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Caffeine is widely used to promote alertness and cognitive performance under challenging conditions, such as sleep loss. Non-digestive modes of delivery typically reduce variability of its effect. In a placebo-controlled, 50-h total sleep deprivation (TSD) protocol we administered four 200 mg doses of caffeine-infused chewing-gum during night-time circadian trough and monitored participants' drowsiness during task performance with infra-red oculography. In addition to the expected reduction of sleepiness, caffeine was found to disrupt its degrading impact on performance errors in tasks ranging from standard cognitive tests to simulated driving. Real-time drowsiness data showed that caffeine produced only a modest reduction in sleepiness (compared to our placebo group) but substantial performance gains in vigilance and procedural decisions, that were largely independent of the actual alertness dynamics achieved. The magnitude of this disrupting effect was greater for more complex cognitive tasks.

Self-assessment is the most common method for monitoring performance and safety in the workplace. However, discrepancies between subjective and objective measures have increased interest in physiological assessment of performance. In a double-blind placebo-controlled study, 23 healthy adults were randomly assigned to either a placebo (n = 11; 5 F, 6 M) or caffeine condition (n = 12; 4 F, 8 M) while undergoing 50 h (i.e. two days) of total sleep deprivation. In previous work, higher salivary alpha-amylase (sAA) levels were associated with improved psychomotor vigilance and simulated driving performance in the placebo condition. In this follow-up article, the effects of strategic caffeine administration on the previously reported diurnal profiles of sAA and performance, and the association between sAA and neurobehavioural performance were investigated. Participants were given a 10 h baseline sleep opportunity (monitored via standard polysomnography techniques) prior to undergoing sleep deprivation (total sleep time: placebo = 8.83 ± 0.48 h; caffeine = 9.01 ± 0.48 h). During sleep deprivation, caffeine gum (200 mg) was administered at 01:00 h, 03:00 h, 05:00 h, and 07:00 h to participants in the caffeine condition (n = 12). This strategic administration of caffeine gum (200 mg) has been shown to be effective at maintaining cognitive performance during extended wakefulness. Saliva samples were collected, and psychomotor vigilance and simulated driving performance assessed at three-hour intervals throughout wakefulness. Caffeine effects on diurnal variability were compared with previously reported findings in the placebo condition (n = 11). The impact of caffeine on the circadian profile of sAA coincided with changes in neurobehavioural performance. Higher sAA levels were associated with improved performance on the psychomotor vigilance test during the first 24 h of wakefulness in the caffeine condition. However, only the association between sAA and response speed (i.e. reciprocal-transform of mean reaction time) was consistent across both days of sleep deprivation. The association between sAA and driving performance was not consistent across both days of sleep deprivation. Results show that the relationship between sAA and reciprocal-transform of mean reaction time on the psychomotor vigilance test persisted in the presence of caffeine, however the association was relatively weaker as compared with the placebo condition., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Caffeine is known for its capacity to mitigate performance decrements. The metabolic side-effects are less well understood. This study examined the impact of cumulative caffeine doses on glucose metabolism, self-reported hunger and mood state during 50 hr of wakefulness. In a double-blind laboratory study, participants were assigned to caffeine (n = 9, 6M, age 21.3 ± 2.1 years; body mass index 21.9 ± 1.6 kg/m 2 ) or placebo conditions (n = 8, 4M, age 23.0 ± 2.8 years; body mass index 21.8 ± 1.6 kg/m 2 ). Following a baseline sleep (22:00 hours-08:00 hours), participants commenced 50 hr of sleep deprivation. Meal timing and composition were controlled throughout the study. Caffeine (200 mg) or placebo gum was chewed for 5 min at 01:00 hours, 03:00 hours, 05:00 hours and 07:00 hours during each night of sleep deprivation. Continual glucose monitors captured interstitial glucose 2 hr post-breakfast, at 5-min intervals. Hunger and mood state were assessed at 10:00 hours, 16:30 hours, 22:30 hours and 04:30 hours. Caffeine did not affect glucose area under the curve (p = 0.680); however, glucose response to breakfast significantly increased after 2 nights of extended wakefulness compared with baseline (p = 0.001). There was a significant main effect of day, with increased tiredness (p < 0.001), mental exhaustion (p < 0.001), irritability (p = 0.002) and stress (p < 0.001) on the second day of extended wake compared with day 1. Caffeine attenuated the rise in tiredness (p < 0.001), mental exhaustion (p = 0.044) and irritability (p = 0.018) on day 1 but not day 2. Self-reported hunger was not affected by sleep deprivation or caffeine. These data confirm the effectiveness of caffeine in improving performance under conditions of sleep deprivation by reducing feelings of tiredness, mental exhaustion and irritability without exacerbating glucose metabolism and feelings of hunger., (© 2018 European Sleep Research Society.)

