If you are dealing with brain fog, 3 a.m. wake-ups, or fatigue in perimenopause and want to know which supplements are worth taking, the evidence-grounded answer has two parts. First: before any supplement, rule out the deficiencies that mimic perimenopause symptoms — low iron stores, low vitamin D, and thyroid dysfunction have all been shown to produce the same fatigue and fog, and they are fixable with a blood test and a targeted correction. Second: of the supplements most often recommended in perimenopause communities, creatine has the broadest evidence base, magnesium L-threonate and glycine each rest on small but real trials, L-theanine has one modest supporting study, and several popular picks have less behind them than their reputations suggest. None of them is a treatment for perimenopause itself, and none of this is an argument against hormone therapy — it is the adjacent territory: what may help, what probably won’t, and what to check first.
Before the supplement list: three rule-outs that come first
The most common mistake in this category is treating a deficiency with a nootropic. The fatigue that gets attributed to perimenopause — or to a discipline problem — sometimes has a measurable, correctable cause, and the trials here are stronger than for most of the supplements below. This is the same measure-first logic behind why longevity medicine starts with bloodwork.
Iron is the clearest case. In a randomized controlled trial of 198 menstruating women with significant fatigue who were not anemic but had ferritin below 50 µg/L, twelve weeks of oral iron reduced fatigue scores by roughly half, significantly more than placebo (Vaucher et al., CMAJ 2012). That is a population a standard workup can miss, because hemoglobin looks normal — ferritin, the storage measure, is the number that matters, and perimenopausal cycle changes can drain it. It is one reason perimenopause exhaustion can persist even when standard labs come back “normal”. Vitamin D behaves similarly: in a double-blind randomized trial of 120 otherwise healthy adults with fatigue and low vitamin D levels, a single corrective dose improved fatigue scores significantly versus placebo, and the improvement tracked the rise in blood levels (Nowak et al., Medicine 2016). Thyroid dysfunction and B12 deficiency round out the standard rule-out panel; both are routine tests, and both produce fog and exhaustion that no sleep supplement will touch.
The order of operations, then: baseline labs first, correction of anything found, and only then a considered look at the list below. This is also the honest limitation of that list — a supplement chosen without a baseline is a guess.
Creatine — the strongest general evidence, with an honest caveat
Creatine monohydrate is the most-studied supplement in this conversation, and the brain rationale is real: the brain is an energy-expensive organ, and creatine participates in cellular energy buffering. A systematic review and meta-analysis of randomized controlled trials found that creatine supplementation improved memory performance in healthy individuals compared with placebo, with the clearest effect in older adults (Prokopidis et al., Nutrition Reviews 2023). The caveat belongs next to the claim: a subsequent statistical re-analysis of that meta-analysis argued that, after correcting for double-counted outcomes, the overall memory effect was no longer significant (Eckert and Pascher, Nutrition Reviews 2023). The part of the signal that best survives that scrutiny is the older-adult subgroup, where the original meta-analysis found its largest effect.
The fair summary: creatine is inexpensive, has decades of safety data at standard doses, and may help memory — with the strongest signal in midlife and beyond, which happens to be the population reading this. It is not a guarantee, and a meaningful share of people notice nothing cognitively. You will see much higher doses discussed in community threads for cognitive effects; those doses are running ahead of the safety and benefit evidence for non-athletes, and gastrointestinal upset is a common cost. Standard dosing of 3–5 g daily is where the evidence lives. Anyone with kidney disease should involve their clinician before starting — a caution stated here as standard clinical practice rather than a trial finding.
Magnesium L-threonate — one small, promising trial
Magnesium L-threonate is the form designed to raise brain magnesium, and it has one randomized, double-blind, placebo-controlled trial worth knowing: 44 older adults (age 50–70) with self-reported cognitive complaints, treated for 12 weeks, showed significantly improved overall cognitive ability versus placebo, with a large effect size for a supplement trial (Liu et al., J Alzheimers Dis 2016). That is genuinely encouraging — and it is one trial, small, in a specific population, funded by the ingredient’s developer. Grade it as plausible with preliminary support, not established. It is generally well tolerated; people with significant kidney impairment should not supplement magnesium without clinical supervision. If the choice is between this and confirming your ferritin and vitamin D status, the labs come first.
Glycine — small trials, one specific job
Glycine, taken as roughly 3 g before bed, has small human trials showing improved subjective sleep quality and shorter time to fall asleep, with polysomnographic changes to match, in people persistently unhappy with their sleep (Yamadera et al., Sleep and Biological Rhythms 2007). The trials are small and short, so hold the claim to its actual size: this is a gentle aid for falling asleep, with a plausible mechanism and low cost. What glycine has not been shown to do is fix the 3 a.m. wake-up specifically — the middle-of-the-night pattern so common in perimenopause has its own physiology, and no supplement on this list has trial evidence against it directly. If that is your dominant symptom, it deserves its own conversation with a clinician rather than a longer supplement list.
L-theanine — one modest trial, honestly labeled
L-theanine, the amino acid from tea, has a randomized, placebo-controlled, crossover trial in 30 healthy adults in which four weeks at 200 mg/day improved sleep-quality scores versus placebo — including sleep latency and sleep disturbance — and lowered depression and anxiety scale scores over the four weeks (Hidese et al., Nutrients 2019). It was small, and the study’s L-theanine was supplied by a manufacturer whose employees co-authored the paper — a disclosure worth knowing when weighing it. L-theanine is well tolerated and non-sedating, which makes it a low-risk trial for the “wired but tired” evening state many women describe. Expectations should be calibrated to the evidence: modest, subtle, and not universal.
What about NAC and the rest of the longer lists?
