Why ‘How To Heal Adrenal Fatigue’ Isn’t the Right Question

Written by Dr. Ruscio on February 12, 2021

Written by Dr. Ruscio on February 12, 2021 — Reviewed by Robert Abbott

Dr. Michael Ruscio is a DC, Naturopathic Practitioner, researcher, and clinician. He serves as an Adjunct Professor at the University of Bridgeport and has published numerous papers in scientific journals as well as the book Healthy Gut, Healthy You. He also founded the Ruscio Institute of Functional Health, where he helps patients with a wide range of GI conditions and serves as the Head of Research.

How To Improve Your Energy Levels, Chronic Fatigue, and Stress Levels

Adrenal Fatigue|
Causes of Fatigue|
How To Heal Fatigue|
Medical Assessment|
Improve Gut Health|
Heal the Thyroid|
Anemia|
Diet|
Stress Relief|
Supplements|
The Bottom Line|
Recommended Products|

When it comes to how to heal adrenal fatigue, we need to take a few steps back. Though your fatigue is real, adrenal fatigue is not recognized as a medical condition and is even being questioned by many in alternative medicine.

Instead of talking about how to heal “adrenal fatigue”, we need to discuss what may really be causing your fatigue symptoms.

Treat the cause, not the symptom. The truth is that your gut health, thyroid function, iron levels, blood sugar levels, food sensitivities, and stress tolerance are more likely to be underlying causes of your fatigue. Diagnosing and treating the true cause of your fatigue is the key to getting your energy back.

In this article, we’ll explain the theory of adrenal fatigue and why many experts don’t consider it valid. We’ll explore other possible root causes of fatigue symptoms and how to improve fatigue with research-backed solutions.

What Is Adrenal Fatigue?

Adrenal fatigue is a theoretical health condition where your adrenal glands are no longer able to produce an appropriate hormonal response to stress.

Normally, when you experience stress, your adrenal glands produce hormones — cortisol, adrenaline, and aldosterone — for the “fight or flight” response.

The adrenal fatigue theory proposes that prolonged chronic stress levels can “fatigue” your adrenal function, leaving them less able to muster the hormones needed for a stress response.

Purported Symptoms of Adrenal Fatigue and Adrenal Health Dysfunction

When people think of adrenal fatigue, they associate it with the following symptoms:

Chronic fatigue or ongoing low energy levels
Low blood pressure
Weight gain or weight loss
Lightheadedness or brain fog
Low sex drive
Low immune system function (frequent colds or illnesses)
Hormone imbalances (like hypothyroidism)

However, there is not yet clear evidence that adrenal fatigue exists as a medical condition.

According to a systematic review of research on adrenal fatigue, cortisol levels on saliva tests and blood tests don’t correlate with fatigue symptoms 50-80% of the time [1].

Other studies suggest a similar conclusion. A systematic review of post-traumatic stress disorder (PTSD) patients found they had similar cortisol levels to healthy individuals [2]. An additional systematic review and meta-analysis showed that neither trauma nor PTSD affected cortisol levels [3].

Addison’s disease — an autoimmune disease characterized by very low cortisol (adrenal insufficiency) — is a real medical condition. However it’s extremely rare, affecting only .01% of Americans [4].

Even though Endocrinologists don’t recognize adrenal fatigue as a real condition, fatigue is definitely a real and troublesome symptom that can be caused by many health issues.

A Better Response To ‘How To Heal Adrenal Fatigue‘

There are many other, very common reasons for fatigue that have nothing to do with your adrenal glands and adrenal fatigue.

Fatigue symptoms are most often caused by:

Gut dysfunction
Thyroid imbalances (hypothyroidism)
Iron deficiency anemia
Low blood sugar
Inflammation from food sensitivities or autoimmune conditions
Sleep problems like sleep apnea
Other physiological effects of stress

To effectively heal your fatigue symptoms, make sure you are focusing on the right causes.

Address the Root Causes of Your Fatigue

Overcoming your fatigue is about addressing the true underlying causes. You may need some help figuring out what these are. Once you know where your fatigue is coming from, focusing on your digestion, your thyroid health, your iron levels, your diet, or your unique stressors can have you feeling energetic again in no time.

Get a Good Medical Assessment

Understanding what’s causing your fatigue is vitally important to forming the best treatment plan. For example, if your fatigue is due to gut dysbiosis, taking iron may not improve your fatigue.

