4.1 Indications

Hardy Nutritionals^® Daily Essential Nutrients (DEN) is indicated for the treatment of mood and behavioral symptoms. The effect of predecessor formulations of DEN in the treatment of mental, emotional, and cognitive dysregulation across a wide range of central nervous system-related diagnoses* has been documented in more than 20 case-control studies, within-subject crossover case studies, open-label case series, case reports, two database analyses, and randomized controlled trials (RCTs). 

Significant evidence exists to indicate that a wide range of mood, anxiety, and behavioral symptoms can result from inadequate intake of vitamins and minerals and/or poor nutrient status.²⁸ Pervasive improvement across such a wide range of symptoms and disorders with DEN therapy suggests that micronutrients may be addressing physiological root causes of central nervous system aberrations, regardless of diagnostic differentiations (see also 3.2 Mechanism of action).

*The following is a non-exhaustive list of diagnoses or conditions confirmed to be present among the various populations in peer-reviewed positive outcome studies (in most cases it is not known which conditions, if any, were highest represented among treatment responders): attention deficit and hyperactivity disorder (ADHD), disruptive mood dysregulation disorder, various specific phobias, social anxiety disorder (SAD), generalized anxiety disorder (GAD), obsessive compulsive disorder (OCD), separation anxiety disorder, oppositional defiant disorder (ODD), conduct disorder, learning disabilities, enuresis, encopresis, tics, Asperger’s, pervasive developmental disorders (PDD) including autism and autism spectrum disorders, bipolar disorder (including sub-types), depression and dysthymic disorders (including sub-types), panic disorders, Prader-Willi syndrome, psychoses, post-traumatic stress disorder (PTSD), insomnia, stress.

4.2 Dosage

DEN should be administered throughout the day with food. The recommended therapeutic dose is 12 capsules per day in divided doses. Four capsules taken 3 times per day is preferable, though parents limited to dosing children before and after school may choose to administer doses of 6 capsules twice daily to good effect. Both adults and children older than 6 years of age dosed at or approximately at this level of nutrient intake during clinical trials have demonstrated the most consistent and marked improvements. 

4.2.1 Initial and Maintenance Dosing

A person making a drastic diet change would expect significant gastrointestinal discomfort. To avoid similar discomfort and foster optimal tolerability, the therapeutic dose of DEN should be reached by gradual titration over the course of 4 days, or more, if needed (see 2.1.1 Instructions for DEN use, and 5.1.2 Digestive system).

Maintenance treatment consists of whatever DEN dose is efficacious in maintaining symptom remission. Optimal maintenance dosage will vary with individual needs.

4.2.2 Treatment Discontinuation

Discontinuation by patients usually results from:

1. The cost of uninsured treatment (most common)
2. Inability to tolerate the transition process, usually because of drug withdrawal effects (especially when use of abusable drugs is not disclosed to the prescriber)
3. Lack of benefit
4. Inability to swallow many pills

Techniques to facilitate pill swallowing may be helpful (Kaplan et al. 2010; see also video at http://research4kids.ucalgary.ca/pillswallowing).¹ Rucklidge et al. employed the techniques developed by Kaplan et al. in an attempt to help 38 otherwise eligible children meet the capsule swallowing capability inclusion criterion for a double-blind study and had a success rate of nearly 50% within 2 weeks (18 children).¹⁷

4.2.3 Dosing young children

For children ages 6 years and younger, doses lower than 12 capsules per day are usually adequate. The following are typical therapeutic dosages of DEN for children with diagnosable psychiatric conditions, based on published research and clinical experience:

• 1-3 years: Work up to 4 capsules/day (with food).
• 4-6 years: Work up to 8 capsules/day (with food).
• 7 years and older: Work up to 12 capsules/day (with food).

Obviously, the above age ranges group children of widely varying size and metabolism, so the dosages presented here need not be viewed as strict minimums or maximums. One might better visualize a typical therapeutic dose across the age ranges presented by assigning the listed doses to 2 years, 5 years, and 7 years and interpolating between so as to create a smooth continuum of dosing recommendations for any age. As with any treatment, clinical observations should inform dosing recommendations by balancing symptom response with any emergence of side effects. 

4.3 Safety

Nutrient intake from DEN is well within known safe intake ranges for most ingredients (see 5.1 Side effects), and conservative tolerable upper intake levels, extrapolated from primarily single-nutrient data,^40-45 are likely to over-estimate risk from a broad-spectrum formula such as DEN. 

