What are the best brain supplements that actually work?
Only 7 brain supplements have meaningful clinical evidence: Omega-3s (1,000-2,500mg/day), B-vitamins in methylated forms, Citicoline (250-500mg), Creatine (5g/day), Bacopa monnieri (300-450mg), Magnesium L-Threonate (1,000-2,000mg), and Phosphatidylserine (100-300mg). However, supplements work best for specific populations—people with deficiencies, elevated homocysteine, sleep deprivation, or who don't eat fish regularly. For most healthy adults eating a balanced diet, the evidence suggests food sources outperform isolated supplements.
Jump To:
🔬 Latest Clinical Evidence (January 2025)
-
2025 Meta-Analysis — Scientific Reports
Optimal omega-3 dose: 1,000-2,500mg/day. Significant improvements in attention and memory at 2,000mg/day. -
Lopresti & Smith (2025) — Frontiers in Nutrition
Magnesium L-Threonate (2g/day) improved cognitive performance in 18-45 year olds over 6 weeks. -
EFSA (2024) — EFSA Journal
Creatine cognitive health claim: Evidence currently insufficient for approval. Benefits appear real but mainly in stressed states. -
Smith et al. (2025) — Alzheimer's & Dementia: TRCI
First human trial: 20g/day creatine in Alzheimer's patients showed 11% brain creatine increase and moderate cognitive improvements.
The Honest Truth About Brain Supplements
Before we get into the 7 supplements, you need to hear this: Harvard Health's position is "don't buy into brain health supplements." Not because the nutrients don't matter—they do—but because isolated supplements haven't shown the same benefits as getting these nutrients from food.
⚠️ Reality Check
"There is not much, if any, evidence from randomized clinical trials—the gold standard for research—on isolated vitamins or minerals and brain health... Any benefit [from omega-3s] seems to come from a greater intake of fish and not from taking fish oil supplements."
So why write this guide? Because:
- Some people can't or won't eat fish 3x/week. A supplement is better than nothing.
- Specific populations (vegans, elderly, those with MTHFR mutations, people with elevated homocysteine) have documented deficiencies that supplements can correct.
- Certain conditions (sleep deprivation, high stress, post-viral syndromes) may benefit from targeted supplementation where food alone falls short.
- The supplement industry is full of garbage, and people deserve to know which compounds have actual evidence vs. marketing hype.
This guide is for people who've already optimized the basics (sleep, exercise, diet) and want to know if supplements can provide an additional edge—with honest caveats about what the science actually shows.
"In my post-COVID recovery clinic, I saw patients who did everything right—sleep, exercise, Mediterranean diet—and still plateaued. For some, targeted supplementation made a measurable difference. For others, it didn't. The key is knowing which camp you're in before spending money."
— Dr. Alexandru Amarfei, M.D., Senior Consultant in Geriatric Medicine
⚗️ Why "All-in-One" Brain Pills Are a Scam
The Physics: An effective dose of Omega-3 is ~2,000mg (2 large gelcaps). Creatine is 5,000mg (a full scoop). Magnesium L-Threonate is 1,000-2,000mg.
The Math: To get clinical doses of all 7 supplements, you'd need to swallow 10-15 pills daily. Any product claiming to deliver everything in 2 capsules is "fairy dusting"—listing ingredients at 1/10th the effective dose.
The Strategy: Buy bulk compounds (Omega-3, Creatine, Magnesium) as standalones. Use targeted formulas only for compounds that work at smaller doses (Huperzine A at 60mcg, Benfotiamine at 50mg).
1. Omega-3 Fatty Acids (DHA/EPA) Strong Evidence
Effective Dose
1,000-2,500mg combined EPA+DHA
Optimal Ratio
≥60% EPA for neuroinflammation
Time to Effect
8-12 weeks (membrane incorporation)
Best Time to Take
With largest meal containing fat
What the Evidence Actually Shows
A 2025 dose-response meta-analysis of 58 RCTs in Scientific Reports found the optimal range is 1,000-2,500mg/day, with significant improvements in attention (SMD: 0.98) and memory at 2,000mg/day. According to Wei et al. (2023) in the American Journal of Clinical Nutrition, long-term fish oil users showed 64% reduced Alzheimer's risk.
