3,5-diiodo-L-thyronine (T2)

updated

3,5-diiodo-L-thyronine (T2) has no FDA application, and its published human record is two euthyroid volunteers in one uncontrolled report. Rodent results conflict: about 50% less fat mass in one rat study, no effect on weight or liver fat in another, and dose-dependent falls in TSH, T3 and T4 in a 90-day rat study. An FDA laboratory found up to 740 micrograms per day of 3,5-T2 and up to 2700 of the 3,3' isomer in retail products.

Diiodothyronine (thyroid hormone-like compound)

  • An openFDA query on 9 October 2026 found no FDA application for 3,5-diiodothyronine, while T3 (CYTOMEL) was approved on 8 May 1956.
  • The only published human report is 2 euthyroid volunteers: resting metabolic rate rose in each, and body weight fell about 4% after a further 3 weeks at 300 micrograms per day, with free T3, free T4 and TSH unchanged.
  • In Wistar rats given T2 subcutaneously for 90 days, serum TSH, T3 and T4 fell in a dose-dependent way, which contradicts the claim of less thyroid-axis suppression than T3.
  • An independent rat study found no effect of T2 on weight, adiposity or liver fat, and a mouse study found enlarged heart weights.
  • 3,5-T2 and 3,3'-T2 are different isomers with the same formula, and a label that says only 'T2' does not specify which one a product contains.
  • An FDA laboratory analyzed 58 online supplements bought in 2017 and 2018 and found up to 740 micrograms per day of 3,5-T2 and 2700 of 3,3'-T2.

What is 3,5-diiodothyronine, and is it approved?

3,5-diiodo-L-thyronine (T2) has no FDA application, while T3 (liothyronine, CYTOMEL) has been an approved prescription medicine since 1956. A product labeled only 'T2' does not say which isomer it contains.

3,5-diiodo-L-thyronine is C15H13I2NO4 (525.08 g/mol, CAS 1041-01-6, PubChem CID 92859). Listed synonyms include diiodo-L-thyronine and L-3,5-diiodothyronine.

3,5-T2 and 3,3'-diiodothyronine (3,3'-T2) are different positional isomers with the same formula, and the FDA supplement survey measured them as separate analytes. A product labeled only 'T2' or 'diiodothyronine' does not specify which isomer it contains.

An openFDA Drugs@FDA exact-name query for 3,5-diiodothyronine returned no matching application on 9 October 2026. The same database returns CYTOMEL (liothyronine sodium, T3) under NDA 010379, approved 8 May 1956, plus multiple generic liothyronine applications. T3, the drug that sellers offer T2 as a gentler alternative to, has been an approved prescription medicine for 70 years with a label. T2 has neither an approval nor a label.

PubChem CID 92859: C15H13I2NO4, 525.08 g/mol; isomer caution

Chemical identity record

National Library of Medicine. PubChem compound record CID 92859 (3,5-diiodo-L-thyronine).

3,5-diiodo-L-thyronine: PubChem CID 92859, C15H13I2NO4, 525.08 g/mol, CAS 1041-01-6. Listed synonyms include diiodo-L-thyronine and L-3,5-diiodothyronine. 3,5-T2 and 3,3'-diiodothyronine (3,3'-T2) are different positional isomers with the same formula and were measured as separate analytes in the FDA supplement survey. A product labeled only 'T2' or 'diiodothyronine' does not specify which isomer it contains.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule, no approved formulation
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
FDA laboratory survey: 58 online supplements, up to 740 micrograms per day of 3,5-T2 and 2700 of 3,3'-T2

Regulatory record

Pawar RS et al. Drug Test Anal. 2022;14(3):578-586. PMID 33855795.

An LC-MS/MS method was developed and validated for T4, T3, reverse T3, 3,5-T2 and 3,3'-T2 in dietary supplements, with recovery between 78 and 116%. Fifty-eight products making thyroid-management claims were purchased over the internet from 2017 to 2018 and analyzed. Eleven of 19 glandular products contained quantifiable amounts of hormones, with maximum daily servings reaching 210 micrograms per day of T4, 32 of T3 and 7.6 of reverse T3. In nonglandular products, labeled to contain plant extracts, vitamins, minerals, diiodo compounds and so forth, the amounts of 3,5-T2 and 3,3'-T2 reached up to 740 and 2700 micrograms per day.

Participants / model
58 retail dietary supplement products, not a clinical population
Treatment
Oral dietary supplement products purchased online
Follow-up
Products purchased from 2017 to 2018
Study design
FDA laboratory analysis of retail products
Funding
not stated in the source

Content per maximum daily serving as measured, not a recommendation. The survey measured the two isomers separately.

Read the original source
Drugs@FDA: no T2 application; T3 (CYTOMEL) approved 8 May 1956

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record for NDA 010379 (CYTOMEL, liothyronine sodium), with generic liothyronine applications, and an openFDA exact-name query for 3,5-diiodothyronine run on 9 October 2026. Dates read from the openFDA Drugs@FDA records.

An openFDA Drugs@FDA exact-name query for 3,5-diiodothyronine returned no matching application on 9 October 2026. The same database returns CYTOMEL (liothyronine sodium, T3) under NDA 010379 approved 8 May 1956, plus multiple generic liothyronine applications. The drug that sellers offer T2 as a gentler alternative to has been an approved prescription medicine for 70 years with a label; T2 has neither an approval nor a label.

Participants / model
FDA application database, not a clinical population
Treatment
Exact substance-name searches
Follow-up
Query run on 9 October 2026
Study design
FDA application records and database query
Funding
not stated in the source

A US-scoped search result. The record shown is for T3, the comparator, not for T2.

Read the original source

What does the human data on 3,5-T2 show?

The only published human report is two euthyroid volunteers. Resting metabolic rate rose in each, body weight fell about 4% after a further 3 weeks, and free T3, free T4 and TSH were unchanged, but a two-person report cannot establish an effect.

Two euthyroid volunteers underwent T2 administration, with body weight, BMI, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3, free T4, T2, TSH and resting metabolic rate measured at baseline and at the end of treatment. Resting metabolic rate increased significantly in each subject. After continuing T2 for a further 3 weeks at 300 micrograms per day, body weight was reduced significantly (p<0.05), by about 4%, while serum free T3, free T4 and TSH were unchanged. No side effects were observed at the cardiac level in either subject, and no significant change was observed in the same subjects taking placebo.

This is a two-person report, not a trial. It has no randomization, no blinding and no power to detect an effect, so it cannot establish metabolic or safety effects of T2.

Two euthyroid volunteers: resting metabolic rate up, weight down about 4%, free T3, free T4 and TSH unchanged

Human study

Antonelli A et al. J Biol Regul Homeost Agents. 2011;25(4):655-60. PMID 22217997.

