Risk of cardiac, neuropsychiatric and musculoskeletal adverse events with levothyroxine: Systematic review

Levothyroxine (LT4) is the standard treatment for hypothyroidism and the most widely prescribed medication worldwide. Although generally safe, regulatory reports list potential cardiac, neuropsychiatric and musculoskeletal adverse events (AEs). Clarifying their clinical relevance is essential. We systematically searched MEDLINE, Embase, CENTRAL and Google Scholar for randomized controlled trials (RCTs) and observational studies reporting predefined AEs. Eligible comparators included placebo, no treatment, liothyronine (LT3), usual-dose LT4 or LT4 monotherapy when LT4/T3 combination therapy was studied. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated. TSH values at baseline and post-treatment were recorded to contextualize AEs by thyroid status (euthyroid, suppressed or hypothyroid). Twelve studies (n = 1817) were included: seven RCTs, two crossover trials, two case-control studies and one quasi-experimental study. Cardiac AEs (tachycardia, palpitations, angina, atrial fibrillation), neuropsychiatric AEs (headache, tremor, insomnia, anxiety, depression) and musculoskeletal AEs (myalgia) were reported; however, most comparisons were statistically nonsignificant and clinically not meaningful, indicating that LT4 at replacement doses is generally safe. AEs primarily occurred when TSH was suppressed, whereas in euthyroid patients, blinded placebo-controlled trials showed no significant differences, confirming a very low risk of LT4-related side effects. Some subjective symptoms may reflect placebo or nocebo effects rather than true drug toxicity. LT4 at replacement doses is safe, and AEs are predominantly associated with suppressed TSH or subjective effects. Interpretation of AEs should always consider thyroid status, highlighting the importance of maintaining euthyroidism.