Milk thistle alters thyroid hormone transport

Milk thistle (also known as silybum marianum) is plant in the Asteraceae family. Milk thistle is widely promoted as a liver supplement. It is sometimes sold as “Silymarin” or “Chardon-Marie” (derived from carduus marianus).

On the internet, many websites and blogs are proclaiming that milk thistle can support thyroid hormone health simply by means of promoting liver health.

Milk thistle extract is selling like hot cakes!

However, in light of recent scientific discovery, caution — and hope! — is needed with regard to milk thistle’s downstream effects on thyroid hormone metabolism and signaling.

First, let me introduce to you some terminology we need to be clear:

  1. The milk thistle plant provides an extract consisting of many flavonolignans. The extract is called “silymarin” (SY).
  2. One component of silymarin is the flavonolignan called “silychristin” (SC).

Silychristin derived from milk thistle is an endocrine disruptor.

According to the U.S. National Institutes of Health, endocrine disruptors “interfere with the body’s hormones, known as the endocrine system” (NIH). Both SY and its active ingredient SC fit within this definition as a selective T3- and T4-transport inhibitor.

However, this does not necessarily mean milk thistle is bad for everyone in all circumstances and at all doses.

Thyroid endocrine disruptors have the power to intervene therapeutically. It depends on whether they are used strategically in the right circumstances or naively in the wrong circumstances.

Silychristin acts like a drug. The general drug class of “membrane transport modulators” contains 86 drugs in the DrugBank database. By changing different transport pathways, they have the ability to treat hypertension, angina, seizures, and so on.

Many insights into thyroid hormone metabolism are revealed by two studies of milk thistle and thyroid hormones.

  • In 2008, an experiment on mice showed that T3 levels as well as T4-T3 conversion via deiodinase type 1 (D1) in liver rise significantly during SY treatment of chemically-induced liver fibrosis. As T3 rose, so did recovery of liver and kidney function (Jatwa & Kar, 2008).
  • In 2016, scientists found that milk thistle’s silychristin (SC) is the most potent inhibitor of MCT8 known to science. At concentrations used in clinical settings, it can directly compete with T3 and T4 transport into cells. (Johannes et al, 2016)

The MCT8 transporter is important to many aspects of health. Almost every tissue listed in the Human Protein Atlas expresses the genetic mRNA for this transporter. It is a major portal for T4 and T3 to enter hypothalamus, pituitary and thyroid tissue. Therefore, it is a transporter that enables the hypothalamus-pituitary-thyroid axis to function. It is also the main thyroid hormone transporter in the blood-brain barrier (BBB) essential for healthy fetal brain development (Groeneweg et al, 2020).

In their 2016 study, Johannes and team were very emphatic about the unforeseen health risks of inhibiting MCT8 transporter by dosing milk thistle.

  • They said that pregnant women should be “discouraged” from dosing milk thistle (silymarin, SY) until we understand more.
  • They also suggested that people with hypo- and hyperthyroid diagnosis “are at risk” from regular SY dosing, though they did not explain how.

Yet paradoxically, Jatwa & Kar’s 2008 study hints that some of milk thistle’s beneficial effects on the liver may be caused by its selective MCT8 inhibition in liver tissue. Thanks to Johannes’ team, we can now understand that it’s because SC won’t inhibit other transporters in the liver like MCT10.

Therefore, SC performs a “MCT8 bypass” maneuver in tissues that have transporter redundancy. It can deliver T3 and T4 to cells in the liver and kidney by alternate routes. This bypass appears to boost T3 levels and restore D1 activity during illness in mice (Jatwa & Kar, 2008).

Jatwa & Kar’s study of silymarin dosing raises hope that it may even aid patients’ recovery from the illness-driven thyroid metabolism dysregulation known as nonthyroidal illness syndrome (NTIS), formerly called low T3 syndrome.

But let’s not get too excited. The same bypass mechanism cannot occur in astrocyte cells in the brain. In astrocytes, MCT10 isn’t a backup system for inhibited MCT8. In Johannes’ study of SC, astrocytes suffered badly.

SC effects are hard to predict. It will have different effects on the liver, brain, kidney, pituitary, thyroid, heart, and so on. It depends on the tissue-specific expression of not only MCT8 but also other transporters. It depends on the dose of milk thistle one takes and SC’s half-life in blood.

The effects of SC may be different in each person depending on whether they have mild or severe thyroid disorders, concurrent cardiovascular or neurological disorders, whether they dose thyroid hormones, and if they do, even the ratio of T3 and T4 they dose.

Therefore, to use milk thistle wisely and safely, we should strive to understand it and harness it.

In this post, I first provide a summary of milk thistle research, then more detail on Johannes’ article on milk thistle’s effect on the MCT8 transporter, then Jatwa & Kar’s insight into T3 and T4 and D1 during milk thistle therapy.

I conclude by calling on patients, clinicians, and researchers to do their part in spreading awareness of this discovery and observing its effects on the human body.

Milk thistle and its uses

Milk thistle’s widespread use and many applications are explained by a recent scientific review:

“Herbalists and clinicians alike used the milk thistle for hundreds of years to treat a wide range of liver pathology, including fatty liver disease, hepatitis, cirrhosis, and to protect the liver from environmental toxins.

Today, millions of people consume milk thistle to support healthy liver function.”

