Laura M. Juliano, PhD, Sergi Ferré, MD, PhD, and Roland R. Griffiths, PhD
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Caffeine is the most widely used mood altering drug in the world. Caffeine is not associated with any life-threatening illnesses and is associated with decreased risk for some diseases (e.g., Parkinson’s disease). However, caffeine is not completely innocuous. It can produce negative physiologic and psychological effects, tolerance, withdrawal, discrete psychiatric disorders, and interact with other recreational and therapeutic drugs. Understanding caffeine’s pharmacologic actions and potential clinical implications aids in the prevention and detection of caffeine-associated problems.
DRUGS IN THE CLASS
Caffeine (1,3,7-trimethylxanthine) is a member of the methylxanthine class of alkaloids, which includes the structurally related dimethylxanthines, theophylline, and theobromine. More than 60 types of plants containing caffeine have been identified, including coffee, tea, cola, guarana, cacao, and yerba mate.
HISTORY
The chemical structure of caffeine was identified in 1875. Presently, coffee is the second largest agricultural import in the United States. In the late 1880s, entrepreneurs began selling carbonated beverages with caffeine, and the last century has seen a steady increase in caffeinated soft drink consumption. In recent years, there has been widespread marketing of caffeinated energy drinks and dietary supplements.
EPIDEMIOLOGY
It is estimated that 87% of the population in the United States, 2 years and older, regularly consume caffeine. The mean daily intake for adult caffeine consumers is approximately 280 mg, the equivalent of approximately one to two servings of coffee. The heaviest consumers of caffeine are individuals aged 35 to 64 years.
SOURCES OF CAFFEINE
Caffeine is found naturally in many common food products (e.g., coffee, tea, chocolate) and is added by manufacturers to a variety of beverages, foods (e.g., jelly beans, potato chips), dietary supplements, and over-the-counter and prescription medications. Coffee and soft drinks are the major dietary sources of caffeine in the United States.
THERAPEUTIC USES
Caffeine is taken to increase energy and prevent sleepiness. Because of its putative analgesic-enhancing effects, caffeine is added to some over-the-counter and prescription analgesic medications. As a respiratory stimulant, caffeine is used to treat neonatal apnea. Because of its lipolytic and thermogenic effects, caffeine is commonly used in weight loss preparations and nutritional supplements.
NEUROBIOLOGY
The primary cellular site of action of caffeine is the adenosine receptor. Adenosine is an endogenous purine nucleoside found throughout the brain. It is formed from the breakdown of adenosine triphosphate and modulates a variety of central and peripheral nervous system effects. Caffeine is structurally similar to adenosine. As a competitive A1 and A2A adenosine receptor antagonist, caffeine produces a variety of effects that are opposite to the effects of adenosine (e.g., central nervous stimulation, vasoconstriction).
An important amount of experimental evidence supports a key role of dopamine in the psychostimulant and reinforcing effects of caffeine in animals and humans. Caffeine produces its motor and reinforcing effects by releasing the brake that adenosine imposes on striatal dopaminergic neurotransmission. By releasing the presynaptic brake, caffeine induces glutamate-dependent and glutamate-independent release of dopamine. These presynaptic effects of caffeine are potentiated by the release of the postsynaptic brake imposed by antagonistic adenosine–dopamine receptor interactions.
The effects of caffeine on sleep do not seem to be dopamine dependent and are related to the ability of adenosine to act as an endogenous sleep-promoting substance by acting on A1 and A2A receptors localized in the brain stem, basal forebrain, and hypothalamic areas, and A2A receptors localized in the ventral part of the striatum.
PHARMACOKINETICS
Caffeine is rapidly and completely absorbed after oral administration and readily distributed throughout the body, with peak levels reached in 30 to 45 minutes. Caffeine is metabolized by the cytochrome P-450 liver enzyme system. On average, the half-life of caffeine is 4 to 6 hours. However, there are wide individual differences in rates of caffeine elimination, which are due in large part to CYP 1A2 genetic variation across individuals. Cigarette smoking decreases caffeine half-life by as much as 50%. Caffeine’s half-life is increased when taking oral contraceptives and in the later stages of pregnancy.