Two euthyroid subjects volunteered to undergo T2 administration, with body weight, BMI, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3, free T4, T2, TSH and resting metabolic rate measured at baseline and at the end of treatment. Resting metabolic rate increased significantly in each subject. After continuing T2 for a further 3 weeks at 300 micrograms per day, body weight was reduced significantly (p<0.05), by about 4%, while serum free T3, free T4 and TSH were unchanged. No side effects were observed at the cardiac level in either subject, and no significant change was observed in the same subjects taking placebo.

Participants / model
2 euthyroid human volunteers
Treatment
Oral T2, 300 micrograms per day for a further 3 weeks
Follow-up
A further 3 weeks after the initial treatment period
Study design
Two-person human report, not a randomized trial
Funding
not stated in the source

The report has no randomization, no blinding and no power to detect an effect, so it cannot establish metabolic or safety effects of T2.

Read the original source
PubMed search, 9 October 2026: 60 records, one reports giving 3,5-T2 to people (2 subjects)

PubMed search record

PubMed search run on 9 October 2026: ("3,5-diiodo-L-thyronine" OR "3,5-diiodothyronine" OR "3,5-T2") AND ("resting metabolic rate" OR "body weight" OR obesity OR "energy expenditure" OR "fat mass"). 60 records returned.

The search returned 60 records. The only one reporting administration of 3,5-T2 to people is the two-subject study. The remainder are rodent, fish, chicken, cell and analytical-chemistry studies, plus reviews. In the records reviewed, there is no randomized, controlled or blinded human trial of 3,5-T2 for any metabolic endpoint, and so no human effect size, human dose-response or human safety dataset to quote.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source

Does T2 raise metabolic rate and cut fat with less thyroid suppression than T3?

No controlled human data support it. Two animal studies that examined the thyroid axis found suppression, which contradicts the claim of less suppression than T3, and the fat-loss half of the claim has no controlled human evidence.

Sellers describe T2 as raising metabolic rate and driving fat loss with potentially less thyroid-axis suppression than T3, suitable as an adjunct during aggressive calorie restriction.

The less-suppression point is the reason to choose T2 over an approved drug. The only human observation supporting it is unchanged free T3, free T4 and TSH in two subjects over a few weeks. In Wistar rats treated for 90 days, serum TSH, T3 and T4 fell in a dose-dependent way, and in diet-induced obese mice T2 suppressed thyroid function with lower T4 and T3 in serum and liver. A separate rat study on a high-fat diet found thyroid hormone and TSH levels were not influenced.

The fat-loss half has no controlled human evidence. ClinicalTrials.gov queries on 9 October 2026 located no interventional trial of 3,5-T2 for metabolic rate, fat loss or body composition. A PubMed search the same day returned 60 records, and only the two-subject study reported giving 3,5-T2 to people.

Wistar rats, 90 days: dose-dependent fall in TSH, T3 and T4, fat pad mass reduced

Animal study

Padron AS et al. J Endocrinol. 2014;221(3):415-27. PMID 24692290.

Wistar rats were treated daily with T2 at 25, 50 or 75 micrograms per 100 g body weight subcutaneously for 90 days, from 3 to 6 months of age. T2 suppressed thyroid function, reducing thyroid iodide uptake, thyroperoxidase, NADPH oxidase 4 and type 1 iodothyronine deiodinase activity and expression. Serum TSH, T3 and T4 were reduced in a dose-dependent manner. Oxygen consumption increased, and after 3 months body mass and retroperitoneal fat pad mass were significantly reduced, while heart rate and heart mass were unchanged. The authors conclude that TSH suppression may develop secondary to T2 administration.

Participants / model
Wistar rats, 3 to 6 months of age
Treatment
Subcutaneous T2, 25, 50 or 75 micrograms per 100 g body weight daily
Follow-up
90 days
Study design
Original animal study
Funding
not stated in the source

Rodent findings. This study contradicts the claim that T2 spares the thyroid axis.

Read the original source
Obese mice: T3-like axis feedback, lower T4 and T3, enlarged hearts, no significant weight loss

Animal study

Jonas W et al. Endocrinology. 2015;156(1):389-99. PMID 25322465.

In diet-induced obese male C57BL/6J mice, T2 produced dose-dependent thyromimetic effects akin to those of T3. It exerted negative feedback on the hypothalamus-pituitary-thyroid axis similar to T3, shown by decreased expression of thyroid-hormone-responsive genes in pituitary and a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver. Hepatic thyroid hormone target genes showed T3-like changes, and type I deiodinase activity increased at 2.5 micrograms per gram body weight. Hepatic triglyceride and serum cholesterol fell. The increase in metabolic rate and reduction of fat depots were compromised by increased food intake, which prevented significant body weight loss. Enlarged heart weights indicate potential cardiac side effects. The authors wrote that these findings raise concern about indiscriminate administration of T2.

Participants / model
Diet-induced obese male C57BL/6J mice
Treatment
T2 administration including 2.5 micrograms per gram body weight; route not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route.

Read the original source
Rats on a high-fat diet: about 50% less fat mass, no change in thyroid hormones or TSH

Animal study

Lanni A et al. FASEB J. 2005;19(11):1552-4. PMID 16014396.

T2 given to rats on a high-fat diet reduced both adiposity and body weight gain without inducing thyrotoxicity. Compared with rats on the high-fat diet alone, rats receiving the diet plus T2 showed a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, approximately 50% less fat mass, a complete disappearance of fat from the liver, and reductions in serum triglyceride and cholesterol of 52% and 18%. Thyroid hormone and TSH serum levels were not influenced. The mechanism involved the carnitine palmitoyltransferase system and mitochondrial uncoupling. The authors state that the results do not exclude deleterious effects of T2 on a longer time scale and do not show that T2 acts in the same way in humans.

Participants / model
Rats receiving a high-fat diet
Treatment
T2 administration; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route, so no comparison with human exposure is possible.

Read the original source
Two euthyroid volunteers: resting metabolic rate up, weight down about 4%, free T3, free T4 and TSH unchanged

Human study

Antonelli A et al. J Biol Regul Homeost Agents. 2011;25(4):655-60. PMID 22217997.

Two euthyroid subjects volunteered to undergo T2 administration, with body weight, BMI, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3, free T4, T2, TSH and resting metabolic rate measured at baseline and at the end of treatment. Resting metabolic rate increased significantly in each subject. After continuing T2 for a further 3 weeks at 300 micrograms per day, body weight was reduced significantly (p<0.05), by about 4%, while serum free T3, free T4 and TSH were unchanged. No side effects were observed at the cardiac level in either subject, and no significant change was observed in the same subjects taking placebo.