(Achufusi & Patel, 2021)

Another scientific review also covered the herb’s long history and popularity:

“Milk thistle … is a therapeutic herb with a 2,000‐year history of use.”

“MT [milk thistle] is among the top‐selling herbal dietary supplements in the USA with retail sales amounting to 2.6 million dollars in the mainstream multioutlet channel in 2015″

(Abenavoli et al, 2018)

Unfortunately, neither review mentions “thyroid” at all, despite their dates of publication after Johannes’ study.

With the exception of one mouse study (Jatwa & Kar, 2008) discussed below, SY liver treatment studies have not been very interested in studying milk thistle’s effects on thyroid hormones and the HPT axis.

Most scientific research on milk thistle and silymarin (SY) has focused on the liver while being blind toward the symbiotic relationship between thyroid hormones and liver.

“Different pharmacological functions of silymarin in liver diseases:

• antioxidant (direct free radical scavenger activity),

• antifibrotic (inhibits the conversion of stellate cells in myofibroblasts),

• regenerative (stimulate hepatic regeneration),

• choleretic (causes an upregulation of the bile salt export pump),

• hepatoprotective (suppress the release of cytokines),

• immunostimulating (prevents inflammasome activation), and

• anti‐inflammatory (inhibition of NF‐κB pathway).”

(Abenavoli et al, 2018, Figure 3)

Despite all the rave about the powers of milk thistle, it is difficult to measure just how much of a difference it might make to a specific patient.

A recent meta-review of studies of silymarin dosing had a hard time finding publications that met the rigorous criteria to enable a systematic comparison:

“An amount of 10904 publications were identified. From those, only 17 were included in the systematic review and 6 in the meta-analysis, according to the used selection criteria.”

(de Avelar et al, 2017)

They ended up reviewing only 6 out of 10,904 studies, and they happened to be narrowly focused on non-alcoholic fatty liver disease (NAFLD).

The analysis covered 437 treated individuals at varying doses with different research methods, but they limited their analysis to three liver biomarkers:

  • Alanine aminotransferase (ALT)
  • Aspartate aminotransferase (AST)
  • Gammaglutamyl transferase (GGT)

All three show poor liver health when values are high, so reductions toward normal are an improvement.

“When the intervention groups were compared with the control groups of all studies included in the meta-analysis,

a reduction of 0.26 IU/mL (95%CI: -0.46-0.07) was observed in the mean ALT serum values and

a reduction of 0.53 IU/mL (95%CI: -0.74-0.32) in the mean AST serum values ​​of the treated group, compared to the control group, both of which are statistically significant.

Silymarin minimally reduced, but without clinical relevance, the serum levels of ALT and AST.”

“There was no significant change in the GGT levels.”

(de Avelar et al, 2017)

However, they admitted that it’s very possible that a greater improvement in liver biomarkers is seen in patients with more severe liver disorders who dose SY.

Thyroid hormone levels powerfully influences ALT, AST and GGT levels (Piantanida et al, 2020, Table 1). Perhaps patients’ FT3 and FT4 levels, even within reference range, had a lot to do with the disappointing average treatment effect of milk thistle.

The average treatment effect of such publications is to permit herbal medicine skeptics to sneer dismissively at milk thistle. But that’s not fair. It might be a lifesaver for part of the population and harmful to another part, while seemingly doing little for people who don’t need much help, and it might do very little at lower doses.

It’s much like the mess of poorly designed studies on LT3-LT4 combination therapy that seem designed to dismiss T3’s potent effects rather than find out why some people are “responders” and some are “non-responders.” Meta-analyses cannot go back to the original data set and discover subgroups of patients who were “responders” vs. “non-responders” to milk thistle.

Like the biased, narrow reviews of equally biased, narrow LT3-LT4 combination trials, the major insight is the apparent lack of harm done, on average:

“The studies [we reviewed] .. showed limited adverse effects and good tolerance to the use of silymarin.”

(de Avelar et al, 2017)

Johannes et al’s 2016 study raises cautions

Despite the research findings showing a lack of harm from milk thistle silymarin extract, Johannes’s research study raised a red flag.

“Because silymarin is a frequently used adjuvant therapeutic for hepatitis C infection and chronic liver disease, our observations raise questions regarding its safety with respect to unwanted effects on the TH axis.”

(Johannes et al, 2016)

I’d like to unpack the bases of their cautions about its effects on the thyroid hormone axis.

How much silychristin is in each dose?

Past research on milk thistle potency seems to have been muddied by the fact that milk thistle extract is a compound consisting of many flavonolignans.

An analogy would be the disagreement on whether a “ketogenic diet” is healthy, since two different ketogenic diets can have different percentages of fat and protein.

Johannes and team used a milk thistle extract that contained only 17% SC:

“A typical milk thistle extract contains, eg, 28% silibinin (silibinin A + B), 17% silychristin, 7% isosilibinin (isosilibinin A + B), less than 1% silidianin and
less than 2% taxifolin”

(Johannes et al, 2016)

In contrast, an analysis of many strains of milk thistle shows that in the most potent “chemotype A”, Silychristin content may be up to 30% (Drouet et al, 2018).

The potency of silychristin versus “SAB” in milk thistle

Most studies of milk thistle have assumed that silibinin A + silibinin B (SAB), not silychristin (SC) constitutes the most active ingredient of silymarin (SY).

