Twynsta Side Effects & Health Impacts

Low folate status contributes to elevated homocysteine, a metabolite that has been associated with endothelial dysfunction, arterial stiffness, and a higher risk of stroke and coronary heart disease. Large observational studies consistently show that individuals with higher homocysteine levels have greater rates of cardiovascular events, and folate intake is one of the key nutritional determinants of homocysteine. Clinically, folic acid supplementation (often combined with vitamins B6 and B12) can lower homocysteine and appears to modestly reduce stroke risk in some populations, making the identification and correction of folate deficiency an important part of broader cardiovascular risk reduction.

Research: Yanping Li, et al. Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta‐Analysis of Randomized Controlled Trials. Journal of the American Heart Association. Volume 5, Number 8. August 15 2016.Yi X, Zhou Y, Jiang D, Li X, Guo Y, Jiang X. Efficacy of folic acid supplementation on endothelial function and plasma homocysteine concentration in coronary artery disease: A meta-analysis of randomized controlled trials. Exp Ther Med. 2014 May;7(5):1100-1110. Kaye AD, Jeha GM, Pham AD, Fuller MC, Lerner ZI, Sibley GT, Cornett EM, Urits I, Viswanath O, Kevil CG. Folic Acid Supplementation in Patients with Elevated Homocysteine Levels. Adv Ther. 2020 Oct;37(10):4149-4164. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006 Apr 13;354(15):1567-77. Wald DS, Bishop L, Wald NJ, et al. Randomized Trial of Folic Acid Supplementation and Serum Homocysteine Levels. Arch Intern Med. 2001;161(5):695–700.

Folate deficiency in the periconceptional period significantly increases the risk of neural tube defects (NTDs) such as spina bifida and anencephaly, because adequate folate is required for proper closure of the embryonic neural tube in the first month of pregnancy. Large observational datasets and randomized trials have shown that appropriate folic acid supplementation before conception and in early pregnancy can reduce NTD risk by roughly 50–70% in the general population, with even greater risk reduction in women with a prior NTD‑affected pregnancy. The practical implication is that all women of childbearing potential, not just those actively planning pregnancy, are typically advised to maintain adequate daily folic acid intake so that red‑cell folate stores are sufficient well before conception occurs.

Research: Viswanathan M, Urrutia RP, Hudson KN, Middleton JC, Kahwati LC. Folic Acid Supplementation to Prevent Neural Tube Defects: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. JAMA. 2023;330(5):460–466. Wald NJ. Folic acid and neural tube defects: Discovery, debate and the need for policy change. J Med Screen. 2022 Sep;29(3):138-146. Mathieu d'Argent E, Ravel C, Rousseau A, Morcel K, Massin N, Sussfeld J, Simon T, Antoine JM, Mandelbaume J, Daraï E, Kolanska K. High-Dose Supplementation of Folic Acid in Infertile Men Improves IVF-ICSI Outcomes: A Randomized Controlled Trial (FOLFIV Trial). J Clin Med. 2021 Apr 26;10(9):1876. Jadhav, S. N., & Pitale, D. L. (2020). Effectiveness of folic acid in unexplained infertility. International Journal of Reproduction, Contraception, Obstetrics and Gynecology, 9(9), 3780–3783.

In older adults, low folate status has been associated with a higher risk of mild cognitive impairment (MCI) and faster cognitive decline over time, likely through effects on one‑carbon metabolism and homocysteine. Several longitudinal cohort studies have found that individuals with lower serum or red‑cell folate and higher homocysteine show steeper declines on memory and global cognition tests, and in some cohorts have a significantly higher incidence of MCI or dementia over follow‑up. The clinically important takeaway is that, when folate deficiency is detected and corrected (usually along with ensuring adequate vitamin B12), some patients demonstrate stabilization or modest improvement in cognitive performance, particularly when interventions are combined with aggressive management of vascular risk factors such as hypertension and diabetes.