However: Harvard notes that benefits in observational studies "seem to come from greater intake of fish and not from taking fish oil supplements." The 2022 VITAL-Cog trial (n=2,310) found no significant cognitive benefits from omega-3 supplementation in healthy older adults.
Who benefits most: People who don't eat fish, those with inflammatory conditions, individuals with low baseline omega-3 index (<4%).
Forms That Matter
- Triglyceride form: Better absorbed than ethyl ester (EE) form
- High-EPA formulas: Better for inflammation and mood
- High-DHA formulas: Better for brain structure (DHA makes up 40% of brain PUFAs)
⚠️ Warnings & Contraindications
- Blood thinners: May increase bleeding risk at doses >3g/day. Separate from Warfarin, aspirin, NSAIDs by 2 hours.
- Surgery: Stop 1-2 weeks before elective surgery
- Fishy burps: Take with food, consider enteric-coated or freeze capsules
- Pregnancy: DHA is essential for fetal brain development. FDA recommends up to 3g/day is safe. Avoid high-EPA formulas in first trimester.
- Quality concern: Fish oil can oxidize. Check for third-party testing (IFOS, ConsumerLab). Reject if smells strongly of fish.
2. B-Complex Vitamins (B6, B9, B12) Strong Evidence*
*Strong for people with elevated homocysteine or deficiency; weak for general population.
Effective Dose
B9: 0.8mg | B12: 0.5mg | B6: 20mg
Critical Forms
Methylfolate, Methylcobalamin, P5P
Time to Effect
12-24 weeks (structural protection)
Best Time to Take
Morning (can be energizing)
What the Evidence Actually Shows
The VITACOG trial by Smith et al. (2010) in PLoS ONE found B-vitamin supplementation slowed brain atrophy by 53% in patients with elevated homocysteine (>11 μmol/L). But here's the catch: in people with normal homocysteine, there was no significant benefit.
Who benefits most: People with elevated homocysteine, MTHFR gene variants (30-40% of population), vegans/vegetarians (B12 deficiency risk), elderly (reduced absorption), those on metformin or PPIs.
Why Forms Matter
| Vitamin | ❌ Cheap Form | ✅ Active Form | Why |
|---|---|---|---|
| B9 | Folic acid | Methylfolate (5-MTHF) | 40% of people can't convert folic acid efficiently due to MTHFR variants |
| B12 | Cyanocobalamin | Methylcobalamin | Cyanocobalamin contains cyanide; requires multiple conversion steps |
| B6 | Pyridoxine HCl | P5P (Pyridoxal-5-Phosphate) | P5P is the active coenzyme form |
| B1 | Thiamine HCl | Benfotiamine | Fat-soluble, 5x more bioavailable, crosses into nerve tissue |
⚠️ Warnings & Contraindications
- B6 toxicity: Doses >100mg/day long-term can cause peripheral neuropathy (tingling, numbness). Keep below 50mg/day unless supervised.
- Levodopa interaction: B6 can reduce effectiveness of Parkinson's medication. Separate by 2 hours or use carbidopa/levodopa combination.
- Masking B12 deficiency: High-dose folate can mask B12 deficiency symptoms while neurological damage progresses. Always take B12 with folate.
- Pregnancy: Folate is essential (prevents neural tube defects). Use methylfolate, not folic acid if you have MTHFR variants.
3. Citicoline (CDP-Choline) Moderate Evidence
Effective Dose
250-500mg (up to 1,000mg)
Form
Citicoline (CDP-Choline) or Cognizin®
Time to Effect
4-12 weeks
Best Time to Take
Morning (supports alertness)
What the Evidence Actually Shows
Nakazaki et al. (2021) in the Journal of Alzheimer's Disease found a +3.78 composite memory score improvement over 12 weeks in healthy older adults taking 500mg/day. A 2023 study found improvements in language and attention in adults with cognitive decline.
