**Background:** Body composition and power-to-weight ratio are key performance determinants in sport, and increasing skeletal muscle mass is a common goal for athletes and recreationally active individuals. Pain management—whether from injury, delayed onset muscle soreness (DOMS), or menstrual pain—is critical for athletes, as pain can reduce training time, impair performance, and negatively affect sleep. Despite this, many athletes use non-steroidal anti-inflammatory drugs (NSAIDs) prophylactically; one study reported elite Olympic athletes are 3.6 times more likely to use NSAIDs than age-matched controls, and 10–20% of elite footballers take NSAIDs before almost every match. However, NSAIDs inhibit cyclooxygenase-2 (COX-2), which negatively affects anabolic signalling pathways that induce the muscle protein synthetic response to exercise, potentially impairing long-term muscular adaptations. Palmitoylethanolamide (PEA) is a nutraceutical with analgesic and anti-inflammatory properties that acts via different mechanisms (PPARα, GPR55, and indirectly via CB1/CB2 and TRVP1 receptors) without inhibiting COX-2. Unlike NSAIDs, orally-dosed PEA increases protein kinase B (PKB) phosphorylation following exercise, which plays an integral role in anabolic pathways promoting skeletal muscle hypertrophy. PEA may also improve sleep quality and duration. Doses of 300–1200 mg/day have been well-tolerated and effective for pain in osteoarthritis and for reducing markers of skeletal muscle damage following damaging exercise.
**Methods:** This is a double-blind, randomised controlled trial conducted at Deakin University, Burwood campus (approved by DUHREC: 2021–312; registered ANZCTR: ACTRN12621001726842p). Recruitment began March 2022 and was expected to finish March 2023. The study spans 11 weeks, including 8 weeks of supervised progressive resistance training (2 sessions/week on non-consecutive days). Participants are males and females aged 18–35 years who are recreationally active (≥150 min/week moderate-intensity physical activity), have stable body mass for 2 months, and BMI ≥18.5 to ≤28 kg/m². Exclusion criteria include major musculoskeletal injury in the past 6 months, regular structured resistance training in the past 6 months, smoking, use of sports supplements or pain medication in the last month, chronic disease, and allergies to supplement contents. A sample size of 42 participants (21 per group) provides 80% power at α=0.05 to detect a 2% difference in percentage lean mass change (assumed SD=2.2%). To allow for ~20% dropout, 52 participants will be recruited. Allocation uses stratified block randomisation (block size 2) by biological sex and appendicular skeletal muscle mass index (SMI). The intervention group receives PEA 350 mg/day (2 × 175 mg Levagen+® capsules); the placebo group receives identical maltodextrin capsules. On training days, one capsule is taken 45–60 min pre-exercise with a standardised meal (388 kcal, 45 g CHO, 21 g PRO, 13 g FAT) and one capsule 60 min pre-sleep. On non-training days, capsules are taken with morning meal and pre-sleep. All participants complete 8 weeks of progressive resistance training: weeks 1–2 (3 sets × 6 reps at 75% 1RM strength, 45% 1RM power), weeks 3–4 (3 sets × 5 reps AMRAP at 80% 1RM strength, 50% 1RM power), weeks 5–6 (4 sets × 4 reps AMRAP at 85% 1RM strength, 55% 1RM power), weeks 7–8 (5 sets × 3 reps AMRAP at 90% 1RM strength, 60% 1RM power). Exercises include leg press, bench press, deadlift, bench pull (strength-focused) paired with countermovement jumps, bench throw, deadlift jumps, and power bench pull (power-focused). A whey protein beverage (250 kcal, 40 g protein) is provided post-exercise. Primary outcomes are total body lean mass (DXA) and regional mid-thigh cross-sectional area (pQCT). Secondary outcomes include: strength (1-RM bench press, isometric mid-thigh pull peak force/power), power (countermovement jump height/peak force/peak power, bench throw peak velocity/power), sleep (ActiGraph GT9X continuously, Pittsburgh Sleep Quality Index), pain (10-point VAS for DOMS, Premenstrual Symptoms Screening Tool for females), subjective wellbeing (Short Recovery and Stress Scale), and blood biomarkers (testosterone, oestradiol by ELISA; pro- and anti-inflammatory cytokines by multiplex ELISA). Statistical analysis uses intention-to-treat and per-protocol (≥80% training attendance and supplement compliance) approaches with linear models adjusting for baseline outcome, sex, and SMI, with two-tailed significance at p<0.05 and multiple imputation for missing data.
**Clinical Implications:** This is the first study to evaluate PEA supplementation in the context of skeletal muscle hypertrophy in an active population. If PEA is found not to interfere with—or to enhance—training-induced muscle hypertrophy, strength, power, and sleep, it may provide a superior pain management alternative to NSAIDs and other COX-2 inhibitors for athletes and active individuals. The findings could inform decision-making for sports physicians, coaches, strength and conditioning professionals, and athletes regarding pain management strategies that do not compromise long-term training adaptations. A limitation is the exclusion of resistance-trained individuals, which may limit generalisability to non-strength-trained populations.