Patients may feel their concerns about fatigue are disregarded by some medical practitioners. Other practitioners broadly label all fatigue as adrenal fatigue, an inaccurate diagnosis that does not help you restore your energy levels. The right health practitioner will take your fatigue seriously and can help you accurately assess your root causes. If you need help, consider applying to become a patient at our clinic.

Improve Your Gut Health

If you have digestive imbalances or conditions like IBS, SIBO, and IBD, your fatigue may be coming from your gut [5]. In a meta-analysis of 24 studies, more than 50% of Irritable Bowel Syndrome (IBS) patients were found to have fatigue [6]. Fatigue is also associated with leaky gut, and repairing leaky gut has been shown to reduce fatigue [7, 8, 9].

Studies have found that using probiotics [10, 5, 6] can improve fatigue. This is likely because probiotics reduce gut inflammation, crowd out bad bacteria, and improve leaky gut [11, 12, 13, 14]. To learn more about how to use probiotics, see our Probiotics Starter Guide.

Address Any Underlying Thyroid Dysfunction

Fatigue is one of the main symptoms of hypothyroidism (underactive thyroid). If you have hypothyroid symptoms, including fatigue, hair loss, weight gain, and dry skin, reach out to your medical provider for evaluation.

If you are hypothyroid, treatment with thyroid medication may significantly help your fatigue. However, some people don’t experience adequate fatigue improvement with thyroid medication. That’s because there is a strong connection between thyroid health and gut health. Thyroid patients usually benefit a lot from improving gut health.

Probiotics have been shown to improve the absorption of thyroid medication and to reduce fatigue in hypothyroid patients [15].
Treating gut dysbiosis has also been shown to improve thyroid lab markers [16, 17, 18] and thyroid antibodies [19].

In short, you may experience fatigue relief by improving your thyroid health along with your gut health.

Assess and Restore Your Iron Levels

Iron deficiency anemia is one of the most common causes of fatigue. Your doctor can test your iron levels with a simple iron or ferritin blood test. If you are low in iron, taking an iron supplement may help improve your fatigue [20].

Adequate stomach acid is necessary to absorb iron well, so low stomach acid can contribute to fatigue [21]. Supplemental betaine hydrochloride (HCL) may help you increase your iron levels and improve your fatigue [22, 23].

Avoid taking iron unless you know you are deficient, as excess iron can cause other problems.

Eat for Blood Sugar Balance

Low blood sugar levels can be a cause of fatigue, yawning, sleepiness, and brain fog. Eating a diet that minimizes blood sugar swings can help.

To keep your blood sugar stable, aim to eat a diet low in processed carbohydrates like bread, pasta, crackers, and chips. Eat more whole foods, such as high-quality proteins, healthy fats, and complex, slow-burning carbs, like fruits, vegetables, nuts, whole grains, and seeds.

The paleo diet is a low-carb diet that helps keep blood sugar steady [24, 25].

If you need help changing your diet, reach out to our clinic to learn more about meeting with our health coach.

Avoid Your Food Sensitivities

Food sensitivities can also be a cause of fatigue. For example, 64% of patients with non-celiac gluten sensitivity reported fatigue when they ate gluten [26].

Eating a diet low in common inflammatory foods, like gluten, dairy, or fermentable carbohydrates may minimize foods that can cause immune reactions and fatigue [27, 28].

The low FODMAP diet has specifically been shown to improve fatigue for people with IBS and fibromyalgia [29, 30]. A gluten-free diet like the paleo diet or a low histamine diet are other options that may help, if appropriate for you.

Increase Your Stress Tolerance

Though stress doesn’t fatigue your adrenal glands, it does have documented effects on your mental wellness, memory, immune system, digestion, sleep, and hormones, and can absolutely cause fatigue [31].

Adaptogens are herbs that help your body tolerate stress better and support good energy levels. Rhodiola (Rhodiola rosea), Eleuthero (Eleutherococcus senticosus), and Ginseng (Panax ginseng) have been shown to help reduce fatigue, stress, and exhaustion [32, 33, 34, 35, 36, 37, 38]. Licorice root is commonly recommended to help with fatigue, but there is virtually no research to confirm this.

