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1.  Reinforcing effects of caffeine in coffee and capsules. 
In a residential research ward the reinforcing and subjective effects of caffeine were studied under double-blind conditions in volunteer subjects with histories of heavy coffee drinking. In Experiment 1, 6 subjects had 13 opportunities each day to self-administer either a caffeine (100 mg) or a placebo capsule for periods of 14 to 61 days. All subjects developed a clear preference for caffeine, with intake of caffeine becoming relatively stable after preference had been attained. Preference for caffeine was demonstrated whether or not preference testing was preceded by a period of 10 to 37 days of caffeine abstinence, suggesting that a recent history of heavy caffeine intake (tolerance/dependence) was not a necessary condition for caffeine to function as a reinforcer. In Experiment 2, 6 subjects had 10 opportunities each day to self-administer a cup of coffee or (on different days) a capsule, dependent upon completing a work requirement that progressively increased and then decreased over days. Each day, one of four conditions was studied: caffeinated coffee (100 mg/cup), decaffeinated coffee, caffeine capsules (100 mg/capsule), or placebo capsules. Caffeinated coffee maintained the most self-administration, significantly higher than decaffeinated coffee and placebo capsules but not different from caffeine capsules. Both decaffeinated coffee and caffeine capsules were significantly higher than placebo capsules but not different from each other. In both experiments, subject ratings of "linking" of coffee or capsules covaried with the self-administration measures. These experiments provide the clearest demonstrations to date of the reinforcing effects of caffeine in capsules and in coffee.
doi:10.1901/jeab.1989.52-127
PMCID: PMC1338955  PMID: 2794839
2.  Coffee Consumption and Prostate Cancer Risk and Progression in the Health Professionals Follow-up Study 
Background
Coffee contains many biologically active compounds, including caffeine and phenolic acids, that have potent antioxidant activity and can affect glucose metabolism and sex hormone levels. Because of these biological activities, coffee may be associated with a reduced risk of prostate cancer.
Methods
We conducted a prospective analysis of 47 911 men in the Health Professionals Follow-up Study who reported intake of regular and decaffeinated coffee in 1986 and every 4 years thereafter. From 1986 to 2006, 5035 patients with prostate cancer were identified, including 642 patients with lethal prostate cancers, defined as fatal or metastatic. We used Cox proportional hazards models to assess the association between coffee and prostate cancer, adjusting for potential confounding by smoking, obesity, and other variables. All P values were from two-sided tests.
Results
The average intake of coffee in 1986 was 1.9 cups per day. Men who consumed six or more cups per day had a lower adjusted relative risk for overall prostate cancer compared with nondrinkers (RR = 0.82, 95% confidence interval [CI] = 0.68 to 0.98, Ptrend = .10). The association was stronger for lethal prostate cancer (consumers of more than six cups of coffee per day: RR = 0.40, 95% CI = 0.22 to 0.75, Ptrend = .03). Coffee consumption was not associated with the risk of nonadvanced or low-grade cancers and was only weakly inversely associated with high-grade cancer. The inverse association with lethal cancer was similar for regular and decaffeinated coffee (each one cup per day increment: RR = 0.94, 95% CI = 0.88 to 1.01, P = .08 for regular coffee and RR = 0.91, 95% CI = 0.83 to 1.00, P = .05 for decaffeinated coffee). The age-adjusted incidence rates for men who had the highest (≥6 cups per day) and lowest (no coffee) coffee consumption were 425 and 519 total prostate cancers, respectively, per 100 000 person-years and 34 and 79 lethal prostate cancers, respectively, per 100 000 person-years.
Conclusions
We observed a strong inverse association between coffee consumption and risk of lethal prostate cancer. The association appears to be related to non-caffeine components of coffee.
doi:10.1093/jnci/djr151
PMCID: PMC3110172  PMID: 21586702
3.  Can coffee prevent caries? 
Aim:
To determine the anti-carious effect of coffee in humans. Coffee represents one of the most consumed products by the population.
Materials and Methods:
A random sample of 1000 individuals, of both sexes, who consumed only coffee as a beverage and who visited the Out-Patient Department of KLE Society's Institute of Dental Sciences, with a dental complaint and no history of any major illness, were considered as subjects. The patients' histories with regard to the coffee intake, such as, period of consumption, frequency of consumption, whether taken with milk or wihout milk, with sugar or without sugar, and the brand make, was noted. History of the type of diet, consumption of sweets, periodicity of brushing, and whether they had undergone fluoride applications were also noted. A thousand patients who consumed beverages other than coffee were taken as the control.
Results:
The results showed that coffee most consumed was roasted coffee, and the frequency on an average was about three cups per day, for an average period of 35 years. The Decayed/Missing/Filled Surface (DMFS) scores varied from 2.9, in subjects who drank black coffee, to 5.5 in subjects who consumed coffee together with sweeteners and creaming agents. The DMFS score was 3.4 in subjects who consumed coffee together with milk but no sugar. The DMFS score of the control subjects was 4, indicating that coffee if consumed alone had anticaries action, but in the presence of additives the antibacterial and anticaries action was totally minimized.
Conclusion:
Thus coffee can help in prevention of dental caries if consumed without additives.
doi:10.4103/0972-0707.53336
PMCID: PMC2848806  PMID: 20379435
Caries; coffee; DMFS score; milk; sugar; Streptococcus mutans
4.  Coffee, Tea, and Caffeine Consumption and Incidence of Colon and Rectal Cancer 
Background:
Frequent coffee consumption has been associated with a reduced risk of colorectal cancer in a number of case–control studies. Cohort studies have not revealed such an association but were limited in size. We explored the association between consumption of coffee and tea and the incidence of colorectal cancer in two large prospective cohorts of women and men.
