Thyroxine (T4) is the main hormone made by the thyroid gland. Its synthetic form, levothyroxine sodium, is chemically identical to the hormone the thyroid produces. It is sold as Synthroid, Levoxyl, Unithroid, Tirosint and many generics, and it is the standard treatment for an underactive thyroid (hypothyroidism).
T4 is largely a prohormone. Most of its effect comes after the body strips off one iodine atom and turns it into the more active hormone T3 (liothyronine). Outside medicine, thyroid hormones are misused to speed up fat loss. The single most important fact for that use is printed in a boxed warning on the levothyroxine label: thyroid hormone should not be used for obesity or weight loss, normal replacement doses do not reduce weight in people with a healthy thyroid, and larger doses can cause serious or life-threatening toxicity.
This page summarizes what the FDA label, clinical trials and large cohort studies report. It is for education only and is not medical advice.
| Property | Detail |
|---|---|
| Drug class | Thyroid hormone (synthetic L-thyroxine, T4) |
| Brands / approval | Synthroid (NDA 021402, 2002), Levoxyl, Unithroid, Levo-T, Tirosint; generics |
| Routes | Oral tablet, capsule and solution; intravenous injection |
| Tablet strengths | 25, 50, 75, 88, 100, 112, 125, 137, 150, 175, 200 and 300 mcg (Synthroid) |
| Labeled adult dose | Full replacement about 1.6 mcg/kg/day, titrated by TSH or free T4 |
| Half-life (label) | 6–7 days in people with normal thyroid function; 3–4 days in hyperthyroidism; 9–10 days in hypothyroidism |
| Key mechanism fact | About 80% of circulating T3 is made from T4 in peripheral tissues |
| Therapeutic index | Narrow, per the label: small dose errors cause over- or undertreatment |
| US status | Prescription only; not a controlled substance |
| WADA status | Not on the 2026 Prohibited List |
What it is
Levothyroxine is L-3,3’,5,5’-tetraiodothyronine: two linked tyrosine-derived rings carrying four iodine atoms (PubChem). The free hormone has the formula C₁₅H₁₁I₄NO₄ (776.9 g/mol). The drug is the sodium salt, C₁₅H₁₀I₄NNaO₄, at 798.86 g/mol anhydrous (Synthroid label). By weight, iodine makes up roughly two-thirds of the molecule.
The structure was worked out and the hormone first synthesized in the laboratory in 1927 (Harington and Barger, Biochem J 1927).
T4 versus T3
T4 and T3 act through the same nuclear thyroid hormone receptors, which switch genes on and off. Through them, thyroid hormone regulates protein, fat and carbohydrate metabolism, raises oxygen consumption and heat production, and stimulates the heart (62 FR 43535). The two hormones differ mainly in potency and how long they last. The Synthroid label gives these figures for people with normal thyroid function:
| Parameter | Levothyroxine (T4) | Liothyronine (T3) |
|---|---|---|
| Ratio stored in thyroglobulin (the thyroid’s hormone store) | 10–20 | 1 |
| Relative biologic potency | 1 | 4 |
| Half-life | 6–7 days | 2 days or less |
| Protein binding | 99.96% | 99.5% |
The label states that the effects of thyroid hormone come “predominantly” from T3, and about 80% of the body’s T3 is made from T4 by deiodination (removal of one iodine atom) in tissues such as the liver and kidney. T4 therefore works as a long-lived reservoir that the body converts to T3 as needed. For the faster, shorter-acting hormone given directly, see T3 (liothyronine sodium).
Pharmacokinetics
From the Synthroid label:
| Parameter | Value |
|---|---|
| Oral absorption | 40–80%, mainly in the jejunum and upper ileum |
| Tablet vs oral solution | Relative bioavailability about 93% |
| Effect of food | Absorption increases when fasting; soy, walnuts, dietary fiber, cottonseed meal and grapefruit juice can reduce or delay it |
| Protein binding | Over 99% bound to thyroxine-binding globulin (TBG), transthyretin and albumin; only the free fraction is active |
| Metabolism | Mainly sequential deiodination in the liver; about 80% of a daily T4 dose becomes equal amounts of T3 and reverse T3 |
| Elimination | Mainly by the kidneys; about 20% of T4 is eliminated in stool |
| Time to full effect of a dose change | Peak therapeutic effect may take 4–6 weeks |
The long half-life is why levothyroxine is taken once a day and why blood levels move slowly. With a half-life of about a week, a dose change takes several weeks to reach a new steady state, so the label advises rechecking TSH (thyroid-stimulating hormone, the pituitary signal that drives the thyroid) 6–8 weeks after any dose change in adults.
