8 Possible Limiting Factors

Since 1996, we have observed that various factors can significantly limit responses to nutrient therapy. Recognizing these factors and taking appropriate steps can make a significant difference to Hardy Nutritionals^® Daily Essential Nutrients (DEN) treatment response.

8.1 Psychiatric medications

Changing psychiatric medications inappropriately during DEN therapy can be a significant limiting factor. Improper medication dosages can lead to fluctuations in brain chemistry that complicate symptom management.

8.1.1 Discontinuation

Gradually tapering off psychiatric medications generally provides the greatest stability for patients during treatment with DEN. Abrupt discontinuation of any psychiatric medication is not recommended (see 2.4 Clinical response – CNS drug use).

Reducing psychiatric medications as needed when overmedication effects increase should prevent pronounced discontinuation symptoms as well as rebound (a significant return of the original symptoms). The rate at which medications are terminated and the duration of the pharmacological treatment are key factors that influence discontinuation symptoms. Discontinuation effects are typically more acute with drugs that have a relatively short half-life.

8.1.2 Increasing dose

Increasing psychiatric medication dosages while using DEN may increase the possibility of drug-nutrient interactions (see 5.2.2 Psychoactive drugs).

8.2 Non-psychiatric medications

Worsening of symptoms has been observed when various non-psychiatric medications have been used together with DEN. These effects have been most pronounced with the following medications:

8.2.1 Anesthetics

Anesthetics have potential interactions with DEN due to their potential psychiatric effects. Psychiatric medication status is an important consideration in the management of the patient about to undergo anesthesia and surgery.^49-51 For example, benzodiazepines are commonly administered for many surgical procedures to sedate and relax patients. Anesthetic use may be considered increasing or changing medications (see 8.1 Psychiatric medications).

Some unmedicated individuals taking DEN have reported withdrawal or post-withdrawal symptoms following surgery which have responded to standard post-withdrawal drug symptom alleviation measures (see 8.6.3 Prior psychiatric drug use).

8.2.2 Antacids

Antacids (such as Zantac, Prilosec, Tagamet, etc.) neutralize or inhibit the production of stomach acid which is necessary for digestion. Acidic denaturation is a major step in the process of extracting food-bound nutrients. Inhibiting this step of the digestive process can reduce the bioavailability of critical nutrients during the absorption phase.

Chronic antacid use may also induce dysbiosis of gut microbiota in the form of small intestinal bacterial overgrowth (SIBO), which can negatively affect the response to micronutrient therapy.

8.2.3 Antibiotics

Antibiotics have saved countless lives, but the dangers of overuse are becoming increasingly well-documented and widely recognized. For example, oral antibiotics may vastly impact beneficial gut microflora in addition to the pathogenic target species, resulting in reduced nutrient absorption (and for  some vitamins, reduced synthesis), depression, anxiety, and other effects.^52,53

“Oral antibiotic and antifungal treatments usually require an adjustment in micronutrient dosing. The intestinal microbiome is crucially involved in micronutrient absorption (and for some vitamins, synthesis), so antibiotics sharply reduce nutrient absorption and can lead to a return of psychiatric symptoms. This problem is avoided by increasing the micronutrient dose by 40%-50% during the antibiotic therapy plus 4 additional days. For chronic antibiotic treatment (e.g., acne), the micronutrient dose can be adjusted around the antibiotic dose.”¹

Worsening of psychiatric symptoms has not been observed with intravenous antibiotics, suggesting that this antibiotic effect occurs in the gastrointestinal tract.

Adding a probiotic-prebiotic combination such as Hardy Nutritionals^® Greens & Probiotics during the course of antibiotic treatment (taken between antibiotic doses), plus at least one to two weeks after completion, is also recommended.

A natural antibiotic/antifungal agent may sometimes also be indicated during and shortly after the antibiotic treatment, especially if the individual has a history of fungal/microbial infections. Possibilities include olive leaf extract (such as Hardy Nutritionals^® Olive Leaf Extract), caprylic acid, garlic  capsules, and oil of oregano.

8.2.4 Antihistamines

Clinically significant increases in psychiatric symptoms have been observed when some individuals have used certain antihistamines and related drugs (e.g. Zyrtec, Benadryl, etc.) together with DEN.

8.2.5 Contraceptives

Hormone-containing contraceptives may worsen depression, alter mood, and/or increase nervousness and irritability. Cautious use is warranted.

