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19 Reasons Why You May Be Reacting To Supplements

Written by Joe Cohen, BS | Last updated:

Here are some armchair theories about why people react to supplements. There are few citations because these are armchair theories and I did a little research for this post. Writing sometimes helps me form ideas – and why not share em 😉 Maybe I’ll add to it later on.

I became more curious because there’s a minority of people who can’t follow my protocols because they react to many or sometimes all supplements.

1) Oxidative Stress or Too Little Negative Charge in Cells

Electrons neutralize toxins and if we suffer from too much oxidative stress, it depletes our electrons.

If you have too much oxidative stress, then any chemical will add to it.

Most herbs cause some oxidative stress as well. This will especially be the case if you have an infection because the main bullets of your immune system are superoxide and other free radicals.

So any treatment that’s truly effective in combating an infection will increase free radicals and make you feel worse. All antibiotics, herbs, ozone, megadose vitamin C increase oxidative stress, but this is fine when you do it in bursts and to combat an infection.

2) Low Glutathione

Glutathione is the master detox chemical and this is usually depleted. It detoxes metals and other toxins. In phase 2 detox, glutathione binds to molecules to modify their toxicity and expel them (glutathione conjugation). This is done by glutathione S-transferases.

If this is the case, you need to take Liposomal Glutathione (Liquid) and NAC.

3) Low Methylation

Important for Phase 2 detox, Methylation is the addition of a methyl group to a compound. Certain SNPs influence this.

Methylation is very important for phase 2 detox. If you don’t methylate well, your detox abilities will be off.

If you have methylation issues, take SAM-e, Methylcobalamin, Methyl folate and P5P.

4) Low Sulfation

Important for Phase 2 detox, Sulfation is the addition of a sulfate to a drug/toxin and most often it makes it less toxic. Sulfation is important in the synthesis of glycosaminoglycans (GAGs) and intestinal mucins.

Low sulfation is a problem in people with Autism, Asthma, CFS, MCS, Intestinal disorders, Joint Disorders, Migraines, etc.

Sulfoxidation pathway is the main source of sulfate in the human body. Approximately 64% of the body’s total sulfate pool originates from the sulfoxidation of both exogenous and endogenous sulfur compounds into inorganic sulfate. This is because of the dietary absorption of sulfate, from food sources, across the gastrointestinal tract, is relatively inefficient.

You can increase sulfates by taking Glucosamine, Chondroitin, and MSM, Magnesium Sulfate/Epsom Salt baths. Also, Garlic and NAC increase sulfur compounds via cysteine.

Care should be taken as cysteine is toxic to the cells and it’s better to take down inflammation first.

Chronic inflammation in the form of TNF and TGF-b decrease the enzyme that turns cysteine to sulfate (cysteine dioxygenase), which results in higher cysteine and lower sulfate. Hence, raw garlic is probably the best option.

Low cortisol or aldosterone will also result in decreased cysteine dioxygenase.

A deficiency of iron, histidine, B5 or B6 will also lower the cysteine dioxygenase enzyme…Iron is generally lower if you are suffering from a chronic infection. You’ll also need molybdenum and B2 to convert sulfites to sulfate. Magnesium deficiency will lower active sulfates (PAPS).

As you see in the picture below, your mitochondria need to be functioning to create adequate ATP.

People have a higher cysteine to sulfate ratio in the morning because cysteine dioxygenase is lower at night. (I don’t know, but it may also be a good idea to take Tyrosine).

Screenshot 2015-05-29 12.51.40(R)

5) Low Glucuronidation

Important for Phase 2 detox, glucuronidation is often involved in detoxing drugs, pollutants, bilirubin, androgens, estrogens, cortisol, fatty acid derivatives, retinoids, and bile acids. Low glucuronidation may be why some have high bilirubin and health issues.

It’s more likely that our glucuronidation system is overloaded in the modern environment of drugs, pollutants, estrogenic compounds, stress and consumption of too many calories (the more fat you eat, the more bile and fatty acid derivatives that need glucuronidation).

Women, underweight people and people with liver problems also have less glucuronidation.

Fix this by boosting thyroid with LLLT (hypothyroidism decreases glucuronidation), Probiotic (Garden of Life) or Probiotics (Swanson), Licorice Root, Kombucha, Black Pepper, Cumin, Calcium Glucarate, Reishi, Gotu Kola…

Others/beta-glucuronidase inhibitors: Licorice/Glycyrrhizin [1], Fruits and fiber [2], L. brevis [3], L. acidophilus [3], B. longum [3], B. Infantis [4], Silymarin [5], Reishi [6], Gotu Kola [7], Black Pepper [8], Cumin [8], Calcium glucarate (Cruciferous veg, oranges apples, grapefruit), Camu.

Beware of: Chilli [8], citrus fruit, crucifers, and soy [9], Germanium [10].