Methods:
We used data from the Nurses' Health Study (women) and the Health Professionals' Follow-up Study (men). Consumption of coffee and tea and total caffeine intake were assessed and updated in 1980, 1984, 1986, 1990, and 1994 among women and in 1986, 1990, and 1994 among men. The incidence of cancer of the colon or rectum was ascertained through 1998. Hazard ratios were calculated using Cox proportional hazards models that adjusted for potential confounders. All tests of statistical significance were two-sided.
Results:
During almost 2 million person-years of follow-up, 1438 cases of colorectal cancer were observed. Consumption of caffeinated coffee or tea with caffeine or caffeine intake was not associated with the incidence of colon or rectal cancer in either cohort. For both cohorts combined, the covariate-adjusted hazard ratio for colorectal cancer associated with consumption of each additional cup of caffeinated coffee was 0.99 (95% confidence interval [CI] = 0.96 to 1.03). However, participants who regularly consumed two or more cups of decaffeinated coffee per day had a 52% (95% CI = 19% to 71%) lower incidence of rectal cancer than those who never consumed decaffeinated coffee (crude incidence rate of 12 cases of rectal cancer per 100 000 person-years of follow-up among participants consuming two or more cups of decaffeinated coffee per day and crude incidence rate of 19 cases of rectal cancer per 100 000 person-years of follow-up among participants who never consumed decaffeinated coffee).
Conclusions:
Consumption of caffeinated coffee, tea with caffeine, or caffeine was not associated with incidence of colon of rectal cancer, whereas regular consumption of decaffeinated coffee was associated with a reduced incidence of rectal cancer.
doi:10.1093/jnci/dji039
PMCID: PMC1909914  PMID: 15713963
5.  Effects of Alcohol, Coffee, and Tobacco, Alone or in Combination, on Physiological Parameters and Anxiety in a Young Population 
Journal of Caffeine Research  2012;2(2):70-76.
Objective
The objective was to evaluate the effects of a single dose of alcohol, caffeine, and nicotine, alone or in combination, on physiological parameters (systolic and diastolic blood pressure [SBP and DBP] and heart rate [HR]) and state-trait anxiety in healthy young volunteers.
Method
The procedure reproduces the conditions under which the subjects (n=76) usually ingest alcohol (through an alcoholic beverage), caffeine (through a cup of coffee), and nicotine (by smoking a cigarette), separately or in combination, according to their consumption habits of each individual. SBP and DBP, HR, and state anxiety (SA) were registered before (phase 1) and after (phase 2) treatment.
Results
Intake of alcohol or alcohol-nicotine reduced DBP. Comparisons between control and combined treatment (coffee-alcohol-nicotine) groups revealed a decrease in HR in the former group but not in the latter. The coffee consumers alone exhibited a tendency toward an increase in SA, while the control group showed a tendency toward a decrease in this measure. When Phase 1 and Phase 2 were compared, a decrease was observed in SBP (alcohol and coffee-alcohol groups), DBP (alcohol and alcohol-nicotine groups), HR (all groups, except coffee-alcohol and coffee-alcohol-nicotine groups), and SA (coffee-alcohol-nicotine group).
Conclusions
(i) A low dose of alcohol, either alone or in combination with a cigarette, decreases DBP but not SBP; (ii) the polyconsumption of coffee, alcohol, and nicotine blocks the adaptation response (the reduction in HR in control subjects in the second phase); (iii) an increase of SA is observed after consuming coffee, while the opposite occurs in control subjects (a decrease of SA).
doi:10.1089/jcr.2012.0018
PMCID: PMC3621324  PMID: 24761267
6.  Coffee and acute ischemic stroke onset 
Neurology  2010;75(18):1583-1588.
Objective:
Prior research suggests an acutely elevated risk of myocardial infarction and sudden cardiac death in the hour after coffee intake. However, the risk of ischemic stroke associated with transient exposure to coffee remains unclear. We hypothesized that caffeine intake is associated with a transiently increased risk of ischemic stroke.
Methods:
In this multicenter case-crossover study, we interviewed 390 subjects (209 men, 181 women) between January 2001 and November 2006 a median of 3 days after acute ischemic stroke. Each subject's coffee consumption in the hour before stroke symptoms was compared with his or her usual frequency of consumption in the prior year.
Results:
Of the 390 subjects, 304 (78%) drank coffee in the prior year, 232 within 24 hours and 35 within 1 hour of stroke onset. The relative risk (RR) of stroke in the hour after consuming coffee was 2.0 (95% confidence interval [CI], 1.4–2.8; p < 0.001). There was no apparent increase in risk in the hour following consumption of caffeinated tea (RR = 0.9, 95% CI 0.4–2.0; p = 0.85) or cola (RR = 1.0, 95% CI 0.4–2.4; p = 0.95). The association between ischemic stroke in the hour after coffee consumption was only apparent among those consuming ≤1 cup per day but not for patients who consumed coffee more regularly (p for trend = 0.002). Relative risks remained similar when the sample was restricted to those who were not simultaneously exposed to other potential triggers and the results remained significant after stratifying by time of day.
Conclusion:
Coffee consumption transiently increases the risk of ischemic stroke onset, particularly among infrequent drinkers.
doi:10.1212/WNL.0b013e3181fb443d
PMCID: PMC3120108  PMID: 20881275
7.  Coffee consumption and CYP1A2 genotype in relation to bone mineral density of the proximal femur in elderly men and women: a cohort study 
Background
Drinking coffee has been linked to reduced calcium conservation, but it is less clear whether it leads to sustained bone mineral loss and if individual predisposition for caffeine metabolism might be important in this context. Therefore, the relation between consumption of coffee and bone mineral density (BMD) at the proximal femur in men and women was studied, taking into account, for the first time, genotypes for cytochrome P450 1A2 (CYP1A2) associated with metabolism of caffeine.
