Journal of Caffeine Research

Background: Caffeine is the most widely consumed psychoactive substance in the world, even during pregnancy. Its stimulatory effects are mainly due to antagonism of adenosine actions by blocking adenosine A1 and A2A receptors. Previous studies have shown that caffeine can cross the placenta and therefore modulate these receptors not only in the fetal brain but also in the heart. Methods: In the present work, the effect of caffeine chronically consumed during pregnancy on A1 and A2A receptors in Wistar rat heart, from both mothers and their fetuses, were studied using radioligand binding, Western-blotting, and adenylyl cyclase activity assays, as well as reverse transcription polymerase chain reaction. Results: Caffeine did not significantly alter A1R neither at protein nor at gene expression level in both the maternal and fetal heart. On the contrary, A2AR significantly decreased in the maternal heart, although mRNA was not affected. Gi and Gs proteins were also preserved. Finally, A1R-mediated inhibition of adenylyl cyclase activity did not change in the maternal heart, but A2AR mediated stimulation of this enzymatic activity significantly decreased according to the detected loss of this receptor. Conclusions: Opposite to the downregulation and desensitization of the A1R/AC pathway previously reported in the brain, these results show that this pathway is not affected in rat heart after caffeine exposure during pregnancy. In addition, A2AR is downregulated and desensitized in the maternal heart, suggesting a differential modulation of these receptor-mediated pathways by caffeine.

Caffeine is a known vasoconstrictor that reduces resting cerebral blood flow (CBF) throughout the brain. This effect may be problematic in functional magnetic resonance imaging (fMRI) research, as the blood oxygen level-dependent (BOLD) signal is a complex interaction of CBF and other factors that are dependent on changes in neural activity. It is unknown whether changes in the BOLD signal during an fMRI experiment could be affected by subjects' recent use or abstinence from dietary caffeine. Here, we report two similar studies (n=45 and 17) that measure the effects of caffeine on BOLD activation, BOLD time course parameters, and CBF. Using a factorial design, low, moderate, and high caffeine consumers received either caffeine (250 mg) or placebo during normal caffeine use (satiated state) or after 30 hours of abstention (abstinent state). The fMRI of a reaction time task and resting-state CBF were collected. In general, acute caffeine administration reduced the time to peak and full width at half maximum of the BOLD time course, and CBF across both studies. Caffeine also produced a small reduction in BOLD activation. The majority of these reductions across measures were moderated by neither the level of caffeine use, nor the abstinent or satiated state. These results suggest that dietary caffeine use does not produce a significant effect on task-related BOLD activation.

BACKGROUND: A growing body of evidence suggests that caffeinated beverages may impair chronic glucose control in type 2 diabetes. This pilot study tested the chronic effects of caffeine abstinence on glucose control in type 2 diabetic patients who were daily coffee drinkers. METHODS: Twelve coffee drinkers (six males) with established type 2 diabetes participated. Seven (five males) completed 3 months of total caffeine abstinence. Measures of chronic glucose control, long-term (hemoglobin A1c [HbA1c]) and short-term (1,5-anhydroglucitol [1,5-AG]), were collected at baseline and during follow-up. Abstinence was established by diaries confirmed by saliva caffeine assays. RESULTS: Abstinence produced significant decreases in HbA1c and increases in 1,5-AG, both indicating improvements in chronic glucose control. Fasting glucose and insulin did not change, nor were changes in body weight observed. CONCLUSIONS: Although preliminary, these results suggest that caffeine abstinence may be beneficial for patients with type 2 diabetes. This hypothesis should be confirmed in larger controlled clinical trials.

The impact of caffeine on the behavioral effects of ethanol, including ethanol consumption and abuse, has become a topic of great interest due to the rise in popularity of the so-called energy drinks. Energy drinks high in caffeine are frequently taken in combination with ethanol under the popular belief that caffeine can offset some of the intoxicating effects of ethanol. However, scientific research has not universally supported the idea that caffeine can reduce the effects of ethanol in humans or in rodents, and the mechanisms mediating the caffeine-ethanol interactions are not well understood. Caffeine and ethanol have a common biological substrate; both act on neurochemical processes related to the neuromodulator adenosine. Caffeine acts as a nonselective adenosine A1 and A2A receptor antagonist, while ethanol has been demonstrated to increase the basal adenosinergic tone via multiple mechanisms. Since adenosine transmission modulates multiple behavioral processes, the interaction of both drugs can regulate a wide range of effects related to alcohol consumption and the development of ethanol addiction. In the present review, we discuss the relatively small number of animal studies that have assessed the interactions between caffeine and ethanol, as well as the interactions between ethanol and subtype-selective adenosine receptor antagonists, to understand the basic findings and determine the possible mechanisms of action underlying the caffeine-ethanol interactions.

The use of acupuncture in the treatment of pain conditions has been extensively investigated. However, the influence of dietary ingredients on acupuncture-induced analgesia (AA) remains unexplored. Recently, the role of adenosine receptors in AA has been shown, and caffeine, one of the world's most commonly consumed dietary ingredients, is an antagonist of these receptors. In this study, the postincisional pain model was used to investigate caffeine's influence on AA. Mice submitted to plantar incision surgery were treated with acupuncture needling after administration of acute or chronic caffeine. Acupuncture needling was performed using two different types of stimuli, manual acupuncture and electroacupuncture bilaterally in the acupoint SP6. We found that acute preadministration of caffeine (10 mg/kg, i.p.) completely reversed AA in both types of acupuncture. In the chronic preadministration, we used two doses that mimicked the average daily caffeine consumption in Western countries and China. Interestingly, the Western dose of caffeine (70 mg/kg/day) administered during 8 days in the drinking water reversed AA and the Chinese dose (4 mg/kg/day) administered during the same period did not. These results indicate that the use of caffeine can inhibit the analgesic effect of different forms of acupuncture. In addition, our findings suggest that doses of caffeine relevant to dietary human intake levels could be a confounding factor in the context of acupuncture research.

Caffeine withdrawal was included in the research appendix of the DSM-IV to encourage additional research to assist with determining its status for the next version of the manual. Caffeine dependence was not included because of a lack of empirical research at the time of publication. This study assessed the beliefs of addiction professionals about the clinical importance of caffeine withdrawal and dependence. A 6-item survey was developed and delivered electronically to the members of six professional organizations that focus on addiction. Open-ended comments were also solicited. Five hundred members responded. The majority (95%) thought that cessation of caffeine could produce a withdrawal syndrome, and that caffeine withdrawal can have clinical importance (73%); however, only half (48%) thought that caffeine withdrawal should be included in the Diagnostic and Statistical Manual of Mental Disorders (DSM). A majority (58%) believed that some people develop caffeine dependence; however, only 44% indicated that it should be in the DSM. Comments suggested that trepidation about inclusion of caffeine diagnoses was due to the concerns about the field of psychiatry being criticized for including common disorders with a relatively low clinical severity. Others, however, expressed an urgent need to take caffeine-related problems more seriously. The majority of addiction professionals believe that caffeine withdrawal and dependence disorders exist and are clinically important; however, these professionals are divided in whether caffeine withdrawal and dependence should be included in DSM. Wider dissemination of the extant literature on caffeine withdrawal and additional research on caffeine dependence will be needed to provide additional guidance to policymakers and healthcare workers.

