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The ergogenic effect of acute caffeine ingestion has been widely investigated; however, scientific information regarding tolerance to the performance benefits of caffeine, when ingested on a day-to-day basis, is scarce. The aim of this investigation was to determine the time course of tolerance to the ergogenic effects of a moderate dose of caffeine. Eleven healthy active participants took part in a cross-over, double-blind, placebo-controlled experiment. In one treatment, they ingested 3 mg/kg/day of caffeine for 20 consecutive days while in another they ingested a placebo for 20 days. Each substance was administered daily in an opaque unidentifiable capsule, and the experimental trials started 45 min after capsule ingestion. Two days before, and three times per week during each 20-day treatment, aerobic peak power was measured with an incremental test to volitional fatigue (25 W/min) and aerobic peak power was measured with an adapted version of the Wingate test (15 s). In comparison to the placebo, the ingestion of caffeine increased peak cycling power in the incremental exercise test by ~4.0 ±1.3% for the first 15 days (P<0.05) but then this ergogenic effect lessened. Caffeine also increased peak cycling power during the Wingate test on days 1, 4, 15, and 18 of ingestion by ~4.9 ±0.9% (P<0.05). In both tests, the magnitude of the ergogenic effect of caffeine vs. placebo was higher on the first day of ingestion and then progressively decreased. These results show a continued ergogenic effect with the daily ingestion of caffeine for 15-18 days; however, the changes in the magnitude of this effect suggest progressive tolerance.

RationalAt all times humans have made attempts to improve their cognitive abilities by different means, among others, with the use of stimulants. Widely available stimulants such as caffeine, but also prescription substances such as methylphenidate and modafinil, are being used by healthy individuals to enhance cognitive performance.ObjectivesThere is a lack of knowledge on the effects of prescription stimulants when taken by healthy individuals (as compared with patients) and especially on the effects of different substances across different cognitive domains.MethodsWe conducted a pilot study with three arms in which male participants received placebo and one of three stimulants (caffeine, methylphenidate, modafinil) and assessed cognitive performance with a test battery that captures various cognitive domains.ResultsOur study showed some moderate effects of the three stimulants tested. Methylphenidate had positive effects on self-reported fatigue as well as on declarative memory 24 hours after learning; caffeine had a positive effect on sustained attention; there was no significant effect of modafinil in any of the instruments of our test battery. All stimulants were well tolerated, and no trade-off negative effects on other cognitive domains were found.ConclusionsThe few observed significant positive effects of the tested stimulants were domain-specific and of rather low magnitude. The results can inform the use of stimulants for cognitive enhancement purposes as well as direct further research to investigate the effects of stimulants on specific cognitive domains that seem most promising, possibly by using tasks that are more demanding.

In a randomized trial, coffee consumption was not associated with more premature atrial contractions than caffeine avoidance but was associated with more premature ventricular contractions and daily steps and less sleep.

Restless Legs Syndrome (RLS) is a common sleep disorder characterized by an urge to move the legs that is responsive to movement (particularly during rest), periodic leg movements during sleep, and hyperarousal. Recent evidence suggests that the involvement of the adenosine system may establish a connection between dopamine and glutamate dysfunction in RLS. Transcranial magnetic stimulation (TMS) is a non-invasive electrophysiological technique widely applied to explore brain electrophysiology and neurochemistry under different experimental conditions. In this pilot study protocol, we aim to investigate the effects of dipyridamole (a well-known enhancer of adenosinergic transmission) and caffeine (an adenosine receptor antagonist) on measures of cortical excitation and inhibition in response to TMS in patients with primary RLS. Initially, we will assess cortical excitability using both single- and paired-pulse TMS in patients with RLS. Then, based on the measures obtained, we will explore the effects of dipyridamole and caffeine, in comparison to placebo, on various TMS parameters related to cortical excitation and inhibition. Finally, we will evaluate the psycho-cognitive performance of RLS patients to screen them for cognitive impairment and/or mood-behavioral dysfunction, thus aiming to correlate psycho-cognitive findings with TMS data. Overall, this study protocol will be the first to shed lights on the neurophysiological mechanisms of RLS involving the modulation of the adenosine system, thus potentially providing a foundation for innovative “pharmaco-TMS”-based treatments. The distinctive TMS profile observed in RLS holds indeed the potential utility for both diagnosis and treatment, as well as for patient monitoring. As such, it can be considered a target for both novel pharmacological (i.e., drug) and non-pharmacological (e.g., neuromodulatory), “TMS-guided”, interventions.

