Pill Dispenser

A problem that can’t go away

As the chemical complexity of both pharmaceuticals and supplements increases, it becomes progressively more difficult to evaluate potentially-harmful interactions when ‘mixtures’ of these are ingested simultaneously.  In pharmaceutical medicine, these interactions are largely determined by flow-charts, algorithms and statistical analyses – in other words, they are estimates.1  Laboratory tests are seldom, if ever done to establish interactions.

The ‘polypharmacy’ dilemma

In the pharmaceutical model, many patients, especially as they age, are typically prescribed multiple medications.  Every patient’s response to each prescription is unique and dependent on a host of physiological factors, not the least of which is the presence of genetic polymorphisms that help in determining how the drug will be metabolised.  Combine two drugs and the interpretation is possible but becomes more difficult.  Combine half a dozen and I think it would be true to say that nobody has any idea how many biochemical pathways have been impacted!  There is simply no way to predict the outcome of such cocktails of complex pharmaceuticals.

Add a supplement – what does the clinician do now?

Attempts have been made to adapt the same methods to interactions of drugs with supplements. There is a variety of online databases which allow a clinician to add a pharmaceutical in one field and a supplement or ingredient in another.  The programme then provides a response in relation to the potential for adverse effects.  Seems simple enough.

How reliable are the findings?

Clearly, such information could be helpful for a clinician wanting to ensure the safety of combining prescriptions.  But a closer look reveals just how difficult it is to obtain meaningful information from these databases.  If a database concludes that there is an unwanted interaction when combining two drugs or supplements or both without consideration of other factors, what does it mean?

The Importance of Dose

One of the most problematic issues is that such databases do not consider dose. When evaluating a pharmaceutical or a supplement, be it a nutrient, a phytochemical or other food-derived molecule, both dose and bioavailability must be considered.   Although many dietary supplements include nutrient quantities that are many times higher than could be practically consumed in food, there are others with lower levels that are closer to those obtained from diet.  Logically, the responses could be quite different.

Is it even possible to know the dose cut-off point above which an interaction with a drug is likely?  Many supplements include supraphysiological doses (megadoses) of nutrients like Vitamins A, D, and E and trace elements like zinc.  How do we allow also for the uncertain dose-related effects of the pharmaceutical?  And do we know anything of the patient’s unique metabolic capacity?

A Case in Point

Unlike most multi-nutrient formulae, Cell-Logic’s DefenCell® contains nutrigenomically-active plant ingredients with close to dietary levels of micronutrients.  When DefenCell® is considered in one online Drug-Supplement database against the pharmaceutical, Prednisolone (anti-inflammatory steroid), DefenCell® is flagged as a CAUTION, specifically identifying potential interactions with its Vitamin A, Vitamin D3 and Vitamin E and Prednisolone.

When the amounts of DefenCell® micronutrients are considered alongside the EAR as well as the UL, the DefenCell Vitamin A dose of 132 mcg is much less than the EAR of 7900-900 mcg and well below the 3,000 mcg UL.  Similarly, DefenCell® levels of Vitamin D3 and Vitamin E approximate the EAR but are much lower than the UL. 

Therefore, a clinician may erroneously avoid prescribing DefenCell® by relying on such inappropriate data.


DefenCell® – Suggested Daily Dose = 4 capsules


Quantity per capsule

Daily Quantity in 4 capsules

Estimated Average Requirement (EAR)

Maximum Safe
Upper Limit (UL)

Vitamin A

33 mcg

132 mcg

700-900 mcg

3,000 mcg

 Vitamin D3

6.25 mcg

25 mcg

15 mcg

80 mcg

Vitamin E (mixed tocopherols)

3.9 mg

15.6 mg

7-10 mg

300 mg


So what is the worth of these cautionary flags derived from such databases – and what can a clinician meaningfully conclude? 

Back to First Principles

If the Drug-Supplement Interaction databases are confusing, why not go back to basic principles and analyse this yourself?

  1. UNDERSTANDING THE MECHANISM OF ACTION: If you know the mechanism of action of a drug and the mechanism of action of the supplement, a bit of online searching will surely help you to see whether there is likely to be any type of interaction that might produce an adverse effect.
  2. SLOW, OBSERVANT INTRODUCTION: Where there is suspicion of an adverse interaction, slow introduction of the supplement can enable monitoring of responses.  If there is a drug marker, such as the coagulation-related INR, this can be useful.  Effects on digestion, blood pressure, pulse rate and other convenient indicators can be useful.
  3. CAN FOOD SUBSTITUTE FOR THE SUPPLEMENT? Where a patient is taking multiple pharmaceuticals and perhaps multiple supplements, a sensible approach might be to consider if specific foods could be substituted.  The advantage of suggesting specific foods is that a food provides multiple nutrients in a form to which humans are well-adapted.  For example, a magnesium supplement containing 150 mg elemental magnesium could be replaced with 50 grams of raw cashews.  Pepitas supply even more magnesium at 300 mg per 50 gram serve together with manganese, zinc, iron and selenium among others.


SUMMARY:   In light of the issues raised here, it is clear that Drug-Supplement Databases must remain no more than a guide.   Implementing their findings too literally can result in poor clinical decision-making.  Closer examination of the dose and bioavailability of each intervention, the number of combined interventions and the health status of the patient are all essential considerations.  The patient’s relevant gene polymorphisms contributing to the response are unlikely to be available. 

The case of DefenCell®, a nutrigenomically-active formulation targeting core biochemical pathways, illustrates that the data derived from these databases must be interpreted with great caution.


Christine Houghton PhD.,BSc.,R.Nutr.

Nutritional Biochemist


April, 2021.



  1. Ide K, Yamada H, Kitagawa M, et al. Methods for estimating causal relationships of adverse events with dietary supplements. BMJ Open. 2015;5(11):e009038.