Study Objectives: Existing mathematical models of neurobehavioral performance cannot predict the beneficial effects of caffeine across the spectrum of sleep loss conditions, limiting their practical utility. Here, we closed this research gap by integrating a model of caffeine effects with the recently validated unified model of performance (UMP) into a single, unified modeling framework. We then assessed the accuracy of this new UMP in predicting performance across multiple studies., Methods: We hypothesized that the pharmacodynamics of caffeine vary similarly during both wakefulness and sleep, and that caffeine has a multiplicative effect on performance. Accordingly, to represent the effects of caffeine in the UMP, we multiplied a dose-dependent caffeine factor (which accounts for the pharmacokinetics and pharmacodynamics of caffeine) to the performance estimated in the absence of caffeine. We assessed the UMP predictions in 14 distinct laboratory- and field-study conditions, including 7 different sleep-loss schedules (from 5 h of sleep per night to continuous sleep loss for 85 h) and 6 different caffeine doses (from placebo to repeated 200 mg doses to a single dose of 600 mg)., Results: The UMP accurately predicted group-average psychomotor vigilance task performance data across the different sleep loss and caffeine conditions (6% < error < 27%), yielding greater accuracy for mild and moderate sleep loss conditions than for more severe cases. Overall, accounting for the effects of caffeine resulted in improved predictions (after caffeine consumption) by up to 70%., Conclusions: The UMP provides the first comprehensive tool for accurate selection of combinations of sleep schedules and caffeine countermeasure strategies to optimize neurobehavioral performance., (© 2016 Associated Professional Sleep Societies, LLC.)

The current study investigated the effects of repeated caffeine administration on performance and subjective reports of sleepiness and fatigue during 50h extended wakefulness. Twenty-four, non-smokers aged 22.5±2.9y (mean±SD) remained awake for two nights (50h) in a controlled laboratory environment. During this period, 200mg of caffeine or placebo gum was administered at 01:00, 03:00, 05:00 and 07:00 on both nights (total of 800mg/night). Neurobehavioral performance and subjective reports were assessed throughout the wake period. Caffeine improved performance compared to placebo, but did not affect overall ratings of subjective sleepiness and fatigue. Performance and sleepiness worsened with increasing time awake for both conditions. However, caffeine slowed performance impairments such that after 50h of wakefulness performance was better following caffeine administration compared to placebo. Caffeine also slowed the increase in subjective sleepiness and performance ratings, but only during the first night of wakefulness. After two nights of sleep deprivation, there was no difference in sleepiness ratings between the two conditions. These results demonstrate that strategic administration of caffeine effectively mitigates performance impairments associated with 50h wakefulness but does not improve overall subjective assessments of sleepiness, fatigue and performance. Results indicate that while performance impairment is alleviated, individuals may continue to report feelings of sleepiness. Individuals who use caffeine as a countermeasure in sustained operations may feel as though caffeine is not effective despite impairments in objective performance being largely mitigated., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Rationale: Various occupational groups are required to maintain optimal physical and cognitive function during overnight periods of wakefulness, often with less than optimal sleep. Strategies are required to help mitigate the impairments in cognitive function to help sustain workplace safety and productivity., Objectives: To test the effectiveness of repeated 200 mg doses of caffeine on cognitive function and live-fire marksmanship with soldiers during three successive nights of sustained wakefulness followed by 4-h afternoon sleep periods., Methods: Twenty Special Forces personnel (28.6 ± 4.7 years, 177.6 ± 7.5 cm and 81.2 ± 8.0 kg) were randomly assigned to receive four 200-mg doses of caffeine (n = 10) or placebo (n = 10) during the late evening and early morning hours during three successive days. An afternoon 4-h sleep period followed. The psychomotor (PVT) and field (FVT) vigilance, logical reasoning (LRT) tests and a vigilance monitor assessed cognitive function throughout the study. Live-fire marksmanship requiring friend-foe discrimination was assessed., Results: Caffeine maintained speed on the PVT (p < 0.02), improved detection of events during FVT (p < 0.001), increased number of correct responses to stimuli as assessed by the vigilance monitor (p < 0.001) and increased response speed during the LRT (p < 0.001) throughout the three overnight testing periods. Live-fire marksmanship was not altered by caffeine., Conclusions: A total daily dose of 800 mg caffeine during successive overnight periods of wakefulness is an effective strategy to maintain cognitive function when optimal sleep periods during the day are not available.

Caffeine is the most widely consumed stimulant to counter sleep-loss effects. While the pharmacokinetics of caffeine in the body is well-understood, its alertness-restoring effects are still not well characterized. In fact, mathematical models capable of predicting the effects of varying doses of caffeine on objective measures of vigilance are not available. In this paper, we describe a phenomenological model of the dose-dependent effects of caffeine on psychomotor vigilance task (PVT) performance of sleep-deprived subjects. We used the two-process model of sleep regulation to quantify performance during sleep loss in the absence of caffeine and a dose-dependent multiplier factor derived from the Hill equation to model the effects of single and repeated caffeine doses. We developed and validated the model fits and predictions on PVT lapse (number of reaction times exceeding 500 ms) data from two separate laboratory studies. At the population-average level, the model captured the effects of a range of caffeine doses (50-300 mg), yielding up to a 90% improvement over the two-process model. Individual-specific caffeine models, on average, predicted the effects up to 23% better than population-average caffeine models. The proposed model serves as a useful tool for predicting the dose-dependent effects of caffeine on the PVT performance of sleep-deprived subjects and, therefore, can be used for determining caffeine doses that optimize the timing and duration of peak performance., (Published by Elsevier Ltd.)