However, Johannes and team found that other flavonolignans of SY are much less potent MCT8-inhibitors than SC.

In scientific studies of inhibition, the lower the “half maximal inhibitory concentration” (IC50) value, the more powerful the inhibitory effect is. These are the IC50 values in µM (micromoles) they reported:

  • 9.90 µM — silibinin A + silibinin B (SAB), major components of silymarin (SY)
  • 0.44 µM — Milk thistle extract, silymarin (SY) mixture
  • 0.11 µM — silychristin (SC)

The comparison shows that milk thistle owes its MCT8-inhibiting effect mainly to silychristin, not SAB.

Scientists had assumed SAB is the most important active ingredient because it is most abundant and remains in blood the longest. (This sounds a little like the bias toward focusing on T4, the most abundant thyroid hormone with the longest half-life, when T3 is the most potent thyroid hormone.)

This assumption that SAB is the active ingredient has led to further assumptions about dosing.

For example, a dose selection study by Hawke et al, 2010 wanted to achieve “antiviral” effects with silymarin by achieving the concentrations found to be effective in vitro. They focused on SAB concentrations. As a result, they ended up recommending high doses of 700 mg per day divided into 3 doses to achieve steady-state SAB blood concentration targets.

It was reasonable for Johannes to say this about studies like Hawke’s:

“Studies on SAB might therefore strongly underestimate the potential risk of SY regarding the HPT axis.”

(Johannes et al, 2016)

We still do not know whether SC or SAB or other flavonolignans are responsible for the antiviral effects of silymarin, but now we know that SC powerfully affects the hypothalamus-pituitary-thyroid axis.

Can Johannes’ study translate to common doses of silymarin?

Yes, Johannes and team make good arguments that it can.

First, their study affirmed that individuals dosing 600 mg of milk thistle extract (SY) had enough SC in blood to inhibit T3 (and T4) transport into cells by MCT8.

“Our results question the postulated safety of these [milk thistle / SY] preparations.

Indeed, comprehensive pharmacokinetic studies measuring the plasma concentrations of SY compounds in three healthy volunteers underline a possible physiological impact of SC.

After a single oral administration of 600 mg milk thistle extract, SC reached a peak plasma concentration (after 1–3 h) of 53.8 ng/mL. This is equal to approximately 110nM and in the range of our in vitro IC50 values (29).”

(Johannes et al, 2016)

As shown above, SC had an IC50 of 0.11 µM (micromoles), which is mathematically equivalent to 110 nM (nanomoles).

Next, Johannes emphasized that SC was “even more likely” to have an effect than MCT8-inhibiting anticancer drugs called Tyrosine Kinase Inhibitors (TKIs).

“Because TKIs have significant effects on the TH axis with plasma levels, even 1 order of magnitude below their IC50 (7), an in vivo effect of SC is even more likely.”

(Johannes et al, 2016)

An earlier study by members of the same research team showed that TKIs can cause TSH to rise in people without thyroid function on LT4 therapy by hindering TH transport into the pituitary and hypothalamus (Braun et al, 2012).

Johannes reported that SC is more potent than TKIs by “one order of magnitude,” which means 10 times more potent.

If TKIs can raise TSH in treated patients without thyroid function, SC is even more likely to do so.

Much like fast-release synthetic liothyronine (LT3) thyroid hormone dosing, SY is fast acting within 1-3 hours, and LT3 achieves its peak around 3 hours post-dose.

However, a fast clearance rate is not a bar to therapeutic benefit. The peak concentration and half-life of SC is only part of the equation. The overall effect of this substance on the human body depends partly on downstream events such as T3-signaling upregulation of D1 enzyme in liver. D1 has a half-life of 12 hours (Maia et al, 2011).

The effect of SC may endure long after its blood concentration falls, so it is reasonable to hypothesize the following:

Dysregulations of the TH axis are not always resulting in overt and acute states of disease, but a constant dysregulation will likely lead to adverse effects in the long run.

(Johannes et al, 2016)

Who is most likely to be at risk of adverse effects?

One of the longest-term effects SC may have is on the brain development of a fetus. This is why it was wise for Johannes and team to study astrocyte (brain) cells and compare them with MCT8-rich kidney cells:

SC might significantly block TH import into target cells, causing metabolic and developmental dysregulations. By its high specificity, this will happen in an organ- or even cell type-specific manner, eg, in astrocytes.

Several rat studies report beneficial effects on oxidative stress markers in the young and adult brain, implying that SY is able to cross the blood-brain barrier and enter the central nervous system (30, 31). Because THs are, for example, important for proper development of the human brain, the use of SY during pregnancy should be discouraged until the proof of its safety.

(Johannes et al, 2016)

Johannes’s concern was cited and echoed in Barbara Demeneix’s 2019 article in the European Thyroid Journal. It was titled “Evidence for Prenatal Exposure to Thyroid Disruptors and Adverse Effects on Brain Development.” She concluded:

“TH disruption in utero may contribute to an increased risk of neurodevelopmental disease, learning difficulties, and IQ loss.”

