This section needs more medical references for verification or relies too heavily on primary sources

In a healthy liver, caffeine is mostly broken down by the hepatic microsomal enzymatic system. The excreted metabolites are mostlyparaxanthines—theobromine and theophylline—and a small amount of unchanged caffeine. Therefore, the metabolism of caffeine depends on the state of this enzymatic system of the liver. The primary psychoactive chemical in coffee is caffeine, an adenosine antagonist that is known for its stimulant effects. Coffee also contains the monoamine oxidase inhibitors β-carboline and harmane, which may contribute to its psychoactivity.

Extensive scientific research has been conducted to examine the relationship between coffee consumption and an array of medical conditions. The general consensus in the medical community is that moderate regular coffee drinking in healthy individuals is either essentially benign or mildly beneficial. In 2012, the National Institutes of Health–AARP Diet and Health Study analysed the relationship between coffee drinking and mortality. They found that the amount of coffee consumed correlated negatively with risk of death, and that those who drank any coffee lived longer than those who did not. However the authors noted, "whether this was a causal or associational finding cannot be determined from our data." A similar study with similar results was published in the New England Journal of Medicine in 2012. Researchers involved in an ongoing 22-year study by the Harvard School of Public Health stated that "Coffee may have potential health benefits, but more research needs to be done."

Findings have also been contradictory as to whether coffee has any specific health benefits, and results are similarly conflicting regarding the potentially harmful effects of coffee consumption. Furthermore, results and generalizations are complicated by differences in age, gender, health status, and serving size.

According to Cancer Research UK, the results of a large-scale study published in 2012 provided insight into the effect of coffee drinking on cancer, highlighting that there was indeed no association between the two. Study results showed that drinking coffee "had no effect on the risk of dying from cancer."

Other studies suggest coffee consumption reduces the risk of Alzheimer's disease, dementia, Parkinson's disease, heart disease, diabetes mellitus type 2, non-alcoholic fatty liver disease, cirrhosis, gout and cancer of liver, skin, prostate, bowel, brain, gullet, colon, endometrium, breast, mouth andthroat.

The fact that decaffeinated coffee also exhibits preventative effects against diseases such as prostate cancer and type 2 diabetes suggests that coffee's health benefits are not solely a product of its caffeine content. Specifically, the antidiabetic effect of caffeine has been attributed to caffeic acid and chlorogenic acid. The presence of antioxidants in coffee have been shown to prevent free radicals from causing cell damage, which could lead to cancer. Antioxidant levels vary depending on how the beans are roasted as well as for how long. Evidence suggests that roasted coffee has a stronger antioxidant effect than green coffee.

Coffee is no longer thought to be a risk factor for coronary heart disease. A 2012 meta-analysis concluded that people who drank moderate amounts of coffee had a lower rate of heart failure, with the biggest effect found for those who drank more than four cups a day. Moreover, habitual coffee consumption is associated with improved vascular function. In a ten year study among 50,739 US women (mean age, 63 years) free of depressive symptoms at baseline (in 1996), coffee consumption was negatively correlated with risk of developing clinical depression. A review published in 2004 indicated a negative correlation between suicide rates and coffee consumption. It was suggested that the action of caffeine in blocking the inhibitory effects of adenosine on dopamine nerves in the brain reduced feelings of depression. Coffee consumption is also associated with improved endothelial function. Coffee extracts have been shown to inhibit 11β-Hydroxysteroid dehydrogenase type 1, an enzyme which converts cortisone to cortisol and is a current pharmaceutical target for the treatment of diabetes type 2 and metabolic syndrome.

Excessive amounts of coffee can cause very unpleasant and even life-threatening adverse effects. Coffee's adverse effects are more common when taken in excess. Many of coffee's health risks are due to its caffeine content and can therefore be avoided by drinking decaffeinated coffee.

Oily components called diterpenes are present in unfiltered coffee and coffee brewed using metal filters, but not in coffee brewed using paper filters; diterpenes may increase the risk of coronary heart disease.^[4]

Although some chemicals in coffee are carcinogens in rodents at very high doses, research suggests that they are not dangerous at the levels consumed by humans. Instant coffee has a much greater amount of acrylamide than brewed coffee. Research suggests that drinking caffeinated coffee can cause a temporary stiffening of arterial walls. Coffee may aggravate pre-existing conditions such as migraines, arrhythmias, and cause sleep disturbances. It was once thought that coffee aggravatesgastroesophageal reflux disease but recent research suggests no link.

Coffee consumption has been found to transiently increase the risk of ischemic stroke onset, particularly among infrequent drinkers.

Caffeine can cause anxiety, especially in high doses and in those with pre-existing anxiety disorders.

Some research suggests that a minority of moderate regular caffeine consumers experience some amount of clinical depression, anxiety, low vigor, or fatigue when discontinuing their caffeine use. However, the methodology of the these studies has been criticized. Withdrawal effects are more common and better documented in heavy caffeine users.

About 15% of the U.S. general population reports having stopped drinking coffee altogether, citing concerns about their health and the unpleasant side effects of caffeine.

A 2013 study by Liu et al. published in Mayo Clinic Proceedings established a correlation between coffee consumption >28 cups per week (>4 cups per day) and an increase in all-cause mortality in the total population of men and in men and women younger than 55 years. This correlation was not statistically significant for people aged 55 years and older. The authors noted that certain limitations exist in the study, such as a lack of data on different coffee preparations that can vary the overall composition of coffee's constituent compounds (e.g., cafestol, kahweol), which could impact CVD risk factors; a lack of data on marital status and total energy consumption; and possible residual confounding from health-risk factors such as smoking. One of the study's co-authors stated, "We're not saying that coffee is the cause of death; we just noticed coffee is associated with increased risk of death," which addresses the distinction between correlation and causation.

Caffeine alleviates headaches acutely and is used medically for this purpose, generally in combination with a painkiller such as ibuprofen. However, chronic caffeine use and withdrawal can cause headaches. Research has consistently linked caffeine withdrawal to headaches, even in those who drink coffee in moderation. Additionally, studies have suggested that those that drink four or more cups of coffee a day experience headaches more often than controls, even without discontinuing their coffee consumption.

Caffeine withdrawal causes consistent withdrawal effects.

The caffeine content of a cup of coffee varies depending mainly on the brewing method, and also on the variety of seed.^[172]

According to an article in the Journal of the American Dietetic Association, coffee has the following caffeine content, depending on how it is prepared:

While the percent of caffeine content in coffee seeds themselves diminishes with increased roast level, the opposite is true for coffee brewed from different grinds and brewing methods using the same proportion of coffee to water volume. The coffee sack (similar to the French press and other steeping methods) extracts more caffeine from dark roasted seeds; the percolator and espresso methods extract more caffeine from light roasted seeds.