PHYSIOLOGIC EFFECTS
At moderate dietary dose levels, caffeine increases systolic and diastolic blood pressure but has minor effects on heart rate. Caffeine constricts blood vessels in the head and neck. Caffeine stimulates gastric acid secretions and is a diuretic and colonic stimulant. Caffeine is a respiratory stimulant and bronchodilator at high doses. Caffeine increases plasma epinephrine, norepinephrine, renin, free fatty acids, adrenocorticotropic hormone, insulin, and cortisol.
SUBJECTIVE EFFECTS
Low-to-moderate doses of caffeine (i.e., 20 to 200 mg) produce positive subjective effects including increased well-being, happiness, energy, arousal, alertness, and sociability. Negative subjective effects are associated with higher acute doses of caffeine (>200 mg) and include anxiety, nervousness, jitteriness, negative mood, upset stomach, sleeplessness, and “bad effects.” Caffeine-induced anxiety disorder is a diagnosis recognized by the DSM-5 characterized by anxiety disorders or anxiety symptoms caused by or made worse by caffeine.
SLEEP AND PERFORMANCE EFFECTS
Caffeine delays sleep onset, reduces total sleep time, alters the normal stages of sleep, and decreases the reported quality of sleep. Caffeine-induced sleep disorder is a diagnosis recognized by the DSM-5 characterized by a prominent sleep disturbance etiologically related to caffeine use.
Compared to placebo, caffeine has been shown to improve cognitive and psychomotor performance. These effects are shown most reliably when performance has been degraded by fatigue, sleep deprivation, or caffeine withdrawal. Caffeine can also enhance performance during long-term aerobic exercise, reduce ratings of perceived exhaustion, and improve speed or power output in simulated race conditions. Among high-dose habitual caffeine consumers, performance enhancements above and beyond withdrawal reversal appear to be modest.
DISCRIMINATIVE STIMULUS EFFECTS
Most people can learn to reliably discriminate caffeine from placebo at doses 100 mg or greater. Much lower doses can be detected after discrimination training (e.g., 10 mg). Drug discrimination studies in humans and animals have demonstrated both similarities and differences between caffeine and other stimulant drugs.
REINFORCING EFFECTS
Caffeine is the most widely self-administered mood-altering drug in the world and, historically, repeated efforts to restrict or eliminate consumption of caffeinated foods have been completely unsuccessful. In controlled research, caffeine reinforcement has been demonstrated with various participant populations, using a variety of methodologic approaches, and across different caffeine vehicles. Doses as low as 25 mg per cup of coffee and 33 mg per serving of soft drink function as reinforcers. Avoidance of caffeine withdrawal symptoms plays a central role in the reinforcing effects of caffeine among regular caffeine consumers. Caffeine reinforcement has also been demonstrated in animals using self-injection and conditioned place preference paradigms.
CAFFEINE TOLERANCE
Caffeine tolerance has been demonstrated in both animals and humans. The degree of tolerance depends on the caffeine dose, the dose frequency, the number of doses, and the individual’s elimination rate. Complete tolerance does not occur at low daily dietary doses. High daily doses of caffeine (750 to 1,200 mg/day) produce “complete” tolerance to some but not all effects. Tolerance develops to the sleep-disrupting effects of caffeine and to physiologic effects including diuresis, parotid gland salivation, increased metabolic rate, increased plasma norepinephrine and epinephrine, and increased plasma renin activity. Incomplete tolerance also develops to the pressor effects of caffeine.
CAFFEINE INTOXICATION
Caffeine intoxication is a diagnosis in the DSM-5 and in the ICD-10. It is defined by the DSM-5 as the emergence of five or more of the following symptoms after excess ingestion of caffeine (>250 mg): restlessness, nervousness, gastrointestinal disturbance, excitement, insomnia, flushed face, diuresis, muscle twitching, rambling flow of thought and speech, tachycardia or cardiac arrhythmia, inexhaustibility, and psychomotor agitation.
