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Genetic Influence on Caffeine Tolerance and Withdrawal
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Genetic Influence on Caffeine Tolerance and Withdrawal

Anna Schreiner

Brief summary

This paper discusses genetic effects of caffeine tolerance, withdrawal, etiology, possible contributing factors, assessment techniques, mechanisms of action of the causative agents, and also intervention techniques. Dager (et al, 1999) measured the effects of caffeine ingestion on two groups of people, those who were regular caffeine users and those who were caffeine intolerant (and therefore didn’t use caffeine), after both groups had refrained from caffeine ingestion for a month or more-referred to as a caffeine holiday. 

The researchers found that after significant caffeine ingestion (equivalent to 5-8 cups of coffee), the caffeine intolerant individuals experienced substantial psychological and physiological distress after ingesting caffeine while those individuals who had previously imbibed in caffeine regularly did not. However, even the caffeine users saw an increase of brain lactate over their baseline after their caffeine holiday. They also found that individuals in both groups showed significant rises in brain lactate regardless of the clinical reaction of the individuals. As a result, Dager (et al, 1999) suggest that caffeine intolerance is a result of something other than a metabolic response to caffeine.

Dager et al. (1999) states that caffeine is a member of the methylxanthine family of drugs, is the most widely used psychostimulant in the world. Dager et al. (1999) points out that a cup of coffee contains, on the average, between 100 mg and 150 mg of caffeine and since the per capita consumption in the United States is approximately one to two cups a day it can be estimated that more than 15 billion grams of caffeine are consumed annually in this country alone. Researchers stress that despite caffeine's effects on stimulating cerebral metabolism, it also causes substantial and prolonged reductions in cerebral blood flow (CBF).

Carlson (2004) says that caffeine is a bitter-tasting alkaloid found in coffee, tea, cocoa beans, and other plants. He emphasizes that in much of the world a majority of the adult populations ingests caffeine every day without any apparent harm to them. Despite this, about 15% of the general population report having stopped caffeine use completely, citing concern about health and unpleasant side effects (Johns Hopkins University School of Medicine, 2003). 

According to the Johns Hopkins University School of Medicine (2003), coffee is the leading dietary source of caffeine among adults in the United States, while soft drinks represent the largest source of caffeine for children. Caffeine consumption from soft drinks has dramatically increased over the last few decades and 70% of all soft drinks contain caffeine (Johns Hopkins University School of Medicine, 2003). 

A number of non-cola drinks such as root beer, orange soda, cream soda, and lemon-lime drinks contain caffeine in amounts similar to those in the cola drinks. Some, but not all, coffee ice creams and yogurts deliver a significant dose of caffeine. Although chocolate milk, cocoa, and milk chocolate candy also contain caffeine, the dose delivered in a usual serving is generally below the threshold for readily detectable mood and behavioral effects (<10 mg). The one exception is that a serving of dark chocolate candy may contain about 30 mg of caffeine (Johns Hopkins University School of Medicine, 2003). 

Some medicinal products also often contain significant amounts of caffeine. Over-the-counter stimulant medications such as NoDoz and Vivarin contain between 100-200 milligrams per tablet, while caffeine-containing analgesics such as Anacin, Excedrin, and Midol deliver 64 to 130 milligrams per two tablet dose (Johns Hopkins University School of Medicine, 2003). 

Typical Caffeine Content of Common Foods and Medications

Serving Size
Caffeine Content
Caffeine Content

Volume or Weight 

6 oz 
77-150 mg 
100 mg 
6 oz 
20-130 mg 
70 mg 
1 oz 
30-50 mg 
40 mg 
6 oz 
2-9 mg 
4 mg 

6 oz 
30-90 mg 
40 mg 
6 oz 
10-35 mg 
30 mg 
Canned or Bottled 
12 oz 
8-32 mg 
20 mg 
Caffeinated Soft Drinks 
12 oz 
22-71 mg 
40 mg 
Caffeinated Water 
16.9 oz 
50-125 mg 
100 mg 
Cocoa/Hot Chocolate 
6 oz 
2-10 mg 
7 mg 
Chocolate Milk 
6 oz 
2-7 mg 
4 mg 
Coffee Ice Cream or Yogurt 
1 cup (8 oz) 
8-85 mg 
50 mg 
Chocolate Bar

Milk Chocolate 
1.5 oz 
2-10 mg 
10 mg 
Dark Chocolate 
1.5 oz 
5-35 mg 
30 mg 
Caffeinated Gum 
1 stick 
50 mg 
50 mg 
Caffeine-Containing OTC Products

2 tablets 
64-130 mg 
64 or 130 mg 
1 tablet 
75-350 mg 
100 or 200 mg 
Weight-loss products 
2-3 tablets 
80-200 mg 
80-200 mg 
Sports Nutrition 
2 tablets 
200 mg 
200 mg 

Foods of the same type can contain different amounts of caffeine. For example, the caffeine in coffee can vary over a 10-fold range depending on the serving size and strength of the coffee. Soft drinks are similarly widely variable. (Johns Hopkins University School of Medicine, 2003). 