8.2.6 Hormone replacement therapy (HRT), including thyroid hormones

HRT may worsen depression, alter mood, and/or increase nervousness and irritability. Cautious use is warranted.

Thyroid hormone therapy can cause strong interactions with DEN. Iodine, selenium, and other supportive nutrients boost endogenous thyroid function and peripheral thyroid hormone metabolism. This often necessitates a dose reduction of prescription thyroid hormone to avoid potentiated side effects. Levothyroxine absorption is also known to be enhanced by calcium, further magnifying the interaction.

As micronutrients are implicated in the conversion of thyroxine to its various forms as well as in its production, a full thyroid panel should be used to evaluate oral thyroid hormone dosing during DEN therapy, including all of the following tests: TSH, Free T3, Reverse T3, Total T3, Free T4, Thyroid    antibodies, Sex hormone binding globulin. However, DEN supplementation should be discontinued temporarily as per lab protocols before biological samples are taken, or the lab test results may turn out to be misleading due to biotin interference (see 4.4.1 Interpreting clinical laboratory tests during DEN therapy).

8.2.7 Opioid Analgesics

Individuals taking opioid analgesics may experience an increase in opioid side effects while taking DEN, perhaps as a result of cytochrome p450 enzyme interaction effects (see 5.2.2 Psychoactive drugs and Appendix F).

8.3 Recreational drugs

Recreational substances (including, but not limited to caffeine, marijuana, alcohol and nicotine) cause psychotropic effects, and their interactions with DEN may cause mood and mind-altering effects.¹ Keep in mind that many individuals who are addicted to substances may try to conceal their addictive behaviors, and a patient’s lack of progress or unexplained symptoms may be the result of consuming these substances. Specialized nutrient therapy has been used to successfully treat addictions.⁵⁴

8.4 Supplements

8.4.1 Vitamins

Although taking extra vitamins while taking DEN is not usually necessary, adding individual vitamins for specific clinical purposes may be useful (see 2.8 Addressing residual symptoms). For example, where long-standing, specific vitamin deficiencies or genetic conditions predisposing individuals  to higher vitamin needs exist, it may be necessary to add therapeutic amounts of specific vitamins in order to optimize clinical response to DEN.

8.4.2 Minerals

Although taking extra minerals while taking DEN is not usually necessary, adding individual minerals for specific clinical purposes may be useful (see 2.8 Addressing residual symptoms). Generally, we recommend that the minerals copper, zinc, calcium and magnesium should not be added to DEN    therapy, as they can alter critical mineral balances of the DEN formulation and render it less effective. Additional iron may be added to DEN while still remaining well within recommended intake levels.

8.4.3 Psychoactive supplements

Any psychoactive supplement has the potential to interfere with DEN effects. These include (but are not limited to) St. John’s wort, ginseng, kava kava, skullcap, valerian root, and certain modified amino acids such as S-adenosyl methionine (SAMe) and 5-hydroxytryptophan (5-HTP). If patients  choose to use psychoactive supplements during DEN therapy, advise cautious dosing and monitor their responses carefully.

8.4.4 Amino acids

Caution is advised with the use of psychoactive amino acids and metabolites. These include, but are not limited to, S-adenosyl methionine (SAMe), 5-hydroxytryptophan (5-HTP), phenyl-GABA, and N-acetyl cysteine. Typical dose-response relationships of amino acids and amino acid metabolites  can be expected to become dramatically more sensitive in the context of DEN therapy, as DEN provides the micronutrients involved in the endogenous function of the implicated pathways. Extensive clinical experience has shown that a balanced combination of amino acids, such as Hardy Nutritionals^® Balanced Free-Form Aminos, is better tolerated longterm than isolated amino acids which target only one neurotransmitter pathway.

8.4.5 Fatty acids

DEN provides all the vitamin and mineral cofactors required by elongation and desaturation enzymes in the endogenous production of beneficial long-chain fatty acids. As a result, individuals with adequate intake of essential fats may have less need for supplemental fatty acids. Nevertheless, while  taking DEN, some individuals report enhanced mental clarity and focus from omega-3 supplements such as Hardy Nutritionals^® Essential Omegas, especially in the beginning stages of DEN therapy.