Methods
Dietary intakes of 359 men and 358 women (aged 72 years), participants of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), were assessed by a 7-day food diary. Two years later, BMD for total proximal femur, femoral neck and trochanteric regions of the proximal femur were measured by Dual-energy X-ray absorptiometry (DXA). Genotypes of CYP1A2 were determined. Adjusted means of BMD for each category of coffee consumption were calculated.
Results
Men consuming 4 cups of coffee or more per day had 4% lower BMD at the proximal femur (p = 0.04) compared with low or non-consumers of coffee. This difference was not observed in women. In high consumers of coffee, those with rapid metabolism of caffeine (C/C genotype) had lower BMD at the femoral neck (p = 0.01) and at the trochanter (p = 0.03) than slow metabolizers (T/T and C/T genotypes). Calcium intake did not modify the relation between coffee and BMD.
Conclusion
High consumption of coffee seems to contribute to a reduction in BMD of the proximal femur in elderly men, but not in women. BMD was lower in high consumers of coffee with rapid metabolism of caffeine, suggesting that rapid metabolizers of caffeine may constitute a risk group for bone loss induced by coffee.
doi:10.1186/1743-7075-7-12
PMCID: PMC2842270  PMID: 20175915
8.  A Prospective Cohort Study of Coffee Consumption and Risk of Endometrial Cancer over a 26-year of Follow-Up 
Background
Coffee has been reported to lower levels of estrogen and insulin, two hormones implicated in endometrial carcinogenesis, but prospective data on the relation between coffee consumption and risk of endometrial cancer are limited.
Methods
We prospectively assessed coffee consumption in relation to endometrial cancer risk in the Nurses’ Health Study (NHS) with 67,470 female participants aged 34–59 in 1980. Cumulative average coffee intake was calculated with all available questionnaires to assess long-term effects. Cox regression models were used to calculate incidence rate ratios (RR), controlling for other risk factors.
Results
Fewer than 4 cups of coffee per day were not associated with endometrial cancer risk. However, women who consumed 4 or more cups of coffee had 25% lower risk of endometrial cancer than those who consumed less than 1 cup per day (multivariable RR=0.75; 95% CI =0.57–0.97; Ptrend = 0.02). We found the similar association with caffeinated coffee consumption (RR for ≥ 4 vs. <1 cup/day = 0.70; 95% CI = 0.51–0.95). For decaffeinated coffee consumption, a suggestive inverse association was found among women who consumed 2 or more cups per day vs. <1 cup/month. Tea consumption was not associated with endometrial cancer risk.
Conclusions
These prospective data suggest that 4 or more cups of coffee per day are associated with a lower risk of endometrial cancer.
Impact
Drinking of coffee, given its widespread consumption, might be an additional strategy to reduce endometrial cancer risk. However, addition of substantial sugar and cream to coffee could offset any potential benefits.
doi:10.1158/1055-9965.EPI-11-0766
PMCID: PMC3237942  PMID: 22109346
coffee; caffeine; tea; endometrial cancer; prospective cohort study
9.  Human coffee drinking: manipulation of concentration and caffeine dose. 
In a residential research ward coffee drinking was studied in 9 volunteer human subjects with histories of heavy coffee drinking. A series of five experiments was undertaken to characterize adlibitum coffee consumption and to investigate the effects of manipulating coffee concentration, caffeine dose per cup, and caffeine preloads prior to coffee drinking. Manipulations were double-blind and scheduled in randomized sequences across days. When cups of coffee were freely available, coffee drinking tended to be rather regularly spaced during the day with intercup intervals becoming progressively longer throughout the day; experimental manipulations showed that this lengthening of intercup intervals was not due to accumulating caffeine levels. Number of cups of coffee consumed was an inverted U-shaped function of both coffee concentration and caffeine dose per cup; however, coffee-concentration and dose-per-cup manipulations did not produce similar effects on other measures of coffee drinking (intercup interval, time to drink a cup, within-day distribution of cups). Caffeine preload produced dose-related decreases in number of cups consumed. As a whole, these experiments provide some limited evidence for both the suppressive and the reinforcing effects of caffeine on coffee consumption. Examination of total daily coffee and caffeine intake across experiments, however, provides no evidence for precise regulation (i.e., titration) of coffee or caffeine intake.
doi:10.1901/jeab.1986.45-133
PMCID: PMC1348223  PMID: 3958660
10.  The Relationship between Caffeine and Coffee Consumption and Exfoliation Glaucoma or Glaucoma Suspect: A Prospective Study in Two Cohorts 
Purpose.
We examined the association between caffeine and caffeinated beverage consumption in relation to the risk of exfoliation glaucoma or exfoliation glaucoma suspect (EG/EGS).
Methods.
We followed 78,977 women from the Nurses' Health Study (NHS) and 41,202 men from the Health Professionals Follow-up Study (HPFS) who were at least 40 years of age, did not have glaucoma, and reported undergoing eye examinations from 1980 (NHS) or 1986 (HPFS) to 2008. Information on consumption of caffeine-containing beverages and potential confounders were repeatedly ascertained in validated follow-up questionnaires. Confirmation with medical record review revealed 360 incident EG/EGS cases. Multivariate rate ratios (RRs) for EG/EGS were calculated in each cohort and then pooled using meta-analytic techniques.
Results.
Compared with participants whose cumulatively updated total caffeine consumption was <125 mg/day, participants who consumed ≥500 mg/day had a trend toward increased risk of EG/EGS that was not statistically significant (RR = 1.43; 95% confidence interval [CI], 0.98–2.08); P trend = 0.06). Compared to abstainers, those who drank ≥3 cups of caffeinated coffee daily were at increased risk of EG/EGS (RR = 1.66; 95% CI, 1.09–2.54; P trend = 0.02). These results were not materially altered after adjustment for total fluid intake. Associations were stronger among women with a family history of glaucoma (P interaction = 0.06 for coffee; P interaction = 0.03 for caffeine). We did not find associations with consumption of other caffeinated products (caffeinated soda, caffeinated tea, decaffeinated coffee or chocolate) and risk of EG/EGS (P trend ≥0.31).
