Coffee, café, 咖啡, قهوة, コーヒー, КоΦέ, Kahvi. No matter what you call it, that bitter, dark brown drink is universally recognized as a crisp beacon that cuts through mental fog. People around the world rely on coffee as a means of waking up and staying alert throughout their busy days. A 2015 report estimated that roughly 80% of adults in America consume coffee every year, with 60% drinking it daily [1]. These percentages translate to nearly 26 million 60-kilogram bags of coffee being consumed in the year 2020-2021 [2]. The numbers become even larger when we consider the global panorama. In 2020-2021, around 166.63 million 60-kilogram bags of coffee were consumed globally [3]. Clearly, the allure of coffee spans worldwide, with that first sip serving as many individuals’ much-needed kickstart for each morning. While many coffee users can attest to feeling that familiar surge in stimulation and focus promptly after consumption, their understanding of caffeine’s actual mechanism and biological impact might be limited. In experienced coffee enthusiasts, for example, the beverage does not even have to enter the bloodstream to have an effect. Just the thought, sight, or smell of coffee can elicit a caffeine-like response in the body [4]. Provided this seemingly confounding piece of evidence, how does caffeine actually work? What stimulates the body to produce caffeine-like responses? Let’s explore how caffeine functions and impacts our bodies and minds in the short- and long-run to unveil the potency of this intriguing elixir.

Biomechanics and Acute Effects of Caffeine

Once consumed, the doses of caffeine typically found in an average cup of coffee have several observed effects. Blood pressure and positive mood may all increase after your daily drink, thus creating a feeling of wakefulness and readiness to take on the day ahead [5]. Some people may also get the “coffee jitters,” a sort of restless feeling that occurs after ingestion. This is all quite common coffee knowledge if you are familiar with the drink, but why exactly are these physical feelings evoked?

Caffeine is classified as a central nervous system stimulant and is also the world’s most widely used psychoactive drug [6]. The most well-studied mechanism that scientists believe produces the wakeful effects of coffee is caffeine’s ability to block adenosine receptors. Adenosine is a chemical that aids in cell energy transfer, is an integral building block of important molecules such as ATP and RNA, and an inhibitory neuromodulator involved in sleep–wake regulation [7]. The main types of adenosine receptors in the brain are called the inhibitory A1 receptors (A1R) and the facilitatory A2A receptors (A2AR), which serve to regulate neurotransmitter release [44]. When caffeine molecules antagonize, or block, these adenosine receptors, a reduction in the activity of adenosine itself occurs. This causes an upregulation of neurotransmitters such as dopamine and norepinephrine in the CNS [8]. Research has shown that high dopamine levels cause increased energy and “good feelings,” and high norepinephrine levels cause increased alertness, arousal, and attention [9]. Such physical effects are consistent with how many people feel following coffee consumption. This adenosine-blocking mechanism appears to be the most fundamental in explaining caffeine’s stimulatory abilities. When it comes to the nervous system, caffeine acutely increases sympathetic nerve activity, which is the portion of the CNS that responds to dangerous or stressful situations [12]. Acute caffeine consumption has also been shown to increase circulating epinephrine and norepinephrine, chemicals that act as neurotransmitters and hormones and trigger the familiar “fight-or-flight” response to stress [13]. In coffee, these hormones are the ones responsible for the feeling of wakefulness after coffee consumption. Neurophysiological responses are influenced by caffeine ingestion, but such acute dosages are not harmful and rather serve to induce a pick-me-up feeling.

Many consumers of coffee are conscious of the physical wakeful effects the drink has on them, but what about other acute bodily changes may we be unaware of? Caffeine can also induce effects on the cardiovascular and central nervous systems, though studies show that this requires high doses of the drug [10]. Some studies have looked at the effects of caffeinated coffee on atrial contractions and showed that there was no significant acute difference between caffeinated and non-caffeinated groups of subjects. The only real effects that researchers from such studies have concluded is that individuals who drink coffee regularly may experience less sleep and a mild increase in steps on a daily basis [11]. Other studies, however, have suggested that coffee can acutely increase blood pressure and arterial stiffness in some individuals, but tolerance develops very quickly as consumption increases over time. The researchers therefore concluded that coffee ingestion may be harmful to only some hypertension-prone subjects [45].

Long-term Impacts on Health

In addition to short-term effects, coffee consumption has also been shown to influence long-term health, specifically related to the cardiovascular, immune, and nervous systems [14,15,16,18]. In one observational study, scientists followed and analyzed coffee/tea and non-coffee/tea drinkers over fourteen years [19]. Both coffee and many teas contain caffeine, so may exert similar effects on the body. The consumption of both coffee and tea correlated with a 32% decreased risk of stroke and a 28% reduced risk of dementia development compared to non-coffee/tea drinkers [19]. Similar studies have observed significant reductions in the development of cardiovascular disease, asthma, cancer and various other diseases in long-term coffee consumers [20,21,22].

