Investigation on the Chronic Effects of Nepalese Pepper (Zanthoxylum Armatum DC) on Cognitive Function, Mood and Gaming Performance in Young, Healthy, Action Video Gamers

Zanthoxylum armatum DC (ZA), also known as Nepalese pepper, contains numerous activechemicals throughout all parts of the organism. Traditionally used in the treatment ofintestinal disorders, depression and as topical treatment for toothache, it is commonlyingested through the form of Daikenchuto, a traditional combination of the Zanthoxylumfruit with ginseng root, ginger rhizome and rice gluten. In recent years it has beenestablished that ZA also possesses cognitive enhancing properties, with the primaryactive component revealed to be the fatty acid amide hydroxy α‐sanshool. Additionally, ZAis rich in monoterpenes which have also been shown to positively affect cognition, andthe combination of these compounds may lead to numerous improvements in brain function.Through a double‐blind placebo‐controlled study, acute single dose administration of 80mgof ZA was shown to improve cognitive performance in 'Speed of Attention' and Rapid VisualInformation Processing, a sustained attention task. In the same study, chronic (56 day)administration resulted in overall improvement in 'Speed of Performance', with morecorrect Serial 3 subtractions 3h post dose and lower mental fatigue compared to placeboduring performance of the Cognitive Demand Battery (CDB). In both acute and chroniccases, the mechanisms underpinning the effects are currently unknown. For the acuteeffects there may be a cholinergic mechanism at play, with previous research suggesting acholinesterase inhibitory effect from ZA. Meanwhile, the observed chronic improvementssuggest a more general improvement in neural efficiency and processing speeds rather thanthe memory/attention benefits generally expected from cholinergic agents.An increasing area of interest for performance research is in the world of Esports andcompetitive gaming, where cognitive abilities are paramount. Esport competition incursphysical and mental demands, including motor skills, mental agility, processing speed,motivation, executive function and, to a lower degree, physical exertion. Success hingeson mastering cognitive tasks such as visuospatial processing, cognitive workload,attention and cognitive control, hand‐eye coordination, fast reaction times and quickdecision‐making. Within esports, viewership is overwhelmingly dominated by Massive OnlineBattle Arenas (MOBA) and First Person Shooters (FPS); despite sharing a similarlyfast‐paced, high‐intensity element, the contrast in player character control mechanismsbetween these genres creates distinct performance metrics, meaning studies analysing gameperformance across genres should incorporate genre‐specific measurement tools.One aspect common to all esports players is the prolonged nature of training andgameplay, requiring sustained attention and resulting in high mental demand and fatigue.Energy drink consumption is high within gamers, and an emerging area of researchconsiders the potential to enhance gaming performance via various nootropics, primarilyhighly caffeinated products. However, the high caffeine content in these products islinked to undesirable side effects including jitteriness, tension, and decreased sleepduration and quality, which can negatively impact both short‐ and long‐term gamingperformance. As gaming becomes a more viable career, gamers are likely to seek healthieralternatives, sparking interest in non‐caffeinated options to combat mental fatigue andenhance gaming performance.The previous acute study conducted by our group (53BS2) administered single doses of150mg and 300mg of a powdered ZA formulation (SaraPepp™ Nu) to assess acute cognitive andmood effects against placebo and caffeine. The main aim of the current study is toinvestigate the chronic cognitive and mood effects of 275mg ZA administered daily over 42days in young, healthy action video gamers, building on the chronic findings of Kennedyet al. (2019), in which 56‐day ZA administration improved 'Speed of Performance' andreduced subjective mental fatigue relative to placebo. A crossover design with a 2‐weekwashout period will allow for within‐participant comparisons while controlling forindividual differences. Additional aims include ascertaining whether chronic cognitiveimprovements translate into objective and subjective in‐game performance improvements,deepening understanding of how action video game genres present differing cognitivegameplay requirements, and developing robust methods of assessing gameplay performanceover an extended supplementation period.Primary objectivesThe primary objectives of this study are to evaluate the chronic effects of 275mg dailyZA supplementation within a young, healthy population, with focus on: ‐ Speed of Performance (Serial 3 subtractions, SRT, CRT, Numeric Working Memory, RVIP,Delayed Picture Recognition, Delayed Word Recognition) ‐ Subjective fatigue (CDB)These were the areas of improvement ascertained under chronic supplementation by Kennedyet al. (2019), and these results will be tested for replicability. Participants will betested using computerised cognitive tasks (COMPASS) in a randomised, double‐blind,placebo‐controlled crossover design, with assessments at pre‐dose baseline and 1hrpost‐dose at both the baseline and endpoint visit of each 42‐day treatment arm.Secondary objectivesThe secondary objectives of this study are to evaluate other cognitive areas where nosignificant changes were revealed in the previous study, to test for replication and seeif any other changes appear. These include: ‐ Accuracy of Attention (RVIP and CRT) ‐ Speed of Attention (RVIP, SRT and CRT) ‐ Accuracy of Performance (Immediate Word Recall, CRT, Corsi Blocks, RVIP, Stroop,Delayed Word Recall, Delayed Picture Recognition, Delayed Word Recognition) ‐ Working memory (Numeric Working Memory, Corsi Blocks) ‐ Speed of memory (Numeric Working Memory, Delayed Picture Recognition, Delayed WordRecognition) ‐ Episodic memory (Immediate Word Recall, Delayed Word Recall, Delayed PictureRecognition, Delayed Word Recognition) ‐ Executive Function (Peg and Ball, Stroop interference)To fulfil these objectives, the full battery of COMPASS tasks will be tested at pre‐dosebaseline and 1hr post‐dose on each testing visit, under both treatment conditions.In addition, subjective alertness and mental fatigue will be assessed following each of 3completions of the Cognitive Demand Battery (CDB), a 10‐minute battery of tasks completedthree times in immediate succession (30 minutes continuous). In addition to this, moodand sleep will also be recorded on testing visits through the Positive and NegativeAffect Schedule (PANAS), Visual Analogue Mood Scales (VAMS), and the sleep disturbanceshort form (PROMIS). Heart Rate Variability will also be assessed at rest upon arrival ateach testing visit, prior to task performance or supplementation.Further secondary objectives are to implement gaming tests to assess if any differencescan be observed in gameplay‐related outcomes following treatment. These include: an aimtrainer (Aim Labs), a Massive Online Battle Arena (MOBA) control simulator, aMulti‐Tasking Framework (MTF), a Finger Tapping Task (FTT), a Fitts' Law Task (visuomotorspeed‐accuracy trade‐off), a Multiple Object Tracking Task (MOT; divided visualattention), and a Collision Prediction Task (anticipation and trajectory prediction).In addition to this, gameplay monitoring of at‐home play will be implemented as asecondary outcome measure to assess real‐world gameplay ability across the 42‐daysupplementation period, via the Subjective Performance Gameplay Scale and gameplaytracking where possible.Investigational planThis study follows a randomised, placebo‐controlled, double‐blind, crossover design withtwo treatment arms (275mg ZA, Placebo). Participants attend the lab on five occasions: ascreening/training visit, two baseline testing visits, and two endpoint testing visits,following the structure Baseline 1 → 42‐day supplementation → Endpoint 1 → 14‐day washout→ Baseline 2 → 42‐day supplementation → Endpoint 2. Total study duration is approximately20 weeks per participant. A total sample of 70 participants will be recruited.