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Tricyclic antidepressants (drug interactions)

Tricyclic antidepressants (TCAs) are a class of medications primarily used to treat depression, though they have largely been replaced by serotonin reuptake inhibitors in recent years. However, understanding their potential drug interactions is crucial for safe and effective treatment. TCAs can interact with a variety of supplements and medications, which may lead to serious side effects. For instance, combining TCAs with supplements like St. John's wort, 5-hydroxytryptophan (5-HTP), or S-adenosylmethionine (SAMe) may dangerously elevate serotonin levels. Additionally, St. John's wort can reduce the effectiveness of TCAs.

Other interactions include valerian root, which may enhance sedative effects, and ginkgo biloba, which might increase bleeding risks. Patients are also advised to avoid concurrent use with monoamine oxidase inhibitors (MAOIs), as this can lead to severe complications. Furthermore, caution is needed when combining TCAs with other medications that affect serotonin, anticholinergic agents, or central nervous system depressants, as these combinations could amplify the side effects of TCAs. Understanding these interactions is essential for individuals considering or currently using tricyclic antidepressants.

Full Article

DEFINITION: Antidepressant medications mostly superseded by serotonin reuptake inhibitors.

  • INTERACTIONS: Coenzyme Q10, 5-hydroxytryptophan (5-HTP), S-adenosylmethionine (SAMe), St. John’s wort, yohimbe, valerian root, ginkgo biloba, ginseng, various prescription medications
  • DRUGS IN THIS FAMILY: Amitriptyline hydrochloride (Elavil), clomipramine hydrochloride (Anafranil), desipramine hydrochloride (Norpramin), doxepin hydrochloride (Sinequan), imipramine (Tofranil), nortriptyline hydrochloride (Aventyl, Pamelor), protriptyline hydrochloride (Vivactil), trimipramine maleate (Surmontil)

Coenzyme Q10 (CoQ10)

Effect: Supplementation Possibly Helpful

Preliminary evidence suggests that tricyclic antidepressants might deplete the body of CoQ10, a substance that appears to be important for normal heart function. Based on this observation, it has been suggested (but not proved) that CoQ10 supplementation might help prevent the heart-related side effects that can occur with the use of tricyclic antidepressants.

St. John’s Wort, Yohimbe, 5-Hydroxytryptophan (5-HTP), S-Adenosylmethionine (SAMe)

Effect: Possible Dangerous Interactions

Based on one case report and general knowledge about the actions of these supplements, taking any of these in combination with some tricyclic antidepressants could present a risk of elevating serotonin levels too high.

St. John’s Wort

Effect: Possible Harmful Interaction

St. John’s wort might decrease the effectiveness of tricyclic antidepressants by reducing blood levels of the drug. Conversely, if one is taking St. John’s wort already and one’s physician adjusts one’s dose of medication, suddenly stopping the herb could cause blood levels of the drug to rise dangerously high.

Other Interactions

Many potential interactions exist between tricyclic antidepressants and other herbs, supplements, and medications. Valerian root can intensify the sedative effects of tricyclic antidepressants. Ginkgo biloba may elevate the risk of bleeding, while ginseng can potentially worsen side effects.

Patients taking Monoamine Oxidase Inhibitors (MAOIs) should avoid taking tricyclic antidepressants within two weeks of each other due to the risk of severe complications. Combining tricyclic antidepressants with serotonergic, anticholinergic, or cardiac medications is not recommended. Central nervous system depressants should also be avoided, as they can amplify the effects of tricyclic antidepressants.


Bibliography

Fink, Jennifer. "Tricyclic Antidepressants (TCAs): Uses, Side Effects, and More." Healthline, 2 Sept. 2018, www.healthline.com/health/depression/tricyclic-antidepressants-tcas. Accessed 29 Dec. 2025.

Iruela, L. M., et al. "Toxic Interaction of S-Adenosylmethionine and Clomipramine." American Journal of Psychiatry, vol. 150, 1993, p. 522.

Johne, A., et al. "Decreased Plasma Levels of Amitriptyline and Its Metabolites on Comedication with an Extract from St. John’s Wort (Hypericum perforatum)." Journal of Clinical Psychopharmacology, vol. 22, 2002, pp. 46-54.