6) Low Acetylation

Important for Phase 2 detox, people deficient in acetylation capacity (slow acetylation) may have prolonged or toxic responses to normal doses of certain drugs because of decreased rates of metabolism. Certain SNPs influence this.

To increase acetylation, take:

  • NAC
  • S-Acetyl Glutathione
  • N-Acetyl-Tyrosine

7) Low Glycine Conjugation

Important for Phase 2 detox, there’s a lot of research on glycine being an anti-toxin. Certain SNPs influence this.

Modern diets are lower in glycine because we don’t include enough joints or bone broth in our diet.

8) Drug Interactions

Drugs and supplements increase or decrease various enzymes (CYPs) needed to detox chemicals. Genetics also determines the level of enzymes.

9) Not Enough Oxygen/Hypoxia

Oxygen is needed for the first phase to detox drugs and chemicals. People with chronic issues often suffer from low oxygen.

Pulse Oximeter, RBC, and hematocrit are some measures of oxygenation.

10) Increased Immune System

I find that I’m more likely to get negative effects if a supplement increases Th1 dominance or costimulatory molecules, natural killer cells, and their activity, etc.

Any time you stimulate the immune system, you are increasing some aspect of inflammation, although supplements usually stimulate the most benign forms of inflammation/immunity.

11) Leaky Gut and Brain Barrier

If you’ve got a leaky gut and brain barrier, all kinds of stuff will enter.

12) Decreased Immune system

Most supplements decrease the immune system in some beneficial ways by decreasing cytokines. This is good, but if you have a severe underlying infection, that will exacerbate it.

Many of the supplements are anti-microbial, so they balance this out, but this still can contribute to reactions.

TNF and IL-1b are harmful cytokines, but when they tried to give monoclonal drugs to inhibit both, people became very sick.

13) Lectin sensitivity

Many supplements have lectins and you can react to them in the same way you react to grains, legumes or other lectins.

14) Too Much Stimulation In A Way That You Don’t Need

Most supplements that I recommend will increase neurotransmitters to one degree or another (while stabilizing glutamate). Or it could stimulate the immune system too much in a way that your immune system is already robust.

15) Anxiety

In some circumstances, I believe supplement reactions are just from anxiety from ingesting a product that you’re not comfortable with.

Many supplements increase BDNF, which increases the stress response if you already have high levels.

Whenever you have a change in your body, you experience more stress because of the unknown and that stress can exacerbate your issues.

The nocebo effect is when people feel harmed by an inert substance. Now imagine what would happen if a substance caused an actual change. People freak out and this causes negative effects.

16) Herxheimer reactions

This is the most overhyped cause of a reaction, but it’s not without merit.

For people with infections, the death of bacteria can cause toxins to be released and a spike of cytokines like IL-6 and TNF results [11].

17) Hormesis

Somewhat general, but many supplements act as a stressor in order to stimulate beneficial responses and this stressor can overburden your system.

In this case, any kind of stressor will make people feel worse such as cold therapy, heat, etc…

18) Detoxing

Many treatments stimulate an increase in toxic burden.

For example, the lipoic acid will bring heavy metals out of your tissues, but that increases the circulation of these metals. So if your system is weak and you don’t have good detox abilities, you’ll get a bad reaction simply because of increased circulation of heavy metals.

19) Low Blood Pressure

Many people chronic fatigue issues have low blood pressure and taking various supplements may make that worse.

Good Reaction Mistaken For Bad Ones

Sometimes what we think a bad reaction is simply a strong reaction.

I used to feel that my cognition declined after supplements because my brain pathways were used to being run on anxiety/CRH and it took years to transition away from that.

Most supplements that I recommend block the stress pathway and your cognition/mood can temporarily go down because CRH stimulates orexin/wakefulness and leads to the release of endorphins.

If you want to analyze your genome, SelfDecode is the best tool out there to do that.

SelfDecode is a sister company of SelfHacked. The proceeds from your purchase of this product are reinvested into our research and development, in order to serve you better. Thank you for your support.

About the Author

Joe Cohen, BS

Joe Cohen, BS

Joe Cohen flipped the script on conventional and alternative medicine…and it worked. Growing up, he suffered from inflammation, brain fog, fatigue, digestive problems, insomnia, anxiety, and other issues that were poorly understood in traditional healthcare. Frustrated by the lack of good information and tools, Joe decided to embark on a learning journey to decode his DNA and track his biomarkers in search of better health. Through this personalized approach, he discovered his genetic weaknesses and was able to optimize his health 10X better than he ever thought was possible. Based on his own health success, he went on to found SelfDecode, the world’s first direct-to-consumer DNA analyzer & precision health tool that utilizes AI-driven polygenic risk scoring to produce accurate insights and health recommendations. Today, SelfDecode has helped over 100,000 people understand how to get healthier using their DNA and labs.
Joe is a thriving entrepreneur, with a mission of empowering people to take advantage of the precision health revolution and uncover insights from their DNA and biomarkers so that we can all feel great all of the time.


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