Research: Ma, F., Wu, T., Zhao, J. et al. Folic acid supplementation improves cognitive function by reducing the levels of peripheral inflammatory cytokines in elderly Chinese subjects with MCI. Sci Rep 6, 37486 (2016). Wang M, Fang M, Zang W. Effects of folic acid supplementation on cognitive function and inflammation in elderly patients with mild cognitive impairment: A systematic review and meta-analysis of randomized controlled trials. Arch Gerontol Geriatr. 2024 Nov;126:105540. O’Connor, D.M.A., Scarlett, S., De Looze, C. et al. Low folate predicts accelerated cognitive decline: 8-year follow-up of 3140 older adults in Ireland. Eur J Clin Nutr 76, 950–957 (2022).Putu Eka Widyadharma. Folic acid supplementation improves cognitive function: A systematic review. December 2020 Romanian Journal of Neurology 19(4):219-223.

Low zinc status has been linked to a higher risk and faster progression of age-related macular degeneration (AMD), in part because zinc is concentrated in the retina and supports antioxidant defenses there. In the landmark AREDS trial, a supplement formula containing zinc (80 mg as zinc oxide), along with antioxidants, reduced the risk of progression to advanced AMD by about 25% in people with intermediate disease or advanced disease in one eye over roughly 5 years. Other research has shown that inadequate zinc intake is more common in older adults with AMD, reinforcing the idea that maintaining healthy zinc levels may be an important, and often overlooked, strategy for preserving macular health with age.

Research: Smailhodzic D, van Asten F, Blom AM, Mohlin FC, den Hollander AI, van de Ven JPH, et al. (2014) Zinc Supplementation Inhibits Complement Activation in Age-Related Macular Degeneration. PLoS ONE 9(11): e112682. Lengyel D, Török B. Erworbene vorübergehende Nachtblindheit bei Vitamin-A- und Zinkmangel bei Anorexia nervosa neun Jahre nach Nierentransplantation [Acquired temporary night blindness in vitamin A and zinc deficiency in anorexia nervosa nine years after kidney transplantation]. Klin Monbl Augenheilkd. 2006 May;223(5):453-5. German.Blasiak J, Pawlowska E, Chojnacki J, Szczepanska J, Chojnacki C, Kaarniranta K. Zinc and Autophagy in Age-Related Macular Degeneration. Int J Mol Sci. 2020 Jul 15;21(14):4994. Benjamin P. Nicholson, et al. Chapter 37 - Zinc Deficiency and the Eye. Handbook of Nutrition, Diet and the Eye 2014, Pages 371-376.

Impacted through 2 nutrients: Folic Acid, Zinc.

In pregnancy, inadequate folate status not only increases neural tube defect risk but is also associated with maternal megaloblastic anemia, which can worsen fatigue, reduce exercise tolerance, and increase the likelihood of transfusion around delivery. Observational studies have linked low folate and elevated homocysteine with a higher risk of miscarriage, placental complications, and low birth weight, and some data suggest that suboptimal folate status may contribute to certain infertility contexts, particularly when combined with other nutritional or metabolic stressors. The clinical takeaway is that maintaining sufficient folate intake before conception and throughout pregnancy is a key strategy to reduce anemia and support healthier fertility and pregnancy outcomes beyond neural tube defect prevention.

Research: Murto, T. et al. Folic acid supplementation and IVF pregnancy outcome in women with unexplained infertility. Dey M, Dhume P, Sharma SK, Goel S, Chawla S, Shah A, Madhumidha G, Rawal R. Folic acid: The key to a healthy pregnancy - A prospective study on fetomaternal outcome. Tzu Chi Med J. 2023 Oct 31;36(1):98-102. Hariz A, Bhattacharya PT. Megaloblastic Anemia. [Updated 2023 Apr 3]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan. Lazar VMA, Rahman S, Chowdhury NH, Hasan T, Akter S, Islam MS, Ahmed S, Baqui AH, Khanam R. Folate deficiency in pregnancy and the risk of preterm birth: A nested case-control study. J Glob Health. 2024 Jul 12;14:04120. Zheng J-S, Guan Y, Zhao Y, et al. Pre-conceptional intake of folic acid supplements is inversely associated with risk of preterm birth and small-for-gestational-age birth: a prospective cohort study. British Journal of Nutrition. 2016;115(3):509-516. Reproductive BioMedicine Online, Volume 28, Issue 6, 766 - 772

