Is My Medication or Dietary Supplement Making Me Tired and Depressed?

fatigued man with head in hands

The Bottom Line

Multiple medications, including dietary supplements, can cause fatigue or other mood disorders. People with excessive fatigue, depression, or anxiety should seek medical care for further evaluation, including a review of all medications and supplements used.

woman with medication in hand

The Full Story

Fatigue is common throughout our society. Nearly half of the population reports fatigue, including over one-third of all workers in the United States. Fatigue impairs our ability to work effectively and is also associated with many medical conditions including asthma, chronic pain, and depression. Fatigue may be central (affecting the brain) or peripheral (affecting the muscles).

There are many medical causes for fatigue. Anemia, thyroid disease, and COVID-19 infection are a few of these causes.

  • Anemia is a condition that occurs when there are not enough red blood cells. Red blood cells carry oxygen throughout the body, and organs such as the brain and heart use oxygen to perform their vital functions. Without enough red blood cells, anemic patients have less oxygen delivered to their organs, and the organs do not work as well as they should. This can cause fatigue as well as other potentially life-threatening symptoms.
  • The thyroid gland is an important part of the endocrine system that helps regulate energy levels throughout the body. The thyroid gland produces thyroid hormones that have a role in metabolism and other body functions. People with thyroid dysfunction can have too much or too little thyroid hormone, causing metabolic disturbances including fatigue.
  • Many infections cause fatigue. Think about the fatigue that accompanies the flu or mononucleosis. COVID-19 also causes both acute and chronic fatigue. Some patients who recover from the initial manifestations of COVID-19 still have significant fatigue and other symptoms. This syndrome is often called “long-haul” COVID-19 infection.

All medications have potential side effects, and these can be another significant source of fatigue. Diphenhydramine (Benadryl) and benzodiazepines (e.g., lorazepam [Ativan] or alprazolam [Xanax]) are known for their ability to cause drowsiness. Many people consider dietary supplements to be safe, but some may also cause fatigue. Two examples of supplements associated with fatigue are tryptophan and collagen.

Collagen (derived from the Greek words kola [“gum”] and gen [“producing”]) is found throughout the human body. It is a protein that is composed of different amino acids including glycine and proline, but it does not naturally contain another amino acid called tryptophan. Collagen is present in connective tissues (including bones, joints, and skin) and acts as a building block for these tissues. The collagen content of skin decreases as we age, resulting in thin and wrinkled skin. Because of this, the use of collagen supplements as an anti-aging therapy has become popular.

Similar to naturally occurring collagen, there is no tryptophan present in many oral collagen dietary supplements, although some collagen formulations are enhanced with tryptophan and marketed as “complete” protein supplements. Since tryptophan is not found in many collagen formulations, individuals who regularly take oral collagen supplements in high doses may become deficient in tryptophan, unless they are also getting tryptophan from dietary sources such as poultry or dairy products. This happens because a tryptophan-free diet causes the human body to increase protein production by incorporating any available tryptophan and other amino acids into new proteins. In animal and human studies, administration of tryptophan-free amino acid mixtures (similar to the ingredients found in collagen supplements) results in rapid and significant decreases in blood and brain tryptophan levels. Since tryptophan is a precursor for synthesis of the “happy hormone” serotonin, low tryptophan levels may decrease serotonin production and cause depression, anxiety, and chronic fatigue. This connection between tryptophan, serotonin, and mood disorders has been explored in multiple human studies, but a clear relationship between these factors has not been established. Fatigue is reported to occur when there is an excess of tryptophan in the brain, as well as when there is tryptophan depletion in the rest of the body. Multiple factors likely contribute to fatigue, depression, and anxiety, and tryptophan is only one part of the puzzle. Additionally, even though tryptophan deficiency can decrease serotonin synthesis, this may not significantly affect the ability of serotonin to exert its mood-altering effects.

In the absence of robust evidence suggesting that collagen supplements cause fatigue due to tryptophan deficiency, it is likely safe to use these products at recommended doses. Since tryptophan is present in other dietary sources such as poultry, milk, beans, red meat, and fish, tryptophan deficiency is unlikely in people who eat a balanced diet. Given the many medical causes of mood disorders, individuals with unexplained or excessive fatigue, anxiety, or depression should seek medical care for further evaluation and treatment. A thorough review of all medications and dietary supplements taken may reveal a potential and reversible cause of these symptoms.

