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Supplements with Genetic Connections

Understanding your genetic variants (SNPs), along with clinical trials and quality research studies, can help you narrow down the natural supplements that may actually help – versus the supplements that are likely a waste of money. Genes can also come into play with whether you’re likely to have side effects from a supplement.

Below are links to Genetic Lifehacks articles that reference specific natural supplements. My goal here is to highlight the different genes, as well as the various health topics, that interact with a supplement.

Please be sure to click through to the full article on the supplement. It contains additional information on clinical trials, safety, lab tests on supplement brands, and other considerations.

Always talk to your doctor or pharmacist about interactions with prescription medications or for medical advice.

Looking for help with vitamins and minerals? Check out the nutrients topic summary report for now. (I’ll do a vitamin-gene interaction article soon.)

Ashwagandha (Full Article)

Ashwagandha is a traditional Ayurvedic herb used for centuries to counter stress and anxiety. Research shows that it has many benefits beyond just mood including:

  • strength training, muscle gains
  • subclinical hypothyroidism
  • anxiety and stress relief
  • cognitive function, focus, mood
  • decreased food cravings if due to stress
  • testosterone
  • sleep quality
  • sexual function (women)

Ashwagandha may work well for:

Cortisol and HPA axis dysfunction:
This article explains the genetic variants that increase susceptibility to issues with the HPA (hypothalamus – pituitary – adrenal) axis, including altered cortisol rhythm. Research shows ashwagandha effectively regulates cortisol levels in people with HPA axis dysfunction.

Cortisol and HPA Axis genes (Please read the full article for details):

Genetics and Anxiety:
Ashwagandha has many studies on it showing that it impacts cortisol and may help with anxiety if it is due to stress and high cortisol. One study tested 300 mg, 2x a day vs. placebo. After 8 weeks, cortisol was reduced by an average of 22%, which is significant. Weight also went down for the Ashwagandha group.[ref]

Anxiety genes (Please read the full article for details):

Testosterone genes:
Ashwagandha increases testosterone levels in men who lift weights or do muscle-building exercises.One study used a supplement containing 21 mg of withanolide glycosides/day for eight weeks and showed an average increase in testosterone of about 15%.[ref] In another eight-week placebo-controlled trial of ashwagandha in younger men who were lifting weights, the men taking 300 mg ashwagandha root extract 2x/day increased muscle strength, arm size, and more than tripled testosterone levels.[ref]

Testosterone genes (Please read the full article for details):

Cautions for Ashwagandha:

BChE and Nightshades:
Ashwagandha is a nightshade plant.  People with BChE severe mutations may have problems with nightshades.

Additional Articles that reference Ashwagandha:

  1. Leptin: Ashwagandha, an adaptogenic Ayurvedic herb, appears to be a leptin sensitizer.
  2. Thyroid: A randomized, double-blind, placebo-controlled trial in adults with hypothyroidism found that ashwagandha reduced serum TSH levels.[ref]
  3. Male infertility: Ashwagandha increases sperm count, volume, and motility.[ref]
  4. Sleep report: For sleep issues due to stress, ashwagandha may help.[ref][ref]

Luteolin (full article)

Luteolin is a flavonoid found in abundance in broccoli, parsley, and celery. It possesses a variety of anti-inflammatory and antibacterial properties, according to research. Clinical trials and research on luteolin show:

  • mast cell stabilizer, reduced histamine release
  • neuroprotective, brain fog
  • anti-inflammatory (TNF-alpha inhibitor)
  • improves sleep
  • anti-microbial
  • improving intestinal barrier integrity

Luteolin may work well for:

Brain Fog:
While there are a lot of reasons for brain fog (see the article for many reasons and genes), for people with inflammation-related genes, luteolin may be a good option.

