Answer: Understanding these 3 important factors will make all the difference in your success using Daily Essential Nutrients (DEN).
Answer: Some individuals see dramatic results within a few days; however, Daily Essential Nutrients (DEN) typically produces results gradually over a period of several months (and sometimes longer for certain conditions). Dozens of medical journal publications have reported impressive results in people who took our product at recommended levels for at least 8 weeks. But it’s safe to say that no one will see the full benefits of DEN in just 8 weeks— many people continue to report subtle improvements for years after.
The recommended clinical dose of Daily Essential Nutrients—4 capsules, 3 times per day, with meals—is based on extensive experience addressing various symptoms in thousands of people, including adults, adolescents, and children. Independent university research has shown that people respond best, particularly in the first few months, by consistently taking the recommended dose.
In general, we recommend the following initial dosages of Daily Essential Nutrients for children diagnosed with psychiatric conditions, based on published research and clinical experience:
(1 level scoop of Daily Essential Nutrients Powder is equivalent to 4 capsules).
For individual cases, the dose required to address mood, anxiety, behavioral, and other symptoms may be slightly higher or lower than the initial recommended doses listed above. Optimal dosing of Daily Essential Nutrients appears to be more dependent on individual nutrient needs than on age or body weight.
Based on clinical experience, individuals who are experiencing psychiatric symptoms have significantly higher nutrient needs than most others of the same age and weight. Also, children and adolescents who are growing quickly may actually have higher nutrient needs than many adults.
Children taking Daily Essential Nutrients should be monitored by a medical doctor.
Answer: The simplest way is to take 1 capsule 3 times per day the first day, two capsules 3 times per day the second day, and so on. By the fourth day, you’ll be taking the full recommended dose of 4 capsules 3 times per day. Most people have no problem tolerating Daily Essential Nutrients when they gradually introduce it in this way. Those who may be sensitive can choose to increase the dose more gradually (for example, increasing their dose by one capsule per day so it takes 12 days to reach the recommended therapeutic dose of 12 capsules per day).
Answer: Supplying your body with nutrients on a regular daily basis will ensure your body gets the critical and essential ingredients it needs for maximum wellness and optimal results. Consistently eating nutrient-rich food is also very important, but even if you’re carefully choosing your diet, it’s still very difficult to get all the nutrition you need from food alone. This is especially true for anyone with mood or anxiety issues, because according to research, these people often have higher-than-average nutrient needs.
Over the years, researchers have documented many cases where people with mood, anxiety, or behavioral issues responded favorably to our nutrient therapy and then stopped taking it, thinking they didn’t need it anymore. The unfavorable symptoms returned. Restoring the nutrients improved their symptoms dramatically again. Most people who experience this contrast decide that it’s worth taking Daily Essential Nutrients regularly to enjoy the stability it provides.
Answer: Some have found that they can maintain stable health on a little less than the full therapeutic dose of 12 capsules per day after their symptoms have been eliminated for a few months (for example, 10 capsules instead of 12). On the other hand, some people find that they don’t get an optimal response until they take 15 or more capsules per day. It’s important to find a threshold that works for you, keeping in mind that if you go too low, your symptoms will eventually return. Daily Essential Nutrients is like food for a starving brain.
Think of Daily Essential Nutrients as a part of your daily food intake. Taking 4 capsules per meal is like getting a single spoonful of food packed with nutrients to compensate for empty calories (or for some people, simply to meet a higher-than-average need for certain nutrients that can be determined by genetics and other factors).The average person in the United States consumes enough added sugars to make up one-sixth of total daily calories! That’s one-sixth of our food that contains NO essential nutrients at all! Bruce Ames, a renowned nobel prize winning scientist stated: “We are starving! Even though we’re all getting fat, we’re starving for vitamins and minerals.”
The reason for our recommended dosage is that we’re focused on helping individuals achieve real-life results! Extensive scientific research has shown that the recommended dosage delivers the most consistent and marked improvements for serious mood and anxiety-related disorders. This research includes careful safety monitoring which showed no safety concerns at the therapeutic equivalent of the recommended 12 capsule per day dosage.
Answer: There are 3 important reasons:
Answer: Occasionally, when people begin taking Daily Essential Nutrients, they may have looser stools than usual for a few days, but as the body adjusts to the additional nutrients, this typically normalizes, as it does when you introduce a new food to your diet. It is also normal for a person’s urine to be brighter yellow in color while they are taking Daily Essential Nutrients. This is a harmless side effect of taking vitamin B2 (also called riboflavin).