Closely linked to reproductive and hormonal problems in both men and women, zinc deficiency can contribute to hypogonadism, low testosterone, reduced sperm count, and menstrual irregularities. In men, low zinc status has been associated with decreased serum testosterone, reduced sperm density and motility, and poorer overall semen quality, while zinc repletion in deficient individuals has been shown to improve some of these parameters. In women, inadequate zinc intake is tied to more frequent cycle disturbances, dysmenorrhea, and potential impacts on ovulation and fertility, underscoring zinc’s important role in healthy hormonal balance and reproductive function.

Research: Zhao J, Dong X, Hu X, Long Z, Wang L, Liu Q, Sun B, Wang Q, Wu Q, Li L. Zinc levels in seminal plasma and their correlation with male infertility: A systematic review and meta-analysis. Sci Rep. 2016 Mar 2;6:22386. Mohan H, Verma J, Singh I, Mohan P, Marwah S, Singh P. Inter-relationship of zinc levels in serum and semen in oligospermic infertile patients and fertile males. Indian J Pathol Microbiol. 1997 Oct;40(4):451-5. PMID: 9444854. Zečević N, Veselinović A, Perović M, Stojsavljević A. Association Between Zinc Levels and the Impact of Its Deficiency on Idiopathic Male Infertility: An Up-to-Date Review. Antioxidants (Basel). 2025 Jan 29;14(2):165. Dhar S, Yadav R, Tomar A. Serum Zinc Levels in Women with Polycystic Ovarian Syndrome are Lower as Compared to Those without Polycystic Ovarian Syndrome: A Cohort Study. J Hum Reprod Sci. 2024 Jan-Mar;17(1):25-32.

Folate deficiency has been associated with a higher risk of depressive symptoms, irritability, and other mood disturbances, likely through its role in one‑carbon metabolism, monoamine neurotransmitter synthesis, and methylation processes in the brain. Clinical and epidemiologic studies have found that people with low folate or elevated homocysteine are more likely to experience major depression, and lower folate status has been linked to poorer response to certain antidepressant medications. The encouraging clinical point is that, in folate‑deficient individuals, correcting folate status (often with folic acid or methylfolate, and alongside vitamin B12 when indicated) may improve mood symptoms and, in some cases, enhance antidepressant treatment response, especially when combined with comprehensive psychiatric and lifestyle interventions.

Research: David Mischoulon, Maurizio Fava. Folate in Depression: Efficacy, Safety, Differences in Formulations, and Clinical Issues. The Journal of Clinical Psychiatry. 2009. Gao S, Khalid A, Amini-Salehi E, Radkhah N, Jamilian P, Badpeyma M, Zarezadeh M. Folate supplementation as a beneficial add-on treatment in relieving depressive symptoms: A meta-analysis of meta-analyses. Food Sci Nutr. 2024 Mar 8;12(6):3806-3818. Reynolds EH, Crellin R, Bottiglieri T, Laundy M, Toone BK, et al. Methylfolate as Monotherapy in Depression. A Pilot Randomised Controlled Trial. J Neurol Psychol. 2015;3(1): 5. Reynolds EH. Folic acid, ageing, depression, and dementia. BMJ. 2002 Jun 22;324(7352):1512-5. Gilbody S, Lightfoot T, Sheldon T. Is low folate a risk factor for depression? A meta-analysis and exploration of heterogeneity. J Epidemiol Community Health. 2007 Jul;61(7):631-7.