Brain Fog Inflammation genes (Please read the full article for details):

Inflammation and TNF alpha:
In a study of children with autism spectrum disorder, luteolin supplementation has significantly decreased TNF levels. The supplement used in the study was NeuroProtek.[ref]TNF genes (Please read the full article for details):

Histamine intolerance:
Studies have shown Luteolin to inhibit histamine release from mast cells.[ref]Histamine intolerance genes (Please read the full article for details):

Cautions with Luteolin:

COMT interaction:
Luteolin is metabolized using the COMT enzyme, so individuals with slow COMT may want to use with caution and watch for mood changes. This may be more important if taking more than one supplement that utilizes COMT (or at high doses).

More articles that reference luteolin:

  1. Long Covid:
    A researcher theorizes that supplemental luteolin or quercetin can block the inflammasome production initiated by activating the toll-like receptors. The researcher notes that luteolin is a natural flavonoid considered ‘neuroprotective’ and has been shown to reduce brain fog. The researcher suggests combining luteolin, quercetin, and olive oil (for absorption and additional antiviral properties).[ref]
  2. NAFLD (fatty liver): Luteolin protects against fatty liver by improving intestinal barrier integrity. It also increases microbial diversity in the gut, according to animal studies.[ref]
  3. Chronic Lyme: A study looked at baicalein and luteolin, combined with either iodine or rosmarinic acid, and found that they may be effective against the typical spirochaete form and persistent forms as well.[ref]
  4. Autophagy: Luteolin seems to activate autophagy after a traumatic brain injury (TBI).[ref]



Curcumin (full article)

Curcumin, a polyphenol found in turmeric, is a spice used in traditional Indian cuisine and other areas of Asia. It has a long history of use as a spice and in traditional Ayurvedic medicine. Research on curcumin shows that is is anti-inflammatory and decreases oxidative stress. Additionally, research studies show benefits for:

  • preventing progression to diabetes from prediabetes
  • improving depression (if depression is due to inflammation)
  • decreasing joint pain in arthritis
  • decreasing blood glucose in POS
  • improving liver markers in NAFLD
  • helping cognitive function in middle age

Curcumin may work well for:

Mold detoxification:
Curcumin increases the UGT enzymes and upregulates the glucuronidation pathway, essential for mycotoxin elimination.[ref] Migraines:
Curcumin has been shown to reduce inflammatory cytokines in the brain, including TNF-alpha. A clinical trial found that the combo of curcumin and CoQ10 effectively reduced the number of migraines.[ref][ref]Your migraine genes (see full article on Migraines): Depression and Inflammation:
A randomized clinical trial showed curcumin (500 mg/2x per day) to be more effective than a placebo for improving depression.[ref]

Cautions with Curcumin:

Curcumin may increase oxalate excretion in the urine. People with genetic SNPs that increase susceptibility to kidney stones (or with a history of kidney stones) may want to consult their physician before starting curcumin.

Check your kidney stone variants.

More articles that reference curcumin:

  1. Mercury detoxification: Curcumin increases the GLCM, the rate-limiting enzyme for glutathione production, which is important in mercury detoxification.[ref][ref]
  2. Fatigue: Curcumin inhibits TNF-alpha production.[ref]
  3. Diabetes and blood glucose genes: The curcumin-treated group had a decrease in HOMA-IR.[ref]
  4. PCOS genes: Curcumin decreased blood glucose levels as well as LDL cholesterol.[ref]
  5. Estrogen metabolism: Curcumin induces the expression of GSTP1 (glutathione S-transferase P1), which is important in estrogen metabolism.
  6. Boosting BDNF: Curcumin reverses the decrease in BDNF levels from chronic stress.[ref]
  7. Rheumatoid Arthritis: Curcumin is beneficial in reducing inflammation in RA.[ref]
  8. IL-17 and Autoimmune Risk: Curcumin was found to decrease IL-17 (in an animal study).[ref]
  9. HMGB1 and Inflammasome activation: In animal studies, Curcumin inhibits HMGB1 release.[ref][ref]
  10. Osteoarthritis: A natural TNF-alpha blocker, curcumin has been shown in several studies to be effective for osteoarthritis.[ref][ref] A clinical trial found that curcumin (500mg / 3x per day) was as effective as diclofenac for osteoarthritis – but with fewer side effects.[ref]
  11. MRGPRX2 receptor on Mast Cells: Curcumin is likely a MRGPRX2 receptor blocker (animal and cell studies).[ref]

