Cognitive Performance and Sleep Quality Following Caffeinated Chewing Gum in Night-shift Emergency Physicians: A Double-blind Randomized Crossover Controlled Trial
Phase: NA
Conditions: Cognitive Performance, Sleep Quality
Sponsor: China Medical University Hospital

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Cognitive Performance Following Caffeinated Chewing Gum in 
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night-shift Emergency Physicians: A Double-blind Randomized 
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Crossover Controlled Trial 
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China Medical University Hospital, Taichung, Taiwan. 404. 
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Document Date: Nov. 13, 2024 
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Project summary 
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This study aimed to examine the impact of caffeinated chewing gum on the cognitive 
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performance of night-shift emergency physicians in a partially sleep-deprived state. A 
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randomized, double-blind crossover controlled experimental design was employed in 
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which fourteen (Age: 29.9 ± 1.44; height: 176.5±5.3; weight: 78.1±13.4) emergency 
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physicians consumed either caffeinated chewing gum (CAF) containing 200 mg 
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caffeine or a caffeine-free placebo gum (PLA) for 10 minutes at 03:30 am during their 
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first 8-hour night shift after at least one day off, and completed cognitive performance 
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tests before shift, mid-shift (10 minutes after gum chewing), and after shift, including 
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included Corsi block test, Task-switching paradigm, Stroop Test, Visual search, and 
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Wisconsin Card Sorting Task. Sleep quality was assessed subjectively by a single 
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question score, and objectively by ActiGraph for one night on the off day and the last 
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sleep before the first night shift, to evaluate the effect of sleep quality on cognitive 
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performance. 
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Keywords: Reaction time, cognitive function, Stoop test, Visual search, Patient safety 
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Introduction 
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A substantial body of research has demonstrated that the cognitive function of night 
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shift doctors declines significantly before work [1-4], particularly in the context of the 
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first consecutive night shift [5]; This raises concerns about the potential impact on 
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patient safety. Consequently, there has been a significant focus on night shift scheduling 
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and working hours [6], to identify the most appropriate rotation method and working 
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hours for emergency physicians to ensure patient safety [7]. 
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Caffeine is a psychoactive substance found in many drinks and certain foods. The 
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most widely known and consumed source of caffeine is coffee, but caffeine is also 
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found in tea, energy drinks, carbonated soft drinks, fruit, and foods containing cocoa [8, 
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9]. It is a recognized stimulant with psychomotor activation and alertness effects [10] 
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and is often consumed by night shift workers, drivers, or the general public. Recent 
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studies have also found that caffeine may reduce the risk of dementia and cognitive 
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decline in the elderly and improve cognitive decline in people with cognitive 
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impairment [11]. Low-dose caffeine's primary mechanism of action as a 
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psychostimulant is based on central antagonism at A1 and A2A adenosine receptors at 
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doses typically consumed orally with caffeinated foods and beverages. Caffeine's 
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ability to bind to adenosine receptors helps to inhibit the brakes exerted by endogenous 
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adenosine on the ascending dopamine and arousal systems, thereby enhancing 
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cholinergic and dopaminergic transmission [12, 13]. Thus, caffeine intake helps to 
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improve self-reported energy, mood, and cognitive functions such as attention; it may 
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also improve simple reaction time, choice reaction time, memory, or fatigue [11, 14]. 
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The ability of caffeine supplementation to improve cognitive function has been 
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studied in several areas. For example, caffeine supplementation was found to be 
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effective in improving visual search and engagement speed in an alert state one hour 
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before a test in e-sports athletes [15], as well as increasing the speed of keyboard 
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tapping [16], increasing reaction time, and improving shot precision in e-sports 
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shooting events [17, 18], and decreasing reaction time in a Stroop task [17, 19]. In 
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addition, players in such video games must utilize different control strategies to respond 
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quickly to fast-paced, high-stress visual and auditory stimuli, and they must have 
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autonomy to adapt to changing environments [20]. This is similar to emergency 
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physicians, who must respond quickly to changes in patient conditions in a high-
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pressure work environment. Zabelina et al., Crawford et al. and Marsden et al. have 
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also shown that caffeine significantly improves problem-solving abilities [21-23]. 
