3,3'-DIINDOLYLMETHANE (DIM)

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This monograph is intended to serve as a guide to industry for the preparation of Product Licence Applications (PLAs) and labels for natural health product market authorization. It is not intended to be a comprehensive review of the medicinal ingredient.

Notes

• Text in parentheses is additional optional information which can be included on the PLA and product label at the applicant's discretion.
• The solidus (/) indicates that the terms and/or statements are synonymous. Either term or statement may be selected by the applicant.

Date

January 26, 2024

Proper name(s), Common name(s), Source information

Table 1. Proper name(s), Common name(s), Source information

Proper name(s)	Common name(s)	Source information
		Source ingredient(s)	Source material(s)	Part(s)	Preperation(s)
3,3'-Diindolylmethane 3,3'-Methylenebis-1H-indole	3,3'-Diindolylmethane DIM	N/A	Brassica oleracea var. botrytis Brassica oleracea var. capitata Brassica oleracea var. gemmifera Brassica oleracea var. italica	Whole plant	Isolate
		3,3'-Diindolylmethane	N/A	N/A	Synthetic

References: Proper names: NIH 2023; Common names: NIH 2023; Source information: Pradhan et al. 2005, Jongen 1996, Kwon et al. 1994, Bradfield and Bjeldanes 1991.

Route of Administration

Oral

Dosage Form(s)

This monograph excludes foods or food-like dosage forms as indicated in the Compendium of Monographs Guidance Document.

Acceptable dosage forms for oral use are indicated in the dosage form drop-down list of the web-based Product Licence Application form for Compendial applications.

Use(s) or Purpose(s)

• Source of (an) antioxidant(s)/Provides (an) antioxidant(s) (Fowke et al. 2006; Reed et al. 2005; Herraiz et al. 2004).
• Source of (an) antioxidant(s)/Provides (an) antioxidant(s) that help(s) fight/protect (cell) against/reduce (the oxidative effects of/the oxidative damage caused by/cell damage caused by) free radicals (Fowke et al. 2006; Reed et al. 2005; Herraiz et al. 2004).
• Helps to support/promote healthy estrogen metabolism/balance (Reed et al. 2005; Bell et al.2000; Wong et al. 1997; Bradlow et al. 1994).
• Helps reduce the severity and duration of symptoms associated with recurrent breast pain (cyclical mastalgia) (Reed et al. 2005; Zeligs et al. 2005).

Note: If 3,3'-Diindolylmethane (DIM) is combined with other medicinal ingredients with antioxidant properties, there is an option to use the claim in plural. The singular should be used when the product only contains one chemical substance (e.g. DIM) as the medicinal ingredient associated with the claim.

Dose(s)

Subpopulation(s)

Adults 18 years and older

Quantity(ies)

Antioxidant

Not to exceed 200 milligrams of DIM, per day (Laidlaw et al. 2010; Reed et al. 2008; Naik et al. 2006; Reed et al.2005; McAlindon et al. 2001; Bell et al. 2000; Wong et al. 1997; Bradlow et al. 1994).

Healthy Estrogen Metabolism; Recurrent Breast Pain

60 - 200 milligrams of DIM, per day (Laidlaw et al. 2010; Reed et al. 2008; Naik et al. 2006; Reed et al. 2005; Zeligs et al. 2005; McAlindon et al. 2001; Bell et al. 2000; Wong et al. 1997; Bradlow et al. 1994).

Direction(s) for use

No statement required.

Duration(s) of Use

No statement required.

Risk Information

Caution(s) and warning(s)

Products making healthy estrogen balance/metabolism claim

Ask a health care practitioner/health care provider/health care professional/doctor/physician before use to exclude the diagnosis of a serious cause of hormonal imbalance (UpToDate 2023).

Recurrent breast pain

Ask a health care practitioner/health care provider/health care professional/doctor/physician if symptoms persist or worsen.

Products providing 6 milligrams or more of DIM, per day

• Ask a health care practitioner/health care provider/health care professional/doctor/physician before use if you are taking medications or natural health products (Brinker 2010; Linus Pauling Institute 2008; Reed et al. 2005; Bradlow et al. 1994).
• Ask a health care practitioner/health care provider/health care professional/doctor/physician before use if you are attempting to conceive (Bennetts et al. 2008; Michnovicz et al. 1997).
• Stop use and ask a health care practitioner/health care provider/health care professional/doctor/physician if you develop liver-related symptoms (e.g. yellowing of the eyes and/or skin, dark urine, abdominal pain, jaundice) or symptoms of low estrogen (Reed et al. 2005; Dalessandri et al. 2004; Bell et al. 2000; Michnovicz et al. 1997; Wong et al. 1997; Bradlow et al. 1994).

