current research on caffeine addiction

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New insight into caffeine use disorder.

Johns Hopkins researchers recently conducted the most thorough evaluation to date of the prevalence and clinical significance of caffeine use disorder, as well as the correlates of meeting proposed criteria for the condition.

A new study finds potential for caffeine to cause anxiety, insomnia and other symptoms that interfered with subjects’ lives.

Mary “Maggie” Sweeney wants to make one thing clear: She has no intention of convincing people to give up their coffee or favorite caffeinated beverage. That said, the psychiatry researcher at Johns Hopkins Bayview Medical Center’s Behavioral Pharmacology Research Unit feels compelled to raise awareness about caffeine’s potential to cause distress.

Building on a long-running grant project in collaboration with Roland Griffiths , psychiatry researcher, a recent study on caffeine use disorder revealed responses to questions about caffeine use that Sweeney says were eye-opening and complementary to clinical trials conducted at Johns Hopkins — one in 2016 and one in 2019 . The  Diagnostic and Statistical Manual of Mental Disorders (DSM-5) recognized caffeine use disorder as “a condition for further study.”

Caffeine use disorder is a problematic pattern of caffeine consumption characterized by a persistent desire to cut down or control use of the substance along with unsuccessful efforts to do so despite problems caused or worsened by caffeine. Significant withdrawal symptoms or use of the drug to relieve or avoid withdrawal are also characteristics of the condition.

Sweeney, Griffiths and colleagues conducted the online research survey with 1,006 caffeine-consuming adults from across the U.S. Data were collected by an online survey panel aggregator used in other peer-reviewed research studies. The goal was to better understand caffeine use disorder’s prevalence and clinical significance in the general population.

Milligrams of caffeine per serving were calculated using typical milligrams per ounce for brewed/drip coffee (200 mg/12 oz.); brewed tea (40 mg/6 oz.); and soft drinks (40 mg/12 oz.). Total caffeine intake in a typical week from all sources was summed and divided by seven to estimate daily caffeine consumption. To qualify for the study, participants needed to report consuming some caffeine-containing beverage or supplement in a typical week.

The researchers found that 8% of the sample fulfilled DSM- proposed criteria for caffeine use disorder when the structured caffeine use disorder interview questions were adapted to the online survey format.

“What I find fascinating,” says Sweeney, “is how little people think about coffee or other caffeinated drinks as stimulants. Although for many people consumption of caffeine is benign, we learned from our study that there is a small but important subset of caffeine consumers who report that caffeine has interfered with their lives in clinically meaningful ways.”

People who met criteria for caffeine use disorder reported problems such as insomnia, gastrointestinal troubles and anxiety, which were caused by or exacerbated by caffeine. The study also found that participants who met criteria for caffeine use disorder tended to consume more caffeine, and were younger and more likely to be cigarette smokers. A larger sample or sample with greater substance use history may be necessary to detect the association between caffeine use disorder and other substance use.

About 90% of adults in the United States use caffeine regularly, says Griffiths, and their average consumption exceeds 200 milligrams of caffeine per day — more caffeine than is contained in two 6-ounce cups of coffee, or five 12-ounce cans of soft drinks.

This latest research study, notes Sweeney, is the most thorough evaluation to date of the prevalence and clinical significance of caffeine use disorder. These data complement results from their recent clinical trial, which showed that people seeking treatment for caffeine reduction were able to reduce their caffeine consumption and decrease their symptoms following the study intervention.

“In our clinical trial , our hypothesis was that people who have had trouble cutting back on caffeine on their own may be able to reduce their caffeine consumption with our guidelines to cut back over several weeks,” says Sweeney. “We also thought this could help people reduce their caffeine-related distress, such as withdrawal symptoms or consuming more caffeine than they intended.”

In both the online survey study and clinical trial, it was common for participants who met criteria for caffeine use disorder to report withdrawal symptoms from caffeine that reduced their function. Caffeine withdrawal symptoms can include headache, fatigue and irritability, which tend to peak at 24 to 48 hours after stopping caffeine, but can last for as long as 10 days in some individuals.

Prior research has also revealed that caffeine can result in withdrawal symptoms following cessation of much lower doses than previously thought. A 6-ounce cup of regular coffee delivers 100 milligrams of caffeine. Even this small amount of caffeine can cause withdrawal symptoms in some people when they stop using it regularly. Other studies have shown that caffeine doses as low as 10–20 milligrams are psychoactive.

The researchers acknowledge that caffeine can have positive health effects, such as reducing the risk of type 2 diabetes and boosting some aspects of cognition. “I want to be clear that caffeine isn’t all good or bad,” says Sweeney. “We’re not arguing that everyone needs to cut back on their consumption. A moderate amount of caffeine — up to 400 milligrams/day (about two 12-ounce cups of coffee) — is not generally associated with negative health effects. But, caffeine reduction is a good goal if caffeine causes significant impairment through withdrawal symptoms or by worsening an underlying problem, such as insomnia or anxiety.”

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• Published: 20 April 2021

Habitual coffee drinkers display a distinct pattern of brain functional connectivity

• Ricardo Magalhães 1 , 2 , 3 , 4   na1 ,
• Maria Picó-Pérez   ORCID: orcid.org/0000-0002-1573-2445 1 , 2 , 3   na1 ,
• Madalena Esteves 1 , 2 , 3   na1 ,
• Rita Vieira   ORCID: orcid.org/0000-0001-6762-406X 1 , 2 , 3 ,
• Teresa C. Castanho 1 , 2 , 3 ,
• Liliana Amorim 1 , 2 , 3 ,
• Mafalda Sousa 1 , 2 , 3 ,
• Ana Coelho 1 , 2 , 3 ,
• Henrique M. Fernandes 5 ,
• Joana Cabral   ORCID: orcid.org/0000-0002-6715-0826 1 , 2 , 3 , 5 ,
• Pedro S. Moreira 1 , 2 , 3 , 6 &
• Nuno Sousa   ORCID: orcid.org/0000-0002-8755-5126 1 , 2 , 3 , 7  

Molecular Psychiatry volume  26 ,  pages 6589–6598 ( 2021 ) Cite this article

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• Neuroscience

Coffee is the most widely consumed source of caffeine worldwide, partly due to the psychoactive effects of this methylxanthine. Interestingly, the effects of its chronic consumption on the brain’s intrinsic functional networks are still largely unknown. This study provides the first extended characterization of the effects of chronic coffee consumption on human brain networks. Subjects were recruited and divided into two groups: habitual coffee drinkers (CD) and non-coffee drinkers (NCD). Resting-state functional magnetic resonance imaging (fMRI) was acquired in these volunteers who were also assessed regarding stress, anxiety, and depression scores. In the neuroimaging evaluation, the CD group showed decreased functional connectivity in the somatosensory and limbic networks during resting state as assessed with independent component analysis. The CD group also showed decreased functional connectivity in a network comprising subcortical and posterior brain regions associated with somatosensory, motor, and emotional processing as assessed with network-based statistics; moreover, CD displayed longer lifetime of a functional network involving subcortical regions, the visual network and the cerebellum. Importantly, all these differences were dependent on the frequency of caffeine consumption, and were reproduced after NCD drank coffee. CD showed higher stress levels than NCD, and although no other group effects were observed in this psychological assessment, increased frequency of caffeine consumption was also associated with increased anxiety in males. In conclusion, higher consumption of coffee and caffeinated products has an impact in brain functional connectivity at rest with implications in emotionality, alertness, and readiness to action.

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Introduction.

Coffee is the most widely consumed beverage, with particular interest for human health in view of its short-term effects on attention, sleep, and memory and its long-term impact on the appearance of different diseases and on healthy span of ageing [ 1 , 2 ]. Coffee has several constituents able to impact on human health, amongst which stems caffeine, which is the most widely consumed psychostimulant in the world [ 3 ]. Despite its widespread use it is surprising to note that a thorough characterization of the chronic effects of coffee upon the human brain is still lacking. In the present work we aim to begin addressing that issue.

In the brain, caffeine acts as an antagonist of adenosine A1 and A2A receptors, leading to hyperexcitability of the central nervous system [ 3 , 4 ]. This induces acute effects in diverse domains, such as physical endurance [ 1 , 5 ], vigilance, dexterity [ 6 ], mood [ 7 , 8 ], memory [ 9 ], and cognitive function [ 1 , 8 , 10 ]. There is also evidence that coffee/caffeine intake can normalize anxiety [ 11 ], although higher doses of caffeine may be anxiogenic [ 1 , 12 ] by disrupting the HPA axis [ 13 ]. On the other hand, epidemiological and animal studies converge in concluding that coffee, caffeine and adenosine receptor antagonists attenuate the burden of neurodegenerative disorders such as Alzheimer’s [ 14 ], or psychiatric disorders such as depression [ 15 ]. Indeed, chronic antagonism of either A1 or A2 receptors seems to induce an upregulation of the former, but not the latter. The resulting altered receptor ratio may explain the shift from the acute psychomotor effects (e.g., attention, vigilance) to the longer-term actions of coffee (e.g., stress resistance, neuroprotection) effects [ 4 , 16 ].

Functional magnetic resonance imaging (fMRI) allows studying, in a noninvasive way, the function of the human brain during execution of different tasks or at rest [ 17 ]. So far, most studies using fMRI were focused on measuring the acute effects of caffeine intake in the brain. Briefly, they have reported caffeine-related increases in blood oxygenation-dependent-level (BOLD) signal in different cortical and subcortical areas during a visuomotor task [ 18 ]; an impact in working memory and perfusion in elderly subjects [ 19 , 20 ]; an increase in BOLD activation in the frontopolar and cingulate cortex during a 2-back verbal working memory task [ 21 , 22 ]; and a global caffeine-induced increase in brain entropy, possibly representing an increased processing capacity [ 23 ]. Very few studies, however, were performed to study the acute effects of caffeine in functional connectivity (FC) at rest [ 24 , 25 ]. Those few studies reveal a general trend for a caffeine-induced reduction in FC, associated with neuro-electric power fluctuations as measured through magnetoencephalography and exacerbated anticorrelations. Despite this existing literature, many aspects of the characterization of the impact of caffeine on the brain remain unexplored. Critical amongst these is the characterization of the chronic effects of habitual coffee and caffeine consumption upon the functional architecture of the brain. We are only aware of a single study that touched on this subject [ 26 ]. That work revealed an association between different habits of coffee consumption and the magnitude of BOLD signals in the visual cortex; however, it did not address possible effects on the functional connectome or resting state networks. Pursuit of the latter can present significant challenges in finding and recruiting participants with sufficient variation in consumption habits and who are willing to undergo necessary, even if short, abstinence procedures.

To tackle this gap, herein we will use whole brain approaches [ 27 , 28 , 29 ], as well as the study of brain functional dynamics [ 30 ] to compare FC and its dynamics between habitual and non-habitual coffee consumers. In addition, and because of the potential anxiogenic and HPA-disrupting role of caffeine, measures of psychological state (depression, anxiety, and stress) will also be acquired, in order to explore the potential association of habitual coffee consumption with these variables.

Subject recruitment and assessment

Participants were recruited through advertisement on the Institute’s social media, institutional e-mail, and press releases distributed among Portuguese local and national newspapers. Exclusion criteria included the presence of neurological or psychiatric disorders, habitual consumption of mind-altering substances, and the inability to undergo MRI. Two experimental groups were created according to participants’ coffee consumption habits: coffee drinkers (CD), who drank a minimum of one cup of caffeinated coffee per day; and non-coffee drinkers (NCD), who had no habits of regular consumption of coffee (less than one cup per week). Consumption of coffee as well as other caffeinated products was confirmed in a structured interview. Participants were instructed to abstain from caffeinated products for 3 h before the assessment, in order to avoid acute influence of caffeine. Fifty-six subjects were recruited (32 CD and 24 NCD). One participant from the CD group was excluded due to imaging artifacts, rendering a final sample of 31 CD and 24 NCD. Characterization of subjects was done in two (CD) or three (NCD) parts within a 3 h time-period: participants were first interviewed by a certified psychologist. This was followed by an MRI scanning session, and, in the case of the NCD, the first scanning session was followed by ingestion of coffee (Nespresso ® Ristretto, ~50 cc) before a rs-fMRI scan ~30 min thereafter. During the interview, the following data were gathered: demographic data; habits of coffee and other caffeinated products consumption; and assessment of depression, anxiety, and stress scores through the Depression, Anxiety and Stress Scales (DASS-21, [ 31 , 32 ]).

Demographic and psychological data analysis

CD and NCD groups were compared in terms of sociodemographic variables, frequency of consumption of caffeinated products, and psychological variables. Since the variables did not follow a normal distribution, nonparametric tests were applied (Wilcoxon test). Moreover, multiple regression analyses were performed, aiming to determine the association between daily consumption of caffeinated products such as coffee, tea, chocolate, etc. (0 = <1/day; 1 = 1/day; 2 = 2/day; 3 = 3 or more/day) and the psychological data measured with the DASS-21 questionnaire (controlled for sex, age, and education), independently of the groups. These analyses were performed on Matlab2020a software (The Mathworks, Inc.) and p  < 0.05 was considered the threshold for statistical significance. Linear regression representations were generated in Prism 7 software (GraphPad Software, Inc.).

MRI brain imaging

Magnetic resonance imaging scans were conducted using a Siemens Verio 3T (Siemens, Erlangen, Germany) located in Hospital de Braga (Braga, Portugal) using a 32-channel head antenna. The scanning session included as an anatomical acquisition a T1-weighted sagittal magnetization-prepared rapid acquisition with gradient echo (TE/TR = 2420/4.12 ms, FA = 9°, 1 mm 3 isometric voxel size, Field-of-View = 176 × 256 × 256 mm 3 ). The resting-state fMRI (rs-fMRI) acquisition used a multi-band echo planar imaging sequence, CMRR EPI 2D (R2016A, Center for Magnetic Resonance Research, University of Minnesota, Minnesota, USA [ 33 , 34 , 35 ]) sensitive to fluctuations in the BOLD contrast (TR/TE = 1000/27 ms, FA = 62°, 2 mm 3 isometric voxel size, 64 axial slices over an in plane matrix of 100 × 100). The rs-fMRI acquisition had a duration of 7.5 min, during which subjects were instructed to remain with their eyes closed, relaxed, and let their minds wander freely.

Preprocessing of MRI data

MRI results included in this manuscript were preprocessed using fMRIPrep 1.4.1 ([ 36 ]; RRID:SCR_016216), which is based on Nipype 1.2.0 ([ 37 , 38 ]; RRID:SCR_002502). A full description of the preprocessing pipeline can be found in the Supplementary material.

Resting-state analysis

Independent component analysis.

Resting-state network (RSN) maps were analyzed voxel-wise through a probabilistic independent component analysis (ICA) as implemented in Multivariate Exploratory Linear Optimized Decomposition into Independent Components, distributed with FSL [ 39 ]. For further details check the Supplementary material.

The RSNs FC was compared between CD and NCD groups, using a nonparametric permutation procedure implemented in the randomize tool from FSL [ 40 ]. Threshold-free cluster enhancement (TFCE) was used to detect widespread significant differences and control the family-wise error rate (FWE-R) at α  = 0.05. In total, 5000 permutations were performed.

Static functional connectomics analysis

To assess differences between the two groups in the functional connectome, the mean time series of the 268 regions of the Shen Atlas [ 41 ] were extracted. The Pearson correlation between time series, followed by Fisher r-to-Z transformation, were calculated to obtain matrices of FC for each subject. To overcome the issue of multiple comparisons induced by the large number of connections in the network, we applied the network-based statistics (NBS) approach [ 42 ]. A total of 5000 permutations were used, together with a FWE corrected network significance of 0.05. For more details check the Supplementary material.

Dynamic functional analysis

We applied the leading eigenvector dynamics analysis (LEiDA, [ 30 ]) approach to study the changes in the functional dynamics associated with habitual caffeine consumption. Instantaneous FC was calculated for each subject at each time point for all 268 regions of interest of the Shen atlas, using the time series extracted for the static analysis. To help visually identify phase locked (PL) states, the overlap between each anatomical region of each state to the 7 Yeo RSN’s [ 43 ], plus two other labels for the cerebellum and subcortical units, was calculated and anatomical units color coded in accordance to the best match. For more details check the reference paper or the Supplementary material.

Effects of acute coffee consumption and frequency of caffeine consumption

The significant findings obtained with ICA, NBS, and LEiDA were further explored, aiming to assess the effects of acute coffee consumption in NCD and of frequency of consumption of caffeinated products in both groups. The first were assessed by comparing NCD after coffee consumption with data from CD (independent sample t -test) and NCD (before coffee consumption; paired sample t -test). The second were evaluated by performing multiple regression analyses following the same approach described for the DASS-21 questionnaire.

Demographic analysis

CD and NCD groups did not differ in terms of age (range 19–57; p  = 0.28; Z  = 1.09; r  = 0.15) or number of formal years of education (range 12–25; p  = 0.07; Z  = 1.84; r  = 0.25). Frequency of consumption of caffeinated products was, as expected, higher in the CD group ( p  < 0.001; Z  = 6.17; r  = 0.83). Sex distribution was not significantly different between groups ( χ 2 (1, N  = 55) = 0.52, p  = 0.42), despite the CD group presenting a slightly higher proportion of males (41.94%) in comparison with the NCD group (33.33%). Descriptive statistics can be found in Table  1 .

Effect of habitual caffeine consumption on rs-fMRI data

Independent components analysis.

Thirty components were obtained from the probabilistic ICA of CD and NCD (before consuming coffee). Fifteen of these components were found to be representative of the most typical RSNs. A tendency toward lower FC patterns in the CD group can be seen in most of these networks (see Supplementary Fig.  1 ). Despite this, we only found significant FWE-R TFCE corrected between-group differences in two of them, namely, in the somatosensory network and the limbic network (Fig.  1 ). Regarding the somatosensory network, NCD presented a pattern of higher connectivity with the right precuneus (MNI coordinates = 30, −72, 38; 7 voxels; peak t value = 4.4). Moreover, for the limbic network, NCD had higher FC in the right insula compared to CD (MNI coordinates = 42, −12, 2; 4 voxels; peak t value = 5.09). Of note, these effects were also linearly associated with the caffeinated products’ frequency of consumption. Negative correlations were found for both right precuneus ( p  = 0.003; β  = −1.433; adjusted R 2  = 0.162; Fig.  1B ) and right insula ( p  < 0.001; β  = −2.384; adjusted R 2  = 0.267; Fig.  1B ). Detailed statistics can be found in Supplementary Table  1 .

A Sagittal, coronal, and axial view of the clusters showing significant between-group differences in the connectivity between the somatosensory network and the right precuneus (top) and the limbic network and the right insula (bottom). The FWE-R TFCE corrected clusters are shown in dark blue overlaid over a more extended non-significant after multiple comparison correction cluster in hot color scale scheme, for visualization purposes. B Associations of frequency of consumption of caffeinated beverages with the mean FC of the right precuneus and the right insula. C Scatter plots showing the mean FC of the right precuneus and the right insula for the NCD before drinking coffee (NCD), the NCD after drinking coffee (NCD pos), and the CD.

