Highs and Lows: Our twisted relationship with caffeine
Question: What mind and mood altering drug is legal at any age, easily available in almost every country in the world and socially acceptable to consume at any occasion?
(Hint: It is a crystalline compound belonging to a group of naturally produced drugs called methylxanthines which act as adenosine receptor blockers and phosphodiesterase inhibitors.)
Answer: Caffeine, of course.
The Real Black Gold
That miracle ingredient most often ingested via coffee that injects instant courage and optimism into billions of sleep-deprived people around the world every morning.
Global consumption of caffeine has been estimated at 120,000 tons per annum making it the world's most popular psychoactive substance, equating to one serving of a caffeinated beverage for every person, per day. (1) Ninety percent of North American adults make caffeine a part of their daily diet.
And why not? Caffeine reduces fatigue, increases alertness, focus, clarity of thought, improves general body coordination and supposedly has a host of long-term health benefits including longevity. What’s not to love? Except, perhaps, insomnia, nervousness, restlessness, irritability, an upset stomach, a racing heart, muscle tremors and a whole host of supposed long-term health hazards.
That’s about the state of modern research when it comes to caffeine. It can make you feel better. It can make you feel terrible. Some people can knock back eight cups of coffee a day. Others can’t even tolerate one cup. Nobody’s sure why. Age, lifestyle and medical history are possible reasons. Genetics probably plays a role. (2,3)
What is Caffeine and what does it do to me?
Caffeine reaches a peak level in the blood within 30 to 60 minutes of ingestion and has a half-life of three to five hours, according to the American Academy of Sleep Medicine. (4) The half-life is the time it takes for the drug to be eliminated from the body.
“Coffee is an amazingly potent collection of biologically active compounds,” says Dr. Walter C. Willet of Harvard School of Public Health. “Like any food-like substance, coffee has far-reaching effects on the body and needs to be respected as a potent drug.” (5)
The advice most commonly offered by experts is for individuals to be aware of the influence that caffeine is having on their body. “Caffeine is a drug and can affect people differently just like any other substance. It’s important that consumers understand how caffeine interacts with their bodies in regards to their personal health histories,” warns caffeineinformer.
Where does caffeine come from and how long has it been used?
Caffeine, a white, bitter powder in its pure form, is found in the beans, leaves, and fruit of over 60 plants, where it acts as a natural pesticide, paralyzing and killing predatory insects. These plants include coffee beans, tea leaves, guarana, cocoa seeds and Kola nuts which are used to make tea in parts of West Africa. The world's primary source of caffeine is the coffee bean. Around 70 countries produce coffee, with the overwhelming majority of the supply coming from the developing countries of Brazil, Vietnam, Colombia, Indonesia, and Ethiopia. (6)
“Without my morning coffee I’m just like a dried up piece of roast goat,” said Johann Sebastian Bach in the eighteenth century, but caffeine had been a popular stimulant long before that. Humans have consumed caffeine since the Stone Age. (7) Coffee has been popular in Arabia since the 13th century, though there is no record that pumpkin spice lattes were on the menu back then. Tea has been consumed in China for several thousand years. Popular myth traces coffee’s discovery to Ethiopia. Domesticated goats became elated and sleepless after browsing on certain shrubs and, upon trying the berries from the bushes, the goat herder experienced the same reaction.
In 1819, the German chemist Friedrich Ferdinand Runge isolated relatively pure caffeine for the first time. According to a legend, he did this at the behest of Johann Wolfgang von Goethe. (8) Today it is produced synthetically for use in foods, beverages and medications.
How much is too much?
Despite its long history and enduring popularity, caffeine’s impact on health is still poorly understood. A much-quoted observational study, celebrated by coffee lovers everywhere showed that coffee consumption even at high levels is tied to longevity. (9) (However, the study didn’t actually show it was the caffeine in coffee that bestowed the benefit of extra years.) The FDA has cited 400 milligrams of caffeine a day—about four or five cups of coffee—as a moderate amount not generally associated with negative effects. (10) “That's roughly the amount of caffeine in four cups of brewed coffee, 10 cans of cola or two "energy shot" drinks,” agrees the Mayo Clinic. (11) The John Hopkins Medical Center suggests, 200–300 mg. (12) There’s no lower limit because there is no nutritional need for caffeine.