Rationale: While caffeine is widely used as a countermeasure to sleep loss, mathematical models are lacking., Objective: Develop a biomathematical model for the performance-restoring effects of caffeine in sleep-deprived subjects., Methods: We hypothesized that caffeine has a multiplicative effect on performance during sleep loss. Accordingly, we first used a phenomenological two-process model of sleep regulation to estimate performance in the absence of caffeine, and then multiplied a caffeine-effect factor, which relates the pharmacokinetic-pharmacodynamic effects through the Hill equation, to estimate the performance-restoring effects of caffeine., Results: We validated the model on psychomotor vigilance test data from two studies involving 12 subjects each: (1) single caffeine dose of 600mg after 64.5h of wakefulness and (2) repeated doses of 200mg after 20, 22, and 24h of wakefulness. Individualized caffeine models produced overall errors that were 19% and 42% lower than their population-average counterparts for the two studies. Had we not accounted for the effects of caffeine, the individualized model errors would have been 117% and 201% larger, respectively., Conclusions: The presented model captured the performance-enhancing effects of caffeine for most subjects in the single- and repeated-dose studies, suggesting that the proposed multiplicative factor is a feasible solution., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Naps are an effective strategy for maintaining alertness and cognitive performance; however, upon abrupt wakening from naps, sleep inertia (temporary performance degradation) may ensue. In the present study, attenuation of post-nap sleep inertia was attempted by administration of caffeine gum. Using a double-blind, placebo-controlled crossover design, 15 healthy, non-smoking adults were awakened at 1 hr. and again at 6 hr. after lights out (0100 and 0600, respectively) and were immediately administered a gum pellet containing 100 mg of caffeine or placebo. A 5-min. psychomotor vigilance task was administered at 0 min., 6 min., 12 min., and 18 min. post-awakening. At 0100, response speed with caffeine was significantly better at 12 min. and 18 min. post-awakening compared to placebo; at 0600, caffeine's effects were evident at 18 min. post-awakening. Caffeinated gum is a viable means of rapidly attenuating sleep inertia, suggesting that the adenosine receptor system is involved in sleep maintenance.

Low-dose caffeine administered in chewing gum does not enhance cycling to exhaustion. The purpose of the current investigation was to examine the effect of low-dose caffeine (CAF) administered in chewing gum at 3 different time points during submaximal cycling exercise to exhaustion. Eight college-aged (26 ± 4 years), physically active (45.5 ± 5.7 ml·kg(-1)·min(-1)) volunteers participated in 4 experimental trials. Two pieces of caffeinated chewing gum (100 mg per piece, total quantity of 200 mg) were administered in a double-blind manner at 1 of 3 time points (-35, -5, and +15 minutes) with placebo at the other 2 points and at all 3 points in the control trial. The participants cycled at 85% of maximal oxygen consumption until volitional fatigue and time to exhaustion (TTE) were recorded in minutes. Venous blood samples were obtained at -40, -10, and immediately postexercise and analyzed for serum-free fatty acid and plasma catecholamine concentrations. Oxygen consumption, respiratory exchange ratio, heart rate, glucose, lactate, ratings of perceived exertion, and perceived leg pain measures were obtained at baseline and every 10 minutes during cycling. The results showed that there were no significant differences between the trials for any of the parameters measured including TTE. These findings suggest that low-dose CAF administered in chewing gum has no effect on TTE during cycling in recreational athletes and is, therefore, not recommended.

Previous research suggests that sleep deprivation is associated with declines in metabolic activity within brain regions important for judgement and impulse control, yet previous studies have reported inconsistent findings regarding the effects of sleep loss and caffeine on risk-taking. In this study, 25 healthy adults (21 men, four women) completed the Balloon Analog Risk Task (BART) and Evaluation of Risks (EVAR) scale at regular intervals to examine behavioral and self-reported risk-taking propensity during 75 h of continuous sleep deprivation. Participants received either four double-blind administrations of 200 mg caffeine (n=12) or indistinguishable placebo (n=13) gum bi-hourly during each of the 3 nights of sleep deprivation. No significant effects of drug group or sleep deprivation were evident on the BART or EVAR when measured at 51 h of wakefulness. However, by 75 h, the placebo group showed a significant increase in risk-taking behavior on the cost-benefit ratio and total number of exploded balloons on the BART, whereas the caffeine group remained at baseline levels. On the EVAR, several factors of self-reported risk-taking propensity, including total risk, impulsivity and risk/thrill seeking, were reduced among subjects receiving caffeine across the 3 days of sleep deprivation, but remained at baseline levels for the placebo group. These results suggest that 3 nights of total sleep deprivation led to a significant increase in behavioral risk-taking but not self-reported perception of risk-propensity. Overnight caffeine prevented this increase in risky behavior., (Published 2010. This article is a US Government work and is in the public domain in the USA.)