Importantly, the group differences described were reduced after NCD drank coffee (see Fig.  1C ; somatosensory network: pre vs post NCD t value = 1.86, p  = 0.075, post NCD vs CD t value = −2.89, p  = 0.006; limbic network: pre vs post NCD t value = 3.88, p  < 0.001, post NCD vs CD t value = −1.46, p  = 0.15). This points to a potential causality link between coffee drinking and the above-described changes in lower connectivity in the somatosensory and in the limbic networks.

Connectomics analysis

From the connectomics analysis done using NBS, a single network of significantly higher connectivity was found in the NCD group (pre-coffee) between the thresholds of 0.005 and 0.0005 (for statistics of all thresholds see Supplementary Table  2 ). For ease of visualization, we present only the results found at the highest significant threshold of p  = 0.0005 ( t (threshold) = 3.71, df = 54, p (network) = 0.043, Hedge’s g  = 1.08 (large effect size), 24 nodes, 46 edges; Fig.  2A ). The full list of nodes with significant different edges between groups across all thresholds can be found in Supplementary Table  3 . Of these we highlight the Thalamus (nodes #262 and #126), the Cerebellum (left anterior Culmen #245 and bilateral Tonsils #238 and #119), the right Postcentral Gyrus (#33), the left Middle Temporal Gyrus (#197), the left Precentral Gyrus (#160), and the bilateral Caudate (#260 and #122) and Putamen (#124 and #261) as having the most strongly affected connections within the network.

A Sagittal, coronal, and axial view of the network with nodes and edges colored in red–yellow color scheme representing the statistical t value of the difference between groups. B Scatter plot of the mean FC within the significant network for each experimental group. C Associations of frequency of consumption of caffeinated beverages with the mean FC of the network found in NBS.

When observing the average network connectivity from this network, NCD post-coffee drink displayed a significant reduction in connectivity (Fig.  2B ), leading to a profile more similar to CD ( p  = 0.037, t  = 2.13, df = 54) than to NCD pre-coffee drink ( p  = 1.3 × 10 −7 , t  = 7.4, df = 23). NBS mean FC was negatively associated with frequency of caffeine consumption ( p  < 0.001; β  = −0.101; adjusted R 2  = 0.506; Fig.  2C ). Detailed statistics can be found in Supplementary Table  1 .

From the dynamic FC analysis, one functional subsystem (Fig.  3A , PL state 4) was found to last significantly longer in CD (Fig.  3B , 17.95 ± 18.32 s) compared to pre-coffee NCD (8.95 ± 6.13 s) surviving correction for multiple comparisons with a corrected p  = 0.038 and a medium effect size with Hedge’s g  = 0.62. No BOLD phase-locking state was found to significantly differ in terms of probability of occurrence (see Supplementary Table  4 for all p values for all partition models).

A sagittal and axial views representing the state anatomical areas of each phase locked (PL) state. B Bar plot representing the group differences between coffee and non-coffee drinkers. Differences of p  < 0.05 are indicated in red, while multiple comparison surviving effects are indicated in green. C Associations of frequency of consumption of caffeinated beverages with the average duration (in seconds) of PL state 4. D Bar plot of the probability of state 4 for the CD, NCD, and NCD post caffeine consumption groups. E Life time of state 4 for the CD, NCD, and NCD post caffeine consumption groups. F Colored labels used to match each anatomical area of the PL states to different resting state networks.

This BOLD phase-locking state, corresponding to the fourth most probable state when partitioning the data into nine states, comprises a large number of nodes in the cerebellum, visual network as well as several subcortical nodes such as the bilateral thalamus and parahippocampal gyrus (mapped and color coded through the reference shown in Fig.  3F ). While this was the only result that survived correction for multiple comparisons, it is relevant to note that the equivalent LEiDA state for k  = 10 is just below the threshold ( p  = 0.051, Supplementary Table  4 and Supplementary Figs.  2 and 3 ). Furthermore, LEiDA lifetime results were positively correlated with frequency of caffeine consumption ( p  = 0.012; β  = 2.176; adjusted R 2  = 0.083; Fig.  3C ).

After drinking coffee, both the lifetime and the probability of this state in NCD became closer to the values observed in CD, with the probability not being significantly different from CD ( p  = 0.5, t  = 0.67, df = 54), while being significantly higher than NCD pre-coffee ( p  = 0.037, t  = 2.31, df = 23, Fig.  3D ). For the life time of state 4, post-coffee drink NCD were not significantly different from CD ( p  = 0.177, t  = 1.37, df = 54) nor the pre-drink NCD ( p  = 0.107, t  = 1.68, df = 23, Fig.  3E ). All results across the different k’ s can be found in Supplementary Figs.  2 and 3 and Supplementary Table  4 .

Effect of habitual caffeine consumption on psychological data

The association between coffee consumption and stress, anxiety, and depression (DASS-21) was assessed. When comparing CD and NCD groups, only stress was significantly different between groups (stress— p  = 0.025; Z  = 2.237; r  = 0.307; anxiety— p  = 0.851; Z  = −0.188; r  = −0.026; depression— p  = 0.085; Z  = 1.724; r  = 0.237), with CD showing higher levels of stress than NCD (median (Med) = 6.0; interquartile range (IQR) = 6.0 vs Med = 4.0; IQR = 4.0, respectively). Of notice, particular items of the DASS-21 Stress subscale that can be related to arousal were increased in CD. Items #1 and #12, which measure difficulty to relax, presented statistically significant differences ( p  = 0.007, Mann–Whitney test), while item #8, that relates to nervous arousal, presented a trend in the same direction ( p  = 0.083). Interestingly, item #7 (Anxiety subscale), that is associated with skeletal musculature, despite not achieving a statistically significant difference between groups, tended to be lower in CD ( p  = 0.113), suggesting a segregation between the motor and arousal loops.

When assessing the effects of frequency of caffeine consumption in self-reported variables (controlling for sex, age, and education), the positive correlation with stress was maintained ( p  = 0.004; β  = 1.292; adjusted R 2  = 0.135; Fig.  4A ). Moreover, a sex by anxiety interaction was found ( p  = 0.023; β  = 0.683; adjusted R 2  = 0.085; Fig.  4B ), which seems to be driven by a positive correlation in males. No significant effects were found for the depression subscale ( p  = 0.128; β  = 0.450; adjusted R 2  = 0.108; Fig.  4C ). Detailed statistics can be found in Supplementary Table  1 .

Associations of frequency of consumption of caffeinated products with the DASS-21 subscales of stress ( A ) and anxiety ( B ), and non-significant association with the depression subscale ( C ).

Herein we describe for the first time the effects of habitual coffee consumption on the human brain networks. We show that habitual CD have different patterns of FC in comparison with NCD. Our rs-fMRI analysis revealed decreased FC of the somatosensory and limbic networks in CD that correlated with the frequency of consumption of caffeinated products. Such changes were replicated in NCD after a single coffee, suggesting possible causality between coffee intake and altered patterns of brain network connectivity. Previous studies have described a reduction of similar RSN connectivity after acute caffeine ingestion [ 25 , 44 ].

Decreased FC in somatosensory and related networks in CD likely represents a more efficient and beneficial pattern of connections with respect to motor control and alertness; importantly this fits our findings of trends of increased scores in CD in the specific items of the DASS-21 scale that measure these dimensions. The other network impacted by coffee intake was the limbic network, which is involved in processing the sensory input from the external and internal environment which, by modulating memory and motivation, determine emotional, autonomic, motor, and cognitive responses [ 45 ]. A previous resting-state PET study showed reduced metabolic activity in components of this network after caffeine ingestion [ 18 ] and a study using a hedonic fMRI task showed decreased activation in neuronal areas associated with memory and reward [ 46 ] in caffeine consumers compared to non-consumers; the present FC data are consistent with those reports.

Analysis of the global functional connectome using NBS revealed a network impacted by the habitual consumption of caffeine. This widespread network of reduced FC comprised cerebellar, subcortical (striatal and thalamic), and motor cortex regions, partially matching previously reported effects of acute caffeine ingestion [ 24 , 25 ]. Interestingly, there is a clear bilateral involvement of striatal nodes and of the thalamus which, respectively, have the highest densities of A2A and A1 receptors in the brain [ 47 , 48 ]. The action of caffeine in these regions has an influence on cortico-striatal-thalamic and cerebellar-thalamocortical loops that are relevant for a variety of neuronal processes. Thus, the observed decrease in FC at rest in this network in regular caffeine-ingesting individuals reveals greater segregation of these areas with less inter-regional dependencies, favoring greater efficiency within these loops. It is relevant to note here that, even though A1 and A2A receptors are thought to mediate differential actions [ 49 ], similar effects were observed in both loops. This likely reflects the fact that fMRI provides proxy aggregate measurements of functional connections among a network of brain areas.

A previous study reported that caffeine increases brain entropy, indicating higher information processing capacity across the cerebral cortex [ 23 ]. Our LEiDA analysis revealed a dynamic state involving several cerebellar and subcortical areas, with a longer average lifetime in habitual CD. This network comprises several nodes, including the cerebellum, thalamus, and parahipocampal, lingual, and inferior occipital gyri which are relevant in the context of caffeine consumption—caffeine is known to decrease mind wandering [ 50 ] and to increase attention, alertness, and arousal [ 51 ]. In fact, the nodes implicated in this network are linked by visual processing; among these, the thalamus is critical for distributing cognitive control [ 52 ]. The lingual and inferior occipital gyrus are also implicated in visual processing, while the parahippocampus is involved in memory encoding and retrieval [ 20 , 21 ]; the latter may explain why caffeine reportedly facilitates memory processes [ 9 ]. Lastly, evidence of strong rsFC between the cerebellum, known to be also implicated in sensory processing [ 53 ] and a number of sensorial cortices [ 54 ], explains the observed increased visual alertness/attention and readiness to sensorial perception among CD individuals. While similar findings have been previously reported [ 6 ], only one other study assessed habitual CD using MRI, and did not characterize changes in FC [ 26 ]. Importantly, similarly to the other neuroimaging findings, a common pattern of connectivity dynamics was found in CD individuals and NCD subjects who drank a single coffee before scanning.

In order to provide a link with other neuropsychologic dimensions, we also assessed our subjects in the DASS-21. Interestingly, we observed habitual CD to display increased levels of stress; there was a clear positive association between the indices of stress and the amount of consumption of caffeinated drinks. Interestingly, items of the DASS-21 sub-score that showed greater variance between CD vs NCD were those related with difficulty to relax (items #1 and #12), and those related to nervous arousal (item #8), consistent with the common attribution of alertness and arousal to coffee intake. It also deserves to be mentioned that, despite the display of a higher anxiety among CD (particularly in males), there was a decrease in DASS-21 item (#7) which matches the effects on the skeletal muscles in CD; this, in turn, fits the findings of better segregation of the above-described loops. The present results extend previous studies that described an association between coffee/caffeine consumption and stress and anxiety [ 1 , 13 , 16 , 55 ] and sex [ 13 , 16 ]. It is important to note, however, that causality cannot be inferred from our study design. Our results are open to two interpretations: higher coffee/caffeine consumption leads to increased stress and anxiety; or, alternatively, higher stress and anxiety induce higher coffee/caffeine consumption. Moreover, given that resting-state studies using stress and anxiety samples have shown both decreases and increases in FC [ 56 , 57 , 58 ], the possibility that coffee/caffeine consumption elicits decreases in FC or compensates for FC beyond a certain threshold, must also be considered. While the first possibility is in line with studies showing increased anxiety upon both acute caffeine administration in humans [ 1 , 12 ] and prolonged ingestion in rodents [ 59 ] reports that greater caffeine consumption under periods of stress may help maintain synaptic homeostasis [ 60 ] as well as prevent mood disorders warrant further study in future.

The methodologies applied in the present study do not allow us to draw precise relationships between the psychological and neuroimaging results and the dosage and metabolism of caffeine among individual subjects. To study the individual responses to the acute and chronic effects of caffeinated product intake would be a complex undertaking, requiring subjects to adapt their daily habits and strict abstinence regimens. Based on our experience, recruitment of subjects for a properly balanced study is also difficult since NCD subjects are insufficiently motivated to engage in studies on the actions of caffeine. Nevertheless, we are currently developing alternative strategies that would allow us to deliver calibrated doses of caffeine during fMRI scanning sessions to better discriminate its effects from other factors (e.g., stress). Our future work will also examine inter-individual differences in response to caffeine consumption, the subjective experience of coffee consumption, as well as the influence of additional factors as the consumption of alcohol and tobacco. Despite such gaps, the data presented here represent a contribution to the knowledge of the “caffeinated brain” and how these changes underlie the behavioral effects triggered by coffee intake, with implications for physiological and pathological conditions.

Code availability

In-house scripts used in the NBS analysis are fully available online at open science framework website ( https://osf.io/qepc8/ ) and LEiDA scripts at github ( https://github.com/juanitacabral/LEiDA ).

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This study was funded by the Institute for the Scientific Information on Coffee (ISIC) (ISIC_2017_NS); ISIC did not influence the experimental design or data analysis/interpretation. The laboratory was also supported by the project NORTE‐01‐0145‐FEDER000013 through the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER). RM, MP-P, and ME were supported by post-doctoral grants from the project ISIC_2017_NS. PSM was supported by a fellowship grant from the Fundação para a Ciência e a Tecnologia (FCT; grant number PDE/BDE/113601/2015) from the PhD-iHES program. RV was supported by a research fellowship of the project funded by FCT (UMINHO/BI/340/2018). AC was supported by a scholarship from the project NORTE-08-5639-FSE-000041 (NORTE 2020; UMINHO/BD/51/2017).

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Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Campus de Gualtar, Braga, Portugal

Ricardo Magalhães, Maria Picó-Pérez, Madalena Esteves, Rita Vieira, Teresa C. Castanho, Liliana Amorim, Mafalda Sousa, Ana Coelho, Joana Cabral, Pedro S. Moreira & Nuno Sousa

ICVS/3B’s, PT Government Associate Laboratory, Braga/Guimarães, Portugal

Clinical Academic Center - Braga, Braga, Portugal

NeuroSpin, CEA, CNRS, Paris-Saclay University, Gif-sur-Yvette, France

Ricardo Magalhães

Center for Music in the Brain, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark

Henrique M. Fernandes & Joana Cabral

Psychological Neuroscience Lab, CIPsi, School of Psychology, University of Minho, Braga, Portugal

Pedro S. Moreira

P5 Medical Center, Braga, Portugal

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Magalhães, R., Picó-Pérez, M., Esteves, M. et al. Habitual coffee drinkers display a distinct pattern of brain functional connectivity. Mol Psychiatry 26 , 6589–6598 (2021). https://doi.org/10.1038/s41380-021-01075-4

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Caffeine Use Disorder: A Review of the Evidence and Future Implications

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The latest edition of the Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-5) has introduced new provisions for caffeine-related disorders. Caffeine withdrawal is now an officially recognized diagnosis, and criteria for caffeine use disorder have been proposed for additional study. Caffeine use disorder is intended to be characterized by cognitive, behavioral, and physiological symptoms indicative of caffeine use despite significant caffeine-related problems, similar to other substance use disorders. However, since non-problematic caffeine use is so common and widespread, it may be difficult for some health professionals to accept that caffeine use can result in the same types of pathological behaviors caused by alcohol, cocaine, opiates, or other drugs of abuse. Yet there is evidence that some individuals are psychologically and physiologically dependent on caffeine, although the prevalence and severity of these problems is unknown. This article reviews the recent changes to the DSM, the concerns regarding these changes, and some potential impacts these changes could have on caffeine consumers.

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Introduction

After centuries of cultivation and consumption, our relationship with caffeine has just undergone a major change. The latest version of the Diagnostic and Statistical Manual of Mental Disorders (5th edition; DSM-5) now includes caffeine withdrawal disorder and proposes a set of criteria for caffeine use disorder (CUD) [ 1 ]. What effect will this have on us and America’s most popular psychostimulant?

Caffeine is generally considered a functional or beneficial drug because it can improve mood and alertness at low doses. At high doses, caffeine produces aversive intoxicating effects. For this reason, caffeine consumption is typically self-limiting and compatible with a social and productive life [ 2 ]. Caffeine is thought to have little to no abuse liability, but perhaps its modest reinforcing effects enhance the desirability of beverages that already have pleasant flavors and aromas, such as coffee, tea, and soft drinks. For many of us who sit behind computer screens all day, these caffeinated beverages help us focus our attention and provide a welcome excuse to get up from our chairs once in a while. Although the question of whether we are all collectively dependent on caffeine has been raised [ 3 ], coffee drinking is thought to be “more a dedicated habit than a compulsive addiction” [ 4 ].

The majority of people who use caffeine safely every day may find it difficult to understand how caffeine use could become disordered or problematic. Of course, many coffee drinkers probably have had a personal experience with withdrawal symptoms if they skipped their morning coffee, but the remedy for that is simply a cup of coffee. But what if someone were convinced he could not function without caffeine? What if he took increasingly greater amounts of caffeine to improve his ability to function, until he began to experience the effects of caffeine intoxication or withdrawal more days than not? What if he were told that his caffeine use was physically harming his body, but he could not reduce his use? At what point does caffeine use become disordered?

A few studies have suggested that some individuals meet the criteria for substance dependence regarding their caffeine use. However, many questions remain regarding the prevalence, development, and severity of disordered caffeine use. To help answer these questions and guide future research on this topic, the DSM-5 proposes a set of criteria for CUD. This article reviews the caffeine-related changes to the DSM and the recent research and evidence for disordered caffeine use.

Diagnostic and Statistical Manual of Mental Disorders , 4th Edition (DSM-IV) Caffeine-Related Diagnoses

Caffeine withdrawal.

The fourth edition of the DSM (DSM-IV) recognized four caffeine-related diagnoses: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified (NOS) [ 5 ]. The criteria for caffeine intoxication included recent caffeine use, usually in excess of 250 mg, and five or more symptoms that develop shortly thereafter, such as restlessness, nervousness, insomnia, gastrointestinal disturbance, and tachycardia. Of the caffeine-related diagnoses included in the DSM-IV, caffeine withdrawal is notably absent, although a proposed set of criteria was included to encourage future research. The DSM-IV recognized that “some individuals who drink large amounts of coffee display some aspects of dependence on caffeine and exhibit tolerance and perhaps withdrawal. However, the data are insufficient at this time to determine whether these symptoms are associated with clinically significant impairment that meets the criteria for Substance Dependence or Substance Abuse” (page 212) [ 5 ].