Conclusions.
We observed a positive association between heavier coffee consumption with risk of EG/EGS in this large prospective study.
In a large 28-year-old prospective study including 360 incident cases, caffeinated coffee consumption was significantly associated with an increased risk of exfoliation glaucoma or exfoliation glaucoma suspect. The association between caffeine consumption was particularly strong among those with a positive family history of glaucoma
doi:10.1167/iovs.12-10085
PMCID: PMC3450917  PMID: 22918628
11.  Effects of coffee on driving performance during prolonged simulated highway driving 
Psychopharmacology  2012;222(2):337-342.
Rationale
Coffee is often consumed to counteract driver sleepiness. There is limited information on the effects of a single low dose of coffee on prolonged highway driving in non-sleep deprived individuals.
Objectives
The aim of this study was to examine the effects of a single cup of coffee (80 mg caffeine) on simulated highway driving performance.
Methods
Non-sleep deprived healthy volunteers (n = 24) participated in a double-blind, placebo-controlled, crossover study. After 2 h of monotonous highway driving, subjects received caffeinated or decaffeinated coffee during a 15-min break before continuing driving for another 2 h. The primary outcome measure was the standard deviation of lateral position (SDLP), reflecting the weaving of the car. Secondary outcome measures were speed variability, subjective sleepiness, and subjective driving performance.
Results
The results showed that caffeinated coffee significantly reduced SDLP as compared to decaffeinated coffee, both in the first (p = 0.024) and second hour (p = 0.019) after the break. Similarly, the standard deviation of speed (p = 0.024; p = 0.001), mental effort (p = 0.003; p = 0.023), and subjective sleepiness (p = 0.001; p = 0.002) were reduced in both the first and second hour after consuming caffeinated coffee. Subjective driving quality was significantly improved in the first hour after consuming caffeinated coffee (p = 0.004).
Conclusions
These findings demonstrate a positive effect of one cup of caffeinated coffee on driving performance and subjective sleepiness during monotonous simulated highway driving.
doi:10.1007/s00213-012-2647-7
PMCID: PMC3382640  PMID: 22315048
Caffeine; Automobile driving; Fatigue; Sleepiness
12.  Coffee, but not caffeine, has positive effects on cognition and psychomotor behavior in aging 
Age  2013;35(6):2183-2192.
The complex mixture of phytochemicals in fruits and vegetables provides protective health benefits, mainly through additive and/or synergistic effects. The presence of several bioactive compounds, such as polyphenols and caffeine, implicates coffee as a potential nutritional therapeutic in aging. Moderate (three to five cups a day) coffee consumption in humans is associated with a significant decrease in the risk of developing certain chronic diseases. However, the ability of coffee supplementation to improve cognitive function in aged individuals and the effect of the individual components in coffee, such as caffeine, have not been fully evaluated. We fed aged rats (19 months) one of five coffee-supplemented diets (0, 0.165, 0.275, 0.55, and 0.825 % of the diet) for 8 weeks prior to motor and cognitive behavior assessment. Aged rats supplemented with a 0.55 % coffee diet, equivalent to ten cups of coffee, performed better in psychomotor testing (rotarod) and in a working memory task (Morris water maze) compared to aged rats fed a control diet. A diet with 0.55 % coffee appeared to be optimal. The 0.165 % coffee-supplemented group (three cups) showed some improvement in reference memory performance in the Morris water maze. In a subsequent study, the effects of caffeine alone did not account for the performance improvements, showing that the neuroprotective benefits of coffee are not due to caffeine alone, but rather to other bioactive compounds in coffee. Therefore, coffee, in achievable amounts, may reduce both motor and cognitive deficits in aging.
doi:10.1007/s11357-012-9509-4
PMCID: PMC3824984  PMID: 23344884
Antioxidant; Anti-inflammatory; Spatial learning and memory; Chlorogenic acid
13.  Genome-Wide Gene-Environment Study Identifies Glutamate Receptor Gene GRIN2A as a Parkinson's Disease Modifier Gene via Interaction with Coffee 
PLoS Genetics  2011;7(8):e1002237.
Our aim was to identify genes that influence the inverse association of coffee with the risk of developing Parkinson's disease (PD). We used genome-wide genotype data and lifetime caffeinated-coffee-consumption data on 1,458 persons with PD and 931 without PD from the NeuroGenetics Research Consortium (NGRC), and we performed a genome-wide association and interaction study (GWAIS), testing each SNP's main-effect plus its interaction with coffee, adjusting for sex, age, and two principal components. We then stratified subjects as heavy or light coffee-drinkers and performed genome-wide association study (GWAS) in each group. We replicated the most significant SNP. Finally, we imputed the NGRC dataset, increasing genomic coverage to examine the region of interest in detail. The primary analyses (GWAIS, GWAS, Replication) were performed using genotyped data. In GWAIS, the most significant signal came from rs4998386 and the neighboring SNPs in GRIN2A. GRIN2A encodes an NMDA-glutamate-receptor subunit and regulates excitatory neurotransmission in the brain. Achieving P2df = 10−6, GRIN2A surpassed all known PD susceptibility genes in significance in the GWAIS. In stratified GWAS, the GRIN2A signal was present in heavy coffee-drinkers (OR = 0.43; P = 6×10−7) but not in light coffee-drinkers. The a priori Replication hypothesis that “Among heavy coffee-drinkers, rs4998386_T carriers have lower PD risk than rs4998386_CC carriers” was confirmed: ORReplication = 0.59, PReplication = 10−3; ORPooled = 0.51, PPooled = 7×10−8. Compared to light coffee-drinkers with rs4998386_CC genotype, heavy coffee-drinkers with rs4998386_CC genotype had 18% lower risk (P = 3×10−3), whereas heavy coffee-drinkers with rs4998386_TC genotype had 59% lower risk (P = 6×10−13). Imputation revealed a block of SNPs that achieved P2df<5×10−8 in GWAIS, and OR = 0.41, P = 3×10−8 in heavy coffee-drinkers. This study is proof of concept that inclusion of environmental factors can help identify genes that are missed in GWAS. Both adenosine antagonists (caffeine-like) and glutamate antagonists (GRIN2A-related) are being tested in clinical trials for treatment of PD. GRIN2A may be a useful pharmacogenetic marker for subdividing individuals in clinical trials to determine which medications might work best for which patients.