In Europe, citicoline is prescribed as a drug for stroke recovery and cognitive decline. In the US, it's sold as a supplement.
How it works: Citicoline provides choline for acetylcholine synthesis (the learning neurotransmitter) and cytidine for neuronal membrane repair.
Citicoline vs Alpha-GPC: Both provide choline. Citicoline also provides cytidine for membrane support. Alpha-GPC has more choline per gram but may increase TMAO (a cardiovascular risk marker) at high doses.
⚠️ Warnings & Contraindications
- Headaches: Some people experience headaches, especially at higher doses. Start with 250mg.
- Insomnia: Can be stimulating. Avoid evening dosing.
- Depression history: Cholinergic compounds may worsen depression in some individuals. Monitor mood.
- Pregnancy: Limited human data. Choline is essential during pregnancy, but stick to food sources unless advised by physician.
4. Creatine Monohydrate Moderate Evidence
Effective Dose
5g/day (standard) | 20g/day (brain-focused, emerging)
Form
Creatine monohydrate only
Time to Effect
2-4 weeks (saturation)
Best Time to Take
Anytime (consistency > timing)
What the Evidence Actually Shows
The 2024 meta-analysis by Xu et al. in Frontiers in Nutrition found significant effects on memory (SMD: 0.31) and processing speed. However, EFSA (2024) evaluated a health claim for creatine and cognition and found the evidence insufficient for approval.
The nuance: Benefits appear most pronounced in:
- Sleep-deprived individuals
- Vegetarians/vegans (who have lower baseline creatine)
- Older adults
- People under cognitive stress
A 2025 pilot study at University of Kansas gave 20g/day to Alzheimer's patients and found an 11% increase in brain creatine levels with moderate improvements in working memory and executive function. This suggests the standard 5g dose may be insufficient for brain effects.
Why the brain is different: Creatine enters muscle easily but crosses the blood-brain barrier poorly. Higher doses (10-20g) may be needed for brain-specific effects, though this isn't yet established.
⚠️ Warnings & Contraindications
- Kidney disease: Creatine increases creatinine levels (a kidney marker), which can confuse blood tests. It doesn't damage healthy kidneys, but avoid if you have existing kidney disease.
- Water retention: May cause 1-3 lbs weight gain from water. Not fat.
- GI upset: High doses (>10g at once) can cause cramping, diarrhea. Split doses.
- Hair loss claims: One study found increased DHT. No replications. Likely not a concern at 5g/day.
- Caffeine interaction: Some older research suggested caffeine negates creatine benefits. More recent studies don't support this.
- Pregnancy: Limited data. Creatine is naturally present in the body. Likely safe at normal doses, but consult physician.
5. Bacopa monnieri Moderate Evidence
Effective Dose
300-450mg (standardized to ≥45% bacosides)
Form
Standardized extract (BacoMind®, Synapsa®)
Time to Effect
8-12 weeks (slow onset)
Best Time to Take
With fat-containing meal
What the Evidence Actually Shows
Peth-Nui et al. (2012) in Evidence-Based Complementary and Alternative Medicine found 40% improvement in delayed recall after 12 weeks. A systematic review by Pase et al. (2012) concluded Bacopa has potential to improve attention, cognitive processing, and working memory.
Important: Bacopa is NOT fast-acting. Most people who quit early ("it didn't work") stopped before the 8-12 week mark where benefits emerge.
How it works: Bacosides modulate acetylcholine, serotonin, and dopamine. Also has antioxidant effects and may promote dendrite branching (neuroplasticity).
⚠️ Warnings & Contraindications
- GI upset: Most common side effect. Take with food. Consider starting at 150mg and increasing gradually.
- Fatigue/sedation: Some people find it calming to the point of drowsiness. May be better for evening.
- Thyroid: Animal studies suggest Bacopa may increase T4 levels. Use caution if you have thyroid conditions.
- Fertility: Animal studies show reduced sperm count at very high doses. Human relevance unknown.
- Drug interactions: May interact with anticholinergics, thyroid medications, sedatives.
