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Caffeine Effects, Half-Life, Overdose, Withdrawal
What is caffeine?
Caffeine is not a nutrient but a drug that is a mild stimulant of the central nervous system . In regular caffeine consumers, a partial or complete tolerance to most of caffeine effects often develops [32,36,38,39].
Chemical and Physical Properties
Caffeine is an alkaloid–a natural, alkaline nitrogen-containing compound–with the chemical name 1,3,7-trimethylxanthine and chemical formula C8H10N4O2 .
Pure caffeine is an odorless, white, crystalline powder of bitter taste, soluble in water, fats and alcohol .
Caffeine can be extracted from the coffee beans , tea leaves , kola nuts , cocoa pods , guarana seeds , yerba maté . Caffeine can be also artificially synthesized .
Chat 1. Caffeine Sources
|SOURCE||AMOUNT OF CAFFEINE in mg (range)|
|Brewed, decaffeinated (8 oz, 237 mL)||5 (2-12)|
|Espresso, restaurant style, decaffeinated (1 oz, 30 mL)||5 (0-15)|
|Espresso, restaurant style (1 oz, 30 mL)||40 (30-90)|
|Instant (8 oz, 237 mL)||70 (30-170)|
|Drip coffee (8 oz, 237 mL)||100 (65-120)|
|Brewed, Arabica (8 oz, 237 mL)||100 (70-120)|
|Fast-food-size coffee (16 oz, 480 mL)||125 (100-330)|
|Brewed, Robusta (8 oz, 237 mL)||150 (130-220)|
|Herbal and fruit tea||0|
|Black tea, decaffeinated (8 oz, 237 mL)||5 (0-12)|
|Iced tea (8 oz, 237 mL)||10 (5-50)|
|Kombucha tea (8 oz, 237 mL)||25|
|Green, black, white and oolong tea (8 oz, 237 mL)||40 (15-110)|
|Other teas (8 oz, 237 mL)||Up to 70 (0-120)|
|Cola, soda, root beer; caffeinated (12 oz, 355 mL)||40 (30-120)|
|ENERGY DRINKS (4-10 oz, 120-300 mL)||100 (50-280)|
|1 can (4-16 oz, 120-480 mL); smaller cans do not necessarily contain less caffeine||80 (30-350)|
|Caffeinated water (16.9 oz, 500 mL)||50-100|
|CAFFEINATED ALCOHOLIC BEVERAGES (CABs)|
|1 can (8-23.5 oz, 240-695 mL); smaller cans do not necessarily contain less caffeine||100 (20-350)|
|Coffee liqueur (1 jigger, 1.5 oz, 45 mL)||4|
|Caffeinated vodka (1 jigger, 1.5 oz, 45 mL)||10|
|Hot chocolate (6 oz, 180 mL)||4|
|Milk with cocoa (1 cup, 237 mL)||5|
|Chocolate cake (1 piece, 3.5 oz, 100 g)||0-6|
|Milk chocolate (1 oz, 28 g)||6|
|Dark chocolate, 70-85% cacao (1 oz, 28 g)||23|
|Ice creams and yogurts – caffeinated (8 oz, 237 mL)||50 (8-85)|
|Mints with caffeine (1 mint)||10-100|
|Chewing gum – caffeinated (1 piece)||50 (40-100)|
|Chocolate chips (1 cup)||105|
|Dark chocolate-coated coffee beans (28 pieces, 40 g)||335|
|MEDICATIONS and SUPPLEMENTS [34,35]|
|Analgesics, diuretics, weight-loss pills, stimulants with caffeine (1 tablet or capsule)||Up to 400|
|Workout supplements (1 serving)||Up to 400|
Chart 1 sources: [10,11,12,13,14,15,16,223]
Picture 1. Caffeine content of common beverages
Caffeine Absorption, Distribution, Metabolism and Elimination
99% of caffeine is absorbed in the stomach and small intestine within 45 minutes of ingestion [2,22,23]. Some caffeine from a chewing gum, chewable tablets and lozenges can be absorbed in mouth .
The caffeine dose, taking alcohol or oral contraceptives along with caffeine, exercise, age or sex do not significantly affect the caffeine absorption rate  but taking caffeine with food can slow it .
Caffeine Distribution and Blood Concentration
After absorption, caffeine is distributed throughout the body tissues, but it does not accumulate in them [2,29].
