{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T21:15:51Z","timestamp":1790716551879,"version":"4.1.0"},"reference-count":37,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T00:00:00Z","timestamp":1768867200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2010dose 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\u2010treatment were recorded to contextualize AEs by thyroid status (euthyroid, suppressed or hypothyroid). Twelve studies (n\u2009=\u20091817) were included: seven RCTs, two crossover trials, two case\u2013control studies and one quasi\u2010experimental 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\u2010controlled trials showed no significant differences, confirming a very low risk of LT4\u2010related 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.<\/jats:p>","DOI":"10.1002\/bcp.70455","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T03:54:13Z","timestamp":1768967653000},"page":"1023-1039","source":"Crossref","is-referenced-by-count":3,"title":["Risk of cardiac, neuropsychiatric and musculoskeletal adverse events with levothyroxine: Systematic review"],"prefix":"10.1002","volume":"92","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-9476-6358","authenticated-orcid":false,"given":"Bala Swetha","family":"Baskaran","sequence":"first","affiliation":[{"name":"ICES Western  London ON Canada"},{"name":"Department of Physiology and Pharmacology Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6847-0699","authenticated-orcid":false,"given":"Mohammad Ali","family":"Omrani","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pharmacology Western University  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4682-6564","authenticated-orcid":false,"given":"Flory T.","family":"Muanda","sequence":"additional","affiliation":[{"name":"ICES Western  London ON Canada"},{"name":"Department of Physiology and Pharmacology Western University  London Ontario Canada"},{"name":"Department of Epidemiology &amp; Biostatistics Western University  London ON Canada"},{"name":"Lawson Health Research Institute, London Health Sciences Centre  London Ontario Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1177\/1060028017705393"},{"key":"e_1_2_11_3_1","unstructured":"Enhanced Reader. 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