A 2025 narrative review on antidepressants and lung toxicity describes amitriptyline as a tricyclic antidepressant with reported pulmonary adverse effects, although the available evidence is limited. While amitriptyline is primarily associated with systemic toxicity at high doses (≥750 mg), pulmonary manifestations have been reported in specific contexts, including pulmonary edema following acute overdose and hypoxia-related pulmonary hypertension with prolonged exposure. The review also cites an isolated case of eosinophilic pneumonia in a dialysis-dependent patient with end-stage renal disease, in which clinical improvement followed drug discontinuation, suggesting a possible association (see Table 1). Overall, the findings suggest that pulmonary toxicity related to amitriptyline appears uncommon, but the drug may be considered a potential contributor to unexplained pulmonary findings after more common causes have been excluded. [1]
A 2018 retrospective review evaluated published case reports of drug-induced eosinophilic pneumonia from 1990 to 2017. A total of 196 reports were identified, with daptomycin, mesalamine, sulfasalazine, and minocycline being the most commonly implicated drugs. Notably, amitriptyline and maprotiline were grouped together and listed as one of the many medications, accounting for a total of 4 drug-induced eosinophilic pneumonia cases. While not specific to amitriptyline or TCA use, the authors noted that although eosinophilic pneumonia is rare, nearly every medication class had been implicated, with some classes reported more frequently than others. Both serotonin and eotaxin have been described as having an eosinophil chemoattractant profile, which may potentially explain the connection between the pathogenesis of acute/chronic eosinophilic pneumonia and antipsychotic and antiepileptic drugs. Overall, the findings suggest that regardless of age or sex, drug-induced eosinophilic pneumonia should be suspected in any patient who has recently started taking a new medication and presents with onset of dyspnea, bilateral infiltrates on chest radiography, and peripheral blood eosinophilia with a negative eosinophilia work-up. [2]
A 2025 animal study utilizing rat precision-cut lung slices assessed the effects of amitriptyline on bronchial tone and demonstrated that the tricyclic antidepressant inhibits bronchoconstriction independently of direct receptor binding while simultaneously reducing the number of caveolae in lung tissue. Bronchial asthma, a chronic inflammatory disease with rising prevalence worldwide, is influenced not only by immune-mediated mechanisms but also, as emerging evidence suggests, by direct effects of inhaled amitriptyline on airway smooth muscle. The study found that amitriptyline, at concentrations ranging from 0 to 5 micromolars, significantly attenuated bronchoconstriction induced by acetylcholine and serotonin. Mechanistic investigations revealed that classical signaling pathways were not involved: neither the muscarinic antagonist ipratropium, the phospholipase C inhibitor U73122, nor the protein kinase C inhibitor chelerythrine diminished the bronchodilatory effect of amitriptyline, and inhibition of calcium sensitization or calcium induction failed to alter its activity. Amitriptyline also dramatically reduced the number of caveolae, specialized plasma membrane microdomains that regulate signal transduction, in a manner similar to methyl beta-cyclodextrin, a known caveolae disruptor. Unlike methyl beta-cyclodextrin, however, this reduction was not due to cholesterol depletion, as cholesterol repletion did not reverse the effect, and neither simvastatin nor cytochalasin D influenced its activity. Importantly, these findings suggest a potential bronchodilatory mechanism of amitriptyline but do not provide evidence of lung injury, toxicity, or mechanisms specifically associated with pulmonary damage. Furthermore, while animal models such as this provide mechanistic insight into airway physiology, they cannot directly predict the rare instances of amitriptyline-associated lung injury observed in humans. [3]