Caffeine may appear in the blood within 5 minutes  and reach its peak blood level within 15-120 minutes of consumption [25,27].
Ingestion of 1.1 mg of caffeine per kilogram of body weight may result in blood caffeine levels 0.5-1.5 mg/liter blood . Drinking of 1 cup of coffee with different caffeine contents may result in blood caffeine levels ranging from 0.25 to 2 mg/liter .
Most of the consumed caffeine is broken down in the liver to theophylline, theobromine, paraxanthine and 1,3,7-trimethyluric acid with the help of the enzyme CYP1A2 [24,25]. Only about 1% of caffeine is excreted unchanged in the urine .
Elimination Half Life
The average elimination rate (clearance) of caffeine from the human body in adults is 155 mg/kg body weight/hour; in newborns it is ~30 mg/kg/h; it may reach adult levels at about 4th month of life [25,26].
The caffeine blood half life–the time in which 50% of caffeine is eliminated from the blood–in healthy non-smoking adults is about 3-8 hours [16,24,27]; in smokers it may be shorter by 30-50% [2,25] and in newborns may be longer than 80 hours .
Caffeine elimination half time may be prolonged when large amounts of caffeine are consumed (16 hours in one case) , in the last trimester of pregnancy (up to 15 hours), in women taking oral contraceptives (by ~50%), in regular alcohol drinkers (by ~70%) and in individuals with liver cirrhosis (up to 96 hours) [2,25].
Caffeine Effects and Mechanism of Action
Caffeine effects depend on the individual genetically determined caffeine sensitivity  and tolerance , caffeine dose, expectancy of the effects [55,56,57] and eventual drugs consumed along with it [22,24]. Caffeine effects (400 mg or 2 cups of coffee) may appear within less than 1 hour and last for 3-6 hours or more .
Caffeine inhibits the inhibitory effects of the neurotransmitter adenosine and thus acts as a mild stimulant of the central nervous system [22,30].
Acute caffeine consumption stimulates the release of norepinephrine (noradrenaline) and epinephrine (adrenaline) in the body, which results in increased breakdown of the body fats into fatty acids [33,40], increased synthesis of glucose (gluconeogenesis), breakdown of glycogen into glucose (glycogenolysis) and dilation of bronchi [27,31,33]. Caffeine in a dose 6 mg/kg body weight (2-3 cups of coffee) can increase epinephrine release during exercise by about 40% .
In some studies, caffeine increased the basal or resting metabolic rate [41,42,43,44], but it did not in others .
According to some studies, caffeine may have a thermogenic effect [40,41,52,53,54], but according to others it does not . Results of studies about caffeine effect on the body temperature are inconclusive .
In regular caffeine consumers a partial or complete tolerance to the abovementioned caffeine effects often develops [32,36,38,39].
Moderate and Excessive Caffeine Intake
Consumption of up to 200-300 mg of caffeine (~2 cups of coffee) per day is considered moderate intake and of more than 500-600 mg (> 5 cups of coffee) per day heavy or excessive intake [48,49].
Possible Caffeine Benefits
- Increased alertness and vigilance, probably more in tired in sleepy individuals than those who are already alert [58,59,60,61,62,134,135].
- Shorter reaction time [64,65,67]
- Improved athletic performance during endurance exercise lasting more than 30 minutes (running) [28,45,68,103,138,139,140]
- A slight increase of the analgesic effect of aspirin, acetaminophen and ibuprofen [72,73,74,75], for example in tension headache .
NOTE: Improved mood and performance often reported by regular caffeine consumers may be due to reversal of withdrawal symptoms by consuming caffeine rather than by the effect of caffeine itself . In regular caffeine consumers a partial or complete tolerance to most of caffeine effects often develops [32,36,38,39].
There is INSUFFICIENT EVIDENCE about the beneficial effects of caffeine consumption athletic performance during short-term exercise, such as sprints or lifting , attention deficit hyperactivity disorder (ADHD) , asthma [85,86], cognitive function in Alzheimer’s disease [191,192], depression , diabetes mellitus type 2 [22,23,187,205], gallstones [87,88], gout [83,84], hepatitis C or liver cirrhosis , improving breathing in preterm infants with apnea [150,174], leg cramps due to narrowed arteries (intermittent claudication) , liver cancer , memory [16,67], migraine headache [176,207,209] ,muscle soreness during exercise , obsessive-compulsive disorder (OCD) , orthostatic hypotension [78,80], postprandial hypotension (a drop of blood pressure after meals) , seizures , skin itching , stroke  or weight loss .