Lifestyle changes to increase your sleep, and to manage your stress can help you feel less overwhelmed and fatigued by day-to-day stress. Going to bed early, handling sleep problems like sleep apnea, and practicing stress reduction activities like yoga, meditation, exercise, and time in nature can help too.

Supplements to Improve Fatigue

Magnesium [39, 40], B vitamins [40], and vitamin C [41, 42] have been shown to benefit fatigue. Supplementing daily for a short while may improve your fatigue.

Low blood levels of vitamin D have been proposed as a contributor to fatigue in a number of autoimmune health conditions, including lupus [43], rheumatoid arthritis [44], and multiple sclerosis [45]. However, there are few studies that confirm the relationship. So, though there are numerous reasons to take vitamin D, fatigue isn’t one of them.

The Bottom Line

Adrenal fatigue isn’t a real condition, but that doesn’t mean that your fatigue doesn’t need attention.

Healing fatigue is about choosing a strategy that is right for your individual underlying causes. A gut imbalance, anemia, a high stress load, or a poor diet are just a few possible things to consider.

➕ References

Cadegiani FA, Kater CE. Adrenal fatigue does not exist: a systematic review. BMC Endocr Disord. 2016 Aug 24;16(1):48. doi: 10.1186/s12902-016-0128-4. Erratum in: BMC Endocr Disord. 2016 Nov 16;16(1):63. PMID: 27557747; PMCID: PMC4997656.
Schumacher S, Niemeyer H, Engel S, Cwik JC, Laufer S, Klusmann H, Knaevelsrud C. HPA axis regulation in posttraumatic stress disorder: A meta-analysis focusing on potential moderators. Neurosci Biobehav Rev. 2019 May;100:35-57. doi: 10.1016/j.neubiorev.2019.02.005. Epub 2019 Feb 19. PMID: 30790632.
Klaassens ER, Giltay EJ, Cuijpers P, van Veen T, Zitman FG. Adulthood trauma and HPA-axis functioning in healthy subjects and PTSD patients: a meta-analysis. Psychoneuroendocrinology. 2012 Mar;37(3):317-31. doi: 10.1016/j.psyneuen.2011.07.003. Epub 2011 Jul 29. PMID: 21802212.
https://www.niddk.nih.gov/health-information/endocrine-diseases/adrenal-insufficiency-addisons-disease/definition-facts
Frändemark Å, Jakobsson Ung E, Törnblom H, Simrén M, Jakobsson S. Fatigue: a distressing symptom for patients with irritable bowel syndrome. Neurogastroenterol Motil. 2017 Jan;29(1). doi: 10.1111/nmo.12898. Epub 2016 Jul 11. PMID: 27401139.
Han CJ, Yang GS. Fatigue in Irritable Bowel Syndrome: A Systematic Review and Meta-analysis of Pooled Frequency and Severity of Fatigue. Asian Nurs Res (Korean Soc Nurs Sci). 2016 Mar;10(1):1-10. doi: 10.1016/j.anr.2016.01.003. Epub 2016 Feb 1. PMID: 27021828.
Maes M, Leunis JC. Normalization of leaky gut in chronic fatigue syndrome (CFS) is accompanied by a clinical improvement: effects of age, duration of illness and the translocation of LPS from gram-negative bacteria. Neuro Endocrinol Lett. 2008 Dec;29(6):902-10. PMID: 19112401.
Maes M, Coucke F, Leunis JC. Normalization of the increased translocation of endotoxin from gram negative enterobacteria (leaky gut) is accompanied by a remission of chronic fatigue syndrome. Neuro Endocrinol Lett. 2007 Dec;28(6):739-44. PMID: 18063928.
Maes M, Kubera M, Leunis JC. The gut-brain barrier in major depression: intestinal mucosal dysfunction with an increased translocation of LPS from gram negative enterobacteria (leaky gut) plays a role in the inflammatory pathophysiology of depression. Neuro Endocrinol Lett. 2008 Feb;29(1):117-24. PMID: 18283240.