Over the past 30 years, there have been a large number of studies characterizing caffeine withdrawal symptoms (for reviews, see Griffiths and Woodson [ 6 ] and Juliano and Griffiths [ 7 ]). As a result, the DSM-5 includes diagnostic criteria for caffeine withdrawal, which consists of prolonged daily use of caffeine and three or more withdrawal symptoms occurring within 24 h of abrupt cessation or reduction of caffeine use. These symptoms include headache, marked fatigue or drowsiness, dysphoric mood/depressed mood/irritability, difficulty concentrating, and flu-like symptoms [ 1 ].

Caffeine Dependence

Concurrent with research on caffeine withdrawal, investigators have also been studying caffeine’s abuse potential. Although the DSM-IV included a substance dependence diagnosis for every other recognized substance, there were no criteria or proposed criteria for caffeine dependence. Therefore, investigators adapted the DSM-IV substance dependence criteria for caffeine use to use in their research. The criteria for substance dependence consisted of a maladaptive pattern of substance use with clinically significant impairment manifested by three or more symptoms within a 12-month period. These symptoms included (1) tolerance; (2) withdrawal; (3) substance used in larger amounts or over a longer period than intended; (4) a persistent desire or unsuccessful effort to control use; (5) a great deal of time spent obtaining, using, or recovering from the substance; (6) forgoing important activities because of the substance; and (7) substance use continued despite knowledge of having a persistent or recurrent physical or psychological problem likely to be caused or exacerbated by the substance (i.e., ‘use despite harm’) [ 5 ].

There have been four notable studies that have investigated caffeine dependence. Strain et al. recruited participants who believed they were psychologically or physiologically dependent on caffeine. The authors reported that 16 out of 27 subjects met three of four criteria for caffeine dependence, including tolerance, withdrawal, persistent desire/unsuccessful efforts to control use, and ‘use despite harm’ (e.g., using caffeine against medical advice) [ 8 ]. A similar study by Juliano et al. reported that 93 % of 94 subjects met three of seven criteria for caffeine dependence, and 55 % of subjects met five of seven criteria. Most of the interviewees reported at least one serious attempt to quit or reduce caffeine without success and 43 % were advised by a health professional to reduce caffeine use for health reasons (including cardiovascular problems, fibrocystic breast disease, pregnancy, anxiety, headaches, sleep difficulties, or to reduce caloric intake from caffeinated soft drinks) [ 9 ]. Another study by Striley et al. recruited subjects who were expected to have high rates of drug use/abuse. The authors reported that 35 % of 167 subjects endorsed three of seven caffeine dependence criteria [ 10 ]. Lastly, Hughes et al. conducted random phone surveys of Vermont residents. They reported that 30 % of 162 subjects endorsed three or more criteria, with the highest percentage of people endorsing a desire to control caffeine use, followed by spending a great deal of time with the drug, and using more caffeine than intended [ 11 ].

In summary, these studies suggest that caffeine use has the features of substance dependence for some individuals. Furthermore, they suggest that not all caffeine users can simply quit on their own, which is an attitude probably held by some health professionals [ 9 ]. However, these studies have several limitations. Three of the studies used targeted subject samples [ 8 – 10 ], and so the prevalence of caffeine dependence in the general population cannot be estimated. Additionally, in two of the studies, interviews were not conducted by psychiatric clinicians, so issues of severity and harm related to caffeine dependence may not have been adequately addressed [ 10 , 11 ]. The studies on caffeine dependence reviewed here were conducted prior to the publication of the DSM-5 in 2013. Although caffeine dependence did not become an officially recognized diagnosis in this edition, these and other studies elicited interest in the psychiatric community to learn more about disordered caffeine use.

DSM, 5th Edition (DSM-5) Caffeine-Related Diagnoses

The DSM-5 includes caffeine intoxication, caffeine withdrawal, other caffeine-induced disorders (e.g., anxiety and sleep disorders), and unspecified caffeine-related disorder. In this edition, substance abuse and substance dependence are now represented by substance use disorder (SUD), which is applied to all classes of substances except for caffeine. For this diagnosis, individuals must endorse at least two of the following criteria: (1) substance used in larger amounts or over longer period than intended; (2) a persistent desire or unsuccessful effort to control use; (3) a great deal of time spent obtaining, using, or recovering from the substance; (4) craving the substance; (5) substance use interfering with ability to fulfill major obligations; (6) substance use despite social problems related to use; (7) important occupational or social activities given up because of substance use; (8) recurrent use in situations when it is physically hazardous; (9) ‘use despite harm’; (10) tolerance; and (11) withdrawal [ 1 ].

The DSM-5 does not include a diagnosis of CUD because, according to the American Psychiatric Association (APA), it is not yet clear to what extent it is a clinically significant disorder. However, CUD is included in Section III (“Emerging Measures and Models”) of the DSM-5 to encourage further research on the impact of this condition [ 12 ]. The proposed CUD criteria are the same as other SUDs; however, the CUD diagnosis is designed to be more conservative. For a CUD diagnosis, all three of the following criteria need to be endorsed: (1) a persistent desire or unsuccessful effort to control use; (2) ‘use despite harm’; and (3) withdrawal. This higher threshold is intended to prevent over-diagnosis of CUD given the prevalence of non-problematic caffeine use in the general population [ 1 ]. These proposed criteria are intended to encourage more research on the reliability, validity, and prevalence of CUD, as well as its functional consequences on the lives of those affected by it.

Current Literature on Caffeine Use Disorder

There are three notable articles that summarize the current attitudes and information regarding caffeine withdrawal and CUD. First, a roundtable discussion with Drs. Hughes, Griffiths, Juliano, and Budney provides an excellent overview of the caffeine-related changes to the DSM-5 and explains some of the decision-making process behind the revisions, as well as the concerns about caffeine withdrawal and CUD over-diagnosis [ 13 ••]. The discussants explain how the more conservative criteria for CUD than other SUDs should help prevent over-diagnosis, but, at the same time, diagnoses included in the DSM should not be exceedingly rare. Thus, more information is needed on the prevalence of CUD before deciding whether it belongs in the DSM. Another issue raised by the panel is that there is a common perception of caffeine being a functional drug; in fact, there has been a substantial amount of research on its benefits (for review, see Glade [ 14 ]). However, once caffeine (or any other substance) has been determined to be an addictive drug, then prejudices against discussing any potentially beneficial effects often develop in the psychiatric community [ 13 ••]. This conflict of interest could interfere with future caffeine research.

A second article complements some of the issues raised by the roundtable concerning attitudes among the psychiatric community, including both researchers and clinicians. Budney et al. (2013) investigated popular opinions about caffeine dependence/CUD among members of professional societies relevant to addiction. An overwhelming majority (95 %) of those surveyed believed that caffeine cessation can produce withdrawal and 73 % thought withdrawal could have clinical importance, but fewer than half thought caffeine withdrawal should be in the DSM. A small majority (58 %) of respondents thought that some individuals could develop CUD, and 44 % believed CUD should be a DSM diagnosis [ 15 ]. These attitudes will be influenced by research published over the next few years and could affect what caffeine-related diagnoses are included in the next edition of the DSM.

Lastly, Meredith et al. provides a comprehensive review of studies on caffeine use/abuse/dependence and summarizes the existing evidence in support of the three primary CUD criteria. The authors also present a number of research directions needed to further support and understand CUD. As the authors note, the prevalence of CUD is difficult to estimate from existing studies since DSM-IV criteria for caffeine dependence were used previously and the current criteria for CUD are slightly different [ 16 ••].

Use Despite Harm

Before CUD can become an official diagnosis, more research is needed on the severity of symptoms of the three primary criteria: (1) a persistent desire or unsuccessful effort to control use; (2) substance use continued despite knowledge of having a persistent or recurrent physical or psychological problem likely to be caused or exacerbated by the substance (i.e., ‘use despite harm’); and (3) withdrawal [ 1 ]. In this author’s opinion, criterion 2 is the most contentious issue and in need of clarification. Some authors appear to accept that caffeine consumption is associated with negative health effects (e.g., Juliano et al. [ 9 ] and Striley et al.[ 10 ]), while others believe that it is not (e.g., Morelli and Simola [ 2 ], Hughes et al. [ 11 ], and Lara [ 17 ]). These opinions can influence research directions and hypotheses; therefore, closer examination of this criterion is needed to promote consensus on what health problems can define ‘use despite harm’ for CUD.

Evidence for Physical Problems Caused or Exacerbated by Caffeine

Large, acute doses of caffeine are known to cause caffeine intoxication, which can cause a significant threat to one’s health and require medical attention. McCarthy et al. reviewed caffeine-related calls to a state poison control center. Out of 254 reported cases of caffeine abuse, 106 patients were managed in an emergency department and 34 were hospitalized and/or admitted to an intensive care unit [ 18 •]. In addition, Ogawa and Ueki presented two case reports of individuals whose daily caffeine use escalated until symptoms of caffeine intoxication made medical intervention necessary [ 19 •]. Clearly, caffeine intoxication is a medically significant health problem. However, could an otherwise healthy individual meet the criterion for ‘use despite harm’ by consuming a low to moderate daily dose of caffeine? A review by Nawrot et al. on caffeine and health recommended that doses up to 400 mg/day are safe [ 20 ]; however, it is difficult to determine the health effects of low to moderate daily doses of caffeine because the effects of caffeine cannot be easily separated from the effects of caffeinated beverages, usually coffee, tea, soft drinks, or energy drinks. The antioxidant effects of polyphenols in tea and coffee are thought to have health benefits, while the excess sugars in soft drinks and energy drinks can be detrimental. Despite these confounds, there has actually been a great deal of research on the health effects of caffeine. However, the data are inconsistent.

A review of the literature on caffeine and health is outside the scope of this article, but a brief example may be informative: caffeine causes a small, temporary increase in blood pressure in normotensive adults. Tolerance to these effects may develop in some people, but caffeine could pose a threat to patients with, or at risk for, hypertension. Some studies have suggested an increased risk of sustained hypertension following coffee consumption (e.g., Palatini et al. [ 21 ]), while others have not found a significant relationship (e.g., Klag et al. [ 22 ]). Even two recent meta-analyses on caffeine and hypertension arrived at different conclusions: one found no evidence of a relationship [ 23 ] and the other found an elevated risk of hypertension associated with 1–3 cups of coffee per day, but not with 3 or more cups per day [ 24 ].

Clinicians make recommendations to their patients based on their knowledge of the literature, but the literature on caffeine and health is enormous and complicated. In at least two of the studies on caffeine dependence, subjects met the criteria for ‘use despite harm’ if they admitted using caffeine against medical advice [ 8 , 9 ]. If a clinician who read about an association between caffeine and hypertension (e.g., Palatini et al. [ 21 ]) recommended to her hypertensive patient to stop drinking coffee and he did not, should that patient meet the criteria for ‘use despite harm’ even though another physician who read a different article (e.g., Klag et al. [ 22 ]) would not have made the same recommendation?

To this author’s knowledge, low to moderate daily caffeine intake has not been proven to cause significant and irreversible health problems that would warrant medical intervention. That is not to say that caffeine does not or cannot have negative health effects, but researchers and clinicians need to agree on what physical health problems can be caused by chronic low to moderate caffeine intake. Whether or not low to moderate daily doses of caffeine can cause physical harm is an important issue to resolve since medical professionals recommend limiting/eliminating caffeine intake to some of their patients, and health concerns are a common reason for individuals to want to modify their caffeine use [ 9 ]. Furthermore, the fate of CUD in the next edition of the DSM may depend on the definition of ‘use despite harm,’ since the other two primary criteria for CUD (i.e., a persistent desire or unsuccessful effort to control use and withdrawal) could potentially be endorsed at any daily dose, even while consuming as little as 100 mg/day [ 25 ].

Evidence for Psychological Problems Caused or Exacerbated by Caffeine

The DSM-5 recognizes that some features of CUD may be positively associated with other psychiatric diagnoses [ 1 ], and there have been studies investigating whether caffeine use or withdrawal can exacerbate existing psychiatric symptoms. In particular, the anxiogenic effects of high caffeine doses can aggravate symptoms of anxiety, panic disorder, and insomnia (for reviews, see Lara [ 17 ] and Winston et al. [ 26 ]). In fact, a review of eight studies that administered a caffeine challenge to patients with panic disorder found that caffeine aggravated symptoms of anxiety and panic disorder in every study [ 27 ]. While this review provides strong evidence that caffeine can exacerbate anxiety and panic disorder, these studies were caffeine challenges and not representative of the patients’ normal caffeine intake. Patterns of actual caffeine consumption among psychiatric patients have been shown to be similar to matched controls; however, maximum lifetime intake was higher among patients [ 28 ]. In addition, the prevalence of caffeine dependence and intoxication was reportedly higher in patients, who endorsed consuming more caffeine than intended, having a desire to cut down, and using caffeine despite harm more often than controls [ 28 ]. However, even among psychiatric patients, caffeine can act as a functional drug. Low to moderate daily doses of caffeine can reduce anxiety and elevate mood, and may even improve symptoms of attention–deficit hyperactivity disorder, although large-scale clinical trials have not been conducted [ 17 ]. To date, the evidence suggests that caffeine use is associated with, but does not cause, psychiatric and substance use disorders [ 29 ]. The research on caffeine use and psychiatric disorders raises the possibility of increased risk for CUD or caffeine intoxication due to disordered use among certain patient populations and more studies are needed on the prevalence of caffeine use among individuals with psychiatric problems.

Co-Use with Other Substances

Another potential contribution to disordered caffeine use is co-use with other substances. Caffeine may facilitate the effects of other drugs of abuse [ 2 ]. In particular, combining caffeinated energy drinks with alcoholic beverages has become a popular phenomenon because high doses of caffeine may offset the subjective intoxicating effects of alcohol; this is problematic because the objective intoxicating effects of alcohol are not affected [ 30 ]. Furthermore, the co-use of caffeine and sugary soft drinks may cause cross-sensitization, especially among children, and this could lead to poor dietary habits across the lifespan [ 31 ••]. Too many caffeinated soft drinks in one’s diet could increase the risk of obesity [ 32 ] and dental caries [ 33 ] in children and adolescents.

In conclusion, future research on CUD must demonstrate that enough people, but not too many, meet the criteria for disordered caffeine use, and that the severity and frequency of problems resulting from this use significantly interfere with their well-being and daily function. In addition, tests of the reliability and validity of CUD criteria are needed, as well as clinical treatment options and their efficacy. If the same standard of harm can be met for caffeine as for other drugs of abuse, then perhaps in another 20 years CUD will be an official diagnosis in the sixth edition of the DSM (DSM-6). Official recognition of CUD could significantly impact popular opinions towards caffeinated beverages and affect their legal regulation. After all, 20 years ago, caffeine withdrawal was not an officially recognized diagnosis in the DSM-IV [ 5 ], but now there is sufficient evidence of caffeine withdrawal to warrant inclusion in the DSM-5. Many people are now aware that chronic caffeine use can result in physical dependence and there has been pressure on manufacturers of caffeinated beverages to disclose their products’ caffeine content. Some researchers have even recommended warning labels on caffeinated beverages [ 34 ].

The roundtable discussion raised an important issue: if caffeine use were proven harmful in some capacity, then a bias may develop among researchers against discussing any of its potential benefits on health, cognition, or arousal [ 13 ••]. In this event, could there also be public backlash against caffeine consumption? If so, there may be legislative pressure to limit access to caffeine, or to apply age restrictions on who can purchase and consume caffeine, in order to reduce the likelihood of caffeine-related problems among the general population. However, considering the amount of trade and commerce surrounding caffeinated beverages, caffeine use is not only a public health concern, but a major economic concern as well. It would not be surprising if coffee, tea, soft drink, and energy drink industries took an active role in dissuading official recognition of CUD in the DSM, especially if that recognition meant increased regulation of caffeinated products.

The recent research on caffeine has important considerations for health professionals and consumers. It appears that not all consumers are aware they are dependent on caffeine, or realize that their fatigue, headache, nausea, or other symptoms are related to caffeine withdrawal, instead of an illness [ 13 ••]. Several authors recommend increasing awareness among both clinicians and patients about the relationship between caffeine use, health, and psychiatric disorders [ 19 •, 28 , 34 ], and also recommend including caffeine use assessments during psychiatric evaluations [ 26 ]. Importantly, the last survey of caffeine use in America was published in 2005 [ 35 ] and this information needs updating. Lastly, a survey of what clinicians are recommending to their patients regarding caffeine use would be valuable information for researchers and health professionals. In addition to these recommendations, there are many more potential avenues for future caffeine research. On the other hand, since caffeine is the most widely used psychoactive drug in the world and there are upwards of 20,000 research articles on caffeine, there may be little left to learn about this substance and our relationship with it.

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

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Acknowledgments

This work was supported by National Institutes of Health grants K01 DA033347 (National Institute on Drug Abuse).

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Merideth A. Addicott declares she has no conflict of interest.

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Addicott, M.A. Caffeine Use Disorder: A Review of the Evidence and Future Implications. Curr Addict Rep 1 , 186–192 (2014). https://doi.org/10.1007/s40429-014-0024-9

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Caffeine and Health

• 1 Associate Editor, JAMA
• Original Investigation Association of Coffee Drinking With Mortality by Genetic Variation in Caffeine Metabolism Erikka Loftfield, PhD; Marilyn C. Cornelis, PhD; Neil Caporaso, MD; Kai Yu, PhD; Rashmi Sinha, PhD; Neal Freedman, PhD JAMA Internal Medicine
• Original Investigation Assessment of Caffeine Consumption and Maternal Cardiometabolic Pregnancy Complications Stefanie N. Hinkle, PhD; Jessica L. Gleason, PhD, MPH; Samrawit F. Yisahak, PhD; Sifang Kathy Zhao, PhD; Sunni L. Mumford, PhD, MSc; Rajeshwari Sundaram, PhD, MS; Jagteshwar Grewal, PhD; Katherine L. Grantz, MD, MS; Cuilin Zhang, MD, PhD, MPH JAMA Network Open

Caffeine is a natural chemical stimulant that can also be created synthetically for consumption.

Natural caffeine is found in coffee beans, tea leaves, cacao beans, guarana berries, and yerba maté leaves. Caffeine preparations can be added to drinks, food, tablets, or powdered supplements. In the US, about 85% of adults consume caffeine daily, and average intake is 135 mg per day (equivalent to 12 oz of coffee). The most common source of caffeine is coffee for adults and soft drinks and tea for teenagers.

How Does the Body Absorb and Metabolize Caffeine?

Caffeine is absorbed into the bloodstream within 45 minutes after ingestion. Metabolism of caffeine varies among individuals, but its duration of action is typically 2.5 to 4.5 hours. Pregnancy and some medications (oral contraceptives, certain antidepressants, cardiovascular medications, and antibiotics) slow caffeine removal from the bloodstream. In contrast, cigarette smoking increases the rate of caffeine removal from the bloodstream.

Beneficial Effects of Caffeine

Caffeine in moderate doses (40-200 mg) acts within the brain to decrease fatigue, increase alertness, and decrease reaction time. Caffeine also may decrease appetite and slightly reduce weight gain. In moderate doses, caffeine has been associated with decreased risk of depression and suicide in some studies.

