Managing Hypermobile Ehlers-Danlos Syndrome: A Naturopathic Approach to Whole-Body Wellness

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder primarily characterized by joint hypermobility, chronic pain, and a range of other systemic symptoms. Though often underdiagnosed, hEDS can have a significant impact on a patient's quality of life. Naturopathic medicine offers a holistic approach to managing hEDS, focusing on treating the whole person and addressing underlying issues.

What is hEDS?

Ehlers-Danlos Syndromes (EDS) are a group of heritable connective tissue disorders affecting collagen, a key protein that provides structure and strength to various tissues in the body. Hypermobile Ehlers-Danlos Syndrome (hEDS) is the most common subtype, marked by joint hypermobility, musculoskeletal pain, and frequent dislocations or subluxations. In addition to joint-related symptoms, patients with hEDS may experience:

• Gastrointestinal issues (e.g. irritable bowel syndrome – IBS)

• Dysautonomia (e.g. postural orthostatic tachycardia syndrome – POTS)

• Fatigue and sleep disturbances

• Easy bruising and poor wound healing

• Anxiety and mood disorders

The condition can vary widely in its severity, from mild joint hypermobility to disabling chronic pain and multi-systemic issues. Diagnosis of hEDS is primarily clinical, relying on a combination of patient history, physical examination, and established criteria.

Conventional Management of hEDS

Conventional treatment of hEDS often involves a multidisciplinary approach, including physical therapy, pain management, and medications to control symptoms. While these interventions can help manage some aspects of the condition, many patients seek additional support to address the chronic and systemic nature of hEDS. This is where naturopathic medicine can offer valuable adjunctive care.

Naturopathic Approach to hEDS

Naturopathic doctors (NDs) focus on treating the underlying causes of disease while emphasizing lifestyle changes, natural therapies, and patient education. For hEDS patients, a naturopathic approach includes:

1. Nutritional Support

   An anti-inflammatory diet incorporating omega-3 fatty acids to help reduce systemic inflammation can be helpful in managing chronic pain associated with hEDS. Other essential nutrients to include are vitamin C (a key co-factor in collagen synthesis) and zinc (important for tissue repair and immune function).

2. Digestive Health

   Irritable bowel syndrome (IBS) is a common symptom in patients with hEDS, utilizing probiotics to maintain a balanced gut microbiome, recommending a high fiber diet to support gut motility and identify and eliminating food sensitives can also be beneficial for patients with hEDS to reduce inflammation within the body and alleviate symptoms of IBS.

3. Movement

   Exercise programs that focus on low-impact activities and emphasize gentle, controlled movements to support muscle recovery and alleviate pain would be ideal for patients with hEDS.

4. Nervous System Support

   Using mind-body practices such as meditation, yoga and/or breathing exercises can support the autonomic regulation and reduce anxiety and pain perception in patients with hEDS. Adaptogenic herbs has also been shown to help modulate the body’s stress response.

5. Pain Management

   Anti-inflammatory herbs such as ginger, turmeric or Boswellia can help reduce inflammation and pain. Acupuncture has also been beneficial for some patients who experience chronic pain from hEDS.

6. Sleep Optimization

   Sleep disturbances can be common in patients with hEDS. Utilizing herbal supports and nutraceuticals such as passionflower and magnesium can help promote relaxation and improve quality of sleep in hEDS patients.

Hypermobile Ehlers-Danlos Syndrome is a complex condition that affects multiple body systems. While conventional management is crucial for stabilizing joints and managing acute symptoms, naturopathic medicine offers a comprehensive approach that addresses the underlying causes, supports overall health, and empowers patients with hEDS to take an active role in their care. Through nutritional support, digestive health optimization, nervous system regulation, pain management and sleep optimization, NDs can help patients with hEDS improve their quality of life and manage symptoms more effectively.