This double-blind, placebo-controlled, within-subject experiment examined the effects of low-dose caffeine on pain reported during an exhaustive grip task. The grip task consisted of holding a metal block attached to standard Olympic weight plates with the arm at the side until the participants could no longer maintain their grip. Apparently healthy recreationally trained college-aged adults (men, n = 5; women, n = 5) were given either a piece of Stay Alert™ gum that delivered 85% of the effective dose of 100 mg of caffeine in 5 minutes or an identical placebo gum that contained no caffeine. Subsequently, pain perception and ratings of perceived exertion were recorded during an exhaustive grip task every 15 seconds and the overall time to exhaustion. No significant difference was found in time to exhaustion between treatments. A significant main effect of treatment for reported pain (p < 0.001, Φ = 0.377) was observed. Thus, in a population of recreationally trained college-aged adults, low-dose caffeine may attenuate the individual's perception of pain during a grip to exhaustion task.

Sleep loss, as well as concomitant fatigue and risk, is ubiquitous in today's fast-paced society. A biomathematical model that succeeds in describing performance during extended wakefulness would have practical utility in operational environments and could help elucidate the physiological basis of sleep loss effects. Eighteen subjects (14 males, 4 females; age 25.8 +/- 4.3 years) with low levels of habitual caffeine consumption (<300 mg/day) participated. On night 1, subjects slept for 8 h (2300-0700 h), followed by 77 h of continuous wakefulness. They were assigned randomly to receive placebo or caffeine (200 mg, i.e., two sticks of Stay Alert gum) at 0100, 0300, 0500, and 0700 during nights 2, 3, and 4. The psychomotor vigilance test (PVT) was administered periodically over the 77-h period of continuous wakefulness. Statistical analysis reveals lognormality in each PVT, allowing for closed-form median calculation. An iterative parameter estimation algorithm, which takes advantage of MatLab's (R2007a) least-squares nonlinear regression, is used to estimate model parameters from subjects' PVT medians over time awake. In the model, daily periodicity is accounted for with a four-component Fourier series, and a simplified binding function describes asymptotic fatigue. The model highlights patterns in data that suggest (1) the presence of a performance inhibitor that increases and saturates over the period of continuous wakefulness, (2) competitive inhibition of this inhibitor by caffeine, (3) the persistence of an internally driven circadian rhythm of alertness, and (4) a multiplicative relationship between circadian rhythm and performance inhibition. The present inhibitor-based minimal model describes performance data in a manner consistent with known biochemical processes.

Caffeine is a popular stimulant often used to counter the effects of sleep loss and fatigue. Withdrawal from caffeine may produce mild declines in simple cognitive capacities such as attention and concentration, but it is unclear whether more complex cognitive functions, such as abstract reasoning or concept formation, may be similarly affected. To assess the effect of acute caffeine withdrawal on executive functioning during sleep deprivation, 26 healthy volunteers were administered in double-blind form either repeated doses of caffeine or placebo over two nights of continuous wakefulness. The 108-item Short Category Test was administered after 56 hr. of total sleep deprivation (9 hr. post-caffeine administration). The caffeine group scored significantly more poorly, making approximately 57% more errors on the test than the placebo group. These findings suggest that acute caffeine withdrawal during prolonged sleep deprivation has an adverse effect on abstract reasoning and concept formation.

Introduction: Recent research indicates that sleep deprivation impairs decision making. However, it is unknown to what extent such deficits are exacerbated in a dose-response manner by increasing levels of sleepiness, and the extent to which such sleep-loss-induced deficits can be reversed by caffeine., Methods: At three time points, 26 healthy subjects completed alternate forms of the Iowa Gambling Task (IGT): rested baseline, 51 h awake, and 75 h awake. Every 2 h each night, 12 volunteers also received 4 200-mg doses of caffeine, with the last dose occurring 3 h prior to the IGT., Results: At baseline, volunteers readily learned to avoid disadvantageous high-risk card decks while progressively choosing more frequently from advantageous low-risk card decks. When sleep deprived, however, these same subjects showed impaired performance, choosing more frequently from the disadvantageous high-risk card decks, particularly during the latter half of the game. Contrary to expectations, the severity of performance impairment did not increase significantly from 51 to 75 h of wakefulness, and caffeine had no significant effects on IGT performance during sleep deprivation., Discussion and Conclusions: As a provisional extension of our previous study, these preliminary findings further suggest that the ability to integrate emotion with cognition to guide decision making, a capacity believed to be mediated by the ventromedial prefrontal cortex, may be particularly vulnerable to sleep loss. Moreover, these capacities may not be significantly improved by moderate doses of caffeine, suggesting that they may function separately from simple arousal and alertness systems.

