The Effects of 8-Week Creatine Hydrochloride and Creatine Ethyl Ester Supplementation on Cognition, Clinical Outcomes, and Brain Creatine Levels in Perimenopausal and Menopausal Women (CONCRET-MENOPA): A Randomized Controlled Trial.

Objective: To investigate the effects of an 8-week supplementation with varying doses of creatine hydrochloride, administered alone or in combination with creatine ethyl ester, on cognitive function, clinical outcomes, brain creatine concentrations, and biochemical markers in perimenopausal and postmenopausal women. This study specifically aimed to evaluate the potential of low-dose creatine formulations with enhanced solubility as a targeted intervention for menopause-related neurocognitive and metabolic changes.

Methods: A total of 36 apparently healthy perimenopausal and menopausal women (mean age 50.1 ± 5.7 years) were randomly allocated to one of four groups: low-dose creatine hydrochloride (750 mg/day), medium-dose creatine hydrochloride (1,500 mg/day), creatine hydrochloride plus creatine ethyl ester (800 mg/day), or placebo, in this randomized controlled double-blind trial. Menopausal women were defined as having no menstrual cycle for 12 consecutive months without other causes, while perimenopausal women were still menstruating but reported at least one symptom such as hot flashes, sleep disturbances, mood swings, or concentration difficulties.

Results: Supplementation with medium-dose creatine hydrochloride was found to be superior to placebo in enhancing reaction time (1.2 vs. 6.6%; p < 0.01), increasing frontal brain creatine levels (0.9 vs. 16.4%; p < 0.01), and favorably modulating serum lipid profiles (p < 0.05). Moreover, medium-dose creatine hydrochloride demonstrated a potential advantage over other treatments in reducing the severity of mood swings (p = 0.06). All interventions were well tolerated, with no severe adverse effects reported.

Conclusion: Our findings suggest that this supplementation protocol may be a promising, safe, effective, and practical dietary strategy for improving clinical outcomes and elevating brain creatine concentrations in perimenopausal and menopausal women. The trial was registered at ClinicalTrials.gov (NCT06660004).