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, 72 Suppl 1 (0 1), 34-47

Cumulative Neurobehavioral and Physiological Effects of Chronic Caffeine Intake: Individual Differences and Implications for the Use of Caffeinated Energy Products


Cumulative Neurobehavioral and Physiological Effects of Chronic Caffeine Intake: Individual Differences and Implications for the Use of Caffeinated Energy Products

Andrea M Spaeth et al. Nutr Rev.


The use of caffeine-containing energy products has increased worldwide in recent years. All of the top-selling energy drinks contain caffeine, which is likely to be the primary psychoactive ingredient in these products. Research shows that caffeine-containing energy products can improve cognitive and physical performance. Presumably, individuals consume caffeine-containing energy products to counteract feelings of low energy in situations causing tiredness, fatigue, and/or reduced alertness. This review discusses the scientific evidence for sleep loss, circadian phase, sleep inertia, and the time-on-task effect as causes of low energy and summarizes research assessing the efficacy of caffeine to counteract decreased alertness and increased fatigue in such situations. The results of a placebo-controlled experiment in healthy adults who had 3 nights of total sleep deprivation (with or without 2-hour naps every 12 hours) are presented to illustrate the physiological and neurobehavioral effects of sustained low-dose caffeine. Individual differences, including genetic factors, in the response to caffeine and to sleep loss are discussed. The review concludes with future directions for research on this important and evolving topic.

Keywords: alertness; caffeine; circadian rhythm; energy drinks; fatigue.

Conflict of interest statement

Andrea Spaeth and Namni Goel, Ph.D.have no conflicts of interest to disclose.


Figure 1
Figure 1. Overview of Chronic Caffeine Study Protocol
Fifty-eight healthy male subjects (mean age, 29 years) with a history of moderate caffeine intake were admitted to the Hospital of the University of Pennsylvania. Subjects did not use any caffeine, alcohol, tobacco or other medications in the two weeks prior to or during the experiment. The laboratory experiment began with one adaptation day and two baseline (BL) days with bedtimes from 23:30h-07:30h. Subjects then underwent 88 hours of extended wakefulness (i.e. three nights of total sleep deprivation; TSD). If subjects were randomized to the NAP condition, they were provided with seven 2-hour nap opportunities scheduled every 12 hours from 14:45h-16:45h and from 02:45h-04:45h. Starting 22 hours into the 88-hour period of extended wakefulness, subjects received a pill containing either 0.3 mg/kg caffeine or placebo every hour (except during naps). After the 88-hour period of extended wakefulness, subjects remained in the laboratory for 1-2 nights of recovery sleep.
Figure 2
Figure 2. Plasma Caffeine Levels among Subjects Administered Caffeine during Extended Wakefulness
Subjects were administered placebo or caffeine (0.3 mg/kg) every hour from hours 22-88 of extended wakefulness (i.e. they received 66 pills). For example, a 75 kg subject would have received 22.5 mg of caffeine per pill which results in a total cumulative dose of 1485 mg caffeine (540 mg caffeine per day). Blood samples were taken via an indwelling intravenous catheter for assessment of plasma concentrations of caffeine at 90 minute intervals. Caffeine levels were assessed using standardized radioimmunoassay techniques. Caffeine levels rose steadily within 3.25 hours of the first administration. There were marked individual differences in plasma caffeine levels (indicated by SD and the CMax range: 2.0-9.4 mg/l). Following the end of administration, there was a steady decline in plasma caffeine levels. Data shown as Mean ± SD for n=25 subjects receiving caffeine (unpublished findings).
Figure 3
Figure 3. Core Temperature among Subjects Administered Caffeine or Placebo during 88 hours of Extended Wakefulness
Core temperature was monitored continuously from Baseline Day 3 until the end of the 88 hour period of extended wakefulness (total sleep deprivation). Core temperature was sampled at 2-minute intervals using a Steri-Probe 491B rectal thermistor (YSI, Yellow Springs, OH) connected to an Actillume ambulatory recording system (Ambulatory Monitoring, Inc., NY). Core temperature was significantly higher in the caffeine group relative to the placebo group 4-22 hours after the first caffeine administration (p< 0.0001). As expected, both groups demonstrated a significant circadian rhythm in core temperature. Data presented as raw means (unpublished findings).
Figure 4
Figure 4. Plasma Noradrenaline Levels among Subjects Administered Caffeine or Placebo during 88 hours of Extended Wakefulness
Plasma noradrenaline levels were assessed in blood samples taken every 90 minutes beginning on Baseline Day 3 (BL 3), through the 88 hours of extended wakefulness (total sleep deprivation; TSD1-3) and ending during the first recovery day (REC). Although sleep loss did not significantly affect noradrenaline levels, sustained low-dose caffeine administration significantly increased plasma noradrenaline levels compared to placebo administration (p=0.016). There were notable individual differences in plasma noradrenaline levels in response to caffeine (the standard deviation on TSD Day 3 was much larger among subjects in the caffeine group (SD=389.1) compared to subjects in the placebo group (SD=161.7). Data shown as Mean ± SEM for n=17 subjects in the TSD Condition (unpublished findings).
Figure 5
Figure 5. Neurobehavioral Performance across 88 hours of Extended Wakefulness
Subjects were randomized to one of four conditions during 88 hours of extended wakefulness: No nap opportunities with placebo treatment (TSD/Placebo), No nap opportunities with caffeine treatment (TSD/Caffeine), 2-hour nap opportunities every 12 hours with placebo treatment (NAP/Placebo) and 2-hour nap opportunities every 12 hours with caffeine treatment (NAP/Caffeine). Standardized measures of performance were collected every 2 hours using a 30-minute computerized assessment battery. This test battery included the Psychomotor Vigilance Test (PVT), the Digit Symbol Substitution Test (DSST) and the Probed Recall Memory Task (PRM). The PVT is a simple reaction time test of behavioral alertness that is free of a learning curve and is highly sensitive to sleep deprivation. During the DSST, subjects are presented with nine different symbols which each correspond to a number (1-9) and must type in the correct number when each symbol that appears on the screen. In the PRM task subjects are presented with a list of six word pairs for 30 seconds and then after taking another test for 10 minutes, subjects are given one word from each set of pairs and have 2.5 minutes to fill in the complementary word. Sleep deprivation led to significantly slower reaction times (A) and an increase in the number of lapses in attention (B) on the PVT, a decreased number of correct responses on the DSST, reflecting slowed cognitive throughput (C) and a decrease in the number of words correctly recalled on the PRM, indicating impaired memory (D). Caffeine administration improved reaction time and reduced attentional lapses during the first 22 hours of administration (hours 24-46 of extended wakefulness; p< 0.05) but had no significant effect on DSST or PRM performance. Naps in combination with caffeine improved performance on all three tasks across the entire period of extended wakefulness. Data presented as raw means (unpublished findings).
Figure 6
Figure 6. Caffeine and Sleep Inertia
Performance lapses (> 500 ms reaction time; total per test bout) on the PVT are shown. Dotted lines indicate the placebo condition; solid lines indicate the caffeine condition. The data are presented as collapsed over the consecutive 12-hour segments around the last five naps of the experiment. Thus, the abscissa is collapsed over AM and PM times of day; naps (gray bar) took place from 14:45h-16:45h and from 02:45- 04:45h. Sleep inertia (increases in the number of PVT lapses) was consistently observed immediately after each nap in the placebo condition, but not in the caffeine condition. Data presented as Mean ± SEM for n=28 subjects in the NAP condition. (Figure reprinted with permission from Van Dongen et al., 2001, Sleep).

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