 In health,

Dr. Sami Leung, ND

References:

1. Castori, M., Morlino, S., Pascolini, G., Blundo, C., & Grammatico, P. (2015). Gastrointestinal and nutritional issues in joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. American journal of medical genetics. Part C, Seminars in medical genetics, 169C(1), 54–75. https://doi.org/10.1002/ajmg.c.31431

2. Chopra, P., Tinkle, B., Hamonet, C., Brock, I., Gompel, A., Bulbena, A., & Francomano, C. (2017). Pain management in the Ehlers-Danlos syndromes. American journal of medical genetics. Part C, Seminars in medical genetics, 175(1), 212–219. https://doi.org/10.1002/ajmg.c.31554

3. Demes, J. S., McNair, B., & Taylor, M. R. G. (2020). Use of complementary therapies for chronic pain management in patients with reported Ehlers-Danlos syndrome or hypermobility spectrum disorders. American journal of medical genetics. Part A, 182(11), 2611–2623. https://doi.org/10.1002/ajmg.a.61837

4. Do, T., Diamond, S., Green, C., & Warren, M. (2021). Nutritional Implications of Patients with Dysautonomia and Hypermobility Syndromes. Current nutrition reports, 10(4), 324–333. https://doi.org/10.1007/s13668-021-00373-1

5. Doyle, T. A., & Halverson, C. M. E. (2022). Use of complementary and alternative medicine by patients with hypermobile Ehlers-Danlos Syndrome: A qualitative study. Frontiers in medicine, 9, 1056438. https://doi.org/10.3389/fmed.2022.1056438

6. Guedry, S. E., Langley, B. O., Schaefer, K., & Hanes, D. A. (2024). Integrative medicine for hypermobility spectrum disorders (HSD) and Ehlers-Danlos syndromes (EDS): a feasibility study. Disability and rehabilitation, 1–14. Advance online publication. https://doi.org/10.1080/09638288.2024.2314713

7. Hakim, A. (2004). Hypermobile Ehlers-Danlos Syndrome. In M. P. Adam (Eds.) et. al., GeneReviews®. University of Washington, Seattle.

8. Heds Body System. The Ehlers Danlos Society. (2024, September 12). https://www.ehlers-danlos.com/heds/

9. Langevin, H. M., Churchill, D. L., Wu, J., Badger, G. J., Yandow, J. A., Fox, J. R., & Krag, M. H. (2002). Evidence of connective tissue involvement in acupuncture. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 16(8), 872–874. https://doi.org/10.1096/fj.01-0925fje

10. Mantle, D., Wilkins, R. M., & Preedy, V. (2005). A novel therapeutic strategy for Ehlers-Danlos syndrome based on nutritional supplements. Medical hypotheses, 64(2), 279–283. https://doi.org/10.1016/j.mehy.2004.07.023

11. Pullar, J. M., Carr, A. C., & Vissers, M. C. M. (2017). The Roles of Vitamin C in Skin Health. Nutrients, 9(8), 866. https://doi.org/10.3390/nu9080866

12. Topan, R., Pandya, S., Williams, S., Ruffle, J. K., Zarate-Lopez, N., Aziz, Q., & Fikree, A. (2024). Comprehensive Assessment of Nutrition and Dietary Influences in Hypermobile Ehlers-Danlos Syndrome-A Cross-Sectional Study. The American journal of gastroenterology, 119(4), 727–738. https://doi.org/10.14309/ajg.0000000000002586

13. Song, B., Yeh, P., Nguyen, D., Ikpeama, U., Epstein, M., & Harrell, J. (2020). Ehlers-Danlos Syndrome: An Analysis of the Current Treatment Options. Pain physician, 23(4), 429–438.

Harnessing the Power of Fibre

It is easy to overlook the importance of dietary choices in safeguarding against various ailments. One such silent protector in our diet is fibre, a nutrient with profound implications for our digestive health and, notably, in the prevention of colorectal cancer. Colorectal cancer is the 4th most diagnosed cancer in Canada[i], and lifestyle factors such as diet can play a significant role in its development.

At Saskatoon Naturopathic Medicine, we practice a comprehensive approach to wellness, and understanding the role of fibre in colorectal cancer is paramount.

What is fibre?

Fibre is the portion from plant-based foods that our bodies cannot fully digest and end up being fermented or broken down by the bacteria that live in our digestive tracts (called the gut microbiome).

The fermentation of fibre by our gut bacteria produces short-chain fatty acids (SCFAs) including butyrate, which is the main source of energy for colon cells.

Why is fibre important?

Fibre helps move substances through our GI system, thereby facilitating the elimination of carcinogenic substances. Additionally, the SCFAs (including butyrate) have anti-inflammatory, immune-modulating, and anti-carcinogenic effects on the cells of our colon and help slow the growth of colon cancer cells.

