Soy

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Soy

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Soy

Common Names

  • Soybean
  • Soya
  • Tofu
  • Miso
  • Tempeh

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For Patients & Caregivers

How It Works

Whether soy helps relieve menopausal symptoms is still unclear. It may reduce the risk of some cancers.

Soy is a plant that is grown worldwide. The beans are rich in protein and other nutrients and are widely consumed as food. Extracts are sold as dietary supplements to treat hot flashes, high cholesterol, and for cancer prevention. Soy contains large amounts of isoflavones that act like estrogen in the body. Studies in animals suggest that soy can prevent or reduce bone loss. In laboratory studies, isoflavones slowed down the growth of several different types of cancer cells, including breast and prostate cancers. Animal studies showed that genistein, one of the isoflavones, may interfere with tamoxifen that is used for breast cancer. But a new study showed that soy foods can benefit women with breast cancer.

Patients should consult their physicians about use of soy supplements.

Purported Uses
  • To prevent cancer
    Laboratory and some clinical studies suggest that soy intake was associated with a lower risk of developing breast cancer. High intake of isoflavones may also reduce risk of lung cancer.
  • To prevent heart disease
    Clinical trials show that soy protein, not pills, reduces LDL (bad) cholesterol levels, which may help prevent heart disease.
  • To reduce high cholesterol
    Clinical trials show that soy protein, not pills, reduces LDL (bad) cholesterol levels and may increase HDL (good) cholesterol levels.
  • To treat menopause symptoms such as hot flashes, vaginal dryness, sleep disturbances, mood problems
    Clinical studies have conflicting results.
  • To prevent bone loss
    Some clinical trials and animal studies support this use.
Do Not Take If
  • You are hypersensitive to soy products.
  • You are taking tamoxifen: Animal studies have shown that genistein may reduce the effects of tamoxifen on estrogen-dependent breast cancer.
  • You are taking aromatase Inhibitors: Soy-based supplements may reduce the effects of aromatase inhibitors used in breast cancer treatment.
  • You are taking cytochrome P450 substrate drugs: Soymilk and miso may make them less effective.
  • You are taking P-Glycoprotein substrate drugs: Soymilk and miso may make them less effective.
  • You are taking UGT (Uridine 5’-diphospho-glucuronosyltransferase) substrate drugs: Soy can increase the side effects of these drugs.
Side Effects
  • Flatulence
  • Allergic reactions

Case Reports

  • Underactive thyroid: In a 72-year-old woman who had chronic thyroid disease. She had taken a health drink containing soy isoflavones for 6 months. Symptoms improved with medical treatment and discontinuation of the health drink.
  • Breast enlargement: In a 60-year-old man following consumption of soy milk over a period of 6 months. Symptoms resolved after discontinuing use.
  • Abnormal uterine bleeding: In 3 women after a high intake of soy products. Symptoms improved following withdrawal of use.
  • Loss of sex drive and erectile dysfunction: In a 19-year-old diabetic man who was otherwise healthy, following intake of large amounts of soy-based products in a vegan-style diet. Symptoms improved 1 year after discontinuing the diet.
Special Point

The isoflavone content is minimal in soy sauce or soy oil.

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For Healthcare Professionals

Scientific Name
Glycine max
Clinical Summary

Soybeans, derived from Glycine max, are rich in protein and other essential nutrients and are widely consumed as food. Soy also contains significant amounts of isoflavones — genistein (4’,5,7-trihydroxyisoflavone), daidzein (4’,7-dihydroxyisoflavone), and glycitein (4’,7-dihydroxy-6-methoxyisoflavone) (1). They are marketed as dietary supplements to treat hot flashes, high cholesterol, and for cancer prevention. Isoflavones exhibit both selective estrogen receptor modulator activity and non-hormonal effects. Studies of soy for menopausal symptoms are inconclusive (2) (3) (4) (5) (6) (7) (8) (9). While some trials indicate slower bone density loss (10) (11) (91), others report no such effects in postmenopausal women (12) (13). But there may be cardiovascular benefits (17), as soy reduces low-density-lipoprotein (LDL) cholesterol (14) (15) along with having beneficial effects on blood pressure in postmenopausal women (16) (97) and in healthy adults (90). A meta-analysis confirmed that consumption of soy leads to reductions in both total cholesterol and LDL in adults (99).

