When dosing T3, you get higher levels of Triac

Surprise! You get a little bonus of Triac if you dose NDT or T3, and you might want to tell your doctor about its benefits & side effects.

Triac is a naturally-occurring thyroid hormone metabolite that powerfully suppresses TSH without causing thyrotoxicosis. Most doctors are unaware of it.

Triac’s full chemical name is “3,3′,5-triiodothyroacetic acid,” and it is also known as Tiratricol, and less commonly, TA3 for short. It’s an acetic-acid metabolite of T3.

A little-known study in 1980 found that in thyroidless patients rendered euthyroid by dosing synthetic T3 hormone alone, about 14% of their daily dose turned into Triac.

In contrast, in thyroidless people who dosed LT4 about 2.9% of their daily dose converted to Triac.

This an aspect of the “T3 dosing effect” that could, in part, explain why people who take desiccated thyroid (NDT) and/or higher doses of T3 hormone tend to be metabolically euthyroid when TSH is below reference or suppressed.

In this post, I review the research to answer some key questions:

• What is Triac?
• What are normal Triac levels?
• How is Triac used in thyroid therapy today?
• What about Triac abuse?
• What did the 1980 Triac study find about T3 dosing?
• How many micrograms of Triac does it take to suppress TSH?
• What else do we know about Triac as of 2019?
• (References are on page 2 of this article)

What is Triac?

(Here I mainly summarize recent information from Groeneweg et al, 2017’s article “Triiodothyroacetic acid in health and disease.”)

Triac is a naturally-occurring product of thyroid hormone conversion that is extremely potent at suppressing TSH without causing thyrotoxicosis in tissues.

In research studies, it has been proven that high (supraphysiological) doses of Triac will suppress TSH while maintaining metabolic health, much like full replacement T3 monotherapy does at mildly supraphysiological circulating T3 levels when T4 is absent. (See Busnardo, et al, 1980 & 1983 for more explanation of this T3-monotherapy dosing effect.)

This is because Triac is active in thyroid hormone receptors just like its metabolic precursor, the T3 hormone.

In addition, like T3 dosing, Triac reduces TSH and thereby reduces thyroidal secretion of T4 in thyroid-healthy subjects. The TSH is wisely making room for Triac’s effects and preventing thyrotoxicosis from occurring via peripheral T4-T3 conversion. Nature’s induction of lower FT4 can be protective unless Triac is dosed too high.

Triac levels peak at 40 minutes after dosing (compared to Free T3’s peak around 2.5 to 3 hours post-dose). Triac’s half-life is 6 hours (compared with T3’s half life of 24 hours, though T3 has a high initial peak over the first 8-10 hours followed by a long low-concentration tail).

Science still has not discovered the precise route by which T3 or T4 becomes Triac. It is not via the same methods that T4 becomes T3 or T3 becomes T2 (It is not by deiodination, the removal of an iodine atom). All we know for sure is that T3 is the major precursor of Triac, given the findings of Gavin et al’s 1980 study discussed below.

However, science has discovered the pathway by which it leaves the body. Triac (TA3) can be deiodinated into TA0 (TA zero) which is excreted in urine, and it is excreted as TA3G in bile. There is also a sulfate form, TA3S, like there is for T3 (T3S) that is poorly understood. Both sulfate forms of T3 are broken down by Deiodinase Type 1 (Rutgers et al, 1989).

Science still has not discovered which transporters carry Triac into cells. It seems not to use the transporters that carry other thyroid hormones into cells. According to Groeneweg and team, scientists suspect there is a Triac-specific transporter and that it transports Triac into most, if not all, tissue types in the human body.

What are normal Triac levels?

Triac, like Free T3 and Free T4, normally circulates in blood at extremely low concentrations.

It is present in normal human blood at a concentration averaging around 2.3 to 2.5 ng/100 mL (in other units of measure as converted by Unitslab.com, that’s equal to 2.5 ng/dL or 0.025 ng/mL or 0.0384 nmol/L or 38.4 pmol/L). That’s a lot lower concentration than Total T3

However, the full range goes quite higher than the average. Triac ranges “between 2.6 and 15.2 ng/dL (42–244 pmol/L) in healthy human subjects” (Groeneweg et al, 2017).

In comparison, the concentrations of Triac are in the range of Free T3 and Free T4, which are in the pmol/L range, with FT3 concentrations from 3.5 to 6.5 pmol/L on some lab assays, and FT4 concentrations from 10 to 25 pmol/L on some assays, compared to total Triac (not “Free” Triac) at 42 to 244 pmol/L.

