Treatment Guidelines

2.1 Critical treatment considerations

Unless contraindications (see 7.2 Contraindications) or precautions (see 6.2 Precautions) direct otherwise, Hardy Nutritionals® Daily Essential Nutrients (DEN) can generally be administered to patients as outlined in this section. Individual patient characteristics may require adaptations according to clinical judgment. Important clinical considerations include:

• Assess gastrointestinal health3 (see 2.6 Managing gastrointestinal issues, 8.5 Gastrointestinal problems, and Appendix B)

Researchers at John Radcliffe Hospital in Oxford, England, observed that 90% of the patients who repeatedly sought treatment for digestive tract symptoms (more than 12 visits in the previous 12 months) had at least one current psychiatric diagnosis; 48% had at least two.4,5

• Assess medication use3 (see 2.3 Potentiation of psychiatric medications, 2.4 Clinical response – CNS drug use, 8.1 Psychiatric medications, and 8.2 Non-psychiatric medications)

The online Merck Professional Manual indicates that drug interactions are changes in a drug’s effects due to recent or concurrent use of another drug or drugs (drug-drug interactions), ingestion of food (drug-nutrient interactions), or ingestion of dietary supplements (dietary supplement-drug interactions).6 For the purposes of this text we use the term drug-nutrient interactions.

2.1.1 Instructions for DEN use

Generally, DEN can be titrated up to an appropriate therapeutic dose (see 4.0 Indications & Dosage) within 4 days as directed on the label (see Figure 1): Very sensitive patients may benefit from starting with 1 capsule per day and increase to therapeutic levels as they are comfortable. Patients who have difficulty falling asleep should take the evening dose of DEN as early as is practical (see 8.7.3 Sleep).

Suggested Use: “Consistently take 4 capsules 3 times daily, or a level recommended by your health professional. If desired, start with 1 capsule 3 times daily and increase gradually. Take with food.”

Taking DEN with food further helps to avoid uncommon gastrointestinal side effects (see 5.1 Side effects). Children should take DEN under adult supervision (see 6.2 Precautions).

2.2 Clinical response – medication-naïve

“Broad-spectrum micronutrient treatments are straightforward for psychiatric patients who are drug-naïve as well as for individuals who are seeking benefits for normal brain functioning, assuming they are not using other CNS-active drugs. Micronutrient use is usually not complicated for patients who have been free of CNS drugs for several weeks or months, except if those medications have significant withdrawal symptoms.”1 (See Figure 2).

The average response time for an adult is approximately three weeks. Children and adolescents typically respond sooner. In open-label trials, approximately 80% of individuals responded to nutrients alone by 2 months without conventional psychiatric medication. For individuals with no recent medication use who are taking the recommended dose of DEN, it is possible to see benefits beginning as follows:7

• Mania - within 5 days

• Depression - within 4-8 weeks (longer if chronic or psychotic)

• Non-comorbid panic and anxiety may require adjuncts for best response (see 2.8 Addressing residual symptoms)

2.3 Potentiation of psychiatric medications

Drug interactions can be triggered by ingestion of food or by ingestion of dietary supplements.6 In this document, we will refer to both of these interactions as drug-nutrient interactions.

Both clinicians and patients using DEN consistently report that the effects (including known side effects) of “virtually all CNS-active drugs”1 are amplified by apparent drug-nutrient interactions (rough estimates range from 3-5 times). Notably, lithium may be more powerfully potentiated (from 10-100 fold), perhaps via unique mineral-mineral interactions. Therefore, side effects of psychiatric medications, including lithium, must be monitored carefully during DEN therapy and dosages adjusted accordingly (see 6.1 Warnings). As medication side effects increase, medication dosages should be gradually reduced (see Figure 3).

“In contrast [to drug-naïve or drug-free patients], cross tapering patients from ongoing psychiatric drug regimens to broad-spectrum micronutrients generally requires gradual and skillful management because of apparent interactions between broad spectrum micronutrients and CNS-active drugs.”1

This apparent potentiation of psychoactive medications generally emerges gradually over time. When pre-existing medication side effects increase in severity or additional drug side effects emerge, gradually reduce medication dosages (see 5.2 Drug interactions). Ideally, medication reductions should minimize patient discomfort by avoiding potentiated side effects (due to inadequate dose reduction), as well as symptom rebound or discontinuation effects (due to premature, overly rapid, or excessive dose reduction - see 8.1 Psychiatric medication). Figures 3 and 5 illustrate the importance of minimizing drug-related symptoms during the medication reduction process.

