A caffeine and theacrine combination improves cognitive performance in tactical personnel under physically fatiguing conditions.

Background: Optimizing human performance under stressful physical and cognitive conditions is paramount during high-stakes military operations. As such, interventions to improve warfighter performance by mitigating task-induced cognitive performance deficits are necessary. While caffeine is the most widely consumed psychoactive substance in the world, common side effects (i.e. anxiousness, micro-saccades, irritability) may be detrimental to warfighter operations. Theacrine, a purine alkaloid similar in structure to caffeine but with a longer half-life, less habituation, and fewer side effects, is proposed as a caffeine-alternative to enhance cognitive resilience.

Methods: Tactically trained participants (n = 20; F = 5; M = 16; age = 21.5 ± 3.8 y) completed one baseline and three experimental visits. Baseline included familiarization with cognitive tasks and a graded exercise test to determine VO_2max. Experimental sessions, separated by ≥96 hours, were double-blind, placebo-controlled, and randomized. Participants completed cognitive testing (Dynavision, Trazer, Object Hit and Avoid, Anti-Saccade, Two-Back), consumed either 300 mg caffeine (CAF), 150 mg caffeine +150 mg theacrine (CTC), or placebo (PLA), and repeated cognitive tests 60-min post supplementation. After a high-intensity interval exercise session (10 intervals at >90% VO_2max with recovery), reaction time (RT) tests were repeated after the 4th and 8th intervals, as well as immediately and 30-min post-exercise. Heart rate was measured continuously. Change scores were calculated from baseline, and data analyzed using repeated measures ANOVA (α = 0.05) with Bonferroni correction.

Results: Both CAF and CTC consistently enhanced cognitive and physical performance compared to PLA. In the Two-Back task, CTC showed significantly higher total accuracy (p < 0.01), while both CAF and CTC had fewer target (p < 0.01) and non-target errors (CAF: p = 0.03; CTC: p < 0.01) than PLA. CTC also had significantly faster RTs (p = 0.03) and lower RT variability for non-target trials compared to both PLA and CAF (p < 0.01). For the Dynavision Go/NoGo task, both CTC (p = 0.01) and CAF (p = 0.03) had significantly faster RTs than PLA, regardless of time point. Post-exercise, accuracy (p = 0.01) and RTs (p < 0.01) improved significantly compared to post-supplement. In the Object Hit & Avoid task, CAF and CTC significantly improved task accuracy (p < 0.01) while reducing omission (p < 0.01) and commission errors (p < 0.01) compared to PLA. HRV measures (RMSSD, NN intervals, SDNN) significantly increased post-supplementation (p < 0.01) but decreased immediately (p < 0.01) and 30 min post-exercise (p < 0.01). Blood lactate significantly declined at 5 (p < 0.01) and 10 min (p < 0.01) post-exercise compared to immediately post-exercise.

Conclusion: SIngestion of CAF and CTC improved various measures of cognitive performance before, and after fatiguing exercise. Furthermore, CTC had additional cognitive benefits beyond CAF. Thus, combining lower-dose caffeine and theacrine may improve cognitive-behavioral performance before and after fatiguing exercise to an equal or greater degree than higher doses of caffeine alone. This combination offers a non-pharmacological intervention for those who experience side effects with caffeine to mitigate the impact of physical and cognitive stress. Future research should examine higher doses of theacrine alone or with caffeine, chronic supplementation, extended exercise durations, and different cognitive metrics under varied stress and environmental conditions.