Levothyroxine
Levothyroxine replaces T4 when the thyroid cannot supply enough. That earns its S grade. People with normal thyroid tests have not shown the same energy or cognitive benefit, and persistent symptoms during treatment need more explanation than a normal TSH alone.
Synthetic thyroxine sodium, or T4, used for thyroid-hormone replacement
- Levothyroxine is T4; liothyronine is T3 and has different kinetics.
- The strongest purpose is replacement of documented deficiency, including congenital hypothyroidism.
- Older subclinical-hypothyroidism and later-started pregnancy trials found important null results.
- Food, supplements, drugs, illness, and thyroid state can materially change exposure or interpretation.
What is levothyroxine approved to treat?
Levothyroxine is synthetic T4. The US label covers replacement for primary, secondary, tertiary, congenital, or acquired hypothyroidism and adjunctive TSH suppression in selected differentiated thyroid cancer. Tissues convert T4 to active T3; liothyronine is a separate compound with different kinetics.
US Synthroid label · T4 replacement, PK, boxed warning
FDA prescribing information
AbbVie Inc. SYNTHROID (levothyroxine sodium) tablets. DailyMed setid 1e11ad30-1041-4520-10b0-8f9d30d30fcc. Updated February 20, 2024.
The US label covers thyroid-hormone replacement, including congenital hypothyroidism, and adjunctive TSH suppression in differentiated thyroid cancer. It carries the thyroid-hormone obesity/weight-loss boxed warning; documents 40 to 80% oral absorption, thyroid-state-dependent biological half-life, narrow therapeutic index, and numerous absorption, anticoagulant, diabetes, digoxin, and sympathomimetic interactions; and says suppression is not indicated for benign nodules in iodine-sufficient patients.
- Participants / model
- Adults and pediatric patients, including neonates, with labeled hypothyroid indications; selected differentiated thyroid-cancer patients
- Treatment
- Oral levothyroxine sodium tablets
- Follow-up
- Current product record; initial US Synthroid approval 2002
- Study design
- Regulatory prescribing information
Biological half-life and absorption vary with thyroid state, food, GI conditions, formulation, and interacting products; a label figure is not a universal individual value.
Read the original sourcePubChem CID 5819 · levothyroxine/T4 identity
Government substance database
National Library of Medicine. PubChem Compound Summary for CID 5819, Thyroxine.
Identifies levothyroxine/L-thyroxine/T4 base as C15H11I4NO4, molecular weight 776.87 g/mol, CID 5819.
- Participants / model
- Not applicable
- Treatment
- Not applicable
- Follow-up
- Living database record
- Study design
- Curated chemical identity record
The Synthroid label supplies levothyroxine sodium monohydrate, which has a different formula and molecular weight from T4 base.
Read the original sourceDoes the TRUST null result mean thyroid replacement does not work?
TRUST randomized 737 adults aged 65 or older with persistent subclinical hypothyroidism and normal free T4. At 12 months, levothyroxine lowered TSH to 3.63 versus 5.48 mIU/L, but symptom scores were 16.7 versus 16.6 (adjusted difference 0.0; p=0.99) and tiredness scores were 28.6 versus 28.7 (difference 0.4; p=0.77). Many participants had little symptom burden at baseline, and the trial was not powered for cardiovascular events. It does not answer overt or congenital deficiency.
TRUST · 737 older adults, symptoms null
Randomized double-blind placebo-controlled trial
David J. Stott, Nicolas Rodondi, Patricia M. Kearney, et al.; TRUST Study Group. New England Journal of Medicine. 2017. PMID 28402245.
At 12 months, TSH was 3.63 versus 5.48 mIU/L. Hypothyroid-symptom scores were 16.7 versus 16.6 (adjusted difference 0.0, 95% CI −2.0 to 2.1; p=0.99) and tiredness scores 28.6 versus 28.7 (difference 0.4, 95% CI −2.1 to 2.9; p=0.77).
- Participants / model
- 737 adults aged 65 or older with persistent subclinical hypothyroidism and normal free T4
- Treatment
- Levothyroxine with laboratory-guided adjustment versus mock-adjusted placebo
- Follow-up
- 1 year for primary outcomes
- Study design
- Randomized double-blind placebo-controlled parallel-group trial
- Funding
- European Union Seventh Framework Programme and public/institutional funders; Merck supplied study tablets without a trial-management role
Mostly mild biochemical disease with low baseline symptom burden; 638 had 12-month primary data. The study was not powered for cardiovascular events or mortality and does not address overt or congenital hypothyroidism.