Medical Uses of Caffeine

Caffeine is used to treat intermittent pauses in breathing (apnea) in premature infants. Addition of caffeine to commonly prescribed pain relievers (such as acetaminophen) can decrease acute pain from certain conditions, such as migraines.

Common Negative Effects of Caffeine

Caffeine leads to temporary increases in blood pressure in individuals with minimal or no prior use. Caffeine, particularly in higher doses, can cause anxiety, as well as difficulty falling asleep if consumed late in the day. Abrupt cessation of caffeine in regular users may result in withdrawal symptoms, which typically peak at 1 to 2 days and include headache, fatigue, and depressed mood. Because higher caffeine intake in pregnancy is associated with lower infant birth weight, caffeine consumption should not exceed 200 mg per day during pregnancy.

Effects of Caffeine in Very High Doses

Ingestion of very high doses of caffeine (1200 mg or more) can cause agitation, severe anxiety, elevated blood pressure, and palpitations. This may occur with overuse of caffeine tablets or supplements in liquid form (energy drinks) or powdered form. Consuming caffeinated energy drinks or energy shots together with alcohol is dangerous and has resulted in deaths.

Possible Health Benefits of Drinking Coffee

Some studies have shown decreased mortality associated with drinking 2 to 5 standard cups of caffeinated or decaffeinated coffee per day. In some reports, regular consumption of both caffeinated and decaffeinated coffee has been associated with a reduced risk of type 2 diabetes and endometrial cancer. In other reports, both caffeinated and decaffeinated coffee consumption was associated with lower risk of liver cancer, gallstones, and gallbladder cancers, but the potential benefit was stronger with caffeinated coffee. Consumption of caffeinated coffee has also been associated with a reduced risk of Parkinson disease and liver cirrhosis.

For More Information

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Conflict of Interest Disclosures: None reported.

Source: van Dam RM, Hu FB, Willett WC. Coffee, caffeine, and health. N Engl J Med . 2020;383(4):369-378. doi: 10.1056/NEJMra1816604

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Caffeine and cardiovascular diseases: critical review of current research

Affiliations.

• 1 Centre for Chronic Disease (CCD), College of Health and Biomedicine, Victoria University, Melbourne, VIC, Australia.
• 2 Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Martin, Slovakia.
• 3 2nd Department of Internal Medicine, St. Anne's University Hospital and Masaryk University, Brno, Czech Republic.
• 4 Department of Physiology, Masaryk University, Brno, Czech Republic.
• 5 Division of Clinical Nutrition, Faculty of Home Economics, Kyoritsu Women's University, Tokyo, Japan.
• 6 Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic.
• 7 Bogomolets National Medical University, Kiev, Ukraine.
• 8 Cardiology Center Medika, St. Petersburg, Russia.
• 9 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University, Odborarov 10, 832 32, Bratislava, Slovak Republic.
• 10 Human Anatomy Section, Department of Experimental Biomedicine and Clinical Neurosciences, University of Palermo, Palermo, Italy.
• 11 Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy.
• 12 Laboratory of Structural Biology and Proteomics, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Palackeho tr 1/1946, Brno, 612 42, Czech Republic. [email protected].
• PMID: 26932503
• DOI: 10.1007/s00394-016-1179-z

Caffeine is a most widely consumed physiological stimulant worldwide, which is consumed via natural sources, such as coffee and tea, and now marketed sources such as energy drinks and other dietary supplements. This wide use has led to concerns regarding the safety of caffeine and its proposed beneficial role in alertness, performance and energy expenditure and side effects in the cardiovascular system. The question remains "Which dose is safe?", as the population does not appear to adhere to the strict guidelines listed on caffeine consumption. Studies in humans and animal models yield controversial results, which can be explained by population, type and dose of caffeine and low statistical power. This review will focus on comprehensive and critical review of the current literature and provide an avenue for further study.

Keywords: Caffeine; Cardioprotective effects; Cardiovascular diseases; Clinical studies; Experimental studies; Pathogenesis.

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REVIEW article

The safety of ingested caffeine: a comprehensive review.

• 1 Department of Exercise and Nutrition Sciences, University at Buffalo, Buffalo, NY, USA
• 2 Department of Community Health and Health Behavior, University at Buffalo, Buffalo, NY, USA
• 3 Aix Marseille Univ, INSERM, INS, Inst Neurosci Syst, Marseille, France
• 4 Wayne State University School of Medicine, Children’s Hospital of Michigan, Detroit, MI, USA

Caffeine is the most widely consumed psychoactive drug in the world. Natural sources of caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to promote arousal, alertness, energy, and elevated mood. Over the past decade, the introduction of new caffeine-containing food products, as well as changes in consumption patterns of the more traditional sources of caffeine, has increased scrutiny by health authorities and regulatory bodies about the overall consumption of caffeine and its potential cumulative effects on behavior and physiology. Of particular concern is the rate of caffeine intake among populations potentially vulnerable to the negative effects of caffeine consumption: pregnant and lactating women, children and adolescents, young adults, and people with underlying heart or other health conditions, such as mental illness. Here, we review the research into the safety and safe doses of ingested caffeine in healthy and in vulnerable populations. We report that, for healthy adults, caffeine consumption is relatively safe, but that for some vulnerable populations, caffeine consumption could be harmful, including impairments in cardiovascular function, sleep, and substance use. We also identified several gaps in the literature on which we based recommendations for the future of caffeine research.

Introduction

Caffeine is the most widely consumed psychoactive drug in the world ( 1 ) and one of the most comprehensively studied ingredients in the food supply. It occurs naturally in the leaves and seeds of many plants and has a taste bitter enough to deter pests ( 2 ). Natural sources of dietary caffeine include coffee, tea, and chocolate. Synthetic caffeine is also added to products to enhance their stimulant properties. Historically, this addition was limited to soda-type beverages, but over the past decade, caffeine has been added to a diverse variety of foods and non-food items to promote arousal, alertness, energy, and elevated mood ( 3 – 5 ). This recent increase in caffeine-containing food products, as well as changes in patterns of consumption of the more traditional sources of caffeine, has increased scrutiny by health authorities and regulatory bodies of the overall consumption of caffeine and its potential cumulative effects on behavior and physiology. Of particular concern is the rate of caffeine intake among populations potentially vulnerable to its negative effects. Health and regulatory authorities have recently highlighted the risk of consumption among pregnant and lactating women, children, adolescents, young adults, and people with underlying heart and other health conditions.

In light of these concerns, we conducted a comprehensive review of all relevant published clinical and intervention trials, observational studies, systematic reviews, meta-analyses, and expert reviews on the use and safety of caffeine in humans, complemented where needed (e.g., for aspects of safety or mechanisms of action) with evidence from animal studies. We evaluated the strengths and limitations of the evidence on the safety of ingested caffeine, specifically focusing on the safety of caffeine-containing foods (e.g., beverages and solid foods). We summarize here what is known and what remains to be learned about caffeine intake and safety in healthy and vulnerable populations and highlight needed research.

Dietary Sources of Caffeine

Adults commonly consume caffeine in coffee and tea, both of which contain natural caffeine in their leaves or beans ( 6 ). Energy drinks often contain caffeine from natural products such as extracts from guarana leaves. In addition to coffee, tea, and energy drinks, caffeine is also naturally present in cocoa beans and thus in chocolate. The amount of caffeine in chocolate varies by the percentage of cocoa it contains, with 100% cocoa chocolate (unsweetened baking chocolate) containing around 240 mg caffeine/100 g, 55% cocoa (bittersweet) containing 124 mg caffeine/100 g, and 33% cocoa (milk chocolate) containing 45 mg caffeine/100 g ( 7 ). Synthetic caffeine is also added to soda and energy drinks ( 8 ), which are commonly consumed by children and adolescents worldwide, and to other food and non-food products with niche markets for subsets of consumers, such as juice, chewing gum, water, cookies, hot sauce, candy, beef jerky, mints, syrup, waffles, shampoo, soap, lip balm, eye cream, body scrub, and body lotion. These products are primarily marketed with claims that they provide energy, alertness, or are “age-defying.” Last year, the FDA announced that it will begin investigating the safety of caffeine added to food products, with a special emphasis on children and adolescents. 1

Caffeine is a constituent of many over-the-counter pain relievers and prescription drugs because the vasoconstricting and anti-inflammatory effects of caffeine act as a compliment to analgesics, in some cases increasing the effectiveness of pain relievers by up to 40% ( 9 – 14 ). Caffeine is used for general pain relief in medications such as Midol™ and Vanquis™, which contain doses ranging from 33 to 60 mg. It is used therapeutically in combination with ergotamine to treat migraine headaches and in combination with non-steroidal anti-inflammatory analgesics. Anacin™, Excedrin™, Goody’s™ headache powder, and pain reliever plus contain between 32 and 65 mg of caffeine, and prescription headache medications, including Fiorinal, Orphenadrine, and Synalgos, contain between 30 and 60 mg of caffeine.

Alone, caffeine is used as a somnolytic to counteract drowsiness (e.g., NoDoze™ and Vivarin™ each contain 200 mg of caffeine), to enhance seizure duration in electroconvulsive therapy, and to treat respiratory depression in neonates, postprandial hypotension, and obesity ( 15 – 18 ). Similar synergistic additive effects of caffeine and medications also occur in treatments for asthma and gall bladder disease, attention deficit-hyperactivity disorder, shortness-of-breath in newborns, low blood pressure, and weight loss ( 19 – 24 ). Between 50 and 200 mg of caffeine is added to some weight-loss supplements (Dexatrim™, Hydroxycut™, and Nutrisystem™ Energi-Zing Shake) for its purported effects on appetite suppression and increased metabolism ( 25 ).

Estimates of Caffeine Consumption

Recent estimates in adults suggest that more than 85% of adults in the U.S. regularly consume caffeine, with an average daily intake of about 180 mg/day, about the amount of caffeine in up to two cups of coffee ( 6 , 26 ). Among children and adolescents, caffeine use appears to be either stable or slightly decreasing over time, despite the influx of new caffeine-containing products on the market. For example, a study by Ahluwalia and Herrick using NHANES data reports that about 75% of U.S. children between 6 and 19 years old consume caffeine, with an average consumption of 25 mg/day in children 2–11 years old and 50 mg/day in children 12–17 years old ( 8 ). Another study also using the NHANES dataset reports average caffeine consumption in children and adolescents as 35 mg/day, with 4–8 years old consuming 15 mg/day, 9–13 years old consuming 26 mg/day, and 14–19 years old consuming 61 mg/day ( 27 ).

Coffee consumption varies worldwide: Finland and Norway are at the top of the list, with averages of 9.6 and 7.2 kg of coffee consumed per capita per year. The U.S. ranks 22nd, with 3.1 kg. A 1984 study showed that Canada and the U.S. had per capita rates of caffeine consumption that were triple the worldwide average but that were still half of what was consumed in countries such as Sweden and the United Kingdom (U.K.) ( 28 ). A more recent study from the Canadian Community Health Survey found that coffee was the second most popular drink among Canadian adults, with water being the first ( 29 ). The U.K.’s National Diet and Nutrition Survey also collected information on caffeine consumption through foods and beverages from adults and children. These data show that, on average, adults in the U.K. consume about 130 mg/day of caffeine and that children consume about 35 mg/day ( 30 ). A study from Japan using 4-day food diaries reported average daily caffeine consumption as about 260 mg/day in adults ( 31 ). Finally, people in Finland, Norway, the Netherlands, and Sweden are consistently reported to drink the most caffeine, primarily from coffee. However, these estimates are derived from sales of coffee and not from surveys of individual intake.

Trends in Caffeine Consumption

Trends in caffeine consumption have been stable among adults for the past two decades ( 6 ). Among children aged 2–19 years old, caffeine consumption increased significantly from the 1970s through the 1990s ( 5 , 32 ). This increase was also marked by a decrease in dairy consumption and an increase in soda consumption ( 32 ). More recent data suggest that caffeine consumption has remained stable among this age group since the 1990s ( 8 , 33 ), a finding similar to that in adults. This stability is somewhat surprising, given the marked increase in the number, variety, and availability of caffeinated beverages introduced in the past decade. Some researchers speculate that this stability reflects a lag in data collection or in consumption trends from when products are introduced to the market to when data are collected (for example, the most recent NHANES data on caffeine consumption are from 2011). Another potential explanation is that a possible decline in consumption among younger children has been offset by increased consumption among older adolescents and young adults attracted to the increasing number of new caffeine-containing products. Targeted marketing strategies seem to support this explanation. Advertisements for caffeinated energy drinks, the fastest growing segment of the beverage market ( 34 , 35 ), are specifically aimed at adolescent and young adult males ( 36 , 37 ). Given the popularity and prevalence of energy drinks, caffeine consumption could reasonably be expected to increase quickly among children and adolescents.

Caffeine intake usually begins in childhood, most often in the form of chocolate, soda, and chocolate milk ( 8 ). As children become adolescents, they increase consumption of soda and begin to add beverages with greater caffeine content, such as coffee and energy drinks ( 8 ). Average caffeine intakes increase from about 50 mg/day in childhood (aged 2–11 years) to 180 mg/day in adulthood ( 6 ). This amount is about 2 mg/kg/day in children, 2.4 mg/kg/day in women, and 2.0 mg/kg/day in men. This shift in absolute caffeine intake from childhood to adulthood is related to changes in the pattern of consumption, with adults adopting a more regular, daily pattern of consumption relative to children ( 6 ). In addition, the dietary sources of caffeine shift over the lifespan: adults primarily consume coffee and tea, whereas children and adolescents consume primarily soda and chocolate, which contain much lower amounts of caffeine.

The pattern of caffeine use changes across the lifespan has not been studied, but tolerance to the effects of caffeine has been speculated to increase the desire for larger doses to reverse the impact of overnight caffeine withdrawal ( 38 ). In addition, once caffeine intake is great enough to disrupt sleep, or if sleep duration is shortened by other factors, caffeine is often used to promote morning arousal, which can further disrupt sleep, creating a pattern in which caffeine is both the cause and the cure for too little sleep ( 38 , 39 ). Variations in caffeine sensitivity and consumption may relate to polymorphisms in enzymes that degrade caffeine and in adenosine receptors, which are the primary targets of caffeine ( 40 ).

The Pharmacokinetics of Caffeine

Caffeine works by binding to adenosine receptors located in the central and peripheral nervous systems as well as in various organs, such as the heart, and blood vessels. Adenosine is a molecule involved in numerous biochemical pathways, mostly for energy transfer (in the form of adenosine triphosphate, the basic fuel of cells) and signaling. Adenosine is a neuromodulator that can promote sleep, affect memory and learning, and protect cells after insults. Adenosine can also act on several types of cognate receptors: for example, A1, A2a, A2b, and A3, which are G-coupled proteins. In the central nervous system, activating A1 receptors inhibits the release of neurotransmitters, whereas activating A2a receptors promotes their release ( 41 ). During early stages of brain development, the predominant effect of caffeine is to antagonize type 2A adenosine receptors, slowing down the migration speed of some neurons ( 42 ). At toxic doses (i.e., extreme doses that humans rarely absorb), caffeine can alter other cellular functions, releasing Ca 2+ from intracellular stores at lethal levels ( 43 ). The toxic dose effects are not considered here because, although they are of great concern to the medical profession and may be on the rise, they are still rare compared to other, non-lethal caffeine effects and the precise mechanism of caffeine toxicity has not been investigated in humans.

Absorption and Metabolism

Caffeine is usually ingested. Caffeine is soluble in water and lipids, easily crosses the blood–brain barrier, and can be found in all body fluids, including saliva and cerebrospinal fluid. Importantly, caffeine ingested by women perinatally will be present in the umbilical cord and breast milk. Hence, it will also be present in the fetus and in breastfed infants. Caffeine is absorbed rapidly and totally in the small intestine in less than 1 h ( 44 ) and diffuses rapidly in other tissues ( 45 ). Absorption by the small intestine does not seem to vary by sex, genetic background, environmental factors, or other variables ( 46 ), although specific studies are still needed to confirm this premise. Caffeine concentrations peak in saliva 45 min after ingestion ( 47 ) and in serum after about 2 h ( 48 ). Caffeine has a relatively long half-life of 3–7 h in adults. In neonates, the half-life is even longer—between 65 and 130 h—because of their immature kidneys and liver. Peak concentrations are important because the effects of caffeine depend in part on the length of time it remains in tissues. Clearly, the effects are age dependent and depend on complex genetic and environmental interactions.

Caffeine is primarily metabolized in the liver by the cytochrome P450 oxidase enzyme system; in particular, by the CYP1A2 enzyme. However, this oxidase enzyme system is also present in other tissues, including the brain ( 49 ). Caffeine metabolism is affected by several factors, described in detail below.

Genetic Variation

The CYP1A2 gene, which encodes for a cytochrome P450 enzyme, has a large genetic variability. At least 150 single-nucleotide polymorphisms can accelerate caffeine clearance ( 50 ). The metabolic consequences of this polymorphism on caffeine downstream effects should be studied in humans. Genetic variation (i.e., increased or decreased activity of the cytochrome P450 oxidase enzyme) may increase or decrease the possible harmful effects of caffeine (e.g., during pregnancy) and any beneficial effects (e.g., on memory and learning during aging or in pathologies, such as Alzheimer’s disease). The half-life of caffeine may also be increased in liver diseases, which decreases P450 activity ( 50 ).

The molecular targets of caffeine, namely the adenosine receptors, also have great genetic variability. For example, common variants of the gene encoding for the A2a receptor can disrupt sleep ( 51 ) or cause anxiety in some individuals ( 52 ) after ingesting caffeine. More studies are needed to determine the effects of genetic variants on the consequences of caffeine consumption ( 53 ), not only in the central nervous system but also in other organs, such as the heart ( 40 ).

Circadian Rhythms

The expression of the cytochrome P450 epoxygenases is regulated in a circadian manner ( 54 ). Although this effect was discovered in cultured rodent cells, it may apply to many species, including humans ( 55 ). The implications are particularly important because the effects of caffeine (at least the duration of its activity) will differ during the circadian cycle. Because caffeine can alter sleep, it may also change the circadian rhythm, leading to a change in expression patterns for the cytochrome P450. One interesting hypothesis is whether caffeine consumption in adolescents and adults disrupts the expression of P450 in relation to its circadian rhythm. If the expression is downregulated, the effects of caffeine could be prolonged and produce a negative feedback loop.

Steroid Hormones

The cytochrome P450 oxidase enzyme system is the same enzyme that metabolizes steroid hormones ( 56 ). Thus, steroid hormones slow caffeine metabolism. In women, this effect slows the metabolism of caffeine during pregnancy and when taking oral contraceptives ( 57 ). However, studies have not found marked differences in caffeine metabolism between the luteal and follicular phases of the menstrual cycle ( 57 , 58 ). Oral contraceptives tend to double the half-life of caffeine ( 59 ).