Although observational studies have been helpful in identifying associations between coffee consumption and various markers of health, experimental studies are better for indicating causal relationships or providing information as to the potential mechanisms behind coffee’s modulation of health. One such study isolated known antioxidative compounds of coffee, caffeic acid (CA) and chlorogenic acid (CGA), and provided them to mice with pesticide-induced neurodegeneration [16]. The researchers found CA and CGA to mitigate the toxicity caused by the pesticides in neurons and glial cells, suggesting coffee may play an antioxidative and anti-inflammatory role in the body that leads to neuroprotection [16]. Glia play several roles in the brain, some of which include neuronal support, regulation of synapses, modulation of neural activity, and neuroinflammation [17]. Another study using data from the UK Biobank showed that coffee consumption was associated with thickened nerve fibers, suggesting that the neuroprotective properties of coffee could be the result of increased protection of neurons by glial cells [23].

The antioxidative mechanism of CA is well-researched and may help explain the neuroprotection and anti-cancer benefits provided by coffee consumption. CA, and antioxidants in general, inhibit the production of reactive oxygen species (ROSs), which disrupt cell replication, differentiation and death [18]. This inhibition of ROS formation classifies CA as a tumor suppressor because it helps prevent unregulated cell proliferation and tumor formation. Interestingly, this ROS-suppressing property is also crucial for CA’s neuroprotective benefits. ROS development has been implicated in the mitochondrial disruption associated with Alzheimer’s Disease [18]. A study evaluating CA and another antioxidant called CAPE in the hippocampus of mice revealed significantly reduced ROS aggregation and damage in hippocampal cells when each antioxidant was administered, supporting the hypothesized mechanism of CA-induced neuroprotection [24].

In addition to its neuroprotective and tumor-suppressing properties, coffee consumption may also contribute to improved mental health when consumed in moderation [25]. A correlational study on members of a non-working community demonstrated an overall reduction in reported depression associated with caffeine consumption, although its relationship to cognitive ability was deemed insignificant after adjusting for confounding variables [26]. Similarly, an experiment studying the effects of coffee on microbiomes and depressive symptoms in rats indicated that both instant and decaffeinated coffee improved their symptoms and supported the development of a healthy gut [27]. These results imply caffeine may not be the only compound providing health benefits in coffee and indicate a need for further research into other contributors to improved mental wellbeing.

Although several studies have highlighted the potential for coffee consumption to improve mental health, others have actually suggested the opposite. Correlational studies have often found coffee consumption to increase rather than improve symptoms of anxiety, panic attacks, and depression [28,29]. However, these studies often fail to account for the amount consumed. For example, a study reporting increased incidents of panic attacks in regular coffee consumers observed this response in those consuming around five cups of coffee per day [29]. Other studies have suggested two to three cups to be optimal for health benefits, and only coffee consumption above this range to be potentially harmful [30,31].

Further research is needed to better elucidate the role of coffee in both mental and physical health at different doses. Regardless, there is substantial evidence of long-term chemical impacts of coffee consumption on health.

Long-Term Dependence & Conditioning

As coffee consumption becomes more routine, consumers often observe that they need more than one cup to stay energized. Thus, it is not unusual to spot these coffee enthusiasts ordering double - or even triple - shots of espresso at your local Starbucks. While experts continue to debate the scientific accuracy of labeling caffeine as a truly “addictive” substance, caffeine dependence is clinically recognized as a substance use disorder (SUD) [32]. Chronic caffeine use meets all of the SUD criteria, including a rise in dependence, changes in tolerance, and the emergence of withdrawal consequences. As one begins drinking coffee regularly, more and more caffeine is eventually required to produce the same stimulating effects. Attempts to break free from this dependency can be onerous, resulting in decreased cognitive performance and overwhelming fatigue [33]. For many, coffee has become essential to their work life and daily functioning.

Interestingly, the addictive potential of caffeine carries some biomechanical resemblance to more formidable drugs of dependence, such as amphetamines and cocaine. As an antagonist to adenosine receptors, caffeine upregulates dopaminergic activity and is ultimately believed to increase dopamine release in an area of the brain called the nucleus accumbens [34]. This site serves as a central structure of the brain’s intrinsic reward system by translating motivation into action. It also happens to be a critical target for many drugs, including the notoriously addictive amphetamines and cocaine [35]. Just like caffeine, these drugs cause increased dopamine concentrations in the nucleus accumbens. However, amphetamines and cocaine trigger much higher levels of dopamine release than caffeine, which may explain why they are so dangerous. Caffeine-induced changes in dopamine levels are lower and more similar to those from nicotine, morphine, and ethanol [34]. Despite its lower impact, caffeine’s addictive potential should not be underestimated, as these neurochemical changes in the nucleus accumbens are key to the development of drug dependence.