Approved medical use
The label approves levothyroxine for adults, children and newborns in two settings:
- Hypothyroidism. Replacement therapy for primary (thyroid), secondary (pituitary) and tertiary (hypothalamic) hypothyroidism, whether congenital or acquired.
- TSH suppression in thyroid cancer. As an add-on to surgery and radioiodine for well-differentiated thyroid cancer whose growth depends on TSH.
The label lists two limitations. It is not indicated to shrink benign thyroid nodules or nontoxic goiter in people with enough iodine, because there is no benefit and overtreatment can cause hyperthyroidism. It is also not indicated during recovery from subacute thyroiditis.
Labeled dosing
| Population | Starting dose (label) | Titration |
|---|---|---|
| Adults with hypothyroidism | Full replacement 1.6 mcg/kg/day; some need less | 12.5–25 mcg steps every 4–6 weeks until TSH normalizes |
| Older adults, or risk of atrial fibrillation or heart disease | Below 1.6 mcg/kg/day | Every 6–8 weeks |
| Children 0–3 months | 10–15 mcg/kg/day | Every 2 weeks by TSH or free T4 |
| Pregnancy, new hypothyroidism with TSH ≥10 mIU/L | 1.6 mcg/kg/day | TSH every 4 weeks |
The label notes that doses above 200 mcg/day are seldom needed, and that poor response to more than 300 mcg/day usually points to missed doses, malabsorption or drug interactions. It is taken once daily on an empty stomach, 30–60 minutes before breakfast, and at least 4 hours apart from drugs that block its absorption.
Why levothyroxine products needed new approvals
Levothyroxine was sold before 1962 without an approved new drug application. In 1997, FDA declared all oral levothyroxine products to be new drugs that needed formal approval (62 FR 43535). The notice cited stability and potency problems:
- at least 10 firm-initiated recalls since 1991, covering 150 lots and more than 100 million tablets;
- in all but one, tablets were subpotent or could not be shown to keep their potency to the expiry date;
- one recalled product tested at 74.7–90.4% of its labeled strength.
FDA stressed that because levothyroxine has a narrow therapeutic index, even small differences in tablet potency matter. FDA records show Unithroid approved in August 2000 (Drugs@FDA, NDA 021210), Levoxyl in May 2001 (NDA 021301) and Synthroid in July 2002 (NDA 021402).
What the research shows
Levothyroxine alone remains the standard for hypothyroidism
The American Thyroid Association’s 2014 guideline reviewed the alternatives, including T4 plus T3 combinations, animal thyroid extract and T3 alone. It concluded that levothyroxine should remain the standard of care, with no consistently strong evidence that any alternative improved health outcomes (Jonklaas et al., Thyroid 2014).
A meta-analysis of 11 randomized trials with 1,216 patients compared T4 plus T3 with T4 alone (Grozinsky-Glasberg et al., JCEM 2006):
| Outcome | Standardized mean difference, combination vs T4 alone (95% CI) |
|---|---|
| Fatigue | −0.12 (−0.33 to 0.09) |
| Depression | 0.07 (−0.20 to 0.34) |
| Quality of life | 0.03 (−0.09 to 0.15) |
| Bodily pain | 0.00 (−0.34 to 0.35) |
There was also no difference in body weight, cholesterol, triglycerides or adverse events.
Mild (subclinical) hypothyroidism in older adults
The TRUST trial randomized 737 adults aged 65 or older with persistent subclinical hypothyroidism (TSH 4.60–19.99 mIU/L with normal free T4) to levothyroxine or placebo (Stott et al., NEJM 2017). At a median dose of 50 mcg/day, TSH fell to 3.63 mIU/L vs 5.48 mIU/L on placebo. After one year, there was no difference in hypothyroid symptoms (difference 0.0; 95% CI −2.0 to 2.1) or tiredness (0.4; 95% CI −2.1 to 2.9), and no secondary outcome improved. Lowering a mildly raised TSH did not make these patients feel better.
Weight loss and body composition
Thyroid hormone raises energy expenditure, which is why it has been tried for obesity. A systematic review of randomized and prospective controlled studies of T3 or T4 given during calorie restriction could not establish consistent effects on weight loss, protein breakdown, metabolic rate or heart rate (Kaptein et al., JCEM 2009). The authors noted that the studies were few and small, but that the evidence did show such therapy produces subclinical hyperthyroidism. The FDA boxed warning reflects the same conclusion.