Caffeine and Sleep
Caffeine may help overcome sleepiness after awakening (sleep inertia), possibly by increasing blood cortisol levels [37,38,160].
Caffeine, generally in amounts greater than 200 mg (~1-2 cups of coffee), consumed up to 8 hours before bed, may delay the sleep onset, shorten the sleeping time and decrease the sleep quality, more likely in occasional than regular users [16,25].
Caffeine, Brain, Memory and Behavior
The consumption of 250 mg of caffeine (1-2 cups of coffee) in a single dose can constrict the brain arteries and decrease the brain blood flow by up to 30% [188,189]. It is not yet clear if this increases the risk of stroke or transient ischemic attack [189,190].
Caffeine consumption probably does not have any significant effect on memory while studying [16,67]. A good sleep or daytime nap can have better effect on the learning performance than consuming caffeine .
In one 2006 study, there was no association between caffeine consumption and impulsiveness, sociability, extraversion or trait anxiety [130,193].
Caffeine and Exercise Performance
In 2004, caffeine was removed from the World Anti-Doping Agency (WADA) list of prohibited substances .
Caffeine in doses 3-9 mg/kg of body weight may modestly increase the endurance performance and decrease fatigue during physical exercise lasting for more than 30 minutes [28,45,68,103,138,139,140]. In some studies, caffeine consumption in doses 1-9 mg/kg body weight (1-7 cups of coffee) 60 minutes before exercise was associated with better short-term (<90 seconds) anaerobic physical performance, such as sprints or weight lifting [145,146,147,148,149] but in others was not [103,142,143,144].
It is not clear which caffeine dose has the optimal effect on physical performance; repeated bouts of coffee may decrease it [45,68,138].
Caffeine in high doses (8 mg/kg body weight or ~5 cups of coffee) may help restore glycogen stores after exercise .
At doses higher than 3 mg/kg, caffeine may increase heart rate during exercise .
Caffeine does not likely cause hyperthermia or heat intolerance during exercise in a hot environment [91,93].
Caffeine added to sport drinks does not seem to increase the risk of gastrointestinal symptoms during exercise .
It is still not clear by which mechanism caffeine could increase physical performance. Possible mechanisms: increasing caffeine doses are associated with increased blood epinephrine levels [154,155,156], calcium availability in the cells  and glucose absorption .
Caffeine, Appetite and Weight Loss
In some studies [25,163,164], caffeine consumption was associated with lower appetite, but in others it was not [37,54,162].
In several short-term studies taking caffeine-ephedrine supplements, but neither ephedrine or caffeine alone, was associated with weight loss of 1-2 pounds per month, but the long-term effect of caffeine on weight loss is not known [165,166,167,168]. These supplements are not approved as weight-loss pills in the U.S., since they may have serious side effects, including death .
In some studies [41,163], caffeine alone in doses 150-300 mg/day was associated with weight loss, but in others it was not .
There is insufficient evidence about the effectiveness of black or green tea in promoting weight loss [169,170].
Caffeine, Frequent Urination and Dehydration
In several studies, consumption of up to 226 mg of caffeine (~2 cups of coffee) did not result in any significant increase in urine excretion (diuresis) [69,91]. Acute ingestion of at least 240 mg of caffeine (1-2 cups of coffee or 5-6 cups of tea) may temporarily increase the urine excretion, but the tolerance to this caffeine effect may develop in as little as 1 day [92,177]. In conclusion, caffeinated beverages consumed by healthy individuals in usual doses do not likely cause dehydration and can be even used for rehydration [28,69,91,92,141].
In individuals with overactive bladder or urge incontinence , or a non-infectious bladder inflammation called interstitial cystitis or painful bladder syndrome (PBS), caffeine consumption may trigger urination urgency and increase urination frequency [179,180].
Coffee, Caffeine and Heart
In some studies, moderate coffee drinking (3-5 cups/day) was associated with a lower risk of cardiovascular disease [49,70,76, 185], but in others it was not [22,181]. It is not clear is it caffeine or some other substance in coffee that might be associated with a lower risk of heart disease.
Regular caffeine consumption may increase the risk of heart attack in genetically predisposed individuals who metabolize (break down) caffeine slowly [183,184].