Tired and Wired
One of the most common and possibly serious complaints about caffeine even at moderate consumption levels is its impact on sleep. (13) This is important because sleep deprivation has become a "public health epidemic" linked to a wide range of medical issues, including hypertension, diabetes, depression, obesity, and cancer, according to the U.S. Centers for Disease Control and Prevention (CDC). (14)
Another concern about caffeine consumption is that it will become an easy substitute for healthier methods of increasing energy such as regular exercise and eating a diet rich in fruit, nuts, and vegetables. (15)
Like most drugs, caffeine’s impact decreases with usage. The more coffee a person drinks, the more they will have to drink in order to get the same energy boost. One study found that complete caffeine tolerance occurred after just one to four days. (16) Another study showed caffeine tolerance occurs in part because the brain develops more adenosine receptors to compensate for those blocked by the caffeine molecule. (17)
According to a study involving 379 volunteers published in Neuropsychopharmacology, caffeine did not provide a mood boost at all, but only counterbalanced the negative feeling of caffeine withdrawal. (18) "With frequent consumption, substantial tolerance develops to the anxiogenic effect of caffeine, even in genetically susceptible individuals, but no net benefit for alertness is gained, as caffeine abstinence reduces alertness and consumption merely returns it to baseline.”
Up and then down, way down
Research conducted by the Walter Reed Army Institute of Research showed that caffeine improved performance only for the first two days of the simulated work week. (19) “During the last 3 days of sleep restriction, alertness and performance declined. Those in the coffee group also rated themselves to be “more annoyed” than those in the placebo group over the final days of the study.”
Because caffeine has become so ubiquitous, available today in beverages, candies, food staples, and medications, many people experience caffeine-related problems - stress, irritability, trouble sleeping, panic attacks, difficulty concentrating, gastrointestinal issues - without even realizing it is their caffeine intake that is to blame. (20) A Consumer Reports investigation of 27 popular energy drinks showed eleven didn't list the amount of caffeine on the label. (21)
There is also a question of how the caffeine is being ingested. says Murray Carpenter, author of Caffeinated: How Our Daily Habit Helps, Hurts and Hooks Us. People often underestimate just how powerful this drug is, he said. "A tablespoon — about 10 grams — will kill you," he warns, recounting the story of a college student who went into a seizure and died after chasing down spoonfuls of caffeine with an energy drink. Most of the caffeine used in soft drinks is actually synthetically produced in Chinese pharmaceutical plants which he described in an NPR interview as “sketchy.” (22)
What are the long-term effects of caffeine?
Unreliable, inconclusive and often conflicting - that is the case with most of the studies involving long term use of caffeine. Most are observational which means that scientists using fast computers and statistical software analyze information that has already been published. Most are self reporting which is notoriously unreliable and most are heavily influenced by the food and beverage industries. Depending on how data is sorted, a variety of dubious and often opposing conclusions are drawn. One study, for example, showed that people who drank their coffee black were more likely to be psychopaths.
Regular caffeine consumption has been claimed as a preventative aid for a wide range of health issues, from Altzheimers to liver cancer. (23, 24). The scientific evidence supporting most of these claims is not robust.
“These studies often involve methodological flaws and biases that can be difficult for readers or reviewers to detect, frequently detect associations that can be mistaken for cause-and-effect relationships, and are rarely corrected,” says Gautam Naik in a Wall Street Journal article. (25)
Flaws, flaws and more flaws
These studies also have other problems, points out a comprehensive review published online in Frontiers of Psychology. (26) “First, it is not clear how much caffeine is being consumed from “uncommon” or unidentified sources of caffeine, such as foods and medications. These sources are often overlooked in large national surveys and, thus, caffeine intake may be underestimated. Second, caffeine may be indirectly harmful because it is consumed with other substances that are harmful. For example, coffee drinking may promote donut eating or cigarette smoking, or energy drink consumption may promote alcohol intake. Third, future studies need to investigate absorption, distribution, metabolism, and excretion of caffeine occurring in non-natural forms (such as encapsulated forms), which may influence pharmacokinetics, and thus effects. Finally, most research has relied on self-report and correlational analysis, which limits the ability to determine causality and directionality.”