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Therefore, emergency physicians, who may be exposed to fast-paced, high-stress visual 
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and auditory stimuli, may be able to find strategies to overcome these challenges by 
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improving their problem-solving abilities through caffeine. 
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Graham Marsden and John Leach also found that caffeine improved visual search 
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performance in experienced navigators [21], which may also be related to emergency 
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physicians' ability to search for lesions on diagnostic clues and medical images. In 
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addition, caffeine has been shown to improve performance and cognitive functioning 
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in shift workers in a review of the literature [24]. In recent years, caffeine chewing gum 
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has been marketed to facilitate and accelerate caffeine intake [25], and studies have 
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examined the effects of caffeine gum on cognitive performance in e-sports players [17]. 
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However, no studies have been conducted on the effects of caffeine supplementation on 
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cognitive functioning in night-shift emergency physicians with caffeinated chewing 
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gum. 
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This study aims to investigate whether caffeine supplementation with caffeinated 
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chewing gum can be used by emergency physicians during night shifts to maintain 
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proper cognitive functioning and thus patient safety. At the same time, sleep monitoring 
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was performed to observe whether caffeine supplementation affected subsequent sleep. 
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This is to provide emergency physicians with a reference for caffeine supplementation 
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with caffeine gum during night shift work. 
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2. Methods 
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2.1. Design 
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    This experiment was a double-blind, repeated-measures, crossover design 
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according to the guidelines of CONSORT 2010[26] and was divided into either a 
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caffeine trial (CAF) or a placebo trial (PL). To eliminate the impact of individual 
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physical differences, a crossover trial was conducted with the same group of subjects. 
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Randomized groups were created using Microsoft 365-Excel (Microsoft, Redmond, 
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Washington, United States), and allocation was randomized and unpredictable. Each 
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trial was separated by at least four weeks to avoid interactive effects. This study 
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compared CAF and PL trial to determine the effects of caffeinated chewing gum on 
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cognitive performance in emergency physicians engaged in night shift work., and 
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subjective, objective sleep quality. Caffeinated chewing gum and placebo chewing gum 
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are very similar in appearance, color, size, shape, and flavor and are difficult to 
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distinguish. The randomization was carried out by a research assistant, with another 
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resident performing the experiment, and neither the subjects themselves nor the resident 
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experimenting knew which group the subjects were assigned to or what type of gum 
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they were assigned. Once the data has been collected, it will be forwarded to the group's 
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statistical analyst for statistical analysis, who was also unaware of the group 
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assignments. At least one week before the formal experiment, all subjects participated 
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in three to five familiarization tests for the cognitive function tests. Sleep quality was 
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also assessed subjectively by a single question score, and objectively by ActiGraph for 
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one night on the off day and the last sleep before the first night shift. The primary 
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outcome was the results of cognitive function tests, and the secondary outcome was the 
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sleep quality. 
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2.2. Participants 
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Fourteen healthy male emergency physicians were recruited in this study and 
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based on previous research on caffeine in e-sport athletes [17, 18], we used the G*power 
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3.1 software 24 to achieve an alpha value of 5% and a power of 0.8, which was 
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sufficient for the study with only six subjects. However, due to the lack of relevant 
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studies on the effects of caffeine and caffeinated chewing gum on cognitive functioning 
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in night-shift healthcare workers, reference was made to a recent study that examined 
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the cognitive performance of emergency physicians after 24 consecutive hours of on-
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call duty, which included 13 subjects [3]. Therefore, it should be adequate to interpret 
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the data derived and statistics from the study.  