A 2002 animal study investigated the acute and chronic cardiopulmonary effects of tricyclic antidepressants, with a particular focus on amitriptyline, to better understand mechanisms underlying ARDS-like manifestations observed after overdose. Using a combination of in vivo anesthetized cat models and ex vivo blood-perfused rat lungs, the investigators demonstrated that acute administration of overdose-level amitriptyline caused dose-dependent, sustained increases in pulmonary artery pressure, accompanied by bronchoconstriction and pulmonary edema. In isolated rat lungs, amitriptyline induced persistent pulmonary vasoconstriction that was attenuated by calcium channel inhibition or nitric oxide donors, indicating involvement of calcium-dependent vascular tone and impaired nitric oxide signaling. Importantly, these pressor effects were not mediated by release of histamine, serotonin, noradrenaline, or by cyclooxygenase or lipoxygenase pathways, and endothelial nitric oxide synthase and endothelin-converting enzyme activity remained intact. Ultrastructural analysis revealed that large acute doses of amitriptyline caused rupture of alveolar epithelium and capillary endothelium with fulminant edema, providing direct morphological evidence of drug-induced lung injury. Functionally, acute amitriptyline exposure also suppressed hypoxic pulmonary vasoconstriction and attenuated pulmonary vascular responses to serotonin and noradrenaline, likely due to inhibition of amine uptake by the pulmonary endothelium, a known pharmacologic property of tricyclic antidepressants. Chronic exposure studies showed persistent blunting of serotonin-mediated pressor responses but did not consistently produce pulmonary hypertension with amitriptyline, in contrast to iprindole, suggesting drug-specific differences within the TCA class. [4]
Another animal study, published in 2001, investigated mechanisms underlying amitriptyline-induced acute lung function impairment in isolated perfused and ventilated rat lungs. Exposure to amitriptyline (50-100 micromolars) caused rapid, dose-dependent vasoconstriction and bronchoconstriction, with maximal decreases in perfusion flow of 28 ± 2.9% (50 micromolars) and 80 ± 4.5% (100 micromolars), and maximal decreases in airway conductance of 29 ± 4.7% and 68 ± 5.0%, respectively. Mechanistic studies showed that the protein kinase inhibitor staurosporine, the nitric oxide donor S-nitrosoglutathione, and the combined endothelin A/endothelin B receptor antagonist PD145065 attenuated amitriptyline-induced vasoconstriction. Amitriptyline-induced bronchoconstriction was reduced by the β2-agonist salbutamol and the platelet-activating factor antagonist WEB2086. These results indicate that endothelin-1, platelet-activating factor, and protein kinase activation are key mediators of amitriptyline-induced lung impairment, resembling features of acute respiratory distress syndrome (ARDS) or acute lung injury (ALI). The study concluded that amitriptyline exposure in this rat model recapitulates multiple aspects of ARDS/ALI, including endothelial and epithelial dysfunction, decreased pulmonary compliance, and airway constriction, providing insight into potential pathways involved in drug-induced and clinical acute lung injury; however, caution is warranted in interpretation, as animal models may not fully replicate findings and mechanisms potentially relevant in humans. [5]
Lastly, a final animal study, published in 1997, evaluated whether tricyclic antidepressants (TCAs), including amitriptyline, can directly induce acute lung failure using an isolated, perfused, and ventilated rat lung model. In this experimental system, exposure to six TCAs (amitriptyline, nortriptyline, imipramine, desipramine, mianserine, and maprotiline) produced rapid and pronounced impairments in lung function, including reductions in airway conductance, dynamic compliance, and pulmonary perfusion flow, with effects appearing within 5-15 minutes of exposure. Amitriptyline was examined in greater detail and demonstrated a clear dose-dependent effect across concentrations ranging from 0.01 to 1.0 mM, with higher concentrations producing severe functional decline and, at the highest dose, lung collapse. At elevated concentrations, amitriptyline also induced marked pulmonary edema, as evidenced by increased wet-to-dry lung weight ratios and confirmed by transmission electron microscopy. Morphological analysis revealed dose-related edema, endothelial disruption, and thickening of the alveolar-capillary membrane, with extensive structural damage observed at 1.0 mM. Similar, though variably pronounced, pulmonary effects were observed with the other TCAs, suggesting a class effect rather than a mechanism unique to amitriptyline. The authors noted that these experimental findings closely resembled clinical descriptions of ARDS, like presentations reported in cases of TCA overdose, supporting the possibility of a noncardiogenic pulmonary edema component in severe intoxication. Similarly, while this animal study also provides mechanistic and morphological evidence that high, supratherapeutic concentrations of amitriptyline can directly impair lung function and integrity, caution is warranted in extrapolating these results to humans. [6]