Read the original sourceUS Synthroid label · T4 replacement, PK, boxed warning
FDA prescribing information
AbbVie Inc. SYNTHROID (levothyroxine sodium) tablets. DailyMed setid 1e11ad30-1041-4520-10b0-8f9d30d30fcc. Updated February 20, 2024.
The US label covers thyroid-hormone replacement, including congenital hypothyroidism, and adjunctive TSH suppression in differentiated thyroid cancer. It carries the thyroid-hormone obesity/weight-loss boxed warning; documents 40 to 80% oral absorption, thyroid-state-dependent biological half-life, narrow therapeutic index, and numerous absorption, anticoagulant, diabetes, digoxin, and sympathomimetic interactions; and says suppression is not indicated for benign nodules in iodine-sufficient patients.
- Participants / model
- Adults and pediatric patients, including neonates, with labeled hypothyroid indications; selected differentiated thyroid-cancer patients
- Treatment
- Oral levothyroxine sodium tablets
- Follow-up
- Current product record; initial US Synthroid approval 2002
- Study design
- Regulatory prescribing information
Biological half-life and absorption vary with thyroid state, food, GI conditions, formulation, and interacting products; a label figure is not a universal individual value.
Read the original sourceDid later-started treatment improve children's cognition?
Two separate trials randomized 677 women with subclinical hypothyroidism and 526 with hypothyroxinemia after adherence run-in, at mean 16.7 and 17.8 gestational weeks. Median child IQ was 97 versus 94 in the first trial (p=0.71) and 94 versus 91 in the second (p=0.30); pregnancy, neonatal, and other neurocognitive outcomes were also null. Overt disease, preconception treatment, and materially earlier initiation were outside the design.
Two pregnancy trials · child cognition null
Two randomized double-blind placebo-controlled trials
Brian M. Casey, Elizabeth A. Thom, Alan M. Peaceman, et al.; NICHD Maternal to Fetal Medicine Units Network. New England Journal of Medicine. 2017. PMID 28249134.
The subclinical-hypothyroidism trial randomized 677 and had primary child-IQ data for 649; median IQ was 97 versus 94 (p=0.71). The hypothyroxinemia trial randomized 526 and had data for 507; IQ was 94 versus 91 (p=0.30). Pregnancy, neonatal, and other neurocognitive outcomes were null.
- Participants / model
- 1,203 pregnant women across separate subclinical-hypothyroidism and hypothyroxinemia trials
- Treatment
- Laboratory-adjusted levothyroxine versus sham-adjusted placebo
- Follow-up
- Monthly pregnancy monitoring; children tested through 5 years
- Study design
- Two randomized double-blind placebo-controlled multicenter trials
- Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
Randomization occurred at mean 16.7 and 17.8 gestational weeks after adherence run-in. Overt disease and treatment before conception or materially earlier in pregnancy were not tested; many secondary comparisons were nominal.
Read the original sourceWhat if symptoms remain on T4?
Persistent symptoms are real, but trials do not show that everyone benefits from adding or switching to T3. Selected symptomatic patients have shown improvements, with important limits.
In a nonblinded crossover of 59 women with residual symptoms, 47 completed both treatments. T3 improved several fatigue and disease-specific scores versus T4, including a 4.4-point difference in total fatigue. Five women withdrew for symptoms on T3 versus one on T4. Selection, expectation and incomplete follow-up make blinded confirmation important.
A 2025 combination trial randomized 158 people and analyzed 151 after seven combination-arm withdrawals. Physical function and pain subscales favored T4/T3; overall physical and mental summary scores and weight did not. Several registration and statistical details were internally inconsistent.
A separate 2025 study after thyroidectomy randomized 13 and analyzed 12. Hormone concentrations changed, but weight, lipid and quality-of-life differences were nonsignificant. Earlier whole-group comparisons were also mixed. These results do not validate a treatment rule based only on reverse T3 or DIO2 genotype.
Bjerkreim et al., selected symptomatic women crossing T4 and T3
Randomized controlled human trial
Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Omdal LJ, Lee-Ødegård S, Eriksen EF. Effect of Liothyronine Treatment on Quality of Life in Female Hypothyroid Patients With Residual Symptoms on Levothyroxine Therapy: A Randomized Crossover Study. Frontiers in endocrinology. 2022. DOI 10.3389/fendo.2022.816566.