Caffeine intoxication resolves rapidly (consistent with caffeine’s average half-life of 4 to 6 hours) and usually with no long-lasting consequences. However, caffeine can be lethal after ingestion of very high doses (i.e., about 5 to 10 g). Accidental overdoses and suicides by caffeine ingestion have been documented. The emergence of highly caffeinated energy drinks in recent years may be increasing the incidence of caffeine intoxication. A recent report by the Drug Abuse Warning Network found that the number of emergency department visits involving energy drinks doubled from 2007 to 2011.
CAFFEINE WITHDRAWAL
Caffeine withdrawal has been documented in humans and animals. Caffeine withdrawal syndrome is currently defined by the DSM-5 as the presence of three or more of the five following symptom clusters within 24 hours after abrupt cessation of or reduction in caffeine use, along with clinically significant distress or impairment in social, occupational, or other important areas of functioning: (1) headache; (2) fatigue or drowsiness; (3) dysphoric mood, depressed mood, or irritability; (4) difficulty concentrating; and (5) flu-like somatic symptoms— nausea, vomiting, and muscle pain/stiffness. Headache is a hallmark feature of caffeine withdrawal with approximately 50% of users reporting headache by the end of the first day of abstinence. Caffeine withdrawal usually occurs 12 to 24 hours after terminating caffeine intake and usually lasts for 2 to 9 days. Greater incidence and severity of caffeine withdrawal are roughly associated with greater daily caffeine dose. However, caffeine withdrawal occurs after abstinence from as little as 100 mg/day. Lower than usual doses of caffeine can suppress caffeine withdrawal. Caffeine withdrawal has been identified as a significant cause of postoperative headaches, the risk of which can be reduced if regular caffeine users are given caffeine on the day of the surgical procedure.
CAFFEINE USE DISORDER
The ICD-10 includes a diagnosis of substance dependence due to caffeine, and caffeine use disorder is now recognized by the DSM-5 as a condition for further study. The DSM-5 research criteria for caffeine use disorder consist of a more restrictive set of criteria than the generic DSM-5 substance use disorder criteria that apply to other recreational drugs. That is, individuals must show a problematic pattern of caffeine use leading to clinically significant impairment or distress, as manifested by all three of the following criteria occurring within a 12-month period: (1) a persistent desire or unsuccessful efforts to cut down or control caffeine use; (2) continued caffeine use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by caffeine; and (3) withdrawal, as manifested by either of the following: (a) the characteristic withdrawal syndrome for caffeine or (b) caffeine (or a closely related substance) is taken to relieve or avoid withdrawal symptoms. As is intended with a research diagnosis, additional research is needed to more fully characterize the features and prevalence of caffeine use disorder, its clinical significance and prognosis, associated features, and effective treatment strategies.
GENETICS
Relative to dizygotic twins, monozygotic twins have higher concordance rates for total caffeine consumption, heavy caffeine consumption, coffee and tea intake, caffeine intoxication, caffeine withdrawal, caffeine tolerance, and caffeine-related sleep disturbances with heritability estimates between 30% and 77%. Research has shown that 28% to 41% of the heritable effects of caffeine use (or heavy use) are shared with alcohol and smoking. The CYP 1A2 gene, which codes for the primary enzyme responsible for caffeine metabolism, and the ADORA2A gene, which codes for the adenosine A2A receptor, have been shown to be associated with caffeine use, effects of caffeine (e.g., anxiety responses), and some health outcomes.
EFFECTS ON PHYSICAL HEALTH
Although the U.S. Food and Drug Administration does not provide guidelines on safe levels of caffeine intake, the United Kingdom Food Standards Agency and Health Canada have suggested a 200 mg/day limit for pregnant women. Health Canada recommends a limit of 400 mg/day for healthy adults and 2.5 mg/kg for children under 12.