Participants / model
2 euthyroid human volunteers
Treatment
Oral T2, 300 micrograms per day for a further 3 weeks
Follow-up
A further 3 weeks after the initial treatment period
Study design
Two-person human report, not a randomized trial
Funding
not stated in the source

The report has no randomization, no blinding and no power to detect an effect, so it cannot establish metabolic or safety effects of T2.

Read the original source
Registry searches, 9 October 2026: no interventional trial of 3,5-T2 for metabolism or body composition

Trial registry record

ClinicalTrials.gov searches run on 9 October 2026 for diiodothyronine (1 study) and for 3,5-T2 thyronine (2 studies).

ClinicalTrials.gov queries run on 9 October 2026 for diiodothyronine returned 1 study, NCT04392258, an observational and diagnostic study of thyroid function after cardiopulmonary resuscitation, which is not a T2 intervention. A query for 3,5-T2 thyronine returned 2 studies, NCT06033456 (radiofrequency ablation at the T2 and T3 spinal levels for post-mastectomy pain) and NCT03907280 (a phase 1 PK study of an unrelated compound), neither involving 3,5-diiodothyronine. In the registry records reviewed, no interventional trial of 3,5-T2 for metabolic rate, fat loss or body composition was located.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Searches run on 9 October 2026
Study design
Registry search
Funding
not stated in the source

A search result shows what the registry returned on that date. It is not proof that no unregistered study exists.

Read the original source
PubMed search, 9 October 2026: 60 records, one reports giving 3,5-T2 to people (2 subjects)

PubMed search record

PubMed search run on 9 October 2026: ("3,5-diiodo-L-thyronine" OR "3,5-diiodothyronine" OR "3,5-T2") AND ("resting metabolic rate" OR "body weight" OR obesity OR "energy expenditure" OR "fat mass"). 60 records returned.

The search returned 60 records. The only one reporting administration of 3,5-T2 to people is the two-subject study. The remainder are rodent, fish, chicken, cell and analytical-chemistry studies, plus reviews. In the records reviewed, there is no randomized, controlled or blinded human trial of 3,5-T2 for any metabolic endpoint, and so no human effect size, human dose-response or human safety dataset to quote.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source

What did the rodent studies find?

The rodent results conflict. One rat study found about 50% less fat mass without thyroid hormone changes, an independent rat study found no effect on weight, adiposity or liver fat, a 90-day rat study found dose-dependent falls in TSH, T3 and T4, and a mouse study found T3-like axis feedback, enlarged hearts and no significant weight loss.

In rats on a high-fat diet, T2 reduced adiposity and body weight gain without inducing thyrotoxicity. Compared with rats on the diet alone, rats receiving the diet plus T2 had 13% lower body weight, 42% higher liver fatty acid oxidation, approximately 50% less fat mass, a complete disappearance of fat from the liver, and serum triglyceride and cholesterol reductions of 52% and 18%. Thyroid hormone and TSH serum levels were not influenced. The authors state that the results do not exclude deleterious effects of T2 on a longer time scale and do not show that T2 acts in the same way in humans.

Wistar rats were treated daily with T2 at 25, 50 or 75 micrograms per 100 g body weight subcutaneously for 90 days, from 3 to 6 months of age. T2 suppressed thyroid function, reducing thyroid iodide uptake, thyroperoxidase, NADPH oxidase 4 and type 1 iodothyronine deiodinase activity and expression. Serum TSH, T3 and T4 were reduced in a dose-dependent manner. Oxygen consumption increased, and after 3 months body mass and retroperitoneal fat pad mass were significantly reduced, while heart rate and heart mass were unchanged. The authors conclude that TSH suppression may develop secondary to T2 administration.

In diet-induced obese male C57BL/6J mice, T2 produced dose-dependent thyromimetic effects akin to those of T3. It exerted negative feedback on the hypothalamus-pituitary-thyroid axis similar to T3, with decreased expression of thyroid-hormone-responsive genes in pituitary and a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver. Hepatic triglyceride and serum cholesterol fell. The increase in metabolic rate and reduction of fat depots were compromised by increased food intake, which prevented significant body weight loss.

An independent group fed male Sprague Dawley rats a safflower-oil based high-fat diet and treated them with T2 at 0.25 mg/kg per day or vehicle. Neither 10 nor 30 days of T2 had an effect on weight, adiposity, plasma fatty acids or hepatic steatosis, and a hyperinsulinemic-euglycemic clamp found no difference in whole body insulin sensitivity. Insulin-stimulated Akt phosphorylation was about 2.5-fold greater in the T2 group (p=0.003), a signaling change without a matching whole-body effect. The authors conclude that, in contrast with previous reports, T2 failed to improve NAFLD or whole body insulin sensitivity.

Rats on a high-fat diet: about 50% less fat mass, no change in thyroid hormones or TSH

Animal study

Lanni A et al. FASEB J. 2005;19(11):1552-4. PMID 16014396.

T2 given to rats on a high-fat diet reduced both adiposity and body weight gain without inducing thyrotoxicity. Compared with rats on the high-fat diet alone, rats receiving the diet plus T2 showed a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, approximately 50% less fat mass, a complete disappearance of fat from the liver, and reductions in serum triglyceride and cholesterol of 52% and 18%. Thyroid hormone and TSH serum levels were not influenced. The mechanism involved the carnitine palmitoyltransferase system and mitochondrial uncoupling. The authors state that the results do not exclude deleterious effects of T2 on a longer time scale and do not show that T2 acts in the same way in humans.

Participants / model
Rats receiving a high-fat diet
Treatment
T2 administration; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route, so no comparison with human exposure is possible.

Read the original source
Wistar rats, 90 days: dose-dependent fall in TSH, T3 and T4, fat pad mass reduced

Animal study

Padron AS et al. J Endocrinol. 2014;221(3):415-27. PMID 24692290.

Wistar rats were treated daily with T2 at 25, 50 or 75 micrograms per 100 g body weight subcutaneously for 90 days, from 3 to 6 months of age. T2 suppressed thyroid function, reducing thyroid iodide uptake, thyroperoxidase, NADPH oxidase 4 and type 1 iodothyronine deiodinase activity and expression. Serum TSH, T3 and T4 were reduced in a dose-dependent manner. Oxygen consumption increased, and after 3 months body mass and retroperitoneal fat pad mass were significantly reduced, while heart rate and heart mass were unchanged. The authors conclude that TSH suppression may develop secondary to T2 administration.

Participants / model
Wistar rats, 3 to 6 months of age
Treatment
Subcutaneous T2, 25, 50 or 75 micrograms per 100 g body weight daily
Follow-up
90 days
Study design
Original animal study
Funding
not stated in the source

Rodent findings. This study contradicts the claim that T2 spares the thyroid axis.

Read the original source
Obese mice: T3-like axis feedback, lower T4 and T3, enlarged hearts, no significant weight loss

Animal study

Jonas W et al. Endocrinology. 2015;156(1):389-99. PMID 25322465.