2.3.1 Managing withdrawal syndromes

Common symptoms of drug discontinuation (withdrawal) include:7

• Odd head feeling, headache, mental fog

• Odd gastrointestinal feeling, nausea, GI upset, flu-like symptoms

• Light-headedness, dizziness, fatigue, malaise, myalgia

• Anxiety, irritability, insomnia, agitation, confusion, vertigo, hot and cold flashes, tremors, parathesias (pins and needles), “buzzing all over,” generalized itching, “electric shock-like sensations,” visual “jolts,” sweating, pupil dilation, anorexia.

Hardy Nutritionals® Balanced Free-Form Aminos or protein powders, taken as needed, may temporarily ameliorate drug discontinuation symptoms. Amino acids in free form are essentially predigested and are rapidly absorbed, providing higher blood plasma concentrations compared to normal protein digestion8,9 (see Appendix C for possible therapeutic mechanisms). Absorption of protein products will be expedited if taken between meals. 

Due to the diversity of physiological functions performed by amino acids, a variety of possible mechanisms could contribute to their psychiatric effects. Amino acids are direct biochemical precursors to neurological pathways targeted by psychiatric medications. As such, amino acids may act as neurotransmitter mimetics, as substrates for increased endogenous production of neurotransmitters, or both. Amino acids may therefore help temporarily to ameliorate discontinuation syndromes after a drug dose reduction (see Figure 4).

As the fundamental building blocks for all enzymes and tissues, other potential mechanisms of amino acids include increased enzymatic activity and enhanced ability for cellular repair or replication. For instance, supplying amino acids to gastrointestinal epithelial cells, which are exposed to high levels of insult and subject to rapid turnover, can have very significant implications for the gut-brain axis. Glutamine, for example, is both required for proper intestinal barrier function,10,11 and used for GABA production.12

A balanced complement of amino acids may be preferable to high doses of single amino acids (or amino acid metabolites), as stimulating only one neurotransmitter pathway at a time using a single amino acid can result in undesirably powerful dose-response sensitivity, especially when a drug is selectively acting on the same pathway simultaneously (see 8.4.4 Amino acids).

2.3.2 Managing post-withdrawal medication effects

Some patients report symptoms that appear to be medication side effects even after discontinuing all medications (see 8.6.3 Prior psychiatric drug use; 8.7 Lifestyle factors).

Some researchers and patients have reported that protein isolate or vitamin C can attenuate apparent post-withdrawal medication side-effects, tardive akathisia, or dyskinesia.

Oral doses of protein isolate (a concentrated protein source), taken as needed, may provide relief of mild to moderate medication effects and may last for several hours. (see Appendix C).

Oral doses of up to 3-5 grams of vitamin C at a time (or 1 gram of liposomal vitamin C), taken at least 30 minutes apart as needed, may provide relief of mild to moderate medication effects. Relief of severe medication-related symptoms have been reported to require up to 8-10 grams (about 2 grams of liposomal vitamin C). Relief may vary with the adequacy of the dose, but if benefit is to be had, it is usually recognizable within 30 minutes of ingestion and may last for several hours (see Appendix D).

There is some evidence that vitamin C bowel tolerance increases when it is in higher physiological demand, but there is potential for bloating and osmotic diarrhea at therapeutic doses. As the maximum dose tolerance varies between individuals and may even vary from in the same individual based on physiological conditions, it is important to administer oral vitamin C on a case by case basis and only in the quantity and frequency necessary for symptom relief. Gastrointestinal side effects may be avoided by using liposomal or intravenous vitamin C.

2.4 Clinical response – CNS drug use

For some individuals taking DEN with CNS-active medication(s), benefits may be difficult to perceive until a significant portion of these medication(s) have been tapered.

We recommend that each patient and/or caregiver, together with the prescribing doctor when feasible, review the known side effects of the patient's medication(s) at least weekly while using DEN in order to detect any increases in the number or intensity of side effect as early as possible. These regular side effect assessments are critical to determine the ideal rate of medication tapering and thus allow the patient to enjoy optimal benefits from DEN treatment.

2.4.1 Polypharmacy

Multiple psychiatric medications are often prescribed together to manage symptoms for which one medication alone may not be effective. Normally, these medications should be reduced at the same rate relative to each other, such that they are terminated simultaneously. This approach maintains, throughout discontinuation, the balance that the medications exert together on the central nervous system (e.g. an antipsychotic in combination with an antidepressant).

2.5 Other medications

All medications should be monitored by a physician during DEN therapy (see 6 Warnings & Precautions and Appendix F).

Medications for health conditions such as thyroid, insulin, and heart issues, high blood pressure, high cholesterol, and cancer need to be monitored closely as dosing for a wide variety of medication types may require adjustment during micronutrient therapy.