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All participants had experience working regular rotating shifts on the emergency 
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clinical front line and regularly accepted night shift assignments each month. The 
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inclusion criteria were: (i) healthy male adults, those individuals who are free of pain, 
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insomnia, or other injuries recently, without any medication used in recent 2 months, 
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(ii) underwent rotating shifts on the emergency clinical front line with regularly 
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accepted night shift more than two years. The exclusion criteria were: (i) allergy to 
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caffeine, (ii) experience of adverse effects of caffeine, (iii) with cardiovascular diseases 
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or any disease that made subjects feel ill. Two weeks before the main trial, all the 
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participants were asked to avoid ingestion of more than 80 mg of caffeine a day. Before 
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the experiment, all participants were fully informed of the experimental procedures and 
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risks and provided informed consent. This study received approval from the 
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Institutional Review Board of China Medical University Hospital (CMUH111-REC2-
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169). This study was conducted following the Declaration of Helsinki. 
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2.3. Protocol 
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2.3.1. Experimental procedure 
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The entire study was conducted in the office of the emergency department of China 
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Medical University Hospital, and the indoor ambient temperature was set at 22°C. 
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Participants’ diet and mealtimes were recorded for the 3 days before the first formal 
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experiment, and the participants were required to follow the same diet 3 days before 
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the next formal experiment. They were also required to avoid food and beverages with 
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caffeine (e.g., coffee, energy drinks, chocolate, chocolate drink, and tea) 3 days before 
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the formal experiment. 
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On the day of the formal experiment, participants had breakfast and lunch at 08:00 
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and 12:00, respectively. The participants arrived at the office at approximately 23:20 
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for the experiment. A brief explanation was given and the cognitive test was 
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administered at 23:30, which took about 20 minutes to complete, after which the 
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subjects were ready to go to work. At 03:30, according to the randomized results, the 
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subjects were given two pieces of caffeinated chewing gum at an absolute dose of 200 
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mg (Military Energy Gum®, Ford Gum and Machine Go, Akron, NY, USA) (CAF trial) 
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or two pieces of similar looking and tasting placebo gum that did not contain caffeine 
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(xylitol, lime mint, green; Lotte, Saitama, Japan) (PLA trial). After 10 minutes of 
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chewing, cognitive function tests were administered. Finally, the last cognitive function 
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tests were performed after duty at 08:20. All subjects used a dedicated computer with a 
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screen frame rate of at least 240 Hz and a mouse response rate of 1ms.  
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To explore the validity of the blinding method, we asked the participants (before 
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and after the test) to identify the supplements they ingested. To do this, the question 
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was as follows: “Which supplement do you think you ingested?” There are three 
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possible answers to this question: (a) caffeine; (b) placebo; and (c) don't know. 
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Furthermore, the occurrence of side effects or complications was recorded during the 
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trial. 
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2.3.2. Outcome measure 
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2.3.2.1. Cognitive function tests  
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Subjects were sequentially given five tests: Corsi block test, Task-switching 
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paradigm, Stroop Test, Visual search, and Wisconsin Card Sorting Task. All the above 
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cognitive function tests were conducted using Psych/Lab for Windows. Measures used 
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in the literature have satisfactory reliability and validity[27]. 
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2.3.2.1.1. Corsi block test 
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There will be 9 purple squares in the screen, when the test starts, it will flash a 
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number of them randomly in yellow color (the more the number increases), then you 
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will hear “Go”, then you have to click the order of the flashing ones, and then press 
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“DONE” in the lower right corner. The smiley face means correct, the crying face 
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means wrong. The maximum number of correct answers will be displayed at the end of 
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the test, which is mainly to test the ability of situational awareness and working memory. 
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The whole process takes about 2 minutes[28-30].  
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2.3.2.1.2. Task-switching paradigm 
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There are two shapes (circle, square) and two colors (yellow, blue), four 
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combinations in total. At the beginning of the test, you will see “SHAPE” or “COLOR” 
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(which means that the answer to the question will be based on the shape or color), and 
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then a colorful pattern (e.g., yellow square or blue circle) will appear, then answer the 
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question according to the answer you have just seen (shape or color) as soon as possible. 
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Press B for circles, N for squares, B for yellow, N for blue, and finally the average 
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reaction speed is displayed, which is a test of cognitive structure, flexibility, and 
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plasticity in task processing. The whole test takes about 4 minutes[31, 32].  