Lifestyle habits after middle age significantly impact the maintenance of cognitive function in older adults. Nutritional intake is closely related to lifestyle habits; therefore, nutrition is a pivotal factor in the prevention of dementia in the preclinical stages. Matcha green tea powder (matcha), which contains epigallocatechin gallate, theanine, and caffeine, has beneficial effects on cognitive function and mood. We conducted a randomized, double-blind, placebo-controlled clinical study over 12 months to examine the effect of matcha on cognitive function and sleep quality. Ninety-nine participants, including 64 with subjective cognitive decline and 35 with mild cognitive impairment were randomized, with 49 receiving 2 g of matcha and 50 receiving a placebo daily. Participants were stratified based on two factors: age at baseline and APOE genotype. Changes in cognitive function and sleep quality were analyzed using a mixed-effects model. Matcha consumption led to significant improvements in social acuity score (difference; -1.39, 95% confidence interval; -2.78, 0.002) (P = 0.028) as evaluated by the perception of facial emotions in cognitive function. The primary outcomes, that is, Montreal Cognitive Assessment and Alzheimer's Disease Cooperative Study Activity of Daily Living scores, showed no significant changes with matcha intervention. Meanwhile, Pittsburgh Sleep Quality Index scores indicated a trend toward improvement with a difference of 0.86 (95% confidence interval; -0.002, 1.71) (P = 0.088) between the groups in changes from baseline to 12 months. The present study suggests regular consumption of matcha could improve emotional perception and sleep quality in older adults with mild cognitive decline. Given the widespread availability and cultural acceptance of matcha green tea, incorporating it into the daily routine may offer a simple yet effective strategy for cognitive enhancement and dementia prevention.

We explored the effect of 3 mg/kg of caffeine supplementation on the cognitive ability and shooting performance of elite e-sports players. Nine e-sports players who had received professional training in e-sports and had won at least eighth place in national-level e-sports shooting competitions. After performing three to five familiarization tests, we employed a single blind, randomized crossover design to divide participants into caffeine trial (CAF) and placebo trial (PL). The CAF trial took capsules with 3 mg/kg of caffeine, whereas the PL trial took a placebo capsule. After a one-hour rest, the Stroop task, the visual search ability test, and the shooting ability test were conducted. The CAF trial’s performance in the Stroop task in terms of congruent condition ( P  = 0.023) and visual search reaction time with 20 items ( P  = 0.004) was significantly superior to those of the PL trial. In the shooting test, the CAF trial’s kill ratio ( P  = 0.020) and hit accuracy ( P  = 0.008) were significantly higher, and the average time to target ( P  = 0.001) was significantly shorter than those of the PL trial. Caffeine supplementation significantly improves e-sports players’ reaction times and shooting performance.

In this study, the authors examine the effects of caffeine on long-term memory. They find that a specific caffeine dose administered shortly after participants studied images improves image-recognition performance a day later. This suggests that caffeine may enhance memory consolidation separately from other cognition-enhancing effects. It is currently not known whether caffeine has an enhancing effect on long-term memory in humans. We used post-study caffeine administration to test its effect on memory consolidation using a behavioral discrimination task. Caffeine enhanced performance 24 h after administration according to an inverted U-shaped dose-response curve; this effect was specific to consolidation and not retrieval. We conclude that caffeine enhanced consolidation of long-term memories in humans.

PurposeTo determine the influence of two commonly occurring genetic polymorphisms on exercise, cognitive performance, and caffeine metabolism, after caffeine ingestion.MethodsEighteen adults received caffeine or placebo (3 mg kg−1) in a randomised crossover study, with measures of endurance exercise (15-min cycling time trial; 70-min post-supplementation) and cognitive performance (psychomotor vigilance test; PVT; pre, 50 and 95-min post-supplementation). Serum caffeine and paraxanthine were measured (pre, 30 and 120-min post-supplementation), and polymorphisms in ADORA2A (rs5751876) and CYP1A2 (rs762551) genes analysed.ResultsCaffeine enhanced exercise performance (P < 0.001), but effects were not different between participants with ADORA2A ‘high’ (n = 11) vs. ‘low’ (n = 7) sensitivity genotype (+ 6.4 ± 5.8 vs. + 8.2 ± 6.8%), or CYP1A2 ‘fast’ (n = 10) vs. ‘slow’ (n = 8) metabolism genotype (+ 7.2 ± 5.9 vs. + 7.0 ± 6.7%, P > 0.05). Caffeine enhanced PVT performance (P < 0.01). The effect of caffeine was greater for CYP1A2 ‘fast’ vs. ‘slow’ metabolisers for reaction time during exercise (− 18 ± 9 vs. − 1.0 ± 11 ms); fastest 10% reaction time at rest (− 18 ± 11 vs. − 3 ± 15 ms) and lapses at rest (− 3.8 ± 2.7 vs. + 0.4 ± 0.9) (P < 0.05). There were no PVT differences between ADORA2A genotypes (P > 0.05). Serum caffeine and paraxanthine responses were not different between genotypes (P > 0.05).ConclusionCaffeine enhanced CYP1A2 ‘fast’ metabolisers’ cognitive performance more than ‘slow’ metabolisers. No other between-genotype differences emerged for the effect of caffeine on exercise or cognitive performance, or metabolism.