Common non-psychiatric medications that have been reported to interact with DEN are listed in 8.2 Non-psychiatric medications.

2.6 Managing gastrointestinal issues

Healthy gastrointestinal function is critical for optimal digestion and absorption of nutrients from foods and supplements. Various gastrointestinal issues, such as bowel disorders, constipation, diarrhea, parasite infection, and gut microflora imbalance (dysbiosis) can limit response to DEN therapy (see 8.5 Gastrointestinal problems).

If the symptom response to DEN is poor or atypical and cannot be explained by drug side effect potentiation, the individual may very likely benefit from a combination of pre- and probiotics such as Hardy Nutritionals® Greens & Probiotics. Nutrition-fueled “aggravation of pre-existing Candida (yeast) infections” has been documented with DEN use, but clinical experience has shown that these “can be adequately managed with antifungal medication, olive leaf extract, and probiotics.”3,13

In using Hardy Nutritionals® Olive Leaf Extract or Hardy Nutritionals® Greens & Probiotics, patients and physicians should be aware of a possible Jarisch–Herxheimer reaction. This reaction is a self-limiting transient response traditionally associated with antimicrobial treatment of syphilis. It is thought to be triggered by the lysis of microbial cell membranes and the consequent release into the bloodstream of lipoproteins, resulting in a systemic inflammatory response. It manifests clinically with short-term constitutional symptoms such as fever, chills, headache and myalgias.14 Similar symptoms have been observed with the use of Olive Leaf Extract and occasionally Greens & Probiotics.

Some individuals have reported that vitamin C attenuates the systemic symptoms of the Herxheimer effect. Oral doses of 2-5 grams of ascorbic acid at a time, taken as needed, may provide relief within 30 minutes. While there is some evidence that vitamin C bowel tolerance may increase when this nutrient is in higher physiological demand, potential osmotic effects of bloating or diarrhea can occur at these doses. Gastrointestinal side effects can be avoided by using liposomal vitamin C, which may be equally effective at a dose of 1 gram.

In addition to prebiotics and probiotics, amino acid supplementation, such as with Hardy Nutritionals® Balanced Free-Form Aminos, may significantly improve gut health during DEN therapy. Gastrointestinal epithelial cells are highly vulnerable to damage and subject to rapid turnover, making the protein-intensive activities of cellular repair and division extremely important to the gut-brain axis. Glutamine and arginine are two well-studied examples of amino acids which enhance intestinal barrier function.15

2.7 Other considerations for clinical management

2.7.1 Evaluation

Standard psychiatric evaluation with the patient and ruling out contraindications is best done before beginning DEN therapy (see 7.2 Contraindications, 6.2 Precautions, and 8 Possible limiting factors). During the transition from psychiatric or CNSactive medications to      micronutrients, ongoing evaluation should occur weekly, if possible, in order to review potential treatment-limiting factors, assess drug side effect potentiation, and adjust medication dosing if necessary (see 2.3 Potentiation of psychiatric medications and 2.5 Other medications). For medication-free patients, bi-weekly ongoing evaluation may be adequate until symptoms are well-managed.

The most common and most disruptive interfering factors are medications and gut health (see 2.1 Critical treatment considerations). Additional patient characteristics that commonly influence the use of DEN and/or adjunct treatments include the following:

• Patient history (see 8.6 Patient history)

• Lifestyle factors (see 8.7 Lifestyle factors)

• Recreational drug use (see 8.3 Recreational drugs)

• Supplement use (see 8.4 Supplements)

• Other factors influencing nutritional requirements (see 8.8 Physical health and life stage factors)

2.7.2 Informed consent

We endorse the informed consent section of Chapter 6 in the 2017 American Psychiatric Association (APA) publication Complementary and Integrative Treatments in Psychiatric Practice:

“Informed consent should be thorough and well-documented for any nonestablished treatment." In particular, "Documentation should specify reasons for using a nonestablished treatment, such as patient preference and potential for fewer adverse effects or better clinical response.”1

It is often critical that clinical judgement overrule a protocol-based approach, especially when using micronutrient therapy in a medicated patient. “If transitioning a patient from psychiatric drugs, the medical record should explain the reason each time a psychiatric drug dose is lowered, such as adverse effects detected, withdrawal symptoms, or other specific clinical observations in the individual patient; it is not sufficient to appeal to a general protocol1 (emphasis added).