Kendler & Prescott (1999) state that caffeine is by far the most commonly used psychoactive substance and that coffee is consumed daily by approximately 80% of the world's population. They stress that even though the adverse health consequences of caffeine consumption may be small, given widespread use, even minimal risk could produce substantial public health effects. They postulate that, caffeine use is influenced by the reinforcing properties of taste, hedonic psychoactive effects, and the desire to avoid withdrawal. Kendler & Prescott (1999) emphasize that there are wide inter-individual variations in preference for caffeine and in sensitivity to withdrawal.

Chatterjee, (1999) warns that caffeine likely performs like other psychoactive substances of abuse. He also states that like its more hard-hitting counterparts-alcohol, cigarettes and drugs-its ill effects seem to depend partly on your genes (Chatterjee, 1999).

Kendler, a professor of psychiatry at Virginia Commonwealth University Medical College, cited by Chatterjee, (1999) examined 1,000 sets of female twins to see if caffeine use ran in the family. In this study Kendler looked at several markers of caffeine addiction: whether the women used tea, soda or coffee heavily (the equivalent to five cups of coffee, a day), how tolerant they were to it (did they need to consume more to achieve the desired effect), and whether they experienced withdrawal (headaches, depression or nausea) when they stopped drinking the beverages (Chatterjee, 1999). Kendler cited by Chatterjee, (1999) found that the likelihood of inheriting a taste for caffeine is extremely high for women, as is their tolerance for it and the set of withdrawal symptoms they experience when they cease to drink it.

Arnon Perry (1986) states that there is evidence that demonstrates that personality in itself is affected by heredity. Perry also did an exploratory study on heredity, personality traits, product attitude, and product consumption towards the consumption of alcohol, cigarettes, and coffee on twins. Perry’s underlying principles of the twin method is that MZ (monozygous-identical) twins have identical genotypes, and therefore any observed dissimilarity within pairs must be related to environmental factors. DZ (dizygous-fraternal), same sex twins, while on the average differing 50% of their genes provide a measure of environmental control not otherwise possible by sharing such factors as birth rank and mothers age. 

An article in JAMA, (2006) says that caffeine is metabolized primarily by the enzyme cytochrome P450 1A2 (CYP1A2) in the liver. Variations of the gene for this enzyme can slow or quicken caffeine metabolism. Carriers of the gene variant CYP1A2*1F allele are "slow" caffeine metabolizers, while individuals with the gene variant CYP1A2*1A allele are "rapid" caffeine metabolizers (JAMA, 2006).


Carlson, (2004) says that adenosine is known to be released, apparently by glial cells and also neurons, when cells are short of fuel or oxygen. According to Carlson, the release of adenosine activates receptors on nearby blood vessels and causes them to dilate, increasing the flow of blood and helping bring more of the needed substances to the region. Additionally, adenosine also acts as a neuromodulator, through its action on at least three different types of adenosine receptors. Furthermore, the adenosine receptors are coupled to G proteins, and their effect is to open potassium channels, producing inhibitory postsynaptic potentials. Due to the fact that adenosine is present in all cells, Carlson (2004) says investigators have not yet succeeded in distinguishing neurons that release this chemical as a neuromodulator. Carlson, (2004) points out that circuits of adenosinergic neurons have not yet been identified.

Due to the fact that adenosine receptors suppress neural activity, adenosine and other adenosine receptor agonists have generally inhibitory effects on behavior. Caffeine being a very common drug blocks adenosine receptors and produces excitatory effects (Carlson, 2004).


Dager et al. (1999) state that there are studies to support a phenomenon of caffeine tolerance or habituation with chronic use. The example Dager et al. gives is the effects of caffeine on subjective psychostimulation or sleep latency, but not cerebral blood flow (CBF) reduction.

Johns Hopkins University School of Medicine (2003) points out that tolerance refers to a decrease in responsiveness to a drug after repeated drug exposure. Johns Hopkins University School of Medicine (2003) states that caffeine in higher doses (750 to 1200 mg/day spread throughout the day) administered on a daily bases, has shown to produce complete tolerance (i.e., caffeine effects are no longer different from baseline or placebo) to some, but not all of the effects of caffeine. Johns Hopkins University School of Medicine, (2003) stress that lower or typical dietary doses of caffeine produce incomplete tolerance. They give as an example that sleep may continue to be disrupted in regular caffeine users.


PsychiatryOnline (2006a) states that with caffeine withdrawal an essential feature is a characteristic withdrawal syndrome due to the abrupt cessation of, or reduction in, the use of caffeine-containing products after prolonged daily use. This includes headache and one (or more) of the following symptoms: marked fatigue or drowsiness, marked anxiety or depression, or nausea or vomiting (PsychiatryOnline, 2006a). 
Withdrawal is typically more prevalent in individuals with heavy use (500 mg/day) but may occur in individuals with light use (100 mg/day). Additionally, symptoms must cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. Finally, these symptoms must not be due to the direct physiological effects of a general medical condition and must not be better accounted for by another mental disorder (PsychiatryOnline, 2006a). 