(Demeneix, 2019)

Because SY can affect both the “young and adult brain,” according to Johannes’ passage quoted above, one should not only be cautious about pregnancy, but also be careful about the way it may change thyroid hormones’ influence on depression, or neurological degeneration in dementia and Alzheimer’s. (See “Low-normal FT3 increases Alzheimer’s Disease risk).

No studies of milk thistle (that I’m aware of) have examined its effects during hypo- or hyperthyroidism, but in light of the impact of TKIs, it makes sense for Johannes and team to add this:

Also, people with manifested diseases of the thyroid gland, eg, hypo- or hyperthyroidism, are at risk by regular consumption of SY-containing preparations.

(Johannes et al, 2016)

However, Johannes and team have a negative bias.

Although the researchers briefly express interest in SC as a tool in research and its potential in “a new class of drugs,” fear of the unknown potency and effects of unregulated supplements poses a clinical “risk.”

This fearful response is a view commonly held by conservative thyroid scientists. It seems to say, “Let’s strongly discourage its therapeutic use indefinitely until we decide it’s time to know more.” It’s inconsiderate to create prohibitions based on ignorance. Ignorance, due to researchers’ apathy and neglect, could remain in place for decades.

The lack of urgency to study silymarin’s benefits during therapy for “manifested diseases of the thyroid gland” is an attitude that assumes everything is going fine with everyone’s thyroid therapy and the guidelines for thyroid hormone in pregnancy. From this standpoint, unregulated use of unregulated over-the-counter supplements like milk thistle threaten to complicate or mess up this state of therapeutic perfection.

“Regular consumption” of milk thistle certainly could harm patients if they and their physicians don’t realize what it could be doing to them.

Intermittent dosing of milk thistle, not addressed by Johannes, has relatively less risk. It may also destabilize thyroid therapy. But stability without health is worthless.

Informed thyroid patients who struggle with chronic low FT3 while on LT4 therapy — and patients whose T3 has plummeted due to a nonthyroidal illness — might look to milk thistle with hope of benefit today because they are suffering today. They are not going to wait for researchers.

If educated patients use SY cautiously and with some knowledge of thyroid hormone transporters and enzymes, it could become a cheap and relatively harmless way for patients to experiment with adjusting the effect of their circulating thyroid hormones without their physician changing their hormone dose.

Though occasional dosing experiments might backfire with unwanted symptoms, it couldn’t be worse than a physician’s decision to induce “regular underconsumption” of thyroid hormone, which could render a person hypothyroid for months or years. (I write that sentence from personal experience.) Which disruption to endocrine health is riskier to their health and well being?

Jatwa & Kar’s study on liver T3, T4 and D1 enzyme response to silymarin

Let’s now look at the other side of the coin of milk thistle — not just risks but benefits.

Jatwa & Kar’s research was published many years before Johannes’ study, but they complement each other. We can now view this earlier study through the lens of recent findings.

Jatwa & Kar’s study demonstrates that this potent selective MCT8 transport modulator can actually enhance tissue T3 levels and restore depressed D1 enzyme function during nonthyroidal illness.

Therefore, milk thistle’s effect on the HPT axis isn’t just something to be feared, but something quite exciting — a new tool in the arsenal of thyroid therapy.

Strengths of the study

Jatwa & Kar’s article is the only study I have found that gives insight into silymarin’s beneficial impact on liver and kidney health at the same time as its impact on tissue T3 and T4 levels.

They also go far beyond other studies by examining the activity of deiodinase type 1 (D1), which converts T4 to T3 in the liver and kidney.

Jatwa and Kar’s inquiry appears to be unprecedented. They were justly puzzled that no one had yet thought to study thyroid hormone outcomes during this type of treatment, given the power of thyroid hormones over the entire body:

“to the best of our knowledge no report is available till date on the impact of lornit or silymarin on renal oxidative stress and thyroid metabolism; although thyroid hormones regulate almost all body functions (Ganong, 2005) and chronic medication with some drugs may result in altered levels of thyroid hormones (Vigersky et al., 2006; Isidro et al., 2007).”

(Jatwa & Kar, 2008)

However, their ground-breaking study seems to have been overlooked because the journal is not indexed in PubMed. It deserves to be highlighted.

Most importantly, by studying silymarin’s restorative effect in severe oxidative stress, their research gives hope for the treatment of nonthyroidal illness (NTIS).

A brief background on NTIS

Nonthyroidal illness syndrome is well explained by Van den Berghe:

“Patients suffering from critical illnesses who require treatment in the intensive care unit (ICU) uniformly present with alterations in circulating thyroid hormone levels. …

The most typical alterations are
• low plasma concentrations of triiodothyronine (T3),
• low or normal plasma concentrations of thyroxine (T4),
• or elevated plasma rT3
• in the presence of normal thyrotropin (TSH)….

The most striking and universal finding, however, is the low plasma T3 concentration, which explains the most neutral name, the “low T3 syndrome.”

(Van den Berghe, 2014)

Severe illnesses of all kinds can trigger NTIS — heart attacks, liver failure, kidney failure, severe trauma from a car accident, or infections. Mortality and morbidity rates in NTIS are high. Lower FT3 levels in spite of normal TSH and normal FT4 can significantly increase the mortality rate of patients in ICU with COVID-19 (Gao et al, 2021).