“The problem is one of signal to noise,” observed Gina Kolata in a 2017 New York Times article about lifestyle studies. “You can’t discern the signal — a lower risk of dementia, or a longer life, or less obesity, or less cancer — because the noise, the enormous uncertainty in the measurement of such things as how much you exercise or what exactly you eat, is overwhelming. The signal is often weak, meaning if there is an effect of lifestyle it is minuscule, nothing like the link between smoking and lung cancer, for example.”
Causation or correlation
Caffeine’s benefits are often inferred from studies involving coffee consumption. However coffee has its own rich chemical construction aside from caffeine and it could be one of those elements responsible for study results.
Nutrition research is deeply influenced by food and beverage companies who are copying the subversive tactics notoriously used by the cigarette industry, warns Marion Nestle — a nutrition researcher at New York University. (27) “The American Beverage Association insists that sugar-sweetened beverages have no role in obesity or Type 2 diabetes, for example, despite much suggestive evidence that they do,” she notes.
“One question I raise in this book is whether industry-funded research is good work. I see evidence that sometimes it is. But there is also plenty of evidence that industry-funded work can be biased in ways that researchers don’t see or recognize.”
Myths and legends
A massive observational study published in the journal JAMA Internal Medicine indicated that coffee drinkers, even those with an eight-cup a day habit, have a lower risk of death. (28) (The sampling of people with an eight-cup a day habit was very small, however.)
"Although these findings may reassure coffee drinkers, these results are from an observational study and should be interpreted cautiously," said lead study author Erikka Loftfield, a research fellow at the National Cancer Institute (NCI). The fact that decaf coffee was associated with longevity suggests that the many other compounds in coffee, besides caffeine, may be responsible," she noted.
Effect on the heart
Heart disease is the leading cause of death in the United States, according to government statistics. A 2018 review in the Journal of the American College of Cardiology that suggested that caffeine doses up to 500 mg daily (approximately six cups of coffee) did not increase the severity or rate of ventricular arrhythmias in people with heart history was also welcomed by coffee drinkers. (29)
“There is a public perception, often based on anecdotal experience, that caffeine is a common acute trigger for heart rhythm problems,” said Peter Kistler, MBBS, Ph.D., lead author of the review and director of electrophysiology at Alfred Hospital and Baker Heart and Diabetes Institute in Melbourne, Australia. (30) “Our extensive review of the medical literature suggests this is not the case.”
Not everybody agrees with this conclusion, however.
“My clinical experience has shown me over and over that caffeine can indeed be problematic for people with poor heart rate variability or whose hearts are compromised by disease or a previous heart attack,” says Dr. Stephen T. Sinatra from the Heart Md Institute. (31) “When caffeine enters the body, it stimulates the sympathetic nervous system. This causes blood pressure to rise, adrenaline to be released, and instantly requires that the heart beat harder and faster. If your heart function is already less than ideal, this can be a recipe for real trouble.”
Sinatra also points out there is evidence that unfiltered coffee also has the power to increase LDL cholesterol. “Generally I don’t take issue with LDL levels unless they exceed 300 mg/dL—so if your cholesterol is extremely elevated, make sure your brew is filtered.”
“People at high risk for a heart attack who are occasional or regular coffee drinkers might consider quitting coffee altogether," says Ana Baylin, a research associate at Brown University School of Medicine in Providence, RI referencing a study based on 503 cases of nonfatal heart attacks in Costa Rica. (32) For those less accustomed to caffeine, a cup of coffee could be "the straw that broke the camel's back, she warns.
A study published in The Journal of The North American Menopause Society showed that menopausal women who consumed caffeine had a greater degree of vasomotor symptoms (33)
Individuals with anxiety disorders are advised to minimize or avoid caffeine. (34) The American Psychiatric Association has added three caffeine-related disorders to its list of official diagnoses: caffeine intoxication, caffeine-related anxiety, and caffeine-related sleep disorders.
Glaucoma patients and people at risk for glaucoma should limit caffeine consumption. (35) One cup of coffee is unlikely to cause any harm, but those who drink large amounts of coffee should consider switching to decaffeinated. (36)
Type 2 diabetes
Studies have suggested that coffee reduces the risk of diabetes. (37) But, it might not be the caffeine, says Marilyn Cornelis, Ph.D., a nutritionist and assistant professor at Northwestern University Feinberg School of Medicine. (38) “Coffee is an important source of caffeine, but it’s also got other chemicals that might be protective.”