N-acetylcysteine appears on many community lists for brain fog. Its evidence in cognitively healthy midlife adults is thin — the research interest is mostly in psychiatric and neurodegenerative conditions, and it has not demonstrated the kind of trial support in this population that the entries above have. That does not make it useless; it makes it unproven for this purpose, and this article grades on evidence. The same discipline applies to the rotating cast of newer entries: the burden of proof sits with the supplement, and “someone in a thread felt better” is a starting hypothesis, not a result. There is also a subtraction case worth naming — a long daily supplement list is itself a cognitive and financial load, and paring back to the two or three things with evidence and a job is a legitimate intervention.
One boundary matters more than any single grade: supplements are regulated as foods, not drugs. None of the products above has been evaluated by the FDA to diagnose, treat, or prevent any condition, including perimenopause — and any product marketed to you with that promise has already told you something about its seller.
Where this fits alongside hormone therapy
Nothing on this list is an alternative to hormone therapy, and this article takes no position on whether HRT is right for you — that is a clinical decision between you and a clinician who knows your history. What the community conversation makes clear is that many women want both things at once: some are not candidates for hormones, some are choosing not to use them, and some are on HRT and still dealing with residual symptoms. That last group is real and underserved — hormone therapy being necessary is not the same as it being sufficient. The structure that serves all three groups is the same: measure first, correct what the labs actually show, add supplements by evidence grade rather than by list length, and re-measure so you know what is working rather than guessing.
How Trellis approaches this
Trellis Vitality is the accessibly-priced, patient-first alternative to premium-gated longevity clinics — on-demand and at home, without a five-figure annual membership. The through-line of everything above is the one Trellis is built on: a free Vitality Lab Kit and baseline labs come first, so the rule-outs that explain most perimenopausal fatigue — ferritin, vitamin D, thyroid, B12 — are checked before anything is added, and so any supplement or therapy is judged against your own numbers on a re-test rather than against a forum thread. Where hormone therapy is the right question, that is decided in a licensed clinical relationship, not on this page.
This article is educational and is not medical advice. Dietary supplements are not intended to diagnose, treat, or prevent any disease, and none of the products discussed has been evaluated by the FDA for use in perimenopause. Supplement and medication decisions — including whether a supplement is safe alongside your medications or conditions — should be made with a licensed clinician who knows your history.
Perimenopause supplements FAQ
What supplements actually help perimenopause symptoms? The rule-outs come first — correcting low ferritin, vitamin D, thyroid, or B12 resolves more perimenopausal fatigue and fog than any supplement. Among the supplements themselves, creatine has the broadest evidence (clearest in older adults), magnesium L-threonate and glycine have small supportive trials, and L-theanine has one modest study. None treats perimenopause itself.
What should I test before taking supplements for perimenopause fatigue? Ferritin (iron stores, which can look normal on a standard hemoglobin test), vitamin D, thyroid function, and B12. These are routine blood tests, and each can produce fatigue and brain fog that no supplement will fix.
Does creatine help with brain fog? A meta-analysis found creatine improved memory in healthy people, with the clearest effect in older adults; a later statistical re-analysis argued the overall effect was no longer significant after correcting for double-counted outcomes, with the older-adult subgroup the most durable part of the signal. It is inexpensive with decades of safety data at 3–5 g/day, may help, and is not guaranteed. Anyone with kidney disease should involve their clinician first.
Are these supplements an alternative to hormone therapy (HRT)? No. Nothing on this list is an alternative to hormone therapy, and this is not an argument for or against HRT — that is a clinical decision with a clinician who knows your history. Supplements are adjacent: they may help specific symptoms, but they do not replace hormones.
Is it safe to take magnesium or creatine in perimenopause? Both are generally well tolerated at standard doses, but people with kidney disease or significant renal impairment should not supplement creatine or magnesium without clinical supervision. As with any supplement, start one at a time and let your own labs guide whether it earned its place.
The measured way to decide is to look at your own numbers first. Begin your assessment →
Sources
- Vaucher P, et al. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial. CMAJ. 2012;184(11):1247–1254. https://www.cmaj.ca/content/184/11/1247
- Nowak A, et al. Effect of vitamin D3 on self-perceived fatigue: a double-blind randomized placebo-controlled trial. Medicine (Baltimore). 2016;95(52):e5353. https://pubmed.ncbi.nlm.nih.gov/28033244/
- Prokopidis K, et al. Effects of creatine supplementation on memory in healthy individuals: a systematic review and meta-analysis of randomized controlled trials. Nutr Rev. 2023;81(4):416–427. https://pubmed.ncbi.nlm.nih.gov/35984306/
- Eckert A, Pascher B. Letter to the Editor: double-counting due to inadequate statistics leads to false-positive findings. Nutr Rev. 2023. https://pubmed.ncbi.nlm.nih.gov/36644917/
- Liu G, et al. Efficacy and safety of MMFS-01, a synapse density enhancer, for treating cognitive impairment in older adults: a randomized, double-blind, placebo-controlled trial. J Alzheimers Dis. 2016;49(4):971–990. https://pubmed.ncbi.nlm.nih.gov/26519439/
- Yamadera W, et al. Glycine ingestion improves subjective sleep quality in human volunteers, correlating with polysomnographic changes. Sleep Biol Rhythms. 2007;5(2):126–131. https://onlinelibrary.wiley.com/doi/10.1111/j.1479-8425.2007.00262.x
- Hidese S, et al. Effects of L-theanine administration on stress-related symptoms and cognitive functions in healthy adults: a randomized controlled trial. Nutrients. 2019;11(10):2362. https://pubmed.ncbi.nlm.nih.gov/31623400/