- Pregnancy: Not recommended. Insufficient safety data.
6. Magnesium L-Threonate Emerging Evidence
Effective Dose
1,000-2,000mg MgT (= 144-288mg elemental Mg)
Form
Magnesium L-Threonate (Magtein®)
Time to Effect
4-8 weeks
Best Time to Take
Split: morning + evening (can be calming)
What the Evidence Actually Shows
A January 2025 RCT by Lopresti & Smith in Frontiers in Nutrition found that 2g/day of Magtein® significantly improved cognitive performance, hand-eye coordination, and reaction time in 18-45 year olds over 6 weeks.
A 2024 RCT in Sleep Medicine found MgT improved deep sleep and REM sleep quality in adults with sleep problems after just 21 days.
Why L-Threonate specifically: Most magnesium forms (oxide, citrate) don't cross the blood-brain barrier well. L-Threonate is chelated to a vitamin C metabolite that enhances brain uptake. Animal studies show it increases CSF magnesium levels more than other forms.
Magnesium Form Comparison
| Form | Brain Availability | Best For |
|---|---|---|
| Oxide | Negligible (<4% absorbed) | Constipation (laxative effect) |
| Citrate | Low | General deficiency correction |
| Glycinate | Moderate | Sleep, anxiety, muscle relaxation |
| L-Threonate | High | Cognitive function, synaptic plasticity |
⚠️ Warnings & Contraindications
- Drowsiness: Some find it sedating. Start with evening dose only.
- Loose stools: Less common than with citrate, but can occur.
- Kidney disease: Magnesium is cleared by kidneys. Avoid or use with caution if eGFR <30.
- Medication interactions: Separate from antibiotics (fluoroquinolones, tetracyclines) and bisphosphonates by 2-4 hours. May reduce absorption.
- Low elemental magnesium: L-Threonate provides only ~8% elemental magnesium. If you need magnesium for muscle cramps or general deficiency, you may need another form in addition.
- Pregnancy: Magnesium is important in pregnancy. L-Threonate specifically lacks human pregnancy data. Glycinate may be safer choice.
7. Phosphatidylserine (PS) Moderate Evidence
Effective Dose
100-300mg/day (300mg optimal)
Form
Soy-derived or Sunflower-derived PS
Time to Effect
4-12 weeks
Best Time to Take
With fat-containing meal
What the Evidence Actually Shows
According to the Alzheimer's Drug Discovery Foundation, small trials suggest PS "might slightly improve cognition for Alzheimer's patients, but effects were short-lived or detectable only in severely impaired patients."
Kato-Kataoka et al. (2010) found soy-derived PS (100-300mg/day) improved memory in elderly Japanese subjects with memory complaints—but mainly in those with lower baseline scores.
Glade & Smith (2015) in Nutrition reviewed the evidence and found consistent benefits at 300mg/day for age-related cognitive decline.
Important context: The original studies used bovine (cow brain) PS, which may be more effective than plant-derived PS due to its DHA content. Modern supplements use soy or sunflower PS due to mad cow disease concerns.
How it works: PS is a phospholipid that makes up 15% of the brain's phospholipid pool. It supports cell membrane fluidity, signal transduction, and cortisol regulation.
⚠️ Warnings & Contraindications
- Insomnia: Some experience sleep disturbances at doses >300mg
- GI upset: Gas, stomach upset at higher doses
- Blood thinners: PS may have mild anticoagulant effects. Use caution with Warfarin.
- Soy allergy: Soy-derived PS may trigger reactions. Use sunflower-derived instead.
- Weight gain: Some studies noted slight weight gain.
- Pregnancy: Limited data. PS is naturally present in the body and likely safe, but consult physician.
