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 active chemicals throughout all parts of the organism. Traditionally used in the treatment of intestinal disorders, depression and as topical treatment for toothache, it is commonly ingested through the form of Daikenchuto, a traditional combination of the Zanthoxylum fruit with ginseng root, ginger rhizome and rice gluten. In recent years it has been established that ZA also possesses cognitive enhancing properties, with the primary active component revealed to be the fatty acid amide hydroxy α-sanshool. Additionally, ZA is rich in monoterpenes which have also been shown to positively affect cognition, and the combination of these compounds may lead to numerous improvements in brain function.

Through a double-blind placebo-controlled study, acute single dose administration of 80mg of ZA was shown to improve cognitive performance in 'Speed of Attention' and Rapid Visual Information Processing, a sustained attention task. In the same study, chronic (56 day) administration resulted in overall improvement in 'Speed of Performance', with more correct Serial 3 subtractions 3h post dose and lower mental fatigue compared to placebo during performance of the Cognitive Demand Battery (CDB). In both acute and chronic cases, the mechanisms underpinning the effects are currently unknown. For the acute effects there may be a cholinergic mechanism at play, with previous research suggesting a cholinesterase inhibitory effect from ZA. Meanwhile, the observed chronic improvements suggest a more general improvement in neural efficiency and processing speeds rather than the memory/attention benefits generally expected from cholinergic agents.

An increasing area of interest for performance research is in the world of Esports and competitive gaming, where cognitive abilities are paramount. Esport competition incurs physical and mental demands, including motor skills, mental agility, processing speed, motivation, executive function and, to a lower degree, physical exertion. Success hinges on mastering cognitive tasks such as visuospatial processing, cognitive workload, attention and cognitive control, hand-eye coordination, fast reaction times and quick decision-making. Within esports, viewership is overwhelmingly dominated by Massive Online Battle Arenas (MOBA) and First Person Shooters (FPS); despite sharing a similarly fast-paced, high-intensity element, the contrast in player character control mechanisms between these genres creates distinct performance metrics, meaning studies analysing game performance across genres should incorporate genre-specific measurement tools.

One aspect common to all esports players is the prolonged nature of training and gameplay, requiring sustained attention and resulting in high mental demand and fatigue. Energy drink consumption is high within gamers, and an emerging area of research considers the potential to enhance gaming performance via various nootropics, primarily highly caffeinated products. However, the high caffeine content in these products is linked to undesirable side effects including jitteriness, tension, and decreased sleep duration and quality, which can negatively impact both short- and long-term gaming performance. As gaming becomes a more viable career, gamers are likely to seek healthier alternatives, sparking interest in non-caffeinated options to combat mental fatigue and enhance gaming performance.

The previous acute study conducted by our group (53BS2) administered single doses of 150mg and 300mg of a powdered ZA formulation (SaraPepp™ Nu) to assess acute cognitive and mood effects against placebo and caffeine. The main aim of the current study is to investigate the chronic cognitive and mood effects of 275mg ZA administered daily over 42 days in young, healthy action video gamers, building on the chronic findings of Kennedy et al. (2019), in which 56-day ZA administration improved 'Speed of Performance' and reduced subjective mental fatigue relative to placebo. A crossover design with a 2-week washout period will allow for within-participant comparisons while controlling for individual differences. Additional aims include ascertaining whether chronic cognitive improvements translate into objective and subjective in-game performance improvements, deepening understanding of how action video game genres present differing cognitive gameplay requirements, and developing robust methods of assessing gameplay performance over an extended supplementation period.

Primary objectives

The primary objectives of this study are to evaluate the chronic effects of 275mg daily ZA 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 Kennedy et al. (2019), and these results will be tested for replicability. Participants will be tested using computerised cognitive tasks (COMPASS) in a randomised, double-blind, placebo-controlled crossover design, with assessments at pre-dose baseline and 1hr post-dose at both the baseline and endpoint visit of each 42-day treatment arm.

