Caffeine: Mechanisms of Action, Effects on Cognition, and Potential Toxicity

Written by Brett Weiss

July 2019

Image by OpenClipart-Vectors from Pixabay

More than 80% of the US population consumes caffeine (1,3,7-trimethylxanthine) (McLellan et al., 2016).  Many people who consume this psychoactive stimulant do so to enhance cognition and physical performance.  Recent scientific research has provided evidence that caffeine enhances attention, vigilance, and motivation.  Athletes and military personnel also use caffeine for physical performance enhancement (caffeine as an ergogenic agent).  Questions remain regarding toxicity of habitual consumption of large quantities of caffeine throughout a lifetime; however, some studies point to potential neuroprotective effects of caffeine consumption in older adults.  The following will review what scientists have found out about caffeine: its mechanisms of action, cognitive benefits, associated health hazards, and what dosages may facilitate toxicity.

Following consumption, caffeine reaches peak levels in circulation during the first hour, although this varies between people (McLellan et al., 2016).  Studies have shown that the most efficient method for caffeine absorption comes from chewing caffeine gum, as the buccal tissue of the mouth transfers caffeine to circulation rapidly (Kamimori et al., 2015).  Once in circulation, caffeine rapidly distributes to all tissues and crosses the blood-brain barrier, exerting its effects on all tissues.  The half-life of caffeine is generally 3-5 hours, meaning that half the initial quantity consumed will degrade after this amount of time (Fredholm, 1995).  Smoking, different dietary choices, pregnancy, liver disease, and use of oral contraceptives can affect the half-life of caffeine (McLellan et al., 2016).

The structure of caffeine is similar to adenosine, a molecule that modulates neurons.  Adenosine receptor density and sensitivity varies between people, and adenosine receptor density increases as caffeine intake increases (McLellan et al., 2016).  Although caffeine can have effects resulting from phosphodiesterase inhibition and promotion of intracellular Ca2+ release, it is known now that the concentrations in circulation resulting from moderate doses of caffeine block A1 and A2a adenosine receptors primarily (McLellan et al., 2016; Fredholm, 1979).  It is currently thought that both adenosine receptor subtypes are involved in the behavioral effects of caffeine; however, their individual contributions have not been established.  Both receptor subtypes are found in the brain and peripheral tissue.  The A2a adenosine receptor subtype is found in high concentrations in areas of the brain containing dopamine fibers (dopamine is involved in pleasure and motor activity) (McLellan et al., 2016).  Adenosine inhibits the release of many neurotransmitters in the brain.  Thus, since caffeine has a similar structure to adenosine, caffeine can block adenosine receptors (act as an antagonist to adenosine receptors), which would result in decreased inhibition of the release of these neurotransmitters.  Essentially, higher concentrations of these neurotransmitters would be available after caffeine intake.  Two of the neurotransmitters that caffeine affects include noradrenaline and dopamine (McLellan et al., 2016).  Hence, an adenosine receptor blocker (antagonist) such as caffeine would promote release of these neurotransmitters. 

Through blocking adenosine A1 and A2a receptors, caffeine can theoretically promote excitation of neurons sensitive to dopamine (striatonigral neurons) and can reduce inhibitory inputs to other dopamine neurons (striatopallidal neurons).  These responses to caffeine likely increase arousal and improve psychomotor activity from caffeine intake during sleep loss (McLellan, 2016).  Another factor affecting individual response to caffeine entails genetics and adenosine A2a receptors.  For example, in the gene encoding these receptors, 15-20% of individuals have one genetic code (homozygous for thymine), while 35% have another genetic code (homozygous for cytosine).  The other ~50% would have a mix of these genetic codes (heterozygous).  The different genetic codes at this gene appear to affect individual response to caffeine; however, the exact effects remain unknown (Bodenmann et al., 2012; McLellan et al., 2016; Yang et al., 2010).  It is possible that these genetic codes influence receptor number and sensitivity, which would impact an individual’s response to a dose of caffeine.