Fifty-nine women with residual symptoms were randomized to nonblinded 12-week T4/T3-monotherapy periods; 47 completed both. T3 improved several disease-specific and fatigue measures versus T4. The between-treatment total-fatigue difference was −4.4 points; not all SF-36 domains differed. Five withdrew for symptoms on T3 versus one on T4. Expectation bias, recruitment of dissatisfied patients, no blinding and incomplete follow-up matter. The selected symptomatic population and open design limit the result’s applicability to other patients.
- Study design
- Randomized controlled trial; blinding and comparator details are stated in the source result.
2025 Iranian randomized combination trial
Randomized controlled human trial
Hajtalebi F, Alaei-Shahmiri F, Golgiri F, Shahini N, Akbari H, Assadian K, Mosalamiaghili S. Early effects of LT3 + LT4 combination therapy on quality of life in hypothyroid patients: a randomized, double-blind, parallel-group comparison trial. BMC endocrine disorders. 2025. DOI 10.1186/s12902-025-01840-4.
The abstract describes 151 participants, while the full report says 158 randomized and 151 analyzed after seven combination-arm withdrawals. At six months, physical-function and bodily-pain subscales favored combination treatment, but overall physical and mental summary comparisons were nonsignificant (p=.07 and .84), with no weight advantage. Multiple subscales and inconsistencies in registration dates and confidence-interval reporting constrain interpretation. It supplies mixed evidence, not blanket combination superiority.
- Study design
- Randomized controlled trial; blinding and comparator details are stated in the source result.
Phan et al., 2025 postsurgical feasibility trial
Primary human study
Phan et al., 2025 postsurgical feasibility trial. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1522753/full
Thirteen people were randomized and 12 analyzed after total thyroidectomy. Combination therapy altered circulating T3/T4 measures, but weight, lipid and quality-of-life between-group results were not significant. The feasibility sample used last-observation carry-forward without multiplicity correction and had COVID-era recruitment disruption.
Read the original source46 hypothyroid patients · combination therapy null
Randomized double-blind placebo-controlled trial
Patrick W. Clyde, Amir E. Harari, Eric J. Getka, and K. M. Mohamed Shakir. JAMA. 2003. PMID 14665656.
Forty-six were randomized and 44 analyzed. Hypothyroid quality-of-life scores improved in both groups but did not differ (p=0.54); body weight, lipids, heart rate, and blood pressure were unchanged. Twelve of 13 cognitive tests were null and the remaining pegboard test favored levothyroxine alone.
- Participants / model
- 46 adults with primary hypothyroidism randomized; 44 analyzed
- Treatment
- Levothyroxine/liothyronine combination versus continued levothyroxine
- Follow-up
- 4 months
- Study design
- Randomized double-blind placebo-controlled trial
- Funding
- National Naval Medical Center institutional support
Single military facility, selected stable patients, self-reported adherence without pill counts, and one combination strategy. One combination participant withdrew with tremor, fatigue, and work impairment despite normal laboratory values.
Read the original sourceThree-way crossover · 75 completers, whole-group null
Prospective randomized double-blind three-period crossover trial
K. M. Mohamed Shakir, David I. Brooks, Elizabeth A. McAninch, et al. Journal of Clinical Endocrinology & Metabolism. 2021;106(11):e4400 to e4413. PMID 34185829.
Ninety enrolled and 75 completed all three 22-week periods. Whole-group thyroid symptoms, general health, depression, memory, weight, lipids, and preference did not differ among T4, T4/T3, and desiccated thyroid; the latter raised heart rate by 2.2 beats/min. A most-symptomatic-third analysis was post hoc.
- Participants / model
- 90 military-health-system beneficiaries aged 18 to 65 with primary hypothyroidism; 75 completed; 77% women and 77% White among completers
- Treatment
- Levothyroxine, levothyroxine/liothyronine, and desiccated thyroid in randomized crossover order with TSH adjustment
- Follow-up
- Three 22-week treatment periods
- Study design
- Prospective randomized double-blind three-period crossover trial
- Funding
- Walter Reed National Military Medical Center Institutional Research Board
Fifteen withdrew before randomization because of relocation or time constraints. Cardiac disease and several common comorbidities/medications were excluded. The symptomatic-third result was post hoc and vulnerable to regression to the mean.
Read the original sourceWhy does the Chinese nodule study not create a US indication?