Milder NTIS even affects people with severe chronic diseases who are not hospitalized, such as people with heart failure or cancers. In these populations, the paradox is that high FT4 does not help — it can worsen mortality rates (Ataoğlu et al, 2018). (See Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.“)

In a large population of non-hospitalized people, several chronic disorders associate with isolated low FT3 and/or high-normal FT4 more strongly than they associate with an abnormal TSH (See Prevalence rates for 10 chronic disorders at various FT4, TSH and FT3 levels“).

Due to medical controversies about the causes of NTIS and the lack of treatment protocols, it is routinely left untreated, as nature is left to take its course and the patient lives, dies, or languishes longer in illness.

For some people with liver and kidney NTIS, appropriate doses of milk thistle might offer a way out of this metabolic high-risk condition.


They studied two groups of female mice.

  1. Female healthy control mice
  2. Female mice suffering chemically-induced liver trauma

Females were chosen for a noble reason: “As women are known to be more prone to thyroid abnormalities.”

Low T3 Syndome / Nonthyroidal illness syndrome (NTIS) was induced by “Renal and hepatic lipid peroxidation (LPO) … by the administration of carbon tetrachloride (CCl4) for 2 weeks.”

This mouse model of human liver damage is commonly used in research:

“In animal models of liver fibrosis, the insult induced by carbon tetrachloride (CCl4) resembles important properties of human liver fibrosis including inflammation, regeneration, and fiber formation. This model is commonly used to study acute liver injury, advanced fibrosis, as well as fibrosis reversal.”

(Melior Discovery, n.d.)

They studied two separate treatments, not just one, over 14 days:

  1. L-ornithine-L-aspartate (lornit) 200 mg/kg/day, OR
  2. silymarin 100mg/kg/day

These are very large doses of silymarin for a mouse or a human, but they were referring to a prior study that used 100 mg/kg/day .


Here is a selection of their results, focusing only on silymarin. (See the original study to discover their findings on L-ornithine-L-aspartate [lornit]).

Before presenting changes in thyroid hormone levels and D1 activity, let’s look at silymarin’s effects on liver and kidney biomarkers.

Jatwa & Kar studied many liver and kidney biomarkers in blood before and during treatment:

  • aspartate aminotransferase (AST),
  • lanine aminotransferase (ALT),
  • alkaline phosphahatase (ALP) and
  • hepatic and renal superoxide dismutase (SOD),
  • catalase (CAT) and
  • reduced glutathione content (GSH)
  • fasting glucose
  • insulin

They reported the following:

“CCl4 administration significantly increased serum ALT, AST and ALP activities as well as insulin and glucose concentrations.

However, … silymarin administration to CCl4 treated animals reversed all these changes bringing down the values to nearly normal levels (Table 2).

(Jatwa & Kar, 2008)

Perhaps not coincidentally, both hypothyroidism and hyperthyroidism increase ALT and AST, while hyperthyroidism is associated with high ALP (Piantanida et al, 2020)

I’ve used Jatwa & Kar’s table of data to create bar graphs for the remaining data, the changes in antioxidants:

  1. Superoxide dismutase (SOD),
  2. Catalase (CAT) and
  3. Reduced glutathione.

First, here are these three biomarkers levels in liver (hepatic) tissue:

Now, see the same biomarkers in kidney (renal) tissue:

The SY effect was present in controls, but even more exaggerated in CCl4 treated mice.

Now let’s look at the similar patterns shown in graphs showing thyroid hormone biomarkers. The four experimental conditions are in the same order from left to right:

As stated under the graph, the researchers mathematically adjusted the circulating hormone levels to liver D1’s activity level as it generated T3 from T4.

  • In healthy controls, silymarin did not do much for the healthy controls’ T3 and T4 levels, but the liver and kidney health improved, possibly due to changes in intracellular T3 and T4.
  • In the NTIS state, silymarin had a much greater impact on T3 levels and D1 enzyme activity — but T4 was relatively unchanged. As SY enables tissue T3 to rise above the level in controls, liver and kidney biomarkers recover.

It is possible that their T3 and D1 results would have been even more exaggerated if they had included male mice, since healthy male mice have significantly higher liver T3 and lower liver T4 than female mice (Fu et al, 2017).

What are the likely mechanisms behind these results?

In healthy controls, effects on circulating T3 and T4 were limited because the mice’s HPT axis was intact and resilient. These were not hypothyroid mice treated with thyroid hormones. Their thyroid gland could maintain homeostasis in spite of changes in peripheral transport.

But in the CCl4 mouse model, the HPT axis is first disturbed by NTIS, which induces abnormal TSH-T3-T4 relationships by limiting TSH, decreasing the metabolic production of T3 while increasing the clearance rate of T3. Silymarin intervened in this metabolic dysfunction by aiding the recovery of D1 enzyme and elevating T3 above healthy control levels.

It is reasonable to suggest that SY, by creating a T3 shunt around MCT8, contributed to T3 recovery, which then permitted antioxidants to recover, enhanced liver and kidney biomarkers:

  • SY does not inhibit alternate transporters of T3 and T4 in liver and kidney, such as MCT10 and others. (Johannes and team revealed that MCT10 function was unchanged.)
  • It is possible that MCT8 bypass could redirect T3 into cells expressing D1, while reducing T3 supply to cells that express D3 enzyme, and cells that upregulate oxidative stress and inflammatory cytokine production.
  • MCT8 inhibition may also enhance T3 signaling by slowing down T3 efflux from cells. (Johannes and team revealed that T3 efflux from certain cell types, not just influx, was also inhibited.) Some types of cells may hold onto T3 longer, reducing the adverse metabolic impacts of lower T3 and higher T4.