For centuries, people have consumed caffeine through coffee or tea for enhancement of cognition (McLellan et al., 2016: Snel & Lorist, 2011).  The functional benefits of caffeine remain controversial, though.  For example, there is general agreement that caffeine improves “lower” cognitive functions such as reaction time.  Caffeine’s effects on “higher” cognitive functions such as problem solving and decision making remain debated (McLellan et al., 2016).  Kamimori et al. (2015) performed a study that attempted to find out whether caffeine administration in 200 mg doses mitigated impairments in cognition with restricted opportunities for sleep.  The study used Special Forces personnel in groups that received caffeine in four 200 mg doses in late evening and early morning hours and another group that received placebo (no caffeine).  The study involved giving the caffeine doses and placebo during three successive days with a four-hour sleep period that followed.  The study design included six tests administered during the experiment: a psychomotor vigilance test, a logical reasoning test, a vigilance monitor, an actigraphy, a field vigilance test, and a live-fire marksmanship test.  The psychomotor vigilance test presented a vigilance cue (bull’s-eye) that approaches the middle of a screen.  The goal of this test is for the subject to press a designated button as soon as possible after the visual cue appears.  This test measures reaction time speed.  The logical reasoning test measures ability to correctly describe the relationship of two presented symbols in English grammar and syntax.  For each trial, two symbols were presented (i.e. “#&” or “&#”) along with a statement under the symbols that correctly or incorrectly describes the order in which the symbols were presented.  The subjects had to decide whether the statement was true or false.  The number of correct responses were measured along with average correct mean response time in seconds.  The vigilance monitor presented a vibrating stimulus that the subjects had to respond to.  The vibrations were presented randomly every five to twenty minutes.  Correct responses and latency to respond were measured.  The subjects also wore an actigraph during the study, which is about the size of a watch.  Data from the actigraph downloaded to a computer with measurements of whether the subjects were scored as “asleep” or “awake.”  The Field vigilance test involved observing a building façade with exterior and interior lights lighting the building.  The subjects were required to record where, when, and what of any activity occurring around the building during an observational period.  The live-fire marksmanship test involved scenarios where subjects had to evaluate friend-foe identifications under time pressure.  The subjects had to distinguish cardboard pictures of targets that were friends (hostages) or foes (terrorists).  The percentages of correctly identified targets were recorded for each trial. 

The study demonstrates that caffeine can effectively offset impairments in cognition associated with successive days of reduced sleep.  All of the tests administered in the experiment showed that the caffeine group outperformed the placebo group (no caffeine) in cognition.  The only test that did not give statistically significant results between groups was the live-fire marksmanship test.  Reaction times were not measured during the live-fire marksmanship test, though.  If the caffeinated group outperformed the non-caffeine group in reaction time in the live-fire marksmanship test, this may have applicability in the field.  Identifying friend from foe and making quick decisions is an essential function of a Special Forces member.  Future studies of a similar nature should apply measurements of reaction time to the live-fire marksmanship test.  The Kamimori et al. (2015) study demonstrates that high doses of caffeine (800 mg) during successive nights of wakefulness is effective for maintaining cognitive function.

The consensus regarding basic cognitive functions without sleep deprivation is that 32-300 mg of caffeine can improve aspects of cognition, including attention, vigilance, and reaction time (McLellan et al., 2016).  The effects of caffeine on arousal occur in a dose-dependent manner, with low doses reducing anxiety and higher doses increasing symptoms of anxiety, nervousness, and jitteriness (McLellan et al., 2016).  Nehlig (2010) suggested an inverted U-shaped arousal-performance curve that could explain the extent that caffeine improves or inhibits function.  According to the Yerkes-Dodson law (Yerkes & Dodson, 1908), a relationship exists between arousal and performance, with low arousal associated with poor performance and increased mental arousal associated with better performance.  The increased arousal and better performance only occur up to a certain point, though.  When arousal levels exceed a threshold, performance decreases.  Under normal circumstances, evidence suggests that people consume caffeine to reach a peak-level of arousal, modulating their caffeine intake until they reach a self-selected optimal arousal level (McLellan et al., 2016; Harvanko et al, 2015).