In diet-induced obese male C57BL/6J mice, T2 produced dose-dependent thyromimetic effects akin to those of T3. It exerted negative feedback on the hypothalamus-pituitary-thyroid axis similar to T3, shown by decreased expression of thyroid-hormone-responsive genes in pituitary and a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver. Hepatic thyroid hormone target genes showed T3-like changes, and type I deiodinase activity increased at 2.5 micrograms per gram body weight. Hepatic triglyceride and serum cholesterol fell. The increase in metabolic rate and reduction of fat depots were compromised by increased food intake, which prevented significant body weight loss. Enlarged heart weights indicate potential cardiac side effects. The authors wrote that these findings raise concern about indiscriminate administration of T2.

Participants / model
Diet-induced obese male C57BL/6J mice
Treatment
T2 administration including 2.5 micrograms per gram body weight; route not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route.

Read the original source
Sprague Dawley rats: no effect on weight, adiposity, liver fat or insulin sensitivity

Animal study

Vatner DF et al. PLoS One. 2015;10(10):e0140837. PMID 26485433.

Male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 at 0.25 mg/kg per day or vehicle. Neither 10 nor 30 days of T2 had an effect on weight, adiposity, plasma fatty acids or hepatic steatosis. A hyperinsulinemic-euglycemic clamp found no difference in fasting plasma glucose or insulin, no change in basal endogenous glucose production, and no difference in insulin-stimulated whole body glucose disposal. Insulin suppressed endogenous glucose production by 60 +/- 10% in T2-treated rats versus 47 +/- 4% in vehicle (p=0.32). Insulin-stimulated Akt phosphorylation was about 2.5-fold greater in the T2 group (p=0.003), a signaling change without a matching whole-body effect. No change was seen in the genes said to mediate T2's hepatic action. The authors conclude that, in contrast with previous reports, T2 failed to improve NAFLD or whole body insulin sensitivity.

Participants / model
Male Sprague Dawley rats on a safflower-oil high-fat diet
Treatment
T2, 0.25 mg/kg per day, or vehicle; route not stated in the abstract
Follow-up
10 and 30 days
Study design
Original animal study
Funding
not stated in the source

An independent rodent attempt with a null result. The abstract does not state the route.

Read the original source

What is actually in the products sold as T2?

An FDA laboratory found up to 740 micrograms per day of 3,5-T2 and up to 2700 micrograms per day of the 3,3' isomer in nonglandular supplements, and thyroid hormones in 11 of 19 glandular products. A label that says only 'T2' does not establish which compound is present.

An FDA laboratory developed and validated an LC-MS/MS method for T4, T3, reverse T3, 3,5-T2 and 3,3'-T2 in dietary supplements, with recovery between 78 and 116%. It then analyzed 58 products making thyroid-management claims that were purchased over the internet in 2017 and 2018.

Eleven of 19 glandular products contained quantifiable amounts of hormones, with maximum daily servings reaching 210 micrograms per day of T4, 32 of T3 and 7.6 of reverse T3. In nonglandular products, labeled to contain plant extracts, vitamins, minerals, diiodo compounds and so forth, the amounts of 3,5-T2 and 3,3'-T2 reached up to 740 and 2700 micrograms per day. For comparison, the two-person study gave 300 micrograms per day of T2.

The two isomers were measured separately and found at different concentrations in the same survey, so a product label that says only 'T2' does not establish which one is in the bottle.

FDA laboratory survey: 58 online supplements, up to 740 micrograms per day of 3,5-T2 and 2700 of 3,3'-T2

Regulatory record

Pawar RS et al. Drug Test Anal. 2022;14(3):578-586. PMID 33855795.

An LC-MS/MS method was developed and validated for T4, T3, reverse T3, 3,5-T2 and 3,3'-T2 in dietary supplements, with recovery between 78 and 116%. Fifty-eight products making thyroid-management claims were purchased over the internet from 2017 to 2018 and analyzed. Eleven of 19 glandular products contained quantifiable amounts of hormones, with maximum daily servings reaching 210 micrograms per day of T4, 32 of T3 and 7.6 of reverse T3. In nonglandular products, labeled to contain plant extracts, vitamins, minerals, diiodo compounds and so forth, the amounts of 3,5-T2 and 3,3'-T2 reached up to 740 and 2700 micrograms per day.

Participants / model
58 retail dietary supplement products, not a clinical population
Treatment
Oral dietary supplement products purchased online
Follow-up
Products purchased from 2017 to 2018
Study design
FDA laboratory analysis of retail products
Funding
not stated in the source

Content per maximum daily serving as measured, not a recommendation. The survey measured the two isomers separately.

Read the original source
PubChem CID 92859: C15H13I2NO4, 525.08 g/mol; isomer caution

Chemical identity record

National Library of Medicine. PubChem compound record CID 92859 (3,5-diiodo-L-thyronine).

3,5-diiodo-L-thyronine: PubChem CID 92859, C15H13I2NO4, 525.08 g/mol, CAS 1041-01-6. Listed synonyms include diiodo-L-thyronine and L-3,5-diiodothyronine. 3,5-T2 and 3,3'-diiodothyronine (3,3'-T2) are different positional isomers with the same formula and were measured as separate analytes in the FDA supplement survey. A product labeled only 'T2' or 'diiodothyronine' does not specify which isomer it contains.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule, no approved formulation
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
Two euthyroid volunteers: resting metabolic rate up, weight down about 4%, free T3, free T4 and TSH unchanged

Human study

Antonelli A et al. J Biol Regul Homeost Agents. 2011;25(4):655-60. PMID 22217997.

Two euthyroid subjects volunteered to undergo T2 administration, with body weight, BMI, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3, free T4, T2, TSH and resting metabolic rate measured at baseline and at the end of treatment. Resting metabolic rate increased significantly in each subject. After continuing T2 for a further 3 weeks at 300 micrograms per day, body weight was reduced significantly (p<0.05), by about 4%, while serum free T3, free T4 and TSH were unchanged. No side effects were observed at the cardiac level in either subject, and no significant change was observed in the same subjects taking placebo.

Participants / model
2 euthyroid human volunteers
Treatment
Oral T2, 300 micrograms per day for a further 3 weeks
Follow-up
A further 3 weeks after the initial treatment period
Study design
Two-person human report, not a randomized trial
Funding
not stated in the source

The report has no randomization, no blinding and no power to detect an effect, so it cannot establish metabolic or safety effects of T2.

Read the original source

How does T2 work, and what does the body do with it?

In rats on a high-fat diet the effect involved the carnitine palmitoyltransferase system and mitochondrial uncoupling, but later rodent studies found T3-like feedback on the thyroid axis. The sources reviewed give no half-life and no pharmacokinetic data for people.