Berberine (full article)

Berberine is a natural supplement with some amazing research for reducing high blood glucose levels and high cholesterol. The drawback, though, is poor absorption in the intestines, decreasing its effectiveness. Research on berberine shows:

  • lowers blood glucose
  • improves LDL cholesterol and triglyceride levels
  • helpful for NAFLD (fatty liver disease)
  • improves intestinal barrier function
  • beneficial for PCOS
  • reducing IBS-D symptoms

Berberine may work well for:

PCSK9 variant with high LDL cholesterol:
Berberine is a natural inhibitor of PCSK9 and has been shown in human studies[ref][ref] and cell studies[ref] to decrease cholesterol.For someone with variants that increase PCSK9 and increase cholesterol (below), berberine may be beneficial for lowering cholesterol. Talk to your doctor, of course, if you have questions. Lipoprotein(a):
Berberine has been shown to decrease cholesterol levels as well as decrease Lp(a) levels.[ref][ref](Be sure to read the full article on Lp(a) if you have either of the first two variants.)

Cautions with berberine:

Berberine uses CYP3A4 and CYP2D6 enzymes for metabolism. Thus, it may interact with medications that also use those enzymes. If you are on prescription medications, talk with your doctor before adding in a bunch of berberine.

Check your CYP2D6 genetic variants and check your CYP3A4 variants here.

The interaction with berberine may be important if you have slower CYP2D6 or CYP3A4 function – along with taking a medication that utilizes these enyzmes.

Researchers also caution that people with G6PD deficiency may have side effects from berberine.

Your G6PD gene (read full article):

More articles that reference berberine:

  1. NAFLD: Berberine (500mg, 3x per day) resulted in a more significant decrease in liver fat and a greater reduction in weight, HOMAR-IR, and lipid profiles.[ref]
  2. PCOS: Several randomized clinical trials have found that berberine is as effective as metformin for PCOS.[ref][ref]
  3. SCD1 and metabolism: Berberine decreases SCD1 levels and decreases fatty liver in animal studies.[ref][ref]
  4. Leptin: Improved leptin ratios and decreased BMI after three months of berberine (300mg/3x per day).[ref]
  5. Psoriasis: Berberine decreases psoriasis symptoms when used topically.[ref][ref]

Quercetin (full article)

Quercetin is a natural flavonoid that acts as both an antioxidant and an anti-inflammatory. This potent flavonoid is found in low levels in many fruits and vegetables, including elderberries, apples, and onions. As a supplement, quercetin has many positive health benefits including:

  • combating oxidative stress
  • reducing blood pressure
  • acting as a senolytic
  • decreasing high uric acid levels
  • reducing upper respiratory infections
  • blocking mast cell activation

Quercetin may work well for:

Histamine intolerance:
Quercetin stabilizes mast cells and inhibits histamine release.[ref]Histamine intolerance genes (Please read the full article for details):
Gout genes:
A clinical trial using 500mg/day of quercetin for four weeks found that it decreased uric acid by 26·5 µmol/l on average.[ref]

Cautions with Quercetin:

COMT interaction:
Quercetin has a catechol structure and is partly metabolized through the COMT enzyme. If you carry the slower version of COMT, you may want to be careful and not go overboard with quercetin. This may be more important if taking more than one supplement that utilizes COMT (or at high doses).