The Chinese publisher abstract reports smaller nodule and thyroid-volume measures after 12 months in 62 treated versus 62 observed patients, with lower TSH and higher free T4. The abstract does not report full methods or patient-important outcomes. The current US label excludes benign-nodule suppression in iodine-sufficient patients because clinical benefit is unproven and over-treatment can cause hyperthyroidism.
Chinese abstract · benign-nodule suppression surrogates
Chinese randomized clinical study
李杰宝. 海南医学院学报. 2015;21(1):41 to 43. DOI 10.13210/j.cnki.jhmu.20141028.014.
The publisher's Chinese and translated English abstracts report 124 patients randomized 62 per group to low-dose levothyroxine or observation for 12 months. Nodule cross-sectional diameter and thyroid volume were smaller, TSH lower, and free T4 higher in the treatment group.
- Participants / model
- 124 patients with benign thyroid nodules
- Treatment
- Levothyroxine suppression versus clinical follow-up without drug
- Follow-up
- 12 months
- Study design
- Randomized two-group clinical study reported in abstract
- Funding
- Wuhan municipal science and technology plan listed on publisher page
The Chinese and publisher-translated abstracts do not report blinding, allocation concealment, attrition, detailed adverse events, or patient-important outcomes. Current U.S. labeling says suppression is not indicated for benign nodules in iodine-sufficient patients.
Read the original sourceUS Synthroid label · T4 replacement, PK, boxed warning
FDA prescribing information
AbbVie Inc. SYNTHROID (levothyroxine sodium) tablets. DailyMed setid 1e11ad30-1041-4520-10b0-8f9d30d30fcc. Updated February 20, 2024.
The US label covers thyroid-hormone replacement, including congenital hypothyroidism, and adjunctive TSH suppression in differentiated thyroid cancer. It carries the thyroid-hormone obesity/weight-loss boxed warning; documents 40 to 80% oral absorption, thyroid-state-dependent biological half-life, narrow therapeutic index, and numerous absorption, anticoagulant, diabetes, digoxin, and sympathomimetic interactions; and says suppression is not indicated for benign nodules in iodine-sufficient patients.
- Participants / model
- Adults and pediatric patients, including neonates, with labeled hypothyroid indications; selected differentiated thyroid-cancer patients
- Treatment
- Oral levothyroxine sodium tablets
- Follow-up
- Current product record; initial US Synthroid approval 2002
- Study design
- Regulatory prescribing information
Biological half-life and absorption vary with thyroid state, food, GI conditions, formulation, and interacting products; a label figure is not a universal individual value.
Read the original sourceWhy does levothyroxine exposure vary so much?
Only 40 to 80 percent of an oral amount may be absorbed, mainly in the upper small intestine. Food, gastric conditions, formulation, and binding or chelating products change that. The biological half-life is about 6 to 7 days when euthyroid, shorter in hyperthyroidism and longer in hypothyroidism, so steady-state changes are slow and thyroid-state dependent.
US Synthroid label · T4 replacement, PK, boxed warning
FDA prescribing information
AbbVie Inc. SYNTHROID (levothyroxine sodium) tablets. DailyMed setid 1e11ad30-1041-4520-10b0-8f9d30d30fcc. Updated February 20, 2024.
The US label covers thyroid-hormone replacement, including congenital hypothyroidism, and adjunctive TSH suppression in differentiated thyroid cancer. It carries the thyroid-hormone obesity/weight-loss boxed warning; documents 40 to 80% oral absorption, thyroid-state-dependent biological half-life, narrow therapeutic index, and numerous absorption, anticoagulant, diabetes, digoxin, and sympathomimetic interactions; and says suppression is not indicated for benign nodules in iodine-sufficient patients.
- Participants / model
- Adults and pediatric patients, including neonates, with labeled hypothyroid indications; selected differentiated thyroid-cancer patients
- Treatment
- Oral levothyroxine sodium tablets
- Follow-up
- Current product record; initial US Synthroid approval 2002
- Study design
- Regulatory prescribing information
Biological half-life and absorption vary with thyroid state, food, GI conditions, formulation, and interacting products; a label figure is not a universal individual value.
Read the original sourceWhich everyday products can disrupt absorption?
Calcium, iron, antacids, bile-acid sequestrants, sevelamer, sucralfate, proton-pump inhibitors, food, and certain enteral products can lower or destabilize absorption. Levothyroxine can also change anticoagulant, diabetes-medication, and digoxin requirements. Biotin can distort thyroid assays, creating a measurement problem even when exposure itself has not changed.