Background: Inflammation is considered to be a major initiator to angioplasty-induced vascular restenosis. Proinflammatory cytokines stimulate vascular smooth muscle cell (VSMC) migration and proliferation leading to neointimal hyperplasia. It has been reported that chronic caffeine use suppresses the production of proinflammatory cytokine TNF-α (tumor necrosis factor Alpha) and alters adenosine receptor expression in human neutrophils, indicating that caffeine may attenuate vascular injury-induced inflammation and subsequent neointimal hyperplasia. Our current study was designed to test the hypothesis that chronic caffeine treatment decreases vascular injury-induced neointimal hyperplasia by suppressing VSMC migration and proliferation. Methods and Results: The experiments were carried out using both in vivo (rat carotid artery injury model) and in vitro (VSMCs isolated from rat aorta) models. Male Sprague-Dawley rats that received chronic caffeine treatment (10 and 20 mg/kg per day, through oral gavage) showed a significant decrease in neointimal hyperplasia when compared to rats that received vehicle. To understand the underlying mechanisms, we tested if caffeine inhibits fetal bovine serum (FBS)-induced VSMC migration and proliferation. We found that caffeine substantially suppressed FBS-induced VSMC migration and proliferation. The attenuation of FBS-stimulated cell migration is dose dependent. Conclusion: Together, our results suggest that chronic treatment with high concentrations of caffeine attenuates vascular injury-induced neointimal hyperplasia by suppressing smooth muscle cell migration and proliferation in rats.

Background: Recent research has linked caffeine consumption with a lower risk for depression and cognitive decline. However, no studies have examined the relationship in an African American compared to a white, socioeconomically diverse representative urban sample. Methods: Data from a cross-sectional study were used to determine the associations of caffeine use with depressive symptomatology and cognition in a sample of 1,724 participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study. The United States Department of Agriculture's Automated Multiple Pass Method was used by trained interviewers to collect two, in-person 24-hour dietary recalls. Depressive symptoms and global cognition were assessed using two well-validated measures: the Center for Epidemiologic Studies Depressive Scale (CES-D) and Mini Mental State Examination (MMSE), respectively. Usual caffeine intake was based on both recalls. Data were analyzed with t- and chi-square tests, correlation analysis, and ordinal logistic regression. Results: African Americans consumed significantly less caffeine than did whites (89.0±3.2 and 244.0±8.7 mg respectively). Caffeine consumption was not associated with depressive symptomatology or global cognition. Age, less than 5th grade literacy, and less than high school education were significantly associated with both depressive symptoms and cognitive function. Smokers had a 43% greater risk for depression but only a 3% higher risk for cognitive impairment. Conclusion: The low level of dietary caffeine intake in combination with smoking among HANDLS study participants may have influenced the lack of association with depressive symptomatology or global cognition. For this sample, low literacy and education appear more highly associated with depressive symptoms and cognitive function than caffeine intake.

In chronic heart failure (CHF) due to left ventricular dysfunction, diminished heart rate variability (HRV) is an independent predictor of poor prognosis. Caffeine has been shown to increase HRV in young healthy subjects. Such an increase may be of potential benefit to patients with CHF. We hypothesized that intravenous infusion of caffeine would increase HRV in CHF, and in age-matched healthy control subjects. On two separate days, 11 patients (1F) with CHF (age=51.3±4.6 years; left ventricular ejection fraction=18.6±2.7%; mean±standard error) and 10 healthy control subjects (age=48.0±4.0) according to a double-blind randomization design, received either saline or caffeine (4 mg/kg) infusion. We assessed HRV over 7 minutes of supine rest (fast Fourier Transform analysis) to determine total spectral power as well as its high-frequency (HF) (0.15-0.50 Hz) and low-frequency (LF) (0.05-0.15 Hz) components, and recorded muscle sympathetic nerve activity (MSNA) directly from the peroneal nerve (microneurography). In healthy control subjects, compared with saline, caffeine reduced both heart rate and sympathetic nerve traffic (p≤0.003) and increased the ratio of HF/total power (p≤0.05). Baseline LF power and the ratio LF/HF were significantly lower in CHF compared with controls (p=0.02), but caffeine had no effect on any element of HRV. Caffeine increases cardiac vagal heart rate modulation and reduces MSNA in middle-aged healthy subjects, but not in those with CHF.

Caffeine is the most commonly used drug in the world. Although consumption of low to moderate doses of caffeine is generally safe, an increasing number of clinical studies are showing that some caffeine users become dependent on the drug and are unable to reduce consumption despite knowledge of recurrent health problems associated with continued use. Thus, the World Health Organization and some health care professionals recognize caffeine dependence as a clinical disorder. In this comprehensive literature review, we summarize published research on the biological evidence for caffeine dependence; we provide a systematic review of the prevalence of caffeine dependence and rates of endorsement of clinically meaningful indicators of distress and functional impairment among habitual caffeine users; we discuss the diagnostic criteria for Caffeine Use Disorder-a condition for further study included in the Diagnostic and Statistical Manual of Mental Disorders (5(th) ed.); and we outline a research agenda to help guide future clinical, epidemiological, and genetic investigations of caffeine dependence. Numerous controlled laboratory investigations reviewed in this article show that caffeine produces behavioral and physiological effects similar to other drugs of dependence. Moreover, several recent clinical studies indicate that caffeine dependence is a clinically meaningful disorder that affects a nontrivial proportion of caffeine users. Nevertheless, more research is needed to determine the reliability, validity, and prevalence of this clinically important health problem.

College students who consume caffeinated alcoholic beverages (CaffAlc) are at increased injury risk. This study examines the extent to which a sensation-seeking personality accounts for the relationship between consumption of CaffAlc and negative outcomes. A Web-based survey was administered to stratified random samples of 4907 college students from eight North Carolina universities in Fall 2009. Sensation seeking was assessed using the Brief Sensation-Seeking Scale (BSSS) (α=0.81). Data were analyzed using linear and logistic regression. 3390 students (71.2%) reported past 30-day drinking, of whom 786 (23.2%) consumed CaffAlc. CaffAlc past 30-day drinkers had higher BSSS scores (3.8 vs. 3.4; p<0.001), compared to non-CaffAlc drinkers. Consumption of CaffAlc was associated with more frequent binge drinking (p<0.001) and drunken days in a typical week (p<0.001), even after adjusting for the BSSS score. CaffAlc students were more likely to be taken advantage of sexually (adjusted odds ratio [AOR]=1.70, p=0.012), drive under the influence of alcohol (AOR=2.00, p<0.001), and ride with a driver under the influence of alcohol (AOR=1.87, p<0.001). Injury requiring medical treatment was more prevalent among CaffAlc students with higher BSSS-8 scores (interaction p=0.024), even after adjustment for drinking levels and student characteristics. Sensation seeking does not fully account for the increase in risky drinking among college students who consume CaffAlc, nor does it moderate the relationship between CaffAlc and drinking behaviors. Sensation seeking moderates the risk of alcohol-associated injury requiring medical treatment among college students who consume CaffAlc. Those with strong sensation-seeking dispositions are at the highest risk of alcohol-associated injury requiring medical treatment.