Purpose: This study examined caffeine (CAF) effects on physical performance and vigilance during 4 d and 3 nights of sustained operations in Special Forces personnel., Methods: There were 20 soldiers (28.6 +/- 4.7 yr, 177.6 +/- 7.5 cm, 81.2 +/- 8.0 kg) who were divided equally into placebo (PLAC) and CAF groups. A 4-km run that included three obstacles (OBST) was completed each morning with the performance on Day 2 representing control (CON) after familiarization on Day 1 and an 8-h sleep. From 01:30 to 06:15 of Days 3-5, soldiers performed two 2-h vigilance (VIG) sessions in the field. PLAC or 200 mg of CAF was administered at 21:45 of Days 2-4 and at 01:00, 03:45, and approximately 07:00 on Days 3-5. The run commenced within 30 min of the final dose. Soldiers were provided a 4-h sleep period from 13:30-17:30 during Days 3 and 4., Results: VIC during Days 3-5 was greater for CAF vs. PLAC and not different from CON. Total run time was faster for CAF (29.7 +/- 2.0 min) compared with PLAC (30.7 +/- 2.9 min) on Day 3 due to faster completion of OBST (8.7 +/- 0.7 min vs. 9.2 +/- 1.0 min for CAF and PLAC, respectively). Thereafter, run times decreased for both groups on Days 4 and 5 compared with CON due primarily to an increased pace between OBST., Conclusions: it was concluded that CAF maintained both vigilance and physical performance during sustained operations that require periods of overnight wakefulness and restricted opportunities for daytime sleep.

This study examined the combined effects of caffeine and the personality attribute of trait-anger on the speed of psychomotor vigilance performance during sleep deprivation. 23 young adult soldiers (19 male) were administered the State-Trait Anger Expression Inventory-2 when well-rested. Participants were then sleep deprived for three consecutive nights (77 hours total) during which they completed repeated psychomotor vigilance testing. Half of the participants received four doses of oral caffeine (200 mg every 2 hr.; 800 mg total) each night, while the other half were administered a placebo. For the first night, higher scores on trait-anger, outward anger expression, and intensity of anger expression predicted better sustained overnight vigilance performance, but only for those volunteers receiving caffeine. These correlations were not significant for the subsequent nights. Findings suggest a possible synergistic effect between personality traits associated with arousal of the central nervous system and vigilance-promoting effects of caffeine.

Unlabelled: The purpose of this study was to examine the pharmacokinetics of three doses of caffeine administered as Stay Alert chewing gum in a multiple dose regimen., Methods: A double-blind, parallel randomized, four-treatment study design was employed. The treatment groups were: 50, 100 and 200 mg caffeine and placebo. Subjects were 48 (n = 12 per group), healthy, non-smoking, males and females who had abstained from caffeine ingestion for at least 20 h prior to dosing, who were randomly assigned to the treatment groups. Caffeine was administered at 2,400, 0200 and 0400 h depending on the treatment group. Blood samples were collected pre-dose and at 5, 15, 30, 45, 60, 75, 90 and 105 min after each caffeine dose. Samples were also collected at 7.5, 8.5 and 18 h after the last dose of caffeine. Plasma caffeine levels were analysed by a validated UV-HPLC method., Result: The mean T(max) after the third dosing ranged from 0.37 to 1.12 h. C(max) for 50, 100 and 200 mg was 2.69, 3.45 and 6.33 mg/l, respectively. AUC(inf) for 50, 100 and 200 mg group was 33.2, 46.94 and 86.94 mg/l * h, respectively. AUC(inf) values suggested a dose proportionate increase. Dose normalized C(max) and AUC(0-tau) values across doses were not significantly different, suggesting linearity was maintained after multiple doses of the Stay Alert chewing gum. There were no group related differences in elimination., Conclusions: The results suggest that caffeine administered in the gum formulation (Stay Alert chewing gum) via a multiple dosing regimen provides an effective and convenient means of maintaining effective concentrations of caffeine that would in some operational scenarios be desirable for maintaining alertness and performance in sleep deprived individuals.

Introduction: When used to counteract the effects of sleep deprivation, multiple doses of caffeine are typically ingested across an extended period of time. The goal of this study was to determine the optimal dose of caffeine for sustaining performance during sleep loss with administration of multiple doses., Methods: There were 48 subjects (28 men, 20 women) who were randomly assigned to 1 of 4 groups (placebo, 50, 100, or 200 mg caffeine). After an overnight 8-h sleep period, subjects were required to remain awake for the ensuing 29 h. Control data were collected until 03:00 (Day 3), followed by three 2-h test blocks. At 03:00, 05:00, and 07:00 subjects chewed two sticks of gum (Stay Alerts chewing gum) containing caffeine or placebo. Six 10-min sessions on a version of the Psychomotor Vigilance Test (PVT) were completed during each 2-h test block. The Stanford Sleepiness Scale (SSS) was administered after each PVT., Results: Lapses on the PVT were categorized as response times greater than 1, 3, or 5 s. Lapses in all categories significantly increased in the placebo group. Caffeine significantly reduced the number of lapses in a dose-related manner; and performance was maintained at baseline levels for the entire sleep loss period with multiple doses of 200 mg caffeine. There was a significant main effect for session on the SSS, the score increasing over time, but no significant differences between groups., Discussion: These results indicate that a bi-hourly administration of 200 mg of caffeine maintains vigilance performance across a single night without sleep.