Weight lost under excess thyroid hormone is not only fat. Studies in patients with naturally overactive thyroids (Graves’ disease and similar conditions, not drug users) show how much muscle a thyrotoxic state costs:
| Study | Patients | Finding after restoring normal thyroid function |
|---|---|---|
| Nørrelund et al., Clin Endocrinol 1999 | 5 | Thigh muscle area rose 24%; arm and leg strength rose about 48–51%. Authors estimated muscle mass was reduced about 20% and strength about 40% while thyrotoxic |
| Lönn et al., JCEM 1998 | 9 | Fat-free mass rose 2.7 kg at 3 months and 3.5 kg at 12 months; thigh muscle plus skin area rose 25% by 12 months |
Recovery of normal muscle mass and function took 5–9 months in the first study. These are small studies of endogenous hyperthyroidism, so they show the direction of the effect rather than what a given dose of levothyroxine would do in a healthy person.
Side effects and risks
Boxed warning
The Synthroid label carries this boxed warning (Synthroid label):
- thyroid hormones, alone or with other drugs, should not be used to treat obesity or for weight loss;
- in people with normal thyroid function, doses within the normal daily hormonal requirement do not reduce weight;
- larger doses may cause serious or life-threatening toxicity, especially when combined with sympathomimetic amines such as appetite suppressants.
Overtreatment: what too much T4 does
The label states that adverse reactions are mainly those of hyperthyroidism from overdosage:
- heart: palpitations, fast heart rate, arrhythmias, raised blood pressure, angina, heart failure, heart attack and cardiac arrest;
- nervous system: nervousness, anxiety, irritability, insomnia, tremor, headache;
- body and metabolism: weight loss, increased appetite, heat intolerance, sweating, fever, diarrhea;
- muscle and bone: muscle weakness, decreased bone mineral density;
- reproduction: menstrual irregularities and impaired fertility.
Overdose can also cause confusion, and cerebral embolism, shock, coma and death have been reported. Symptoms may not appear until several days after an overdose, reflecting the long half-life.
Overtreatment is common even under medical supervision. In the US Cardiovascular Health Study, 41% of 339 adults aged 65 or older who were taking thyroid hormone had a TSH below 0.45 mU/L, a sign of excess dosing (Somwaru et al., JCEM 2009).
Atrial fibrillation and cardiovascular disease
In the Framingham cohort, 2,007 people aged 60 or older were followed for 10 years (Sawin et al., NEJM 1994). Those with a TSH of 0.1 mU/L or less had a 28% cumulative incidence of atrial fibrillation, compared with 11% in those with a normal TSH, an adjusted relative risk of 3.1 (95% CI 1.7–5.5).
A Scottish cohort of 17,684 patients on long-term T4 linked outcomes to TSH levels (Flynn et al., JCEM 2010):
| TSH on treatment | Cardiovascular disease, HR (95% CI) | Arrhythmias, HR (95% CI) | Fractures, HR (95% CI) |
|---|---|---|---|
| Suppressed (≤0.03 mU/L) | 1.37 (1.17–1.60) | 1.6 (1.10–2.33) | 2.02 (1.55–2.62) |
| Low but not suppressed (0.04–0.4 mU/L) | No significant increase | No significant increase | No significant increase |
| Raised (over 4.0 mU/L) | 1.95 (1.73–2.21) | 1.80 (1.33–2.44) | 1.83 (1.41–2.37) |
Both too much and too little hormone were linked to harm, compared with a TSH in the reference range. These are observational studies, so they show associations, not proof of cause.
Bone loss and fractures
The label warns that over-replacement increases bone resorption and lowers bone mineral density, particularly in postmenopausal women. In an Ontario study of 213,511 levothyroxine users aged 70 or older, current use was associated with an 88% higher odds of fracture than remote use (adjusted OR 1.88; 95% CI 1.71–2.05) (Turner et al., BMJ 2011). The risk rose with dose:
| Cumulative daily dose in the prior year | Fracture odds vs low dose (95% CI) |
|---|---|
| Low (under 0.044 mg/day) | Reference |
| Medium (0.044–0.093 mg/day) | 2.62 (2.50–2.76) |
| High (over 0.093 mg/day) | 3.45 (3.27–3.65) |
Suppression of the body’s own thyroid
Taking thyroid hormone switches off TSH through negative feedback, and the thyroid’s own output falls. In seven women with normal thyroid glands who stopped long-term thyroid hormone, TSH stayed undetectable at first, returned to detectable levels after 2–3 weeks, and T4 took at least 4 weeks to return to normal (Vagenakis et al., NEJM 1975). During that window, thyroid hormone levels were below normal.