The objective was to evaluate the effects of a single dose of alcohol, caffeine, and nicotine, alone or in combination, on physiological parameters (systolic and diastolic blood pressure [SBP and DBP] and heart rate [HR]) and state-trait anxiety in healthy young volunteers. The procedure reproduces the conditions under which the subjects (n=76) usually ingest alcohol (through an alcoholic beverage), caffeine (through a cup of coffee), and nicotine (by smoking a cigarette), separately or in combination, according to their consumption habits of each individual. SBP and DBP, HR, and state anxiety (SA) were registered before (phase 1) and after (phase 2) treatment. Intake of alcohol or alcohol-nicotine reduced DBP. Comparisons between control and combined treatment (coffee-alcohol-nicotine) groups revealed a decrease in HR in the former group but not in the latter. The coffee consumers alone exhibited a tendency toward an increase in SA, while the control group showed a tendency toward a decrease in this measure. When Phase 1 and Phase 2 were compared, a decrease was observed in SBP (alcohol and coffee-alcohol groups), DBP (alcohol and alcohol-nicotine groups), HR (all groups, except coffee-alcohol and coffee-alcohol-nicotine groups), and SA (coffee-alcohol-nicotine group). (i) A low dose of alcohol, either alone or in combination with a cigarette, decreases DBP but not SBP; (ii) the polyconsumption of coffee, alcohol, and nicotine blocks the adaptation response (the reduction in HR in control subjects in the second phase); (iii) an increase of SA is observed after consuming coffee, while the opposite occurs in control subjects (a decrease of SA).

This study examined the confluence of several behaviors common to U.S. young adults: caffeinated energy drink use, alcohol use, and sexual risk-taking. The author examined relationships between the use of energy drinks mixed with alcohol (AmEDs) and three sexual risk behaviors: casual sex (i.e., intercourse with a nonexclusive and/or nonromantic partner), intoxicated sex (i.e., intercourse while under the influence of alcohol and/or illicit drugs), and unprotected sex (i.e., intercourse without use of a condom). Logistic regression analyses were employed to analyze data from a cross-sectional survey of 648 sexually active undergraduate students at a large public university. After controlling for risk-taking norms and frequency of noncaffeinated alcohol use, AmED use was associated with elevated odds of casual sex and intoxicated sex but not unprotected sex. Although further studies are needed to test for event-level relationships, AmED use should be considered a possible risk factor for potentially health-compromising sexual behaviors.

Although it is widely believed that caffeine antagonizes the intoxicating effects of alcohol, the molecular mechanisms underlying their interaction are incompletely understood. It is known that both caffeine and alcohol alter adenosine neurotransmission, but the relationship is complex, and may be dose dependent. In this article, we review the available literature on combining caffeine and alcohol. Ethical constraints prohibit laboratory studies that would mimic the high levels of alcohol intoxication achieved by many young people in real-world settings, with or without the addition of caffeine. We propose a possible neurochemical mechanism for the increase in alcohol consumption and alcohol-related consequences that have been observed in persons who simultaneously consume caffeine. Caffeine is a nonselective adenosine receptor antagonist. During acute alcohol intake, caffeine antagonizes the "unwanted" effects of alcohol by blocking the adenosine A1 receptors that mediate alcohol's somnogenic and ataxic effects. The A1 receptor-mediated "unwanted" anxiogenic effects of caffeine may be ameliorated by alcohol-induced increase in the extracellular concentration of adenosine. Moreover, by means of interactions between adenosine A2A and dopamine D2 receptors, caffeine-mediated blockade of adenosine A2A receptors can potentiate the effects of alcohol-induced dopamine release. Chronic alcohol intake decreases adenosine tone. Caffeine may provide a "treatment" for the withdrawal effects of alcohol by blocking the effects of upregulated A1 receptors. Finally, blockade of A2A receptors by caffeine may contribute to the reinforcing effects of alcohol.

Dr. O'Brien: Thank you all for participating in the inaugural roundtable discussion for Journal of Caffeine Research. Let us begin with the popular perception of caffeine as an “antidote” to alcohol intoxication. The neurochemical relationship between alcohol and caffeine appears to be complex. Alcohol influences the interaction of several neurotransmitters, and this has important implications in terms of the mixture of caffeine and alcohol, particularly with respect to activities that require sustained attention and executive function. I am interested in your comments, Jonathan. Your research speaks to the safe execution of activities that require sustained attention.

Caffeine reduces the amount of analgesic medications necessary to provide postoperative pain (POP) relief and augments treatments for headaches and dental pain. Despite considerable evidence of its beneficial effects, little is understood about the role of dietary caffeine consumption on baseline pain sensitivity or POP following oral surgery. Baseline experimental pain testing (quantitative sensory testing [QST]) using four stimulus modalities was conducted on 30 healthy adults (53% females) before surgical extraction of four third molars. Self-reported caffeine ingestion was reported before QST, and on the day of surgery, preoperative and postoperative caffeine plasma concentrations (CPC) were measured by mass spectrometry. POP ratings were obtained at timed intervals. In QST, compared to subjects who self-reported no caffeine intake, those who self-reported caffeine ingestion demonstrated a higher pain sensitivity, particularly, on ramp and hold sustained heat at 44°C and 46°C, as well as a lower heat pain threshold and tolerance (p=0.05). Differences approached significance (p=0.06) in POP between subjects with CPC above 300 ng/mL and those with CPC below 300 ng/mL. Specifically, those with >300 ng/mL CPC had a slightly lower POP (mean 2.43, range 0-5) compared to those with <300 ng/mL CPC whose POP ratings were slightly higher (mean 2.89) with a greater variability (range 0-9.5). Self-reported, dietary caffeine intake was associated with higher QST ratings with lower threshold and tolerance particularly on heat pain modalities. External factors (i.e., analgesic dosage) may have played a role in the analgesic effects of caffeine on POP in oral surgery, especially in individuals with CPC exceeding 300 ng/mL who reported lower pain.

It has previously been shown that during gestation, the mother's brain has an increase in glial fibrillary acidic protein (GFAP)-immunoreactivity (-ir) and a decrease in the mRNA level of A1 adenosine receptor. Little is known about the A2A adenosine receptor in the maternal brain, and whether caffeine consumption throughout gestational period modifies GFAP and adenosine receptor density in specific brain areas. This study was undertaken to investigate the protein density of GFAP and adenosine receptors (A1 and A2A subtypes) in different regions of pregnant rat brain and the possible effect of caffeine on these proteins. For this purpose, we examined the GFAP-, A1- and A2A-ir in the cingulate cortex (Cg2), dentate gyrus (DG), medial preoptic area (mPOA), secondary somatosensory cortex (S2), and striatum (Str) of pregnant Wistar rats (drug-free tap water or water with 1g/L diluted caffeine). We show a consistent and highly significant reduction of GFAP-ir in caffeine-treated pregnant rats in most of the areas analyzed. Our data demonstrate that caffeine consumption induces a significant increase of A2A-ir in Str. Concerning A1 receptor, the observed changes are dependent on the region analyzed; this receptor density is increased in Cg2, DG, and mPOA and decreased in the somatosensory cortex and Str. The results were confirmed by Western blotting. Our results suggest that chronic caffeine exposure could modify the physiolological situation of gestation by a reorganization of the neural circuits and the adenosine neuromodulator system.