The half-life of caffeine is on average 8.3 h longer during pregnancy and may be as much as 16 h longer than usual ( 60 , 61 ). This longer half-life means that the effects of caffeine will be longer lasting in women and in the fetus. Given the effects that caffeine may have on brain development, this increased half-life in pregnant women should be taken into account when considering safety issues.

Caffeine is eliminated more slowly during early infancy, requiring perhaps 80 h in preterm and healthy-term neonates, because of the reduced efficiency of cytochrome P450 ( 62 , 63 ). Elimination is likely to be at least as slow in the fetus. Fetal exposure to caffeine during pregnancy may potentially have long-lasting effects, especially in the brain. By age 6 months, infants eliminate caffeine at the same rate as that of adults ( 62 ).

Substance Use

Cigarette smoking doubles the rate of caffeine clearance by increasing liver enzyme activity, which may explain the higher rate of caffeine consumption among smokers ( 64 ). Substantial alcohol intake increases the half-life of caffeine and decreases its clearance ( 65 ).

Central and Peripheral Effects of Caffeine

The general effects of caffeine on body functions are summarized in Table 1 .

Table 1. Summary of outcome measures investigated .

Cognitive Effects

Caffeine can influence objective and perceived cognitive performance by increasing alertness and wakefulness ( 66 – 68 ). Acute caffeine can also improve performance on memory tasks ( 69 , 70 ). Finally, caffeine improves psychomotor vigilance, such as reaction time ( 71 – 73 ). The impact of caffeine appears to be greater under conditions that would negatively impact performance, such as acute caffeine withdrawal ( 74 – 76 ) or sleep deprivation ( 71 , 77 ). In fact, studies that have employed long-term caffeine withdrawal methodology have consistently failed to find cognitive enhancing effects of acute caffeine ( 78 – 82 ). Nevertheless, in 2001, the Institute of Medicine’s Food and Nutrition Board Committee on Military Nutrition Research reported that ingesting 150 mg of caffeine enhances cognitive performance for at least 10 h ( 83 ), and this recommendation has not been updated in light of more recent empirical findings.

Numerous preclinical studies have found that antagonizing adenosine receptors, including with caffeine, has neuroprotective effects during aging and in neurological disorders by slowing cognitive decline and the progression of the disorders [reviewed in Ref. ( 84 , 85 )]. Based on these animal studies, several large longitudinal clinical studies in different countries have established an inverse relationship between coffee consumption and memory decline during normal aging ( 86 – 88 ). However, a study of 4,200 women and 1,800 men reported that caffeine consumption reduced cognitive decline only in women ( 69 ). In addition, a more recent study in a small group of women ( 89 ) failed to replicate the findings of the Ritchie study, demonstrating that more work is needed to understand the relationship between habitual caffeine consumption and cognitive performance. Finally, large cohort studies of men and women have also found an inverse relationship between caffeine consumption and the risk of Parkinson’s disease ( 90 – 92 ) and Alzheimer’s disease ( 93 – 95 ).

Pain Relief

Caffeine has long been used to treat pain. However, its pain-reduction effects were not properly studied until 1984, when Lachance ( 96 ) documented that additive caffeine reduced the dose of acetaminophen necessary to achieve the target of a 40% reduction in pain scores ( 96 ). Since then, the vasoconstricting action of caffeine, secondary to adenosine receptor antagonism, has been associated with pain relief ( 97 ). Several studies have reported that acute dietary caffeine consumption can reduce pain ( 98 , 99 ). In addition, caffeine in doses of between 300 and 500 mg can soothe post-dural puncture headaches, which is the most common complication of lumbar puncture procedures ( 100 ).

Cardiovascular Effects

In general, acute intake of caffeine stimulates a modest increase in blood pressure (both systolic and diastolic), effects on heart rate (bradycardia or tachycardia, depending on dose), and neuroendocrine effects (release of epinephrine, norepinephrine, and renin) ( 101 ). These effects suggest that the mechanism of action is an increase in intracellular calcium concentrations, the release of norepinephrine, and the sensitization of dopamine receptors. These events may lead to supraventricular and ventricular tachyarrhythmias, especially at high doses. One proposed mechanism for caffeine-related cardiac arrhythmias is, again, the blockade of adenosine receptors ( 102 , 103 ).

Patients with cardiac disease are often warned about the potential harmful effects of caffeine. For example, 94% of several hundred physicians from Minnesota and Vermont recommended reducing or stopping caffeine for patients reporting heart palpitations ( 104 ). However, this advice has been based primarily on anecdote and folklore ( 105 , 106 ). Many of caffeine’s health effects occur after sympathetic excitation. Today, however, data suggest that caffeine does have cardiac effects, and arrhythmia is among them ( 107 ). Moreover, effects that do exist differ by dose and between habitual and non-habitual users. This severity of these threats often depends on such factors as preexisting medical conditions as well as the quantity of the ingredients taken and the length of time a person has been exposed to these substances. Many of the ingredients that include caffeine alone or in combination with other active substances have the potential to interact with prescription and over-the-counter medications. At typical caffeine doses, however, studies have documented mild changes in heart rate and blood pressure, a slight increase in sympathetic activity, and small changes in cardiac electrophysiological properties ( 105 , 108 – 110 ).

Vascular System Effects

Caffeine is believed to improve endothelial cell function at rest by increasing intracellular calcium concentrations, which stimulates the expression of endothelial nitric oxide synthase, which in turn stimulates the endothelial cells to produce nitric oxide. The nitric oxide then diffuses into vascular smooth muscle, which lies just underneath the endothelial cells, causing vasodilation ( 111 ). Caffeine can also bind directly to the vascular smooth muscle cell receptors and, through similar mechanisms, cause vasoconstriction ( 112 ).

The above information not withstanding, consuming caffeine immediately before or during exercise can be harmful and may increase the risk for myocardial ischemia ( 113 ). Indirect laboratory measures indicate that caffeine consumed immediately before exercising substantially reduces myocardial blood flow in healthy individuals ( 114 ). Several mechanisms may explain this reduction ( 114 ), including the ability of caffeine to block adenosine receptors that modulate coronary vasomotor tone. This vasoconstrictive effect might be more pronounced among caffeine-naïve individuals or in those who quickly ingest higher amounts of caffeine: for example, by consuming energy drinks. When caffeine blocks adenosine receptors, it reduces the ability of the coronary arteries to improve their flow commensurate with the increased myocardial demand of exercise, which could result in supply demand ischemia ( 114 ).

Caffeine Toxicity

Seifert et al. ( 115 ) examined data from calls to the U.S. National Poison Data System made between October 1, 2010 and September 30, 2011 related to caffeine exposure and energy drink consumption ( 115 ). Of 2.3 million calls, 4,854 (0.2%) were energy drink related. Of the 1,480 calls related to exposures not involving alcohol, 51% concerned children under the age of 6, and 77% were the result of unintentional ingestion. The overall incidence of moderate-to-major adverse effects of energy drink-related toxicity was 15.2% for non-alcoholic energy drinks. The seven cases with major adverse effects consisted of three with seizure, two with non-ventricular dysrhythmia, one with ventricular dysrhythmia, and one with tachypnea. Of the same 1,480 calls, 946 concerned products containing caffeine only and 534 concerned products with caffeine-containing additives, such as guarana (a plant whose seeds are high in caffeine) or taurine (a naturally occurring organic acid often used as a nutritional supplement). Compared to energy drinks with additives, caffeine-only exposures involved a significantly greater proportion of cases less than 6 years old (50.7%) and a greater proportion of unintentional exposures (76.7%). The proportion of cases involving additives referred to a health-care facility was also significantly greater, as was the incidence of toxic effects of any severity. One caveat to this study is that information on preexisting medical conditions was not available for the cases studied. Research in this area should attempt to include and account for preexisting health conditions.

Researchers have also expressed concern about unintentional caffeine consumption and an increase in overconsumption of caffeinated energy drinks in children and young adults. For example, Bronstein et al. ( 116 ) identified 48,177 poison center calls related to caffeine consumption and 6,724 calls related specifically to energy drink consumption. Seifert et al. ( 115 ) also reported that 55% of calls regarding caffeine consumption were related to unintentional exposures ( 115 , 116 ). A study of 13- to 17-year olds admitted to urban emergency rooms in the U.S. found that more than half reported consuming energy drinks in the past month, and those who had were also more likely to report that they had “gotten into trouble at home, school, or work” than those who consumed other types of caffeinated beverages [OR: 3.12 (1.24–7.88)] ( 117 ).

In March 2013, 18 scientific and medical experts sent the FDA commissioner a report summarizing the research findings on energy drink consumption in children. This report concluded “… there is neither sufficient evidence of safety nor a consensus of scientific opinion to conclude that the high levels of added caffeine in energy drinks are safe under the conditions of their intended use, as required by the FDA’s Generally Recognized As Safe standards for food additives. To the contrary, the best available scientific evidence demonstrates a robust correlation between the caffeine levels in energy drinks and adverse health and safety consequences, particularly among children, adolescents, and young adults” ( 118 ). Furthermore, the Institute of Medicine has recommended that drinks containing caffeine should not be sold to children at school ( 119 ). In addition, The American Academy of Pediatrics’ Committee on Nutrition and the Council on Sports Medicine and Fitness recently concluded that “rigorous review and analysis of the literature reveal that caffeine and other stimulant substances contained in energy drinks have no place in the diet of children and adolescents” ( 120 ).

Death from caffeine ingestion appears to be rare. This rarity may be related, in part, to the marked gastric irritation from caffeine that results in spontaneous emesis. Nevertheless, several hospitalizations and some deaths from caffeine toxicity have been reported ( 121 ). For example, between 2005 and 2011, there were 79,438 emergency room visits attributable to overconsumption of energy products containing high levels of caffeine in patients aged 12 years and older ( 121 ). In most of these cases, the mechanism seems to be tachyarrhythmia and involves unusually high doses of caffeine (>3 mg/kg) ( 121 ). Most deaths after caffeine intoxication were caused by overdoses of diet pills and stimulants, and most have occurred in young patients without known underlying heart disease or any variant of normal, such as mitral valve prolapse. In one non-fatal adverse event report, no predisposing factors or structural cardiac abnormality were associated with atrial fibrillation ( 122 ). In this case, caffeine-induced atrial fibrillation spontaneously reverted to normal sinus rhythm.

Reproductive Effects

Caffeine consumption is associated with fertility indices in some studies but not in others. An extensive literature review by the Oak Ridge National Laboratory concluded that chronic caffeine intake in humans is related to adverse effects on conception and reproduction, such as delayed conception and decreased fecundity. These effects appeared at caffeine doses above 200 mg/day ( 121 ). A separate review concluded that for healthy adults, intakes below 400 mg/day were not associated with adverse reproductive effects; however, the authors recommended consumption below 300 mg/day for women of reproductive age ( 123 ). In addition, some researchers argue that any association between caffeine intake and reproductive outcomes may be explained by other variables, such as maternal smoking or substance use and that research should address confounding, as well as errors in measuring exposure ( 124 ).

Reports regarding caffeine consumption and spontaneous abortions have also been conflicting. Weng et al. ( 125 ) reported a hazard ratio of 2.23 for spontaneous abortion among 164 women who consumed 200 mg/day or more of caffeine and of 1.34 for 899 women who consumed less than 200 mg/day ( 125 ). After adjusting for pregnancy symptoms, such as nausea and vomiting, other researchers found that consuming doses of 200 mg/day or more still almost doubled the risk of spontaneous abortion. A meta-analysis by Chen et al. ( 126 ) reported that, compared to a no or very low caffeine intake reference group (0–50 mg/day during pregnancy), every additional 100 mg/day of caffeine (about the amount contained in a typical cup of coffee) increased the risk of pregnancy loss (both miscarriage and stillbirth) by 7% ( 126 ). In addition, among women consuming more than 700 mg/day, the risk of pregnancy loss was increased by 72%. Similar findings were reported by Li et al. ( 127 ), who found in a separate meta-analysis of 26 studies that the risk of pregnancy loss increased by 19% for every additional 150 mg of caffeine consumed per day and by 8% for every additional 2 cups of coffee (about 200 mg) per day ( 127 ). However, Savitz et al. ( 128 ) reported no association among 2407 women who were interviewed regarding caffeine intake before experiencing spontaneous abortion ( 128 ). This finding suggests that recall bias may explain the increased hazards of spontaneous abortion reported by Weng et al. ( 125 ) and potentially other researchers ( 125 ). Other comprehensive reviews have reported some evidence that caffeine intakes of more than 300 mg/day have been associated with spontaneous abortion and low birth weight, but all have stressed the need for further research before a causal relationship can be established ( 129 , 130 ). A recent study from the Nurses Health Study shows pre-pregnancy coffee consumption at levels ≥4 serving/day is associated with an increased risk of spontaneous abortions, particularly at 8–19 weeks gestational age ( 131 ).

Congenital Anomalies

No clear association has been found in humans between moderate doses of caffeine ingestion during pregnancy and birth defects, including congenital heart disease ( 132 ). For example, the National Birth Defects Prevention Study found variable results for this possible association ( 133 ). In another study of 2,030 malformed infants, the risk of congenital anomalies was not related to the total maternal daily caffeine ingestion below 400 mg/day (or up to 4 cups of coffee) during pregnancy ( 134 ). Other studies have found that the frequency of all congenital malformations, including congenital heart defects, was no higher than expected among women who drank between four and eight cups of coffee daily during their pregnancy ( 135 , 136 ). The Institute of Medicine’s Workshop on Potential Health Hazards Associated with Consumption of Caffeine in Food and Dietary Supplements found that risk of congenital defects from caffeine was not increased in the range of amounts women typically consumed during pregnancy ( 121 ).

The consequences of caffeine consumption during pregnancy on offspring have recently been studied in mice ( 137 ). Caffeine consumption by the dam (the human equivalent of two to three cups of coffee per day) was associated with caffeine concentrations in the offspring brain that were similar to those in the umbilical cords of women drinking two to three cups of coffee per day ( 138 ). At early stages of development, specific types of neurons arise in particular brain regions and then migrate to their target areas. Caffeine slowed the migration of these neurons by 50% by antagonizing adenosine type 2A receptors. As a result, these neurons were late at being incorporated into the circuitry, with negative consequences: pups were more susceptible to seizures, and in adulthood, in utero exposed mice had mild cognitive deficits. This study was the first to document that caffeine exposure during pregnancy could harm the offspring. Generalizing the results of animal studies to humans is always speculative, but these results strongly justify conducting prospective studies in humans. Interestingly, in keeping with animal data, greater exposure to caffeine during pregnancy is associated with a lower IQ in children at age 5.5 years ( 139 ). This finding again supports the need for additional studies in humans.

Birth Weight Effects

Several studies have reported a significant negative association between maternal caffeine consumption and birth weight ( 84 , 85 , 140 – 142 ). However, two other large prospective cohort studies reported a dose-dependent positive association between caffeine intake during pregnancy and the risk of adverse birth weight-related outcomes, such as fetal growth restriction and small for gestational age babies ( 143 , 144 ). In these studies, caffeine intake and adverse birth weight-related outcomes were found at all amounts of maternal caffeine intake. In both studies, the risk for adverse birth-related outcomes increased notably at a caffeine dose of 200 mg/day from all nutritional sources. In addition, one study of 1,207 pregnant women reported that, although they tended to reduce consumption of caffeine during pregnancy, a moderate decrease in caffeine intake to 100 mg/day in the third trimester of pregnancy did not decrease the risk of adverse birth weight-related outcomes ( 145 ).

Two separate meta-analyses of different sets of studies by Rhee et al. ( 142 ) and Chen et al. ( 146 ) reported odds ratios of having a newborn classified as low-birth weight (less than 2,500 g) for maternal caffeine consumption above 50 mg/day when compared to intakes below 50 mg/day. Furthermore, both meta-analyses found an increased risk of low-birth weight offspring for every 100 mg/day increase in maternal caffeine consumption (OR, 1.03–1.62). Another study by Hoyt et al. ( 140 ) found the odds ratios of having a low-birth weight baby increased to a range of 1.3–2.1 in women consuming more than 300 mg/day of caffeine during pregnancy ( 140 ).

Taken together, these studies provide substantial evidence of a negative association between maternal caffeine consumption and infant birth weight. Even so, the studies all relied on maternal self-report about caffeine intake; thus, the data may not be accurate. Furthermore, it is possible that additional variables, not controlled for in the analyses, could explain these relationships. For example, chronic sleep loss during pregnancy is also associated with poor birth outcomes, including low birth weight ( 147 ). Thus, pregnant women with disrupted sleep might use more caffeine to increase alertness, so the impact on birth weight could be related to short sleep duration and not to caffeine. Although this conclusion is speculative, it highlights the importance of considering additional variables when interpreting correlational data.

Caffeine may cause irritability and sleep disruption in nursing infants whose mothers consume caffeine ( 148 ), but the findings are equivocal ( 149 ). In addition, some evidence indicates that caffeine intake can reduce production of breast milk ( 148 ). Mothers are often advised by their doctors to reduce or eliminate caffeine intake if they feel that their infant shows signs of caffeine sensitivity, but there is no evidence in the literature of detrimental effects of caffeine ingestion during lactation in the general population. Behavioral issues, such as fussiness, jitteriness, and poor sleep patterns, have been reported among infants breastfed by mothers who consumed 10 or more cups of coffee (~1 g of caffeine) per day ( 121 ). The effects of caffeine in breast milk can be amplified in preterm infants or infants less than 5 months old because they metabolize caffeine so slowly ( 121 ). In addition, an intake of more than 450 mL (about two cups) of coffee per day may decrease breast milk iron concentrations, which could contribute to infant anemia ( 150 ). However, the European Food Safety Authority concluded that a single dose of 200 mg or less of caffeine (about two cups) consumed by lactating women, as well as chronic intakes at or below 200 mg, pose no safety concerns for breastfed infants ( 151 ).

Outcomes after Infancy

Few studies have examined the impact of maternal caffeine intake on outcomes after infancy. One study by Klebanoff and Keim ( 152 , 153 ) using 2,197 mother–child dyads measured child IQ and problem behaviors and examined correlations with maternal paraxanthine concentrations (a metabolite of caffeine) taken between 20 and 26 weeks of gestation ( 152 , 153 ). This study found no meaningful relationship between maternal caffeine intake during pregnancy and a range of behavioral and cognitive measures in children 4–7 years old. However, another study of 1,083 mother–child pairs revealed that children who were born to mothers who estimated caffeine intake >200 mg/day during pregnancy had an odds ratio of 2.3 (95% confidence interval of 1.13–4.69) of having a child with a lower IQ at age of 5.5 years compared to the reference population of mothers reporting <100 mg/day of caffeine consumption ( 139 ). A study by Li et al. ( 154 ) reported that maternal caffeine intake was associated with increased odds of childhood obesity, with each 100-mg increase in daily maternal caffeine intake being associated with a 23% higher odds of obesity at age 15 years ( 127 ), although a study by Klebanoff and Keim found no relationships between maternal caffeine consumption and childhood obesity ( 152 , 153 ).