Zinc deficiency impairs immune defenses by reducing T‑cell activity and weakening resistance to infection. Low zinc levels increase susceptibility to recurrent infections, especially respiratory illnesses such as the common cold, bronchitis, and pneumonia. Clinical studies show that zinc supplementation can strengthen immune response and lower mortality when used alongside standard treatment for severe pneumonia. In a placebo‑controlled trial in elderly participants, zinc supplementation decreased the incidence of infections by 66% and improved cell‑mediated immunity.

Research: Shah UH, Abu-Shaheen AK, Malik MA, Alam S, Riaz M, Al-Tannir MA. The efficacy of zinc supplementation in young children with acute lower respiratory infections: a randomized double-blind controlled trial. Clin Nutr. 2013 Apr;32(2):193-9. Prasad AS. Zinc: role in immunity, oxidative stress and chronic inflammation. Curr Opin Clin Nutr Metab Care. 2009 Nov;12(6):646-52. Wang L, Song Y. Efficacy of zinc given as an adjunct to the treatment of severe pneumonia: A meta-analysis of randomized, double-blind and placebo-controlled trials. Clin Respir J. 2018 Mar;12(3):857-864. Marianna K. Baum, Shenghan Lai, Sabrina Sales, J. Bryan Page, Adriana Campa, Randomized, Controlled Clinical Trial of Zinc Supplementation to Prevent Immunological Failure in HIV-Infected Adults, Clinical Infectious Diseases, Volume 50, Issue 12, 15 June 2010, Pages 1653–1660.

Zinc deficiency during childhood and adolescence is strongly linked to impaired linear growth and delayed sexual maturation, and is a recognized contributor to stunting in many low‑ and middle‑income countries. In some population studies, zinc deficiency has been present in over 30–40% of children, and zinc supplementation programs have been associated with modest but meaningful improvements in height gain over time. Clinically, even marginal zinc deficiency can quietly slow growth velocity and pubertal progression, making adequate zinc intake an important, often overlooked pillar of healthy growth and development.

Research: Abdollahi M, Ajami M, Abdollahi Z, Kalantari N, Houshiarrad A, Fozouni F, Fallahrokni A, Mazandarani FS. Zinc supplementation is an effective and feasible strategy to prevent growth retardation in 6 to 24 month children: A pragmatic double blind, randomized trial. Heliyon. 2019 Nov 1;5(11):e02581. Walravens PA, Krebs NF, Hambidge KM. Linear growth of low income preschool children receiving a zinc supplement. Am J Clin Nutr. 1983 Aug;38(2):195-201. Rerksuppaphol S, Rerksuppaphol L. Zinc supplementation enhances linear growth in school-aged children: A randomized controlled trial. Pediatr Rep. 2018 Jan 4;9(4):7294. Zinc deficiency as risk factor for stunting among children aged 2-5 years. (2017). Universa Medicina, 36(1), 11-18.

Folate (folic acid) deficiency impairs DNA synthesis in rapidly dividing cells, which leads to megaloblastic anemia characterized by enlarged red blood cells, fatigue, pallor, and sometimes shortness of breath. Population studies have shown that folate deficiency and macrocytosis can be present for months before overt symptoms appear, and in some cohorts, up to roughly one quarter of anemic adults had an underlying folate or B12 deficiency rather than iron deficiency alone. The encouraging clinical point is that, once identified, folate‑responsive megaloblastic anemia often improves within weeks of adequate folic acid repletion, with reticulocyte counts rising in about 5–7 days and hemoglobin recovering more gradually over several weeks.