There has been some speculation that caffeine consumption may affect breast cancer. Most case-control studies have not documented evidence of a caffeine-breast cancer incidence link; however, there has been very little analysis of the possible effects of caffeine consumption on breast cancer survival. We examined overall a 20-year survival of 96 women treated for breast cancer between 1990 and 1994. As part of their health history, these women were asked about coffee drinking. Fifty-three women drank one cup a day (79.2% survival), 22 women had two cups a day (72.7% survival), and 21 women drank three or more cups a day (42.9% survival). The effect of coffee consumption on survival was significant (p=0.006, the log rank test). To exclude the effects of lymph node involvement, age at diagnosis, and smoking history, Cox regression was performed. The effect of coffee was significant (p=0.001), independent of the effects of lymph node involvement (p=0.012) and age at diagnosis (p=0.014), and unrelated to a smoking history (p=0.721). Fatigued breast cancer survivors have an abnormal proinflammatory cytokine activity, an average of 5 years after diagnosis, as well as significant serum cortisol derangements compared to other survivors. One possible interpretation of our results suggests that there is an abnormal hypothalamic-pituitary-adrenal axis functioning in breast cancer patients with persistent fatigue, who might be using coffee to self-medicate. In other words, coffee consumption in the present study might be a surrogate marker for fatigue. Because of the paucity of data regarding caffeine intake, poor sleep, fatigue, and breast cancer survival, further studies could be worthwhile.

Soft drinks containing caffeine have been associated with more aggressive forms of dental decay. Cariogenicity of caffeinated soft drinks may be attributed to the effect of caffeine on salivary flow. This study assessed whether caffeinated soft drinks produced short-term oral dryness in healthy adults. The authors collected saliva on two separate days from 35 participants before and one hour after drinking a soft drink. On one of the days the soft drink was caffeinated and on the other day it was not. Saliva collection involved 15 minutes unstimulated whole saliva, 5 minutes paraffin-stimulated whole saliva, and 10 seconds labial minor salivary gland output. Unstimulated and stimulated flow rates slightly increased and minor gland output slightly decreased one hour after the soft drink consumption regardless of caffeine content. These changes were not statistically significant (two-period two-treatment crossover trial using two-stage Grizzle model, p>0.05). A linear mixed model statistic did not show the caffeine effect on salivary flow rate. Caffeinated soft drink consumption had no significant effect on salivary flow rate after one hour by any of the three measures employed in this study. Caffeine's contribution to the cariogenicity of soft drinks is likely by centrally-mediated effects on consumption patterns.

The objective of this study was to estimate the association between caffeine consumption and in vitro fertilization (IVF) outcomes. A total of 2474 couples were prospectively enrolled prior to undergoing their first cycle of IVF, contributing a total of 4716 IVF cycles. Discrete survival analysis adjusting for observed confounders was applied to quantify the relation between caffeine consumption and livebirth. Secondary outcomes of interest were oocyte retrieval, peak estradiol level, implantation rate, and fertilization rate. Overall, caffeine consumption by women was not significantly associated with livebirth (p trend=0.74). Compared with women who do not drink caffeine, the likelihood of livebirth was not significantly different for women who drank low (>0-800 mg/week; odds ratio [OR]=1.00, 95% confidence interval [CI])=0.83-1.21), moderate (>800-1400 mg/week; OR=0.89, 95% CI=0.71-1.12), or high levels of caffeine (>1400 mg/week; OR=1.07, 95% CI=0.85-1.34). Greater caffeine intake by women was associated with a significantly lower peak estradiol level (p trend=0.03), but was not associated with the number of oocytes retrieved (p trend=0.75), fertilization rate (p trend=0.10), or implantation rate (p trend=0.23). There was no significant association between caffeine intake by men and livebirth (p trend=0.27), fertilization (p trend=0.72), or implantation (p trend=0.24). The individual effects of consumption of coffee, tea, or soda by women or men were not related to livebirth. Caffeine consumption by women or men was not associated with IVF outcomes.

Background: Sex differences in cocaine abuse are well established. Females have a higher sensitivity and thus higher vulnerability to cocaine abuse compared to males. There are many studies showing that sensitivity to cocaine reward varies during the estrus cycle. Methods: Vaginal smears were examined through a DIFF staining kit and viewed through a microscope to determine the estrus cycle stage. Smears were taken immediately before and after cocaine and/or caffeine injections. Furthermore, we suggest a new tool to analyze the estrus cycle by using electrical resistance of the vaginal mucosa. Results: In the present study, we discovered that cocaine directly induced changes in the estrus cycle. Interestingly, caffeine did not affect the estrus cycle and nor did the combination of cocaine and caffeine. We observed that caffeine blocked the cocaine-induced estrus cycle changes using conventional exfoliate cytology. Therefore, caffeine may have neuroprotective properties on the changes induced by cocaine. Conclusion: These phase changes in the estrus cycle may be the underlying cause of sex differences in cocaine addiction that can be blocked by caffeine. Thus, we propose a valuable insight into sex differences in cocaine abuse and reveal a possible treatment with antagonizing the adenosine system.

We have shown previously that male and female adolescents differ in their responses to caffeine, but to date, the mechanisms underlying these gender differences are unknown. The purpose of this study was to test the hypothesis that differences in circulating steroid hormones mediate gender differences in response to caffeine. Subjective and physiological responses to caffeine were tested in adolescents using a double-blind, placebo controlled, crossover design. Participants were tested every 2 weeks for 8 weeks and received placebo and caffeine (2 mg/kg) twice each. Females were tested with placebo and caffeine in each phase of their menstrual cycle. Salivary concentrations of testosterone, estradiol, and progesterone were also measured. Males showed greater positive subjective effects than females. In females, higher levels of estradiol were associated with little or no subjective responses to caffeine, but lower levels of estradiol were associated with negative subjective responses to caffeine relative to placebo. There were gender differences in cardiovascular responses to caffeine, with males showing greater decreases in heart rate after caffeine administration than females, but females showing greater increases in diastolic blood pressure than males after caffeine administration. These gender differences may be related to steroid hormone concentrations. Blood pressure responses to caffeine were lower in males when estradiol was high, but higher in females when estradiol was high. When taken together, these findings suggest that males and females differ in their responses to caffeine and that these differences may be mediated by changes in circulating steroid hormones.

Recent results obtained in our laboratory indicate that paraxanthine, the main metabolite of caffeine in humans, produces a significantly stronger locomotor activation in rats than caffeine. Furthermore, paraxanthine also produced a very significant increase in striatal extracellular concentrations of dopamine. Searching for an additional mechanism other than adenosine antagonism responsible for these psychostimulant-like effects, it was found that paraxanthine, but not caffeine, inhibited cGMP-preferring phosphodiesterases. Furthermore, interrupting nitric oxide neurotransmision (inhibiting nitric oxide synthase) significantly decreased both the locomotor-activating and the dopamine-releasing effects of paraxanthine. These results open up some obvious questions about the role of paraxanthine in the pharmacological effects of caffeine.