The above studies are correlational; thus, causation cannot be determined. In addition, the maternal caffeine intake in these studies was estimated based on self-reports. One potential explanation for the discrepancies described above is the method used to determine caffeine use. In the study by Klebanoff and Keim ( 152 , 153 ), which found no significant relationship between maternal caffeine intake and outcomes after infancy, measured serum caffeine concentrations and did not use self-report ( 152 , 153 ). By contrast, the studies that found significant relationships between maternal intake and measures in the offspring after infancy relied exclusively on retrospective self-reports, several years after the fact, about prenatal caffeine consumption by mothers after they gave birth and during the first two trimesters of pregnancy, respectively. Caffeine intake was estimated from food-frequency questionnaires or interviews in which women reported how often and how much they consumed coffee, tea, and soda. Other variables affecting self-reported caffeine consumption and offspring behavioral outcomes might explain these relationships, but in the study that relied entirely on serum concentrations, such variables were not identified. These studies also measured different outcomes in the offspring. Klebanoff and Keim ( 152 , 153 ) had the most comprehensive battery of cognitive and behavioral outcomes, but Galera et al. ( 139 ) only measured IQ (The Wechsler Preschool and Primary Scale of Intelligence Third Edition), and Li et al. ( 127 ) only measured weight and weight gain in the offspring ( 139 , 152 – 154 ). Meaningful comparisons of studies are difficult when the methods for assessing caffeine intake and the outcomes are different. Research with objective measures of caffeine intake and standard outcomes is needed.

Other Existent, Emerging, or Minor Issues

Most of the research examining linkages between caffeine and cancer has been conducted on coffee and tea and not on caffeine specifically, which makes it difficult to determine the mechanism. The International Agency for Research on Cancer has concluded that the evidence is insufficient to conclude that caffeine, as consumed by a typical coffee drinker, is carcinogenic ( 121 ). Several large prospective trials have reached the same conclusion ( 123 , 155 , 156 ). Furthermore, Nawrot et al. ( 123 ) concluded in their review of the research that caffeine is unlikely to be a human carcinogen at levels less than 500 mg/day, to the equivalent of five cups of coffee ( 123 ).

Unstable Bladder

Excessive caffeine intake (more than 400 mg/day) may increase the risk of detrusor instability (unstable bladder) in women ( 157 ). For women with preexisting bladder symptoms, even moderate caffeine intake (200–400 mg/day) may increase the risk for unstable bladder ( 157 ). This finding was confirmed in another case–control study of women who were given 200 mg of caffeine citrate ( 158 ). In addition, caffeine intake of 4.5 mg/kg/day caused early urgency and frequency of urination in men and women with overactive bladder ( 159 ). However, these studies did not examine whether a decrease in caffeine intake was associated with improvements in overactive bladder symptoms. Studies should address this issue.

Caffeine–Drug Interactions

According to www.drugs.com (a site owned by The Drugsite Trust, a privately held Trust administered by two New Zealand Pharmacists), 85 drugs (430 brand and generic names) are known to interact with caffeine, of which 11 can lead to major interactions. 2 Because caffeine consumption is at an all-time high and prescription drug use is more prevalent than ever, the risk of negative caffeine and prescription drug interactions is increasing ( 160 , 161 ). Because of the popularity of caffeine, clinicians should be conscious of the pharmacokinetic interactions between dietary caffeine and over-the-counter and prescription medications, and they should provide the necessary guidance to the patient including dietary restrictions. We also recommend that the potential interaction with these drugs be appropriately addressed on the labeling.

Hydration and Diuresis

Caffeine has a diuretic effect ( 123 , 162 , 163 ). However, in one clinical trial, different doses of caffeine (up to 6 mg/kg body weight) consumed by 59 habitual caffeine consumers after a 6-day run-in period of 3 mg/kg of caffeine did not markedly change hydration-related biomarkers, suggesting that increasing doses of caffeine did not induce hypohydration in these participants ( 164 ). These findings are supported by two similar studies, one in which 5 mg/kg body weight of caffeine was consumed daily for 4 consecutive days by 30 men who normally consumed less than 100 mg/day ( 42 ) and one in which 4 mg/kg body weight/day of caffeine from coffee was consumed for 3 consecutive days by 50 adult male habitual coffee consumers who usually consumed 3–6 cups of coffee/day ( 165 ). These findings suggest that the diuretic effects from consuming between 4 and 6 mg/kg body weight/day of caffeine are not likely to have adverse consequences for healthy adults who are habitual consumers of caffeine. Similar studies should be conducted in populations that vary by health status, age, and sex.

Populations At-Risk for Harmful Effects of Caffeine

Pregnant and lactating women.

Pregnant women and fetuses may be particularly vulnerable to the effects of caffeine. Caffeine is a biologically active molecule that can act on multiple targets and affect numerous functions positively or negatively. At early stages of fetal development, caffeine may have deleterious effects ( 137 ). A recent prospective study suggests that preconception caffeine consumption may also pose a risk to pregnancy, with pre-pregnancy consumption of >400 mg of caffeine/day increasing the risk of spontaneous abortion by 11% compared with women who consumed <50 mg of caffeine/day ( 131 ). Many psychoactive compounds can cross the placental barrier and alter the development of the fetal brain. Once caffeine enters the fetal circulation, it is metabolized slowly because neither the placenta nor the fetus itself has cytochrome P450, the enzyme that metabolizes caffeine ( 166 ). This reduced caffeine metabolism results in a longer half-life and increased caffeine exposure to the fetus ( 141 , 167 ). The American College of Obstetricians and Gynecologists recommends limiting caffeine consumption during pregnancy to less than 200 mg/day ( 168 ). In the late 1970s, most women maintained their intake during pregnancy at an average of about 190 mg/day 3 ( 5 ). In the 1980s and 1990s, the average maternal caffeine consumption declined to about 125 mg/day ( 5 ). Consumption was reported to be about 123 mg/day between 1997 and 2007 ( 84 , 85 ) and was even lower (58 mg/day) in a 1999 survey ( 169 ). This decline has been attributed to FDA warnings that excess caffeine consumption during pregnancy may adversely affect neonates ( 170 ). Interestingly, however, in a small cohort of 105 women who drank coffee before pregnancy, 65% reported an aversion to coffee during the first trimester, and 95% voluntarily reduced their consumption during this trimester ( 171 ), so perhaps women might be naturally averse to caffeinated products during pregnancy.

Data on caffeine consumption during lactation are limited. One small study from Poland reported that average caffeine intake in a sample of lactating women ranged from 127 to 163 mg/day ( 172 ).

Children and Adolescents

Young children may be vulnerable to the effects of caffeine because they weigh less. For example, a typical can of soda contains about 45 mg of caffeine on average. In an adult weighing 70 kg, the effective dose is 0.6 mg/kg, but in a child weighing 20 kg, the effective dose of the same soda would be 2.25 mg/kg. In comparison, the average caffeine intake in adults is 180 mg/day, resulting in an average effective dose of 2.5 mg/kg. Thus, the physiological impact of a single soda in a child may be equivalent to the impact of two cups of coffee in an average-sized adult. Adolescents may also be particularly vulnerable to the sleep-disrupting effects of caffeine because they may also use caffeinated beverages to stay awake ( 173 , 174 ).

Data have been collected in children and adolescents using dose–response and placebo-controlled research methods. Outcomes, such as cardiovascular function ( 175 – 178 ), mood ( 179 – 181 ), and cognitive performance ( 82 , 182 ), have all been measured at caffeine doses ranging from 50 to 300 mg. None of the results suggest that caffeine at these doses is acutely harmful to children and adolescents ( 183 ).

Some studies suggest an association between caffeine consumption and longer term behavioral problems in youth, such as anger, violence, sleep disturbances, and alcohol and drug use ( 180 , 184 ). Researchers in Iceland surveyed 7,400 adolescents (aged 14 and 15 years) and found that most reported consuming caffeine on a typical day and that caffeine intake (primarily from soda and energy drinks) was related to daytime sleepiness and anger for both sexes ( 185 ). In a 2013 study of 3,747 15- to 16-year olds, self-reported caffeine intake was strongly associated with self-reported violent behavior and conduct disorders ( 186 ). In this study, 21% of participants consumed at least one energy drink per day.

Other studies have found that anxiety can be produced at a wide range of doses (200–2,000 mg of caffeine/day), but many of these studies have used psychiatric patients or patients with a preexisting anxiety disorder ( 123 ). Other effects in these studies included nervousness, fidgeting, jitteriness, restlessness, hyperactivity, and sleeplessness ( 123 , 187 , 188 ). When children were stratified by prestudy caffeine intake, emotions and behaviors differed between low- and high-dose consumers ( 187 , 188 ). Children consuming high doses were more easily frustrated and were more nervous during baseline tests than were the children consuming lower doses. Other studies have found that children with attention-deficit/hyperactivity disorder have higher rates of caffeine abuse, perhaps due to the additive effects of caffeine on dopamine action at the dopamine D2 dopamine receptor, similar to the way guanfacine works for children with this disorder ( 189 , 190 ).

The safety of high-dose caffeine and energy drinks in younger individuals and caffeine-naïve individuals has not yet been determined. The consumption of highly caffeinated energy drinks has been associated with elevated blood pressure, altered heart rates, and severe cardiac events in children, adolescents, and young adults, especially those with underlying cardiovascular diseases ( 115 , 177 , 191 , 192 ). For example, a study of 50 young adults found that consuming a sugar-free energy drink containing 80 mg of caffeine (slightly less than the caffeine contained in one cup of coffee) was associated with changes in platelet and endothelial function great enough to increase the risk for severe cardiac events in susceptible individuals ( 193 ). These findings show how the acute effects of caffeine on heart rate might result in cardiovascular events requiring hospitalization, especially in at-risk young adults. In addition, caffeine’s effects on blood pressure are more pronounced among African-American children than among Caucasian children (mean difference in blood pressure averaging 6.5 mm Hg) ( 175 , 194 ). High doses of caffeine may exacerbate cardiac conditions for which stimulants are contraindicated ( 195 – 198 ). In particular, ion channelopathies and hypertrophic cardiomyopathy, which is the most prevalent genetic cardiomyopathy in children and young adults (0.2% of the population), are of concern because of the risk of hypertension, syncope, arrhythmias, and sudden death ( 197 , 199 ).

Patients with Mental Illness

Another population that may be at risk for adverse effects of caffeine are patients with mental illness. Caffeine antagonism of adenosine receptors can result in enhanced dopaminergic signaling, thought to be due to a combination of increased dopamine release ( 200 , 201 ), upregulation of dopamine receptors, and increased affinity of dopamine receptors for dopamine in the striatum and nucleus accumbens ( 202 ). Furthermore, adenosine receptors can form heterodimers with dopamine receptors ( 203 ), which can modulate dopamine signaling. For some psychiatric illness, such as Parkinson’s disease, Alzheimer’s disease, and depression, caffeine antagonism of adenosine receptors may improve symptoms ( 204 , 205 ) and slow the progression of neurodegeneration ( 206 , 207 ), although these findings are equivocal with some studies reporting caffeine increases depressive symptoms ( 208 ). For other mental illness, such as schizophrenia, caffeine may exacerbate psychotic symptoms ( 209 ), although the majority of this literature is informed by case studies, with very few double-blind placebo-controlled studies ( 210 ). There is also good evidence that higher caffeine use is associated with greater reporting of anxiety symptoms ( 211 , 212 ) and may increase risk of symptom relapse ( 213 ) and suicide among bipolar disorder patients ( 214 ). Finally, there is strong empirical evidence that caffeine potentiates the rewarding effects of drugs of abuse ( 215 – 217 ), which suggests that caffeine use can increase vulnerability to substance use disorder ( 218 ). The lack of randomized control trials on the impact of caffeine in patients with mental illness makes it difficult to determine safe doses, effects of acute and chronic caffeine, and potential interactions between caffeine and medications. Currently, there are no specific recommendations for caffeine consumption for individuals with mental or psychiatric illness, but it may be worth consideration by physicians and psychologists treating patients with mental illness.

Caffeine and Alcohol

Another increasingly popular form of caffeine consumption is to mix alcohol with energy drinks. In fact, there are several recent reviews on this topic ( 219 – 221 ). We will briefly highlight this literature here. In 2010, the FDA removed pre-mixed alcohol-energy drinks from the market because caffeine was determined to be an unsafe additive to alcohol, 4 in part because it promoted excessive drinking ( 222 ). However, energy drinks can be legally mixed with alcohol in the U.S. if they are sold separately. In fact, this practice is popular among college students, as suggested by the increase in self-reports over the past 5–10 years ( 223 – 229 ). The research on alcohol-mixed energy drinks is still developing, and the vast majority has been conducted in the U.S. and Australia. Much of this research consists of surveys of college-age young adults immediately after they leave bars where they have been drinking ( 230 – 233 ). Self-report is often unreliable, but self-report while intoxicated may be particularly problematic. Similarly, intoxication may confound retrospective assessments of alcohol consumption and related behaviors and attitudes.

More recently, several well-controlled, objective, laboratory-based studies on the impact of alcohol-mixed energy drinks have been conducted. In many studies, the combination of alcohol and energy drinks results in higher rates of binge drinking, reductions in perceived intoxication, faster rates of self-paced alcohol consumption, or increases in risk taking behavior ( 225 , 234 – 239 ). These data are equivocal, however, with studies showing that caffeine combined with alcohol does not always increase the amount of alcohol consumed ( 240 ) or does not have an impact on risk taking behavior ( 235 , 241 ). Potential reasons for these discrepancies may be difference in the doses of caffeine and alcohol, differences in the administration paradigm, and an influence of expectancy of caffeine effects on alcohol intoxication ( 241 ). More work is needed in this area to be able to draw stronger conclusions.

Caffeine-Related Diagnoses

The American Psychiatric Association’s Diagnostic and Statistical Manual-IV ( 242 ) included four caffeine-related diagnoses: caffeine intoxication, caffeine-induced anxiety disorder, caffeine-induced sleep disorder, and caffeine-related disorder not otherwise specified ( 242 ). Caffeine intoxication is diagnosed if clinically significant impairment results from the following criteria: (1) recent consumption of caffeine, usually in excess of 250 mg, (2) five (or more) of the following: restlessness, nervousness, excitement, insomnia, flushed face, diuresis, gastrointestinal disturbance, muscle twitching, rambling flow of thought and speech, tachycardia or cardiac arrhythmia, periods of inexhaustibility, psychomotor agitation, and (3) the symptoms in criteria (2) have to cause clinically significant distress or impairment in social, occupational, or other important areas of functioning and these symptoms cannot be attributable to another medical condition or mental disorder. Caffeine-induced anxiety and sleep disorder retain the diagnosis for substance/medication-induced anxiety and sleep disorders, but require that clinically significant symptoms occur in association with caffeine intoxication or withdrawal ( 243 ). Caffeine-related disorder not otherwise specified classifies symptoms related to caffeine use or withdrawal that do not fit into the aforementioned categories.

The latest edition of the DSM ( 243 ) has officially recognized caffeine withdrawal disorder and outlines guidelines for criteria for caffeine use disorder in a section on emerging measures and models ( 243 ). The diagnosis of caffeine withdrawal syndrome is empirically based on detailed analyses of decades of studies of symptoms [reviewed by Juliano and Griffiths ( 244 )]. Caffeine withdrawal disorder is diagnosed when an individual experiences clinically significant impairment related to withdrawal symptoms after abrupt cessation of caffeine intake, including headache, difficulty concentrating, fatigue, nausea, flu-like symptoms, and changes in mood. These symptoms typically begin 12–24 h after caffeine cessation and may continue for 3–7 days. Ongoing research on caffeine withdrawal suggests that this continues to be an important problem and will help refine and clarify this diagnosis ( 245 , 246 ). Avoidance of caffeine withdrawal, with or without a diagnosis of caffeine withdrawal disorder, may motivate individuals to consume more caffeine. This could result in chronic, excessive consumption of caffeine. When this excess consumption results in clinically significant impairment, an individual may meet the criteria for caffeine use disorder ( 247 – 249 ). Although not an official DSM diagnosis, the proposed criteria for caffeine use disorder include having all three of the following criteria met: (1) persistent desire or unsuccessful effort to control caffeine use, (2) “use despite harm,” and (3) withdrawal. Having these proposed criteria outlined will allow researchers to collect data to provide reliable and valid empirical studies of the prevalence of this phenomenon ( 250 ). This is critical because the progression of inclusion of caffeine-related diagnoses is directly related to an increase in empirical support for such disorders.

Recommendations on Safe Intake Levels and Limits on Intake

Caffeine reaches maximum plasma concentration 15–120 min after ingestion ( 251 ), which might explain why energy drink-related adverse events are usually reported a few hours after consumption. The threshold of caffeine toxicity appears to be around 400 mg/day in healthy adults (19 years or older), 100 mg/day in healthy adolescents (12–18 years old), and 2.5 mg/kg/day in healthy children (less than 12 years old) ( 123 , 192 ). For comparison, one standard sized can of a popular energy drink provides 77 mg of caffeine (or 1.1 mg/kg/day) for a 70-kg male and twice that, 2.2 mg/kg/day, for a 35-kg pre-teen ( 252 ). Recommended safety thresholds vary, however. For example, the European Food and Safety Authority considers 3-mg/kg body weight/day of habitual caffeine consumption to be safe for children and adolescents ( 253 ). 5

A comprehensive review of the effects of caffeine consumption on human health concluded that for healthy adults, moderate chronic intakes of caffeine up to 400 mg/day are not associated with adverse effects on cardiovascular health, calcium balance and bone status, behavior, cancer risk, or male fertility ( 123 ). However, the recommended intake is much lower for pregnant or nursing mothers. The European Commission’s Scientific Committee of Food Safety Authority and Health Canada both recommend that women consume no more than 300 mg of caffeine/day during pregnancy ( 121 , 253 ). In addition, despite conflicting results regarding the association between caffeine consumption and spontaneous abortion, the American College of Obstetricians and Gynecologists recommends that pregnant women restrict their caffeine intake to less than 200 mg/day ( 121 ).

For most children, adolescents, and young adults, safe levels of caffeine consumption have not been established. Because deleterious effects of heavy caffeine use have been documented in those who have cardiovascular issues, studies of safe doses and the effects of chronic use are paramount in understanding the implications of caffeine. This research should seek to better characterize the effects of caffeine use before, during, and after exercise, the interactions of caffeine use with alcohol and medications, such as stimulants, and the effects of prolonged caffeine use. A better understanding of caffeine’s effects in individuals with cardiac problems will better equip health-care providers to screen and identify at-risk individuals, and in turn, to better educate and counsel these cardiac patients. Such information will also help health-care leaders to work with families, schools, and other community services to change marketing strategies, improve the dissemination of information, and identify at-risk behaviors and age groups. Finally, the health-care providers and regulatory agencies must begin collecting and archiving better data on the adverse events and health effects of caffeine consumption to improve estimates about its scope, effects, and outcomes. Analyses of a comprehensive, centralized database would help direct research, education, and funding to support these populations. In addition, agencies like the U.S. FDA and Health Canada need to initiate programs to educate consumers, especially children and adolescents, about the dangers of highly caffeinated products, to reconsider applying the U.S. FDA’s Generally Recognized as Safe standard to energy drinks and other beverages with added caffeine, and requiring manufacturers to include the caffeine content on product labels. Because of the potentially harmful adverse effects and developmental effects of caffeine, the consensus among the research and medical communities is that any dietary intake of caffeinated energy drinks should be discouraged for all children ( 123 , 192 ).