Author Summary
Parkinson's disease (PD), like most common disorders, involves interactions between genetic make-up and environmental exposures that are unique to each individual. Caffeinated-coffee consumption may protect some people from developing PD, although not all benefit equally. In a genome-wide search, we discovered that variations in the glutamate-receptor gene GRIN2A modulate the risk of developing PD in heavy coffee drinkers. The study was hypothesis-free, that is, we cast a net across the entire genome allowing statistical significance to point us to a genetic variant, regardless of whether it fell in a genomic desert or an important gene. Fortuitously, the most significant finding was in a well-known gene, GRIN2A, which regulates brain signals that control movement and behavior. Our finding is important for three reasons: First, it is a proof of concept that studying genes and environment on the whole-genome scale is feasible, and this approach can identify important genes that are missed when environmental exposures are ignored. Second, the knowledge of interaction between GRIN2A, which is involved in neurotransmission in the brain, and caffeine, which is an adenosine-A2A-receptor antagonist, will stimulate new research towards understanding the cause and progression of PD. Third, the results may lead to personalized prevention of and treatment for PD.
doi:10.1371/journal.pgen.1002237
PMCID: PMC3158052  PMID: 21876681
14.  Coffee consumption and reduced risk of hepatocellular carcinoma: findings from the Singapore Chinese Health Study 
Cancer causes & control : CCC  2011;22(3):503-510.
Background
Coffee consumption has been associated with reduced markers of hepatic cell damage, reduced risk of chronic liver disease, and cirrhosis across a variety of populations. Data on the association between coffee consumption and risk of hepatocellular carcinoma (HCC), especially in high-risk populations, are sparse.
Methods
This study examines the relationship between coffee and caffeine consumption, and the risk of developing HCC within the Singapore Chinese Health Study, a prospective cohort of 63,257 middle-aged and older Chinese men and women, a relatively high-risk population for HCC. Baseline data on coffee consumption and other dietary and lifestyle factors were collected through inperson interviews at enrollment between 1993 and 1998.
Results
As of 31 December 2006, 362 cohort participants had developed HCC. High levels of coffee or caffeine consumption were associated with reduced risk of HCC (p for trend < 0.05). Compared with non-drinkers of coffee, individuals who consumed three or more cups of coffee per day experienced a statistically significant 44% reduction in risk of HCC (hazard ratio 0.56, 95% confidence interval, 0.31–1.00, p = .049) after adjustment for potential confounders and tea consumption.
Conclusion
These data suggest that coffee consumption may reduce the risk of developing HCC in Chinese in Singapore.
doi:10.1007/s10552-010-9725-0
PMCID: PMC3400401  PMID: 21258859
Coffee; Caffeine; HCC; Hepatocellular; Liver cancer; GGT
15.  Thermogenic Effect from Nutritionally Enriched Coffee Consumption 
Background
The purpose of this study was to examine the effect of nutritionally enriched JavaFit™ (JF) coffee (450 mg of caffeine, 1200 mg of garcinia cambogia, 360 mg of citrus aurantium extract, and 225 mcg of chromium polynicotinate) on resting oxygen uptake (VO2), respiratory exchange ratio (RER), heart rate (HR), and blood pressure (BP) in healthy and physically active individuals.
Method
Ten subjects (8 male, 2 female; 20.9 ± 1.7 y; 178.1 ± 10.4 cm; 71.8 ± 12.1 kg) underwent two testing sessions administered in a randomized and double-blind fashion. During each session, subjects reported to the Human Performance Laboratory after at least 3-h post-absorptive state and were provided either 354 ml (1.5 cups) of freshly brewed JF or commercially available caffeinated coffee (P). Subjects then rested in a semi-recumbent position for three hours. VO2 and HR were determined every 5 min during the first 30 min and every 10 min during the next 150 min. BP was determined every 15 min during the first 30 min and every 30 min thereafter. Area under the curve (AUC) analysis was computed for VO2, whereas a session-average was calculated for RER, HR and BP.
Results
Initial analysis revealed no significant differences. However, seven of the ten subjects were considered responders to JF (had a higher AUC for VO2during JF than P). Statistical analysis showed the difference between JF and P (12%) to be significantly different in these responders. In addition, the average systolic BP was higher (p < 0.05) in JF (118 ± 7 mmHg) than P (115 ± 8 mmHg) in both the total sample and the subgroup of responders. No differences in average HR and average diastolic BP were observed between JF and P in both the total sample and the subgroup of responders.
Conclusion
It appears that consuming a nutritionally-enriched coffee beverage may increase resting energy expenditure in individuals that are sensitive to the caffeine and herbal coffee supplement. In addition, this supplement also appears to affect cardiovascular dynamics by augmenting systolic arterial blood pressure.
doi:10.1186/1550-2783-3-1-35
PMCID: PMC2129151  PMID: 18500961
caffeine; citrus aurantium; garcinia cambogia; chromium polynicotinate; herbal supplement
16.  Obesity, coffee consumption and CRP levels in postmenopausal overweight/obese women: Importance of hormone replacement therapy use 
European journal of clinical nutrition  2009;63(12):1419-1424.
Background/Objective
Obesity is associated with an inflammatory state that is often characterized by elevated plasma C-reactive protein (CRP) levels. Although coffee is broadly consumed in Western societies, few studies have examined the relationship between obesity, coffee consumption and CRP levels. The objective of the present study was to assess the relationship between obesity, coffee consumption and variation in CRP in postmenopausal, overweight/obese women with or without hormone replacement therapy (HRT) use.