Gut Dysbiosis

Our diet plays an important role in balancing the bacterial populations that make up our gut microbiome. Diets that are higher in fibre help to promote bacteria that produce butyrate and reduce inflammation. Diets low in fibre can lead to gut dysbiosis (a decrease in the beneficial bacteria and an increase in bacteria that promote inflammation).

We believe in empowering our patients with actionable steps to optimize their health. Here are some practical tips for incorporating more fibre into your diet:

• Embrace whole foods over refined, highly-processed options.

• Load up on produce, aiming for a colorful variety to maximize your nutrient intake.

• Snack smart to curb cravings and boost fibre intake throughout the day.

• Experiment with legumes in soups, salads, and stews.

Great sources of fibre for fermentation, butyrate production, and promoting microbiome diversity include soluble fibres such as:

Beta-glucans – oats, barley, sorghum, rye, mushrooms

Pectins – Apples, oranges, apricots, white beans, black beans

Inulin – Agave, artichokes, asparagus, bananas, chicory root, garlic, onions, leeks, wheat

A diet rich in a variety of dietary sources of fibre is beneficial for health – it helps substances move through the gut, balances sugar and cholesterol levels, and promotes a healthy gut microbiome. Aim for 30 grams of fibre per day from foods including grains, vegetables, fruits, legumes, nuts and seeds.

We stand committed to guiding you on your journey to vibrant health, one fibre-filled meal at a time.

[i] https://www.colorectalcancercanada.com/colorectal-cancer/statistics/

Sources:

Fratila, T. D., Ismaiel, A., & Dumitrascu, D. L. (2023). Microbiome modulation in the prevention and management of colorectal cancer: A systematic review of clinical interventions. Medicine and Pharmacy Reports, 96(2), 131–145. https://doi.org/10.15386/mpr-2526

Madrigal-Matute, J., & Bañón-Escandell, S. (2023). Colorectal Cancer and Microbiota Modulation for Clinical Use. A Systematic Review. Nutrition and Cancer, 75(1), 123–139. https://doi.org/10.1080/01635581.2022.2108468

Rinninella, E., Mele, M. C., Cintoni, M., Raoul, P., Ianiro, G., Salerno, L., Pozzo, C., Bria, E., Muscaritoli, M., Molfino, A., & Gasbarrini, A. (2020). The Facts about Food after Cancer Diagnosis: A Systematic Review of Prospective Cohort Studies. Nutrients, 12(8), 2345. https://doi.org/10.3390/nu12082345

Holscher, H. D. (2017). Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes, 8(2), 172–184. https://doi.org/10.1080/19490976.2017.1290756

Bashir, K. M. I., & Choi, J.-S. (2017). Clinical and Physiological Perspectives of β-Glucans: The Past, Present, and Future. International Journal of Molecular Sciences, 18(9), 1906. https://doi.org/10.3390/ijms18091906

Ross, J. K., English, C., & Perlmutter, C. A. (1985). Dietary fiber constituents of selected fruits and vegetables. Journal of the American Dietetic Association, 85(9), 1111–1116.

Tosif, M. M., Najda, A., Bains, A., Kaushik, R., Dhull, S. B., Chawla, P., & Walasek-Janusz, M. (2021). A Comprehensive Review on Plant-Derived Mucilage: Characterization, Functional Properties, Applications, and Its Utilization for Nanocarrier Fabrication. Polymers, 13(7), 1066. https://doi.org/10.3390/polym13071066

Dhingra, D., Michael, M., Rajput, H., & Patil, R. T. (2012). Dietary fibre in foods: A review. Journal of Food Science and Technology, 49(3), 255–266. https://doi.org/10.1007/s13197-011-0365-5

Probiotics, Your Microbiome and Your Mood

Have you ever noticed that what you eat impacts your mood? Have you felt worse after binging on junk food or after a night of drinking? There is compelling research suggesting that it may not be just the guilt talking - your microbiome may be contributing in a large way to the conversation.  

What is the microbiome?  

There are 10- to 100-trillion symbiotic microbes of various species existing in and around the human body, collectively referred to as the microbiome [1]. These friendly microbes outnumber your own human cells and have recently become popularized for the growing body of evidence detailing the vast impacts they have on human physiology and behaviour. 

The microbes in your intestines make vitamins, amino acids, hormones, neurotransmitters and other signaling molecules that impact the way your brain and body function [2], [3]. They also produce short-chain fatty acids as byproducts that your intestinal cells use for energy, which contributes to healthy gut function [3].  