Jatwa & Kar usefully pointed out D1 enzyme’s role. But before Johannes’ study on MCT8 inhibition, they could not see how MCT8 might have played a role.

Yet they could have seen the HPT axis as a significant driver. Why didn’t they?

Blind spots and myths in this study

There’s a major blind spot Jatwa & Kar’s study. The HPT axis indicator they forgot to measure was TSH.

As many scientists do, they attributed causation to the variables they measured, rather than variables they failed to measure.

How much of this excess T3 in the “CCl4 + silymarin” state is due to TSH stimulation of an enhanced T3:T4 ratio of secretion from the mouse’s healthy thyroid?

As mentioned in the introduction, MCT8 is one of the most important thyroid hormone transporters because it enables T3 and T4 hormone transport in and out of the hypothalamus, pituitary, and thyroid glands.

In human males born with genetic MCT8 deficiency, TSH secretion is not as inhibited as it should be by elevated circulating T3. MCT8 deficiency appears to distort the HPT axis. The inhibited transport of T3 into the hypothalamus and pituitary raises TSH despite the higher T3. In turn, this elevated TSH overstimulates the thyroid to maintain the higher T3 level (Müller & Heuer, 2012).

The effect of MCT8-inhibiting TKI drugs on elevating TSH suggested by Johannes and team implies that silymarin may be even “more likely” to raise TSH without lowering thyroid hormones.

A mouse model of genetic MCT8 deficiency demonstrated that much of the elevated T3 in that condition was from the thyroid gland (Trajkovic-Arsic et al, 2010). Enhanced TSH stimulation would drive T4 and T3 production, but Trajkovic-Arsic reasoned that the lower T4 in MCT8 deficient subjects was due to enhanced T4 metabolism.

In addition, the researchers didn’t seem to be aware of species-specific differences. Unlike human thyroid glands, rodent thyroid glands contribute an average of 40% of circulating T3 (Fu et al, 2017). The mouse’s HPT axis is different from ours even before an MCT8 inhibitor intervention.

In the CCl4 + silymarin condition, if TSH is not responding with a reduction but stays the same or rises rises, it makes sense to consider the thyroid as a significant source of T3 that aids recovery.

Silymarin-induced MCT8 effects on TSH may be just what the doctor ordered for nonthyroidal illness. A rise in TSH-stimulated T3 secretion is part of the process of recovery from NTIS in people with healthy enough thyroids. Therefore, some scientists are recommending agents that can enhance TSH. Milk thistle could be the kind of agent they are looking for.

Next, two prevalent thyroid myths hindered their understanding of the sources of circulating T3:

  1. The liver- and D1-centric thyroid hormone metabolism myth, and
  2. The myth of a fixed and limited healthy thyroidal T3 secretion rate.

1. Liver/D1-centrism.

Jatwa & Kar acquired from a 2005 general physiology textbook the myth that the liver and kidney contribute most of our circulating T3, and this strongly influenced how they displayed and interpreted the data.

By pointing to D1 activity, and by mathematically adjusting T3 and T4 concentrations to D1 activity in their graph, Jatwa & Kar made the mistake of presuming that the liver & kidney’s D1 contributes much more to circulating T3 than it probably does.

One should never underestimate the thyroid. Although the thyroid is smaller than the liver and kidney, it is a powerhouse of T4-T3 conversion. D1 is the dominant thyroid hormone metabolizing enzyme in thyroid, followed by liver, then kidney.

In people with no thyroid function treated on LT4 hormone, blocking D1 reduces circulating T3 by at most 25% (Maia et al, 2011). Peripheral deiodinase type 2 (D2) in other tissues, plus thyroidal T3 synthesis, thyroidal D1, and thyroidal D2 contribute the balance of circulating T3 healthy humans.

2. Thyroidal T3 secretion myths.

Jatwa & Kar’s physiology textbook also spread the far more misleading myth that that the thyroid gland (in humans, not mice) secretes only a miniscule 10-15% of our daily circulating T3 supply. This is not true according to science, either, despite its being echoed by leading thyroid scientists like Wajner & Maia (2012).

The estimate in the most recent in vivo human study is a statistical average secretion rate of 20% of T3 — but the study was limited to subjects who had a baseline TSH stimulation level between 1 and 2 mU/L (Pilo et al, 1990).

In Pilo’s data, only 3 of 14 human subjects secreted less than 10% from the thyroid gland, while 4 out of 14 subjects’ thyroids secreted 35-42% of their circulating T3. (All kinetic studies of thyroid hormone metabolism had very small sample sizes, but they show very wide human diversity.)

There is no T3-throttle on the thyroid that prevents it from secreting more than a fixed percentage of one’s daily T3 supply. TSH drives thyroidal T3 synthesis preferentially, enhancing the T3 side of the T4:T3 secretion ratio (Citterio et al, 2017).

The healthy thyroid gland is a wild card in milk thistle dosing studies! Would mice and humans without thyroid function see the same effects on metabolism and circulating hormones? Likely not.