There is little evidence that caffeine consumption helps people who already have diabetes. “One randomized, crossover, controlled study looked at the short-term effects caffeinated coffee had on glucose metabolism in healthy men. It found that realistic doses of coffee had no significant effect on blood glucose levels.” (39) A study conducted by the American Diabetes Association showed that caffeine impaired glucose metabolism in those with type 2 diabetes. (40)
A study from the Harvard School of Public Health suggested that the risk of suicide for adults who drank two to four cups of caffeinated coffee per day was about half that of those who drank decaffeinated coffee or very little or no coffee. (41) “Caffeine not only stimulates the central nervous system but may act as a mild antidepressant by boosting production of certain neurotransmitters in the brain, including serotonin, dopamine, and noradrenaline,” the researchers reported. (42)
However, The Nursing Times pointed out a number of critical limitations to the study. (43) “Overall, the findings of this study do not prove that coffee is beneficial to mental health.”
“There's no clear link between caffeine intake and depression, says the Mayo Clinic. (44) However, caffeine intake and depression may be linked indirectly for people who are particularly sensitive to the effects of caffeine or who have too much caffeine.”
Caffeine's purported ability to speed up the metabolism and suppress appetite supposedly helps with weight loss but evidence for this is slim. A 2018 study showed caffeine’s small influence quickly fades, suggesting weak, transient effects on energy intake and does not support caffeine as an effective appetite suppressant, according to the study’s authors. (45) The data "reinforces the importance of good eating habits and not relying on unsupported weight loss aids or unhealthy practices," said Carol DeNysschen, chair of the Department of Health, Nutrition, and Dietetics at SUNY Buffalo State College.
Caffeine’s proven ability to impede sleep could actually lead to weight gain. Studies have shown that when people are sleep-deprived, they produce more of the hormone ghrelin, an appetite stimulant, and less leptin, an appetite suppressant. (46) Also, many people who drink coffee for the caffeine also add fattening flavourings like cream and sugar.
Studies are inconsistent, some showing caffeine to have a positive influence. Other show a negative impact and some show no effects. (47) Some experiments have suggested that caffeine can improve some types of memory, particularly the global aspects of memory. Other research shows that caffeine’s benefit is state dependent, meaning that caffeine only improves memory if it is used both at the time of taking the information in and at the time of recalling the information later. (48) Studies looking at the long-term impact of caffeine on cognitive performance have been inconclusive. (49) “In general, while caffeine may help you overcome factors that lower your cognitive performance, it does not seem that caffeine has any significant direct effect on memory, although it may well help you pay attention,” said the author of one study, Dr. Fiona McPherson.
A 2016 study published in the Journals of Gerontology suggested coffee drinkers have up to a 60 percent lower risk of Alzheimer's and dementia. (50) Other studies have not supported such a positive assessment.
“The cumulative body of evidence about lower incidence of Parkinson’s and Alzheimer Disease among coffee drinkers is substantial but not conclusive enough to prove a positive effect of coffee consumption on the development of these diseases, concluded a 2016 literature review. (51)
The most widely recognized symptom of Alzheimer's is memory loss, but the disease can present a number of other symptoms, including delusions, hallucinations, irritability, anxiety, and depression. In 2018 Medical News today reported on a study of mice with Alzheimer's, researchers found that prolonged exposure to caffeine was linked to increases in those behavioral symptoms. “These results confirm that caffeine, despite its everyday use and relative lack of government regulation, is a potent compound with multifaceted effects. Our study adds to the evidence for caffeine and other adenosine-receptor blockers have distinct physiological effects,” said lead researcher Dr. Lydia Giménez-Llort — from the Universitat Autònoma de Barcelona in Spain. (52)
Regular cups of coffee will not ease tremors and movement problems caused by Parkinson's disease, despite prior evidence that caffeine might help, WebMD reported in 2017. (53) Short-term results of a study had shown caffeine improved the motor function of a small group of Parkinson patients, but long-term results revealed no benefits by six to 18 months after starting therapy, said lead researcher Dr. Ronald Postuma, an associate professor of neurology at McGill University Health Center in Montreal.
Other studies have shown that people who don't drink coffee have a higher risk of developing Parkinson's, Postuma said. The initial thought had been that there's some sort of protective effect from either caffeine or something else in coffee or tea. However, there's also the possibility that people apt to develop Parkinson's do not receive the same jolt that most receive from a cup of coffee, he said.