Products providing 6 milligrams or more of DIM, per day

All subpopulations or Female subpopulation only

Ask a health care practitioner/health care provider/health care professional/doctor/physician before use if you have a liver disorder or symptoms of low estrogen such as joint pain, mood changes, changes in libido, hot flashes, night sweats, vaginal dryness or irregular menstruations (Reed et al. 2005; Dalessandri et al. 2004; Bell et al. 2000; Michnovicz et al. 1997; Wong et al. 1997; Bradlow et al. 1994).

Male subpopulation only

Ask a health care practitioner/health care provider/health care professional/doctor/physician before use if you have a liver disorder or symptoms of low estrogen such as joint pain, mood changes or changes in libido (Reed et al. 2005; Dalessandri et al. 2004; Bell et al. 2000; Michnovicz et al. 1997; Wong et al. 1997; Bradlow et al. 1994).

Contraindication(s)

All products

Do not use if you are pregnant or breastfeeding (Reed et al. 2006; Michnovicz et al.1997).

Known adverse reaction(s)

No statement required.

Non-medicinal ingredients

Must be chosen from the current Natural Health Products Ingredients Database (NHPID) and must meet the limitations outlined in the database.

Storage conditions

Must be established in accordance with the requirements described in the Natural Health Products Regulations.

Keep in a cool, dry place protected from light (Zeligs 2001).

Specifications

• The finished product specifications must be established in accordance with the requirements described in the Natural and Non-prescription Health Products Directorate (NNHPD) Quality of Natural Health Products Guide.
• The medicinal ingredient must comply with the requirements outlined in the NHPID.

EXAMPLE OF PRODUCT FACTS:

Consult the Guidance Document, Labelling of Natural Health Products for more details.