Current regulation of caffeine-containing products is incoherent, fails to protect consumers' interests, and should be modified in multiple ways. We make the case for one of the regulatory reforms that are needed: all consumable products containing added caffeine should be required by the Food and Drug Administration (FDA) to include caffeine quantity on their labels. Currently, no foods or beverages that contain caffeine are required to include caffeine content on their labels. Strengthening these lax labeling requirements could prevent direct caffeine-induced harm, protect those most vulnerable to caffeine-related side effects, and enhance consumer autonomy and effective caffeine use. Consumers have an interest in regulating their intake of caffeine and thus, ought to know how much caffeine their foods and beverages contain.

Background: Although caffeine is the most widely used mood-altering drug in the world, few studies have operationalized and characterized Diagnostic and Statistical Manual IV (DSM-IV) substance dependence criteria applied to caffeine. Methods: As a part of a nosological study of substance use disorders funded by the National Institute on Drug Abuse, we assessed caffeine use and dependence symptoms among high school and college students, drug treatment patients, and pain clinic patients who reported caffeine use in the last 7 days and also reported use of alcohol, nicotine, or illicit drugs within the past year (n=167). Results: Thirty-five percent met the criteria for dependence when all seven of the adopted DSM dependence criteria were used. Rates of endorsement of several of the most applicable diagnostic criteria were as follows: 26% withdrawal, 23% desire to cut down or control use, and 44% continued use despite harm. In addition, 34% endorsed craving, 26% said they needed caffeine to function, and 10% indicated that they talked to a physician or counselor about problems experienced with caffeine. There was a trend towards increased caffeine dependence among those dependent on nicotine or alcohol. Within a subgroup that had used caffeine, alcohol, and nicotine in the past year, 28% fulfilled criteria for caffeine dependence compared to 50% for alcohol and 80% for nicotine. Conclusion: The present study adds to a growing literature suggesting the reliability, validity, and clinical utility of the caffeine dependence diagnosis. Recognition of caffeine dependence in the DSM-V may be clinically useful.

Cigarette smokers have an increased risk for coronary artery disease. Nicotine present in cigarettes can adversely affect the cardiovascular system via stimulation of both sympathetic and parasympathetic neurons. Caffeine, another cardiovascular and central nervous system (CNS) stimulant, is commonly found in Ephedra and Ephedra-free dietary supplements. These caffeine-containing supplements also have been linked to cardiovascular toxicities. Although no longer on the U.S market, Ephedra-containing supplements are another source of cardiovascular and CNS stimulants, namely the ephedrine alkaloids. Together caffeine, nicotine, and ephedrine can individually stress the cardiovascular system, and an overlap of these agents is predicted in smokers and dieters. To understand the collective effects of these stimulants on the heart morphology and ultrastructure, rats were exposed to synthetic combinations of nicotine (0.2 mg/kg/day), ephedrine (0-30 mg/kg/day), and/or caffeine (0-24 mg/kg/day) as well as an extract from a caffeine-containing Ephedra supplement (Metabolife 356). After exposure for 3 days, the hearts were removed and examined for hypersensitivity myocarditis and myocardial necrosis. None of the drugs tested alone affected heart tissue morphology, nor were atypical cardiac cells observed. However, in combination, significant interactions were found between caffeine and ephedrine; the interventricular septum was most susceptible, with a significant increase in atypical cardiac cells observed. Nicotine pretreatment caused greater susceptibility to cardiotoxicity associated with combinations of caffeine + ephedrine or Metabolife, particularly in the left ventricle wall. These results indicate that sympathomimetic combinations present in Ephedra supplements may have produced cardiotoxicity reported in consumers of these products. Moreover, the presence of nicotine exacerbates these toxic effects.

Background: It is well known that the reinforcing properties of cocaine addiction are caused by the sharp increase of dopamine (DA) in the reward areas of the brain. However, other mechanisms have been speculated to contribute to the increase. Adenosine is one system that is associated with the sleep-wake cycle and is most important in regulating neuronal activity. Thus, more and more evidence is pointing to its involvement in regulating DA release. The current study set out to examine the role of adenosine in cocaine-induced DA release. Methods: Increasing doses of cocaine, caffeine, and their combination, as well as, 8-cyclopentyltheophylline (CPT), an adenosine A1 antagonist (alone and in combination with cocaine) were used to denote a response curve. A novel biosensor, the BRODERICK PROBE® was implanted in the nucleus accumbens to image the drug-induced surge of DA release in vivo, in the freely moving animal in real time. Results: Combinations of cocaine and caffeine were observed to block the increased release of DA moderately after administration of the low dose (2.5 mg/kg cocaine and 12.5 mg/kg caffeine) and dramatically after administration of the high dose (10 mg/kg cocaine and 50 mg/kg caffeine), suggesting neuroprotection. Similarly, CPT and cocaine showed a decreased DA surge when administered in combination. Thus, the low and high dose of a nonselective adenosine antagonist, caffeine, and a moderate dose of a selective adenosine antagonist, CPT, protected against the cocaine-induced DA release. Conclusions: These results show a significant interaction between adenosine and DA release and suggest therapeutic options for cocaine addiction and disorders associated with DA dysfunction.

Background: Research has reliably demonstrated that caffeine produces a general increase in physiological arousal in humans, but we previously failed to obtain the expected arousal-based changes in manually quantified event-related potential (ERP) components in response to the stimuli in a simple Go/NoGo task. Methods: A single oral dose of caffeine (250 mg) was used in a randomized double-blind placebo-controlled repeated-measures cross-over study. Adult participants (N=24) abstained from caffeine for 4 hours before each of two sessions, approximately 1 week apart. An equiprobable auditory Go/NoGo task was used, with a random mix of 75 tones at 1,000 Hz and 75 at 1,500 Hz. All tones were 50 ms duration (rise/fall time 5 ms) at 60 dB SPL, with a fixed stimulus-onset asynchrony of 1100 ms. Principal component analysis (a form of factor analysis) was used to quantify orthogonal ERP components. Results: ERP components reflected the different sequential processing of each stimulus type in this paradigm, replicating previous results. Caffeine was associated with a reduction in reaction time and fewer omission errors. The major ERP effects of caffeine were apparent as a slightly enhanced Processing Negativity and larger P3b amplitudes to Go stimuli. There were few effects on components to NoGo stimuli. Conclusions: The results confirm our previous findings that caffeine improves aspects of the differential processing related to response production and task performance, but may be interpreted as supporting the simple amplification of ERP component amplitudes predicted by the general arousal induced by caffeine.

Background: Disruptive effects of caffeine on sleep have previously been reported, although measures of next-day mood and performance have rarely been included. The present study aims to evaluate the effects of caffeine on sleep and associated next-day effects in a naturalistic field setting. Methods: Nineteen participants (daily caffeine intake 0-141 mg), assessed as good sleepers, took part in a randomized, placebo-controlled, double-blind, 2-week crossover study to assess the effects of bedtime caffeine use (250 mg) on sleep and next-day cognitive performance and mood, which were assessed on a mobile phone in the morning and afternoon. Sleep was assessed objectively (actiwatch) and subjectively (sleep diary). Results: Caffeine's effects on sleep were largely restricted to the first day of administration, with actigraphically measured reduced sleep efficiency, increased activity score and fragmentation index, decreased self-rated sleep quality, and an increased occurrence of participants waking early; only decreased sleep efficiency remained over the week. Effects on next-day performance and mood were evident over the whole week, although despite disrupting sleep, accuracy on a working memory task was higher after caffeine than placebo administration. Conclusions: Caffeine disrupted sleep, although when assessing next-day performance, which may have been affected by the presence of residual caffeine, performance appeared better after caffeine compared to placebo, although this was most likely due to prevention of the effects of overnight withdrawal from caffeine rather than representing a net benefit. Furthermore, partial tolerance developed to the effects of caffeine on sleep.