Purpose: This study examined the effects of caffeine (CAF) on vigilance, marksmanship, and run performance during 27 h of sustained wakefulness in Special Forces personnel., Methods: There were 31 soldiers (29.8 +/- 5.4 yr, 86.4 +/- 8.6 kg) who were divided into placebo (PLAC, n = 15) and CAF (n = 16) groups. A 6.3-km control run was completed on the morning of Day 1. In the evening of Day 2, soldiers performed a control observation and reconnaissance vigilance task (ORVT) in the field. This 90-min task was repeated twice more between 02:00 and 06:00 on Day 3 during an overnight period of sleep deprivation. Marksmanship was assessed before and after the ORVT. PLAC or 200 mg of CAF gum was administered at 01:45, 03:45, and approximately 06:30 on Day 3. A final 6.3-km run commenced within 30 min of receiving the final dose., Results: ORVT was maintained in CAF at control levels of 77 +/- 13% during the overnight testing. However, values decreased significantly for PLAC from 77 +/- 15% to 54 +/- 29% and 51 +/- 31% during the first and second overnight testing periods, respectively. CAF had no effect on marksmanship but improved 6.3-km run times by 1.2 +/- 1.8 min. Run times slowed for PLAC by 0.9 +/- 0.8 min from approximately 35 min during the control run; the changes in performance were significant between groups., Conclusions: It was concluded that CAF maintained vigilance and improved running performance during an overnight field operation for Special Forces personnel.

Introduction: Caffeine is widely used to reverse alertness and performance decrements. However, caffeine's effects on subsequent recovery sleep and post-recovery performance are not well documented and, therefore, were evaluated., Methods: Six habitually low (LC: < or = 100 mg x d(-1)) and three habitually high (HC: > or = 400 mg x d(-1)) caffeine users completed a randomized crossover design. After 20 h of wakefulness, repeated doses of caffeine gum [0 (placebo) mg, 100 (low dose) mg, or 300 (high dose) mg] were administered at 03:00, 05:00, and 07:00. At 10:00 (27 h sleep deprivation) subjects slept for 8 h, followed by Psychomotor Vigilance Task (PVT) administration at 33 and 65 min post-awakening., Results: Low dose caffeine increased stage 1 minutes only. However, high dose caffeine impaired sleep maintenance (reduced total sleep time/increased wake) and reduced sleep depth (increased stage 1 minutes/percentage and slow-wave sleep (SWS) latency, and reduced SWS minutes during the first third of the sleep period). With high dose caffeine, LC users had less SWS percentage as compared with HC users. The HC users had reduced stage 2 percentage with high dose caffeine as compared with placebo and low dose caffeine. Caffeine dose and habitual caffeine use did not influence post-recovery sleep PVT performance., Discussion: Caffeine exerts mild deleterious dose-response effects on recovery sleep following total sleep deprivation, primarily early in the sleep period, with potential recovery from these effects after sufficient sleep as suggested by lack of post-recovery sleep performance deficits. Habitual caffeine use appears to minimally reduce caffeine effects.

Purpose: The purpose of this study was to examine the effects of caffeine (CAF) on physical, vigilance, and marksmanship tasks in soldiers during a sustained 55-h field exercise., Methods: There were 30 soldiers (23.6 +/- 4.5 yr, 81.8 +/- 10.3 kg) who were divided into a placebo (PLAC) and a CAF group. After a period of restricted sleep of 3 h during the first night, a period of sustained wakefulness began that ended at 11:00 of the third day. PLAC or CAF doses of 100 mg, 200 mg, 100 mg, and 200 mg were administered at 21:45, 23:45, 01:45, and 03:45, respectively. At 22:00 of day 2, subjects began two cycles of marksmanship, urban operations vigilance, and psychomotor vigilance (PVT) testing which ended at 06:00 of day 3., Results: CAF maintained marksmanship vigilance at 85% throughout the second night as compared with PLAC, who significantly declined to 61.4 +/- 28.2% overnight. Marksmanship accuracy also decreased significantly in PLAC from 95.1 +/- 8.3% to 83.3 +/- 19.2%, but no change was observed in CAF. Urban operations vigilance decreased for both groups over the night, but the decrease was less for CAF (81.2 +/- 14.4% to 63.4 +/- 24.1%) compared with PLAC (77.6 +/- 19.2% to 44.0 +/- 30.2%). Reaction time and the number of major and minor lapses with the PVT significantly increased in PLAC but were unaffected in CAF., Conclusions: It was concluded that CAF was an effective strategy to sustain vigilance and psychomotor performance during military operations involving sleep deprivation.

Background: Reductions in both cognitive and physical performance occur during periods of sleep loss with sustained operations. It was the purpose of this study to examine the effects of caffeine on activities chosen to simulate the physical challenges that might occur during a military scenario involving a period of sleep loss., Methods: There were 16 subjects (26.7 +/- 7.8 yr, 83.8 +/- 11.0 kg) who completed a double-blind caffeine and placebo trial involving a control day and sleep period followed by 28 h of sleep deprivation. A 400-mg dose of caffeine was administered at 21:30 followed by subsequent 100-mg doses at 03:00 and 05:00. At 22:00, subjects began a 2-h forced march followed by a sandbag piling task. A treadmill run to exhaustion at 85% of maximal aerobic power was performed at 07:00 of the second day of sleep deprivation., Results: Caffeine had no effect on the heart rate or oxygen consumption, but rating of perceived exertion (RPE) was reduced with caffeine during the forced march. Time to complete the sandbag piling task during set 1 was significantly reduced with caffeine (12.9 +/- 1.0 min) compared with placebo (13.8 +/- 1.0 min) but there was no difference during set 2 and RPE was increased. Time to exhaustion was significantly increased 25% during the run with caffeine (17.0 +/- 4.4 min) compared with placebo (13.5 +/- 3.3 min), and caffeine maintained performance at control levels (16.9 +/- 4.6 min)., Conclusions: It was concluded that caffeine is an effective strategy to maintain physical performance during an overnight period of sleep loss at levels comparable to the rested state.