These microbes live in our digestive tract and survive off the foods that we eat. Just like any other living organism, their health (and therefore ours) depends on consuming a healthy diet. It has been shown that dietary changes (e.g. from animal-based to plant-based), as well as any significant systemic stress and inflammation can alter the composition (i.e. diversity and abundance of species) of your microbiome within just 24 hours [3].  

Altered microbiome composition has been associated with many conditions, such as inflammatory bowel disease (IBD), psoriasis, atopic dermatitis, autoimmune arthritis, type 2 diabetes, obesity, and atherosclerosis [3]. This is not surprising given the significant role these organisms have in regulating metabolism and immunity. In fact, researchers are finding that the microbiome composition in a given disease seem to have a different complement of microbes associated with it. For example, an IBD microbiome has less diversity (fewer species of healthy microbes), and lower numbers of good bacterial species. Therefore, it has lower short-chain fatty acid production [3]. Short-chain fatty acids (SCFAs) are essential to the health of your intestinal cells and are also thought to be anti-inflammatory in the gut [3]. 

The Microbiome’s Effect on Mood & Behaviour  

Gut microbes relay messages to the brain via various direct and indirect mechanisms - bacterial metabolites, metabolic precursors, immune signalling, vagus nerve signalling, and Hypothalamic Pituitary-Adrenal axis activation [4], [5]. It is through these mechanisms that neurodevelopment or neurodegeneration are influenced [5]. A significant portion of the microbiome influence on the brain comes via the gut-brain axis: a bi-directional pathway connecting the nervous system in your digestive tract to the central nervous system (your brain) [4], [5]. As shown in the graphic below, your gut and your brain communicate directly via nerves that transmit different signals and molecules, which can have a profound effect both ways to both systems [6].

Photo credit: https://fhs.mcmaster.ca/forsythe-lab/microbiota_gut_brain_axis.html 

Considering the gut-brain axis and the physical manifestations that different microbiome composition can produce, it should be no surprise that there are mental/emotional implications as well. Many psychiatric and neurological pathologies have gastrointestinal co-morbidities, including schizophrenia, autism, neurodegenerative diseases, anxiety, and depression [7]. As noted above, different pathologies have different microbiome composition. This extends to mood and neurodegenerative disorders, such as major depressive disorder, schizophrenia, Parkinson’s disease, and autism spectrum disorder [2], [5], [8]. There is also data suggesting that alterations in the microbiome from addictions (e.g. alcohol, cocaine) may be associated with substance cravings and increased risk of developing associated psychiatric disorders, such as anxiety and depression [9], [10]. 

Probiotics & Your Mood 

Probiotics are supplements that contain healthy microbes that ,when ingested, influence the health of your microbiome. Probiotics used to benefit mood and cognition have been coined “psychobiotics,” and are a burgeoning new area of interest in research. A study by Tillisch et al. used brain scans (functional magnetic resonance imaging) to demonstrate the ability of probiotics to alter brain activity in areas associated with processing emotion and sensation, and to reduce negative thinking associated with sad mood [4], [7], [11], [12]. While most studies indicate that further research in this area is needed, associations between specific strains of microbial species and their benefits on various conditions are rapidly emerging [7], [13][14]. A recent human clinical trial of adjunctive probiotic intervention for Major Depressive Disorder (MDD) showed that compared with placebo, probiotic intervention exhibited greater improvement in depressive symptoms [15]. Participants who received the probiotic intervention experienced reductions in both depression and anxiety, and the probiotics were well-tolerated, prompting the authors to suggest probiotics as an acceptable adjunctive intervention for adults with MDD [15]. 

How Can I Support My Microbiome? 

Lifestyle 

A healthy lifestyle goes a long way in supporting your microbiome, and healthy eating is just one part of it. As mentioned earlier, dietary changes, significant systemic stress, and inflammation can alter your microbiome within just 24 hours. There are many different types of stress - physical, mental and emotional - that can lead to physiologic changes that can alter the microbiome. Practicing stress management through self-care, meditation, social connection, thoughtful schedule planning, getting adequate sleep, and setting appropriate boundaries with people and responsibilities will help you be more resilient in dealing with stress. The better you are at managing stress, the less likely it will spill over into added physical or mood-related symptoms.  

Digestive Supports 

Probiotics are a great start to improving your gut health and mood, though quality and potency matter!  Our naturopathic doctors are here to assess if and which type of probiotics are most suitable for you, as well as to review if any further testing or treatments are indicated to optimize your digestive and mental health.  