Background: Energy drinks and energy shots are popular consumer beverages that are advertised to increase feelings of alertness. Typically, these products include high levels of caffeine, a mild psychostimulant drug. The scientific evidence demonstrating the specific benefits of energy products to users in terms of subjective state and objective performance is surprisingly lacking. Moreover, there are rising health concerns associated with the use of these products. Therefore, the purpose of this study was to investigate the acute effects of a popular energy shot (5-Hour Energy®) on subjective and objective measures that were assessed hourly for 6 hours following consumption. Methods: Participants (n=14) completed a three-session study where they received the energy shot, a placebo control, and no drink. Following dose administration, participants completed subjective Profile of Mood States ratings hourly for 6 hours. Participants also repeatedly completed a behavioral control task (the cued go/no-go task) and provided blood pressure and pulse rate readings at each hour. Results: Consumption of the energy shot did improve subjective state, as measured by increased ratings of vigor and decreased ratings of fatigue. However, the energy shot did not alter objective performance, which worsened over time. Importantly, the energy shot elevated both systolic and diastolic blood pressure. Conclusions: Consumption of one energy shot may only result in modest benefits to subjective state. Individuals with preexisting hypertension or other medical conditions should be cautious about using these new consumer products.

Caffeine consumption and cigarette smoking tend to occur within the same individuals and at the same time. One potential explanation for this co-use is that caffeine consumption increases subjective smoking reinforcement. Electronic diaries were used to collect momentary reports of smoking, caffeine consumption, temptation/urge to smoke, and subjective smoking reinforcement in 74 prequit smokers. Momentary reports of caffeine consumption and smoking were associated, replicating previous findings. These results remained significant when contextual factors (time of day, weekday/weekend, presence of others, presence of others smoking, location, and past hour alcohol consumption) were covaried. Caffeine consumption was also associated with positive cigarette appraisals and reports of strong temptation/urge to smoke and urge reduction from the prior cigarette. Under the conditions of caffeine consumption versus at other times, smokers were significantly more likely to report their last cigarette as producing a rush/buzz, being pleasant, relaxing, and tasting good. The effects for temptation/urge to smoke and rush/buzz varied as a function of latency since smoking. Caffeine consumption increased reports of urge to smoke and rush/buzz only when smoking occurred more than 15 minutes prior to the diary entry. Findings suggest that caffeine consumption influences some aspects of smoking motivation or affects memorial processing of smoking reinforcement.

Background: Caffeine is one of the most widely used ergogenic aids worldwide. Recently, caffeine has been combined with 1,3-dimethylamylamine (1,3-D) in an attempt to improve exercise performance and related variables. We investigated the effect of caffeine and 1,3-D alone and in combination on exercise performance and blood markers of lipolysis and oxidative stress. Methods: Twelve exercise-trained subjects ingested placebo, caffeine (4 mg·kg⁻¹), 1,3-D (1 mg·kg⁻¹), or caffeine+ 1,3-D, 60 minutes before completing a 10 km run. Blood was collected before intake, immediately pre-exercise, and at 5 and 30 minutes postexercise. Samples were analyzed for glycerol, free fatty acids (FFAs), malondialdehyde, nitrate/nitrite, and trolox equivalent antioxidant capacity (TEAC). Results: Run time (minutes) was not different for placebo (52.55±1.96), caffeine (52.00±1.88), 1,3-D (52.02±1.86), or caffeine+ 1,3-D (52.46±1.94) (p>0.05). Glycerol and FFA were higher 5 and 30 minutes postexercise compared with pretreatment and pre-exercise (p<0.05). A condition effect was noted for glycerol (p=0.01), with higher values for 1,3-D compared with caffeine+ 1,3-D (p<0.05). A condition effect was noted for TEAC (p=0.0001), with higher values for placebo compared with caffeine and caffeine+ 1,3-D, and higher values for 1,3-D compared with caffeine (p<0.05). No other effects were noted for any measured variable (p>0.05). Conclusion: We report for the first time that caffeine+ 1,3D does not improve exercise performance as measured by run time. Isolated ingestion of 1,3-D results in the greatest increase in postexercise glycerol and FFA. Caffeine or 1,3-D alone or in combination does not differently affect oxidative stress biomarkers.

Background: Naturalistic studies of bar patrons suggest that caffeinated alcoholic beverages contribute to excessive alcohol consumption, in comparison to individuals consuming alcohol alone. This study was designed as a rodent model of adolescent caffeinated alcoholic beverage consumption. ETOH acquisition occurred during the adolescent period, postnatal day (PND) 28–39. Method: Male Sprague-Dawley rats (N = 32) were randomly assigned to receive either alcohol (ETOH) or alcohol+caffeine (ETOH+Caffeine) in vehicle “supersac” solution (3% sucrose +0.125% saccharin). Rodents were given free access using a two-bottle choice procedure. Results: During acquisition (PND 31–39), ETOH+Caffeine animals consumed more fluid (mL/kg) at the 6% (v/v) compared to ETOH-only animals (p = 0.014). In addition, ETOH+Caffeine animals had greater fluid preference at the 6% (v/v) compared to ETOH only animals (p = 0.005). Discussion: These results suggest that ETOH+Caffeine may contribute to excessive alcohol consumption during acquisition. They further support continued study of ETOH+Caffeine in rodent models of adolescent alcohol consumption.

In previous studies, most of which have been carried out on male subjects, the effect of caffeine on anaerobic performance and plasma lactate levels was equivocal. Therefore, the aim of this study was to determine the effects of caffeine supplementation on anaerobic power and plasma lactate concentration in female athletes. In this double-blind, cross-over study, 26 female basketball players were asked to attend a laboratory for three sessions. The first session was for familiarization and anthropometric measurements. In the next two sessions, the Wingate test was performed, one week apart as a washout period. Subjects performed a 30 s Wingate test, 70 min after ingestion of capsules containing caffeine (5 mg/kg) or placebo (dextrose). Blood samples were obtained after 10–12 h of fasting and 5 min post exercise for lactate measurements. The Kolmogrov–Smirnov test and paired t-test were used to analyze the data. Caffeine supplementation had no significant effect on peak/mean/end power, power drop, and fatigue index. Plasma lactate concentration significantly (p<0.001) increased in the caffeine group (from 1.72±0.58 to 4.95±0.83 mmol/L) and placebo group (from 1.66±0.73 to 5.37±0.57 mmol/L). However, the increased level in the caffeine group was significantly less than in the placebo group (p=0.01). In general, although caffeine supplementation resulted in a reduced lactate concentration in comparison with placebo, this reduction did not result in a statistically significant improvement in anaerobic power (peak/mean/end power, power drop, and fatigue index) in female athletes. Based on these findings, the administration of caffeine as a sports supplement may be effective for reducing the production of lactate during high-intensity exercise in female athletes.