More articles that reference quercetin:

  1. Alopecia Areata: A mouse model of AA showed that quercetin stopped hair loss.[ref] Cell studies show that topical nano-particle quercetin holds promise for alopecia.[ref]
  2. NLRP3 inflammasome activation: Quercetin inhibits NLRP3 activation in cell and animal studies.[ref]
  3. Fatigue: Quercetin significantly inhibits IL-1B production.[ref]
  4. Inflammation and Depression: Animal studies show that quercetin effectively reduces depression and anxiety behavior.[ref][ref]
  5. Mast Cell Activation Syndrome Genes: Quercetin stabilizes mast cells and inhibits histamine release.[ref]
  6. APOE and Alzheimer’s Risk: Researchers theorize that oxidative stress contributes to Alzheimer’s disease pathology. Animal and cell studies show that quercetin can protect against oxidative stress in the brain and partially prevent the associated neuronal toxicity.[ref]
  7. Sirt3, Aging, and Mitochondrial Function: quercetin also has beneficial effects in part through the SIRT3 pathway.[ref][ref]
  8. Lipedema: Quercetin is another antioxidant supplement that researchers suggest as being a likely candidate to help with lipedema.[ref]
  9. Nickel Allergy: In patients with known nickel allergies, quercetin supplements for three days before nickel contact decreased their reaction by more than 50%.[ref]
  10. Cold Sores: Quercetin has been shown in cell studies to lower herpes simplex virus infectivity.[ref]

Hesperidin (full article)

While not as well known as quercetin or curcumin, the research on hesperidin, a flavonoid found in citrus fruits, shows solid anti-inflammatory benefits — without interacting with slow COMT.

The benefits of hesperidin include:

  • reduced inflammation
  • decreased neuroinflammation
  • better vascular function
  • enhanced immune response

Hesperidin may work well for:

Hesperidin, a natural flavonoid from citrus fruits, inhibits the release of TNF-alpha.[ref][ref] Lupus:
Blocking TNF may benefit lupus patients with specific variants.

Cautions with hesperidin:

Hesperetin is an inhibitor of CYP2C9. If you have variants below, read more here, and then use caution when combining with medications that are metabolized through that pathway.

More articles that reference hesperidin:

  1. Alpha-1 Antitrypsin Deficiency: Hesperidin inhibits inflammation by blocking the release of TNF-alpha.[ref]
  2. Advanced Glycation End Products: Hesperidin can help upregulate glyoxalase 1, which may be helpful with AGEs. It does this by activating the Nrf2 pathway.[ref]
  3. Lipedema: A metabolite of hesperidin is recommended by researchers for lipedema, but there aren’t clinical trials on it yet.[ref][ref]
  4. Flu season: Hesperidin has been shown in several cell studies to inhibit the replication of influenza A. However, there aren’t any clinical trials of hesperidin for the flu.[ref]

Nattokinase (full article):

A natural component of Japanese Natto, nattokinase is an enzyme that helps to break down blood clots. The full article is full of references and clinical trial data on nattokinase.

Consider nattokinase for:

Elevated Fibrinogen:
Nattokinase may be something to consider for anyone with variants related to higher fibrinogen levels Small fiber neuropathy:
Clotting and microclots may factor in small fiber neuropathy.

Cautions with Nattokinase:

While I don’t have any genetic links to cautions, please be sure to talk with your doctor if you are already on any anticoagulant or heart-related medications.

Additionally, nattokinase is derived from natto, which is fermented. It is possible that people with histamine-related issues could notice an increase in histamine from nattokinase.

More articles that reference nattokinase:

  • Factor V Leiden: Mutation in factor V increases the risk of aberrant clotting and DVTs.

CoQ10 (full article):

CoQ10 is used in cells as an antioxidant, immune modulator, and regulator of NAD+ — and for ATP production in the mitochondria. While many know about CoQ10 for heart health and mitochondrial energy, it is also important for:

  • acting as a lipid-soluble antioxidant (prevent oxidized LDL)
  • regulates cell death through ferroptosis
  • acts as an anti-inflammatory by impacting IL-1 and TNF-alpha
  • helps in the immune response against viruses and bacteria

Consider CoQ10 for:

Statins and Brain Fog:
In addition to lowering cholesterol, statins reduce CoQ10 levels. A meta-analysis of randomized controlled trials shows that CoQ10 levels are reduced in all types of statin users.[ref] [ref] Migraine prevention:
CoQ10 (400 mg/day) reduced the frequency and severity of migraines.[ref]

Cautions with CoQ10:

Talk with your doctor if you are on warfarin and have concerns about interactions with CoQ10.