Objective: The purpose of this study was to evaluate the rate of absorption and relative bioavailability of caffeine from a Stay Alert chewing gum and capsule formulation., Methods: This was a double blind, parallel, randomized, seven treatment study. The treatment groups were: 50, 100, and 200 mg gum, 50, 100, and 200 mg capsule, and a placebo. Subjects consisted of 84 (n=12 per group); healthy, non-smoking, males who had abstained from caffeine ingestion for at least 20 h prior to dosing and were randomly assigned to the treatment groups. Blood samples were collected pre-dose and at 5, 15, 25, 35, 45, 55, 65, 90 min and 2, 3, 4, 6, 8, 12, 16 and 29 h post administration. Plasma caffeine levels were analyzed by a validated UV-HPLC method., Results: Mean Tmax for the gum groups ranged from 44.2 to 80.4 min as compared with 84.0-120.0 min for the capsule groups. The Tmax, for the pooled data was significantly lower (P<0.05) for the gum groups as compared with the capsule groups. Differences in Tmax were significant for the 200 mg capsule versus 200 mg gum (P<0.05). The mean ka values for the gum group ranged from 3.21 to 3.96 h-1 and for the capsule groups ranged from 1.29 to 2.36 h-1. Relative bioavailability of the gum formulation after the 50, 100 and 200 mg dose was 64, 74 and 77%, respectively. When normalized to the total drug released from the gum (85%), the relative bioavailability of the 50, 100 and 200 mg dose were 75, 87, and 90%, respectively. No statistical differences were found for Cmax and AUCinf for comparisons of the gum and capsule formulations at each dose. Within each dose level, there were no significant formulation related differences in Cmax. No significant differences were observed in the elimination of caffeine after the gum or capsule., Conclusions: The results suggest that the rate of drug absorption from the gum formulation was significantly faster and may indicate absorption via the buccal mucosa. In addition, for the 100 and 200 mg groups, the gum and capsule formulations provide near comparable amounts of caffeine to the systemic circulation. These findings suggest that there may be an earlier onset of pharmacological effects of caffeine delivered as the gum formulation, which is advantageous in situations where the rapid reversal of alertness and performance deficits resulting from sleep loss is desirable.

Objective: Determine the relationship between caffeine, catecholamines, and alertness during prolonged wakefulness., Methods: Following 49 h of prolonged wakefulness, each of 50 healthy males (18-32 years) orally ingested either a placebo or one of three doses of caffeine, 2.1 (low), 4.3 (medium), or 8.6 mg kg-1 body weight (high), in a randomized double-blind design. Wakefulness continued for an additional 12 h during which venous blood samples were collected for catecholamine and caffeine analysis [determined using high-performance liquid chromatography (HPLC)]. A sleep latency test, the Stanford sleepiness scale, and a choice reaction time test were administered periodically during the post-dosing period and served as measures of alertness (physiological, subjective, and behavioral, respectively)., Results: Caffeine had no significant effect on noradrenaline, but adrenaline was significantly increased between 1 h and 4 h post-dosing in the high dose group compared with a placebo group. Following caffeine administration, responses to sleep latency, sleepiness scores, and reaction time scores showed dose-related changes that were exhibited by significant correlation coefficients., Conclusion: The results indicate that high doses of caffeine have a significant and beneficial effect on alertness during prolonged wakefulness.

Objective: Hormonal fluctuations of estrogen and progesterone in eumenorrheic women may be capable of altering the pharmacokinetics of certain agents. The objective of this study was to determine the effect of the luteal, ovulatory and follicular phases of the menstrual cycle on the pharmacokinetics of caffeine, a low clearance, flow-independent drug., Methods: Subjects were ten healthy, non-smoking, eumenorrheic females who were not pregnant and had not used oral contraceptives for a minimum of 3 months prior to the study. Blood samples were collected during one menstrual cycle for the determination of estradiol and progesterone concentrations during the follicular (days 2-6 post-onset of menses), ovulatory (days 13-16 post-onset of menses) and luteal (days 22-26 post-onset of menses) phases. Caffeine was administered over a single menstrual cycle during the follicular, ovulatory and luteal phases. Each subject was administered a single oral dose of caffeine (300 mg) in 100 ml of lemonade during each phase of the menstrual cycle. A venous catheter was used to collect blood samples at pre-dose and at the following time points: 0.25, 0.5, 0.75, 1, 1.5, 2, 4, 6, 8, 10, 12 and 24 h. Plasma caffeine concentrations were determined using a validated ultraviolet high-performance liquid chromatography method., Results: There were no significant (P < 0.05) differences in the pharmacokinetic parameters of caffeine across the menstrual cycle phases. The average area under the plasma concentration-time curve (AUCinf) was 93.01 mg 1(-1) x h and the absorption rate constant (ka) was 2.88 h(-1) during the ovulatory phase, 83.0 mg 1(-1) h and 2.06 h(-1), respectively, during the luteal phase and 84.7 mg 1(-1) x h and 1.84 h(-1), respectively, during the follicular phase., Conclusions: These findings suggest that the menstrual cycle does not significantly alter the pharmacokinetics of caffeine.