Background: Although there are many reports of caffeine's effects on rodent behavior, little is known of their modification by environmental enrichment. Methods: Newly weaned hooded rats were group-housed for 3 months in standard (n=32) or environmentally enriched cages (n=32), and then observed in an open field and Y-maze following intraperitoneal injection of saline or acute caffeine (30 mg/kg). Each test was separated by 1 week, and the sequence differed for each rat. Injections occurred before the open-field trial, and between an acquisition and retention trial in the Y-maze when each rat encountered two black arms, one of which had changed from white. Ambulation, rearing, self-grooming, defecation, and location were recorded in the open field, along with choices of the changed (novel) Y-maze arm. The caffeine×sex×cage design yielded an n of 8 per cell for the open field, and 5–8 for the Y-maze. Results: Caffeine increased open-field ambulation (p<0.001) and center occupancy (p<0.05), decreased defecation (p<0.05) and habituation of ambulation (p<0.001), and, for rats from enriched cages, increased rearing (p<0.05). Novel Y-maze arm entries were increased for rats from standard cages (p<0.05), while time in this arm was decreased for enriched rats (p<0.05). Conclusions: Caffeine increased activity and may have been mildly anxiolytic. It may have also impaired habituation-associated memory in the open field, and attenuated enrichment-induced enhancement of consolidation in the Y-maze.

Background: When caffeine is added to beverages, it increases beverage liking and the relative reinforcing value (RRV) of these beverages after repeated exposure. The purpose of this study was to test the hypothesis that a single acute exposure to caffeine increases liking and motivation to consume sugar-sweetened beverages (SSBs) relative to placebo. Methods: Participants were children ages 8-9 years (n = 36) and adolescents ages 15-17 years (n = 41) with an approximately equal number of boys and girls. A double-blind, placebo-controlled crossover study was conducted where participants sampled a SSB containing caffeine (1 and 2 mg/kg) on one visit and placebo (quinine 0.01 and 0.02 mg/kg) on a second visit day and then, on a third visit, played a computer game to earn points for the beverages and rated liking and taste sensations. They returned to the laboratory after a 1-week washout and had the alternate dose combination. Results: Acute exposure to the higher dose of caffeine increased the RRV of the SSB relative to placebo, but only when that dose was presented in the first week and only in female participants. The liking of the caffeine-containing SSB at the higher dose was lower than the placebo at all time points. Conclusions: These data suggest that a single exposure to a caffeinated SSB can impact its RRV and liking, but only under certain conditions and only in females. This supports previous work suggesting that caffeine can increase desire to consume SSB.

Background: Physical activity and caffeine consumption induce adaptations to the cardiovascular system, which can change basal and postcaffeine blood pressure (BP) and heart rate (HR) parameters. We hypothesized that physical activity would attenuate the pressor effects of acute caffeine ingestion regardless of caffeine consumption level. Methods: We evaluated the influence of regular physical activity and chronic caffeine consumption on basal and post-caffeine ingestion BP and HR. Sixty subjects (19–50 years old) participated in an interventional study. To evaluate the influence of regular physical activity and caffeine consumption, the participants were divided into four groups: sedentary nonhabitual caffeine consumers (S), sedentary habitual heavy caffeine consumers (SC), physically active nonhabitual caffeine consumers (A), and physically active habitual heavy caffeine consumers (AC). All groups had BP and HR assessed before (basal) and one hour after (post) caffeine ingestion (6 mg.kg⁻¹ of body mass). Results: We found that group A had an increased systolic blood pressure (SBP) from 119.2 ± 11.3 to 124.2 ± 14.3 mmHg after acute caffeine ingestion. Lack of regular physical activity was associated with a significant increase in diastolic BP after caffeine ingestion (group S; 69.1 ± 7.7 vs. 73.8 ± 8.3 and group SC; 71.6 ± 9.5 vs. 75.3 ± 8.4). Group AC showed lower basal DBP than group SC (64.61 ± 8.1 and 71.5 ± 7.8 mmHg, respectively). Conclusion: Acute caffeine ingestion increases the SBP in physically active nonhabitual caffeine consumers.

Background: It has been suggested that those who are habitually high caffeine consumers ingest greater quantities of snack foods both in and outside the laboratory. Sugar-sweetened beverages (SSBs) are a major contributor to caffeine consumption and evidence links SSB consumption with poor dietary intake. Objective: To determine whether varying the concentration of caffeine in SSBs influences snack food consumption and energy intake. Methods: Caffeine taste thresholds were assessed using the International Standards Organization method for assessing taste sensitivity. In a crossover study design, participants (n=23, 26±5 years old, 58% female) were provided with a standardized meal on 4 days and simultaneously consumed SSBs with varied levels of caffeine (0, 0.67, 1.16, and 1.65 mM). The intake of food and beverage was recorded following each meal session. Results: A one way between groups analysis of variance revealed no significant main effect of caffeine concentration on consumption of SSBs [F (3, 92)=0.154, p=0.927] or food [F (3, 92)=0.305, p=0.822]. Pearson correlation analysis identified no significant correlations between the amount of food and SSB consumed (R=−0.031–0.415, p=0.062–0.893), or the amount of food and SSB consumed with body mass index and waist circumference (R=0.000 to −0.380, p=0.073–0.999). An individual's oral sensitivity to caffeine was not associated with SSB consumption (R=0.045 to −0.309, p=0.152–0.839) or the consumption of food (R=−0.052 to −0.327, p=0.128–0.812). Conclusions: The concentration of caffeine in SSBs did not influence the amount of food or SSB consumed.

A1 and CB1 receptors are main targets for the cognitive effects of caffeine and Δ9-tetrahydrocannabinol (THC), two of the most heavily consumed psychoactive substances worldwide. Both receptors can coincide in the same neuronal structures and both couple to similar G proteins and transducing pathways. Ex vivo evidence revealed that A1 and CB1 receptors can interact, and recent in vivo studies showed that those interactions can influence the behavioral actions of cannabinoids. In particular, studies on interactions between the adenosine receptor nonselective antagonist caffeine and CB1 receptor agonists, such as THC, showed that these receptor interactions may have relevant consequences for the function of the hippocampus, which impact upon cognition. In addition, interactions between adenosine A2A receptors, also targeted by caffeine, and CB1 receptors may impact upon the motor and addictive actions of cannabinoids. Being so widely consumed, caffeine habits should therefore be taken into account whenever evaluating the influences of cannabinoids upon neuronal function or dysfunction in humans. Manipulation of the degree of activation of adenosine receptors with caffeine or adenosine receptor selective ligands should also be considered to reduce side effects of CB1 receptor ligands with therapeutic potential.

Caffeine's therapeutic effects have been widely investigated; it has been featured as an important independent variable in psychopharmacological research and has been regarded as a promising addition to the class of stimulant medications. Attention deficit hyperactivity disorder (ADHD) is among the common diagnoses targeted by caffeine researchers. A review of the research methodology applied to understanding the effects of caffeine on ADHD is presented here. This provides researchers with methodological options for investigating the effects of caffeine on other disorders. The focus of this review is not in evaluating the effectiveness of caffeine on ADHD, but rather to describe the experimental methods from which those results were derived. This review will highlight methodology, including participants, preparation of caffeine, dose, methods of administration, dependent measures, and various experimental designs employed.