"Maybe there's something that makes them less likely to enjoy the pleasure of coffee," Postuma said, noting that the brain receptor that responds to caffeine is in the same region that controls movement.
The whole episode shows the dangers of running with evidence from early or small-scale trials before the results have been confirmed in larger and longer-term studies, said Charles Hall, professor of epidemiology and population health with the Albert Einstein College of Medicine in New York City.
"I see that happen over and over again," Hall said. "No matter how many times you say, 'this is a small study that needs to be replicated and verified,' people want to grab onto hope.”
Some research has suggested it is not caffeine at all that provides protection from Parkinson’s, but rather quercetin, one of caffeine component ingredients. (54)
Multiple studies have shown that coffee can lower the risk of cirrhosis. Those who drank four or more cups per day had the most benefit. (55, 56)
A California judge has ruled that businesses like Starbucks that sell coffee in the state need to warn consumers it contains the chemical acrylamide poses which is possibly carcinogenic. The World Health Organization, however, recently removed coffee from their list of possible carcinogens. It cited overwhelming evidence that coffee can promote health and actually inhibit cancer. Studies have shown preventative benefits. (57, 58) Scientists say “moderate” consumption can slash the risk by 40 percent compared to those who don’t drink coffee. The effect was also found in decaffeinated coffee, suggesting that something other than caffeine is responsible. Experts believe that besides, caffeine, coffee oils, kahweol, cafestol and antioxidants also found in coffee help to protect the liver
Will Caffeine help my work-out?
There has been considerable research in this area and the conclusive answer regarding athletes and sports is: maybe.
Many studies have shown athletic performance can benefit from low doses of caffeine,” said a 2014 study. It warned though that “. . . many aspects of consuming low doses of caffeine remain unresolved and suffer from a lack of research. As the response to caffeine consumption is variable, athletes need to determine whether the ingestion of less than 200 mg of caffeine before and/or during training and competitions is ergogenic on an individual basis.” (59)
A recent Spanish study showed that athletes burned 15 percent more calories for three hours after exercise than those who were given a placebo. (60) Scientists at the University of Illinois say that drinking two to three cups’ worth of caffeine an hour before a workout could reduce perceived muscle pain. (61) Other studies have shown that caffeine helps female volleyball players hit the ball harder and jump higher,) rowers go farther, and cyclists go faster in a 20K time trial. (62, 63, 64)
Harder, faster, longer
“A large body of research shows caffeine helps in "pretty much every kind of endurance exercise," giving a performance advantage of 1.5 percent to 5 percent, says Mark Glaister, an exercise physiologist at St. Mary's University in Twickenham, U.K. (65) “The suspicion is that caffeine increases the frequency or size of neural transmissions and suppresses pain.”
More benefits are also noticed in athletes who rarely drink coffee, hence are not tolerant to its stimulant effect. Other studies have found that caffeine helped reduce the perception of effort, allowing athletes to work harder. (66, 67)
Some research suggests caffeine consumption can actually detract from some exercise results. (68,69) Researchers tested the impact of caffeine on 18 members of a sport’s team who were required to take part in 10 40-meter sprints. Athletes who consumed the equivalent of around three or more cups of coffee every day saw their performance decline with repeated sprint tests, even after chewing the caffeinated gum. (70)
Although caffeine does not appear to significantly alter water balance or body temperature during exercise, dehydration is a potential concern because caffeine is a mild diuretic. Some athletes may experience abdominal cramps and diarrhea related to the large intestine contractions caused by caffeine.
I can’t function without my morning cup of coffee. Am I a caffeine addict?
An increasing number of clinical studies indicate caffeine users can become dependent even at low levels and are unable to reduce consumption despite knowledge of recurrent health problems associated with continued use, argues a 2013 review. (71) The World Health Organization and many health care professionals recognize caffeine dependence as a clinical disorder. (72)
“Indeed, an abundance of evidence from controlled laboratory studies with human and nonhuman animal subjects demonstrates the biological plausibility of caffeine dependence. Further, a number of recent clinical studies show that a nontrivial proportion of caffeine users develops clinically meaningful features of caffeine dependence, including a persistent desire or unsuccessful efforts to cut down or control caffeine use, continued use despite harm, and a characteristic withdrawal syndrome,” reported an article in the Journal of Caffeine Research. (73)
“Caffeine activates many of the same behavioral and neuropharmacological mechanisms that are activated by other reinforcers, including other drugs of abuse,” notes Steven E. Meredith, postdoctoral research fellow at The Johns Hopkins University School of Medicine. “And, like many other reinforcers, caffeine is associated with various positive subjective effects like increased well-being, sociability, and feelings of energy and alertness. For this reason and others, a small percentage of the population develops caffeine use disorder.”