Following 49 h of sleep deprivation, 37 healthy males ingested either 2.1, 4.3, or 8.6 mg*kg-1 body weight of caffeine in a randomized double-blind design. Subjects were sleep deprived for additional 12 h and venous blood samples were collected intermittently. Caffeine and primary metabolite concentrations were determined by HPLC. Pharmacokinetics were computed using the Lagran computer program. The ratio of the primary human metabolite, paraxanthine, to caffeine was used to estimate the rate of metabolism. There was a significant (p < 0.05) and disproportional increase in the dose normalized caffeine AUC and a significant decrease in its clearance associated with increasing dose. In addition, the paraxanthine to caffeine ratio significantly decreased with an increase in dose, indicating that the rate of caffeine metabolism decreased. These results demonstrate that under the conditions of severe sleep deprivation caffeine exhibits dose-dependent pharmacokinetics. In addition, these results are consistent with a model of capacity-limited metabolism.

Methods: The pharmacokinetics of caffeine and cardio-green (ICG) were examined in four micro swine at sea level (SEA) and following 21 d continuous exposure to 4600 m (ALT) in a hypobaric chamber. Caffeine (84.7 mg) and ICG (10 mg) were administered as separate intravenous boluses and sequential blood samples collected., Results: Caffeine clearance significantly (p < 0.05) increased in ALT (96.8 +/- 20.0 ml.min-1) as compared to SEA (53.6 +/- 24.8 ml.min-1), demonstrating that liver function increased in ALT. There was no significant change in the ratio of primary metabolites to caffeine, suggesting that the increase in clearance was not due to a change in the rate of caffeine metabolism. ICG clearance significantly increased in ALT (179.8 +/- 57.4 ml.min-1) as compared to SEA (84.4 +/- 28.9 ml.min-1) indicating that hepatic blood flow (HBF) increased., Conclusion: These results demonstrate that chronic exposure to 4600 m increases the clearance of caffeine and ICG in the micro swine model and suggests that the increase in caffeine clearance is related to HBF.

The effects of chronic exposure to high altitude on the pharmacokinetics of caffeine and cardio-green (ICG) were examined in eight healthy males (23-35 y) at sea level (SEA) and following 16 days residence at 4300 m (ALT). ICG (0.5 mg. kg-1) was administered as an intravenous bolus and caffeine (4 mg. kg-1) in an orally ingested solution. The concentration of ICG, caffeine, and the primary metabolites of caffeine (MET) were determined in serial blood samples and their pharmacokinetics computed. In comparison to SEA, ALT resulted in a significant decrease in a caffeine half-life (t1/2, 4.7 vs 6.7 h) and area under the curve (2.5 vs 3.7 g.l-1.min-1), and increased clearance (117 vs 86 ml.min-1.70 kg-1). In ALT the area under the curve the ICG significantly decreased (85 vs 207 mg.l-1.min-1) and the volume of distribution and clearance increased (5.2 vs 2.4 l and 532 vs 234 ml.min-1 respectively) compared to SEA. There was a significant increase in the AUC ratio of MET to caffeine indicating that either metabolite formation or elimination was increased in ALT. These results demonstrate that in humans, chronic exposure to 4300 m results in the modification of the pharmacokinetics of caffeine and ICG.

The effects of obesity, exercise, and the interaction of obesity and exercise were examined in 6 caffeine naive, untrained, nonsmoking, college males (3 lean (LV), 3 obese (OV]. Each subject received caffeine (oral, 5.83 mg X kg-1 lean body weight) or placebo (50 mg citrate) prior to 3 h of seated rest and prior to 90 min of treadmill walking (40% of their maximal aerobic power) followed by 90 min of seated recovery. Serum samples were collected at various times and analyzed for caffeine by HPLC. Pharmacokinetic analysis indicated that at rest, OV had a significantly higher absorption rate constant (Ka 0.0757 vs. 0.0397 min-1), lower elimination rate constant (Ke 0.0027 vs. 0.0045 min-1), and longer serum half-life (t1/2 4.37 vs. 2.59 h) in comparison to LV. In exercise, as well as at rest LV and OV had a large difference in the volume of distribution (43.2 vs. 101.1) (rest, 54.1 vs. 103.1). Exercise consistently resulted in a decrease in the maximal serum concentration of caffeine and the area under the curve in OV while having no consistent effect on LV. The interactive effects of obesity and exercise could not be dissociated. However, these results demonstrate that both obesity and exercise have modified the pharmacokinetics of caffeine.