who retrospectively admitted to heavy garlic intake preoperatively. ¹⁹³ This patient also had a prolonged bleeding time that normalized within 1 week. Significant bleeding during and after transurethral resection of the prostate was described in a man taking garlic tablets. ¹⁹⁴ He had normal cephalin clotting time and prothrombin time at surgery. Platelet function studies that were obtained 3 months after he resumed his normal dose of garlic tablets showed a failure of platelet aggregation in the presence of collagen. Of note, one of the double-blind trials reports a participant with oozing on shaving. He was taking placebo.

Increased INR results have been reported in two patients who were previously stabilized on warfarin and were taking garlic pearls or tablets without changes to medication or other habits. ¹⁹⁵ A small, unpublished double-blind trial that evaluated effects of "aged garlic extract^TM" in patients who were stabilized on warfarin reportedly found no "extra bleeding" with garlic compared with placebo (personal communication from Kyolic^® representative).

Cardiovascular Dysfunctions

An acute inferior myocardial infarction after excessive consumption of garlic was described in a 23-year-old man who had no risk factors for cardiovascular disease. ¹⁹⁶ "Cardiospasm" was described in a 56-year-old man, with probable cutaneous sensitivity to macerated garlic, who was given an oral challenge of an unspecified amount of garlic. ¹³⁶

Gastrointestinal Dysfunctions

Mechanical bowel obstruction was described in a 66-year-old man who ate a whole garlic bulb for his cold-like symptoms. ¹⁹⁷ A report of 309 patients with epigastric pain, hematemesis and/or hematochezia, and associated acute gastric mucosal lesions at endoscopy noted that some of the patients reported garlic ingestion prior to developing symptoms. ¹⁹⁸ Five volunteers who were given 10 to 25 milliliters (ml) of garlic extract containing 100 to 250 g of hulled garlic cloves complained of burning sensations in the mouth, esophagus, and stomach that lasted less than 15 minutes. One of these volunteers, who was given 25 ml of extract, also experienced nausea, diaphoresis, and lightheadedness. ¹⁹⁹ Other volunteers who were given 900 mg of garlic powder reported increased flatulence (n<10). ²⁰⁰ Several of the randomized trials reported that a few persons who were given standardized dehydrated tablets experienced abdominal pain, fullness, anorexia, or flatulence. ^{64 76 78 81 86 88 89 93} As numbers were always very small, comparisons between persons given garlic and those given placebo were not made.

Other Dysfunctions

One case report described a person with symptoms of Meniere's disease after consuming garlic. ²⁰¹ A case-control study reported botulism in 36 persons who ate sandwiches made with garlic-buttered bread. The source was thought to be bottled chopped garlic in soybean oil that had been stored unrefrigerated for 8 months. ²⁰²

Garlic breath was reported "on more than one occasion" in newborn infants delivered to Pakistani mothers. ²⁰³ A randomized, placebo-controlled crossover trial evaluated whether effects of garlic consumption (1.5 g of garlic extract) in eight mothers altered infants' suckling behaviors. A change in the perceived intensity of breast milk odor was noted in each mother 2 hours after garlic ingestion. Infants attached to the breast for statistically significant longer periods of time, but their numbers of feeds and amounts of breast milk consumed did not increase when their mothers were given garlic compared with mothers who were given placebo. ²⁰⁴

Beliefs About Garlic

A survey of 65 persons who were recruited at six supermarkets in Helsinki gave information about attitudes and beliefs that related to garlic. Most participants had positive health beliefs about garlic (62 percent). Positive health beliefs were related to frequent and heavy consumption of garlic. Survey participants perceived garlic odor as disturbing, but less offensive than many other odors. ²⁰⁵