Soy intake also reduced proteinuria in type 2 diabetic patients with nephropathy (19). However, conflicting data suggest no protective effects against diabetes (20). Other studies of soy did not find benefit for Alzheimer’s disease (92) or for poorly controlled asthma (93), but soy isoflavone supplementation alone or with Vitamin D improved some symptoms and quality of life in patients with irritable bowel disease (94); and lactobacillus-fermented soybean was found to enhance cognitive function in subjects with mild cognitive impairment (100). In a study of chronic stroke patients, ingesting soymilk immediately following rehabilitation exercise was reported to improve functional outcomes (101); soymilk consumption along with a low-calorie diet had beneficial effects on some metabolic parameters in patients with non-alcoholic fatty liver disease (102).

Soy has been investigated for its anticancer effects as well. Data show that it may reduce the risk of prostate (21) (22) (23), lung (24) (80), and endometrial (25) (26) cancers, but increase risk of bladder cancer (27) and endometrial hyperplasia (28). It may prolong survival among women with lung cancer (81), reduce mortality (89) and breast cancer recurrence regardless of tamoxifen use (42), or prevent breast cancer (29) (30). However, long-term supplementation did not affect mammographic density in breast cancer patients or in high-risk women (95) and other data suggest adverse effects (31) (32) or that supplementation can stimulate over-expression of breast cancer genes in patients with invasive breast cancer (87). Preclinical findings indicate that soy consumption may increase metastasis (33); and daidzin-rich extracts can promote ER-positive breast cancer growth (88).

Genistein, the most estrogenic isoflavone (34), has been reported to improve fasting blood glucose, insulin levels, and insulin resistance in postmenopausal women (18). It also demonstrated antiproliferative effects in multiple cell lines, including breast cancer (ER+/-) (35), prostate cancer (androgen-dependent/-independent) (36), nasopharyngeal carcinoma (37), neuroblastoma, sarcoma, and retinoblastoma cells (36). However, animal studies show that it antagonizes the effects of tamoxifen (38) (39) and promotes tumor progression in advanced prostate cancer (40). In addition, supplementation may decrease serum PSA levels in prostate cancer patients before (41), but not after (82), prostatectomy. Further research is needed to evaluate the role of genistein in cancer prevention.

Isoflavone supplementation may reduce side effects associated with chemo- or radiotherapy (43) (44), but when used with vitamin E and selenium, did not prevent prostate cancer progression (45). It was also ineffective in reducing hot flashes in patients with prostate cancer (83). Patients should consult their physicians about the use of soy supplements, whose long term-safety remains to be determined.

Food Sources

Raw soybeans, low-fat soy flour, roasted soybeans, dry-roasted soy beans, soy milk, tofu, and soy protein isolate. There are no isoflavones in soy sauce or soy oil.

Purported Uses
  • Cancer prevention
  • Cardiovascular disease
  • High cholesterol
  • Menopausal symptoms
  • Osteoporosis
Mechanism of Action

Animal studies suggest that genistein and daidzein can prevent or reduce bone loss in a manner similar to synthetic estrogen due to increased beta versus alpha estrogen receptor (ER) binding (10). Both isoflavones may modulate bone remodeling through ERs by regulating target gene expression (50). Soy may also contribute to maintaining bone density by causing less calcium to be excreted in the urine (35). Isoflavones may inhibit oxidation of LDL and alter hepatic metabolism with enhanced removal of LDL and VLDL by hepatocytes (17). Serum lipids may also be regulated through modified transcription factor and downstream gene expression and by promoting antioxidant enzyme activity (51).

In addition, several mechanisms have been proposed for soy’s anticancer effects. Genistein affects microRNA expression-targeted translation inhibitors for multiple proteins implicated in regulating various pathobiological processes (52). It also demonstrated an anti-minichromosome maintenance (MCM) effect, a gene family frequently upregulated in various cancers and considered a promising anticancer drug target (53).