Caffeine and Blood Pressure
In non-regular caffeine consumers with or without hypertension, 250 mg of caffeine (2-3 cups of coffee) can temporarily (for several hours) increase the blood pressure by up to 15 mm Hg within 1 hour of consumption [63,116,186]. After few days of caffeine consumption, a partial or complete tolerance to caffeine-induced increase of the blood pressure usually develops, especially in those who consume more than 3 cups of coffee per day [25,117,126,186,191].
In individuals with hypertension, long-term coffee consumption does not seem to be associated with an increase of blood pressure [63,136].
Currently, it is not clear, if regular caffeine consumption increases the blood pressure to the harmful levels. If you have high blood pressure, ask your doctor how much caffeine you may consume.
Caffeine and Diabetes 2
In various systematic reviews of epidemiological studies, regular caffeine or coffee consumption was associated with a lower risk of diabetes type 2 [70,159,182,191] but, according to one study, only in individuals who had previously lost weight . Possible preventative mechanisms of drinking coffee on diabetes include an increase of insulin sensitivity by caffeine and inhibition of glucose absorption by chlorogenic acid (a coffee ingredient) .
In various controlled clinical trials, decreased insulin sensitivity was observed after co-ingestion of carbohydrate meals and caffeine (200-500 mg, comparable with 1-5 cups of coffee) in healthy individuals [105,208] and in those with diabetes type 2 [158,210]. Possible mechanism: caffeine stimulates the release of epinephrine, which decreases the sensitivity of insulin.
In conclusion, the current evidence is not strong enough to recommend consuming caffeine as a preventative measure for diabetes.
Coffee and Gastrointestinal Tract
Coffee stimulates the release of the hormone gastrin and gastric acid secretion [101,194]. Caffeine may damage the gastric and duodenal lining  but does not likely cause peptic ulcer; it can increase pain in an established ulcer, though [77,196,197].
Caffeine, coffee and tea may decrease the pressure in the lower esophageal sphincter and trigger acid reflux and heartburn [101,102,198]. Decaffeinated coffee can also trigger heartburn .
In several studies there was no association between moderate coffee or tea consumption, dyspepsia and gastric emptying or bowel transit time [101,153,200]. However, according to one 2009 study, caffeine may accelerate gastric emptying . Caffeine may promote the motility of the sigmoid colon and rectum .
In individuals with irritable bowel syndrome, caffeine may trigger diarrhea or constipation .
Caffeine intake does not seem to be associated with diverticular disease .
Coffee intake may induce gallbladder contractions and may cause pain in individuals with established gallstones , but it does not seem to increase the risk of gallstones or other gallbladder disease in healthy individuals [87,204].
Caffeine and Parkinson’s Disease
In some epidemiological studies, moderate coffee consumption was associated with a decreased risk of Parkinson’s disease in men [22,78,191]. There is lack of evidence about the effect of caffeine in improving fatigue in individuals with Parkinson’s disease .
Caffeine and Cancer
Several studies suggest that regular caffeine consumption may reduce the risk of liver [22,191,216,217] and endometrial cancer [191,217].
Some, but not all, studies suggest that coffee or caffeine may have a protective effect on kidney  and colorectal cancer .
Caffeine consumption does not seem to increase or decrease the risk of breast, pancreatic, ovarian or gastric cancer .
Caffeine consumption may increase the risk of bladder cancer in men .
Caffeine as an Analgesic
Caffeine may stimulate the release of beta-endorphins, which are endogenous opioids . It is not clear if caffeine alone has any significant analgesic effect [25,171].
Caffeine in doses 100 mg or higher may slightly increase the perceived analgesic effect of certain painkillers, such as aspirin, paracetamol and ibuprofen , in treating headache, post-operative dental pain or pain after birth [72,73,75].
Caffeine does not seem to relieve ischemic pain (angina pectoris) in coronary artery disease .
There is insufficient evidence about the effectiveness of caffeine in relieving migraine headache [176,207,209,214].
Caffeine is LIKELY SAFE for most adults when consumed in usual amounts found in beverages and foods .
Caffeine is POSSIBLY SAFE for most children when used in amounts usually found in beverages or foods (up to 160 mg per day in a 10 year old child) [115,175].
Caffeine as a food additive is considered Generally Recognized As Safe (GRAS) by the U.S. Food and Drug Administration (FDA) until used in cola-type beverages [3,4] and in alcoholic beverages  in amounts up to 0.02 percent (200 ppm) but not automatically when used in other foods.