McFarland LV, Dublin S. Meta-analysis of probiotics for the treatment of irritable bowel syndrome. World J Gastroenterol. 2008 May 7;14(17):2650-61. doi: 10.3748/wjg.14.2650. PMID: 18461650; PMCID: PMC2709042.
Leblhuber F, Steiner K, Schuetz B, Fuchs D, Gostner JM. Probiotic Supplementation in Patients with Alzheimer’s Dementia – An Explorative Intervention Study. Curr Alzheimer Res. 2018;15(12):1106-1113. doi: 10.2174/1389200219666180813144834. PMID: 30101706; PMCID: PMC6340155.
Wang F, Feng J, Chen P, Liu X, Ma M, Zhou R, Chang Y, Liu J, Li J, Zhao Q. Probiotics in Helicobacter pylori eradication therapy: Systematic review and network meta-analysis. Clin Res Hepatol Gastroenterol. 2017 Sep;41(4):466-475. doi: 10.1016/j.clinre.2017.04.004. Epub 2017 May 25. PMID: 28552432.
García-Collinot G, Madrigal-Santillán EO, Martínez-Bencomo MA, Carranza-Muleiro RA, Jara LJ, Vera-Lastra O, Montes-Cortes DH, Medina G, Cruz-Domínguez MP. Effectiveness of Saccharomyces boulardii and Metronidazole for Small Intestinal Bacterial Overgrowth in Systemic Sclerosis. Dig Dis Sci. 2020 Apr;65(4):1134-1143. doi: 10.1007/s10620-019-05830-0. Epub 2019 Sep 23. PMID: 31549334.
Greco A, Caviglia GP, Brignolo P, Ribaldone DG, Reggiani S, Sguazzini C, Smedile A, Pellicano R, Resegotti A, Astegiano M, Bresso F. Glucose breath test and Crohn’s disease: Diagnosis of small intestinal bacterial overgrowth and evaluation of therapeutic response. Scand J Gastroenterol. 2015;50(11):1376-81. doi: 10.3109/00365521.2015.1050691. Epub 2015 May 19. PMID: 25990116.
Talebi S, Karimifar M, Heidari Z, Mohammadi H, Askari G. The effects of synbiotic supplementation on thyroid function and inflammation in hypothyroid patients: A randomized, double‑blind, placebo‑controlled trial. Complement Ther Med. 2020 Jan;48:102234. doi: 10.1016/j.ctim.2019.102234. Epub 2019 Nov 3. PMID: 31987229.
Ribichini D, Fiorini G, Repaci A, Castelli V, Gatta L, Vaira D, Pasquali R. Tablet and oral liquid L-thyroxine formulation in the treatment of naïve hypothyroid patients with Helicobacter pylori infection. Endocrine. 2017 Sep;57(3):394-401. doi: 10.1007/s12020-016-1167-3. Epub 2016 Nov 15. PMID: 27848196.
Bugdaci MS, Zuhur SS, Sokmen M, Toksoy B, Bayraktar B, Altuntas Y. The role of Helicobacter pylori in patients with hypothyroidism in whom could not be achieved normal thyrotropin levels despite treatment with high doses of thyroxine. Helicobacter. 2011 Apr;16(2):124-30. doi: 10.1111/j.1523-5378.2011.00830.x. Erratum in: Helicobacter. 2011 Dec;16(6):482. Albayrak, Banu [corrected to Bayraktar, Banu]. PMID: 21435090.
Centanni M, Gargano L, Canettieri G, Viceconti N, Franchi A, Delle Fave G, Annibale B. Thyroxine in goiter, Helicobacter pylori infection, and chronic gastritis. N Engl J Med. 2006 Apr 27;354(17):1787-95. doi: 10.1056/NEJMoa043903. PMID: 16641395.
Bertalot G, Montresor G, Tampieri M, Spasiano A, Pedroni M, Milanesi B, Favret M, Manca N, Negrini R. Decrease in thyroid autoantibodies after eradication of Helicobacter pylori infection. Clin Endocrinol (Oxf). 2004 Nov;61(5):650-2. doi: 10.1111/j.1365-2265.2004.02137.x. PMID: 15521972.
DeLoughery TG. Iron Deficiency Anemia. Med Clin North Am. 2017 Mar;101(2):319-332. doi: 10.1016/j.mcna.2016.09.004. Epub 2016 Dec 8. PMID: 28189173.