Blood Tests to Consider Before Supplementing
🩸 Recommended Baseline Testing
Don't supplement blindly. These tests help determine if you actually need specific compounds:
| Test | Why | Target Range |
|---|---|---|
| Homocysteine | Determines B-vitamin need. If normal, B-vitamins likely won't help cognition. | <10 μmol/L (optimal <8) |
| Omega-3 Index | Measures EPA+DHA in red blood cells. Better predictor than diet recall. | 8-11% (most people are 4-5%) |
| Vitamin B12 | Deficiency common in elderly, vegans, those on metformin/PPIs. | >400 pg/mL (some say >500) |
| Vitamin D (25-OH) | 53% increased dementia risk with deficiency (Littlejohns 2014) | 40-60 ng/mL (>30 minimum) |
| RBC Magnesium | Serum magnesium is unreliable. RBC magnesium better reflects tissue levels. | 4.2-6.8 mg/dL |
| hs-CRP | Inflammatory marker. If elevated, omega-3s may help more. | <1.0 mg/L (optimal) |
| MTHFR Genetic Test | Determines if you need methylated B-vitamins | — |
Daily Protocol: Timing & Stacking
With Breakfast
B-Complex (methylated) — Energizing; avoid evening
Citicoline 250-500mg — Supports alertness, acetylcholine
Magnesium L-Threonate (half dose) — Optional AM portion if well-tolerated
With Your Largest Meal (Contains Fat)
Omega-3s 1,000-2,500mg — Fat required for absorption
Phosphatidylserine 100-300mg — Fat-soluble phospholipid
Bacopa 300mg — Take with fat; can cause drowsiness
Anytime (Consistency Matters)
Creatine 5g — Timing doesn't matter. Just take it daily.
1-2 Hours Before Bed
Magnesium L-Threonate (remaining dose) — Can be calming, supports sleep
Cycling guidance:
- Don't cycle: Omega-3s, B-vitamins, Creatine, Phosphatidylserine (these need steady-state levels)
- Consider cycling: Bacopa (4-6 weeks on, 2 weeks off), though evidence for cycling is weak
- Definitely cycle: Huperzine A (5 days on, 2 off), adaptogens like Rhodiola
Complete Drug Interaction Table
| Supplement | Interacts With | Effect | Risk |
|---|---|---|---|
| Omega-3s (>3g) | Warfarin, Aspirin, NSAIDs | Increased bleeding risk | HIGH |
| B6 (>50mg) | Levodopa | Reduces medication effectiveness | MODERATE |
| Magnesium | Antibiotics, Bisphosphonates | Blocks absorption of medications | MODERATE |
| Bacopa | Thyroid medications | May alter T4 levels | MODERATE |
| Bacopa | Anticholinergics | Opposing mechanisms | MODERATE |
| Phosphatidylserine | Blood thinners | Possible anticoagulant effect | MODERATE |
| 5-HTP | SSRIs, MAOIs, Tramadol | Serotonin syndrome risk | CRITICAL |
| Huperzine A | Donepezil, Rivastigmine | Cholinergic toxicity | HIGH |
| Ginkgo biloba | Warfarin, Aspirin | Increased bleeding | HIGH |
| St. John's Wort | SSRIs, Birth control, Warfarin | CYP3A4 induction + serotonin effects | CRITICAL |
What If It's Not Working?
🔧 Troubleshooting Guide
Problem: No noticeable effects after 4 weeks
Check:
- Are you taking fat-soluble compounds (omega-3, PS, bacopa) with a fat-containing meal?
- Is your omega-3 supplement oxidized? (Fishy smell = bad)
- Have you waited long enough? Bacopa and omega-3s need 8-12 weeks. B-vitamins need months.
- Are you actually deficient? Get blood tests for homocysteine, B12, omega-3 index.
Problem: GI upset from creatine
Fix: Split into 2-3 smaller doses. Take with food. Ensure adequate hydration. Consider micronized creatine.
Problem: Bacopa makes me tired
Fix: Take at dinner instead of lunch. Some people are sensitive to its GABAergic effects. This is dose-dependent—try 150mg.
Problem: B-vitamins make me anxious or cause insomnia
Fix: Take early morning only. Some people are "overmethylators" and respond poorly to methylated B-vitamins. Try unmethylated forms or lower dose.
