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Here are some armchair theories¬†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 ūüėČ ¬†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.

You can check your methylation status by taking a 23andme test and plugging it into SelfDecode.

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 increases 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 (R), Fruits and fiber (R), L brevis (R), L acidophilus (R),  B longum (R), B Infantis (R), Silymarin (R), Reishi (R), Gotu kola (R), Black Pepper (R), Cumin (R), Calcium glucarate(Cruciferous veg, oranges apples, grapefruit), Camu.

Beware of: Chilli (R), citrus fruit, crucifers, and soy (R), Germanium (R)

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:

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

You can check your methylation status with 23andme and plugging it into SelfDecode.

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. (R)

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.

Health Tools I Wish I Had When I Was Sick

At SelfHacked, it’s our goal to offer our readers all the tools possible to get optimally healthy. When I was struggling with chronic health issues I felt stuck because I didn’t have any tools to help me get better. I had to spend literally thousands of hours trying to read through studies on pubmed to figure out how the body worked and how to fix it.

That’s why I decided to create tools that will help others cut down the guesswork:

  • Lab Test Analyzer – a software tool that will analyze your labs and tell you what the optimal values are for each marker — as well as provide you with actionable tips and personalized health and lifestyle recommendations to help you get there.
  • SelfDecode – a software tool that will help you analyze your genetic data from companies such as 23andme and ancestry. You will learn how your health is being impacted by your genes, and how to use this knowledge to your advantage.
  • SelfHacked Secrets – an ebook where we examine and explain the biggest overlooked environmental factors that cause disease. This ebook is a great place to start your journey if you want to learn the essential steps to optimizing your health.
  • SelfHacked Elimination Diet course – a video course that will help you figure out which diet works best for you
  • Selfhacked Inflammation course – a video course on inflammation and how to bring it down
  • Biohacking insomnia – an ebook on how to get great sleep
  • Lectin Avoidance Cookbook – an e-cookbook for people with food sensitivities
  • BrainGauge – a device that detects subtle brain changes and allows you to test what’s working for you
  • SelfHacked VIP – an area where you can ask me (Joe) questions about health topics

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  • cleo

    I react to every supplement usually with anxeity and panic attacks but sometimes it will give me severe low mood which send me into a panic. I cannot tolerate methylb12 or folate, they make me aggiated and depressed, Niacin makes me depressed, GABA now makes my panic worse and makes me feel detatched, Inositol and Lithium-orotate made my insides feel like electricity was running through it.
    Several supplements have had this pattern- take it and feel drowsy, fall asleep and within a short time I fling up into a panic saying, ” I want to die”…this has happened with Prozac, L-Theanine, GABA, and to a lesser extent Passsionflower. I leave me in distress. Took my first Lexapro 5hrs ago and started feeling that detatched,flat, low feeling until all of the sudden I felt drowsy and off, I had the same reaction of thoughts/feeling ” oh god I want to die” I had 3 mini panic attacks because of it. I can’t figure out what is going on and why I’m so sensitive to everything. Or if there’s something these have in common.

  • Shay

    This is a great article and very informative. I’m still trying to understand some aspects but came across this looking for acetylation info which was helpful. I have a teenage daughter who became very ill we eventually found out resulted from her taking minocycline for her skin. She had a sports injury around the same time and had a couple of orthopedic surgeries so we incorrectly assumed it was all related like some infection. I had never heard of drug reactions presenting as autoimmune issues. She developed drug induced lupus and vasculitis. The doctor explained to us she became so ill that threw her thyroid out of whack (she started losing hair). The lupus affected her breathing. She’s doing better now off the med but still needs more time to resolve we are told. I just keep wondering why. Why can many take these meds without issue and she had such extreme issues. It took a year to find someone to figure this out (rheumatologist) but they offer no help or explanation other than her body will heal itself. I question that. She’s 16. I read there are basically 3 theories associated with cause and wonder your opinion. One is slow acetylation. I can get behind that and makes sense to me especially since once her dosage lowered things improved although we still didn’t make the connection. Second theory was virtually all lupus inducing drugs undergo oxidative metabolism whereas analogous non inducing drugs do not. Okay, guess we need to look out for that. Third was decreased T cell methylation which I’m still trying to understand but your info helps. One person we saw did mention suspected sensitivity to pesticides and metals. And the last theory was genetic differences in individual P450 system which I’m still trying to figure out. I want to try and help her with supplements but honestly afraid to try anything at this point. Minocycline is metabolized in the liver and highly concerned about that. Any insight appreciated.

  • Jonathan Warkentine

    I have noticed that supplementing zinc, whether chelate or picolinate, leaves me wired. I can’t figure out why since it is supposed to be calming.

  • Ole

    I have a problem using hydrolyzed collagen supplements for the maintenance of tendons throughout the body. I get srtange spasms in my middle ear (very annoying) a few hours after supplementation. From what I can read, it might be due to toxic build up of glutamate, which affects the CNS. After a day or two the spasms subside. Of course, I am afraid that levels will cause permanent CNS damage. I have not been able to find glutamate free hydrolyzed collagen. Also, I am suspecting a leaky BBB as being part of the problem, perhaps combined with the fact that the size of the amino acids are below 5000 daltons. Is there anything, which can counteract toxic build up of glutamate, or should I just completely eliminate the use of hydrolyzed collagen due to my sensitivity?

  • Molly

    I feel like this. I seem to react to everything. Last time my doc changed up my supplements and I thought I was dying: heart pounding, woke up the next morning with cold hands and feet, shaky, fatigued, yet heart pounded the whole time. It was awful. I’m scared to take anything st this point. Also, b vitamins seem to make me extremely irritable and angry, like I have an extremely short fuse. I wish I could figure out what I could take.

  • Kelli Mulder

    Joe what happens if you cant tolerate the supplements to help tolerate supplements? ūüôā

    1. Joseph M. Cohen

      You need to start with lifestyle or something gentle like hydrogen machine:

  • peter

    @dylan adenosyl-B12 alone is not sufficient to help methylation.

  • Dylan

    Great article! One thing I wanted to add to the methylation area is using the form of b12; adenosylcobomolain instead of methylb12, or in addition to. The late Dr. Rick Van Konynenburg noted that some people tolerated this form better, and also that it’s important to take b12 forms sublingually for max bioavailability.

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