Toh BH. Pathophysiology and laboratory diagnosis of pernicious anemia. Immunol Res. 2017 Feb;65(1):326-330. doi: 10.1007/s12026-016-8841-7. PMID: 27538411.
Yago MR, Frymoyer AR, Smelick GS, Frassetto LA, Budha NR, Dresser MJ, Ware JA, Benet LZ. Gastric reacidification with betaine HCl in healthy volunteers with rabeprazole-induced hypochlorhydria. Mol Pharm. 2013 Nov 4;10(11):4032-7. doi: 10.1021/mp4003738. Epub 2013 Sep 10. PMID: 23980906; PMCID: PMC3946491.
Yago MR, Frymoyer A, Benet LZ, Smelick GS, Frassetto LA, Ding X, Dean B, Salphati L, Budha N, Jin JY, Dresser MJ, Ware JA. The use of betaine HCl to enhance dasatinib absorption in healthy volunteers with rabeprazole-induced hypochlorhydria. AAPS J. 2014 Nov;16(6):1358-65. doi: 10.1208/s12248-014-9673-9. Epub 2014 Oct 2. PMID: 25274610; PMCID: PMC4389759.
Masharani U, Sherchan P, Schloetter M, Stratford S, Xiao A, Sebastian A, Nolte Kennedy M, Frassetto L. Metabolic and physiologic effects from consuming a hunter-gatherer (Paleolithic)-type diet in type 2 diabetes. Eur J Clin Nutr. 2015 Aug;69(8):944-8. doi: 10.1038/ejcn.2015.39. Epub 2015 Apr 1. PMID: 25828624.
Jönsson T, Granfeldt Y, Ahrén B, Branell UC, Pålsson G, Hansson A, Söderström M, Lindeberg S. Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovasc Diabetol. 2009 Jul 16;8:35. doi: 10.1186/1475-2840-8-35. PMID: 19604407; PMCID: PMC2724493.
Volta U, Bardella MT, Calabrò A, Troncone R, Corazza GR; Study Group for Non-Celiac Gluten Sensitivity. An Italian prospective multicenter survey on patients suspected of having non-celiac gluten sensitivity. BMC Med. 2014 May 23;12:85. doi: 10.1186/1741-7015-12-85. PMID: 24885375; PMCID: PMC4053283.
Whalen KA, McCullough ML, Flanders WD, Hartman TJ, Judd S, Bostick RM. Paleolithic and Mediterranean Diet Pattern Scores Are Inversely Associated with Biomarkers of Inflammation and Oxidative Balance in Adults. J Nutr. 2016 Jun;146(6):1217-26. doi: 10.3945/jn.115.224048. Epub 2016 Apr 20. PMID: 27099230; PMCID: PMC4877627.
Olendzki BC, Silverstein TD, Persuitte GM, Ma Y, Baldwin KR, Cave D. An anti-inflammatory diet as treatment for inflammatory bowel disease: a case series report. Nutr J. 2014 Jan 16;13:5. doi: 10.1186/1475-2891-13-5. PMID: 24428901; PMCID: PMC3896778.
Altobelli E, Del Negro V, Angeletti PM, Latella G. Low-FODMAP Diet Improves Irritable Bowel Syndrome Symptoms: A Meta-Analysis. Nutrients. 2017 Aug 26;9(9):940. doi: 10.3390/nu9090940. PMID: 28846594; PMCID: PMC5622700.
Marum AP, Moreira C, Saraiva F, Tomas-Carus P, Sousa-Guerreiro C. A low fermentable oligo-di-mono saccharides and polyols (FODMAP) diet reduced pain and improved daily life in fibromyalgia patients. Scand J Pain. 2016 Oct;13:166-172. doi: 10.1016/j.sjpain.2016.07.004. Epub 2016 Aug 22. PMID: 28850525.
Yaribeygi H, Panahi Y, Sahraei H, Johnston TP, Sahebkar A. The impact of stress on body function: A review. EXCLI J. 2017 Jul 21;16:1057-1072. doi: 10.17179/excli2017-480. PMID: 28900385; PMCID: PMC5579396.
Olsson EM, von Schéele B, Panossian AG. A randomised, double-blind, placebo-controlled, parallel-group study of the standardised extract shr-5 of the roots of Rhodiola rosea in the treatment of subjects with stress-related fatigue. Planta Med. 2009 Feb;75(2):105-12. doi: 10.1055/s-0028-1088346. Epub 2008 Nov 18. PMID: 19016404.