One of the primary concerns about energy drinks is that the actual caffeine content is not often given on the product’s packaging or on its website ( 120 ). The total amount of caffeine contained in some energy drinks can exceed 500 mg (equivalent to 14 cans of common caffeinated soft drinks or 5 cups of coffee) and is high enough to be toxic in children and young adults ( 34 ). Given these concerns, the American Academy of Pediatrics released the following recommendation to the United States Senate Committee on Commerce, Science, and Transportation:

Due to the potentially harmful health effects of caffeine, dietary intake should be discouraged for all children. Because the actual stimulant content of energy drinks is hard to determine, energy drinks pose an even greater health risk than simple caffeine. Therefore, energy drinks are not appropriate for children and adolescents and should never be consumed (2014).

In 2010, Health Canada convened an Expert Panel 6 on Caffeinated Energy Drinks to develop a plan to more effectively address the safety concerns related to caffeinated energy drinks currently marketed in Canada. The Panel issued their recommendations to Health Canada in the fall of 2010. 7 Health Canada analyzed the recommendations, completed a health risk assessment, and continued to gather and exchange information with major food safety regulators within the country and internationally. This initiative resulted in a proposed management approach that was consistent with the strategies in the Panel’s recommendations. Components of this approach include regulating product formulation and labeling, addressing potential health risks and adverse effects, providing enhanced education and communication to consumers, and addressing uncertainties and data gaps through research on long-term effects. Long-term research was made a priority, to further investigate risks to consumers, to identify serious adverse event signals (such as cardiac events and to a lesser extent, seizures), and finally to better manage caffeine labeling and dosing limits. The data have reconfirmed that moderate daily caffeine intake at dosages of up to 400 mg/day are not associated with adverse effects. However, the data show that women of childbearing age and children may be at higher risk from caffeine, which has therefore led to separate guidelines for these at-risk groups. However, several products containing stimulant drugs do not have a natural health product license and exemption numbers that clearly describe their caffeine content. Therefore, the Panel recommended that Health Canada ensure that all products meet strict labeling that includes a full disclosure of the exact caffeine dose. Finally, the Panel recommended that Health Canada, in collaboration with the provinces and territories, consider beginning a surveillance system in sentinel emergency rooms across the country to actively search for serious adverse drug reactions associated with consuming drinks containing stimulant drugs with or without alcohol or other products. The proposal details how this system could be modeled after the nation’s long-running IMPACT system that monitors immunizations and related adverse events through a network of 12 Canadian centers, representing 90% of all tertiary care pediatric beds. A similar database, The Canadian Health Measures Survey, 8 launched in 2007, contains data from voluntary household interviews that collects important health information (e.g., physical measurements, nutrition, and blood and urine samples).

Future Research

Several questions remain about caffeine consumption and patterns of intake. First, it is not clear how much caffeine is being consumed from “uncommon” or unidentified sources of caffeine, such as foods and medications. These sources are often overlooked in large national surveys and, thus, caffeine intake may be underestimated. Second, caffeine may be indirectly harmful because it is consumed with other substances that are harmful. For example, coffee drinking may promote donut eating or cigarette smoking, or energy drink consumption may promote alcohol intake. Third, future studies need to investigate absorption, distribution, metabolism, and excretion of caffeine occurring in non-natural forms (such as encapsulated forms), which may influence pharmacokinetics, and thus effects. Finally, most research has relied on self-report and correlational analysis, which limits the ability to determine causality and directionality.

Despite all that is known about caffeine intake and safety of caffeine consumption, certain gaps in our knowledge need to be addressed:

(1) Identifying at-risk populations for caffeine toxicity . We already know that small children and pregnant women, as well as individuals with cardiac or vascular disease, are likely to be particularly vulnerable to the harmful effects of caffeine. Furthermore, there is some evidence that individuals with mental illness may also be at risk for harmful effects of caffeine on symptoms, but the majority of these relationships have been described in case studies. More randomized control trials need to be conducted in patients with mental illness to determine safe doses for caffeine ingestion. In addition to the known vulnerable populations, there may be individuals, such as the elderly or individuals with underlying medical conditions, who are not part of any vulnerable population but who, for genetic or metabolic reasons, may be susceptible to harmful effects. The Federal Substance Abuse and Mental Health Services Administration reported that from 2007 to 2011, the number of emergency room visits involving energy drinks doubled across the U.S., from 10,068 to 20,783. However, for adults aged 40 years and older, emergency room visits involving energy drinks nearly quadrupled during that same period (from 1,382 to 5,233). 9 This finding suggests that energy drink consumption in older people is increasing with perhaps a greater risk of negative outcomes. Identifying and warning at-risk individuals to avoid caffeine-containing products would be desirable.

(2) Determining how best to disseminate information about caffeine content in a meaningful and truthful way without causing alarm . Although the preponderance of evidence suggests that caffeine is safe for most people, there may be reasons to limit caffeine use in some populations. Providing more information about safe levels may be useful, but the information must be understandable to the population and based on evidence, rather than on supposition. Adding information about caffeine content on the products themselves may not be enough. The best way to educate consumers about safe levels of caffeine consumption needs to be determined. For example, evidence suggests that “natural frequencies” are an effective way to communicate risk. For example, one could explain “For every 1,000 children who consume energy drinks, XX will have CNS symptoms.” However, research is necessary to fill in the blank in this statement ( 254 ).

(3) Conducting prospective, longitudinal studies to determine how caffeine use relates to behavioral and health-related outcomes , such as the duration and quality of sleep, potential for abuse, and impact on the use of other substances, including controlled (cigarettes and e-cigarettes) and uncontrolled (marijuana, cocaine) drugs. Cross-sectional data suggest that caffeine use is generally safe, but rigorous longitudinal studies have not yet determined the effect of chronic caffeine consumption on development in children and adolescents.

(4) Further exploring the potential health benefits of caffeine . Although much of this document has focused on potential harmful effects of caffeine, some health benefits of caffeine remain under explored. In particular, some research suggests that caffeine may slow age-related cognitive decline ( 255 , 256 ), reduce risk of some neurological disorders ( 90 , 257 , 258 ), and promote longevity ( 156 ).

(5) Developing better systems of documenting and sharing adverse events . In addition to identifying at-risk or vulnerable populations, as mentioned earlier, and potentially dangerous combinations of caffeine with other substances (e.g., alcohol), we need a better system of documenting adverse events and sharing that documentation among scientists and clinicians. Systematically collecting all adverse events, poison center data, and emergency room visits associated with caffeine consumption (for example, energy drink consumption), together with more comprehensive evaluation of additional risk factors, is necessary to accurately determine the risks of toxicity for youth and other vulnerable individuals.

(6) Improving knowledge of the potential dangers from consuming energy drinks before, during, and after athletic activity will be essential to identify the potential dangers of direct and implied claims of enhanced athletic performance, which is common in energy drink marketing. Long-term systematic assessment of energy drink and general caffeine intake at the population level, specifically intake by youth, should be a priority.

When taken together, the literature reviewed here suggests that ingested caffeine is relatively safe at doses typically found in commercially available foods and beverages. There are some trends in caffeine consumption, such as alcohol-mixed energy drinks, that may increase risk of harm. There are also some populations, such as pregnant women, children, and individuals with mental illness, who may also be considered vulnerable for harmful effects of caffeine. Excess caffeine consumption is increasingly being recognized by health-care professionals and by regulatory agencies as potentially harmful. More research needs to be conducted to address these emerging concerns and provide empirical support for the recommendations.

Author Contributions

JT, CB, and SL contributed equally to the preparation of this comprehensive review. JC, JW, and MM helped gather additional references and prepare the manuscript after the initial major review of the literature was conducted.

Conflict of Interest Statement

The authors prepared this comprehensive review at the request of the American Association for the Advancement of Science. Once the draft was completed, we were given permission to publish the manuscript. SL has served as an expert for legal cases involving caffeine-containing energy drinks.

CB is funded by l’Agence Nationale de la Recherche (ANR, ANR-14-CE13-0032-02 ADONIS), JT is funded by the National Institutes of Health (DA021759, DA030386, and DK106265). SL is funded by the National Institutes of Health (HL111459, HL109090, HL078522, HL053392, HL079233, HL087000, HL095127, HD060325, NR012885, CA127642, CA068484, and HD052104).

• ^ https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm350570.htm .
• ^ https://www.drugbank.ca/drugs/DB00201#pharmacology .
• ^ It is difficult to calculate the caffeine intake relative to body weight during pregnancy because women begin pregnancy at a broad range of weights, gain weight at different rates, and gain different amounts of weight. Because of this, only absolute caffeine intake is shown in this section.
• ^ https://www.fda.gov/NewsEvents/PublicHealthFocus/ucm234900.htm .
• ^ http://www.efsa.europa.eu/en/efsajournal/pub/4102 .
• ^ http://www.hc-sc.gc.ca/dhp-mps/prodnatur/activit/groupe-expert-panel/index-eng.php .
• ^ http://www.hc-sc.gc.ca/fn-an/securit/addit/caf/ced-response-bec-eng.php .
• ^ http://www23.statcan.gc.ca/imdb/p2SV.pl?Function=getSurvey&SDDS=5071 .
• ^ http://www.samhsa.gov/data/sites/default/files/DAWN126/DAWN126/sr126-energy-drinks-use.pdf .

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Keywords: caffeine, energy drinks, pregnancy, children, adolescence

Citation: Temple JL, Bernard C, Lipshultz SE, Czachor JD, Westphal JA and Mestre MA (2017) The Safety of Ingested Caffeine: A Comprehensive Review. Front. Psychiatry 8:80. doi: 10.3389/fpsyt.2017.00080

Received: 30 January 2017; Accepted: 24 April 2017; Published: 26 May 2017

Reviewed by:

Copyright: © 2017 Temple, Bernard, Lipshultz, Czachor, Westphal and Mestre. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Jennifer L. Temple, jltemple@buffalo.edu

† These authors have contributed equally to this work.

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Brain scans of coffee drinkers suggest there's more to feeling alert than just the caffeine

Many coffee drinkers will tell you there's something about that morning cup that other sources of caffeine just can't match.

Researchers in Portugal recently set out to investigate that idea: Is caffeine solely responsible for making people feel more alert, or do other parts of the morning ritual — coffee's smell or taste, perhaps — trigger that energetic feeling?

"If you listen to these individuals, they typically say that they need to have coffee in the morning to get ready. We wanted to understand the brain mechanisms and functional connectivity pattern that would justify this claim," said Nuno Sousa, one of the study's authors and a professor at the University of Minho's School of Medicine in Portugal.

The researchers recruited 83 people who drank at least one cup of coffee a day to undergo MRI scans so they could observe the participants' brain activity.

Of that total, 47 people were scanned before drinking their morning cup of coffee, then again 30 minutes after they had a cup. The 36 others were simply given caffeine diluted in hot water — no coffee — and underwent the same types of MRI scans before and after they consumed the beverage.

The results, published last week in the journal Frontiers in Behavioral Neuroscience, suggest that, indeed, certain changes in brain activity were attributable only to coffee, while others were attributable to caffeine, as well.

The scans revealed that both groups — those who consumed caffeine and those who drank coffee — had decreased activity afterward in a part of the brain that puts people in a resting state. That indicated that people were more ready to start their days and engage with others after consuming either beverage. Decades of research has already shown that caffeine, a psychostimulant , can help people feel more aroused and alert.

However, the MRI scans showed that drinking coffee increased activity in parts of the brain involved in short-term memory, attention and focus, whereas ingesting caffeine on its own did not.

The researchers theorized that the sight, smell or taste of coffee may help people feel alert, regardless of the caffeine content.

"The pleasure that is given to an individual that likes coffee in the morning, that actually is part of almost a ritual that really is also important for that individual to feel that 'I'm ready for the day,'" Sousa said.

He added that people who don't regularly drink coffee may not experience the same effect.

Mark Mattson, an adjunct professor of neuroscience at Johns Hopkins University School of Medicine who wasn't involved in the research, said the findings weren't surprising, since people form associations with particular sensory experiences over time, which in turn can influence their future reactions.

"It kind of makes sense, right? Coffee has taste and smell, so when you drink coffee, you're activating brain regions that are involved in the perception of the taste of the coffee, the perception of the smell," Mattson said.

Dr. Uma Naidoo, a nutritional psychiatrist at Harvard Medical School, said the sight of coffee may trigger positive memories or make a person believe they're about to feel more awake.

"The visual impact of coffee is powerful," she said. "It could be like, 'Oh, I think there’s something that gives me energy now. I’m going to have something that gives me that second wind I need at work or to study.'"

That's different from a placebo effect, she added, since the coffee is still inducing a physical, and perhaps emotional, response.

All three researchers said it's also possible that the natural chemicals found in coffee may have independent effects on brain activity, apart from those of caffeine. A group of chemicals in coffee called epicatechins, for instance, has been shown to improve memory in animal studies .

Sousa said the goal of the study is not to influence anyone's coffee consumption habits.

"We are not saying that coffee is good or coffee is bad," he said.

Mattson also pointed out that the study comes with several limitations. For one, the MRI scans measured blood flow, but caffeine can restrict blood flow, so the scans may not give a clear picture of its impact on brain activity. Mattson also noted that the study didn't include people who drank decaf coffee, which might have helped distinguish the effects of coffee versus caffeine on the brain.

Naidoo, meanwhile, highlighted that most of the study participants were women, so there could be sex-based differences in how people's brains respond to coffee.

But one point on which the researchers agreed is that coffee is a healthier way to consume caffeine than energy drinks or soda.

"It has caffeine, but it also is very rich in antioxidants and some polyphenols," Naidoo said, referring to natural compounds that may lower blood pressure, destroy cancer cells and protect against diabetes by improving metabolism.

"There’s also another substance called trigonelline that gives coffee the aroma, the taste, that bitterness, but it also has antibacterial, antiviral properties," Naidoo said.

Aria Bendix is the breaking health reporter for NBC News Digital.

Caffeine Addiction: Symptoms, Effects, and Recovery Strategies

For millions of people, the day doesn’t truly begin until they’ve had their first sip of coffee, but what happens when this morning ritual becomes an unbreakable habit? That steaming cup of joe, once a simple pleasure, can transform into a demanding master, dictating our moods, energy levels, and even our daily routines. It’s a slippery slope from casual consumption to full-blown addiction, and before we know it, we’re caught in a cycle that’s harder to break than we ever imagined.

Let’s dive into the world of caffeine addiction, a topic that hits close to home for many of us. Whether you’re a coffee connoisseur, a tea enthusiast, or an energy drink aficionado, chances are you’ve felt the allure of caffeine’s energizing embrace. But when does this love affair cross the line into dependency?

Caffeine addiction is more than just enjoying your morning brew. It’s a physiological and psychological dependence on caffeine, characterized by a compulsive need to consume caffeinated beverages or products. This addiction is surprisingly common, with estimates suggesting that up to 90% of adults in North America consume caffeine regularly, and a significant portion of these individuals may have developed some level of dependence.

But coffee isn’t the only culprit in this caffeinated conundrum. Caffeine lurks in various sources, from the obvious suspects like tea and cola to more unexpected places like chocolate, certain medications, and even some types of ice cream. It’s this ubiquity that makes caffeine addiction so pervasive and, often, so insidious.

The Telltale Signs: Symptoms of Caffeine Addiction

How do you know if your caffeine habit has crossed the line into addiction? The symptoms can be both physical and psychological, often intertwining in a complex web of dependence.

Physically, caffeine addicts might experience headaches, fatigue, and irritability when they don’t get their fix. These withdrawal symptoms can kick in as soon as 12-24 hours after the last caffeine intake, making it difficult to go even a day without. Some people might also notice increased heart rate, jitters, or difficulty sleeping, especially if they consume caffeine late in the day.

Psychologically, the effects can be just as pronounced. Many caffeine addicts report feeling anxious, restless, or unable to concentrate without their regular dose. There’s often a strong craving for caffeine, similar to what you might see in addiction cravings for other substances. This psychological dependence can be just as challenging to overcome as the physical symptoms.

Behaviorally, caffeine addiction can manifest in several ways. You might find yourself spending excessive amounts of money on caffeinated beverages or going out of your way to ensure you always have access to caffeine. Some people even report feeling panic or distress at the thought of running out of coffee or their preferred caffeinated drink.

But how do you distinguish between caffeine addiction and regular consumption? It’s all about impact and control. If your caffeine use is interfering with your daily life, relationships, or health, and you find it difficult to cut back despite wanting to, you might be dealing with an addiction.

The Perfect Storm: Causes and Risk Factors

Caffeine addiction doesn’t happen overnight, and it’s not solely about willpower. Various factors contribute to the development of this dependency, creating a perfect storm of addiction potential.

Genetic predisposition plays a significant role. Some people are more sensitive to caffeine’s effects due to their genetic makeup, making them more susceptible to developing an addiction. If you find that caffeine affects you more strongly than your friends or family members, genetics might be at play.

Environmental factors also contribute significantly. In many cultures, caffeine consumption is deeply ingrained in social and professional settings. From business meetings over coffee to social gatherings at cafes, our environment often encourages and normalizes high caffeine intake.

Stress and lifestyle choices can push us towards caffeine dependency. In our fast-paced, high-pressure world, many turn to caffeine as a crutch to manage long work hours, lack of sleep, or demanding schedules. It’s a quick fix that can easily become a long-term problem.

Gradual tolerance buildup is another key factor. Over time, regular caffeine consumers may find they need more to achieve the same effects. This tolerance can lead to increased consumption, creating a cycle of dependency that’s hard to break.

The Coffee Conundrum: A Closer Look at Coffee Addiction

While caffeine addiction encompasses various sources, coffee addiction deserves a special mention. After all, for many, coffee isn’t just about the caffeine—it’s a ritual, a comfort, and sometimes even an identity.

Coffee addiction shares many similarities with general caffeine addiction, including the physical and psychological symptoms we’ve discussed. However, coffee addiction often comes with its unique aspects.

The ritual of brewing and drinking coffee can be as addictive as the caffeine itself. The aroma, the warmth of the cup in your hands, the social aspect of sharing a pot with colleagues—these elements create a powerful psychological attachment that goes beyond the chemical effects of caffeine.