However, measuring Triac correctly is extremely tricky because it has a very short half-life. This might account for some of the variability in measurements in research papers. It obviously depends on how long after a dose of T3 or Triac you measure it.

No, unfortunately, Triac lab tests are not available at your local lab, and I could not find one by googling. The effects of Triac are measured indirectly by TSH, FT3 and FT4 and effects throughout the body (see the final section that lists organ effects). Triac comes and goes pretty fast from blood, but its effects can linger.

How is Triac used in thyroid therapy today?

Triac is very rarely used today in thyroid therapy. It is well known among thyroid scientists for being used to treat two thyroid hormone genetics problems:

1. Genetic defects in thyroid hormone transporters such as MCT8. MCT8 causes a severely disabling disease called Allan Hernon Dudley syndrome. The genetic defect found rarely and only in males prevents enough T4 and T3 from being taken into the brain, so brain damage occurs during fetal development and they encounter many health problems after birth. But Triac can enter the brain through transporters other than MCT8, so their brain can get access to thyroid hormone. In 2018, a 15 year old girl became the first patient to be diagnosed with a mutation in the OATP1C1 transporter and was treated with Triac. (Strømme et al, 2018)
2. Resistance to thyroid hormone (RTH), a genetically caused reduction of sensitivity to thyroid receptors, usually in the THRB gene. This syndrome causes high TSH levels at the same time as elevated or high-normal T4 and T3 levels in blood, which is very rarely seen. Triac therapy can reduce the TSH, which benefits the patient by reducing the stimulation to their healthy thyroid gland, reducing hyperthyroidism in the more sensitive THRA-expressing tissues like the heart. At the same time, Triac acts on thyroid receptors in the same way as T3 does, so it provides enough activation of the insensitive THRB receptors.

The American Thyroid Association (Jonklaas et al, 2014) cautions strongly against the use of Triac in routine thyroid hormone therapy. (Keep in mind they also caution against the use of everything else that isn’t Levothyroxine in routine thyroid therapy.)

However, early studies on Triac found success treating normal hypothyroid patients with it. “TA3 effectively restores most clinical and biochemical abnormalities in myxedematous [hypothyroid] patients” regardless of their having RTH or not. (Groeneweg et al, 2017)

In addition, it has recently been used in TSH suppressive therapy after thyroid cancer. (Visser, 2018)

Triac for therapy is not yet commercially available on the pharmaceutical marketplace, so it is obtained off-label by endocrinologists who use it to treat RTH and transport disorders.

What about Triac abuse?

The ATA also warns that Triac’s dosages can be uncontrolled and dangerous when it is found in bodybuilding supplements.

Specifically, Groeneweg et al, 2017, report “Multiple cases have been reported over the last decades on the abuse of dietary supplements, metabolic enhancers and mesotherapies containing TA₃. Subjects presented with clinical signs of thyrotoxicosis, while TH and TSH levels were found to be suppressed.”

It is also reported by WebMd that “In the US, between 1999 and 2001, the Food and Drug Administration (FDA) required several tiratricol-containing products to be recalled, and obtained a court order to prevent companies from marketing them. The FDA determined that tiratricol is not a dietary supplement but an unapproved new drug containing a powerful thyroid hormone, which may cause serious health consequences.”

Like any potent thyroid hormone, Triac dosing needs to be sensitively regulated with lab testing and overall clinical observation of its metabolic effects. It should only be dosed with caution under medical supervision.

If you are already diagnosed as hypothyroid and on thyroid therapy, you can safely get a little bit of Triac by taking your prescribed LT3 or NDT medication, as Gavin et al, 1980 discovered.

What did the 1980 study of Triac find?

This study of Triac thyroid hormone kinetics was conducted by Laurence Gavin, Barbara Livermore, Ralph Cavalieri, Margaret Hammond and James Castle.

Their research technologies were extremely robust for their day. They used complex biochemistry methodology employing radioactive-iodine-labeled thyroid hormones that tracked how T4 and T3 were being metabolized in the body. This was a major development beyond a study done two years earlier which focused on developing a new blood test for Triac (Nakamura et al, 1978). Nakamura’s study only measured patients’ T4 and Triac levels and found no correlation between T4 levels and Triac.

Gavin and team studied 13 people, 8 of whom were thyroidless (athyreotic).

• 5 male control subjects not taking any thyroid hormones
• 5 athyreotic people rendered euthyroid on 150 mcg of LT4 monotherapy, and
• 3 athyreotic people rendered euthyroid on 80 mcg/day LT3 monotherapy taken in 10mcg doses every 3 hours.