Therefore, future studies of milk thistle treatment ought to involve thyroidectomized mice and humans treated with LT4 therapy.

What can we do with this information?

The science is still very thin on milk thistle. But we know enough about its potent effects to know there could be significant dangers as well as significant benefits for patients with thyroid disorders.

Silymarin and its silychristin ingredient should not be ignored. Why haven’t ten clinical trials been performed on treated thyroid patients with severe critical or chronic illnesses by now?

Ask the unanswered questions

Milk thistle’s MCT8-blocking properties raise very practical questions about its effects in various organs and tissues, effects on various types of people, and at various doses and treatment protocols:

  1. How does it modify T4-T3 conversion rates and T3 signaling in other organs and tissues where MCT8 and other transporters are predominantly expressed, such as adrenal glands, adipose tissue, kidney, lungs, and heart?
  2. Can it impact pregnancy outcomes by affecting T3 and T4 transport across the placenta and into the fetal brain, which we now know is performed mainly by MCT8? Can we answer the concerns raised by Johannes et al (2016) and Demeneix (2019) about prenatal exposure to endocrine disruptors like silychristin?
  3. Can it influence women’s menstrual health and fertility by affecting transport of T3 and T4 into MCT8-rich female reproductive tissues such as the ovaries, endometrium, fallopian tubes, and cervix?
  4. Can it change interrelationships between TSH, FT4 and FT3 during the treatment of people without thyroid function by limiting MCT8 transport of thyroid hormones into the hypothalamus and pituitary gland and inhibiting the negative feedback loop?
  5. Can it change how T3 behaves in hypothyroid people who are dosing LT3 hormone? How exactly does it influence T3 signaling in MCT8-dominant tissues during the post-dose FT3 peak, given thyroid patients’ experience of noticeable, measurable effects of milk thistle dosing in T3-dominant therapy?
  6. Can it benefit or harm people with hyperthyroidism or people suffering from thyroid hormone overdose?

Unfortunately, many studies of MCT8 transporter dysfunction or inhibition are performed with cell cultures, rats and mice. Mice and rats have different transporter expression profiles than humans.

Studies tend to focus on the rare human males who have a genetic MCT8 deficiency (Allan-Hernon-Dudley Syndrome, AHDS) causing severe psychomotor disability since birth. In most of these models, the thyroid gland and pituitary TSH response is intact except for an MCT8 genetic problem.

Therefore, ADHS patients and MCT8-deficient mice do not demonstrate what happens to thyroid hormone levels in people dosing milk thistle, especially not pregnant women or patients with no thyroid function.

Raise awareness

Johannes and colleagues performed their study in 2016. As of early 2022, this knowledge about milk thistle’s endocrine-disrupting powers doesn’t seem to have spread very widely among endocrinologists, physicians, or thyroid patients.

I’m doing my part to raise awareness by writing this article.

Do your part. Together we can:

  • Raise therapeutic caution regarding vulnerable individuals.
  • Promote the safer use of cheap, available, milk thistle supplementation.
  • Add momentum to medical and scientific inquiry.
  • Attract the attention of pharmaceutical companies to develop purified, controlled doses of silychristin into a targeted drug.

Practical steps you can take:

  • Share this post with physicians, pharmacists, thyroid patient support groups.
  • Write to supplement producers and ask them how much silychristin is in their preparation of silymarin, citing this research.
  • Ask the owners of milk thistle blog posts and web pages to update their articles with cautions and “ifs” and “buts,” especially for people on thyroid hormone treatment, and pregnant people.
  • Ask thyroid hormone pharmaceutical companies to include in their leaflets cautions about milk thistle — and other newly-discovered endocrine disruptors in our food, supplements, and environment.
  • Ask drug interaction websites to update their information about interactions with levothyroxine (LT4) and liothyronine (LT3). At the time of writing, reports no interactions with levothyroxine and refers people to ask their physicians, who will likely not know anything. has no results for liothyronine & milk thistle, but lists an interaction with injectible LT3 with the brand name of Triostat.
  • If you’re a thyroid patient, you could write up and share the results of your personal experiment with milk thistle’s effects on your vital signs. I have drafted my own case study and hope to post it soon.

If you’re a patient, you could ask your physician or endocrinologist something like this question:

How do you think milk thistle dosing may change my body’s response to circulating thyroid hormones, given the fact that milk thistle is a potent inhibitor of MCT8 thyroid hormone transporters?”

No, they won’t know the answers unless they’ve reviewed the science I’ve covered here. But that’s the point of asking!

It might make doctors wish they had answers.

It might just give them an opportunity to demonstrate to you their “thyroid science humility,” a virtue often lacking in physicians. They might give the noble response of a physician who values inquiry: “That’s a good question. I have no idea.”

If more scientists and clinicians — and even patients — become curious enough to measure the effects of thyroid endocrine disruptors, it may uncover many aspects of thyroid hormone transport, metabolism, and signaling that have been overlooked.

Pursue research

Scientists, we need you. Without your help, doctors and thyroid patients will be lost in an ocean of thyroid ignorance and myth regarding milk thistle.

  • At one extreme will be people dosing this endocrine-disrupting flavonolignan willy-nilly while being unaware of its power to destabilize thyroid therapy, focusing on the benefits on liver and presuming that it can only do good.
  • At the other extreme will be people who are extremely fearful of the effects of milk thistle and imagine it’s like a poison, when it has been proven to have therapeutic effects and little harm in most people.