Subjects/Methods
Cross-sectional analyses of 344 healthy sedentary, overweight/obese postmenopausal women (mean age=57.1±6.4 years and mean body mass index [BMI]=36.1±3.9 kg/m2). Plasma CRP levels were measured by a highly sensitive immunoassay that used monoclonal antibodies coated with polystyrene particles. Diet was assessed using the Food Intake and Analysis System semi-quantitative food frequency questionnaire.
Results
Plasma CRP was positively associated with BMI (p<0.001) and negatively associated with coffee consumption (p≤0.05). In women using HRT, plasma CRP was positively associated BMI in women consuming less than one cup of coffee per month (r2=0.15 [p<0.001]), one cup per day (0.14 [p=0.02]) and more than one cup per day (0.12 [p=0.03]). In women who did not use HRT, CRP was associated BMI only in women consuming less than one cup of coffee per day (r2=0.16 [p<0.001]) but not in women consuming one cup per day (0.06 [p=0.10]) or more than one daily cup of coffee (0.03 [p=0.27]).
Conclusion
Among overweight/obese postmenopausal women coffee consumption is negatively associated with CRP. Coffee consumption appears to attenuate the association between BMI and CRP, but only in women not using HRT.
doi:10.1038/ejcn.2009.112
PMCID: PMC2787671  PMID: 19756031
Obesity; Coffee; CRP; Postmenopausal women; Hormone replacement Therapy
17.  Coffee and black tea consumption and breast cancer mortality in a cohort of Swedish women 
British Journal of Cancer  2012;107(5):874-878.
Background:
Coffee and black tea contain a mixture of compounds that have the potential to influence breast cancer risk and survival. However, epidemiologic data on the relation between coffee and black tea consumption and breast cancer survival are sparse.
Methods:
We investigated the association between coffee and black tea consumption and survival among 3243 women with invasive breast cancer in the Swedish Mammography Cohort. Intake was estimated using a food frequency questionnaire. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% confidence intervals (95% CIs).
Results:
From 1987 to 2010 there were 394 breast cancer-specific deaths and 973 total deaths. Coffee and black tea were not associated with breast cancer-specific or overall mortality. Women consuming 4+ cups of coffee per day had a covariate and clinical characteristics-adjusted HR (95% CI) of death from breast cancer of 1.14 (0.71–1.83; ptrend=0.81) compared with those consuming <1 cup per day. Women consuming 2+ cups of black tea per day had a covariate and clinical characteristics-adjusted HR (95% CI) of death from breast cancer of 1.02 (0.67–1.55; ptrend=0.94) compared with non-tea drinkers. Caffeine was also not associated with breast cancer-specific (HR for top to bottom quartile=1.06; 95% CI=0.79–1.44; ptrend=0.71) or overall mortality.
Conclusion:
Our findings suggest that coffee, black tea, and caffeine consumption before breast cancer diagnosis do not influence breast cancer-specific and overall survival.
doi:10.1038/bjc.2012.337
PMCID: PMC3425971  PMID: 22836509
breast cancer; epidemiology; coffee; tea; caffeine; survival
18.  Pharmacokinetics of Caffeine following a Single Administration of Coffee Enema versus Oral Coffee Consumption in Healthy Male Subjects 
ISRN Pharmacology  2013;2013:147238.
The objective of this study was to determine the pharmacokinetics of caffeine after single administration of a coffee enema versus coffee consumed orally in healthy male subjects. The study design was an open-label, randomized two-phase crossover study. Eleven healthy subjects were randomly assigned either to receive 500 mL of coffee enema for 10 minutes or to consume 180 mL of ready-to-drink coffee beverage. After a washout period of at least 10 days, all the subjects were switched to receive the alternate coffee procedure. Blood samples were collected immediately before and at specific time points until 12 hours after coffee administration in each phase. The mean caffeine content in both the coffee solution prepared for the coffee enema and the ready-to-drink coffee beverage was not statistically different. The Cmax and AUC of caffeine obtained from the coffee enema were about 3.5 times significantly less than those of the coffee consumed orally, despite having slightly but statistically faster Tmax. The t1/2 of caffeine obtained following both coffee procedures did not statistically differ. In summary, the relative bioavailability of caffeine obtained from the coffee enema was about 3.5 times significantly less than those of the coffee consumed orally.
doi:10.1155/2013/147238
PMCID: PMC3603218  PMID: 23533801
19.  Recommendations Regarding Dietary Intake and Caffeine and Alcohol Consumption in Patients With Cardiac Arrhythmias: What Do You Tell Your Patients To Do or Not To Do? 
Opinion statement
The etiology of arrhythmias including atrial fibrillation is multifactorial. Most arrhythmias are associated with comorbid illnesses like hypertension, diabetes, thyroid disease, or advanced age. Although it is tempting to blame a stimulant like caffeine as a trigger for arrhythmias, the literature does not support this idea. There is no real benefit to having patients with arrhythmias limit their caffeine intake. Caffeine is a vasoactive substance that also may promote the release of norepinephrine and epinephrine. However, acute ingestion of caffeine (as coffee or tea) does not cause atrial fibrillation. Even patients suffering a myocardial infarction do not have an increased incidence of ventricular or other arrhythmias after ingesting several cups of coffee. Large epidemiologic studies have also failed to find a connection between the amount of coffee/caffeine used and the development of arrhythmias. As such, it does not make sense to suggest that patients with palpitations, paroxysmal atrial fibrillation, or supraventricular tachycardia, abstain from caffeine use. Energy drinks are a new phenomenon on the beverage market, with 30-50 % of young adults and teens using them regularly. Energy drinks are loaded with caffeine, sugar, and other chemicals that can stimulate the cardiac system. There is an increasing body of mainly anecdotal case reports describing arrhythmias or even sudden death triggered by exercise plus using energy drinks. Clearly, there must be more study in this area, but it is wise to either limit or avoid their use in patients with arrhythmias. Moderate to heavy alcohol use seems to be associated with the development of atrial fibrillation. The term “holiday heart” was coined back in 1978, to describe patients who had atrial fibrillation following binge alcohol use. Thus, it is reasonable to recommend to patients with arrhythmias that they limit their alcohol use, although unfortunately this treatment will likely not completely resolve their arrhythmia.