Moraczewski, Jordan, et al. "Tricyclic Antidepressants - StatPearls." NCBI, 17 Aug. 2023, www.ncbi.nlm.nih.gov/books/NBK557791. Accessed 29 Dec. 2025.

Roots, J., et al. "Interaction of a Herbal Extract from St. John’s Wort with Amitriptyline and Its Metabolites." Clinical Pharmacology and Therapeutics, vol. 67, 2000, p. 159.

“Tricyclic Antidepressants.” Mayo Clinic, 8 Oct. 2024, www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20046983. Accessed 29 Dec. 2025.

Full Article

DEFINITION: Antidepressant medications mostly superseded by serotonin reuptake inhibitors.

  • INTERACTIONS: Coenzyme Q10, 5-hydroxytryptophan (5-HTP), S-adenosylmethionine (SAMe), St. John’s wort, yohimbe, valerian root, ginkgo biloba, ginseng, various prescription medications
  • DRUGS IN THIS FAMILY: Amitriptyline hydrochloride (Elavil), clomipramine hydrochloride (Anafranil), desipramine hydrochloride (Norpramin), doxepin hydrochloride (Sinequan), imipramine (Tofranil), nortriptyline hydrochloride (Aventyl, Pamelor), protriptyline hydrochloride (Vivactil), trimipramine maleate (Surmontil)

Coenzyme Q10 (CoQ10)

Effect: Supplementation Possibly Helpful

Preliminary evidence suggests that tricyclic antidepressants might deplete the body of CoQ10, a substance that appears to be important for normal heart function. Based on this observation, it has been suggested (but not proved) that CoQ10 supplementation might help prevent the heart-related side effects that can occur with the use of tricyclic antidepressants.

St. John’s Wort, Yohimbe, 5-Hydroxytryptophan (5-HTP), S-Adenosylmethionine (SAMe)

Effect: Possible Dangerous Interactions

Based on one case report and general knowledge about the actions of these supplements, taking any of these in combination with some tricyclic antidepressants could present a risk of elevating serotonin levels too high.

St. John’s Wort

Effect: Possible Harmful Interaction

St. John’s wort might decrease the effectiveness of tricyclic antidepressants by reducing blood levels of the drug. Conversely, if one is taking St. John’s wort already and one’s physician adjusts one’s dose of medication, suddenly stopping the herb could cause blood levels of the drug to rise dangerously high.

Other Interactions

Many potential interactions exist between tricyclic antidepressants and other herbs, supplements, and medications. Valerian root can intensify the sedative effects of tricyclic antidepressants. Ginkgo biloba may elevate the risk of bleeding, while ginseng can potentially worsen side effects.

Patients taking Monoamine Oxidase Inhibitors (MAOIs) should avoid taking tricyclic antidepressants within two weeks of each other due to the risk of severe complications. Combining tricyclic antidepressants with serotonergic, anticholinergic, or cardiac medications is not recommended. Central nervous system depressants should also be avoided, as they can amplify the effects of tricyclic antidepressants.


Bibliography

Fink, Jennifer. "Tricyclic Antidepressants (TCAs): Uses, Side Effects, and More." Healthline, 2 Sept. 2018, www.healthline.com/health/depression/tricyclic-antidepressants-tcas. Accessed 29 Dec. 2025.

Iruela, L. M., et al. "Toxic Interaction of S-Adenosylmethionine and Clomipramine." American Journal of Psychiatry, vol. 150, 1993, p. 522.

Johne, A., et al. "Decreased Plasma Levels of Amitriptyline and Its Metabolites on Comedication with an Extract from St. John’s Wort (Hypericum perforatum)." Journal of Clinical Psychopharmacology, vol. 22, 2002, pp. 46-54.

Moraczewski, Jordan, et al. "Tricyclic Antidepressants - StatPearls." NCBI, 17 Aug. 2023, www.ncbi.nlm.nih.gov/books/NBK557791. Accessed 29 Dec. 2025.

Roots, J., et al. "Interaction of a Herbal Extract from St. John’s Wort with Amitriptyline and Its Metabolites." Clinical Pharmacology and Therapeutics, vol. 67, 2000, p. 159.

“Tricyclic Antidepressants.” Mayo Clinic, 8 Oct. 2024, www.mayoclinic.org/diseases-conditions/depression/in-depth/antidepressants/art-20046983. Accessed 29 Dec. 2025.

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