Frequently Asked Questions

Dietary indoles are compounds formed in response to a catastrophic disruption within plant cells. They are found in a wide variety of plants but are most frequently associated with cruciferous vegetables such as broccoli, cauliflower, cabbage, and Brussels sprouts.

When cell walls are broken through chopping, chewing, or juicing, an enzyme called myrosinase is liberated and freely reacts with a family of compounds called glucosinolates to form isothiocyanates, thiocyanates, nitriles, and indoles. Dietary indoles are formed from a glucosinolate called Indole-3-glucobrassicin. There are a wide range of indole compounds with different activities and synergies.

While it is possible to extract various dietary indoles from certain vegetables, their concentration is not sufficient to make extraction economically viable. All commercial sources are almost certainly synthetic. Any source of I3C or DIM claiming to be completely natural is more than likely being misrepresented.

In the stomach, I3C forms numerous compounds of which only a handful have been characterized. Published research indicates that an oral dose of I3C produces at least 24 distinct indole degradation products in vivo. It is possible that some of the minor degradation products also have significant physiological effects not yet identified.

DIM is the primary degradation product of I3C, comprising approximately 10% of the species formed upon ingestion. DIM is also the most prevalent degradation product isolated from liver tissue following ingestion of I3C. Several published studies indicate that DIM may be more effective than I3C at modulating certain estrogen metabolites. In regards to this particular effect, DIM is possibly 10 times more cost effective than I3C.

DIM is slightly more heat stable than I3C but rapidly degrades in the presence of light. I3C provides a broader spectrum of indole metabolites in the digestive tract, while DIM offers greater stability and consistency in finished formulations. The choice between the two depends largely on your formulation targets and desired indole profile.

There are numerous estimates of the amounts of I3C and DIM contained in cruciferous vegetables — and most are significantly overestimated. This is because in most cases, calculations are based on the measured levels of glucobrassicin in vegetables, relying on the erroneous assumption that most glucobrassicin converts to I3C upon chopping, chewing, or juicing. Since most glucobrassicin actually converts to ascorbigen, the calculated amount of I3C based on this method should be reduced to at least one-fifth of what is typically suggested.

If ascorbigen is at least five times more prevalent than I3C — as the literature states — and the measured amounts of ascorbigen in vegetable extracts are 2.4–5.5 mg per 100g fresh weight, then the levels of I3C and DIM in whole vegetables are extremely low.

By this estimate, approximately 18 kg of broccoli would be required to provide roughly 200 mg of I3C and 20 mg of DIM. Contact us if you require supporting documentation.

Indole-3-Carbinol (I3C) is both heat and light sensitive and can degrade under normal storage conditions. Refrigeration at or below 40°F will maintain product purity for years.

However, published studies indicate that all reported benefits associated with I3C actually stem from the degradation products formed upon ingestion. Initial laboratory analysis reveals no difference between the primary degradation products produced in the stomach upon ingestion and those produced by degradation in storage. The total dietary indole content remains constant while the I3C quantity varies.

Formulation recommendation: To address labeling challenges, we suggest reporting "total dietary indole content" rather than I3C content specifically. This approach still delivers the documented benefits without the expense and complexity of refrigeration. If product appearance is a concern, refrigeration or encapsulation with opaque capsules are both effective solutions.

Published research has examined dietary indoles across a range of applications related to hormone metabolism and normal body function. The following reflects the current state of published research on these compounds.

Research has examined dietary indoles in relation to:

• Normal estrogen metabolism and healthy hormonal balance, including the conversion toward favorable estrogen metabolites such as 2-Hydroxyestrone*
• Normal immune function and cellular health*
• Healthy liver function and normal metabolic processing*
• Antioxidant activity and normal cellular protection*

Dietary indoles have also been the subject of U.S. patent filings covering methods of use in relation to fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome, PMS, and menopause. These patents have expired but represent the depth of research behind these ingredients. Ascorbigen is referenced in a Japanese patent for skin conditioning applications.

A scientific basis exists for daily dosages ranging from 200–400 mg in published research. However, based on Designed Nutritional's extensive experience with these compounds, we believe the therapeutic dosage may lie well below these levels.