US Synthroid label · T4 replacement, PK, boxed warning
FDA prescribing information
AbbVie Inc. SYNTHROID (levothyroxine sodium) tablets. DailyMed setid 1e11ad30-1041-4520-10b0-8f9d30d30fcc. Updated February 20, 2024.
The US label covers thyroid-hormone replacement, including congenital hypothyroidism, and adjunctive TSH suppression in differentiated thyroid cancer. It carries the thyroid-hormone obesity/weight-loss boxed warning; documents 40 to 80% oral absorption, thyroid-state-dependent biological half-life, narrow therapeutic index, and numerous absorption, anticoagulant, diabetes, digoxin, and sympathomimetic interactions; and says suppression is not indicated for benign nodules in iodine-sufficient patients.
- Participants / model
- Adults and pediatric patients, including neonates, with labeled hypothyroid indications; selected differentiated thyroid-cancer patients
- Treatment
- Oral levothyroxine sodium tablets
- Follow-up
- Current product record; initial US Synthroid approval 2002
- Study design
- Regulatory prescribing information
Biological half-life and absorption vary with thyroid state, food, GI conditions, formulation, and interacting products; a label figure is not a universal individual value.
Read the original sourceWhat does thyroid-hormone-driven weight loss represent?
The boxed warning says not to use levothyroxine for obesity or weight loss. Excess exposure can cause angina, arrhythmia, myocardial infarction, bone loss, muscle wasting, and metabolic stress. In the Russian rat study, levothyroxine created hyperthyroidism and changed kidney blood flow, filtration, protein loss, electrolyte handling, and oxidative markers. The study measured systemic overexposure and included no selective fat-loss endpoint.
US Synthroid label · T4 replacement, PK, boxed warning
FDA prescribing information
AbbVie Inc. SYNTHROID (levothyroxine sodium) tablets. DailyMed setid 1e11ad30-1041-4520-10b0-8f9d30d30fcc. Updated February 20, 2024.
The US label covers thyroid-hormone replacement, including congenital hypothyroidism, and adjunctive TSH suppression in differentiated thyroid cancer. It carries the thyroid-hormone obesity/weight-loss boxed warning; documents 40 to 80% oral absorption, thyroid-state-dependent biological half-life, narrow therapeutic index, and numerous absorption, anticoagulant, diabetes, digoxin, and sympathomimetic interactions; and says suppression is not indicated for benign nodules in iodine-sufficient patients.
- Participants / model
- Adults and pediatric patients, including neonates, with labeled hypothyroid indications; selected differentiated thyroid-cancer patients
- Treatment
- Oral levothyroxine sodium tablets
- Follow-up
- Current product record; initial US Synthroid approval 2002
- Study design
- Regulatory prescribing information
Biological half-life and absorption vary with thyroid state, food, GI conditions, formulation, and interacting products; a label figure is not a universal individual value.
Read the original sourceRussian study · levothyroxine-induced hyperthyroidism in rats
Russian preclinical animal study
I. G. Dzhioev, A. R. Nanieva, I. A. Khutugova, D. T. Berezova, and M. R. Buzoeva. Современные проблемы науки и образования. 2023;(3):91. DOI 10.17513/spno.32594.
Forty-four Wistar rats underwent baseline study; 34 then received dissolved levothyroxine tablets for 14 days to create hyperthyroidism. Free T3 and T4 rose, and renal blood flow, filtration, diuresis, proteinuria, electrolyte handling, and oxidative-stress markers changed.
- Participants / model
- 44 Wistar rats at baseline; 34 entered the levothyroxine hyperthyroidism phase
- Treatment
- Daily levothyroxine sodium suspension; the readable methods describe preparation but do not explicitly name the administration route
- Follow-up
- 14 days
- Study design
- Within-animal baseline comparison with nested renal physiology experiments
This induced-hyperthyroidism rat study had no randomized parallel placebo group; it is not therapeutic evidence or a weight-loss experiment.
Read the original sourceDoes T4 improve energy when thyroid tests are normal?
In a small placebo-controlled crossover, T4 did not improve cognitive or psychological outcomes in symptomatic people whose thyroid tests were in range. Replacement for confirmed deficiency is a separate clinical use.