Interactions
Selected interactions from the label:
| Drug or factor | Effect |
|---|---|
| Calcium, iron, antacids, phosphate binders, bile acid sequestrants | Bind T4 and reduce absorption; separate by at least 4 hours |
| Proton pump inhibitors, sucralfate | Lower stomach acid and can reduce absorption |
| Phenobarbital, rifampin | Speed T4 breakdown, raising dose needs |
| Androgens and anabolic steroids | Lower TBG, so total T4 falls while free T4 and TSH usually stay normal |
| Oral estrogens and contraceptives | Raise TBG |
| Warfarin | Thyroid hormone increases its effect; INR needs monitoring |
| Insulin and diabetes drugs | Glucose control may worsen |
| Ketamine | Marked hypertension and tachycardia |
| Sympathomimetics | Effects of both may increase; risk of coronary insufficiency |
| Biotin supplements | Distort thyroid lab tests; label advises stopping at least 2 days before testing |
The androgen interaction matters for people using testosterone or other anabolic steroids: a low total T4 on a lab report may reflect lower binding protein rather than true hypothyroidism. The sympathomimetic warning applies to stimulant drugs such as clenbuterol, although no controlled study of that specific combination exists.
Who should not use it
The only label contraindication is uncorrected adrenal insufficiency, because thyroid hormone speeds the clearance of cortisol and can trigger an adrenal crisis. The label also advises:
- starting below the full dose in older adults and people with heart disease;
- not using oral tablets for myxedema coma, which needs intravenous treatment;
- adjusting the dose in pregnancy, where requirements may rise, and returning to the pre-pregnancy dose after delivery.
Legal status and use outside medicine
In the US, levothyroxine is a prescription-only drug. It is not on the DEA’s list of controlled substances (21 CFR 1308.13). Thyroid hormones do not appear on the WADA 2026 Prohibited List, so no therapeutic use exemption is needed for them in sport.
Evidence of misuse in tested sport is limited. In 498 serum samples from Australian anti-doping tests, 2 athletes had biochemical thyrotoxicosis, a prevalence of about 4 per 1,000, and 2 of 509 doping-control forms declared T4 use (Handelsman et al., J Endocr Soc 2023). Endocrinologists describe concealed thyroid hormone intake (factitious thyrotoxicosis) as most often aimed at losing body fat and weight, including among bodybuilders (Persani et al., Ann Endocrinol 2023).
Hidden thyroid hormone in supplements
Thyroid hormone can also be taken unknowingly. When 10 over-the-counter “thyroid support” supplements were tested by chromatography, 9 contained T3 and 5 contained T4 (Kang et al., Thyroid 2013). At the recommended dose, 4 products delivered 8.57–91.6 mcg/day of T4 and 5 delivered more than 10 mcg/day of T3. The authors noted that some exceeded common treatment doses for hypothyroidism.
Key takeaways
- T4 is a slow-acting prohormone. Levothyroxine is identical to the thyroid’s own T4, and most of its effect comes after conversion to T3. Its half-life of about a week means changes take weeks to settle.
- Standard of care for hypothyroidism. Guidelines and trial meta-analyses favor levothyroxine alone over T4 plus T3 combinations or thyroid extracts.
- Labeled against weight loss. The boxed warning states that normal doses do not cause weight loss in people with a healthy thyroid and that larger doses can be life-threatening. Controlled studies of T4 for obesity were small and inconsistent.
- Excess hormone costs muscle and bone. Thyrotoxic patients lose muscle mass and strength, and suppressed TSH on treatment is linked to atrial fibrillation and fractures.
- Narrow therapeutic index. Small differences in dose or tablet potency matter, which is why FDA required oral products to gain formal approval after 1997.
- Not scheduled or banned in sport. It is prescription-only in the US, not a controlled substance, and not on the WADA 2026 Prohibited List.
Sources
- AbbVie. Synthroid (levothyroxine sodium) tablets, prescribing information, revised 2/2024. DailyMed; Drugs@FDA, NDA 021402.
- Food and Drug Administration. Drugs@FDA records for Unithroid (NDA 021210) and Levoxyl (NDA 021301). NDA 021210; NDA 021301.
- National Center for Biotechnology Information. Levothyroxine, PubChem CID 5819. PubChem.
- Harington CR, Barger G. Chemistry of thyroxine: constitution and synthesis of thyroxine. Biochem J. 1927;21(1):169–183. PubMed.
- Food and Drug Administration. Prescription drug products; levothyroxine sodium. Federal Register. August 14, 1997;62(157):43535–43538 (FR Doc 97-21575). govinfo.
- Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–1751. PubMed.
- Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine-triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrinol Metab. 2006;91(7):2592–2599. PubMed.
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- World Anti-Doping Agency. The 2026 Prohibited List. WADA.
- US Drug Enforcement Administration. Schedule III, 21 CFR 1308.13. eCFR.