Research: Koury MJ, Price JO, Hicks GG. Apoptosis in megaloblastic anemia occurs during DNA synthesis by a p53-independent, nucleoside-reversible mechanism. Blood. 2000 Nov 1;96(9):3249-55. Daniel S. Socha, MD, Sherwin I. DeSouza, MD, Aron Flagg, MD, Mikkael Sekeres, MD, MS and Heesun J. Rogers, MD, PhD. Severe megaloblastic anemia: Vitamin deficiency and other causes. Cleveland Clinic Journal of Medicine March 2020, 87 (3) 153-164. H.B. Castellanos-Sinco, et al. Megaloblastic anaemia: Folic acid and vitamin B12 metabolism. Revista Médica del Hospital General de México. Vol. 78. Issue 3. Pages 105-150 (July - September 2015). Anis Hariz, et al. Megaloblastic Anemia. StatPearls April 3, 2023.

Zinc deficiency often first shows up on the skin, with acrodermatitis‑like eruptions around the mouth, perineum, and distal extremities, accompanied by alopecia and sometimes nail changes. Characteristic lesions can be erythematous, scaly, or pustular, and both congenital and acquired zinc deficiency states have been reported to improve dramatically within days to weeks of adequate zinc repletion. Clinically, zinc is also crucial for normal collagen synthesis and immune function in the skin, so deficiency is linked to delayed wound healing and weaker scars, whereas restoring zinc status can enhance re‑epithelialization and reduce wound complications.

Research: Kelly S, Stelzer JW, Esplin N, Farooq A, Karasik O. Acquired Acrodermatitis Enteropathica: A Case Study. Cureus. 2017 Sep 8;9(9):e1667. Alwadany MM, Al Wadani AF, Almarri FH, Alyami HS, Al-Subaie MA. Acrodermatitis Enteropathica: A Rare Case With Lifelong Implications. Cureus. 2023 Apr 18;15(4):e37783. Al-Khafaji Z, Brito S, Bin BH. Zinc and Zinc Transporters in Dermatology. Int J Mol Sci. 2022 Dec 18;23(24):16165. Ogawa Y, Kinoshita M, Shimada S, Kawamura T. Zinc and Skin Disorders. Nutrients. 2018 Feb 11;10(2):199.

In many patients, inadequate zinc status affects the gastrointestinal tract, contributing to chronic or recurrent diarrhea, anorexia, and characteristic changes in taste (hypogeusia) and smell (hyposmia) that further suppress intake. Clinical studies in children with acute and persistent diarrhea have shown that zinc supplementation shortens illness duration and reduces subsequent diarrheal episodes, underscoring how low zinc status both results from and perpetuates gut losses. The practical implication is that, when patients present with otherwise unexplained diarrhea, poor appetite, and altered taste or smell, especially in the setting of malabsorption, restrictive diets, or chronic illness, evaluating and correcting zinc deficiency can be an important step in breaking this cycle and restoring nutritional and gastrointestinal health.

Research: Mozaffar B, Ardavani A, Muzafar H, Idris I. The Effectiveness of Zinc Supplementation in Taste Disorder Treatment: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Nutr Metab. 2023 Mar 8;2023:6711071. Heckmann SM, Hujoel P, Habiger S, Friess W, Wichmann M, Heckmann JG, Hummel T. Zinc gluconate in the treatment of dysgeusia--a randomized clinical trial. J Dent Res. 2005 Jan;84(1):35-8. Mahajan SK, Prasad AS, Lambujon J, Abbasi AA, Briggs WA, McDonald FD. Improvement of uremic hypogeusia by zinc: a double-blind study. Am J Clin Nutr. 1980 Jul;33(7):1517-21. Aliani M, Udenigwe CC, Girgih AT, Pownall TL, Bugera JL, Eskin MN. Zinc deficiency and taste perception in the elderly. Crit Rev Food Sci Nutr. 2013;53(3):245-50. Tanaka H, Mori E, Yonezawa N, Sekine R, Nagai M, Tei M, Otori N. Efficacy of Normalising Serum Zinc Level for Patients with Olfactory Dysfunction and Zinc Deficiency. ORL J Otorhinolaryngol Relat Spec. 2024;86(2):73-81.