Twenty-five symptomatic patients with thyroid tests in range and 19 controls entered a blinded crossover; 22 patients and all controls completed. Twelve-week T4 periods did not outperform placebo. Healthy controls reported lower vitality on T4, 60 versus 73. The study is small, but it tests the normal-labs claim directly.
Pollock et al., normal-thyroid-test symptoms and healthy controls
Randomized controlled human trial
Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, McLaren EH. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ (Clinical research ed.). 2001. DOI 10.1136/bmj.323.7318.891.
Twenty-five symptomatic patients with thyroid tests in range and 19 controls entered a blinded placebo crossover; 22 patients and all controls completed. Twelve-week T4 periods did not improve cognitive or psychological outcomes versus placebo. Healthy controls' vitality was lower on T4 (60 versus 73; p<.01). The study was small and did not test replacement in confirmed deficiency.
- Study design
- Randomized controlled trial; blinding and comparator details are stated in the source result.
Primary abstract and metadata
Read the original sourceStudies and sources
US Synthroid label · T4 replacement, PK, boxed warning
FDA prescribing information
AbbVie Inc. SYNTHROID (levothyroxine sodium) tablets. DailyMed setid 1e11ad30-1041-4520-10b0-8f9d30d30fcc. Updated February 20, 2024.
The US label covers thyroid-hormone replacement, including congenital hypothyroidism, and adjunctive TSH suppression in differentiated thyroid cancer. It carries the thyroid-hormone obesity/weight-loss boxed warning; documents 40 to 80% oral absorption, thyroid-state-dependent biological half-life, narrow therapeutic index, and numerous absorption, anticoagulant, diabetes, digoxin, and sympathomimetic interactions; and says suppression is not indicated for benign nodules in iodine-sufficient patients.
- Participants / model
- Adults and pediatric patients, including neonates, with labeled hypothyroid indications; selected differentiated thyroid-cancer patients
- Treatment
- Oral levothyroxine sodium tablets
- Follow-up
- Current product record; initial US Synthroid approval 2002
- Study design
- Regulatory prescribing information
Biological half-life and absorption vary with thyroid state, food, GI conditions, formulation, and interacting products; a label figure is not a universal individual value.
Read the original sourceTRUST · 737 older adults, symptoms null
Randomized double-blind placebo-controlled trial
David J. Stott, Nicolas Rodondi, Patricia M. Kearney, et al.; TRUST Study Group. New England Journal of Medicine. 2017. PMID 28402245.
At 12 months, TSH was 3.63 versus 5.48 mIU/L. Hypothyroid-symptom scores were 16.7 versus 16.6 (adjusted difference 0.0, 95% CI −2.0 to 2.1; p=0.99) and tiredness scores 28.6 versus 28.7 (difference 0.4, 95% CI −2.1 to 2.9; p=0.77).
- Participants / model
- 737 adults aged 65 or older with persistent subclinical hypothyroidism and normal free T4
- Treatment
- Levothyroxine with laboratory-guided adjustment versus mock-adjusted placebo
- Follow-up
- 1 year for primary outcomes
- Study design
- Randomized double-blind placebo-controlled parallel-group trial
- Funding
- European Union Seventh Framework Programme and public/institutional funders; Merck supplied study tablets without a trial-management role
Mostly mild biochemical disease with low baseline symptom burden; 638 had 12-month primary data. The study was not powered for cardiovascular events or mortality and does not address overt or congenital hypothyroidism.
Read the original sourceTwo pregnancy trials · child cognition null
Two randomized double-blind placebo-controlled trials
Brian M. Casey, Elizabeth A. Thom, Alan M. Peaceman, et al.; NICHD Maternal to Fetal Medicine Units Network. New England Journal of Medicine. 2017. PMID 28249134.
The subclinical-hypothyroidism trial randomized 677 and had primary child-IQ data for 649; median IQ was 97 versus 94 (p=0.71). The hypothyroxinemia trial randomized 526 and had data for 507; IQ was 94 versus 91 (p=0.30). Pregnancy, neonatal, and other neurocognitive outcomes were null.
- Participants / model
- 1,203 pregnant women across separate subclinical-hypothyroidism and hypothyroxinemia trials
- Treatment
- Laboratory-adjusted levothyroxine versus sham-adjusted placebo
- Follow-up
- Monthly pregnancy monitoring; children tested through 5 years
- Study design
- Two randomized double-blind placebo-controlled multicenter trials
- Funding
- Eunice Kennedy Shriver National Institute of Child Health and Human Development
Randomization occurred at mean 16.7 and 17.8 gestational weeks after adherence run-in. Overt disease and treatment before conception or materially earlier in pregnancy were not tested; many secondary comparisons were nominal.