What about pregnancy?
Dr. Adam Urato, a maternal-fetal medicine specialist at Tufts Medical Center in Boston, says that "as a society, we've become too cavalier – too relaxed – about the issue of chemical exposures in pregnancy.” (74)
Some studies have linked drinking more than 200 mg of caffeine a day with an increased risk of miscarriage and low birth weight. And drinking large amounts of caffeine (eight cups of coffee or more a day) has been linked with stillbirth. The American College of Obstetricians and Gynecologists recommends limiting caffeine consumption to fewer than 200 milligrams (mg) per day, about what you'd get from drinking one 10-ounce cup of Starbucks coffee.
The Center for Science in the Public Interest (CSPI) thinks that’s too high. It argues that research points to a higher risk of low birth weight, miscarriage and childhood lukemia among women who consumed as little as 100 milligrams a day.
A study from The University of Nevada School of Medicine showed that caffeine can reduce a woman’s chances of becoming pregnant by about 27 percent. (75)
How much caffeine is safe for children?
Little research has been done on the impact of caffeine and children, but most experts say that there is serious risk. (76)
“Caffeine is absorbed in every body tissue. It increases your heart rate and it increases your blood pressure. Caffeine changes your body temperature and your gastric juices. It changes how attentive you are, and can really cause trouble in terms of sleep,” says Dr. Marcie Schneider, adolescent medicine physician and former member of the American Academy of Pediatrics committee on nutrition.(77)
In 2010, Canadian dieticians protested Health Canada’s decision to allow caffeine to be added to any type of carbonated soft drinks, not just cola. “Even though caffeinated energy drinks (for example) have warning labels, children are not likely to read or understand them.” (78) A 2015 study of Boston toddlers aged one to two years published in the Journal of Human Lactation found 2.5 percent of one-year-olds were drinking coffee. (79)
“Food company executives tell me that marketing to children is their line in the sand. They need kids to pester their parents, become lifetime consumers, and have an emotional attachment to products they loved as kids,” says Marion Nestle in an NPR interview.
Major health organizations like the American Academy of Pediatrics suggests that dietary intake of caffeine should be "should be discouraged for all children.” (80)
Will Caffeine sober me up?
"Even if someone feels like the caffeine causes them to feel more awake and less sluggish, they still need to be aware that the alcohol is still metabolizing in the same way and on the same timeframe as if they haven't had any caffeine ... which means that its effects can still be potentially dangerous," said Melissa Majumdar, a registered dietitian and spokesperson for the Academy of Nutrition and Dietetics. (81)
"Someone may think, 'I can drive now' ... they see a car stop suddenly, and they have to put their foot on the brake quickly, but reaction time could be slow," says Dr. Robert Swift, associate director of the Brown University Center for Alcohol and Addiction Studies. "What you feel is [linked to] a different part of your brain that is the motor system that controls reaction time.” (82)
The Bottom LineCaffeine is here to stay
Caffeine is here to stay, that much is true. And it seems there is many good reasons to use and enjoy caffeine, but like any tool there are times when it isn't appropriate. For those situations try to replace caffeine with more natural options. Energetic adaptogens such as Rhodiola substitute well as they help improve focus and reduce fatigue like coffee without any of the side effects. Be responsible and enjoy your double-double-frappe-latte.
- (What’s your poison: caffeine. Australian Broadcasting Corporation (1997)
- Escohotado, Antonio; Ken Symington (May 1999). A Brief History of Drugs: From the Stone Age to the Stoned Age. Park Street Press. ISBN 0-89281-826-3.
- Weinberg, BA; BK Bealer (January 2001). (The World of Caffeine. Routledge. ISBN 0-415-92722-6.
- https://www.ncbi.nlm.nih.gov/pubmed/14706966; https://www.ncbi.nlm.nih.gov/pubmed/23151535;
- https://www.theglobeandmail.com/life/health-and-fitness/health/why-were-too-cavalier-about-coffee-during-pregnancy/article21974435/How much caffeine should I consume in a day