Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class and is one of the most widely used drugs in the world. Unlike other psychoactive drugs, it is legal, cheap, and not regulated in almost all parts of the world. Individuals who habitually drink caffeine-contained beverages may develop a physical, emotional, and psychological dependence on it and may experience a caffeine withdrawal syndrome after abrupt cessation of caffeine intake. Multiple studies have demonstrated that caffeine withdrawal syndrome is a clinically relevant entity, and is included in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5; American Psychiatric Association, 2013).
Physicians working in the emergency departments (ED) and the hospital must be familiar with this syndrome when they encounter patients with relevant symptoms, as they overlap with symptoms such as anxiety, depression, mood disorders, insomnia. They also can be the cause of abnormal vital signs, such as tachycardia, increased respiratory rate, and low or elevated blood pressure, and as such, can present a diagnostic challenge and/or be a cause of unnecessary workup in ED.
Beverages, containing caffeine, are ingested to prevent or relieve drowsiness, to stimulate the central nervous system, and to improve performance. Regular and chronic use of caffeine produces physical and psychological dependence. The research studies have validated that avoidance of withdrawal symptoms plays a vital role in habitual caffeine consumption in addition to the dread of pure physiologic withdrawal symptoms.
The true incidence of caffeine withdrawal syndrome is unknown. It has been reported that in North America, 80% to 90% of all adults use caffeine regularly. Mean daily intake in the United States (US) is 280 mg, which is equal to about one or two mugs of coffee, or three to five soft drinks. The major sources of caffeine in the US is coffee, tea, and soft drinks. So-called energy drinks are also gaining popularity in recent years. A total intake of no more than 400 mg per day is the accepted safe level; this would typically be four cups of coffee, ten cans of cola, or two energy drinks. There is a wide variation in the caffeine content of beverages.
Caffeine is a competitive adenosine receptor antagonist, thus blocking endogenous adenosine, thus preventing the onset of drowsiness, caused by adenosine. Individuals who regularly consume caffeine have increased the number of adenosine receptors in their central nervous system (CNS) and become more sensitive to normal physiologic effects of adenosine. In classical drugs of abuse, such as amphetamines and cocaine, adenosine stimulates dopaminergic activity in nucleus accumbens, thus producing dopamine-like effects in that part of the brain, which accounts for its addictive potential. However, caffeine does not induce a release of dopamine in the nucleus accumbens but leads to a release of dopamine in the prefrontal cortex, which is consistent with caffeine reinforcing properties. Caffeine also stimulates glucose utilization in a caudate nucleus, which mediates motor activity and regulates the sleep-wake cycle.
After oral ingestion, caffeine is rapidly and completely absorbed into the bloodstream, with peak blood levels reached in 30 min to 45 min. Caffeine is metabolized by the liver and is excreted by kidneys via urine. It is quickly eliminated, with a typical half-life of four to six hours. 
Caffeine produces a variety of physiological effects on the cerebral vascular system, blood pressure, respiratory functioning, gastric and colonic activity, urine volume, and exercise performance. Low to moderate doses of caffeine (20 mg-200 mg) produce reports of increased well-being, happiness, energy, alertness, and sociability, whereas higher doses are more likely to produce symptoms of anxiety, jitteriness, and upset stomach.
Caffeine is known to cross the placenta and decrease blood flow to the placenta, although the specific effects on a fetus are not known. It is also unknown, what effects caffeine withdrawal symptoms in a pregnant mother has on a fetus.
Caffeine is rapidly and completely absorbed in humans within 45 minutes of ingestion. Peak plasma concentrations are achieved between 15 and 120 minutes after oral ingestion. Its physiologic effects are a result of inhibition of adenosine activity, and phosphodiesterase - among others. The mean half-life of caffeine is about five hours. This may range from 1.5 to 9.5 hours depending on some influences (e.g., pregnancy, obesity, use of oral contraceptives, smoking, altitude). Tolerance, especially to the stimulant effects, develops over time and cessation of use results in withdrawal symptoms.
Withdrawal from caffeine causes mild to clinically significant distress and impairment of normal functioning. The severity of symptoms vary from individual to individual, and most commonly include a headache, fatigue, decreased energy/activeness, decreased alertness, drowsiness, decreased contentedness, depressed mood, difficulty concentrating, irritability, and feeling foggy/not clearheaded. The severity of symptoms varies from mild to extreme. The incidence or severity of symptoms increased with increases in the daily dose, but abstinence from low doses, such as about one small cup of coffee per day, also produced symptoms of withdrawal.
Some studies have shown that the incidence of a headache is about 50%, and the incidence of clinically significant distress or functional impairment is 13%. Typically, the onset of symptoms starts 12 to 24 hours after caffeine cessation, peaks at 20–51 hours, and may last up to two to nine days.
One study has demonstrated that caffeine withdrawal occurred after as little as three days of caffeine exposure, with a somewhat increased severity of withdrawal observed after seven or 14 days of exposure.
Thus, in taking a history from a patient with suspected caffeine withdrawal syndrome, it is useful to elicit the information about habitual intake dose (caffeine maintenance dose) and the duration of caffeine consumption, time of the last drink, any history of previous caffeine withdrawal episodes and their severity.
Some signs of caffeine withdrawal include: impaired behavioral and cognitive performance, decreased or increased blood pressure, decreased motor activity, increased heart rate, hand tremor, increased diuresis, skin flushing, flu-like symptoms, nausea/vomiting, constipation, muscle stiffness, joint pains, and abdominal pain.
The evaluation of patients presenting with symptoms of caffeine withdrawal should include an establishment of adequate differential diagnosis in order to exclude other clinically significant conditions, such as migraine headaches, meningitis/encephalitis, intracranial hemorrhage, space-occupying lesion of central nervous system, carbon monoxide poisoning, pre-eclampsia, hypertensive disorders, depression, anxiety, panic attacks, acute glaucoma, dehydration, analgesic or other substances abuse, and mood disorders.
Maintaining a high index of suspicion, as well as taking a thorough history and performing a good physical examination, should be sufficient in establishing a diagnosis of caffeine withdrawal syndrome.
Re-administration of caffeine typically reverses withdrawal symptoms rapidly. Individuals who are determined to rid themselves of caffeine dependence should be advised to decrease caffeine consumption gradually to prevent caffeine withdrawal syndrome.
Some symptoms, such as a headache, can be effectively treated with over-the-counter analgesic medications. Gastrointestinal symptoms, such as nausea or vomiting, can also be treated with over-the-counter medications. On the other hand, constipation that is frequently reported during caffeine withdrawal period can be mitigated by increasing dietary fiber consumption or over-the-counter medications, that promote bowel function. Oral or intravenous hydration and rest/sleep can alleviate many symptoms of caffeine withdrawal as well.
The differential diagnosis for caffeine withdrawal can include, but is not limited to:
Healthcare providers and patients alike must be aware that there are some preliminary studies on mice which showed that caffeine withdrawal in a habitual chonic user may change activity of antidepressant medications within monoamine, adenosine and glutamate systems.
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