In general, moderate caffeine intake (3-5 cups of coffee or up to 400 mg caffeine per day) does not seem to increase the risk of cardiovascular disease (heart attack or irregular heart rhythm) and cancer .
It is currently not clear if caffeine consumption increases the risk of osteoporosis and bone (hip) fractures [22,24,123,133,222].
Caffeine is POSSIBLY SAFE during pregnancy when used in doses up to 200 mg/day (1-2 cups of coffee) [21,22,115].
Drinking caffeinated beverages during pregnancy, even in high amounts, does not seem to increase the risk of miscarriage, birth defects or growth retardation of the fetuses or children [2,96,191,219] but more studies are warranted .
Caffeine withdrawal symptoms, such as irritability and vomiting, lasting for few days after birth, have been observed in infants whose mothers had been drinking coffee during pregnancy .
Caffeine is excreted in the breast milk in small amounts . Consumption of 2-3 cups of coffee probably does not cause adverse effects, but higher caffeine intake may cause irritability and poor sleeping in a breastfed child [20,22].
Acute Side Effects
Caffeine consumption may cause [89,97]:
- Anxiety, panic attack, depression, restlessness, sleeplessness [89,211] and worsening of premenstrual syndrome (PMS) [98,99]
- Dry mouth, unusual thirst 
- Increased breathing and heart rate, pounding heart (palpitations) [71,100]
- Stomach upset, heartburn, nausea, vomiting, diarrhea [96,100,101,102]
Caffeine Intoxication or Overdose
Consuming caffeine in a single dose as low as 250 mg, but usually in doses greater than 600 mg, may result in caffeine intoxication . On the other hand, consumption of up to 900 mg (0.9 g) caffeine through the day without any side effects has been reported .
Symptoms and signs of caffeine intoxication may include [2,25,28,51,97,106,107,108]:
- Nervousness, anxiety, jitters, restlessness, fear, insomnia, rambling flow of thoughts or speech
- Facial flushing
- Ringing in the ears (tinnitus), increased sensitivity to light (photophobia)
- Thirst, stomach upset, abdominal pain, nausea, vomiting, diarrhea
- Increased breathing (hyperventilation) and heart rate (tachycardia), irregular heart beat (arrhythmia), chest pain, high or low blood pressure
- Increased urination (polyuria)
- Dilated pupils
- Tremor, muscle twitching, paralysis or weakness due to hypokalemia
- Depression, delirium, hallucinations, psychosis
- Complications may include heart attack, stroke, muscle disintegration (rhabdomyolysis), acute lung damage, collapse or coma
- References: [2,25,28,51,97,106,107,108]
Possible metabolic changes in caffeine intoxication include hyperglycemia, ketosis, lactic acidosis or hyponatremia . Very high caffeine doses, for example, from caffeine-containing pills , 10 cups of coffee per day , 5 or more liters of caffeinated cola per day [110,111,112] may cause hypokalemia.
Death from caffeine toxicity is rare and can occur when blood caffeine concentration exceeds about 100 mg/liter . Lethal dose of caffeine–the amount that would likely kill an adult–is 10-20 grams or 150-200 mg/kg body weight (~70-120 70 cups of coffee) [27,29,108,114].
Chronic Side Effects
Regular consumption of high amounts of caffeine may cause or worsen:
- Anxiety, restlessness, insomnia, tingling in limbs and around the mouth, pounding heart (palpitations), anorexia, nausea, vomiting, diarrhea, depression or seizures – a cluster of symptoms known as chronic caffeine intoxication or caffeinism, from > 1,000 mg caffeine (>cups of coffee) per day or, in some individuals, from as low as 250 mg caffeine (or 1-2 cups of coffee) per day [25,60,105].
- Frequent urination and other symptoms of benign prostate hyperplasia 
- Fibrocystic breast disease [105,122]
- Migraine 
- Psychosis in healthy individuals and in individuals with schizophrenia 
- Restless leg syndrome [119,120]
- Seizures in individuals with epilepsy [82,118]
Who should avoid caffeine?