The following well-known inter-nutrient relationships illustrate the importance of balanced supplementation:

• either copper or zinc alone can induce a deficiency or the other
• supplemental vitamin B12 alone can mask a folate deficiency
• potassium without sodium will induce heart palpitations
• excessive calcium intake relative to magnesium can cause constipation, while excessive magnesium intake relative to calcium can cause diarrhea

“…single-nutrient or narrow-spectrum treatments might speculatively exert [their] deleterious effects by inducing imbalances and relative insufficiencies among micronutrients…Most adverse micronutrient effects have been associated with treatments involving three or fewer ingredients. The findings become more favorable with formulations of 10 or more micronutrients. This reinforces the principle that a full range of micronutrients is needed for optimal physiological functioning and for reducing potential drawbacks of narrow-spectrum approaches.”¹

Standard toxicology concepts were developed from the study of drugs. Although environmental chemicals may inform medication dosing strategies, they are wholly unfit for nutritional applications. 

Most notable among the differences in nutrition and drug dosing paradigms is the fact that micronutrients are not foreign to the human organism; and therefore, the safest dose is not zero (i.e. the risk curve is u-shaped instead of linear or exponential when plotted against dose). In spite of food fortification programs in most jurisdictions around the world, the majority of people, even in developed nations, are likely to be more at risk due to not meeting recommended dietary intakes (RDI) than to be at risk due to over-intake. 

Additionally, as noted above, instead of compounding risk with combined exposure, safety and dose tolerability increase when multiple micronutrients are ingested together. 

Finally, physiological and metabolic demand seem to predict micronutrient dosing better than do standard toxicology models, which are based primarily on age or body weight. (For more discussion on this topic, see 8.8.4 Developmental growth and puberty and 8.8.5 Physical and metabolic activity).

4.4 Biological safety data

Biological safety data from 144 children and adults was available from eight datasets evaluating predecessor products with comparable therapeutic dosages to DEN. Blood was also analyzed from 93 children with ADHD taking DEN in a double-blind study published in 2017. In these reports, there was not a single reported occurrence of a clinically meaningful negative outcome/effect or an abnormal blood test that could be attributed to toxicity.^3,16 Testing included routine blood samples, heart rate, and blood pressure measurements. 

One dataset included a full laboratory panel at baseline, completion, and at the end of open label extension. A smaller safety panel (hematology, potassium, calcium, alanine aminotransaminase, creatinine, and estimated glomerular filtration rate [eGFR]) was performed every two weeks during each study phase. For each dataset, no significant changes were noted, and all values remained within normal clinical reference ranges.¹⁶ 

After 10 weeks, data reveals only four significant differences between children taking DEN and children taking placebo: DEN users' data registered greatly increased serum vitamin B12 and folate along with decreased homocysteine and eosinophils. Copper status was among the many other measures found to be undifferentiated between the two groups.¹⁷ 

4.4.1 Interpreting clinical laboratory tests during DEN therapy

DEN contains sufficient supplemental biotin to interfere with many routine clinical laboratory analyses. “Biotin interference can occur in immunoassays that employ streptavidin-biotinylated antibodies when high biotin levels in blood samples, resulting from the use of oral biotin supplements, interfere with the streptavidin-biotin binding, thus distorting signal detection in these tests”⁴⁶ (see Appendix H).

Falsely high or low results on clinical lab tests due to biotin interference have been well documented in scientific literature, but the problem often goes unsuspected – and therefore undetected – by health care professionals. “It is important for healthcare personnel to become more aware of immunoassay methods that are vulnerable to biotin interference and to consider biotin supplements as potential sources of falsely increased or decreased test results, especially in cases where a lab result does not correlate with the clinical scenario.”⁴⁷ 

Instructing patients to temporarily discontinue biotin supplementation to allow for biotin clearance before biological samples are collected for analysis will resolve this problem. “The take-home message, therefore, is that clinicians and researchers who order blood levels of vitamins such as Vitamin D, Vitamin B12, and folate, hormones such as thyroid hormones and thyroid-stimulating hormone, or other substances should also enquire about additional medications, including supplements, that the patient may be taking; should biotin supplementation be identified, this should be communicated to the laboratory that performs the tests. Should biotin interference be deemed likely, blood draw for the test should be deferred until after discontinuation of biotin for at least 3–7 days.”^46,47

Even when laboratory results have been confirmed trustworthy, it is worth noting that, for certain nutrients, serum levels outside of the normal reference ranges can be expected during DEN therapy. After all, reference ranges are most likely established using data from largely unsupplemented populations. Therefore, in the absence of a specific clinical concern, supranormal nutrient status due to supradietary intake is, by itself, no cause for alarm. For example, high vitamin B12 is considered relatively harmless if it is simply an artifact of supplementation and neither masks a folate deficiency nor presents with other known indicators of kidney malfunction. (Vitamin B12 is one of multiple B-vitamins with no evidence of toxicity and therefore no established UL.⁴¹)