In rats on a high-fat diet, the mechanism involved the carnitine palmitoyltransferase system and mitochondrial uncoupling, alongside a 42% higher liver fatty acid oxidation rate. The authors state that the results do not show that T2 acts in the same way in humans.

In diet-induced obese mice, T2 produced dose-dependent thyromimetic effects akin to those of T3, including negative feedback on the hypothalamus-pituitary-thyroid axis. A 2020 review states that 3,5-diiodothyronine has been used with success in rat models of dyslipidemia and NAFLD, but that the outcome of a clinical trial with a synthetic T2 analogue was disappointing. The review does not report a controlled clinical trial of T2 itself, and its abstract does not name the analogue.

The sources reviewed give no half-life, no adverse-event rate and no pharmacokinetic data for T2 in people.

Rats on a high-fat diet: about 50% less fat mass, no change in thyroid hormones or TSH

Animal study

Lanni A et al. FASEB J. 2005;19(11):1552-4. PMID 16014396.

T2 given to rats on a high-fat diet reduced both adiposity and body weight gain without inducing thyrotoxicity. Compared with rats on the high-fat diet alone, rats receiving the diet plus T2 showed a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, approximately 50% less fat mass, a complete disappearance of fat from the liver, and reductions in serum triglyceride and cholesterol of 52% and 18%. Thyroid hormone and TSH serum levels were not influenced. The mechanism involved the carnitine palmitoyltransferase system and mitochondrial uncoupling. The authors state that the results do not exclude deleterious effects of T2 on a longer time scale and do not show that T2 acts in the same way in humans.

Participants / model
Rats receiving a high-fat diet
Treatment
T2 administration; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route, so no comparison with human exposure is possible.

Read the original source
Obese mice: T3-like axis feedback, lower T4 and T3, enlarged hearts, no significant weight loss

Animal study

Jonas W et al. Endocrinology. 2015;156(1):389-99. PMID 25322465.

In diet-induced obese male C57BL/6J mice, T2 produced dose-dependent thyromimetic effects akin to those of T3. It exerted negative feedback on the hypothalamus-pituitary-thyroid axis similar to T3, shown by decreased expression of thyroid-hormone-responsive genes in pituitary and a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver. Hepatic thyroid hormone target genes showed T3-like changes, and type I deiodinase activity increased at 2.5 micrograms per gram body weight. Hepatic triglyceride and serum cholesterol fell. The increase in metabolic rate and reduction of fat depots were compromised by increased food intake, which prevented significant body weight loss. Enlarged heart weights indicate potential cardiac side effects. The authors wrote that these findings raise concern about indiscriminate administration of T2.

Participants / model
Diet-induced obese male C57BL/6J mice
Treatment
T2 administration including 2.5 micrograms per gram body weight; route not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route.

Read the original source
2020 review: T2 works in rat models; trial of a synthetic T2 analogue was disappointing

Animal study

Zucchi R. Thyroid. 2020;30(8):1099-1105. PMID 32098589.

A 2020 review states that 3,5-diiodothyronine has been used with success in rat models of dyslipidemia and NAFLD, but that the outcome of a clinical trial with a synthetic T2 analogue was disappointing. The review does not report a controlled clinical trial of T2 itself, and the abstract does not name the analogue, its sponsor or its results.

Participants / model
Rat models and one unnamed clinical trial of a synthetic analogue
Treatment
Not specified in the abstract
Follow-up
not stated in the source
Study design
Narrative review; no controlled trial of T2 itself
Funding
not stated in the source

A summary of development status. The analogue is not identified, so its result is not attributed to T2.

Read the original source

What risks do the animal studies and the product survey point to?

Risks are poorly defined. In mice, T2 enlarged heart weights and the authors raised concern about indiscriminate use, and a 90-day rat course suppressed TSH, T3 and T4. No cardiac side effects were seen in two volunteers, and no human safety dataset exists.

In diet-induced obese mice, enlarged heart weights indicate potential cardiac side effects, and the authors wrote that these findings raise concern about indiscriminate administration of T2. In the 90-day rat study, heart rate and heart mass were unchanged, but serum TSH, T3 and T4 fell in a dose-dependent way. In the two human volunteers, no side effects were observed at the cardiac level.

No randomized, controlled or blinded human trial of 3,5-T2 was found, so there is no human safety dataset and no adverse-event rate to quote.

Product content adds uncertainty. The FDA laboratory found up to 740 micrograms per day of 3,5-T2 and up to 2700 micrograms per day of 3,3'-T2 in nonglandular supplements, and quantifiable thyroid hormones in 11 of 19 glandular products. What is in a given bottle is not established by its label.

Obese mice: T3-like axis feedback, lower T4 and T3, enlarged hearts, no significant weight loss

Animal study

Jonas W et al. Endocrinology. 2015;156(1):389-99. PMID 25322465.

In diet-induced obese male C57BL/6J mice, T2 produced dose-dependent thyromimetic effects akin to those of T3. It exerted negative feedback on the hypothalamus-pituitary-thyroid axis similar to T3, shown by decreased expression of thyroid-hormone-responsive genes in pituitary and a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver. Hepatic thyroid hormone target genes showed T3-like changes, and type I deiodinase activity increased at 2.5 micrograms per gram body weight. Hepatic triglyceride and serum cholesterol fell. The increase in metabolic rate and reduction of fat depots were compromised by increased food intake, which prevented significant body weight loss. Enlarged heart weights indicate potential cardiac side effects. The authors wrote that these findings raise concern about indiscriminate administration of T2.

Participants / model
Diet-induced obese male C57BL/6J mice
Treatment
T2 administration including 2.5 micrograms per gram body weight; route not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route.

Read the original source
Wistar rats, 90 days: dose-dependent fall in TSH, T3 and T4, fat pad mass reduced

Animal study

Padron AS et al. J Endocrinol. 2014;221(3):415-27. PMID 24692290.

Wistar rats were treated daily with T2 at 25, 50 or 75 micrograms per 100 g body weight subcutaneously for 90 days, from 3 to 6 months of age. T2 suppressed thyroid function, reducing thyroid iodide uptake, thyroperoxidase, NADPH oxidase 4 and type 1 iodothyronine deiodinase activity and expression. Serum TSH, T3 and T4 were reduced in a dose-dependent manner. Oxygen consumption increased, and after 3 months body mass and retroperitoneal fat pad mass were significantly reduced, while heart rate and heart mass were unchanged. The authors conclude that TSH suppression may develop secondary to T2 administration.

Participants / model
Wistar rats, 3 to 6 months of age
Treatment
Subcutaneous T2, 25, 50 or 75 micrograms per 100 g body weight daily
Follow-up
90 days
Study design
Original animal study
Funding
not stated in the source

Rodent findings. This study contradicts the claim that T2 spares the thyroid axis.