8.5 Gastrointestinal problems

Impaired digestive health can reduce the absorption of essential vitamins and minerals. Bowel disorders are strongly correlated with psychiatric conditions.^4,5 If bowel dysfunction is an issue, whole foods and probiotics are often useful. Adequate hydration and a healthy diet with plenty of fiber from fruit and vegetables prevent many problems.

 8.5.1 Bowel disorders

 Irritation and inflammation of the intestinal lining is a common occurrence in chronic bowel disorders. These disorders may improve in time while using DEN but can significantly reduce the absorption of key nutritional elements until they are corrected. Restriction diets, probiotics, digestive   enzymes, fatty acids, and various other supplements may be beneficial in restoring and maintaining more normal bowel function (see 2.6 Managing gastrointestinal issues).

 8.5.2 Constipation

 Constipation, regardless of its cause, can be a critical limiting factor of DEN treatment by severely reducing absorption of essential vitamins and minerals. Depending on the cause of constipation, different measures may be appropriate to rectify the problem according to clinical judgment.

 Treatment experience with DEN has shown that a few simple measures can often help constipation. Adequate hydration is essential. Fiber-rich whole foods like prunes, raw fruits and vegetables often help. In addition, patients with constipation often benefit long-term from a probiotic-prebiotic combination such as Hardy Nutritionals^® Greens & Probiotics, which can help restore intestinal microflora balance.

 8.5.3 Diarrhea

 Diarrhea, regardless of its cause, can severely limit the effectiveness of DEN treatment by preventing absorption of essential vitamins and minerals. Depending on the cause of diarrhea, different measures may be appropriate to rectify the problem according to clinical judgment.

 Treatment experience with DEN has shown that certain foods like unripe bananas, peanut butter, and cheddar cheese often help rectify diarrhea related to initiating nutrient therapy. In addition, many patients with chronic diarrhea benefit long-term from a probiotic-prebiotic combination such as Hardy Nutritionals^® Greens & Probiotics, which can help restore intestinal microflora balance.

 8.5.4 Parasites

 Parasites rob their hosts of nutrients and may even induce relative nutrient imbalances, creating unique requirements for select nutrients. The fact that parasites significantly contribute to malnutrition worldwide is widely recognized, but this problem is rarely suspected in parts of the world with   considerable access to clean water, hygienic living conditions, and sanitary food production. However, many vectors for parasite transmission, such as pets, biting insects, and even soil, are common to all areas of the world. At best, essential nutrients will return suboptimal outcomes when one or   more parasites are present, and at worst, micronutrients may fuel the infection.  If the response to DEN is poor, screening for parasites is recommended as part of a thorough evaluation of all the potential treatment-limiting factors. Invariably, a dramatically improved response to DEN is seen after any interfering parasites are successfully treated.

 8.5.5 Microflora imbalance (dysbiosis)

 Factors such as antibiotic use, infections, environmental chemicals, and diet patterns may diminish the population of beneficial microorganisms naturally present in the human gastrointestinal ecosystem relative to the other species. Restorative measures should be taken to ensure optimal tolerability   and bioavailability of micronutrient treatments. 

A probiotic-prebiotic combination product, such as Hardy Nutritionals^® Greens & Probiotics, may be beneficial in restoring healthy gut function in individuals with mild microflora imbalance. If this is not sufficient and symptoms do not improve, then a natural antibiotic/antifungal agent, such as Hardy Nutritionals^® Olive Leaf Extract, may be warranted. In particular, patients with a history of extensive or chronic antibiotic use are often highly susceptible to severe microflora imbalances (see Appendix B).

 Note: Antibiotic/antifungal agents may cause a die-off response, known as the Herxheimer reaction, which presents as flu-like symptoms and can arise any time from the first day to the first couple of weeks after beginning to take the product. If vomiting occurs, reduce the dosage or introduce an alternate antibiotic/antifungal agent (e.g. caprylic acid, garlic capsules, or oil of oregano). Changing antibiotic/anti-fungal products periodically may prevent organisms from adjusting to a single agent. If there is no Herxheimer reaction, complete the course at recommended levels.

8.6 Patient history

8.6.1 Antibiotic use

Oral antibiotic use can negatively impact beneficial intestinal microflora. If an individual has had a lengthy history of oral antibiotic use, particularly as a child, a probiotic-prebiotic combination, such as Hardy Nutritionals^® Greens & Probiotics, which promotes a robust and diverse microbiome, is recommended. Normally, probiotics do not need to be taken on a continual basis for longer than a year. Once the probiotic has had its effect, it may only need to be taken periodically thereafter. If symptoms do not improve with probiotic use, additional measures may be needed (see 8.5.4 Parasites).