We are here to help, so reach out if you are looking for professional guidance! 

In Health,  

Dr. Jacalyn Sieben, ND 

[1] Ursell, L.K. et al. (2012). Defining the human microbiome. Nutrition Reviews. Vol. 70 (Suppl. 1):S38- S44. doi:10.1111/j.1753-4887.2012.00493.x

[2] Dinan, T.G. & Cryan, J.F. Mood by microbe: Towards clinical translation. Genome Medicine. 8:36. DOI  10.1186/s13073-016-0292-1

[3] Corfe, B.M. et al. (2015). The multifactorial interplay of diet, the microbiome, and appetite control:  current knowledge and future challenges. Proceedings of the Nutrition Society. 74, 235-244.  doi:10.1017/S0029665114001670

[4] Dinan, T.G., Stilling, R.M., Stanton, C., Cryan, J.F. (2015). Collective unconscious: How gut microbes shape human behavior. Journal of Psychiatric Research. 63:1-9. http://dx.doi.org/10.1016/ j.jpsychires.2015.02.021

[5] Sharon, G. et al. (2016). The central nervous system and the gut microbiome. Cell. 167. http:// dx.doi.org/10.1016/j.cell.2016.10.027

[6] McMaster University. (2019). The microbiota-gut-brain axis. [Digital Image] Retrieved from: https:// fhs.mcmaster.ca/forsythe-lab/microbiota_gut_brain_axis.html

[7] Sampson, T.R. & Mazmanian, S.K. (2015). Control of brain development, function, and behavior by the microbiome. Cell Host & Microbe. http://dx.doi.org/10.1016/j.chom.2015.04.011

[8] Jiang, H. et al. (2015). Altered fecal microbiota composition in patients with major depressive disorder. Brain, Behavior, and Immunity. 48:186-194. http://dx.doi.org/10.1016/j.bbi.2015.03.016

[9] Hillemacher, T., et al. (2018). Alcohol, microbiome, and their effect on psychiatric disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry. Volume 85, Pages 105-115. https://doi.org/ 10.1016/j.pnpbp.2018.04.015

[10] Kiraly, D.D. et al. (2016). Alterations of the host microbiome affect behavioral responses to cocaine. Scientific Reports. 6:35455. DOI: 10.1038/srep35455

[11] Rea, K., Dinan, T.G., Cryan, J.F. (2016). The microbiome: A key regulator of stress and neuroinflammation. Neurobiology of Stress. 23-33. http://dx.doi.org/10.1016/j.ynstr.2016.03.001

[12] Tillisch, K., Labus, J., Kilpatrick, L., Jiang, Z., Stains, J., Ebrat, B., Guyonnet, D., Legrain-Raspaud, S., Trotin, B., Naliboff, B., et al. (2013). Consumption of fermented milk product with probiotic modulates brain activity. Gastroenter- ology 144, 1394–1401. DOI: https://doi.org/10.1053/j.gastro.2013.02.043

[13] Foster, J.A., Rinaman, L., & Cryan, J.F. (2017). Stress & the gut-brain axis: Regulation by the microbiome. Neurobiology of Stress. 124-136. http://dx.doi.org/10.1016/j.ynstr.2017.03.0 01

[14] Sarkar, A. et al. (2016). Psychobiotics and the manipulation of bacteria-gut-brain signals. Trends in Neurosciences. Vol 39, No. 11. http://dx.doi.org/10.1016/j.tins.2016.09.002

[15] Nikolova VL, Cleare AJ, Young AH, Stone JM. (2023). Acceptability, Tolerability, and Estimates of Putative Treatment Effects of Probiotics as Adjunctive Treatment in Patients with Depression: A Randomized Clinical Trial. JAMA Psychiatry. doi:10.1001/jamapsychiatry.2023.1817

Lower Blood Sugar and Cholesterol and Improve Heart Health with Berberine!

BERBERINE AND CARDIOMETABOLIC HEALTH

Berberis Vulgaris (Barberry)

Berberine is a bright yellow-coloured alkaloid compound found in many plants, some of the more common ones including Hydrastis canadensis (goldenseal), Berberis vulgaris (barberry), Coptis chinensis (Chinese goldthread), and Berberis aquifolium (Oregon grape). Berberine has been used traditionally to combat inflammatory disorders, infectious diseases, diabetes, digestive disorders and many others, and has demonstrated benefits on blood sugar metabolism, cardiovascular effects, cholesterol and atherosclerosis.