Background and Objective Activity of human cytochrome P450 enzymes (CYPs) shows high inter-and intra-individual variability, which is determined by genetic and non-genetic factors. Using a combination of CYP-specific probe drugs, phenotyping cocktails allow simultaneous assessment of the activity of different CYP isoforms. The objective of this study was to characterize the phenotyping metrics of the Basel cocktail in healthy male subjects with induced and inhibited CYP activity. Methods In a randomized crossover study, the probe drugs for simultaneous phenotyping of CYP1A2 (caffeine), CYP2B6 (efavirenz), CYP2C9 (losartan), 2C19 (omeprazole), CYP2D6 (metoprolol), and CYP3A4 (midazolam) were administered to 16 subjects without pretreatment (baseline), after pretreatment with a combination of CYP inhibitors (ciprofloxacin, ketoconazole, and paroxetine), and after CYP induction with rifampicin. All subjects were genotyped. Pharmacokinetic profiles of the probe drugs and their main metabolites and metabolic ratios 2, 4, 6, and 8 h after probe drug application were determined in plasma and compared with the corresponding area under the plasma concentration-time curve (AUC) ratios. Results The Basel phenotyping cocktail was well tolerated by all subjects independent of pretreatment. Good correlations of metabolic ratios with AUC ratios of the corresponding probe drugs and their metabolites for all three conditions (baseline, CYP inhibition, and CYP induction) were found at 2 h after probe drug administration for CYP3A4, at 4 h for CYP1A2 and CYP2C19, and at 6 h for CYP2B6 and CYP2D6. While CYP inhibition significantly changed AUC ratios and metabolic ratios at these time points for all six CYP isoforms, CYP induction did not significantly change AUC ratios for CYP2C9. For CYP3A4, total 1′-hydroxymidazolam concentrations after pretreatment of samples with β-glucuronidase were needed to obtain adequate reflection of CYP induction by the metabolic ratio. Conclusions Inhibition of CYP activity can be detected with the Basel phenotyping cocktail for all six tested CYP isoforms at the proposed time points. The AUC ratio of losartan:losartan carboxylic acid in plasma does not seem suitable to detect induction of CYP2C9. The observed metabolic ratios for inhibited and induced CYP activity need to be confirmed for extensive metabolizers, and typical ratios for subjects with genetically altered CYP activity will need to be established in subsequent studies. ClinicalTrials.gov-ID : NCT01386593.

While previous studies have explored a range of factors governing the optimal use of caffeine (CAF) in athletes, limited research has explored how time of day (TOD) affects the ergogenic effects of various CAF dosages on physical performance. This study aimed to increase knowledge about how different recommended CAF doses (3 mg/kg vs. 6 mg/kg) ingested at different TODs affected maximal high-intensity physical performance and the perception of potential side effects in female athletes. In this double-blind, randomized, and counterbalanced study, 15 low CAF consumer athletes (aged 18.3 ± 0.5 y) underwent six trials, including three testing conditions assessed across two TODs: one in the morning (08:00 a.m.) and one in the evening (06:00 p.m.). During each condition, the participants ingested either a placebo, 3 mg/kg CAF (CAF (3 mg)), or 6 mg/kg CAF (CAF (6 mg)) capsules 60 min before each test with an in-between washout period of at least 72 h. In each trial, the participants performed a countermovement jumps test (CMJ), a modified agility t test (MATT), a repeated sprint ability (RSA), a rating of perceived exertion (RPE), and finally, a CAF side effects questionnaire. Our findings indicate the absence of an ergogenic effect on CMJ, MAT, and RSA performance in the evening after administering CAF (3 mg) or CAF (6 mg) compared to a placebo. Likewise, when CAF was ingested in the morning, there was an improvement in these performances with both CAF (3 mg) and CAF (6 mg), with greater improvement observed after CAF (6 mg). Additionally, neither the CAF dosage nor the TOD had a significant effect on the RPE. The occurrence of side effects increased significantly after the evening ingestion of CAF, particularly with a moderate dose of CAF (6 mg). Our findings indicate that the effectiveness of CAF depends on the TOD and CAF dosage. When ingested in the morning, a moderate dose of CAF (6 mg), rather than CAF (3 mg), is more effective in improving short-term physical performance without affecting CAF side effects in female athletes. Nevertheless, when ingested in the evening, neither dose was sufficient to enhance short-term physical performance, and both dosages increased the incidence of CAF side effects, particularly at a moderate dose.