Disclaimer: This content is not intended as treatment or support for any medical condition. Content for entertainment purposes only. Not medical or health advice.
You take progesterone to help with your PMS…but your mood and water retention worsen instead.
You take magnesium glycinate to help you sleep…but it gives you insomnia.
You take a B-complex to help with your energy levels…but instead start biting your nails and getting angry at minor things.
You take thiamine to help with neurological issues…but nearly erupt in a panic attack.
A paradoxical reaction is a phenomenon in which a supplement causes an effect opposite to that expected or produces otherwise “unexplainable” adverse effects.
While paradoxical reactions are most commonly discussed in the context of pharmaceutical drugs, they also extend to supplements. Reactions to certain nutrient-dense foods may also be considered “paradoxical.”
You may try drinking orange juice for minerals and vitamin C, having liver weekly for vitamin A, minerals, and B vitamins, or eating oysters for their zinc and selenium content, only to experience allergic-like reactions, gut upset, or racing thoughts.
Of course, this is incredibly frustrating, especially when constantly hearing how great these foods or supplements are, or when everyone around you seems to feel like a million bucks when implementing the same interventions that made you spiral.
I am no stranger to paradoxical reactions, as much of my health journey has been characterized by asking myself “Why is my body wired backwards?”
Adverse, hard-to-explain reactions can be incredibly frustrating and demotivating. Yet, I am glad to have experienced them. They gave me perspective. Thanks to them, I am much more humble, far less likely to dismiss concerns or assume that I have all the answers, and extremely cautious about making hyperbolic statements.
“Paradoxical reactions” are common in this corner of the internet, because people usually arrive at the bioenergetic approach precisely because all the things that “work” for others didn’t work for them. It follows that this space is already filled with individuals whose constitutions are delicate and who need special care to undo years or decades of bad health.
Having been somewhat early to the “bioenergetic party” (late 2010s), I was reading Dr. Ray Peat’s articles and interpreting them into actionable steps back when most of the online health space was still busy drinking kale smoothies or jumping onto the carnivore bandwagon. Yet, being early also meant that there weren’t too many people online who’d experienced adverse reactions to seemingly “always safe” foods or compounds, who knew how such reactions may be logically explained, or who were willing to listen and take negative anecdotes seriously. More than once, this lack of answers left me with an overwhelming wave of anger at the fact that I seemingly must arrive at the solution on my own.
Fortunately, I never let my various setbacks and confusing responses convince me to “throw the baby out with the bathwater,” so to speak, and abandon ship. As a result, I’ve arrived at a framework that helps me explain why these paradoxical reactions happen.
Chances are you’re not “built different,” and these reactions are not all that paradoxical either.
In my experience, most paradoxical reactions can be explained by:
Liver function (and other “detox & drainage” pathways) needing some extra tending
Inappropriate formulations, dosing, or “jumping in too quickly”
Underlying micronutrient deficiencies or imbalances
Rampant, unaddressed inflammation
Struggling gut health
All these factors and how to rebuild resilience—by going low and slow when everything appears to backfire—will be the focus of this article series.
This article (part one) focuses on explaining the underlying causes behind paradoxical reactions.
Part two will focus on how to establish a good dietary baseline when dealing with food sensitivities and maximize micronutrient absorption by quenching inflammation.
Part three will dive into how to vet the quality of supplement preparations, how to slowly titrate supplement doses and gauge reactions, and how to navigate the different supplement formulations and know when some may (or may not) be appropriate.
All micronutrients interact. Just like an intricate dance routine, all the micronutrients (vitamins and minerals) work together.
These interactions are part of the reason why rapidly jumping into vitamin or mineral supplementation when in a generally depleted state, or why overdoing certain micronutrients, can backfire. You take too much of one thing for too long and accidentally deplete five others. It’s like tugging on a spider’s web. You touch one string and change the conformation of the whole structure.
As an example, let’s take a look at thiamine (vitamin B1).
Thiamine (B1) helps cells harness energy from foods. While it is especially important for the metabolism of glucose, it is also involved in the metabolism of proteins and fats. But it is not the only micronutrient involved in these reactions.
As it accelerates fuel burning, it increases the need for all the other micronutrients directly involved in turning fuel into energy. This includes vitamins B2, B3, B5, B7 and B12, magnesium, zinc, iron, potassium, sodium, manganese, phosphorus, and copper.
Fuel burning also uses up CoQ10, alpha-lipoic acid (ALA), as well as carnitine (which is needed to burn fats for energy). Producing these cofactors requires micronutrients, including iron and vitamin C. The biosynthesis of CoQ10 relies on S-adenosylmethionine (SAM), the production of which relies on methylation, a reaction that involves vitamins B2, B4 (choline), B6, B9, B12, magnesium, zinc, and the amino acid methionine.
Additionally, the process of converting fuel into energy always generates some amount of reactive oxygen species that need to be neutralized to prevent damage to fuel-burning mitochondria. Thus, pressing on the gas to accelerate fuel burning also increases the need for micronutrients and amino acids involved in powering our antioxidant defences. These include vitamins B2, B3, C and E, selenium, manganese, copper, iron, zinc, magnesium, and the amino acids glycine, cysteine, and glutamate.