The associated symptoms of caffeine withdrawal encompass a strong desire for caffeine and worsened cognitive performance (especially on vigilance tasks). Associated symptoms can begin within 12 hours of cessation of caffeine use, peak around 24–48 hours, and last up to 1 week. Individuals that seek medical treatment for these symptoms may not realize that they are actually due to caffeine withdrawal (PsychiatryOnline, 2006a).

Mood Altering and Reinforcing Effects of Caffeine 

Johns Hopkins University School of Medicine (2003) says that the mood altering effects of caffeine depends on the amount of caffeine consumed and whether the individual is physically dependent on or tolerant to caffeine. They stress that with caffeine non-users or intermittent users, low dietary doses of caffeine (20-200 mg) generally produce positive mood effects such as increased well-being, happiness, energetic arousal, alertness, and sociability. They emphasize that individual differences in sensitivity and tolerance affect the severity and likelihood of experiencing negative of effects of caffeine. 

Johns Hopkins University School of Medicine (2003) states that drug reinforcement refers to the ability of a drug to sustain regular self-administration (i.e. drug-taking). They point out that because caffeine is the most widely consumed mood altering drug in the world that it is clear that caffeine is a reinforcer. Johns Hopkins University School of Medicine (2003) stresses that the historical efforts to restrict or eliminate the use of caffeine containing foods in various cultures have invariably met with failure. In individuals who are regular caffeine users, the avoidance of low grade withdrawal symptoms, such as drowsiness after overnight abstinence, has been identified as a central mechanism underlying the reinforcing effects of caffeine. 

PsychiatryOnline, (2006b) states that caffeine intoxication can lead to restlessness, nervousness, excitement, insomnia, flushing, diuresis, and gastrointestinal complaints. Also, that doses leading to intoxication varies. PsychiatryOnline, (2006b), emphasizes that at high doses, there can be psychosis, arrhythmias, and psychomotor agitation. Caffeine taken in higher doses can cause mild sensory disturbances to occur. Caffeine taken in massive doses can result in grand mal seizures and even respiratory failure. In those individuals who have developed tolerance, intoxication may not occur despite high caffeine intake. PsychiatryOnline, (2006b) points out that the DSM-IV-TR recognizes other caffeine-induced disorders such as anxiety disorder and sleep disorder, and there is a category for caffeine-related disorder NOS (PsychiatryOnline, 2006b).

Differential Diagnosis of Caffeine-Induced Disorders 

PsychiatryOnline, (2006b) stresses that caffeine-induced mental disorders must be differentiated from medical conditions that mimic intoxication. They emphasizes that the temporal relationship of the symptoms to increased caffeine use or to abstinence from caffeine helps to establish the diagnosis. Caffeine intoxication can be mimicked by other disorders such as medication-induced side effects; amphetamine intoxication; sedative, hypnotic, or anxiolytic withdrawal or nicotine withdrawal; sleep disorders; panic disorder or generalized anxiety disorder; and even manic episodes (PsychiatryOnline, 2006b).


Foxx and Rubinoff (cited by James, 2004) did an early controlled study to reduce caffeine intake involving a program of behavioral intervention based on nicotine or cigarette fading methods that had been developed for use with smokers. They said that the available evidence suggested that people can achieve success when attempting to reduce their intake, and that adverse withdrawal effects can be avoided by the gradual removal of caffeine from their diet. Foxx and Rubinoff’s (cited by James, 2004) findings are consistent with other studies of caffeine physical dependence and reinforcement, which show that the reinforcing properties of caffeine are markedly potentiated by abrupt abstinence. In this situation, caffeine functions as a rather strong negative reinforcer in that intermittent ingestion of the drug enables the consumer to avoid aversive withdrawal effects. Foxx and Rubinoff (cited by James, 2004) stress that when withdrawal effects are absent, that studies show that caffeine functions as a weak and unreliable positive reinforcer, and one that is considerably less robust than many other drugs of habitual use, including opioids, alcohol, and nicotine. 
Posen, (2000) stated that a simple intervention plan had had a significant impact on his patients. Posen asked his new patients to try an experiment which had them go off caffeine for three weeks. Posen told them that if they felt better without it, they could choose to stay off it but if they did not feel any better they could go back to drinking the caffeine.

Posen, (2000) found that at least 75%-80% of his patients felt better without the caffeine and that many of his patients felt dramatically better. Posen states that the benefits people notice include feeling more calm and relaxed, sleeping better, having more energy, less heartburn and less muscle ache (Posen, 2000). Posen, (2000) also points out that even though he has read about caffeine being an addictive substance, he has never met anyone who could not give up caffeine within a week or two. 

Lane et al. (2002) state that caffeine may be the most popular drug in the world, but a growing body of evidence suggests that its adverse effects are not inconsequential. Lane et al. suggests that the true magnitude of caffeine’s impact on health and disease is yet to be determined and measured against the supposed benefits from its use. 

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