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PRO: Supplement Research Connections

Natural supplements can be an excellent option for healing and health, but there is a lot of marketing hype out there.

Genetic variants, along with clinical trials and quality research studies, can help you narrow down the supplements that may actually help – versus the supplements that are likely a waste of money for an individual.

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 a supplement may interact with.


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

  • 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.
  • Genetics and Anxiety: Genetic variants can impact your susceptibility to anxiety disorders. The lifehacks section explains the research on ashwagandha for anxiety.
  • Testosterone genes: Ashwagandha increases testosterone levels in men who lift weights or do muscle-building exercises.
  • Male infertility: Ashwagandha increases sperm count, volume, and motility.[ref]
  • BChE and Nightshades: Popular supplements such as ashwagandha and goji berries also fall into the nightshade category.
  • Leptin: Ashwagandha, an adaptogenic Ayurvedic herb, appears to be a leptin sensitizer.
  • Thyroid: A randomized, double-blind, placebo-controlled trial in adults with hypothyroidism found that ashwagandha reduced serum TSH levels.[ref]


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. Furthermore, some studies suggest that luteolin’s benefits may aid in preventing cancer cell proliferation. Luteolin Article

  • Inflammation and TNF alpha: In a study of children with autism spectrum disorder, luteolin supplementation has significantly decreased elevated TNF levels. The supplement used in the study was NeuroProtek.[ref]
  • 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]
  • 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]
  • Histamine intolerance: Studies have shown Luteolin to inhibit histamine release from mast cells.[ref]
  • COMT interaction: Luteolin is metabolized using the COMT enzyme, so use with caution in people with slow COMT if they are also on any other supplements that utilize this enzyme.
  • 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]
  • Autophagy: Luteolin seems to activate autophagy after a traumatic brain injury (TBI).[ref]


Curcumin, a polyphenol found in turmeric, is a spice used in traditional Indian cuisine and other areas of Asia as a drink. Turmeric is harvested from the rhizome of Curcuma longa, a member of the ginger family. It has a long history of use as a spice and in traditional Ayurvedic medicine. Curcumin is anti-inflammatory and decreases oxidative stress. It inhibits TNF-alpha and decreases NF-kB. Curcumin Article

  • Mercury detoxification: Curcumin increases the GLCM, the rate-limiting enzyme for glutathione production, which is important in mercury detoxification.[ref][ref]
  • 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]
  • Fatigue: Curcumin inhibits TNF-alpha production.[ref]
  • Diabetes and blood glucose genes: The curcumin-treated group had a decrease in HOMA-IR.[ref]
  • 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]
  • PCOS genes: Curcumin decreased blood glucose levels as well as LDL cholesterol.[ref]
  • Estrogen metabolism: Curcumin induces the expression of GSTP1 (glutathione S-transferase P1), which is important in estrogen metabolism.
  • Boosting BDNF: Curcumin reverses the decrease in BDNF levels from chronic stress.[ref]
  • Rheumatoid Arthritis: Curcumin is beneficial in reducing inflammation in RA.[ref]
  • IL-17 and Autoimmune Risk: Curcumin was found to decrease IL-17 (in an animal study).[ref]
  • HMGB1 and Inflammasome activation: In animal studies, Curcumin inhibits HMGB1 release.[ref][ref]
  • 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]
  • MRGPRX2 receptor on Mast Cells: Curcumin is like a MRGPRX2 receptor blocker (animal and cell studies).[ref]


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. Berberine article

  • PCSK9 variant, high cholesterol: Berberine is a natural inhibitor of PCSK9 and has been shown in human studies[ref][ref] and cell studies[ref] to decrease cholesterol.
  • 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]
  • PCOS: Several randomized clinical trials have found that berberine is as effective as metformin for PCOS.[ref][ref]
  • Lipoprotein(a): Berberine has been shown to decrease cholesterol levels as well as Lp(a) levels.[ref][ref]
  • SCD1 and metabolism: Berberine decreases SCD1 levels and decreases fatty liver in animal studies.[ref][ref]
  • Leptin: Improved leptin ratios and decreased BMI after three months of berberine (300mg/3x per day).[ref]
  • Psoriasis: Berberine decreases psoriasis symptoms when used topically.[ref][ref]


Quercetin is a natural flavonoid acting as both an antioxidant and anti-inflammatory. This potent flavonoid is found in low levels in many fruits and vegetables, including elderberry, apples, and onions.

As a supplement, quercetin has many positive health benefits. This article focuses on the results of clinical trials involving quercetin and links to specific genetic topics. Using your genetic data, you can make a more informed decision on whether quercetin is worth trying. Quercetin article

  • Mast Cell Activation Syndrome Genes: Quercetin stabilizes mast cells and inhibits histamine release.[ref]
  • 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]
  • Fatigue: Quercetin significantly inhibits IL-1B production.[ref]
  • NLRP3 inflammasome activation: Quercetin inhibits NLRP3 activation in cell and animal studies.[ref]
  • Inflammation and Depression: Animal studies show that quercetin effectively reduces depression and anxiety behavior.[ref][ref]
  • 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]
  • 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]
  • 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.

Nicotinamide Riboside and Nicotinamide Mononucleotide

As we age, our NAD+ levels decline. This may tie into a lot of chronic diseases related to aging. Much of the research here is new (the past ten years). NR and NMN Article

  • Infertility: 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]
  • Tendinitis: Cell and animal studies show that NMN decreases inflammation while promoting healing in tendons.[ref]
  • Long Covid: AgelessRX has a clinical trial underway using low-dose naltrexone and nicotinamide riboside.[ref]
  • Depression and Mitochondrial Function: Nicotinamide riboside (NR) reduces inflammation in the brain and improves cognitive function in animal studies.[ref]
  • 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]



While not as well known as quercetin or curcumin, the research on hesperidin shows solid anti-inflammatory benefits without interacting with slow COMT. Article on Hesperidin

  • TNF-alpha: Hesperidin, a natural flavonoid from citrus fruits, inhibits the release of TNF-alpha.[ref][ref]
  • Alpha-1 Antitrypsin Deficiency: Hesperidin inhibits inflammation by blocking the release of TNF-alpha.[ref]
  • Lupus: Blocking TNF may benefit lupus patients with specific variants.
  • 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]


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

  • Elevated Fibrinogen: Nattokinase may be something to consider for anyone with variants related to higher fibrinogen levels
  • Factor V Leiden: Mutations increase the risk of aberrant clotting and DVTs.
  • Small fiber neuropathy: Clotting and microclots may factor in small fiber neuropathy.


CoQ10 is used in cells as an antioxidant, immune modulator, and regulator of NAD+ — and for ATP production in the mitochondria.

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