Read the original source
Two euthyroid volunteers: resting metabolic rate up, weight down about 4%, free T3, free T4 and TSH unchanged

Human study

Antonelli A et al. J Biol Regul Homeost Agents. 2011;25(4):655-60. PMID 22217997.

Two euthyroid subjects volunteered to undergo T2 administration, with body weight, BMI, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3, free T4, T2, TSH and resting metabolic rate measured at baseline and at the end of treatment. Resting metabolic rate increased significantly in each subject. After continuing T2 for a further 3 weeks at 300 micrograms per day, body weight was reduced significantly (p<0.05), by about 4%, while serum free T3, free T4 and TSH were unchanged. No side effects were observed at the cardiac level in either subject, and no significant change was observed in the same subjects taking placebo.

Participants / model
2 euthyroid human volunteers
Treatment
Oral T2, 300 micrograms per day for a further 3 weeks
Follow-up
A further 3 weeks after the initial treatment period
Study design
Two-person human report, not a randomized trial
Funding
not stated in the source

The report has no randomization, no blinding and no power to detect an effect, so it cannot establish metabolic or safety effects of T2.

Read the original source
PubMed search, 9 October 2026: 60 records, one reports giving 3,5-T2 to people (2 subjects)

PubMed search record

PubMed search run on 9 October 2026: ("3,5-diiodo-L-thyronine" OR "3,5-diiodothyronine" OR "3,5-T2") AND ("resting metabolic rate" OR "body weight" OR obesity OR "energy expenditure" OR "fat mass"). 60 records returned.

The search returned 60 records. The only one reporting administration of 3,5-T2 to people is the two-subject study. The remainder are rodent, fish, chicken, cell and analytical-chemistry studies, plus reviews. In the records reviewed, there is no randomized, controlled or blinded human trial of 3,5-T2 for any metabolic endpoint, and so no human effect size, human dose-response or human safety dataset to quote.

Participants / model
Records returned, not a population
Treatment
Not applicable
Follow-up
Search run on 9 October 2026
Study design
Literature search
Funding
not stated in the source

A search result shows what PubMed returned on that date. It is not proof that no unindexed study exists.

Read the original source
FDA laboratory survey: 58 online supplements, up to 740 micrograms per day of 3,5-T2 and 2700 of 3,3'-T2

Regulatory record

Pawar RS et al. Drug Test Anal. 2022;14(3):578-586. PMID 33855795.

An LC-MS/MS method was developed and validated for T4, T3, reverse T3, 3,5-T2 and 3,3'-T2 in dietary supplements, with recovery between 78 and 116%. Fifty-eight products making thyroid-management claims were purchased over the internet from 2017 to 2018 and analyzed. Eleven of 19 glandular products contained quantifiable amounts of hormones, with maximum daily servings reaching 210 micrograms per day of T4, 32 of T3 and 7.6 of reverse T3. In nonglandular products, labeled to contain plant extracts, vitamins, minerals, diiodo compounds and so forth, the amounts of 3,5-T2 and 3,3'-T2 reached up to 740 and 2700 micrograms per day.

Participants / model
58 retail dietary supplement products, not a clinical population
Treatment
Oral dietary supplement products purchased online
Follow-up
Products purchased from 2017 to 2018
Study design
FDA laboratory analysis of retail products
Funding
not stated in the source

Content per maximum daily serving as measured, not a recommendation. The survey measured the two isomers separately.

Read the original source

Why does T2 sit in D tier?

Two people in one uncontrolled report, contradictory rodent studies and no controlled human data place it at D. The claim of less thyroid-axis suppression than T3 is undercut by the animal studies that examined the axis.

The published human record is two people in one uncontrolled report. The rodent record is contradictory: about 50% less fat mass with no thyroid hormone change in one rat study, no effect on weight, adiposity or liver fat in an independent rat study, dose-dependent TSH, T3 and T4 reductions in a 90-day rat study, and T3-like feedback with enlarged hearts and no significant weight loss in mice.

The supplier's differentiating claim, less thyroid-axis suppression than T3, is the entire reason to choose T2 over an approved drug, and the animal studies that examined the axis found suppression. The claims go further than the data.

Two euthyroid volunteers: resting metabolic rate up, weight down about 4%, free T3, free T4 and TSH unchanged

Human study

Antonelli A et al. J Biol Regul Homeost Agents. 2011;25(4):655-60. PMID 22217997.

Two euthyroid subjects volunteered to undergo T2 administration, with body weight, BMI, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3, free T4, T2, TSH and resting metabolic rate measured at baseline and at the end of treatment. Resting metabolic rate increased significantly in each subject. After continuing T2 for a further 3 weeks at 300 micrograms per day, body weight was reduced significantly (p<0.05), by about 4%, while serum free T3, free T4 and TSH were unchanged. No side effects were observed at the cardiac level in either subject, and no significant change was observed in the same subjects taking placebo.

Participants / model
2 euthyroid human volunteers
Treatment
Oral T2, 300 micrograms per day for a further 3 weeks
Follow-up
A further 3 weeks after the initial treatment period
Study design
Two-person human report, not a randomized trial
Funding
not stated in the source

The report has no randomization, no blinding and no power to detect an effect, so it cannot establish metabolic or safety effects of T2.

Read the original source
Rats on a high-fat diet: about 50% less fat mass, no change in thyroid hormones or TSH

Animal study

Lanni A et al. FASEB J. 2005;19(11):1552-4. PMID 16014396.

T2 given to rats on a high-fat diet reduced both adiposity and body weight gain without inducing thyrotoxicity. Compared with rats on the high-fat diet alone, rats receiving the diet plus T2 showed a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, approximately 50% less fat mass, a complete disappearance of fat from the liver, and reductions in serum triglyceride and cholesterol of 52% and 18%. Thyroid hormone and TSH serum levels were not influenced. The mechanism involved the carnitine palmitoyltransferase system and mitochondrial uncoupling. The authors state that the results do not exclude deleterious effects of T2 on a longer time scale and do not show that T2 acts in the same way in humans.

Participants / model
Rats receiving a high-fat diet
Treatment
T2 administration; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route, so no comparison with human exposure is possible.

Read the original source
Sprague Dawley rats: no effect on weight, adiposity, liver fat or insulin sensitivity

Animal study

Vatner DF et al. PLoS One. 2015;10(10):e0140837. PMID 26485433.

Male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 at 0.25 mg/kg per day or vehicle. Neither 10 nor 30 days of T2 had an effect on weight, adiposity, plasma fatty acids or hepatic steatosis. A hyperinsulinemic-euglycemic clamp found no difference in fasting plasma glucose or insulin, no change in basal endogenous glucose production, and no difference in insulin-stimulated whole body glucose disposal. Insulin suppressed endogenous glucose production by 60 +/- 10% in T2-treated rats versus 47 +/- 4% in vehicle (p=0.32). Insulin-stimulated Akt phosphorylation was about 2.5-fold greater in the T2 group (p=0.003), a signaling change without a matching whole-body effect. No change was seen in the genes said to mediate T2's hepatic action. The authors conclude that, in contrast with previous reports, T2 failed to improve NAFLD or whole body insulin sensitivity.