doi:10.1007/s11936-012-0193-6
PMCID: PMC3742445  PMID: 22865244
Arrhythmias; Energy drink; Atrial fibrillation; Alcohol; Caffeine; Sudden death
20.  Coffee consumption, rheumatoid factor, and the risk of rheumatoid arthritis 
Annals of the Rheumatic Diseases  2000;59(8):631-635.
BACKGROUND—Recent epidemiological studies have suggested that smoking is a risk factor for rheumatoid factor (RF) positive rheumatoid arthritis (RA). Being overweight, high serum cholesterol, and dietary factors have in some studies been found to be associated with the risk of RA. No attention, however, has been paid to coffee consumption as a risk determinant, though it is a shared covariate of the alleged risk factors.
OBJECTIVES—This study aimed at examining coffee consumption for its associations with RF positivity and with the risk of RA.
METHODS—Coffee consumption was studied, firstly, for its association with RF (sensitised sheep cell agglutination titre ⩾128) in a cross sectional survey of 6809 subjects with no clinical arthritis, and secondly, for its prediction of RA in a cohort of 18 981 men and women who had neither arthritis nor a history of it at the baseline examination in 1973-76. Up to late 1989, 126 subjects of the cohort study had developed RA, of whom, 89 were positive for RF by the time of diagnosis.
RESULTS—In the cross sectional survey the number of cups of coffee drunk daily was directly proportional to the prevalence of RF positivity. Adjusted for age and sex this association was significant (p value for linear trend, 0.008), but after further adjustment for smoking the linear trend declined below significance (p=0.06). In the cohort study there was an association between coffee consumption and the risk of RF positive RA that was not due to age, sex, level of education, smoking, alcohol intake, body mass index, or serum cholesterol. After adjustment for these potential confounders the users of four or more cups a day still had a relative risk of 2.20 (95% confidence interval 1.13 to 4.27) for developing RF positive RA compared with those drinking less. Coffee consumption did not predict the development of RF negative RA.
CONCLUSION—Coffee consumption may be a risk factor for RA, possibly through mechanisms contributing to the production of RF. This hypothesis remains to be tested in further studies.


doi:10.1136/ard.59.8.631
PMCID: PMC1753204  PMID: 10913061
21.  Coffee Intake, Smoking, and Pulmonary Function in the Atherosclerosis Risk in Communities Study 
American Journal of Epidemiology  2009;169(12):1445-1453.
Coffee contains polyphenolic antioxidants and caffeine, which may favorably affect pulmonary function. Therefore, the authors studied cross-sectional associations (1987–1989) between coffee intake and pulmonary function in the Atherosclerosis Risk in Communities Study, a population-based cohort study (analytic sample = 10,658). They also conducted analyses stratified by smoking status, since smoking is a strong risk factor for respiratory disease and could influence the effects of caffeine and antioxidants. Self-reported coffee intake was categorized as rare/never, <7 cups/week, 1 cup/day, 2–3 cups/day, and ≥4 cups/day. Pulmonary function was characterized by the spirometric measures forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). After adjustment for demographic factors, lifestyle characteristics, and dietary factors, pulmonary function values increased across increasing categories of coffee consumption in never and former smokers but not in current smokers. In never or former smokers who consumed ≥4 cups of coffee daily, FVC and FEV1 were 2%–3% greater than in never or former smokers who rarely/never consumed coffee (Ptrend values: in never smokers, 0.04 for FVC and 0.07 for FEV1; in former smokers, <0.001 for FVC and <0.001 for FEV1). These data show a possible beneficial effect of coffee (or a coffee ingredient) on pulmonary function, but it appears to be limited to nonsmokers.
doi:10.1093/aje/kwp068
PMCID: PMC2727200  PMID: 19372215
coffee; forced expiratory volume; lung diseases; respiratory function tests; smoking; vital capacity
22.  Coffee and Caffeine Consumption in Relation to Sex Hormone–Binding Globulin and Risk of Type 2 Diabetes in Postmenopausal Women 
Diabetes  2010;60(1):269-275.
OBJECTIVE
Coffee consumption has been inversely associated with type 2 diabetes risk, but its mechanisms are largely unknown. We aimed to examine whether plasma levels of sex hormones and sex hormone–binding globulin (SHBG) may account for the inverse association between coffee consumption and type 2 diabetes risk.
RESEARCH DESIGN AND METHODS
We conducted a case-control study nested in the prospective Women's Health Study (WHS). During a median follow-up of 10 years, 359 postmenopausal women with newly diagnosed type 2 diabetes were matched with 359 control subjects by age, race, duration of follow-up, and time of blood draw.
RESULTS
Caffeinated coffee was positively associated with SHBG but not with sex hormones. Multivariable-adjusted geometric mean levels of SHBG were 26.6 nmol/l among women consuming ≥4 cups/day of caffeinated coffee and 23.0 nmol/l among nondrinkers (P for trend = 0.01). In contrast, neither decaffeinated coffee nor tea was associated with SHBG or sex hormones. The multivariable-adjusted odds ratio (OR) of type 2 diabetes for women consuming ≥4 cups/day of caffeinated coffee compared with nondrinkers was 0.47 (95% CI 0.23–0.94; P for trend = 0.047). The association was largely attenuated after further adjusting for SHBG (OR 0.71 [95% CI 0.31–1.61]; P for trend = 0.47). In addition, carriers of rs6259 minor allele and noncarriers of rs6257 minor allele of SHBG gene consuming ≥2 cups/day of caffeinated coffee had lower risk of type 2 diabetes in directions corresponding to their associated SHBG.