Read the original source46 hypothyroid patients · combination therapy null
Randomized double-blind placebo-controlled trial
Patrick W. Clyde, Amir E. Harari, Eric J. Getka, and K. M. Mohamed Shakir. JAMA. 2003. PMID 14665656.
Forty-six were randomized and 44 analyzed. Hypothyroid quality-of-life scores improved in both groups but did not differ (p=0.54); body weight, lipids, heart rate, and blood pressure were unchanged. Twelve of 13 cognitive tests were null and the remaining pegboard test favored levothyroxine alone.
- Participants / model
- 46 adults with primary hypothyroidism randomized; 44 analyzed
- Treatment
- Levothyroxine/liothyronine combination versus continued levothyroxine
- Follow-up
- 4 months
- Study design
- Randomized double-blind placebo-controlled trial
- Funding
- National Naval Medical Center institutional support
Single military facility, selected stable patients, self-reported adherence without pill counts, and one combination strategy. One combination participant withdrew with tremor, fatigue, and work impairment despite normal laboratory values.
Read the original sourceChinese abstract · benign-nodule suppression surrogates
Chinese randomized clinical study
李杰宝. 海南医学院学报. 2015;21(1):41 to 43. DOI 10.13210/j.cnki.jhmu.20141028.014.
The publisher's Chinese and translated English abstracts report 124 patients randomized 62 per group to low-dose levothyroxine or observation for 12 months. Nodule cross-sectional diameter and thyroid volume were smaller, TSH lower, and free T4 higher in the treatment group.
- Participants / model
- 124 patients with benign thyroid nodules
- Treatment
- Levothyroxine suppression versus clinical follow-up without drug
- Follow-up
- 12 months
- Study design
- Randomized two-group clinical study reported in abstract
- Funding
- Wuhan municipal science and technology plan listed on publisher page
The Chinese and publisher-translated abstracts do not report blinding, allocation concealment, attrition, detailed adverse events, or patient-important outcomes. Current U.S. labeling says suppression is not indicated for benign nodules in iodine-sufficient patients.
Read the original sourceRussian study · levothyroxine-induced hyperthyroidism in rats
Russian preclinical animal study
I. G. Dzhioev, A. R. Nanieva, I. A. Khutugova, D. T. Berezova, and M. R. Buzoeva. Современные проблемы науки и образования. 2023;(3):91. DOI 10.17513/spno.32594.
Forty-four Wistar rats underwent baseline study; 34 then received dissolved levothyroxine tablets for 14 days to create hyperthyroidism. Free T3 and T4 rose, and renal blood flow, filtration, diuresis, proteinuria, electrolyte handling, and oxidative-stress markers changed.
- Participants / model
- 44 Wistar rats at baseline; 34 entered the levothyroxine hyperthyroidism phase
- Treatment
- Daily levothyroxine sodium suspension; the readable methods describe preparation but do not explicitly name the administration route
- Follow-up
- 14 days
- Study design
- Within-animal baseline comparison with nested renal physiology experiments
This induced-hyperthyroidism rat study had no randomized parallel placebo group; it is not therapeutic evidence or a weight-loss experiment.
Read the original sourcePubChem CID 5819 · levothyroxine/T4 identity
Government substance database
National Library of Medicine. PubChem Compound Summary for CID 5819, Thyroxine.
Identifies levothyroxine/L-thyroxine/T4 base as C15H11I4NO4, molecular weight 776.87 g/mol, CID 5819.
- Participants / model
- Not applicable
- Treatment
- Not applicable
- Follow-up
- Living database record
- Study design
- Curated chemical identity record
The Synthroid label supplies levothyroxine sodium monohydrate, which has a different formula and molecular weight from T4 base.
Read the original sourceThree-way crossover · 75 completers, whole-group null
Prospective randomized double-blind three-period crossover trial
K. M. Mohamed Shakir, David I. Brooks, Elizabeth A. McAninch, et al. Journal of Clinical Endocrinology & Metabolism. 2021;106(11):e4400 to e4413. PMID 34185829.