Problem: Supplements are expensive and overwhelming
Prioritize:
- Omega-3s (if you don't eat fish 2-3x/week)
- Vitamin D (if deficient—most people are)
- B-vitamins (only if homocysteine is elevated or you're vegan/elderly)
- Everything else is optional optimization
Quality Verification: Don't Get Scammed
Third-Party Testing to Look For
- ConsumerLab: Tests supplements for accuracy and contamination
- NSF International: "NSF Certified for Sport" for athletes
- USP Verified: US Pharmacopeia verification
- IFOS (International Fish Oil Standards): Specifically for omega-3 purity and freshness
- Certificate of Analysis (COA): Request from manufacturer. Shows actual ingredient amounts and contaminant testing.
🚨 Red Flags to Avoid
"Proprietary blend" — Hides actual amounts. If it says "500mg Cognitive Matrix" with 8 ingredients, you have no idea how much of each.
Unrealistic claims — "Unlock 100% of your brain" is neuroscience-free marketing.
No third-party testing — If they don't test, they don't care.
Mega-doses without justification — 10,000% of B12 DV is marketing, not science.
What About FOG OFF?
Here's where our product fits (and where it doesn't).
FOG OFF is designed for the "Signal" side of brain support—compounds that work at smaller doses:
What FOG OFF isn't: A replacement for omega-3s, creatine, or magnesium. Those require bulk doses you can't fit in a capsule formula.
What FOG OFF is: A targeted nootropic stack for acetylcholine support (Huperzine A), membrane repair (Phosphatidylserine), and mitochondrial function (Benfotiamine, ALA).
Sources
- Harvard Health Publishing. (2023). Don't buy into brain health supplements. Harvard Health
- Scientific Reports. (2025). A systematic review and dose response meta-analysis of Omega 3 supplementation on cognitive function. Nature
- Lopresti AL, Smith SJ. (2025). The effects of magnesium L-threonate (Magtein®) on cognitive performance and sleep quality in adults. Frontiers in Nutrition. Frontiers
- Wei BZ, et al. (2023). The relationship of omega-3 fatty acids with dementia and cognitive decline. Am J Clin Nutr, 117(6):1096-1109. PubMed
- Smith AD, et al. (2010). Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment. PLoS ONE, 5(9):e12244. PubMed
- EFSA Panel. (2024). Creatine and improvement in cognitive function: Evaluation of a health claim. EFSA Journal. EFSA
- Xu C, et al. (2024). The effects of creatine supplementation on cognitive function in adults: A systematic review and meta-analysis. Frontiers in Nutrition, 11:1424972. PMC
- Smith MK, et al. (2025). Creatine monohydrate pilot in Alzheimer's: Feasibility, brain creatine, and cognition. Alzheimer's & Dementia: TRCI. Wiley
- Nakazaki E, et al. (2021). Citicoline and memory function in healthy older adults. J Alzheimers Dis, 79(3):1215-1224. PubMed
- Peth-Nui T, et al. (2012). Effects of 12-week Bacopa monnieri consumption on attention, cognitive processing, working memory. Evid Based Complement Alternat Med, 2012:606424. PMC
- Hausenblas HA, et al. (2024). Magnesium-L-threonate improves sleep quality and daytime functioning in adults. Sleep Medicine. ScienceDirect
- Alzheimer's Drug Discovery Foundation. Phosphatidylserine. Cognitive Vitality
- Glade MJ, Smith K. (2015). Phosphatidylserine and the human brain. Nutrition, 31(6):781-786. PubMed
- Cleveland Clinic. (2023). Phosphatidylserine: What It Is, Benefits, Side Effects. Cleveland Clinic
- Examine.com. Phosphatidylserine. Examine
- NIH Office of Dietary Supplements. (2025). Omega-3 Fatty Acids: Fact Sheet for Health Professionals. NIH ODS
- Littlejohns TJ, et al. (2014). Vitamin D and the risk of dementia and Alzheimer disease. Neurology, 83(10):920-928. PubMed
- Alzheimer's Drug Discovery Foundation. Creatine & Your Brain. Cognitive Vitality