In breast cancer cells, genistein acts as an agonist to estrogen receptor (ER)-alpha in ER-alpha-predominant cells, but likely acts as an antiestrogen in cells with ER-beta alone, suggesting therapeutic potential for premenopausal women with ER-alpha-negative/ER-beta-positive tumors (54). However, genistein induces estrogen-dependent MCF-7 tumor cell growth and increases breast cancer-associated aromatase expression/activity, suggesting that soy-based supplements may affect aromatase inhibitor efficacy (55). Genistein is also known to negate tamoxifen’s inhibitory effect on MCF-7 tumor growth and increase expression of estrogen-responsive genes (38). Alternatively, soy isoflavones may reduce breast cancer risk by decreasing endogenous ovarian steroid levels (56). Studies suggest that some benefits ascribed to dietary isoflavones may depend on early life exposure, thereby impacting gene expression at the epigenetic level (47) (48) (49).

In prostate tumors, soy protein was shown to reduce androgen receptor expression (57). Both genistein and daidzein affect microRNA regulation (58) and induce decreased methylation of gene promoters, including BRCA1 (59). In tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-resistant prostate cancer cells, soy isoflavones enhance TRAIL-mediated apoptosis by engaging apoptotic pathways and regulating NF-κB activity (60) (61). However, in a patient-derived prostate cancer xenograft model, increased proliferation and metastasis in genistein-treated groups were linked to enhanced activities of tyrosine kinases, the epidermal growth factor receptor, and its downstream Src (40). Both genistein and daidzein also act as radiosensitizers for prostate cancer in vitro and in vivo, but pure genistein increased lymph node metastasis, whereas the combination of genistein, daidzein, and glycitein did not. Daidzein may protect against genistein-induced metastasis, and its ability to inhibit cell growth and potentiate radiation appears to be androgen-receptor-independent (62). In addition, soy isoflavones radiosensitized human A549 NSCLC cells, and decreased hemorrhages, inflammation, and fibrosis caused by radiation suggesting protection of normal lung tissue (63).

Contraindications
  • Contraindicated in patients who are hypersensitive to soy products.
Adverse Reactions
  • Flatulence, allergic reactions

Case Reports

  • Severe hypothyroidism: In a 72-year-old woman with chronic thyroid disease who consumed a health drink for 6 months that contained soy isoflavone powder extracts (96).
  • Gynecomastia: In a 60-year-old man following consumption of soy milk over a period of 6 months. Symptoms resolved after discontinuing use (76).
  • Abnormal uterine bleeding: With endometrial pathology in 3 women after a high intake of soy products. Symptoms improved following withdrawal of use (77).
  • Loss of libido and erectile dysfunction: In a 19-year-old diabetic man who was otherwise healthy, following intake of large amounts of soy-based products in a vegan-style diet. Symptoms improved 1 year after discontinuing the diet (78).
Herb-Drug Interactions
  • Tamoxifen: Animal studies suggest that genistein may antagonize the effects of tamoxifen on estrogen-dependent breast cancer (MCF-7) (38) (39). Relevance in humans has yet to be determined.
  • Aromatase inhibitors: Genistein induced MCF-7 tumor cell growth and increased breast cancer-associated aromatase expression and activity, in vitro, suggesting that soy-based supplements may affect the efficacy of aromatase inhibitors used in breast cancer treatment (55).
  • Cytochrome P450 substrates: Soymilk and miso were shown to induce CYP3A4 in vivo, and may affect the intracellular concentration of drugs metabolized by this enzyme (86).
  • P-Glycoprotein: Soymilk and miso were shown to induce P-Gp in vivo, and can affect the intracellular concentration of certain drugs (86).
  • Uridine 5’-diphospho-glucuronosyltransferase (UGT) substrates: Soy modulates UGT enzymes in vitro and can increase the side effects of drugs metabolized by them (75).
  • Membrane organic anion-transporting polypeptides (OATPs): Soy isoflavones and their metabolites were shown to affect transport of drugs across tissue barriers via human OATP2B1, in vitro. Clinical relevance is not known (98).
Dosage (OneMSK Only)
References

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  3. Cassidy A, Bingham S, Setchell KD. Biological effects of a diet of soy protein rich in isoflavones on the menstrual cycle of premenopausal women. Am J Clin Nutr. Sep 1994;60(3):333-340.

  4. Han KK, Soares JM, Jr., Haidar MA, et al. Benefits of soy isoflavone therapeutic regimen on menopausal symptoms. Obstet Gynecol. Mar 2002;99(3):389-394.