CONCLUSIONS
Our findings suggest that SHBG may account for the inverse association between coffee consumption and type 2 diabetes risk among postmenopausal women.
doi:10.2337/db10-1193
PMCID: PMC3012180  PMID: 21030499
23.  Effects of caffeinated coffee consumption on intraocular pressure, ocular perfusion pressure, and ocular pulse amplitude: a randomized controlled trial 
Eye  2012;26(8):1122-1130.
Purpose
To examine the effects of caffeinated coffee consumption on intraocular pressure (IOP), ocular perfusion pressure (OPP), and ocular pulse amplitude (OPA) in those with or at risk for primary open-angle glaucoma (POAG).
Methods
We conducted a prospective, double-masked, crossover, randomized controlled trial with 106 subjects: 22 with high tension POAG, 18 with normal tension POAG, 20 with ocular hypertension, 21 POAG suspects, and 25 healthy participants. Subjects ingested either 237 ml of caffeinated (182 mg caffeine) or decaffeinated (4 mg caffeine) coffee for the first visit and the alternate beverage for the second visit. Blood pressure (BP) and pascal dynamic contour tonometer measurements of IOP, OPA, and heart rate were measured before and at 60 and 90 min after coffee ingestion per visit. OPP was calculated from BP and IOP measurements. Results were analysed using paired t-tests. Multivariable models assessed determinants of IOP, OPP, and OPA changes.
Results
There were no significant differences in baseline IOP, OPP, and OPA between the caffeinated and decaffeinated visits. After caffeinated as compared with decaffeinated coffee ingestion, mean mm Hg changes (±SD) in IOP, OPP, and OPA were as follows: 0.99 (±1.52, P<0.0001), 1.57 (±6.40, P=0.0129), and 0.23 (±0.52, P<0.0001) at 60 min, respectively; and 1.06 (±1.67, P<0.0001), 1.26 (±6.23, P=0.0398), and 0.18 (±0.52, P=0.0006) at 90 min, respectively. Regression analyses revealed sporadic and inconsistent associations with IOP, OPP, and OPA changes.
Conclusion
Consuming one cup of caffeinated coffee (182 mg caffeine) statistically increases, but likely does not clinically impact, IOP and OPP in those with or at risk for POAG.
doi:10.1038/eye.2012.113
PMCID: PMC3420046  PMID: 22678051
caffeine; coffee; intraocular pressure; ocular perfusion pressure; ocular pulse amplitude; primary open-angle glaucoma
24.  Coffee consumption is correlated with serum cholesterol in middle-aged Finnish men and women. 
The association between coffee consumption and serum cholesterol was studied in a cross-sectional epidemiological study in Finland where the annual per capita consumption of coffee (13.0 kg) is the highest in the world. Coffee consumption was assessed by a questionnaire in a representative population sample of 4744 men and 4495 women aged 25 to 64 years. Serum total cholesterol and HDL-cholesterol concentrations were determined in fresh sera by the enzymatic method. Data on a large number of potential confounding variables were also collected. In the age group 25 to 44 years, the level of serum total cholesterol increased linearly with increasing coffee consumption in both sexes, but in people aged 45 to 64 the peak level of serum cholesterol was found in those who consumed 4 to 6 cups of coffee per day. In the analysis of covariance controlling for age, body mass index, intake of fat, sugar, and alcohol, smoking, physical activity, and fasting time, the mean level of serum cholesterol of men was lower (p less than 0.001) in those who drank no coffee (5.9 mmol/l) than in those who drank 1 to 3 cups (6.1 mmol/l) or 4 or more cups (6.2 mmol/l) per day. In women, the corresponding mean serum cholesterol values were 5.8 mmol/l, 6.1 mmol/l, and 6.1 mmol/l (p less than 0.05). Serum HDL-cholesterol levels did not vary significantly with coffee consumption. There was a slight inverse association between tea drinking and serum total cholesterol in men (p less than 0.05) but not in women. Although our results suggest a positive association, the impact of coffee drinking on serum cholesterol seems to be minimal. The results also indicate that the possible mechanisms do not include caffeine.
PMCID: PMC1052628  PMID: 3443818
25.  Influence of coffee drinking and cigarette smoking on the risk of primary late onset blepharospasm: evidence from a multicentre case control study 
Prior coffee and smoking habits were investigated in a multicentre case control study involving 166 patients presenting with primary late onset blepharospasm (BSP), 228 hospital control patients with primary hemifacial spasm and 187 population control subjects from five Italian centres. Information on age at disease onset, smoking and coffee drinking status at the reference age and average number of cups of coffee drunk/cigarettes smoked per day reached high and similar test–retest reproducibility in case and control patients. Unadjusted logistic regression analysis yielded a significant inverse association of prior coffee drinking and cigarette smoking with case status for the control groups. After adjustment for age, sex, referral centre, disease duration, years of schooling and ever coffee drinking/cigarette smoking, as appropriate, the smoking estimate lacked significance whereas the association of coffee intake and BSP did not (cases vs hospital control patients: OR 0.37 (95% CI 0.20 to 0.67); cases vs population control subjects: OR 0.44 (95% CI 0.23 to 0.85)). The strength of the inverse association between BSP and coffee intake tended to increase with the average number of cups drunk per day. There was a significant correlation between age of BSP onset and number of cups per day (adjusted regression coefficient 1.73; p = 0.001) whereas no correlation was found with number of packs of cigarettes per day. Coffee drinking may be inversely associated with the development of primary BSP and this association may partly depend on the amount consumed.
doi:10.1136/jnnp.2007.119891
PMCID: PMC2117757  PMID: 17578856

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