Resources
During menopause, women often experience:
- Memory and focus problems
- Mood swings and anxiety
- Low energy and fatigue
This study explored whether creatine—a compound that helps with energy in the body—could help ease these symptoms.
It looked at how taking creatine supplements for 8 weeks affects the brain and mood of women going through perimenopause and menopause.
In summary, creatine supplementation, especially low-dose CrHCL, appears to be a safe and effective strategy for mitigating cognitive decline, fatigue, and mood disturbances associated with menopause. Low-dose CrHCL supplementation is a promising strategy for improving cognitive function, brain bioenergetics, and clinical outcomes in perimenopausal and menopausal women. It offers a safe and practical approach without adverse effects or weight gain. Further large-scale trials are needed to confirm these findings and explore long-term benefits.
This document is a detailed report of a randomized, placebo-controlled, double-blind trial investigating the effects of 8-week supplementation with creatine hydrochloride (CrHCL) and creatine ethyl ester (CEE) on cognition, clinical outcomes, and brain creatine levels in perimenopausal and menopausal women. The study aimed to address cognitive decline, mood disturbances, and metabolic vulnerabilities associated with estrogen deficiency during menopause.
Key Findings:
-
Cognitive Improvements: Low-dose CrHCL (750 mg/day) significantly improved alertness, executive control, processing speed, and reaction times. Medium-dose CrHCL (1,500 mg/day) enhanced reaction times and reduced mood swings and concentration difficulties. CrHCL-CEE (800 mg/day) alleviated anxiety and improved alertness.
-
Brain Creatine Levels: Low-dose CrHCL led to the largest increase in brain creatine levels across nine of thirteen brain regions, including frontal gray and white matter. Medium-dose CrHCL and CrHCL-CEE also elevated brain creatine concentrations but to a lesser extent.
-
Clinical Outcomes: Medium-dose CrHCL reduced general fatigue and mood swings, while CrHCL-CEE alleviated anxiety. No significant changes were observed in the placebo group.
-
Safety and Tolerability: All interventions were well-tolerated, with no serious adverse effects or weight gain reported. Mild side effects like heartburn were transient.
-
Biochemical Markers: No major changes in circulating creatine, guanidinoacetic acid, or creatinine levels were observed, suggesting enhanced cerebral creatine uptake.
Methodology:
-
Participants: 36 women aged ≥40 years, divided into perimenopausal and menopausal groups.
-
Interventions: Four groups received low-dose CrHCL, medium-dose CrHCL, CrHCL-CEE, or placebo for eight weeks.
-
Outcomes: Cognitive function, fatigue, brain creatine levels (via 1H-MRS), and clinical chemistry markers were assessed.
Conclusion:
Low-dose CrHCL supplementation is a promising strategy for improving cognitive function, brain bioenergetics, and clinical outcomes in perimenopausal and menopausal women. It offers a safe and practical approach without adverse effects or weight gain. Further large-scale trials are needed to confirm these findings and explore long-term benefits.
In More Detail:
Creatine (2-[carbamimidoyl(methyl)amino]acetic acid) is a naturally occurring, semi-essential nutrient that plays a pivotal role in buffering and regulating cellular bioenergetics throughout the human body (1). Initially recognized for its ergogenic benefits in athletic performance during the early 1990s, creatine research has since expanded into broader areas of human nutrition and diverse populations. Over the past two decades, creatine has emerged as a subject of interest in female physiology and health, spanning exercise performance, reproductive health, and clinical medicine. Hormone-driven alterations in endogenous creatine synthesis, transport, and enzymatic machinery suggest that
substantial changes in this cellular energy network occur during distinct phases of a female’s reproductive life (2), highlighting the potential benefits of creatine supplementation under specific conditions, such as menopause.
Menopause and the perimenopausal transition are marked by significant endocrine alterations, most notably a progressive decline in circulating estrogen levels. These hormonal changes have widespread effects across multiple organ systems, including the brain. In addition, the perimenopausal period is often accompanied by pronounced day-to-day fluctuations in estrogen concentrations, contributing to the variability of physiological and neuropsychological symptoms during this phase. Estrogen plays a critical role in modulating cerebral blood flow, mitochondrial function, synaptic plasticity, and neuroprotection. The reduction in estrogen during this transitional period is associated with neurophysiological alterations, such as reduced glucose metabolism in specific brain regions, impaired mitochondrial bioenergetics, and increased vulnerability to oxidative stress and neuroinflammation (3,4). These changes may contribute to commonly reported cognitive disturbances during perimenopause and menopause, including memory lapses, reduced attention, and executive dysfunction, collectively described as brain fog (5,6). Additionally, structural neuroimaging studies have revealed changes in brain morphology during the menopausal transition, including hippocampal volume reduction and cortical thinning, that might underlie the emergence or exacerbation of cognitive complaints, such as memory lapses, reduced processing speed, and impaired executive function (7).
Given its established role in cellular energy metabolism and emerging neuroprotective properties, creatine has been proposed as a potential intervention to mitigate brain-related changes associated with estrogen deficiency. Preclinical evidence indicates that creatine supplementation can enhance mitochondrial function, reduce oxidative damage, and support synaptic integrity under conditions of hormonal fluctuation and metabolic stress (8–10). However, evidence supporting the efficacy of creatine alone in perimenopausal women remains limited, as most preclinical and clinical studies have primarily investigated its effects in conjunction with resistance training (11). A recent population-based cross-sectional study demonstrated that optimal dietary creatine intake (~750 mg per day) was significantly associated with reduced risks of reproductive health issues in U.S. women, including peri- menopausal conditions such as irregular menstrual cycles, pelvic pathology, and hormone replacement therapy use (12).
Despite these promising associations, the potential effects of creatine supplementation on perimenopausal and menopausal outcomes remain largely understudied—particularly in the context of low-dose formulations such as creatine hydrochloride and creatine ethyl ester. These alternative forms may exhibit enhanced solubility and bioavailability while reducing the risk of gastrointestinal discomfort commonly associated with higher doses of creatine monohydrate, the most extensively studied form of creatine supplementation. Preliminary evidence suggests that low-dose creatine formulations may confer beneficial effects across various conditions (13,14), and may elicit outcomes comparable to those observed with substantially higher doses of other creatine compounds (15). Furthermore, it remains unknown whether the co-administration of low-dose creatine salts with distinct physicochemical properties produces synergistic effects that enhance overall creatine uptake and tissue distribution. Consequently, the primary objective of this trial was to investigate the effects of medium-term supplementation with varying doses of creatine hydrochloride, either alone or in combination with creatine ethyl ester, on cognitive function, clinical outcomes, brain creatine levels, and biochemical markers in perimenopausal and menopausal women. We hypothesized that supplementation with creatine hydrochloride, particularly in combination with creatine ethyl ester, would lead to more substantial improvements in cognitive
performance and perimenopausal symptoms and greater increases in brain creatine concentrations compared to placebo, in perimenopausal and menopausal women.