  6. Scambia G, Mango D, Signorile PG, et al. Clinical effects of a standardized soy extract in postmenopausal women: a pilot study. Menopause. Mar-Apr 2000;7(2):105-111.

  9. Jacobs A, Wegewitz U, Sommerfeld C, et al. Efficacy of isoflavones in relieving vasomotor menopausal symptoms - A systematic review. Mol Nutr Food Res. Sep 2009;53(9):1084-1097.

  10. Potter SM, Baum JA, Teng H, et al. Soy protein and isoflavones: their effects on blood lipids and bone density in postmenopausal women. Am J Clin Nutr. Dec 1998;68(6 Suppl):1375S-1379S.

  11. Marini H, Minutoli L, Polito F, et al. Effects of the phytoestrogen genistein on bone metabolism in osteopenic postmenopausal women: a randomized trial. Ann Intern Med. Jun 19 2007;146(12):839-847.

  13. Alekel DL, Van Loan MD, Koehler KJ, et al. The soy isoflavones for reducing bone loss (SIRBL) study: a 3-y randomized controlled trial in postmenopausal women. Am J Clin Nutr. Jan 2010;91(1):218-230.

  15. Allen JK, Becker DM, Kwiterovich PO, et al. Effect of soy protein-containing isoflavones on lipoproteins in postmenopausal women. Menopause. Jan-Feb 2007;14(1):106-114.

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  21. Jacobsen BK, Knutsen SF, Fraser GE. Does high soy milk intake reduce prostate cancer incidence? The Adventist Health Study (United States). Cancer Causes Control. Dec 1998;9(6):553-557.

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  23. Severson RK, Nomura AM, Grove JS, et al. A prospective study of demographics, diet, and prostate cancer among men of Japanese ancestry in Hawaii. Cancer Res. Apr 1 1989;49(7):1857-1860.

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  25. Horn-Ross PL, John EM, Canchola AJ, et al. Phytoestrogen intake and endometrial cancer risk. J Natl Cancer Inst. Aug 6 2003;95(15):1158-1164.

  26. Goodman MT, Wilkens LR, Hankin JH, et al. Association of soy and fiber consumption with the risk of endometrial cancer. Am J Epidemiol. Aug 15 1997;146(4):294-306.

  27. Sun CL, Yuan JM, Arakawa K, et al. Dietary soy and increased risk of bladder cancer: the Singapore Chinese Health Study. Cancer Epidemiol Biomarkers Prev. Dec 2002;11(12):1674-1677.

  28. Unfer V, Casini ML, Costabile L, et al. Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil Steril. Jul 2004;82(1):145-148, quiz 265.

  29. Cline JM, Hughes CL, Jr. Phytochemicals for the prevention of breast and endometrial cancer. Cancer Treat Res. 1998;94:107-134.

  30. Butler LM, Wu AH, Wang R, et al. A vegetable-fruit-soy dietary pattern protects against breast cancer among postmenopausal Singapore Chinese women. Am J Clin Nutr. Apr 2010;91(4):1013-1019.

  31. Trock BJ, Hilakivi-Clarke L, Clarke R. Meta-analysis of soy intake and breast cancer risk. J Natl Cancer Inst. Apr 5 2006;98(7):459-471.

  32. Steinberg FM, Murray MJ, Lewis RD, et al. Clinical outcomes of a 2-y soy isoflavone supplementation in menopausal women. Am J Clin Nutr. Feb 2011;93(2):356-367.

  33. Martinez-Montemayor MM, Otero-Franqui E, Martinez J, et al. Individual and combined soy isoflavones exert differential effects on metastatic cancer progression. Clin Exp Metastasis. Oct 2010;27(7):465-480.

  35. Hasler CM, Finn SC. Soy: just a hill of beans? J Womens Health. Jun 1998;7(5):519-523.

  37. Han H, Zhong C, Zhang X, et al. Genistein induces growth inhibition and G2/M arrest in nasopharyngeal carcinoma cells. Nutr Cancer. 2010;62(5):641-647.

  39. Liu B, Edgerton S, Yang X, et al. Low-dose dietary phytoestrogen abrogates tamoxifen-associated mammary tumor prevention. Cancer Res. Feb 1 2005;65(3):879-886.

