Because adenosine, in part, serves to regulate blood pressure by causing vasodilation, the increased effects of adenosine cause the blood vessels of the head to dilate, leading to an excess of blood in the head and causing a headache and nausea. Reduced catecholamine activity may cause feelings of fatigue and drowsiness. A reduction in serotonin levels when caffeine use is stopped can cause anxiety, irritability, inability to concentrate and diminished motivation to initiate or to complete daily tasks; in extreme cases it may cause mild depression.

Withdrawal symptoms — possibly including headache, irritability, and an inability to concentrate — may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from one to five days - representing the time required for the number of adenosine receptors in the brain to revert to "normal" levels, uninfluenced by caffeine consumption. Analgesics, such as aspirin, can relieve the pain symptoms, as can a small dose of caffeine. Most effective is a combination of both an analgesic and a small amount of caffeine.

Currently caffeine withdrawal is recognized as meriting further study by the Diagnostic and Statistical Manual of Mental Disorders for DSM-IV, although research demonstrating its clinical significance means that it will likely be included as an Axis-1 disorder in the DSM-V.