Shifting the levels of any micronutrient affects the whole, like moving a tiny fragment in a kaleidoscope.
This is why it’s unlikely that you’ll find that one “magic” supplement that will fix all your issues. The body is a system. It doesn’t work like that.
And so, if you take thiamine for example, especially in large doses and your levels of co-participating nutrients are low—especially those of magnesium, potassium, and other B vitamins—an adverse reaction is more likely.
Another piece of the puzzle is that some micronutrients share the same transporters in the gut that help them get absorbed. This is why high-dose vitamin B5 supplements can lead to a biotin (vitamin B7) deficiency, as the two both rely on the same intestinal transporter for absorption.
Getting too much vitamin A when deficient in vitamin B3 can result in a chronic “hangover” of sorts due to aldehyde buildup, as vitamin B3 is needed for the conversion of retinaldehyde to retinoic acid.
Getting too much iodine, especially when deficient in selenium (or in reduced glutathione, more generally), can harm instead of helping the thyroid, by increasing local oxidative stress.
Getting too much vitamin C when deficient in nutrients needed for glutathione synthesis or recycling (e.g., B2, selenium, glycine) can interfere with the conversion of dehydroascorbic acid (“used-up vitamin C”) back to vitamin C, instead causing dehydroascorbic acid to decompose into harmful oxalate, putting stress on the kidneys.
These reactions also extend to how a body may react to certain amino acids.
Getting too much cysteine or methionine when deficient in molybdenum can lead to histamine reactions driven by poor sulphur metabolism and sulfite buildup.
When severely deficient in magnesium, isolated glycine (the main amino acid in gelatin) may be agitating rather than calming.
NMDA receptors—which are key excitatory receptors in the brain—need to remain “blocked” by magnesium to prevent excess excitation. When this magnesium “block” is missing (for example, when in a severely magnesium-depleted or de-energized state), glycine can co-activate NMDA receptors alongside glutamate, leading to restlessness, racing thoughts, and insomnia. This is why some react “paradoxically” to magnesium glycinate when in a severely magnesium-depleted or de-energized state.
Starting with magnesium L-threonate or topical magnesium chloride spray before jumping to magnesium glycinate may produce better outcomes in those individuals.
Of course, this principle also extends to the supplementation of substances that accelerate the metabolic rate in general, such as natural desiccated thyroid, synthetic thyroid hormones, or even caffeine.
As they accelerate fuel burning, they also accelerate the usage of micronutrients that participate in fuel burning, hormone creation, tissue repair and growth, antioxidant functions and more. Using metabolism-boosting substances and practices can reveal or precipitate micronutrient deficiencies.
Getting a good dietary baseline in place helps guard against these imbalances, especially when supplementing.
The capacity and function of our “detox organs” (i.e., the liver, kidneys, gut and bowels, and lungs) and our “drainage pathways” (i.e., the lymphatic system and skin) can dictate how we respond to supplemental substances.
Let’s take bio-identical progesterone as an example.
Some women find that taking progesterone can flare their symptoms of estrogen dominance. This was me. I was one of those rare individuals who responded adversely when first taking progesterone.
Progesterone normally acts as an estrogen antagonist, being able to reduce estrogen secretion and even deactivate estrogen receptors,1 so this reaction is considered “paradoxical.”
However, it becomes less paradoxical once we consider liver function.
When you ingest progesterone, it gets metabolized by the liver. The formulation taken dictates how quickly and rapidly it will reach the liver and how much of it will get immediately deactivated vs. how much will enter the blood.
Micronized progesterone tablets undergo first-pass hepatic metabolism. This means that before this progesterone enters the general circulation, it first passes through the liver, where up to 90% of it becomes deactivated before reaching the general circulation.
Formulations that dissolve progesterone in vitamin E (such as Progest-E) bypass first-phase liver metabolism. Vitamin E is directly absorbed by chylomicrons in your gut, entering the lymphatic fluid, which then drains into your general circulation. It “smuggles” progesterone along, straight into your lymph, then blood, bypassing the liver. Of course, even this progesterone fraction will eventually undergo hepatic (liver) metabolism, but its clearance will be delayed and more gradual.
Now, here is the relevant part: the same Phase I liver detoxification enzymes that clear progesterone also clear estrogens.2
The Phase I liver detoxification cytochrome P450 CYP3A4 enzyme is involved in both estrogen and progesterone metabolism.3 High doses of progesterone, especially micronized progesterone, could theoretically slow estrogen clearance by overwhelming this enzyme. Phase I detoxification enzymes need micronutrients like vitamin B2, B3, iron, zinc, and magnesium to function, so putting more pressure on the liver can deplete these nutrients faster and cause a traffic jam.
Progesterone metabolites are then cleared through Phase II glucuronidation and sulfation pathways. While the specific glucuronidation and sulfation enzymes that clear progesterone vs. estrogens are slightly different, Phase II reactions, in general, rely on molybdenum (an important cofactor for sulfation reactions) and glutathione (the generation and recycling of which depends on multiple nutrients, including selenium, vitamin B2, vitamin B3, glycine, cysteine, and glutamate). Of course, giving the liver more compounds to process puts pressure on these vitamins and can eventually cause a traffic jam and slow liver function.