  42. Shu XO, Zheng Y, Cai H, et al. Soy food intake and breast cancer survival. JAMA. Dec 9 2009;302(22):2437-2443.

  43. Tacyildiz N, Ozyoruk D, Yavuz G, et al. Soy isoflavones ameliorate the adverse effects of chemotherapy in children. Nutr Cancer. 2010;62(7):1001-1005.

  44. Ahmad IU, Forman JD, Sarkar FH, et al. Soy isoflavones in conjunction with radiation therapy in patients with prostate cancer. Nutr Cancer. 2010;62(7):996-1000.

  46. Schultz V, Hansel R, Tyler VE. Rational Phytotherapy: A Physician’s Guide to Herbal Medicine. 4th ed. New York: Springer.

  47. Shu XO, Jin F, Dai Q, et al. Soyfood intake during adolescence and subsequent risk of breast cancer among Chinese women. Cancer Epidemiol Biomarkers Prev. May 2001;10(5):483-488.

  48. Wu AH, Wan P, Hankin J, et al. Adolescent and adult soy intake and risk of breast cancer in Asian-Americans. Carcinogenesis. Sep 2002;23(9):1491-1496.

  49. Korde LA, Wu AH, Fears T, et al. Childhood soy intake and breast cancer risk in Asian American women. Cancer Epidemiol Biomarkers Prev. Apr 2009;18(4):1050-1059.

  53. Majid S, Dar AA, Saini S, et al. Regulation of minichromosome maintenance gene family by microRNA-1296 and genistein in prostate cancer. Cancer Res. Apr 1 2010;70(7):2809-2818.

  54. Rajah TT, Du N, Drews N, et al. Genistein in the presence of 17beta-estradiol inhibits proliferation of ERbeta breast cancer cells. Pharmacology. 2009;84(2):68-73.

  55. van Duursen MB, Nijmeijer SM, de Morree ES, et al. Genistein induces breast cancer-associated aromatase and stimulates estrogen-dependent tumor cell growth in in vitro breast cancer model. Toxicology. Nov 18 2011;289(2-3):67-73.

  56. Dorsher P, Peng Z. Supportive Cancer Care with Chinese Medicine In: Cho WCS, ed: Springer Netherlands; 2010:55-75.

  58. Rabiau N, Trraf HK, Adjakly M, et al. miRNAs differentially expressed in prostate cancer cell lines after soy treatment. In Vivo. Nov-Dec 2011;25(6):917-921.

  59. Adjakly M, Bosviel R, Rabiau N, et al. DNA methylation and soy phytoestrogens: quantitative study in DU-145 and PC-3 human prostate cancer cell lines. Epigenomics. Dec 2011;3(6):795-803.

  60. Szliszka E, Czuba ZP, Mertas A, et al. The dietary isoflavone biochanin-A sensitizes prostate cancer cells to TRAIL-induced apoptosis. Urol oncol. Jul 29 2011.

  63. Hillman GG, Singh-Gupta V, Runyan L, et al. Soy isoflavones radiosensitize lung cancer while mitigating normal tissue injury. Radiother Oncol. Nov 2011;101(2):329-336.

  64. Bielecki A, Roberts J, Mehta R, et al. Estrogen receptor-beta mediates the inhibition of DLD-1 human colon adenocarcinoma cells by soy isoflavones. Nutr Cancer. 2011;63(1):139-150.

  67. Brown NM, Belles CA, Lindley SL, et al. The chemopreventive action of equol enantiomers in a chemically induced animal model of breast cancer. Carcinogenesis. May 2010;31(5):886-893.

  68. Brown NM, Belles CA, Lindley SL, et al. Mammary gland differentiation by early life exposure to enantiomers of the soy isoflavone metabolite equol. Food Chem Toxicol. Nov 2010;48(11):3042-3050.

  73. Setchell KD, Brown NM, Desai P, et al. Bioavailability of pure isoflavones in healthy humans and analysis of commercial soy isoflavone supplements. J Nutr. Apr 2001;131(4 Suppl):1362S-1375S.

  74. Fair WR, Fleshner NE, Heston W. Cancer of the prostate: a nutritional disease? Urology. Dec 1997;50(6):840-848.

  76. Martinez J, Lewi JE. An unusual case of gynecomastia associated with soy product consumption. Endocr Pract. May-Jun 2008;14(4):415-418.