This perspective is supported by the observation that identical benefits are reported for both 200 mg and 400 mg dosages in the literature — suggesting therapeutic limits have not been reached at the higher dose. Considering this, and the concentrations of dietary indoles typically found in food, the effective dosage could potentially be as low as 10–25 mg per day. This remains an active area of research and has not been formally established.

As a formulator, this suggests there may be significant latitude in dosage design. We recommend reviewing the published literature and consulting with a qualified regulatory advisor for your specific product application.

Designed Nutritional is aware of this claim, but it does not hold up to scrutiny. If I3C degradation products were harmful, eating broccoli should also be harmful — which the body of published nutritional science clearly does not support.

While it is true that I3C forms numerous other products in the stomach acid environment, assuming that DIM is the sole benefit provider is not supported by the evidence. Scientists have identified at least 23 different components formed upon the ingestion of I3C. Only a few have even been examined for biological effects. While DIM is the major degradation component at approximately 10%, it is entirely feasible that other minor degradation products exhibit significant biological benefit when compared on a weight-for-weight basis.

Several published studies have demonstrated that the benefits associated with ingesting I3C cannot be attributed solely to DIM — and that the greatest benefit was realized with a mixture of I3C degradation products.

Designed Nutritional draws a parallel to the history of Vitamin C research, where scientists initially focused on L-ascorbic acid in isolation. We now know that Vitamin C exists in numerous forms, each providing unique and important functions. The same principle likely applies to the full spectrum of dietary indole metabolites.

Scientific research clearly shows this is not necessary for the majority of consumers. Admittedly there are a handful of individuals with significant digestion challenges who may benefit from a product with improved absorption — and there are numerous ways to accomplish this — but one must always weigh added cost against added value.

The majority of early DIM literature extrapolates heavily from published I3C research. Significant levels of DIM are reported in the liver following the consumption of I3C. This DIM is clearly not specially treated for absorption and is chemically indistinguishable from the pure form sold as a supplement. Furthermore, published studies clearly exist for pure, unmodified DIM demonstrating physiological effects and positive clinical outcomes.

Can absorption be improved? Absolutely. Is improved absorption necessary to benefit from DIM supplementation? The published evidence says no.

There is genuine scientific disagreement on this question. Some researchers maintain that properly balancing estrogen metabolites is most important, while others argue that the ratio of estrogen to progesterone is the key driver of outcomes.

Designed Nutritional has reviewed compelling evidence on both sides. Much has been said concerning a healthy balance of estrogen metabolites — this appears to be an important effect of both I3C and DIM. However, mounting evidence suggests benefits and positive clinical outcomes with levels of cruciferous vegetable consumption too low to create a measurable shift in estrogen metabolites. This raises the possibility that we may be observing a correlation that is not necessarily causal.

In the Gynecologic Oncology study of I3C and cervical dysplasia, there was virtually no difference in clinical outcome between 400 mg and 200 mg of I3C daily — suggesting that supplementation in excess of what is required for a positive clinical outcome was being used. The maximum therapeutic dose may lie well below what is required to produce a measurable shift in estrogen metabolites.

For formulators, this suggests there may be more flexibility in product design than the conventional literature implies. Designed Nutritional recommends a close reading of the primary literature when designing formulations in this category.

It is commonly recognized that rats do not metabolize estrogen in quite the same manner as humans — this is particularly true in the case of 4OH estrogen. The first successful clinical studies with dietary indoles and cervical dysplasia used I3C, not DIM. DIM is being considered in this application precisely because of the prior clinical success with I3C.

The cervical dysplasia study demonstrated complete remission of both type II and type III cervical dysplasia in 50% of the study population within 12 weeks of 200–400 mg daily administration of I3C, with the remaining 50% showing marked improvement. Those on placebo showed no improvement.

Published research indicates that elevated 4OH estrogen is associated with increased risk in certain hormone-sensitive conditions. If I3C supplementation promoted 4OH estrogen in humans at these dosages, one would expect to see an increase in adverse outcomes rather than the significant improvements demonstrated in the cervical dysplasia study. The evidence does not support the concern.