Secondary objectives

The secondary objectives of this study are to evaluate other cognitive areas where no significant changes were revealed in the previous study, to test for replication and see if 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 Word Recognition)
• Episodic memory (Immediate Word Recall, Delayed Word Recall, Delayed Picture Recognition, 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-dose baseline 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 3 completions of the Cognitive Demand Battery (CDB), a 10-minute battery of tasks completed three times in immediate succession (30 minutes continuous). In addition to this, mood and sleep will also be recorded on testing visits through the Positive and Negative Affect Schedule (PANAS), Visual Analogue Mood Scales (VAMS), and the sleep disturbance short form (PROMIS). Heart Rate Variability will also be assessed at rest upon arrival at each testing visit, prior to task performance or supplementation.

Further secondary objectives are to implement gaming tests to assess if any differences can be observed in gameplay-related outcomes following treatment. These include: an aim trainer (Aim Labs), a Massive Online Battle Arena (MOBA) control simulator, a Multi-Tasking Framework (MTF), a Finger Tapping Task (FTT), a Fitts' Law Task (visuomotor speed-accuracy trade-off), a Multiple Object Tracking Task (MOT; divided visual attention), and a Collision Prediction Task (anticipation and trajectory prediction).

In addition to this, gameplay monitoring of at-home play will be implemented as a secondary outcome measure to assess real-world gameplay ability across the 42-day supplementation period, via the Subjective Performance Gameplay Scale and gameplay tracking where possible.

Investigational plan

This study follows a randomised, placebo-controlled, double-blind, crossover design with two treatment arms (275mg ZA, Placebo). Participants attend the lab on five occasions: a screening/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 approximately 20 weeks per participant. A total sample of 70 participants will be recruited.

Inclusion criteria

• Aged 16 to 39 years inclusive
• Males and females
• Self-report of good health
• Usually a regular (at least 5 hours per week on average) player of action video games, including but not limited to First-Person Shooters (FPS) and Massive Online Battle Arenas (MOBA), (prospective participants will be asked to contact the researchers to discuss their gaming habits if uncertain that they meet the criteria).

Exclusion criteria

• Have any pre-existing medical condition/illness which will impact taking part in the study (i.e. participants may be allowed to progress to screening if they have a condition/illness which would not interact with the active treatments or impede performance).
• Are currently taking prescription medications. NOTE: the explicit exceptions to this are contraceptive treatments for female participants, and those taken 'as needed' in the treatment of asthma and hay fever. There may be other instances of medication use which, where no interaction with the active treatments is likely, and which would not be expected to have any impact on brain function, participants may be able to progress to screening.
• Have high blood pressure (systolic over 139 mm Hg or diastolic over 89 mm Hg); or have low blood pressure (systolic below 90 mm Hg or diastolic below 60 mm Hg)
• Have a Body Mass Index (BMI) outside of the range 18.5-35 kg/m2
• Are pregnant, seeking to become pregnant or lactating
• Have learning and/or behavioural diagnoses such as dyslexia or ADHD
• Have a visual impairment that cannot be corrected with glasses or contact lenses (including colour-blindness)
• Smoke tobacco or vape nicotine or use nicotine replacement products
• Excessive caffeine intake (> 500 mg per day). If participants consume energy drinks they will be asked to refrain from this for 24 hours prior to attending testing.
• Have relevant food intolerances/sensitivities.
• Have taken antibiotics within the past 4 weeks
• Have taken dietary supplements e.g. Vitamins, omega 3 fish oils etc. in the last 4 weeks (Note: participation is possible following a 4-week supplement washout prior to participating and for the duration of the study on the proviso that the supplements taken are out of choice and not medically prescribed or advised)
• Have any health condition that would prevent fulfilment of the study requirements (this includes non-diagnosed conditions for which no medication may be taken)
• Are unable to complete all of the study assessments
• Are currently participating in other clinical or nutrition intervention studies, or have done so in the past 4 weeks
• Has been diagnosed with/ undergoing treatment for alcohol or drug abuse in the last 12 months
• Have been diagnosed with/ undergoing treatment for a psychiatric disorder in the last 12 months
• Suffers from frequent migraines that require medication (more than or equal to 1 per month)
• Sleep disorders or are taking sleep aid medication
• Any known active infections
• Are non-compliant with regards treatment consumption