References Cited

• Bell MC, Crowley-Nowick P, Bradlow HL, Sepkovic DW, Schmidt-Grimminger D, Howell P, Mayeaux EJ, Tucker A, Turbat-Herrea EA, Mathis JM. Placebo-Controlled Trial of Indole-3- Carbinol in the Treatment of CIN. Gynecological Oncology 2000;78:123-129.
• Bennetts LE, De Iuliis GN, Nixon B, Kime M, Zelski K, McVicar CM, Lewis SE, Aitken RJ. Impact of estrogenic compounds on DNA integrity in human spermatozoa: evidence for cross- linking and redox cycling activities. Mutation Research 2008;641(1-2):1-11.
• Bradfield CA, Bjeldanes LF. Modification of carcinogen metabolism by indolylic autolysis products of Brassica oleraceae. Advances in Experimental Medicine and Biology 1991;289:153- 163.
• Bradlow HL, Michnovicz JJ, Halper M, Miller DG, Wong GY, Osborne MP. Long-term responses of women to indole-3-carbinol or a high fiber diet. Cancer Epidemiology, Biomarkers and Prevention 1994;3(7):591-595.
• Brinker F. Herb Contraindications and Drug Interactions, 4^th edition. Sandy (OR): Eclectic Medical Publications. [Accessed 2019 May 14]. Available from: https://www.eclecticherb.com/herb-contraindications-drug-interactions
• Dalessandri KM, Firestone GL, Fitch MD, Bradlow HL, Bjeldanes LF. Pilot study: effect of 3,3'- diindolylmethane supplements on urinary hormone metabolites in postmenopausal women with a history of early-stage breast cancer. Nutrition and Cancer 2004;50:161-167.
• Fowke JH, Morrow JD, Motley S, Bostick RM, Ness RM. Brassica vegetable consumption reduces urinary F2-isoprostane levels independent of micronutrient intake. Carcinogenesis 2006;27(10):2096-2102.
• Herraiz T, Galisteo J. Endogenous and dietary indoles: a class of antioxidants and radical scavengers in the ABTS assay. Free Radical Research 2004;38(3):323-331.
• Jongen, WMF. Glucosinates in Brassica: Occurrence and significance as cancer-modulating agents. Proceedings of the Nutrition Society 1996;55(1B):433-446.
• Kwon, C.S., Grose, K.R., Riby, J., Chen, Y.H. & Bjeldanes, L.F. In vivo production and enzyme inducing activity of indolo[3,2-b]carbazole. Journal of Agricultural and Food Chemistry 1994;42(11):2536-2540.
• Laidlaw M, Cockerline CA, Sepkovic DW. Effects of a breast-health herbal formula supplement on estrogen metabolism in pre- and post-menopausal women not taking hormonal contraceptives or supplements: a randomized controlled trial. Breast Cancer 2010;4:85-95.
• Linus Pauling Institute. Oregon State University. 2008. [Accessed 2019 May 14]. Available from: http://lpi.oregonstate.edu/infocenter/phytochemicals/i3c/.
• McAlindon TE, Gulin J, Chen T, Klug T, Lahita R, Nuite M. Indole-3-carbinol in women with SLEL: effect on estrogen metabolism and disease activity. Lupus 2001;10(11):779-783.
• Michnovicz JJ, Adlercreutz H, Bradlow JL.1997. Changes in Levels of Urinary Estrogen Metabolites After Oral Indole-3-Carbinol Treatment in Humans. Journal of the National Cancer Institute 1997;89(10):718-723.
• Naik R, Nixon S, Lopes A, Godfrey K, Hatem MH, Monaghan JM. A randomized phase II trials of indole-3-carbinol in the treatment of vulvar intraepithelial neoplasia. International Journal of Gynecological Cancer 2006;16(2):786-90.
• NIH 2023: National Institutes of Health. PubChem. Bethesda (MD): National Library of Medicine, US Department of Health & Human Services. [Accessed 2023 October 23]. Available from: https://pubchem.ncbi.nlm.nih.gov/
• Pradhan PK, Dey S, Giri VS, Jaisankar P. InCl3-HMTA as a Methylene Donor: One-Pot Synthesis of Diindolylmethane (DIM) and Its Derivatives. Synthesis 2005 (11): 1179-1782.
• Reed GA, Arneson DW, Putnam WC, Smith HJ, Gray JC, Sullivan DK, Mayo MS, Crowell JA.
• Hurwitz A. Single-dose and multiple-dose administration of indole-3-carbinol to women: pharmacokinetics based on 3,3'-diindolylmethane. Cancer Epidemiology, Biomarkers and Prevention 2006;15(12):2477-2481.
• Reed GA, Peterson KS, Smith HJ, Gray JC, Sullivan DK, Mayo MS, Crowell JA, Hurwitz A. A phase I study of indole-3-carbinol in women: tolerability and effects. Cancer Epidemiology, Biomarkers and Prevention 2005;14(8):1953-1960.
• Reed GA, Sunega JM, Sullivan DK, Gray JC, Mayo MS, Crowell JA, Hurwitz A. Single-Dose Pharmacokinetics and Tolerability of Absorption-Enhanced 3,3'-Diindolylmethane in Healthy Subjects. Cancer Epidemiology, Biomarkers and Prevention 2008;17(10):2619-2624.
• UpToDate 2023. Diagnostic evaluation of polycystic ovary syndrome in adolescents. [Accessed 2023 December 8]. Available from: https://sso.uptodate.com/contents/diagnostic-evaluation-of-polycystic-ovary-syndrome-in-adolescents?search=Diagnostic%20evaluation%20of%20polycystic%20ovary%20syndrome%20in%20adolescents&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
• Wong GY, Bradlow L, Sepkovic D, Mehl S, Mailman J, Osborne M. Dose-ranging study of indole-3-carbinol for breast cancer prevention. Journal of Cellular Biochemistry Supplement 1997;28-29:111-116.
• Zeligs MA. 2001. The Cruciferous Choice: Diindolylmethane or I3C? Phytonutrient Supplements for Cancer Prevention and Health Promotion. [Accessed 2019 May 14]. Available from: http://www.dimfaq.com/site/cruchoice.htm
• Zeligs MA, Brownstone PK, Sharp ME, Westerlind K,Wilsom SM, Johs S. Managing cyclical mastalgia with absorbable diindolylmethane: A randomized, placebo controlled trials. Journal of the American Nutraceutical Association (JANA) 2005;8(1):10-20.