They found

• Controls averaged 5.2 mcg/day Triac (full range 2.8 to 10.9)
• LT4 patients averaged 4.4 mcg/day Triac (full range 3.0 to 5.8)
• LT3-treated people averaged 10.1 mcg/day Triac (full range 9.3 to 10.7)

As you can see, one of the healthy controls could achieve the higher Triac levels of those taking LT3 therapy. Obtaining 10.7 micrograms is not that far from one healthy person’s 10.9 micrograms.

However, the three people taking LT3 had a much higher minimum Triac level.

They also learned that the clearance rate of Triac is 2x faster than RT3 and 6x faster than T3, so Triac disappears from blood very quickly as it is produced by conversion.

Therefore, Triac is only present in significant amounts during the early part of the brief Free T3 peak after a T3 dose.

In their discussion section, they said many interesting things:

• “T3 is probably the major precursor of Triac in vivo [in living subjects].”
• “Triac has not been demonstrated in the thyroid. The present study indicates that thyroidal secretion probably contributes little, if at all, to serum Triac levels.”
• “The greater clearance rate of Triac compared to T3 partially explains the low biological activity of Triac” per microgram.
• They were not sure which tissues in the body were mainly responsible for conversion to Triac. (And today we still aren’t sure.)
• “These serum kinetic studies may underestimate the quantitative significance of Triac formation. Previous T3 kinetics studies in our laboratory on a similar group of C [Control] subjects yielded a T3 PR of 37 nmol/day (14).”

Indeed, other studies have found higher levels of Triac in blood, as cited by Groeneweg et al, above. Therefore, you may also get more Triac out of T3 dosing than they discovered.

How many micrograms of Triac does it take to suppress TSH?

Everts et al, 1994 say “When Triac is used to suppress TSH secretion in patients, it has to be applied in large doses, because of its short half-life.”

However, some doses are smaller and can still have metabolic effects.

Groeneweg et al, 2017 reports:

• From rat studies “it was estimated that 62 µg (mcg) (100 nmol)/kg/day TA3 has an equal TSH-suppressive effect as 16 µg (20 nmol)/kg/day LT₄.” (Keep in mind this dose equivalency is not based on human pharmacokinetic studies.)
• “A dose-dependent reduction of TSH levels was observed within 6–9 h after oral administration of TA₃ to euthyroid human subjects, with a lowest dose of 350 µg (~5 µg/kg) ”
• “Sustained TSH suppression was best achieved upon division of the daily TA₃ dose compared with a single morning administration.”
• “Taken together, TA₃ inhibits TSH production and secretion by acting at the level of the pituitary, thereby regulating thyroid [gland] activity.”

Ueda et al, 1996 studied Triac in comparison with T3 dosing.

• A single-dose administration of 1.4 mg [1400 mcg] of Triac remarkably suppressed serum TSH concentrations after 2 hours in not only normal subjects (-34 ± 11% [mean ± SD] from the basal value) but also in patients with resistance to thyroid hormone (-31 ± 9%), and this TSH suppression continued for 4 hours.
• After 24 hours [of Triac], this TSH suppression persisted in normal subjects (-62 ± 12%) but was relieved in patients with resistance to thyroid hormone (-23 ± 14%).
• In contrast, a short-term administration of 75 μg of T₃ daily for 7 days suppressed serum TSH concentrations almost completely in normal subjects, but suppressed TSH only partially in patients with resistance to thyroid hormone and TSH-secreting pituitary adenoma. A single-dose administration of 75 μg of T₃ gave similar results in regard to TSH suppressibility in these three subjects groups.
• Because the Triac therapy for patients with resistance to thyroid hormone suppressed pituitary-TSH secretion during the early phase of drug ingestion, this drug should be given several times within a day to obtain continuous TSH-suppressive effects.” (Note that the same advice about multi-dosing is given regarding LT3 dosing and NDT dosing due to the peaks & valleys in FT3 and the half life, but to obtain continuous euthyroid metabolic effects not mere TSH suppression.)

Kunitake et al, 1989 did a study of human patients with RTH

• In one woman with hyperthyroidism plus high TSH due to RTH, doses of up to 3.5 mg/day (3500 mcg) suppressed TSH from 16.3 to 1.5 mU/L. In addition, the peak TSH response to hypothalamic TRH reduced from 144 to 12.5, which showed that the effect was at least partly on the pituitary gland.
• In one man with chronic schizophrenia due to RTH (and likely central hypothyroidism), doses of up to 4.2 mg/day (4200 mcg) suppressed TSH from 2.0 to 0.5 mU/L. TRH-TSH stimulus response reduced from 14.2 to 2.8.