  77. Chandrareddy A, Muneyyirci-Delale O, McFarlane SI, et al. Adverse effects of phytoestrogens on reproductive health: a report of three cases. Complement Ther Clin Pract. May 2008;14(2):132-135.

  78. Siepmann T, Roofeh J, Kiefer FW, et al. Hypogonadism and erectile dysfunction associated with soy product consumption. Nutrition. Jul-Aug 2011;27(7-8):859-862.

  79. Furukawa S, Takaya A, Nakagawa T, et al. Fatal hypernatremia due to drinking a large quantity of shoyu (Japanese soy sauce). J Forensic Leg Med. Feb 2011;18(2):91-92.

  80. Yang WS, Va P, Wong MY, et al. Soy intake is associated with lower lung cancer risk: results from a meta-analysis of epidemiologic studies. Am J Clin Nutr. 2011 Dec;94(6):1575-83.

  81. Gong Yang, Xiao-Ou Shu, Hong-Lan Li, et al. Prediagnosis Soy Food Consumption and Lung Cancer Survival in Women. J Clin Oncol. 2013 Apr 20;31(12):1548-53.

  83. Vitolins MZ, Griffin L, Tomlinson WV, Vuky J, Adams PT, Moose D, Frizzell B, Lesser GJ, Naughton M, Radford JE Jr, Shaw EG. Randomized trial to assess the impact of venlafaxine and soy protein on hot flashes and quality of life in men with prostate cancer. J Clin Oncol. 2013 Nov 10;31(32):4092-8.

  84. Centers for Disease Control and Prevention (CDC). Botulism associated with home-fermented tofu in two Chinese immigrants—New York City, March-April 2012. MMWR Morb Mortal Wkly Rep. 2013 Jul 5;62(26):529-32.

  85. Carlberg DJ, Borek HA, Syverud SA, Holstege CP. Survival of acute hypernatremia due to massive soy sauce ingestion. J Emerg Med. 2013 Aug;45(2):228-31.

  86. Yu CP, Hsieh YW, Lin SP, Chi YC, Hariharan P, Chao PD, Hou Y. Potential modulation on P-glycoprotein and CYP3A by soymilk and miso: in vivo and ex-vivo studies. Food Chem. 2014 Apr 15;149:25-30.

  87. Shike M, Doane AS, Russo L, et al. The Effects of Soy Supplementation on Gene Expression in Breast Cancer: A Randomized Placebo-Controlled Study. J Natl Cancer Inst. 2014 Sep 4;106(9).

  88. Johnson KA, Vemuri S, Alsahafi S, Castillo R, Cheriyath V. Glycone-rich Soy Isoflavone Extracts Promote Estrogen Receptor Positive Breast Cancer Cell Growth. Nutr Cancer. 2016 May-Jun;68(4):622-33.

  89. Zhang FF, Haslam DE, Terry MB, et al. Dietary isoflavone intake and all-cause mortality in breast cancer survivors: the Breast Cancer Family Registry. Cancer. 2017 Mar 6. doi: 10.1002/cncr.30615. [Epub ahead of print]

  90. Nozue M, Shimazu T, Sasazuki S. Fermented Soy Product Intake Is Inversely Associated with the Development of High Blood Pressure: The Japan Public Health Center-Based Prospective Study. J Nutr. 2017 Jul 19. pii: jn250282. doi: 10.3945/jn.117.250282. [Epub ahead of print]

  92. Gleason CE, Fischer BL, Dowling NM, et al. Cognitive Effects of Soy Isoflavones in Patients with Alzheimer’s Disease. J Alzheimers Dis. 2015;47(4):1009-1019.

  94. Jalili M, Hekmatdoost A, Vahedi H, et al. Co-Administration of Soy Isoflavones and Vitamin D in Management of Irritable Bowel Disease. PLoS One. 2016;11(8):e0158545.

  96. Nakamura Y, Ohsawa I, Goto Y, et al. Soy isoflavones inducing overt hypothyroidism in a patient with chronic lymphocytic thyroiditis: a case report. J Med Case Rep. Sep 05 2017;11(1):253.

  98. Navrátilová L, Applová L, Horký P, Mladěnka P, Pávek P, Trejtnar F. Interaction of soy isoflavones and their main metabolites with hOATP2B1 transporter. Naunyn Schmiedebergs Arch Pharmacol. 2018 Jun 22.
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