References Reviewed

• Aggarwal BB, Ichikawa H. Molecular targets and anticancer potential of indole-3-carbinol and its derivatives. Cell Cycle 2005;4:1201-1215.
• Aggarwal BB, Shishodia S. Molecular targets of dietary agents for prevention and therapy of cancer. Biochemical Pharmacology 2006;71:1397-1421.
• Anderton MJ, Manson MM, Verschoyle R, Gescher A, Steward WP, Williams ML, Mager DE. Physiological modeling of formulated and crystalline 3,3'-diindolylmethane pharmacokinetics following oral administration in mice. Drug Metabolism and Disposition 2004;32(6):632-638.
• Bradlow HL. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer. In vivo 2008;22:441-446.
• Castanon A, Tristram A, Mesher D, Powell N, Beer H, Ashman S, Rieck G, Fielder H, Fiander A, Sasieni P. Effect of diindolylmethane supplementation on low-grade cervical cytology abnormalities: double-blind, randomised, controlled trial. British Journal of Cancer 2012;106: 45-52.
• Cavalieri E, Rogan E. Catechol quinones of estrogens in the initiation of breast, prostate, and other human cancers: keynote lecture Estrogens and Cancer. Bradlow HL and Carruba G (eds.). Annals of the New York Academy of Sciences 2006;1089:286-301. Cited In: Bradlow (2008).
• Chang YC, Riby J, Chang GH, Peng BC, Firestone G, Bjeldanes LF. Cytostatic and antiestrogenic effectsof 2-(indole-3-ylmethyl)-3,3'-diindolylmethane, a major in vivo product of dietary indole-3-carbinol. Biochemical Pharmacology 1999;58:825-834. [Abstract only]
• ChEBI 2012: Chemical Entities of Biological Interest. [Accessed: 2012 March 12]. Available from: http://www.ebi.ac.uk/chebi/advancedSearchFT.do?searchString=indole-3- carbinol&queryBean.stars=3&queryBean.stars=-1
• Dashwood RH. 1998. Indole-3-carbinol: anticarcinogen or tumor promoter in brassica vegetables? Chemico-Biological Interactions 110(1-2):1-5. [Abstract only]
• Higdon JV, Delage B, Williams DE, Dashwood RH. Cruciferous Vegetables and Human Cancer Risk: Epidemiologic Evidence and Mechanistic Basis. Pharmacological Research 2007; 55(3):224-236.
• Kim YS, Milner JA. Targets for indole-3-carbinol in cancer prevention. Journal of Nutritional Biochemistry 2005;16:65-73.
• Komiyama M, Higuchi K, Noguchi H. Selective synthesis using cyclodextrins as catalysts. Preparation of 3-(hydroxymethyl)indole from indole and formaldehyde. Supramolecular Chemistry 1995;4(4):265-269.
• Michnovicz JJ. Increased estrogen 2-hydroxylation in obese women using oral indole-3-carbinol. International Journal of Obesity and Related Metabolic Disorders 1998;22:227-229. [Abstract only]
• Minich DM, Bland JS. A Review of the Clinical Efficacy and Safety of Cruciferous Vegetable Phytochemicals Nutrition Reviews 2007;65(6):259-267. [Abstract only]
• NCBI 2012: National Center for Biotechnology Information. [Accessed: 2012 March 12]. Available from: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=3712&loc=ec_rcs
• NIH 2012: National Institutes of Health. [Accessed 2012 March 12]. Available from: http://chem.sis.nlm.nih.gov/chemidplus/ProxyServlet?objectHandle=DBMaint&actionHandle=d efault&nextPage=jsp/chemidlite/ResultScreen.jsp&TXTSUPERLISTID=0000700061
• NTP 2012: National Toxicology Program. Background Information Indole-3-carbinol (I3C). [Accessed: 2012 March 12]. Available from: http://ntp.niehs.nih.gov/ntp/htdocs/Chem_Background/ExSumPdf/Indolecarbinol.pdf
• Rogan EG. The natural chemopreventive compound indole-3-carbinol: state of the science. In Vivo 2006;20:221-228.
• Rosen CA, Bryson PC. Indole-3-carbinol for recurrent respiratory papillomatosis: long-term results. Journal of Voice 2004;18:248-253.
• Rosen CA, Woodson GE, Thompson JW, Hengesteg AP, Bradlow HL. Preliminary results of the use of indole-3-carbinol for recurrent respiratory papillomatosis. Otolaryngology - Head and Neck Surgery 1998;118(6):810-815.
• Sarkar FH, Li Y. Indole-3-carbinol and prostate cancer. Journal of Nutrition 2004;134:3493S- 3498S.
• Verhoeven DT, Verhagen H, Goldbohm RA, van den Brandt PA, van Poppe. G. A review of mechanisms underlying anticarcinogenicity by brassica vegetables. Chemico-Biological Interactions 1997;103(2):79-129. [Abstract only]
• WebMD 2012. Women's Health: Normal Testosterone and Estrogen Levels in Women [Accessed 2012 March 12]. Available from: http://women.webmd.com/normal-testosterone-and- estrogen-levels-in-women?page=2
• Yuan Gao-feng, Bo Sun, Jing Yuan, and Qiao-mei Wang. Effects of different cooking methods on health-promoting compounds of broccoli. Journal of Zhejiang University Science B 2009; 10(8):580-588. [Abstract only]