An investigation into the modulation of T cell phenotypes by amitriptyline and nortriptyline

Eur Neuropsychopharmacol. 2020 Feb;31:131-144. doi: 10.1016/j.euroneuro.2019.12.106. Epub 2019 Dec 24.


Amitriptyline is prescribed for treating the symptoms of neuroinflammatory disorders including neuropathic pain and fibromyalgia. As amitriptyline has evidence of modulating the neuroimmune interface; the effects of amitriptyline treatment on T-cell phenotype and function were examined in vitro. Peripheral blood mononuclear cells(PBMCs) were isolated and treated with amitriptyline, nortriptyline and a combination of both drugs. Toxicity for T-cells was assessed by Annexin V/Propidium Iodide staining. Activation status and cytokine expression by T-cells post treatment was assessed by flow cytometry. The levels of secreted cytokines, chemokines and neurotrophins were measured by ELISA in the supernatants. There was no significant increase in T-cell death following 24 or 48 h compared to controls. There were significantly lower frequencies of CD8+ T-cells after treatment with amitriptyline, nortriptyline and a combination of both compared to a Vehicle Control(VC)(p<0.001). The frequencies of naive CD8+CD45RA+ cells were significantly lower after amitriptyline, nortriptyline and a combination of both (p<0001). The frequencies of CD27+CD4+(p<0.05) and CD27+CD8+(p<0.01) T-cells were also significantly lower following combination drug treatment. Significantly lower frequencies of IFN-γ-producing CD8+ T-cells were observed with all treatment combinations(p<0.05) and frequencies of IL-17-producing CD4+ and CD8+ T-cells were significantly lower following amitriptyline treatment (p<0.05). Frequencies of Natural Killer T-cells were significantly higher following treatment with nortriptyline (p<0.05). Significantly higher levels of IL-16 (p<0.001) and lower levels of TNF-β (p<0.05) were observed in supernatants. This data indicates that both amitriptyline and nortriptyline modulate the phenotype and function of T-cells and this may have clinical relevance in the pathologies of its off-label applications.

Keywords: Amitriptyline; Neuroimmune interface; Neuroinflammation; Neuropathic pain; Nortriptyline; T cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amitriptyline / administration & dosage*
  • Antidepressive Agents, Tricyclic / administration & dosage*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / physiology
  • Cell Death / drug effects
  • Cell Death / physiology
  • Cytokines / physiology
  • Dose-Response Relationship, Drug
  • Drug Combinations
  • Female
  • Humans
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / physiology
  • Male
  • Middle Aged
  • Nortriptyline / administration & dosage*
  • Phenotype*
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / physiology


  • Antidepressive Agents, Tricyclic
  • Cytokines
  • Drug Combinations
  • Amitriptyline
  • Nortriptyline