8.6.2 Genetic factors

Excepting cases in which DEN is contraindicated (see 7.2 Contraindications), it is generally well-tolerated by individuals with genetic polymorphisms known to affect nutritional status and/or mood regulation (i.e. COMT, MTHFR, etc.). Some individuals with MTHFR polymorphisms report extreme dose sensitivity to methylfolate supplementation. Such individuals may benefit from supplemental niacin in addition to DEN, with dosing determined on a case by case basis (see Appendix E).

8.6.3 Prior psychiatric drug use

Post-withdrawal medication symptoms may be a result of the metabolism of drug residues stored in poorly perfused tissues, as they are often triggered by such things as physical exertion, weight loss, stress, prolonged exposure to sun or heat, and liver or bowel cleanses. To a lesser extent, post-withdrawal drug symptoms may also be triggered by massage, chiropractic, or acupuncture therapies (see 8.7 Lifestyle factors).

Residual medication-related symptoms can appear months, and in some cases, even years, after psychiatric medications have been discontinued.^56,57 Individuals often report that they feel medicated again despite having taken no medication recently.

Post-withdrawal symptoms are often mistaken for a return of psychiatric symptoms. Some post-withdrawal medication symptoms include insomnia, anxiety, depression, crying spells, agitation, and irritability.

Suggestions for treatment of post-withdrawal drug symptoms include avoiding or moderating ‘trigger’ activities and/or temporarily adding protein isolate to the patient’s treatment regimen. Additional vitamin C (particularly liposomal vitamin C), taken on an as-needed basis, may also provide significant and rapid relief (see 2.3.2 Managing post-withdrawal medication effects).

8.6.4 Sensitivities

Sensitive individuals may require and/or tolerate lower doses of DEN. Sensitive individuals may be identified by their history or by low medication tolerance. They may become restless, agitated, irritable, or have some other anomalous response within hours or days of starting micronutrient products. Often, so-called sensitivities turn out to be attributable to nothing more than medication interactions, gastrointestinal microflora dysbiosis, or some other treatment-limiting factor identified in this document.

8.6.5 Special nutrient needs

Where long-standing specific vitamin or mineral deficiencies exist, including genetic conditions that predispose individuals to higher vitamin or mineral needs, it may be necessary to add therapeutic amounts of specific vitamins or minerals in order to optimize therapeutic response.

8.6.6 Electroconvulsive therapy (ECT)

A history of ECT may result in a slower response time and/or a reduced likelihood of complete response to micronutrient therapy.

8.6.7 Brain trauma & neurodegenerative disease

A history of brain trauma or the presence of advanced neurodegenerative disease may result in a slower response time and/or a reduced likelihood of complete response to micronutrient therapy.

8.7 Lifestyle factors

8.7.1 Heat

Acute heat loading is common in everyday situations such as physical exercise or work in a hot climate. Other forms of heat exposure can include hot tubs, steam baths, saunas, prolonged sunbathing, etc. Drug kinetics and dynamics may become altered as a result of physiological responses in persons exposed to heat.⁵⁸

Possible increases in the rate of chemical reaction and drug metabolism may affect the activity of many drugs. Individuals who are not acclimatized to heat may be hypersensitive to these actions. A possible decrease in the glomerular filtration rate may decrease the clearance of drugs and metabolites,  increasing drug activity and the probability of toxicity.^59,60

Heat-intensive activities have been reported to induce an overmedicated feeling in those who have long since discontinued medications, perhaps due to metabolism of drug residues stored in poorly perfused tissues. For measures that may alleviate post-withdrawal drug symptoms, (see 8.6.3 Prior psychiatric drug use).

8.7.2 Diet

DEN is designed to add vitamin and mineral density to an existing diet. Thus, it is still very important for patients to eat regular, well-balanced meals each day. There are many important nutritional factors that are best obtained from whole foods. Individuals taking DEN should avoid diet extremes and over-consumption of refined foods, especially if they are susceptible to gastrointestinal microflora imbalance (see 8.5.5 Microflora imbalance (dysbiosis)).