To further illuminate the consequences of caffeine dependence, scientists revealed the painful effects of caffeine withdrawal on the brain. In one experiment, a group experiencing withdrawal from caffeine presented with asymmetric activity and impairment of neural networks in their right and left brain hemispheres [36]. Scientists also observed that neural activity was increased in the anterior cingulate cortex and the somatosensory cortex, two major domains of the brain’s central pain processing network. Both of these changes in brain activity are consistent with migraines, a common symptom of caffeine withdrawal. Additionally, the study reported a decrease in prefrontal cortex activity among the caffeine withdrawal group, which is indicative of depression in mice studies. Enhanced activity was also observed in the endopiriform, a brain structure which mediates the activity of other brain structures responsible for the formation of stress and anxiety-filled memories. The results suggested that caffeine withdrawal induced similar effects to a stressor [36]. Altogether, these changes in brain activity are reflected in the common symptoms of caffeine withdrawal, such as irritability, depressed mood, and fatigue [37].

In another light, caffeine dependence can be explained through a basic psychological lens. Overcoming a reliance on caffeine can be difficult because the painful effects of withdrawal can only be immediately relieved by consuming caffeine itself, leading to “relapses” into regular intake. This is a prime example of negative reinforcement, the phenomenon in which a certain behavior is reinforced by the removal of something unpleasant. Additionally, a yearning for coffee or a sudden burst of caffeine-like alertness may arise when chronic caffeine users see a familiar cafe or catch a scent of the coffee’s aroma. These instances serve as “Pavlovian cues”, which are stimuli that, after frequent pairing with other stimuli that already elicit a certain response, are conditioned to trigger the same response. These cues are responsible for the similar phenomenon that causes some individuals to feel impatient upon encountering a McDonald’s logo, since McDonald’s is usually consumed when short on time [42]. When these recognizable cues are sensed, specific brain regions that react to caffeine are activated, thus prompting individuals to hunt down a spontaneous cup of coffee [38]. Notably, chronic coffee consumers may even be conditioned to prefer drinks with the taste of coffee over those without [39,40]. Provided this information, caffeine dependence arises not only from changes in brain activity, but also by psychological conditioning.

A conditioned response to caffeine can appear even in the absence of caffeine itself. In one study, blinded subjects who were exposed to coffee-related cues without actually ingesting caffeine demonstrated responses similar to those induced by caffeine. When exposed to these coffee cues, participants felt more driven to reach their goals and aimed to accomplish them within a shorter time frame. Individuals also self-reported increased arousal and displayed faster heart rates. Importantly, these observations were only significant in participants from the Western hemisphere, which researchers believe is due to caffeine’s predominant cultural influence in Western societies [4]. In another study, frequent coffee users received coffee or orange juice crossed with either placebo or caffeine. Researchers discovered that the caffeine-lacking coffee, in addition to the caffeinated orange juice and coffee, elicited subjective and physiological arousal [41]. Both of these studies represent effects of Pavlovian conditioning. In the two instances, the presentation of coffee-related cues triggered caffeine-like responses even in the absence of caffeine because the cues were associated with coffee stimuli. In other words, the coffee-related cues induced caffeine-like responses because they exemplified the aforementioned “Pavlovian cues.” These findings reinforce conditioning as a powerful tool with the potential to shape behaviors, emotions, and perceptions by establishing connections that persist beyond the original context.

Final Thoughts

Coffee has become a fixation of the modern world, leading to significant interest in understanding the mechanism by which it affects the mind and body– and whether consumption is beneficial or detrimental to health. There is significant research indicating coffee can lead to enhanced alertness due to both conditioning and actual chemical effects [4,9,38]. Some aspect of the immediate alertness experienced during coffee consumption could be due to conditioning that causes the consumer to anticipate the reward of coffee and in turn be rewarded even by this anticipation [4,38]. However, compounds in coffee have been shown to act as antioxidants and anti-inflammatory agents, potentially leading to cardiovascular, immune, and neurological health [20,21,22]. The mechanism behind the effects of coffee can also provide insight into coffee dependence and how to address it. Although coffee has been a hot– or cold– topic in neuroscience research in recent years, much remains to be known about how it impacts our health. Understanding how chemical compounds within coffee act to either support or harm our mental and physical health will help people form more educated decisions about their coffee consumption habits.

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