As liver function slows, Phase I estrogen metabolites (like 2-OH, 4-OH, and 16α-OH catechol estrogens) can build up, failing to be converted into safe, water-soluble forms for elimination. These intermediates can be more reactive than endogenous estrogens, contributing to symptoms of estrogen dominance.
Once past Phase II reactions, progesterone metabolites then need to be eliminated from the body either through the bile and feces or in urine.
Keeping hydrated helps keep the kidneys healthy, which allows them to eliminate metabolic waste products. By diluting waste products found in urine, adequate hydration helps protect against the formation of kidney stones.
For bile to flow, it must be conjugated with taurine or glycine. A deficiency of these amino acids can lead to stagnant bile flow and cholestasis. Not only that, but a traffic jam, whereby too many sulphated progesterone metabolites build up, can actually directly act on receptors in the liver, stopping the flow of bile.4
Lastly, bile that flows to the gut mostly gets reabsorbed, unless it gets bound to dietary fibre, which helps it (and all the toxic metabolites bound to it) exit the body via a bowel movement. Regular, daily bowel movements are a pre-requisite to minimize the reabsorption of bile and hormone metabolites.
To be able to handle hormones (even those pro-metabolic, beneficial ones, like bio-identical progesterone or pregnenolone), detox and drainage pathways must be supported. The liver needs to have the energy and micronutrients to transform and eliminate hormones, and the body must receive adequate hydration.
Additionally, the burden of endocrine-disrupting chemicals and other pollutants needs to be reduced, bile flow needs to be supported, fibre (which acts like a binder) must be eaten, and bowel regularity has to be ensured. Until all of this is addressed, adverse reactions to exogenous hormones are more likely.
And while I only used progesterone for this example, it is not the only compound whose function and effectiveness are affected by liver health. As another example, cholecalciferol—the building block for vitamin D3 that we make when exposed to UVB light or that’s encapsulated in vitamin D3 supplements—needs to undergo a magnesium-dependent hydroxylation in the liver to enter the general circulation as 25-hydroxyvitamin D3 (calcifediol). This is the form of vitamin D3 that blood tests measure. Poor liver function could be one reason for “paradoxically” low vitamin D levels despite getting plenty of UVB light.
The liver is also responsible for making the apoB protein, the primary structural protein making up part of vLDL/LDL cholesterol, which helps deliver vitamin E to tissues. Those unable to synthesize apolipoprotein B (apoB)—due to genetic defects—develop vitamin E-deficiency symptoms.5 While on the topic of vitamin E, it requires bile—created by the liver—to be absorbed. When bile flow is inadequate, vitamin E, especially in high doses, can remain in the gut unabsorbed, irritating it and causing nausea.6
I have already spoken about addressing the foundations before using exogenous hormones at length in my podcast episode on progesterone supplementation that I released here on Substack a few years back.
One of my listeners commented letting me know that, before listening to my podcast episode, she jumped straight into progesterone supplementation and had adverse reactions. After listening to my podcast, she focused on first establishing a good foundation before adding in progesterone: eating a nutrient-dense diet, reducing exposure to environmental pollutants, restoring bowel regularity with the use of fibre, minerals, and natural pro-kinetics, and making sure to get enough of the micronutrients that support liver function and estrogen clearance. After doing so, she was able to handle progesterone.
Once again, getting a good dietary baseline in place before jumping straight to hormone supplementation acts as a guardrail, ensuring that the liver is given all that it needs to process the new, exogenous compound.
Low progesterone levels can contribute to constipation (especially premenstrually), so introducing a small, supplemental progesterone dose if constipation fails to resolve with other interventions can be helpful. Yet, if you react poorly, you should use that as a data point, letting you know that your liver may need some support. Going slow is important to limit the amount of a compound that the liver has to process all at once.
Let’s also not forget the lymphatic system. As mentioned earlier, fat-soluble vitamins are first absorbed into the lymphatic fluid. If lymphatic stagnation is severe, fat-soluble vitamins can get “stuck,” failing to enter the blood for delivery to cells.
Lastly, our sweat, bile, urine, and bowel movements help us eliminate the harmful compounds that we are exposed to in our day-to-day life, including toxic metals and endocrine-disrupting chemicals. If we don’t tend to our “drainage & detox,” these harmful particles can interfere with our cells’ ability to use minerals, drain us of vitamins and antioxidants, and impair the ability of hormones to act on their receptors. We need vitamins and minerals to clear toxins, but we also need to support drainage & detox to reap full benefits from micronutrients. You need to consider all pieces of the puzzle.
The upcoming articles in this series will cover ways to support drainage & detox pathways.
Many people make the mistake of introducing supplements in excessive doses. If someone’s constitution is fragile, this frequently results in adverse reactions. These adverse reactions can then keep the person stuck. Just because a reaction happened doesn’t rule out the possibility that the affected person is deficient in said compound and absolutely needs more of it.
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