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2.3.2.1.3. Stroop Test 
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In this quiz, you will see different colors for different words, but all the answers 
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are based on the colors (no matter what the words are). Press R for red, G for green, B 
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for blue, and Y for yellow; for example, if you see “green in red color”, you have to 
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press R. The test results comprised a congruent condition, in which the key pressed 
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corresponded correctly to the color on the screen, and an incongruent condition, in 
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which the key pressed corresponded incorrectly to the color name on the screen. At the 
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end of the test, the reaction time will be displayed, which is mainly a test of the ability 
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to inhibit cognitive interference. The whole test takes about 5 minutes[33, 34].  
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2.3.2.1.4. Visual search 
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In the visual search test, participants identified orange “T” s on the screen from 
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upside-down orange “T” s, blue “T” s, and upside-down blue “T” s. When an orange 
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“T” would appear, the participants were required to press the spacebar as quickly as 
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possible. If no orange “T” appeared, the participants were required to not react. The test 
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contains 80 search displays, each containing 5, 10, 15 and 20 items, mainly to test the 
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search ability of dynamic vision. Reaction speed was displayed at the end of the test, 
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and the whole test took about 4 minutes[15, 21, 35].  
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2.3.2.1.5. Wisconsin Card Sorting Task 
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There is a trial-and-error component to this test. You have to answer the questions 
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first and then determine what the question is based on what is right or wrong. The test 
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is presented in a matching mode, where a pattern on the left is matched with one of the 
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four patterns on the right, and the matching criteria are color, shape, and number. During 
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the test, the questions will be changed from time to time, so if you find out the rules 
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and then suddenly get a question wrong, it means that the question has been changed. 
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The number of errors is displayed at the end of the test to help measure a person's ability 
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to reason abstractly and to change problem-solving strategies when necessary. The 
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entire test lasted about 4 minutes[36-38].  
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2.3.2.2. Measure Of Sleep 
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Participants wore a wrist ActiGraph (wActiSleep, Pensacola, Florida, United 
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States) on the nondominant hand for 2 sleep periods, including the sleep on off day and 
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the sleep before the first third night duty. The sleep data were obtained from ActiGraph 
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monitors and analyzed by ActiLife software version 6 using the Cole-Kripke algorithm, 
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including eight sleep indices (sleep latency, total counts, sleep efficiency, total sleep 
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time [TST], wake after sleep onset [WASO], number of awakenings, length of 
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awakenings, time in bed)[39, 40]. Participants also recorded the time they went to bed 
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and woke up to enable coordinate checks with the actigraphic data. Daily sleep quality 
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was measured using a question that was chosen because it was easy to conceptualize, 
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simple to understand, and less burdensome for participants. The question asked was: 
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On a scale of 0-10, with 0 being the worst sleep and 10 being the best, rate the quality 
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of the previous sleep[41]. 
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Participants self-reported age, marital status, exercise habits, smoking, caffeine 
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and alcohol consumption, and chronic diseases. Height and weight were measured from 
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which body mass index (BMI) was calculated as weight in kilograms divided by the 
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square of height in meters (kg/m2).  
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Statistical analysis 
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All data are presented as averages ± standard deviations. The Shapiro–Wilk test 
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was used to examine the normality of the data. Cognitive performance, accuracy, and 
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hit reaction time were analyzed through a paired sample t test. Effect sizes were 
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calculated using Cohen's D. Tests were performed (t tests or χ2 tests) to test for 
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differences at baseline between the two groups. A 2 × 2 mixed-design analysis of 
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variance with repeated measures was used to examine the effects of the intervention. 
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The Bang's Blinding Index (BBI ) was used to explore the effectiveness of the blinding 
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whereas the McNemar test was used in the comparison of the incidence of side-effects 
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between the placebo and caffeine conditions. All data were calculated using SPSS 
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(version 20, Chicago, IL, USA), and the significance level was α < 0.05. 
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