Berberine appears to exert its cardiovascular effects through various mechanisms that play a role in protecting the blood vessels, decreasing inflammation and modulating levels of cholesterol and blood sugar. Berberine has been shown to affect the modulation of an enzyme called adenosine monophosphate-activated protein kinase (AMPK). AMPK is responsible for maintaining healthy blood vessels through a variety of different mechanisms, including the regulation of another enzyme, called endothelial nitric oxide synthase (eNOS), which is responsible for producing nitric oxide in the cell layer lining our blood vessels. Nitric oxide is important in regulating how our blood vessels dilate (which plays a role in our blood pressure), platelet and white blood cell activation and adhesion (which plays a role in the development of arterial plaques), and antioxidant functions (which is important for preventing damage from free radicals like glycated blood sugar, which is prevalent in diabetes). In simpler terms, AMPK and eNOS are important for maintaining a healthy cardiovascular system. When eNOS is not functioning properly, it can contribute to the development of high blood pressure, diabetes and high cholesterol. Berberine has been found to increase the production of nitric oxide through enhancing activity of eNOS [1, 2, 6, 7].

Current research on berberine has been focused on its metabolic and cardiovascular properties. A research study suggested that berberine was shown to decrease levels of total cholesterol, triglycerides and LDL cholesterol levels, while increasing HDL-cholesterol (which is thought to be protective, or the “good” cholesterol). A meta-analysis demonstrated that the addition of berberine to simvastatin, a cholesterol-lowering drug, resulted in a greater reduction of triglycerides and total cholesterol, and a reduction in the number of side effects, compared to the use of simvastatin on its own [5].

Berberine also benefits blood sugar levels and reduces body fat mass. A research study on diabetic patients showed that those who were given berberine had a reduction in blood sugar levels and cholesterol levels, and those with metabolic syndrome also experienced a decrease in their body mass index (BMI) and waist circumference [3]. A study on women with polycystic ovary syndrome (PCOS), a disorder characterized by insulin-insensitivity, obesity and high cholesterol, found that berberine decreased waist circumference and waist-to-hip ratio, insulin sensitivity and blood sugars and cholesterol levels comparable and/or superior to that of metformin [4].

Berberine is generally well-tolerated, and side effects of usage are usually mild in nature, such as abdominal discomfort, diarrhea, constipation, decreased appetite, and dermatological rashes. Berberine may interfere with certain medications and may not be suitable for everyone. As always, with any natural health product it is important to consult with your naturopathic doctor to see if berberine is safe for you.

References:

[1] Neag M, Mocan A, Echeverria J, et al. Berberine: Botanical Occurrence, Traditional Uses, Extraction Methods, and Relevance in Cardiovascular , Metabolic, Hepatic, and Renal Disorders. Front Pharmacol. 2018; 9:557. https://pubmed.ncbi.nlm.nih.gov/30186157/

[2] Hoffmann D. (2003). Medical Herbalism: The Science and Practice of Herbal Medicine. Healing Arts Press.

[3] Pirillo A, Catapano AL. Berberine, a plant alkaloid with lipid- and glucose-lowering properties: from in vitro evidence to clinical studies. Atherosclerosis. 2015; 243(2): 449-61. https://pubmed.ncbi.nlm.nih.gov/26520899/

[4] Wei W, Zhao H, Wang A, et al. A clinical study on the short-term effect of berberine in comparison to metformin on the metabolic characteristics of women with polycystic ovary syndrome. Eur J Endocrinol. 2012; 166(1):99-105. https://pubmed.ncbi.nlm.nih.gov/22019891/

[5] Zhang LS, Zhang JH, Feng R, et al. Efficacy and safety of berberine alone or combined with statins for the treatment of hyperlipidemia: a systematic review and meta-analysis of randomized controlled trials. Am J Chin Med. 2019; 47(4):751-767. https://pubmed.ncbi.nlm.nih.gov/31094214/

[6] Affuso F, Mercurio V, Fazio V, et al. Cardiovascular and metabolic effects of berberine. World J Cardiol. 2010; 2(4):71-7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2999047/

[7] Bagade A, Tumbigeremutt V, Pallavi G. Cardiovascular Effects of Berberine: A Review of the Literature. Journal of Restorative Medicine. 2017; 6: 37-45.