More articles that reference CoQ10:

  1. Egg Quality when TTC: CoQ10 may be helpful in improving egg quality for women trying to get pregnant.
  2. Migraine prevention: CoQ10 (400 mg/day) reduced the frequency and severity of migraines.[ref]
  3. Fatigue (ME/CFS): Supplementing with 150mg of ubiquinol, a form of CoQ10, improved cognitive function in people with CFS/ME.[ref]
  4. Inclusion Body Myositis: CoQ10 and carnitine may help reduce symptoms for some individuals.[ref]

Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN)

NAD+ is an essential part of mitochondrial energy production. As we age, our NAD+ levels decline, and researchers believe this may tie into a lot of chronic diseases related to aging. NR and NMN are supplements that can increase NAD+ levels.

Consider NR or NMN for:

Several studies have shown that NMN or NAD+ precursors restore fertility at the end of an animal’s normal reproductive age. It seems to do this through rejuvenating egg quality.[ref]
Cell and animal studies show that NMN decreases inflammation while promoting healing in tendons.[ref]

Cautions with NR or NMN:

While the research is not totally clear on whether NR or NMN could promote cancer growth, I would err on the side of caution until the research is conclusive if I was battling cancer.

Another caution is that NAD+ levels decline significantly with age. I haven’t seen a lot of benefits in research for taking NR or NMN for people who are young and healthy since they are likely to have sufficient NAD+ already.

More articles that reference NR and NMN:

  1. Long Covid: AgelessRX has a clinical trial underway using low-dose naltrexone and nicotinamide riboside.[ref]
  2. Depression and Mitochondrial Function: Nicotinamide riboside (NR) reduces inflammation in the brain and improves cognitive function in animal studies.[ref]
  3. Inclusion Body Myositis: A recent study (Jan. 2021) showed that increasing NAD+ levels via nicotinamide riboside may help with mitochondrial muscle function. The study used animal and cell models (not a randomized trial).[ref]

Creatine (full article):

Creatine is an amino acid important in energy production in brain tissue and muscles. It is produced from a reaction that includes the amino acids glycine and arginine, along with a methyl group.

Consider creatine for:

Creatine synthesis genetic variants: Genetic variants can impact how your cells make creatine.

The MTHFR gene encodes an enzyme that is important in the methylation cycle and production of methyl groups. A methyl group is needed for the synthesis of creatine, so for people who have limitations on the methylation cycle, supplemental creatine may help take the strain off the pathway.

High homocysteine:
Supplemental creatine can help to lower homocysteine levels in healthy people with good kidney function.[ref][ref][ref]

Cautions with creatine:

Creatine is used in clinical trials without side effects, but there are cautions for people with kidney disease.

More articles that reference creatine:

AMPD1 deficiency:
Creatine supplements have been used to prevent muscle soreness in people with AMPD1 deficiency.  Studies have shown varying results for the impact of creatine.[ref][ref]

Mood or depression:
Clinical trials show creatine may help with depression caused by a lack of brain energy or oxidative stress.[ref]


More to come…

Bookmark this page and check back soon for more supplement-gene interactions.

About the Author:
Debbie Moon is the founder of Genetic Lifehacks. Fascinated by the connections between genes, diet, and health, her goal is to help you understand how to apply genetics to your diet and lifestyle decisions. Debbie has a BS in engineering from Colorado School of Mines and an MSc in biological sciences from Clemson University. Debbie combines an engineering mindset with a biological systems approach to help you understand how genetic differences impact your optimal health.