Doctors may advise against consuming caffeine to [25,115]:
- Children under 12 years of age
- Individuals allergic to caffeine
- Individuals suffering from anxiety, attention deficit hyperactivity disorder (ADHD), benign prostatic hyperplasia, bipolar disorder, chronic headache, glaucoma, GLUT-1 deficiency, heart attack (within 1 week thereafter), insomnia, high blood pressure, interstitial cystitis, irregular heart rhythm, irritable bowel syndrome (IBS), liver problems, osteoporosis, premenstrual syndrome (PMS), seizures (epilepsy), stomach ulcers or urinary incontinence
In healthy persons, moderate caffeine intake (<400 mg/day) does not likely cause or increase the risk of cancer , dehydration [91,92], DNA errors (mutations) , electrolyte imbalance , elevated blood cholesterol , excessive sweating , heart disorders , high blood pressure , increased body temperature , inflammation  or stroke .
Caffeine consumption for 1-5 days may result in a partial or complete tolerance to some caffeine effects and side effects [25,32,51,124,125]. The susceptibility to develop caffeine tolerance may vary greatly among individuals and may be genetically determined .
The tolerance for the following caffeine effects often occurs: anxiety, increase of blood pressure , increased heart rate and increased urination . Less often, the tolerance for caffeine-induced alertness and sleep disturbances develops .
Caffeine tolerance can wear off in 20 hours to 4 days after caffeine consumption cessation [32,127].
Chronic caffeine consumers, because of the developed tolerance, may have no net benefits from caffeine, and that increased alertness and performance they experience are in fact a reversal of withdrawal symptoms (“withdrawal relief”) [65,66,128,129].
A long-term caffeine consumer who experiences withdrawal symptoms, such as headache and tiredness, after abruptly stopping consuming caffeine is considered physically addicted to caffeine . People who are physically addicted to caffeine usually do not have any significant social or health problems related to caffeine .
Some individuals who regularly consume caffeine for as little as 3 days in the row in doses as low as 100 mg (1/2 cup of coffee) develop symptoms of caffeine withdrawal 3-36 hours after the last dose of caffeine [16,25,51,130,131,132]. Symptoms usually peak between 20-51 hours after the last caffeine dose, last from 2-9 days and may include [16,25,51,132]:
- Apathy, depression, tiredness, weakness, fatigue, drowsiness or insomnia
- Anxiety or irritability, difficulty concentrating
- Increased heart rate
- Nausea, vomiting or flu-like symptoms, such as stuffy nose
- Muscle aches or stiffness
Gradual caffeine withdrawal may result in fewer unpleasant symptoms than abrupt withdrawal .
Caffeine withdrawal headache is hardly relieved by usual analgesics, but may be relieved by caffeine within 30 minutes of the headache onset .
Some people can experience jitteriness, sleeplessness and irritation of gastrointestinal tract after small amounts of caffeine, for example, after drinking 1 cup of coffee . Hypersensitivity results from low amount of enzymes that break down caffeine, which can be genetically determined .
Caffeine Allergy and Intolerance
In sensitive persons, caffeine ingestion may trigger allergic reaction with rash, hives, itching, difficulty breathing, tightness in the chest, or swelling of the face, lips and tongue .
Caffeine intolerance as a medical term is not known, but individuals with irritable bowel syndrome (IBS) may experience worsening of symptoms (constipation or diarrhea) after caffeine consumption .
Caffeine-Drug and -Nutrients Interactions
- Caffeine may slightly decrease calcium absorption [19,22].
- Caffeine added to sport drinks enhances the absorption of glucose in the small intestine .
- Caffeine does not affect the rate of alcohol absorption or elimination and does not affect the blood alcohol concentration .
- Caffeine may decrease the feeling of sedation after alcohol intoxication, but it does not reduce the intoxication itself [17,18].
- Alcohol does not affect caffeine absorption, but it slows down its elimination; caffeine from alcoholic beverages does not likely cause unsafe blood caffeine levels, though .
Other Caffeine-Drug Interactions
- Caffeine in combination with ephedrine can have serious side effects including death [115,221].
- Caffeine may increase the effects and side effects of acetaminophen, albuterol, aspirin, clozapine, epinephrine and theophylline .
- Caffeine may decrease the effects of lithium  and diazepam .
- Drugs that may increase caffeine effects include certain antibiotics (erythromycin, ciprofloxacin, norfloxacin) cimetidine, disulfiram, echinacea (herbal supplement) erythromycin, mexiletine, oral contraceptives [22,24,27].
- Smoking (nicotine) can decrease caffeine levels by stimulating caffeine elimination by 30-50% .