The authors recommend examples of explicit statements of informed consent for micronutrient therapy, such as:

1. This is not an established treatment.

2. Established treatments are available.

3. Limited randomized controlled trials are available to evaluate safety or efficacy.

4. If transitioning from psychiatric drugs, the following may be expected:

a. Potentiated psychiatric drug side effects

b. Potentiated, protracted, or delayed drug discontinuation symptoms (including anxiety)

c. There may be a period of some symptom relapse and situational anxiety during the transition as drug doses are tapered down.

5. Adverse effects include potential worsening of Candida infections and speculatively of other pre-existing health problems known to be highly micronutrient-dependent (eg. while micronutrients are possibly protective against de novo cancer, pre-existing cancers may thrive with the additional nutrients, including folate).

6. Nutrient interactions with psychiatric and non-psychiatric medications can occur.

7. The prescriber should be contacted when starting any new drug, especially an antibiotic.

8. Reducing or preferably stopping recreational drugs, caffeine, alcohol, smoking, and any other psychoactive substances will enhance treatment effectiveness and safety. People who ingest large amounts of these substances (e.g., four cups of coffee daily, marijuana twice weekly) are likely to notice weaker therapeutic effects of micronutrients.1

2.7.3 Health Professional training

Clinical experience with medication-naïve patients helps immensely in recognizing the surprisingly abundant and complex interactions between DEN and CNS-active medications. “It is strongly advised that clinicians obtain training and/or supervision before attempting to transition patients taking conventional psychiatric medications to broad-spectrum micronutrients.”1

In addition to this document, the following resources offer training in micronutrient therapy with specific applicability to DEN:

• Chapter 6 of the American Psychiatric Association-published clinical guide Complementary and Integrative Treatments in Psychiatric Practice1

• 'Nutrition and Mental Health', a course authored by micronutrient researchers (

• Practitioners experienced with clinical DEN use (

• The Hardy Nutritionals® science team (1-855-955-1114 •

2.7.4 DEN as a first-line treatment

Given that the transition from medications to micronutrients is significantly more difficult than DEN therapy in medication-naïve patients, the fact that long-term outcomes of medications are often suboptimal, and also the fact that most patients consider ‘natural’ alternatives to medications to be potentially safer (especially for children), many patients, parents, and practitioners prefer to use DEN as their firstline treatment for mood disorders.

In Chapter 6 of the American Psychiatric Association-published clinical guide Complementary and Integrative Treatments in Psychiatric Practice, the authors conclude, “Broad-spectrum micronutrients may be comparable in efficacy to conventional medications and appear safer, so first-line use is rational if the clinical presentation is not too acute. Furthermore, just as one might introduce exercise, sleep hygiene, and dietary measures in the initial phase of intervention for some individuals, broad-spectrum micronutrients might be considered in certain cases before conventional psychopharmacotherapy.”

2.8 Addressing residual symptoms

DEN doses may need to be adjusted over time according to patient response and the presence of factors that limit the effectiveness of DEN therapy (see 8 Possible Limiting Factors). Adjunct treatments may also be useful.

2.8.1 Anxiety and stress

Physical symptoms of anxiety may include light-headedness, muscle tension, and ‘butterflies’ in the stomach, which may be accompanied by excessive worrying, poor concentration, and distractibility. Patients who continue to experience symptoms of physical anxiety or stress while taking a therapeutic dose of DEN may benefit from added inositol, such as Hardy Nutritionals® Inositol Powder, or L-theanine.1

Typical dose range of inositol with micronutrients is 1,000-4,000 mg as needed up to six times daily. Typical dose range of L-theanine with micronutrients is 200-600 mg up to four times daily.

2.8.2 Mania

Patients who continue to exhibit rage, aggression, or racing thoughts while taking a therapeutic dose of DEN may benefit from added choline, such as Hardy Nutritionals® Phosphatidyl Choline.

“Lithium may be used for residual symptoms of mania; however, when combined with micronutrient formulas, the lithium dose must not exceed 25 mg daily because of the risk of marked potentiation.”1 (See 2.3 Potentiation of psychiatric medications).

Typical dose range of choline with micronutrients is 50-100 mg up to four times daily.

2.8.3 Depression

Residual depression may respond to 5-hydroxytryptophan (5-HTP) or S-adenosylmethionine (SAMe)1 , although when taken alongside DEN, much lower doses may be necessary than when these same substances are used as monotherapies. Conceptually, one might think of DEN potentiating 5-HTP and SAMe similarly to the interactions observed between DEN and CNS-active medications or other psychoactive substances (see 8.4.3 Psychoactive supplements and 8.4.4 Amino acids).

Typical dose range of 5-HTP with micronutrients is 0.01-1 mg each morning.

Typical dose range of SAMe with micronutrients is 200-400 mg each morning.