Adverse Health Effects
Caffeine can increase blood pressure by 5 to 15 mm Hg systolic and 5 to 10 mm Hg diastolic for several hours in healthy adults. Caffeine can influence heart rate variability and increase arterial stiffness, but the implications of these findings are unclear. There is no evidence that caffeine consumption increases the risk of cancer development. Coffee, but not caffeine per se, has been shown to exacerbate gastroesophageal reflux. Caffeine is a general risk factor for urinary incontinence, and caffeine reduction decreases urinary incontinence. Caffeine increases urinary calcium excretion, but the clinical significance of the calcium loss and risk of osteoporosis is debated. Some large-scale studies and a meta-analysis of previous studies suggest that maternal caffeine use increases the rate of spontaneous abortion in a roughly dose-dependent fashion. High caffeine use has been associated with decreased fecundity and reduced fetal growth.
Health Protective Effects
Case–control and epidemiologic studies have elucidated a relationship between caffeine consumption and reduced risk of Parkinson’s disease. Epidemiologic studies have also reported an association between coffee drinking and reduced incidence of chronic liver disease, although the potential mechanisms are unclear. Epidemiologic studies have reported a protective effect of coffee drinking for risk of developing type 2 diabetes, with the effects attributed to coffee constituents other than caffeine.
DRUG–DRUG INTERACTIONS
Nicotine and Cigarette Smoking
Cigarette smokers consume more caffeine than nonsmokers. Cigarette smoking abstinence can produce substantial increases in caffeine blood levels among heavy caffeine consumers, presumably because of the reversal of cigarette smoking–induced caffeine metabolism. In one study, pregnant women were nine times more likely to report a history of daily cigarette smoking if they met criteria for substance dependence on caffeine.
Alcohol
Heavy use and clinical dependence on alcohol is associated with heavy use and clinical dependence on caffeine. A study of individuals fulfilling DSM-IV diagnostic criteria for substance dependence on caffeine found that almost 60% had a past diagnosis of alcohol abuse or dependence.
Alcohol and Energy Drinks
There is growing concern and some research to suggest that the coingestion of caffeinated energy drinks and alcohol increases the consumption and misuse of alcohol and alters psychological and behavioral effects of alcohol, which could result in increased harm. Studies have concluded that individuals consuming caffeine along with alcohol underestimate their levels of impairment and may be more prone to injury. Survey studies have found that combining energy drinks with alcohol is associated with greater consumption of alcohol and/or binge drinking.
Other Drug Interactions
Animal studies show that caffeine increases acquisition of cocaine self-administration, reinstates self-administration behavior previously maintained by cocaine, and potentiates the stimulant and discriminative stimulus effects of cocaine.
Animal studies also show that caffeine may increase the toxic effects of d-amphetamine, cocaine, and MDMA. Both animal and human studies suggest a mutually antagonistic relationship between caffeine and benzodiazepines. Caffeine inhibits the metabolism of the antipsychotic clozapine. Lithium toxicity may occur after caffeine withdrawal because of decreased renal clearance of lithium.
KEY POINTS
1. Caffeine is the most commonly consumed psychoactive drug in the world and is found naturally in or added to many common food products.
2. Caffeine is a competitive A1 and A2A adenosine receptor antagonist and produces a variety of effects that are opposite to the effects of adenosine including central nervous stimulation.
3. Caffeine metabolism is slower among pregnant women and those taking oral contraceptives and faster among cigarette smokers.
4. Caffeine withdrawal (e.g., headache, fatigue) usually occurs 12 to 24 hours after terminating caffeine intake and lasts for 2 to 9 days.
5. Caffeine can cause a discrete intoxication syndrome as well as can cause or worsen symptoms of anxiety and insomnia.
REVIEW QUESTIONS
1. Which of the following is not a recognized symptom of caffeine withdrawal?
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