Side Effects & Drug Interactions

5 Side Effects & Drug Interactions

5.1 Side effects

Side-effect-free intake ranges for vitamins and minerals have been established by the United States Institute of Medicine and similar authorities around the world based on a comprehensive review of relevant data in adults and children.40-45

According to the intake ranges established by the Institute of Medicine, the most likely clinically relevant side-effect of therapeutic dosage of Hardy Nutritionals® Daily Essential Nutrients (DEN) is mild diarrhea and other mild gastrointestinal complaints in a small percentage of patients who are sensitive to therapeutic doses of magnesium.

Regarding this effect, the Institute of Medicine states, “Although a few studies have noted mild diarrhea and other mild gastrointestinal complaints in a small percentage of patients at levels of 360 to 380 mg (15.0 to 15.8 mmol) per day, it is noteworthy that many other individuals have not encountered such effects even when receiving substantially more than this [level] of supplementary magnesium.”40

Undoubtedly the dietary context contributes to the individual variability in magnesium tolerance. DEN is more easily tolerated than supplemental magnesium alone at the same dose because the magnesium is in the context of other balancing minerals, including calcium, which is likely to have a constipating effect when supplemented alone.

The following treatment-emergent adverse events have been observed in patients with bipolar disorder, depression, ADHD, generalized anxiety disorder, mood lability and explosive rage, oppositional defiant disorder, Asperger syndrome, and Prader Willi syndrome:16

5.11 Body as a Whole

Infrequent: headache (usually transient), insomnia (usually transient)

5.12 Digestive System

            Frequent: harmless change in urine color (a fluorescent yellow color due to riboflavin)

Infrequent: loose stools, nausea (both usually transient and easily managed by temporarily lowering the dose and then increasing it more gradually (see 2.1.1 Instructions for DEN use)), worsening of pre-existing Candida (yeast) infections (managed with reduced dose and adjunct antifungal therapy (see 2.6 Managing gastrointestinal issues))

           Rare: flatulence, diarrhea, stomach ache, vomiting

5.13 Psychiatric Rare: anxiety, agitation, insomnia, impulsivity, or depression (These may be indicative of gastrointestinal dysbiosis or unusual nutrient dependencies and may resolve with adjunct therapies. See 2.6 Managing gastrointestinal issues and 2.8 Addressing residual symptoms)

5.2 Drug interactions

5.2.1 Anticoagulant medications

DEN contains vitamin K, which promotes blood clotting function. Caution is advised when administering DEN to patients on warfarin-type anticoagulant therapy, as vitamin K may alter the hypoprothrombinemic response to anticoagulant drugs.

Periodic monitoring of prothrombin time is essential in determining the appropriate dosage of anticoagulant medications during DEN therapy. Dosage adjustments to anticoagulant medications may be required.

5.2.2 Psychoactive drugs

Strong interactions with psychoactive drugs, including lithium, have been observed in clinical experience with predecessor formulations of DEN. On this issue, researchers commented, “we recommend that, notwithstanding our findings of general safety of the formula when used in medication-free patients, use of multi-nutrient formulations as an adjunct should be monitored closely and with full attention to the possibility that optimum dosing of psychotropic agents may require significant adjustments.”16

Because interactions of DEN with psychiatric medications have not been systematically evaluated, caution is warranted. Any agent with CNS activity has the potential to interact with DEN and complicate the management of micronutrient treatments. These include psychiatric medications, medical drugs with CNS actions (antihistamines, medications for ‘colds’, theophylline, etc.), recreational agents (alcohol, marijuana, heroin, etc.), other commonly used substances that are not necessarily thought of as recreational agents (caffeine, nicotine), and certain hormones (e.g. levothyroxine, glucocorticoids).3 Rapidly Emergent Interactions

Rapidly emergent medication interactions with DEN appear to occur mainly with medications whose absorption or excretion is directly affected by essential nutrients. For example, the absorption of many stimulants is enhanced by calcium and magnesium.48

Other relatively rapid medication interactions with DEN have been observed clinically in patients who metabolize the interacting medications slowly, or who are already experiencing a significant burden of medication side effects when they begin DEN therapy. Generally, these interactions manifest as a marked increase in known medication side effects. Gradual Interactions

Gradually emergent medication interactions with DEN occur with a wide variety of medications. These gradual interactions generally manifest over a period of several weeks as an increase in the number and/or intensity of known medication side effects.

One partial explanation for these interactions is that over time, the vitamins and minerals in DEN boost key outputs of under-functioning biochemical pathways by serving as natural, essential cofactors to numerous enzymes (see Appendix G). As these key outputs become more optimized, the need for biochemical manipulation by medications is reduced, and previously ideal medication dosages begin to result in overmedication effects. Gradual reductions in medication doses over time, as overmedication effects become apparent, can resolve these overmedication effects (see 2.3 Potentiation of psychiatric medications).

Another partial explanation for these gradual interactions is that some of the nutrients in DEN, including vitamin A, vitamin D, vitamin B6, niacinamide, zinc, copper, acetyl-L-carnitine, and ginkgo biloba, serve as substrates for cytochrome p450 (CYP) enzymes or cause CYP enzyme inhibition (see Appendix F).

DEN potentiates lithium much more powerfully than other psychoactive medications, presumably because lithium is metabolized differently than other central nervous system (CNS)-active medications. Treatment guidelines for patients taking lithium are found in 2.3 Potentiation of psychiatric medications.