Anghelescu IG, Edwards D, Seifritz E, Kasper S. Stress management and the role of Rhodiola rosea: a review. Int J Psychiatry Clin Pract. 2018 Nov;22(4):242-252. doi: 10.1080/13651501.2017.1417442. Epub 2018 Jan 11. PMID: 29325481.
Ross SM. Burnout: A Multicenter Exploratory Clinical Trial With a Proprietary Extract of Rhodiola rosea in Patients With Burnout Syndrome. Holist Nurs Pract. 2018 Nov/Dec;32(6):336-339. doi: 10.1097/HNP.0000000000000299. PMID: 30320658.
Edwards D, Heufelder A, Zimmermann A. Therapeutic effects and safety of Rhodiola rosea extract WS® 1375 in subjects with life-stress symptoms–results of an open-label study. Phytother Res. 2012 Aug;26(8):1220-5. doi: 10.1002/ptr.3712. Epub 2012 Jan 6. PMID: 22228617.
Arring NM, Millstine D, Marks LA, Nail LM. Ginseng as a Treatment for Fatigue: A Systematic Review. J Altern Complement Med. 2018 Jul;24(7):624-633. doi: 10.1089/acm.2017.0361. Epub 2018 Apr 6. PMID: 29624410.
Guo M, Ding S, Zhao C, Gu X, He X, Huang K, Luo Y, Liang Z, Tian H, Xu W. Red Ginseng and Semen Coicis can improve the structure of gut microbiota and relieve the symptoms of ulcerative colitis. J Ethnopharmacol. 2015 Mar 13;162:7-13. doi: 10.1016/j.jep.2014.12.029. Epub 2014 Dec 30. PMID: 25554637.
Jacquet A, Grolleau A, Jove J, Lassalle R, Moore N. Burnout: evaluation of the efficacy and tolerability of TARGET 1® for professional fatigue syndrome (burnout). J Int Med Res. 2015 Feb;43(1):54-66. doi: 10.1177/0300060514558324. Epub 2014 Dec 23. PMID: 25537278.
Cox IM, Campbell MJ, Dowson D. Red blood cell magnesium and chronic fatigue syndrome. Lancet. 1991 Mar 30;337(8744):757-60. doi: 10.1016/0140-6736(91)91371-z. PMID: 1672392.
Kennedy DO, Veasey RC, Watson AW, Dodd FL, Jones EK, Tiplady B, Haskell CF. Vitamins and psychological functioning: a mobile phone assessment of the effects of a B vitamin complex, vitamin C and minerals on cognitive performance and subjective mood and energy. Hum Psychopharmacol. 2011 Jun-Jul;26(4-5):338-47. doi: 10.1002/hup.1216. Epub 2011 Jul 12. PMID: 21751253.
Suh SY, Bae WK, Ahn HY, Choi SE, Jung GC, Yeom CH. Intravenous vitamin C administration reduces fatigue in office workers: a double-blind randomized controlled trial. Nutr J. 2012 Jan 20;11:7. doi: 10.1186/1475-2891-11-7. PMID: 22264303; PMCID: PMC3273429.
Johnston CS, Barkyoumb GM, Schumacher SS. Vitamin C supplementation slightly improves physical activity levels and reduces cold incidence in men with marginal vitamin C status: a randomized controlled trial. Nutrients. 2014 Jul 9;6(7):2572-83. doi: 10.3390/nu6072572. PMID: 25010554; PMCID: PMC4113757.
Nguyen MH, Bryant K, O’Neill SG. Vitamin D in SLE: a role in pathogenesis and fatigue? A review of the literature. Lupus. 2018 Nov;27(13):2003-2011. doi: 10.1177/0961203318796293. Epub 2018 Aug 29. PMID: 30157716.
Jelsness-Jørgensen LP, Grøvle L, Julsrud Haugen A. Association between vitamin D and fatigue in patients with rheumatoid arthritis: a cross-sectional study. BMJ Open. 2020 Feb 6;10(2):e034935. doi: 10.1136/bmjopen-2019-034935. PMID: 32034029; PMCID: PMC7044854.
Beckmann Y, Türe S, Duman SU. Vitamin D deficiency and its association with fatigue and quality of life in multiple sclerosis patients. EPMA J. 2019 Nov 20;11(1):65-72. doi: 10.1007/s13167-019-00191-0. PMID: 32140186; PMCID: PMC7028884.