Background: Diabetes mellitus affects the morphology and plasticity of the brain, leading to cognitive and electrophysiological impairment. We aim to determine effects of caffeine on brain Na+/K+-ATPase activity in streptozotocin-induced diabetic female rats. Methods: Female Wistar rats weighing about 180–200 g were used for the study and were divided into three study groups. Study groups A 1, 2, 3 were healthy rats administered 15, 20, 25 mg/kg caffeine intraperitoneally (i.p), respectively, for 5 weeks; study groups B 1, 2, 3 administered 15, 20, 25 mg/kg caffeine (i.p), respectively, for 5 weeks and maintained on caffeine for 3 weeks after diabetes induction; study groups C 1, 2, 3, were diabetic rats administered 15, 20, 25 mg/kg caffeine (i.p), respectively, for 3 weeks; control and diabetic untreated were administered normal saline. After administration, brains were homogenized in sucrose solution and kept at 4°C. Enzyme assay was conducted. Results: A significant (p < 0.05) decrease in Na+/K+-ATPase activity of diabetic untreated (250.9 ± 0.26) when compared with control (415.6 ± 0.26). Study groups A 1, 2, 3 showed an increase in Na+/K+-ATPase activities (1022.0 ± 0.51, 825.0 ± 0.22, 498.6 ± 0.04, respectively). Study groups B 1 and 3 showed a significant decrease in Na+/K+-ATPase activities (280.0 ± 0.40 and 232.4 ± 0.34, respectively) when compared with control and a significant increase in group 2 (374.0 ± 0.34) when compared with diabetic group. Diabetic rats in study C (groups 1, 2, 3) showed an increase in Na+/K+-ATPase activities (468.8 ± 0.51, 428.5 ± 0.50, and 259.9 ± 0.20, respectively) when compared with diabetic untreated. Conclusion: This study shows that caffeine at low to moderate doses improves the brain Na+/K+-ATPase activities in diabetic rats.

Background: Children and adolescents who are anxiety sensitive are attuned to bodily sensations and interpret them as threatening. The objectives of the current study were to test if anxiety sensitivity was related to perceiving greater subjective physiological effects of caffeine and, in turn, lowered levels of naturalistic caffeine use. Developmental differences between children and adolescents in these relations were also tested. Methods: Children (n=135) and adolescents (n=79) completed a measure of naturalistic caffeine intake, daily availability, and subjective effects of caffeine. Youth also completed a measure of anxiety sensitivity. Results: For both children and adolescents, anxiety sensitivity was positively associated with perceived stimulating and withdrawal effects, as well as greater perceived availability of caffeine. For children only, anxiety sensitivity was associated with greater perceived psychological effects of caffeine. Across both age groups, anxiety sensitivity predicted greater reported caffeine intake, and this relation was explained via an indirect effect through withdrawal symptoms. Conclusions: Despite greater perceived sensitivity to caffeine's effects, anxiety sensitivity does not appear to buffer intake for children and adolescents. Rather, anxiety sensitive youth may experience more intense withdrawal symptoms, which subsequently contribute to greater caffeine intake. With one exception, relations of anxiety sensitivity to caffeine effects and consumption appear consistent across middle childhood and adolescence.

Background: Adolescent Long–Evans rats consume relatively high levels of an alcohol-containing liquid diet and show strong withdrawal responses after chronic alcohol consumption. Adolescent rats also show strong adaptive responses to chronic caffeine. Methods: The present study has used this model to investigate caffeine-alcohol co-use with caffeine administered to adolescent rats with and before an alcohol-containing liquid diet. There were four age-matched treatment groups (minimum of 12 rats per group): alcohol alone, alcohol administered with caffeine, caffeine administered before alcohol and caffeine, and caffeine administered before alcohol alone. Subsequent alcohol withdrawal severity was scored on a 4-point scale. Results: Followed through 3 weeks of co-administration, the presence of caffeine with alcohol in the liquid diet had no effect on the severity of subsequent alcohol withdrawal symptoms. After one week of alcohol consumption, withdrawal severity was modest, but it increased significantly by weeks 2 and 3. The same pattern was recorded for rats that were co-administered caffeine with alcohol. In contrast, administration of caffeine before the alcohol-containing diet significantly reduced the severity of alcohol withdrawal. Evidence of adaptive changes to the chronic caffeine pretreatment came in the form of decreased motor behavior during caffeine withdrawal and tolerance to the motor-activating effects of caffeine challenge. Caffeine pretreatment was effective only if caffeine was also included with alcohol in the liquid diet. Conclusion: The results present a pattern of caffeine consumption that can influence adolescent alcohol withdrawal severity and potentially mask this physical symptom of alcohol dependency.

Introduction: Caffeine use has been increasing among adolescents and young adults but much remains to be known about the consequences and context of their use. Methods: With self-reported anger as the key outcome variable, 7348 Icelandic adolescents were surveyed for caf-feine consumption, cigarette smoking, alcohol use, daytime sleepiness, and potential confounders. Structural equation modeling was used to examine direct and indirect effects of seven latent constructs: parental education, parental support, peer support, caffeine consumption, licit substance use (nicotine and alcohol), sleepiness, and anger; and two direct effects were measured using variables for family structure and family financial status. Results: Daily caffeine consumption was reported by 76.3% of participants, and of the four caffeine beverages sur-veyed, cola drinks were most often consumed, followed by energy drinks, tea, and coffee. Boys reported more caf-feine use on average than girls, with the difference being particularly marked for consumption of cola and energy drinks. Girls reported significantly more sleepiness and more anger symptoms overall than boys, but there were no gender differences on the measures of cigarette smoking and alcohol consumption. Amount of caffeine consumed was strongly associated with other substance use (nicotine and alcohol) and strongly associated with daytime sleep-iness. Structural equation modeling showed that a substantial proportion (43% for girls and 48% for boys) of the total relationship between caffeine and anger was due to mediation through sleepiness and licit substance use. Conclusion: High prevalence of daily caffeine consumption and the strength of the observed associations between caffeine and other important biobehavioral and psychosocial variables demonstrate the importance of including measurements of caffeine consumption in future studies of adolescent adjustment and development.

Purpose: Pediatric caffeine use has become increasingly prevalent. The American Academy of Pediatrics discourages caffeine use by children and adolescents due to its adverse impact on sleep and blood pressure. The objective of this study was to measure prevalence of physical and emotional symptoms related to caffeine consumption among adolescents receiving primary care. Methods: A convenience sample of patients (N = 179; 73% female) aged 12-17 presenting for routine primary care completed the Composite International Diagnostic Interview Substance Abuse Module questionnaire, which included questions regarding use of caffeine. Descriptive statistics were used to summarize prevalence of caffeine use and caffeine-related symptoms. Associations of number of caffeine-related symptoms with age, gender, and race/ethnicity were also analyzed. Results: Sixty-seven percent of participants (n = 120) reported past 30-day caffeinated beverage consumption. Of those, 68% (n = 82) reported at least one symptom or problem attributed to caffeine use or withdrawal, including caffeine cravings, 24% (n = 29); frequent urination, 21% (n = 25); difficulty falling asleep, 18% (n = 22); and feeling anxious, 3.3% (n = 4). Conclusions: In our sample, caffeinated beverage consumption by adolescents was frequently associated with physical and emotional symptoms, as well as problems attributed to use.