Participants / model
Male Sprague Dawley rats on a safflower-oil high-fat diet
Treatment
T2, 0.25 mg/kg per day, or vehicle; route not stated in the abstract
Follow-up
10 and 30 days
Study design
Original animal study
Funding
not stated in the source

An independent rodent attempt with a null result. The abstract does not state the route.

Read the original source
Wistar rats, 90 days: dose-dependent fall in TSH, T3 and T4, fat pad mass reduced

Animal study

Padron AS et al. J Endocrinol. 2014;221(3):415-27. PMID 24692290.

Wistar rats were treated daily with T2 at 25, 50 or 75 micrograms per 100 g body weight subcutaneously for 90 days, from 3 to 6 months of age. T2 suppressed thyroid function, reducing thyroid iodide uptake, thyroperoxidase, NADPH oxidase 4 and type 1 iodothyronine deiodinase activity and expression. Serum TSH, T3 and T4 were reduced in a dose-dependent manner. Oxygen consumption increased, and after 3 months body mass and retroperitoneal fat pad mass were significantly reduced, while heart rate and heart mass were unchanged. The authors conclude that TSH suppression may develop secondary to T2 administration.

Participants / model
Wistar rats, 3 to 6 months of age
Treatment
Subcutaneous T2, 25, 50 or 75 micrograms per 100 g body weight daily
Follow-up
90 days
Study design
Original animal study
Funding
not stated in the source

Rodent findings. This study contradicts the claim that T2 spares the thyroid axis.

Read the original source
Obese mice: T3-like axis feedback, lower T4 and T3, enlarged hearts, no significant weight loss

Animal study

Jonas W et al. Endocrinology. 2015;156(1):389-99. PMID 25322465.

In diet-induced obese male C57BL/6J mice, T2 produced dose-dependent thyromimetic effects akin to those of T3. It exerted negative feedback on the hypothalamus-pituitary-thyroid axis similar to T3, shown by decreased expression of thyroid-hormone-responsive genes in pituitary and a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver. Hepatic thyroid hormone target genes showed T3-like changes, and type I deiodinase activity increased at 2.5 micrograms per gram body weight. Hepatic triglyceride and serum cholesterol fell. The increase in metabolic rate and reduction of fat depots were compromised by increased food intake, which prevented significant body weight loss. Enlarged heart weights indicate potential cardiac side effects. The authors wrote that these findings raise concern about indiscriminate administration of T2.

Participants / model
Diet-induced obese male C57BL/6J mice
Treatment
T2 administration including 2.5 micrograms per gram body weight; route not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route.

Read the original source

Studies and sources

PubChem CID 92859: C15H13I2NO4, 525.08 g/mol; isomer caution

Chemical identity record

National Library of Medicine. PubChem compound record CID 92859 (3,5-diiodo-L-thyronine).

3,5-diiodo-L-thyronine: PubChem CID 92859, C15H13I2NO4, 525.08 g/mol, CAS 1041-01-6. Listed synonyms include diiodo-L-thyronine and L-3,5-diiodothyronine. 3,5-T2 and 3,3'-diiodothyronine (3,3'-T2) are different positional isomers with the same formula and were measured as separate analytes in the FDA supplement survey. A product labeled only 'T2' or 'diiodothyronine' does not specify which isomer it contains.

Participants / model
Chemical identity, not a clinical population
Treatment
Defined molecule, no approved formulation
Follow-up
Not applicable
Study design
NLM chemical record
Funding
not stated in the source

Identity record only; it says nothing about efficacy or safety.

Read the original source
Drugs@FDA: no T2 application; T3 (CYTOMEL) approved 8 May 1956

Regulatory record

U.S. Food and Drug Administration. Drugs@FDA application record for NDA 010379 (CYTOMEL, liothyronine sodium), with generic liothyronine applications, and an openFDA exact-name query for 3,5-diiodothyronine run on 9 October 2026. Dates read from the openFDA Drugs@FDA records.

An openFDA Drugs@FDA exact-name query for 3,5-diiodothyronine returned no matching application on 9 October 2026. The same database returns CYTOMEL (liothyronine sodium, T3) under NDA 010379 approved 8 May 1956, plus multiple generic liothyronine applications. The drug that sellers offer T2 as a gentler alternative to has been an approved prescription medicine for 70 years with a label; T2 has neither an approval nor a label.

Participants / model
FDA application database, not a clinical population
Treatment
Exact substance-name searches
Follow-up
Query run on 9 October 2026
Study design
FDA application records and database query
Funding
not stated in the source

A US-scoped search result. The record shown is for T3, the comparator, not for T2.

Read the original source
Two euthyroid volunteers: resting metabolic rate up, weight down about 4%, free T3, free T4 and TSH unchanged

Human study

Antonelli A et al. J Biol Regul Homeost Agents. 2011;25(4):655-60. PMID 22217997.

Two euthyroid subjects volunteered to undergo T2 administration, with body weight, BMI, blood pressure, heart rate, electrocardiogram, thyroid and liver ultrasonography, glycemia, total cholesterol, triglycerides, free T3, free T4, T2, TSH and resting metabolic rate measured at baseline and at the end of treatment. Resting metabolic rate increased significantly in each subject. After continuing T2 for a further 3 weeks at 300 micrograms per day, body weight was reduced significantly (p<0.05), by about 4%, while serum free T3, free T4 and TSH were unchanged. No side effects were observed at the cardiac level in either subject, and no significant change was observed in the same subjects taking placebo.

Participants / model
2 euthyroid human volunteers
Treatment
Oral T2, 300 micrograms per day for a further 3 weeks
Follow-up
A further 3 weeks after the initial treatment period
Study design
Two-person human report, not a randomized trial
Funding
not stated in the source

The report has no randomization, no blinding and no power to detect an effect, so it cannot establish metabolic or safety effects of T2.

Read the original source
Rats on a high-fat diet: about 50% less fat mass, no change in thyroid hormones or TSH

Animal study

Lanni A et al. FASEB J. 2005;19(11):1552-4. PMID 16014396.

T2 given to rats on a high-fat diet reduced both adiposity and body weight gain without inducing thyrotoxicity. Compared with rats on the high-fat diet alone, rats receiving the diet plus T2 showed a 13% lower body weight, a 42% higher liver fatty acid oxidation rate, approximately 50% less fat mass, a complete disappearance of fat from the liver, and reductions in serum triglyceride and cholesterol of 52% and 18%. Thyroid hormone and TSH serum levels were not influenced. The mechanism involved the carnitine palmitoyltransferase system and mitochondrial uncoupling. The authors state that the results do not exclude deleterious effects of T2 on a longer time scale and do not show that T2 acts in the same way in humans.