Ninety enrolled and 75 completed all three 22-week periods. Whole-group thyroid symptoms, general health, depression, memory, weight, lipids, and preference did not differ among T4, T4/T3, and desiccated thyroid; the latter raised heart rate by 2.2 beats/min. A most-symptomatic-third analysis was post hoc.
- Participants / model
- 90 military-health-system beneficiaries aged 18 to 65 with primary hypothyroidism; 75 completed; 77% women and 77% White among completers
- Treatment
- Levothyroxine, levothyroxine/liothyronine, and desiccated thyroid in randomized crossover order with TSH adjustment
- Follow-up
- Three 22-week treatment periods
- Study design
- Prospective randomized double-blind three-period crossover trial
- Funding
- Walter Reed National Military Medical Center Institutional Research Board
Fifteen withdrew before randomization because of relocation or time constraints. Cardiac disease and several common comorbidities/medications were excluded. The symptomatic-third result was post hoc and vulnerable to regression to the mean.
Read the original sourcePollock et al., normal-thyroid-test symptoms and healthy controls
Randomized controlled human trial
Pollock MA, Sturrock A, Marshall K, Davidson KM, Kelly CJ, McMahon AD, McLaren EH. Thyroxine treatment in patients with symptoms of hypothyroidism but thyroid function tests within the reference range: randomised double blind placebo controlled crossover trial. BMJ (Clinical research ed.). 2001. DOI 10.1136/bmj.323.7318.891.
Twenty-five symptomatic patients with thyroid tests in range and 19 controls entered a blinded placebo crossover; 22 patients and all controls completed. Twelve-week T4 periods did not improve cognitive or psychological outcomes versus placebo. Healthy controls' vitality was lower on T4 (60 versus 73; p<.01). The study was small and did not test replacement in confirmed deficiency.
- Study design
- Randomized controlled trial; blinding and comparator details are stated in the source result.
Primary abstract and metadata
Read the original sourceBjerkreim et al., selected symptomatic women crossing T4 and T3
Randomized controlled human trial
Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Omdal LJ, Lee-Ødegård S, Eriksen EF. Effect of Liothyronine Treatment on Quality of Life in Female Hypothyroid Patients With Residual Symptoms on Levothyroxine Therapy: A Randomized Crossover Study. Frontiers in endocrinology. 2022. DOI 10.3389/fendo.2022.816566.
Fifty-nine women with residual symptoms were randomized to nonblinded 12-week T4/T3-monotherapy periods; 47 completed both. T3 improved several disease-specific and fatigue measures versus T4. The between-treatment total-fatigue difference was −4.4 points; not all SF-36 domains differed. Five withdrew for symptoms on T3 versus one on T4. Expectation bias, recruitment of dissatisfied patients, no blinding and incomplete follow-up matter. The selected symptomatic population and open design limit the result’s applicability to other patients.
- Study design
- Randomized controlled trial; blinding and comparator details are stated in the source result.
2025 Iranian randomized combination trial
Randomized controlled human trial
Hajtalebi F, Alaei-Shahmiri F, Golgiri F, Shahini N, Akbari H, Assadian K, Mosalamiaghili S. Early effects of LT3 + LT4 combination therapy on quality of life in hypothyroid patients: a randomized, double-blind, parallel-group comparison trial. BMC endocrine disorders. 2025. DOI 10.1186/s12902-025-01840-4.
The abstract describes 151 participants, while the full report says 158 randomized and 151 analyzed after seven combination-arm withdrawals. At six months, physical-function and bodily-pain subscales favored combination treatment, but overall physical and mental summary comparisons were nonsignificant (p=.07 and .84), with no weight advantage. Multiple subscales and inconsistencies in registration dates and confidence-interval reporting constrain interpretation. It supplies mixed evidence, not blanket combination superiority.
- Study design
- Randomized controlled trial; blinding and comparator details are stated in the source result.
Phan et al., 2025 postsurgical feasibility trial
Primary human study
Phan et al., 2025 postsurgical feasibility trial. https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1522753/full
Thirteen people were randomized and 12 analyzed after total thyroidectomy. Combination therapy altered circulating T3/T4 measures, but weight, lipid and quality-of-life between-group results were not significant. The feasibility sample used last-observation carry-forward without multiplicity correction and had COVID-era recruitment disruption.
Read the original sourceWhy is Levothyroxine in S tier?
S for replacing missing thyroid hormone. Trials in older adults with mild subclinical disease and people with normal thyroid tests did not show the same symptom benefit. Adding T3 has mixed results.