Continue Jatwa and Kar’s line of inquiry.

I hope liver & thyroid scientists would try to answer this question:

To what degree are silychristin’s beneficial effects on liver due to its MCT8-disrupting potency as it forces the liver to rely more on alternate thyroid hormone transporters to access circulating FT3 and FT4?

Consider how MCT8 transport inhibition affects health beyond the liver.

As mentioned in the introduction, the metabolic effects of milk thistle are complex. Its effects on health will depend on:

  • The severity of an individual’s disorders in MCT8-dominant tissues,
  • The circulating FT4 and FT3 levels prior to dosing milk thistle,
  • The integrity of the individual’s HPT axis including thyroid gland secretion rates, and
  • Any type of thyroid hormone dosing that may interfere with FT3’s relationships with other hormones.

Examine how endocrine disruptors influence thyroid therapy.

People with little to no thyroid function are among the most vulnerable to endocrine disruptors like these.

Our thyroid hormone health is already being medically manipulated to treat a metabolic disability. The loss of our gland’s T4-T3 converting enzymes is a metabolic disability that affects some more than others.

Endocrine disruptors can disrupt and destabilize thyroid therapy in many situations:

  • In patients who are poor responders to LT4 monotherapy, who have an FT3:FT4 ratio in pmoll/L below 0.25 (See Midgley, 2015, and our review “Are you a poor T4 converter? How low is your Free T3?“)
  • In a patient on anti-thyroid medication for hyperthyroidism
  • A patient with chronic isolated Low T3 due to a chronic nonthyroidal illness whose TSH-stimulated T3 secretion cannot aid T3 recovery.

Consider research methods that matter

Here are some suggestions for research methods that will make a difference for the most people as soon as possible:

  • Examine milk thistle during thyroid therapy in patients who also have a chronic liver disease or kidney disease. Multi-center research studies can recruit enough patients. Many of us will want to be studied if it can enhance our health outcomes.
  • Do not rely only on finding mere statistical significance based on averages across a diverse population. Look for clinical (not just statistical) significance, look for U-shaped (not just linear) risks, and seek to understand (not ignore) treatment non-responders and outliers. Use scatterplot graphs so we can see the true shape of the distribution and respect metabolic diversity.
  • Do not blind your study to the free fraction of T3 (FT3) that is capable of being carried into cells beyond the pituitary on MCT8 transporters. Total T3 measurement is still commonly used instead of Free T3 in U.S. studies of thyroid therapy, but it says almost as little as Total T4 does about transmembrane transport and metabolism.
  • Do not presume the healthy population’s reference interval boundaries for TSH, FT3 or FT4 are physiologically significant for illness and recovery. A normal TSH protects no one from dying from NTIS. Similarly, a normal TSH does not always prevent disabling thyroid symptoms during thyroid hormone treatment. Therefore, measure relative changes over time not only in individuals’ liver and kidney health, but examine individuals’ changing FT3:FT4 ratios, TSH-FT3 relationships and tissue-specific T3 responses like non-HDL cholesterol, SHBG, eGFR, TBG, serum albumin, urinary T3 and urinary TSH losses, and so on.

Thyroid patients and people with NTIS will benefit more from your insights if your study is not hindered by the biases, blind spots, and myths mentioned above.

Tania S. Smith, PhD,
Thyroid patient and thyroid science analyst,
President, Thyroid Patients Canada.


Click to view reference list

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Braun, D., Kim, T., le Coutre, P., Köhrle, J., Hershman, J., & Schweizer, U. (2012). Tyrosine Kinase Inhibitors Noncompetitively Inhibit MCT8-Mediated Iodothyronine Transport. The Journal of Clinical Endocrinology and Metabolism, 97, E100-5.

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Human Protein Atlas

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Categories: endocrine disruptors, Liver, Transporters

3 replies

  1. Fascinating article.

  2. Thank you Dr. Smith. This is an excellent and, well-needed, exploration of the interactions between Milk Thistle components and liver/thyroid.

    I am wondering if the inhibition of MCT8-mediated transport may actually be a good thing in the long run for the affected cell-types? For example I am thinking if inhibiting TH transport to cells expressing deiodinase-3 (D3) may eventually alter deiodinase gene expression and set the balance back towards D1 enzymes (i.e. more response now to fT3 due to reduced rT3). DNA sensory mechanisms are known to do that in other pathways and it would be great to see this in research if it has not been done already.

    • Dear Dr. Bilal, thanks for your thoughtful comment a month ago (sorry for the delay; I have a full time job that took me away from the website for a while). I wondered the same thing — it matters which enzymes, such as D3, are expressed in the cells that co-express MCT8. I have attempted to scour the science with this question in mind: “is MCT8 preferentially co-expressed on D3-expressing cells?” I can’t get an answer from research to date. Besides, D3 expression in a given tissue can suddenly spike in illness, such as within 24 hours after a heart attack, for instance. Does MCT8 change its expression when affected by severe illness? Yes, it seems to. Can MCT10 compensate when MCT8 is dysregulated? Perhaps at times. Some answers are in this 2021 article by Boelen and Fliers — Sincerely, TSS

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