Cultural and social factors play a significant role in coffee addiction. In many societies, coffee is more than just a beverage; it’s a social lubricant, a work aid, and sometimes even a status symbol. This cultural acceptance can make it harder for individuals to recognize when their coffee consumption has become problematic.

Moreover, coffee contains other compounds besides caffeine that can contribute to its addictive potential. For instance, the combination of caffeine and sugar in many coffee drinks can create a particularly potent and habit-forming mixture.

Light at the End of the Tunnel: Recovery from Caffeine Addiction

If you’ve recognized that your caffeine consumption has become problematic, there’s good news: recovery is possible. However, it’s important to understand that the journey isn’t always easy, and it takes time.

The timeline for caffeine addiction recovery can vary from person to person. Generally, the most intense withdrawal symptoms peak within the first 24-48 hours after quitting and can last for up to a week or more. However, some people may experience lingering effects for several weeks or even months.

Withdrawal symptoms can be challenging to manage. Common experiences include headaches, fatigue, irritability, difficulty concentrating, and in some cases, mild depression. It’s not uncommon to feel like you’re in a fog or that your brain isn’t working at full capacity during this time.

Strategies for managing withdrawal can make the process more bearable. Gradually reducing caffeine intake rather than quitting cold turkey can help minimize symptoms. Staying hydrated, getting plenty of rest, and engaging in light exercise can also help alleviate some of the discomfort.

The long-term effects of quitting caffeine can be surprisingly positive. Many people report improved sleep quality, reduced anxiety, more stable energy levels throughout the day, and even better cardiovascular health. Some individuals also find that they’re more in tune with their body’s natural rhythms and energy cycles.

Breaking Free: Overcoming Caffeine Addiction

Breaking the cycle of caffeine addiction requires a multi-faceted approach. It’s not just about willpower; it’s about creating sustainable lifestyle changes and finding healthier alternatives.

Gradual reduction techniques can be highly effective. Try cutting back by one cup of coffee (or your caffeinated beverage of choice) per week. This slow approach allows your body to adjust gradually, minimizing withdrawal symptoms.

Lifestyle changes and alternatives can make a big difference. Consider swapping some of your caffeinated drinks for herbal teas, water, or other non-caffeinated beverages. Some people find that green tea , with its lower caffeine content, can be a helpful stepping stone in reducing overall caffeine intake.

Exercise can be a powerful tool in overcoming caffeine addiction. Physical activity can boost energy levels naturally, helping to counteract the fatigue often experienced during caffeine withdrawal. Plus, the endorphin release from exercise can help manage mood swings and irritability.

For some individuals, seeking professional help may be necessary. This is particularly true if your caffeine addiction is intertwined with other mental health issues or if you’re struggling to manage withdrawal symptoms on your own. A healthcare provider or addiction specialist can offer personalized strategies and support.

Maintaining a caffeine-free or reduced-caffeine lifestyle is the final challenge. It’s important to be prepared for social situations where caffeine consumption is the norm. Having a plan, such as ordering a decaf option or bringing your own herbal tea, can help you stay on track.

Remember, overcoming caffeine addiction isn’t about deprivation—it’s about finding balance and regaining control over your consumption. Many people find that they can still enjoy caffeine in moderation once they’ve broken the cycle of addiction.

As we wrap up this deep dive into caffeine addiction, it’s worth reflecting on the journey we’ve taken. We’ve explored the symptoms of caffeine addiction, from the physical jitters to the psychological cravings. We’ve delved into the causes, recognizing that genetics, environment, and lifestyle all play a role in how susceptible we are to developing a dependency.

We’ve taken a closer look at coffee addiction, acknowledging the unique cultural and social factors that make this particular form of caffeine addiction so prevalent. And importantly, we’ve discussed the road to recovery, from managing withdrawal symptoms to implementing long-term lifestyle changes.

Understanding your personal relationship with caffeine is crucial. It’s not about demonizing that morning cup of joe or afternoon energy drink—it’s about recognizing when consumption has crossed the line into dependency and taking steps to regain control.

For those of you reading this who might be grappling with caffeine addiction, take heart. Breaking free from any addiction is challenging, but it’s also incredibly rewarding. The journey to overcoming caffeine addiction is one of self-discovery, improved health, and renewed energy—without the need for a constant caffeine fix.

Remember, addiction is a complex issue, and caffeine addiction is no exception. While it might not carry the same stigma as cocaine addiction or nicotine addiction , it can still significantly impact your quality of life. If you’re struggling, don’t hesitate to seek support, whether from friends, family, or professionals.

As you move forward, consider the potential for addiction replacement . It’s important to be mindful of not simply swapping one addiction for another. Instead, focus on developing healthy habits and coping mechanisms that support your overall wellbeing.

Breaking the addiction cycle is possible, whether it’s caffeine, nicotine, or any other substance. With patience, perseverance, and the right support, you can reclaim control over your consumption habits and discover a new, balanced relationship with caffeine.

So, the next time you reach for that cup of coffee or energy drink, pause for a moment. Ask yourself: Is this a choice, or a compulsion? Is it enhancing your life, or controlling it? The power to break free from caffeine addiction is in your hands—and it might just lead to a more energized, balanced you.

References:

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2. Temple, J. L., Bernard, C., Lipshultz, S. E., Czachor, J. D., Westphal, J. A., & Mestre, M. A. (2017). The Safety of Ingested Caffeine: A Comprehensive Review. Frontiers in Psychiatry, 8, 80. https://www.frontiersin.org/articles/10.3389/fpsyt.2017.00080/full

3. Sajadi-Ernazarova, K. R., & Hamilton, R. J. (2022). Caffeine, Withdrawal. In StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK430790/

4. Budney, A. J., & Emond, J. A. (2014). Caffeine addiction? Caffeine for youth? Time to act! Addiction, 109(11), 1771-1772. https://onlinelibrary.wiley.com/doi/full/10.1111/add.12594

5. Turnbull, D., Rodricks, J. V., Mariano, G. F., & Chowdhury, F. (2017). Caffeine and cardiovascular health. Regulatory Toxicology and Pharmacology, 89, 165-185. https://www.sciencedirect.com/science/article/pii/S0273230017301538

6. Nehlig, A. (2016). Effects of coffee/caffeine on brain health and disease: What should I tell my patients? Practical Neurology, 16(2), 89-95. https://pn.bmj.com/content/16/2/89

7. Lara, D. R. (2010). Caffeine, mental health, and psychiatric disorders. Journal of Alzheimer’s Disease, 20(s1), S239-S248. https://content.iospress.com/articles/journal-of-alzheimers-disease/jad01055

8. Reissig, C. J., Strain, E. C., & Griffiths, R. R. (2009). Caffeinated energy drinks—a growing problem. Drug and alcohol dependence, 99(1-3), 1-10. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2735818/

9. Juliano, L. M., & Griffiths, R. R. (2004). A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology, 176(1), 1-29. https://link.springer.com/article/10.1007/s00213-004-2000-x

10. Brice, C. F., & Smith, A. P. (2002). Effects of caffeine on mood and performance: a study of realistic consumption. Psychopharmacology, 164(2), 188-192. https://link.springer.com/article/10.1007/s00213-002-1175-2

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New beanless 'coffee' emerges but does it taste any good?

I am in a high-end coffee shop in a tech-heavy area of San Francisco, staring suspiciously into a cup of espresso. This is no conventional coffee: it is made without using a single coffee bean.

It comes from Atomo, one of a band of alt-coffee start-ups hoping to revolutionise the world of brewed coffee.

“We take great offence when someone says that we're a coffee substitute,” says Andy Kleitsch, the chief executive of Seattle based start-up Atomo, from whose pure, beanless ground product my espresso has been made.

Traditional coffee substitutes have a reputation for not tasting much like coffee and are usually caffeine-free.

However, the newcomers intend to replicate one of the world’s most popular beverages from taste, to caffeine punch, to drinking experience – and the first of this nascent industry’s beanless concoctions have begun to appear.

They say there's a strong environmental argument for their beanless brews.

According to the World Wide Fund for Nature , coffee cultivation is currently the sixth largest cause of deforestation.

That impact is expected to widen as demand increases: consumption is fast rising in traditional tea drinking countries like India and China.

Meanwhile, climate change is pushing plantations to higher altitudes to escape the heat.

So, beanless coffee is potentially a less environmentally damaging alternative.

The newcomers also argue that, if scaled up, beanless coffee could be cheaper than its conventional competition.

And, with coffee prices reaching record levels on the international markets this year, that point is timely.

Also, in December, a new EU regulation is set to come into effect that outlaws the sale of products, coffee included, that can’t prove they are not linked to deforestation.

“A lot of big coffee companies are watching this field,” says Chahan Yeretzian, a professor of analytical chemistry, who heads the Coffee Excellence Centre at the Zurich University of Applied Sciences in Switzerland.

Niels Haak, director of sustainable coffee partnerships at Conservation International, an environmental non-profit, welcomes the innovative approaches to tackling coffee’s deforestation problem, but he also doubts if beanless coffee will be able to make much dent.

Coffee growing provides livelihoods and income to many smallholder farming families globally, he further notes. The conundrum is if they move away from growing coffee, they will likely instead turn to growing more coca – the plant cocaine derives from – which has similar deforestation issues. “There are no silver bullets,” he says.

He notes there is work ongoing – from coffee certification schemes, to efforts aimed at strengthening so-called shade coffee farming where coffee is grown under a canopy of other trees – to make coffee growing more sustainable and support communities. “[The coffee sector] is on a journey to transform,” he says.

Yet the beanless companies counter that transformation isn’t wide enough or quick enough. Coffee is causing massive deforestation and coffee farmers live in poverty.

If alt-coffee could offset even just the extra projected coffee demand it would be a win for the planet that wouldn’t put anyone out of business.

And, as the climate changes, there are plenty of crops beyond illicit ones that coffee farmers could switch to that don’t require slashing more forest.

Atomo, which launched in 2019, is currently sold in more than 70 coffee shops in the US.

Coffee shop chain Bluestone Lane added it to the menu at all its locations in early August, including in San Francisco.

Since June, Atomo has also been selling through its website a blend of beanless and conventional coffee intended for home brewing that I have also purchased to try.

It currently costs slightly more than premium conventional coffee. For example, to make my espresso with Atomo adds on 50 cents (38p).

Atomo’s ingredients aren’t particularly high tech: date seeds, ramón seeds, sunflower seed extract, fructose, pea protein, millet, lemon, guava, fenugreek seeds, caffeine and baking soda.

Things begin with waste date seeds or pits. Rock hard, they are granulated then infused with a secret marinade of ingredients from the list above, before being roasted to create new flavours, aromas and compounds.

Further ingredients then finish things off. Atomo’s caffeine is sourced from green tea decaffeination, though synthetically-made caffeine is also used to provide beanless coffee’s kick.

Atomo operates a facility in southern California, where the date pits are cleaned and washed, and a second facility in Seattle where the manufacturing takes place. Current capacity is four million pounds a year, which Mr Kleitsch describes as a “rounding error” in the world of coffee production: Starbucks buys about 800 million.

As for trying Atomo, both the coffee shop espresso and the brew-at-home version tasted close enough to good coffee for me. Perhaps luckily for these companies, coffee can have many different undertones.

Others have different ingredients and methods.

Over the past year the bean-free coffee products of Dutch start-up Northern Wonder, founded in 2021, has secured space on supermarket shelves in the Netherlands and Switzerland.

Roasted and ground lupin, chickpea, malted barley, and chicory are amongst the major ingredients the company works with, along with an undisclosed natural flavouring.

Though notes David Klingen, the company’s boss, operations are still in the research and development phase. Ingredients may change as it perfects its brew.

Other companies on the scene include Singapore-based Prefer and San Francisco's Minus.

And, though it is further from market, also being pursued is the tantalising possibility of lab-grown or cultured coffee.

In the same way animal cells can be cultivated in a bioreactor and harvested to produce meat cell products – so cells extracted from coffee plants could be similarly grown, then fermented and roasted to produce a brew. Proof of concept was demonstrated in 2021 by Finnish government researchers, who are now trying to help accelerate commercialisation .

Cell-based coffee start-ups include Swiss-based Foodbrewer, US-based California Cultured, and Singapore-based Another.

The approach may provide a closer match to coffee than surrogates like Atomo or Northern Wonder, but regulatory approval for such novel food takes time and money. There are also doubts the technology will be able to scale economically.

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Have swiss scientists made a chocolate breakthrough, crash dummies and robot arms: how airline seats are tested.

Meanwhile, challenges for the beanless firms remain. The house-filling aroma that real coffee generates is still elusive for them. And bean-free coffee doesn’t provide emotional connections to faraway places – Colombia, Ethiopia, Indonesia – the way real coffee can.

Atomo’s main business hurdle now is finding large coffee partners who want to offer their consumers a new choice, while Northern Wonder’s is finding the right investors.

“People aren’t completely sure how big the category will be and when,” says Mr Klingen.

I don’t think I’ll be switching – I can’t help but like that real coffee is grown by people somewhere – but beanless coffee certainly left me thinking I should investigate the sustainability and ethics of my conventional brew.

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The Impact of Caffeine and Coffee on Human Health

Coffee is one of the most widely consumed beverages in the world and is also a major source of caffeine for most populations [ 1 ]. This special issue of Nutrients , “The Impact of Caffeine and Coffee on Human Health” contains nine reviews and 10 original publications of timely human research investigating coffee and caffeine habits and the impact of coffee and caffeine intake on various diseases, conditions, and performance traits.

With increasing interest in the role of coffee in health, general knowledge of population consumption patterns and within the context of the full diet is important for both research and public health. Reyes and Cornelis [ 1 ] used 2017 country-level volume sales (proxy for consumption) of caffeine-containing beverages (CCBs) to demonstrate that coffee and tea remain the leading CCBs consumed around the world. In a large coordinated effort spanning 10 European countries, Landais et al. [ 2 ] quantified self-reported coffee and tea intakes and assessed their contribution to the intakes of selected nutrients in adults where variation in consumption was mostly driven by geographical region. Overall, coffee and tea contributed to less than 10% of the energy intake. However, the greatest contribution to total sugar intake was observed in Southern Europe (up to ~20%). These works not only emphasize the wide prevalence of coffee and tea drinking, but also the need for data on coffee and tea additives in epidemiological studies of these beverages in certain countries as they may offset any potential benefits these beverages have on health.

Doepker et al. [ 3 ] provided a user-friendly synopsis of their systematic review [ 4 ] of caffeine safety, which concluded that caffeine doses (400 mg/day for healthy adults, for example) previously determined in 2003 [ 5 ] as not to be associated with adverse effects, remained generally appropriate despite new research conducted since then. Further concerning caffeine safety is the systematic review of caffeine-related deaths by Capelletti et al. [ 6 ]. Suicide, accidental, and intentional poisoning were the most common causes of death and most cases involved infants, psychiatric patients, and athletes. Both Doepker et al. [ 3 ] and Capelletti et al. [ 6 ] alluded to the increasing interest in the area of between-person sensitivity resulting from environmental and genetic factors, of which the latter is a topic of additional papers in this special issue and thus reiterates this interest.

Advancements in high-throughput analyses of the human genome, transcriptome, proteome, and metabolome have presented coffee researchers with an unprecedented opportunity to optimize their research approach while acquiring mechanistic and causal insight to their observed associations [ 7 ]. Three timely reviews [ 8 , 9 , 10 ] and an original report [ 11 ] addressed the topic of human genetics and coffee and caffeine consumption. Interest in this area received a boost by the success of genome-wide association studies (GWAS), which identified multiple genetic variants associated with habitual coffee and caffeine consumption as discussed by Cornelis and Munafo [ 8 ] in their review of Mendelian randomization (MR) studies on coffee and caffeine consumption. MR is a technique that uses genetic variants as instrumental variables to assess whether an observational association between a risk factor (i.e., coffee) and an outcome aligns with a causal effect. The application of this approach to coffee and health is growing, but has important statistical and conceptual challenges that warrant consideration in the interpretation of the results. Southward et al. [ 9 ] and Fulton et al. [ 10 ] reviewed the impact of genetics on physiological responses to caffeine. Both emphasized a current clinical interest limited to CYP1A2 and ADORA2A variations, suggesting opportunities to expand this research to more recent loci identified by GWAS. Despite the advancements in integrating genetics into clinical trials of caffeine, such designs remain susceptible to limitations [ 9 , 10 , 12 , 13 ]. Some of these limitations were further highlighted by Shabir et al. [ 14 ] in their critical review on the impact of caffeine expectancies on sport, exercise, and cognitive performance. Interestingly, the original findings from a randomized controlled trial of regular coffee, decaffeinated coffee, and placebo suggested the stimulant activity of coffee beyond its caffeine content, raising issues with the use of decaffeinated coffee as a placebo [ 15 ].

The impact of coffee intake on gene expression and the lipidome were investigated by Barnung et al. [ 16 ] and Kuang et al. [ 17 ], respectively. Barnung et al. [ 16 ] reported on the results from a population-based whole-blood gene expression analysis of coffee consumption that pointed to metabolic, immune, and inflammation pathways. Using samples from a controlled trial of coffee intake, Kuang et al. [ 17 ] reported that coffee intake led to lower levels of specific lysophosphatidylcholines. These two reports provide both novel and confirmatory insight into mechanisms by which coffee might be impacting health and further demonstrate the power of high-throughput omic technologies in the nutrition field.

Heavy coffee and caffeine intake continue to be seen as potentially harmful on pregnancy outcomes [ 18 ]. Leviton [ 19 ] discussed the biases inherent in studies of coffee consumption during pregnancy and argued that all of the reports of detrimental effects of coffee could be explained by one or more of these biases. The impact of dietary caffeine intake on assisted reproduction technique (ART) outcomes has also garnered interest. An original report by Ricci et al. [ 20 ] in this special issue found no relationship between the caffeine intake of subfertile couples and negative ART outcomes.

Van Dijk et al. [ 21 ] reviewed the effects of caffeine on myocardial blood flow, which support a significant and clinically relevant influence of recent caffeine intake on cardiac perfusion measurements during adenosine and dipyridamole induced hyperemia. Original observational reports on the association between habitual coffee consumption and liver fibrosis [ 22 ], depression [ 23 ], hearing [ 24 ], and cognition indices [ 25 ] have extended the research in these areas to new populations.

Finally, given the widespread availability of caffeine in the diet and the increasing public and scientific interest in the potential health consequences of habitual caffeine intake, Reyes and Cornelis [ 1 ] assessed how current caffeine knowledge and concern has been translated into food-based dietary guidelines (FBDG) from around the world; focusing on CCBs. Several themes emerged, but in general, FBDG provided an unfavorable view of CCBs, which was rarely balanced with recent data supporting the potential benefits of specific beverage types.

This collection of original and review papers provides a useful summary of the progress on the topic of caffeine, coffee, and human health. It also points to the research needs and limitations of the study design, which should be considered going forward and when critically evaluating the research findings.

Conflicts of Interest

The author declares no conflict of interest.