If someone has an adverse event related to use of dietary supplements, including tryptophan, get personalized advice from webPOISONCONTROL or call 1-800-222-1222. Both options are free for the public, and available 24 hours a day.

Kelly Johnson-Arbor, MD
Medical Toxicologist

Poisoned?

Call 1-800-222-1222 or

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Prevention Tips

  • Do not take medications that are not prescribed for you.
  • Speak with your doctor or pharmacist before starting new medications or dietary supplements, to ensure there are no drug interactions present.
  • A balanced diet can help prevent nutritional deficiencies.

This Really Happened

Fifteen women (age range 21-45 years) with a history of major depression were administered either nutritionally balanced or tryptophan-free oral amino acid mixtures. Plasma tryptophan levels dropped by 75% in women who drank the tryptophan-free mixture. Women who drank the tryptophan-free mixture also experienced significant depressive symptoms that resolved within a day. There were no changes in depressive symptoms noted in the women who drank the nutritionally balanced mixture. 

For More Information

Consumer Reports. The Real Deal on Collagen. Accessed 1.25.22.

National Institute on Aging. Fatigue in Older Adults. Accessed 1.25.22.


References

Asserin J, Lati E, Shioya T, Prawitt J. The effect of oral collagen peptide supplementation on skin moisture and the dermal collagen network: evidence from an ex vivo model and randomized, placebo-controlled clinical trials. J Cosmet Dermatol. 2015 Dec;14(4):291-301.

Jhawar N, Wang JV, Saedi N. Oral collagen supplementation for skin aging: A fad or the future? J Cosmet Dermatol. 2020 Apr;19(4):910-912. 

Neumeister A, Nugent AC, Waldeck T, Geraci M, Schwarz M, Bonne O, Bain EE, Luckenbaugh DA, Herscovitch P, Charney DS, Drevets WC. Neural and behavioral responses to tryptophan depletion in unmedicated patients with remitted major depressive disorder and controls. Arch Gen Psychiatry. 2004 Aug;61(8):765-73. 

Ricci JA, Chee E, Lorandeau AL, Berger J. Fatigue in the U.S. workforce: prevalence and implications for lost productive work time. J Occup Environ Med. 2007 Jan;49(1):1-10.

Smith KA, Fairburn CG, Cowen PJ. Relapse of depression after rapid depletion of tryptophan. Lancet. 1997 Mar 29;349(9056):915-9.

Stuart PS, Bell SJ, Molnar J. Use of tryptophan-fortified hydrolyzed collagen for nutritional support. J Diet Suppl. 2008;5(4):383-400.

van Donkelaar EL, Blokland A, Ferrington L, Kelly PA, Steinbusch HW, Prickaerts J. Mechanism of acute tryptophan depletion: is it only serotonin? Mol Psychiatry. 2011 Jul;16(7):695-713.

Wang H. A review of the effects of collagen treatment in clinical studies. Polymers. 2021;13:2668.

Yamashita M. Potential Role of Neuroactive Tryptophan Metabolites in Central Fatigue: Establishment of the Fatigue Circuit. Int J Tryptophan Res. 2020 Jun 29;13:1178646920936279. 

Young SN. Acute tryptophan depletion in humans: a review of theoretical, practical and ethical aspects. J Psychiatry Neurosci. 2013 Sep;38(5):294-305. 

Poisoned?

Call 1-800-222-1222 or

HELP ME online

Prevention Tips

  • Do not take medications that are not prescribed for you.
  • Speak with your doctor or pharmacist before starting new medications or dietary supplements, to ensure there are no drug interactions present.
  • A balanced diet can help prevent nutritional deficiencies.

This Really Happened

Fifteen women (age range 21-45 years) with a history of major depression were administered either nutritionally balanced or tryptophan-free oral amino acid mixtures. Plasma tryptophan levels dropped by 75% in women who drank the tryptophan-free mixture. Women who drank the tryptophan-free mixture also experienced significant depressive symptoms that resolved within a day. There were no changes in depressive symptoms noted in the women who drank the nutritionally balanced mixture.