8.7.3 Sleep

Adequate sleep is a significant factor in psychiatric health. Poor sleep quality and/or sleeplessness significantly exacerbate mania, psychosis, stress, and anxiety. While micronutrient therapy usually promotes more restful sleep, doses of DEN late in the day (after 6 pm) may contribute to wakefulness in  some people.

In some cases, poor sleep may be a result of overmedication effects due to nutrient-medication interactions (see 5.2 Drug interactions and 8.6.3 Prior psychiatric drug use).

8.7.4 Hydration

Inadequate hydration can compromise gut health, psychiatric health, and overall health. Based on 'Adequate Intake' levels for daily water needs, as established by the US Institute of Medicine, adequate fluid intake ranges from about 5 cups (1.2 L) per day for children ages 4-8 to about 9 cups (2.2 L) per day for women and about 13 cups (3.0 L) for men, in addition to water obtained from foods. Pregnancy and lactation, as well as physical activity, climate and diet can increase individual water needs.⁶¹ Adequate hydration is essential for moving nutrients into cells and flushing wastes out of the body.

8.7.5 Non-compliance

Inconsistent or “as needed” dosing of DEN is not recommended. Clinical results with micronutrient therapy are often achieved gradually over time, and regular, steady dosing is critical to achieve the best results. It may be helpful to think of DEN as food for a starving brain. Non-compliance may indicate that the individual may require additional education and/or assistance.

8.7.6 Physical activity

Healthy physical activity is rightfully encouraged by almost every source of health education. However, intense physical exercise has been reported to induce an overmedicated feeling in those who have long since discontinued medications, perhaps due to metabolism of drug residues stored in poorly perfused tissues. For measures that may alleviate post-withdrawal drug effects, (see 8.6.3 Prior psychiatric drug use).

The effects of exercise on drug distribution are complex. Physical exercise, particularly when a person is not accustomed to it, may affect drug kinetics and dynamics. Exercise or physical work increases the rate and depth of respiration and increases muscular blood flow. Temporary reduction in blood flow to adipose and other inactive tissues may delay the distribution of some drugs that have been stored by these tissues. Lipids released for metabolic purposes may increase the distribution of drugs stored in adipose tissues. Renal plasma flow, urine excretion rate, and urine pH are reduced by exercise, causing an increase in the serum levels of drugs eliminated through the kidneys.^62,63

8.7.7 Weight loss

Weight loss can trigger post-withdrawal drug effects, presumably by facilitating the release of medication residues stored in poorly perfused tissues (related to 8.7.6 Physical activity, above). For measures that may alleviate post-withdrawal drug symptoms, (see 8.6.3 Prior psychiatric drug use).

8.8 Physical health and life stage factors

8.8.1 Menstrual cycle

Psychiatric symptoms may increase during menstruation. In part, this is likely due to changing hormone levels and increasing nutrient demands. Should additional symptoms become apparent during this time, it may be beneficial to increase DEN by at least one full dose of 4 capsules/day for about one week. In subsequent cycles, taking the additional DEN starting a few days prior to menstruation through to its completion may be preventative.

8.8.2 Physical illness

Additional DEN may be beneficial when a person becomes ill with a cold, flu, or other illness. Recurrent illness and infections are a sign of a weakened immune system. Increasing DEN by 4 capsules daily to support the immune system through the illness may lead to faster recovery.

8.8.3 Pregnancy and lactation

Nutritional requirements are significantly increased during pregnancy and lactation. The daily dose of DEN should be increased at least in relative proportion to daily caloric intake, particularly in individuals with psychiatric symptoms. An additional dose of 4 DEN capsules per day may be useful.

8.8.4 Developmental growth and puberty

Significant hormonal changes accompany puberty and growth spurts (adolescent or childhood), and the body’s nutritional demands are often significantly increased during these times – a fact often evidenced by dramatic increases in appetite. To visualize the reality that metabolic demand for micronutrients is not strictly dependent on age or weight, consider that compared with an adult of average body weight, a teenager of equal weight may eat twice as much! Similarly, a small child may eat at least twice as much as an adult relative to body weight.

The onset of many psychiatric symptoms often corresponds with pubescence. For this reason, as well as to meet increased nutrient needs for growth and metabolism, additional DEN may be beneficial during this time.

8.8.5 Physical and metabolic activity

Physical activity significantly increases the need for essential nutrients in humans and in animals. For example, draft horses have significantly higher nutrient needs when working compared with when they are idle.⁶⁴ The same is true for human performance.⁶⁵