What else do we know about Triac as of 2019?

Triac has been studied since the 1950s. Amazing things are now known about Triac’s mode of action on the human body.

• Triac may help explain weight loss and fat loss in T3 therapy: “T3 and Triac raised serum concentrations of unesterified fatty acids within 6 hr in humans and enhanced their release from adipose tissue and their removal from serum in dogs.” (Hoch, 1968)

• Low doses of Triac can increase body temperature and raise metabolic rate in euthyroid (thyroid-healthy) individuals. “The effect of TRIAC at low doses on LPL or leptin reinforces its role in activating energy metabolism. In addition, all these effects are exerted without inhibition of TSH or hypothyroxinemia, contrary to the high doses of TRIAC. Thus, although the administration of high doses of TRIAC should be avoided [due to suppression of TSH and thyroidal T4 secretion], this study shows the physiological relevance of low doses of TRIAC inducing thermogenic effects in adipose tissues, suggesting that an increase in TRIAC production in adipose tissues may be one mechanism to increase energy metabolism and may be of benefit in the treatment of obesity.” (Medina-Gomez et al, 2008)

• However, higher doses may be needed to obtain metabolic effects when treating hypothyroid subjects. Groeneweg et al 2017 reviewed earlier studies that found “In hypothyroid patients, TA₃ stimulates basal metabolic rate (BMR) only at doses above ~4000 µg (mcg)/day (50–75 µg/kg/day)” and “TA₃ dose required to increase BMR greatly exceeds that required for adequate TSH suppression.”

• Triac’s and T3’s combined effect on leptin levels may deepen TSH suppression at the hypothalamus. “Triac, like T3 and serum, inhibits leptin secretion and expression in white and brown adipocytes, whereas insulin has the opposite effect” (Medina-Gomez et al, 2004).” Lower leptin levels overall reduce TRH secretion from the hypothalamus, which reduces TSH secretion (central hypothyroidism).

• “TRIAC and TETRAC are increased in NTIS [critical illness] and starvation,” (Dietrich et al, 2012). In fact, ” Several studies found up to 3-fold increased serum TA₄ and TA₃ levels during fasting and non-thyroidal illness” (Groeneweg, et al, 2017). This may help to explain the mystery by which TSH remains normalized, rather than rising, when thyroid hormones T3 and then T4 become depleted in Low T3 syndrome / nonthyroidal illness (NTIS). In fasting, the TSH is suppressed also by leptin, but perhaps to some degree by Triac as well.

• Effects on the heart: Triac is very mild on the heart. It “is a less potent regulator of TH target genes in the heart than T₃.” “Case-reports of children with RTHβ have not reported any cardiac side effects”; and “In adult human subjects, no detrimental effects of TA₃ have been observed on cardiac structure or function.” (Groeneweg, 2017). This is likely because it mainly acts on THRB thyroid hormone receptors not THRA, which is highly expressed in heart.

• Effects on lowering cholesterol: ” In hypothyroid subjects, TA₃ also reduced serum total and LDL cholesterol as well as apoprotein B levels, generally within 2 weeks.” (Groeneweg et al, 2017)

• Effects on SHBG and Ferritin: “When given at equivalent TSH-suppressive doses to euthyroid or hypothyroid patients, TA₃ induced similar increases in serum sex hormone binding globulin (SHBG) and ferritin levels as LT₄.” (Groeneweg et al, 2017, citing two studies from the 1990s)

• Effects on skin: ” Topical application of TA₃ increases dermal thickness and prevents glucocorticoid-induced skin atrophy in mice and humans, and stimulates procollagen synthesis and keratinocyte proliferation in human skin, but has no beneficial effects on plaque psoriasis. (Groeneweg et al, 2017)

• Effects in pregnancy: “Effects of TA₃ and TA₄ on the developing human brain are largely unknown. However, several cases have been reported where TA₃ has been administered to a pregnant woman for the treatment of fetal hypothyroidism. … In all three cases, the infant showed a normal neuro(psycho)logical development at 20–24 months of age. Obviously, the risks and benefits of TA₃ administration during pregnancy should be carefully weighted. Nevertheless, these studies suggest that TA₃ has T₃-like effects on the developing human brain.” (Groeneweg et al, 2017)