Scientists have studied caffeine’s effects on other facets of cognition, including reaction time, vigilance, attention, acute effects on memory, chronic effects on memory, executive function, and judgment.  Multiple studies have indicated that caffeine improves reaction time to visual cues in doses ranging from 12.5 to 400 mg (McLellan et al., 2016).  Vigilance entails the ability to continue performance throughout long, tedious, or boring tasks.  In rested individuals, doses of around 200 mg can improve performance for several hours (McLellan et al., 2016).  Attention involves focusing on and selecting aspects of task-relevant information while suppressing information not relevant to the task.  Caffeine doses ranging from 40 mg to 280 mg have shown to increase speed and accuracy in rested subjects in repeat digit tasks (McLellan et al., 2016).  More complex attentional tasks including rapid visual information processing tasks, showed that performance benefits from 12.5-400 mg doses in average adults (McLellan et al., 2016).  Broadly speaking, caffeine appears to give a positive effect on attention, reaching optimal performance at doses of 200-300 mg (McLellan et al., 2016).  The effects of caffeine on memory encoding and retention remain debated.  Some studies show benefit of caffeine intake on acute effects of memory while others do not.  Some researchers posit that the discrepancies of findings with memory encoding and retention depend on the memory task under study.  Thus, further studies involving effects of caffeine on memory processing are required to resolve these issues (McLellan et al., 2016).  Regarding chronic effects of caffeine on memory, long-term habitual use of caffeine has been linked to reduced risk for neurodegenerative diseases such as dementia, Alzheimer’s disease, cognitive impairment, and cognitive decline (McLellan et al., 2016).  Jarvis (1993) conducted a study of 9003 adults and found a positive relationship with habitual caffeine consumption and verbal memory, visuospatial reasoning, and reaction time tasks.  The effects found became stronger with increasing age.  Very few studies have examined the effects of caffeine intake on executive function, which refers to high-level reasoning.  In order to conclusively evaluate the effects of caffeine intake on executive function, further studies need to take place (McLellan et al., 2016).  This is also the case for effects of caffeine consumption on judgment.

Caffeine toxicity includes specific symptoms arising from consuming caffeine.  The physical state of caffeine toxicity, also known as “caffeinism,” includes symptoms of anxiety, agitation, restlessness, insomnia, gastrointestinal disturbances, tremors, tachycardia, psychomotor agitation, and in extreme cases death (Cappelletti et al., 2015).  Energy drink consumption may facilitate the risk of caffeine overdose, especially in those who typically abstain from caffeine.  Caffeine intake doses that exceed 500-600 mg, the equivalent of four to seven cups of coffee, can lead to anxiety, tremor, and increased heart rate (tachycardia).  The acute toxic level of caffeine has not been well established but is around 10 g/day in average adults, which is comparable to consumption of about 100 cups of coffee (Cappelletti et al., 2015).  In general, life-threatening caffeine doses involve ingestion of caffeine-containing medications as opposed to caffeinated foods or drinks.  Life-threatening caffeine overdoses have been associated with blood concentrations exceeding 80 mg/L (Cappelletti et al., 2015). 

As studies show, caffeine can have acute effects in improving arousal, attention, and vigilance, while effects on executive function remain ill-established.  Aside from exerting acute cognitive benefits, the effects of caffeine on muscle, including increased release of Ca2+ from the sarcoplasmic reticulum, may improve muscle contraction and subsequent physical performance.  As mentioned, studies also suggest that chronic and habitual use of caffeine may have neuroprotective effects in older adults.  Scientists have not discovered much regarding long-term negative effects on health from moderate and habitual consumption of caffeine.  With the somewhat recent introduction of energy drinks in many societies throughout the world, caffeine toxicity can present as a problem, especially in adolescents.  It remains important to monitor intake levels and dosages of caffeine if one chooses to consume caffeine in order to optimize arousal level throughout the day as the Yerkes-Dodson law proposes.


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