Participants / model
Rats receiving a high-fat diet
Treatment
T2 administration; route and dose not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route, so no comparison with human exposure is possible.

Read the original source
Wistar rats, 90 days: dose-dependent fall in TSH, T3 and T4, fat pad mass reduced

Animal study

Padron AS et al. J Endocrinol. 2014;221(3):415-27. PMID 24692290.

Wistar rats were treated daily with T2 at 25, 50 or 75 micrograms per 100 g body weight subcutaneously for 90 days, from 3 to 6 months of age. T2 suppressed thyroid function, reducing thyroid iodide uptake, thyroperoxidase, NADPH oxidase 4 and type 1 iodothyronine deiodinase activity and expression. Serum TSH, T3 and T4 were reduced in a dose-dependent manner. Oxygen consumption increased, and after 3 months body mass and retroperitoneal fat pad mass were significantly reduced, while heart rate and heart mass were unchanged. The authors conclude that TSH suppression may develop secondary to T2 administration.

Participants / model
Wistar rats, 3 to 6 months of age
Treatment
Subcutaneous T2, 25, 50 or 75 micrograms per 100 g body weight daily
Follow-up
90 days
Study design
Original animal study
Funding
not stated in the source

Rodent findings. This study contradicts the claim that T2 spares the thyroid axis.

Read the original source
Obese mice: T3-like axis feedback, lower T4 and T3, enlarged hearts, no significant weight loss

Animal study

Jonas W et al. Endocrinology. 2015;156(1):389-99. PMID 25322465.

In diet-induced obese male C57BL/6J mice, T2 produced dose-dependent thyromimetic effects akin to those of T3. It exerted negative feedback on the hypothalamus-pituitary-thyroid axis similar to T3, shown by decreased expression of thyroid-hormone-responsive genes in pituitary and a suppressed thyroid function with lower T4 and T3 concentrations in serum and liver. Hepatic thyroid hormone target genes showed T3-like changes, and type I deiodinase activity increased at 2.5 micrograms per gram body weight. Hepatic triglyceride and serum cholesterol fell. The increase in metabolic rate and reduction of fat depots were compromised by increased food intake, which prevented significant body weight loss. Enlarged heart weights indicate potential cardiac side effects. The authors wrote that these findings raise concern about indiscriminate administration of T2.

Participants / model
Diet-induced obese male C57BL/6J mice
Treatment
T2 administration including 2.5 micrograms per gram body weight; route not stated in the abstract
Follow-up
not stated in the source
Study design
Original animal study
Funding
not stated in the source

Rodent findings. The abstract does not state the route.

Read the original source
Sprague Dawley rats: no effect on weight, adiposity, liver fat or insulin sensitivity

Animal study

Vatner DF et al. PLoS One. 2015;10(10):e0140837. PMID 26485433.

Male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 at 0.25 mg/kg per day or vehicle. Neither 10 nor 30 days of T2 had an effect on weight, adiposity, plasma fatty acids or hepatic steatosis. A hyperinsulinemic-euglycemic clamp found no difference in fasting plasma glucose or insulin, no change in basal endogenous glucose production, and no difference in insulin-stimulated whole body glucose disposal. Insulin suppressed endogenous glucose production by 60 +/- 10% in T2-treated rats versus 47 +/- 4% in vehicle (p=0.32). Insulin-stimulated Akt phosphorylation was about 2.5-fold greater in the T2 group (p=0.003), a signaling change without a matching whole-body effect. No change was seen in the genes said to mediate T2's hepatic action. The authors conclude that, in contrast with previous reports, T2 failed to improve NAFLD or whole body insulin sensitivity.

Participants / model
Male Sprague Dawley rats on a safflower-oil high-fat diet
Treatment
T2, 0.25 mg/kg per day, or vehicle; route not stated in the abstract
Follow-up
10 and 30 days
Study design
Original animal study
Funding
not stated in the source

An independent rodent attempt with a null result. The abstract does not state the route.

Read the original source
2020 review: T2 works in rat models; trial of a synthetic T2 analogue was disappointing

Animal study

Zucchi R. Thyroid. 2020;30(8):1099-1105. PMID 32098589.

A 2020 review states that 3,5-diiodothyronine has been used with success in rat models of dyslipidemia and NAFLD, but that the outcome of a clinical trial with a synthetic T2 analogue was disappointing. The review does not report a controlled clinical trial of T2 itself, and the abstract does not name the analogue, its sponsor or its results.

Participants / model
Rat models and one unnamed clinical trial of a synthetic analogue
Treatment
Not specified in the abstract
Follow-up
not stated in the source
Study design
Narrative review; no controlled trial of T2 itself
Funding
not stated in the source

A summary of development status. The analogue is not identified, so its result is not attributed to T2.

Read the original source
FDA laboratory survey: 58 online supplements, up to 740 micrograms per day of 3,5-T2 and 2700 of 3,3'-T2

Regulatory record

Pawar RS et al. Drug Test Anal. 2022;14(3):578-586. PMID 33855795.

An LC-MS/MS method was developed and validated for T4, T3, reverse T3, 3,5-T2 and 3,3'-T2 in dietary supplements, with recovery between 78 and 116%. Fifty-eight products making thyroid-management claims were purchased over the internet from 2017 to 2018 and analyzed. Eleven of 19 glandular products contained quantifiable amounts of hormones, with maximum daily servings reaching 210 micrograms per day of T4, 32 of T3 and 7.6 of reverse T3. In nonglandular products, labeled to contain plant extracts, vitamins, minerals, diiodo compounds and so forth, the amounts of 3,5-T2 and 3,3'-T2 reached up to 740 and 2700 micrograms per day.

Participants / model
58 retail dietary supplement products, not a clinical population
Treatment
Oral dietary supplement products purchased online
Follow-up
Products purchased from 2017 to 2018
Study design
FDA laboratory analysis of retail products
Funding
not stated in the source

Content per maximum daily serving as measured, not a recommendation. The survey measured the two isomers separately.

Read the original source

Why is 3,5-diiodo-L-thyronine (T2) in D tier?

D fits a compound whose published human record is two people in one uncontrolled report and whose rodent record is contradictory: about 50% less fat mass in one rat study, no effect in an independent rat study, dose-dependent TSH, T3 and T4 reductions in a 90-day rat study, and T3-like axis feedback with enlarged hearts in mice. The claim of less thyroid-axis suppression than T3, the reason to choose T2, is contradicted by the animal studies that examined the axis. The claims go further than the data.