• Effects in anti-cancer therapy: In contrast with T4 and Reverse T3, Triac therapy shows promise in promoting cancer cell death even when it binds to the “integrin αvβ3 ” thyroid receptors on cell walls: “Integrin-involvement in triac/T1AM apoptotic action was shown in αvβ3-transfected HEK293 cells.” (Shinderman-Maman et al, 2017). “At αvβ3, T4 is a potent proliferative [cancer-growing], anti-apoptotic and pro-angiogenic hormone and is the primary ligand. rT3 may also be proliferative at this site. In contrast, Tetrac and Triac are antagonists of T4 at αvβ3, but also have anticancer properties at this site that are independent of their effects on the binding of T4.” (Davis et al, 2018)

• Effects on inflammation: There’s potential here in mouse studies. A study titled “3, 5, 3′-Triiodothyroacetic acid (TRIAC) is an anti-inflammatory drug that targets toll-like receptor 2” claimed that “TRIAC alleviates inflammation in mouse models of Con A-induced hepatitis” (Ha et al, 2018)

• Unlike T3, Triac does not universally boost T4-T3 conversion via Deiodinase type 1 (D1) in all organs. “TRIAC (specially the low dose) had almost no effect in D1 activities, except in kidney. Indeed, the basal and T₃-induced expression of D1 is mostly dependent on TR-β₁ … Kidney D1 is also less sensitive to T₃ regulation.” (Medina-Gomez et al, 2008)

• Thyroid hormone receptors really enjoy binding with Triac! In terms of thyroid receptor affinity in rat liver cells, the affinity compared to T3 (set at a value of 1.0) was Triac 3.0 (three times the affinity), LT4 0.10x, and Reverse T3 >0.01x (Samuels et al, 1988).

• In terms of thyroid receptor affinity in pituitary TSH-secreting cells (thyrotropes), Triac rivals T3. “L-T3 and triac were equally potent and D-T3 was one-sixth to one-fifth as potent in binding to the receptor and in regulating TSH production and TRH receptor number. L-T4 was the least potent analogue in each instance.” (Gershengorn et al, 1979)

• At osteoclast bone cells, Triac is slightly more potent than T3 and Parathyroid hormone (PTH) at stimulating resorption, but calcitonin and cortisol can block these responses to Triac and T3. “Since T₃ may be converted to Triac in fasting and nonthyroidal illness, we speculate that Triac could mediate bone loss in these catabolic low‐T₃ states.” (Kawaguchi et al, 1994)

• Thyroid hormone transporters in the pituitary seem to prefer to carry Triac. Everts et al, 1994 found that uptake of radioactive iodine-labelled Triac into pituitary cells was 2x faster than T3. In addition, the speed of both depend on body temperature of 37 degrees Celcius and is slowed down by lower temperatures.

• Dosing Triac can bias Free T3 lab tests higher. “There have been reports of 3-3’,5-triiodothyroacetic acid (TRIAC) interfering in FT3 assays and D-T4 interference in FT4 assays.” (Baloch et al, 2003; ATA lab testing guide) — This guideline cited a study (Piketty et al, 1996) that found that a person dosed with Triac had abnormally high FT3 values on three assays that it tested. Therefore, it’s possible that people who dose T3 might have a little less Free T3 than their lab tests say they do, though the effect would not be as extreme as someone dosing Triac.

• Triac has an unusual Bound vs Free hormone profile. “The free fraction of TA₃ in plasma is relatively low compared to T₃, due to its high affinity for plasma binding proteins, exceeding that of T₃ by 16-fold in rats. In humans, TA₃ particularly binds to transthyretin (TTR), whereas its binding to thyroxine binding globulin [TBG] is negligible.” (Groeneweg et al, 2017).
  
  Therefore, the amount of “free Triac” available to enter cells is NOT affected by higher estrogen levels, whereas T4 and T3 are affected by estrogen fluctuations. In estrogen therapy or even at certain times in menstrual cycle, TBG levels can increase, which can bind more T4 than usual and cause reduced FT4 in persons on LT4 therapy. In persons not dependent on LT4, they simply increase thyroidal secretion to keep Free T4 levels steady.

• To diagnose hypothyroid patients with Resistance to Thryoid Hormone (RTH), the free SPINA-Thyr program can be used to sensitively measure the degree of RTH. It can also be used to measure progress in reducing TSH secretion in relationship to T4 levels, even while FT4 and TSH are within reference range, by providing a “TTSI index” (Dietrich et al, 2016).

References on Page 2