It’s very rare for people to have any other side effects. Those who have pre-existing gut issues are most likely to experience some rare side effects, but the good news is that these problems can largely be addressed with additional nutritional solutions.
Sometimes people who are taking certain medications may think they are experiencing negative effects from Daily Essential Nutrients when in fact, they are feeling over-medication or medication withdrawal effects. Our experience has shown that taking certain medications (or withdrawing too quickly from these medications) can interfere with the positive effects of Daily Essential Nutrients. This is why it is critical for anyone who is currently taking any medication or who recently stopped taking a medication to be very familiar with the side effects that can be caused by their medications. The "Drugs A-Z List" on RxList.com is a great resource for familiarizing yourself with side effects of specific drugs.
If you wonder whether or not Daily Essential Nutrients is causing a negative side effect, feel free to give us a call. We’re also happy to talk with your doctor or other healthcare professional at any time.
Answer: Yes. People with certain rare medical conditions or severe sensitivity to a particular ingredient may not be able to take Daily Essential Nutrients. Feel free to call us to talk about your situation. We’re also happy to talk with your doctor or other health professional. These decisions are best made in consultation with a qualified healthcare professional.
Answer: It’s rare that people need to take additional vitamins or minerals, because Daily Essential Nutrients is designed to meet nearly everyone’s daily needs at the suggested serving. This all-in-one approach gives you clear advantages in terms of convenience and cost-savings. However, some people have a specific need for additional nutrients.
In depression, some people have reported that additional vitamin D may be useful. In the case of iron-deficiency anemia, iron can be added to Daily Essential Nutrients without any issue (ideally, under the supervision of a health professional).
Because the minerals in Daily Essential Nutrients are in careful balance with each other, we advise against adding certain minerals (including zinc, copper, calcium, phosphorus, or magnesium), because adding them could actually create mineral imbalances and lead to adverse health effects. We also advise against adding lithium without a doctor’s supervision, because doctors have observed that lithium appears to be 100 times more powerful when used together with the minerals in Daily Essential Nutrients.
On the other hand, feel free to add extra potassium, a macro-mineral that nearly all of us don’t get enough of. You’re also welcome to add any whole foods that contain naturally-occurring vitamins and minerals.
Answer: Most commonly-used supplements are fine to use with Daily Essential Nutrients. For example, we offer an Essential Omegas product, a Greens & Probiotics product, a Free-form Amino Acid product, and an Inositol Powder product that people often use together with Daily Essential Nutrients.
Our main caution for adding supplements other than vitamins or minerals is that any supplement or substance that affects brain function has the potential to significantly interfere with the positive effects of Daily Essential Nutrients.
If you use any supplement that has mind-altering properties, do it very cautiously and monitor your symptoms carefully. A few common examples include St. John’s wort, ginseng, kava kava, skullcap, valerian root, SAM-e, and 5-hydroxytryptophan (often called 5-HTP). Recreational drugs also affect the mind and can interfere with the positive effects of Daily Essential Nutrients as well.
As Daily Essential Nutrients provides the body with the basic elements it needs to regulate itself, people usually find that these mind-altering supplements are no longer needed.
Answer: Definitely not! Our brains and bodies will always need essential vitamins and minerals for proper function. If it seems that Daily Essential Nutrients isn’t working for you, some interfering factor is standing in the way and causing you to have increased nutrient requirements or limiting the effects of the nutrients. If you don’t find answers for your challenges in our other FAQs or videos be sure to give us a call or have your doctor call us. We’ve worked to provide support and information for thousands of people via phone and e-mail for almost 20 years. We also can refer clients to healthcare professionals in their area, who are familiar with micronutrient treatment, in order to help overcome barriers and find success.
Answer: Antibiotics are actually the most common factor. When we take broad-spectrum oral antibiotics, we wipe out the beneficial gut bacteria that help us digest our food, and this deprives us of essential nutrients. Before taking oral antibiotics, be sure to educate yourself on how you can meet your nutrient requirements and keep your gut healthy during and after the course of antibiotics.
Other factors like physical illness, puberty, and for women, pregnancy, breastfeeding and the menstrual cycle can place higher than usual demands on your body and increase your nutrient needs. At these important times, it may be necessary to temporarily increase your dosage of Daily Essential Nutrients to meet your body’s increased needs and maintain mood stability.
Answer: The simple answer is everything. You’ve heard the saying “you are what you eat”. In reality, “You are what you absorb”. A variety of gut problems can interfere with the absorption of nutrients and limit their effectiveness. If your body isn’t absorbing the essential nutrients that you need, many aspects of your health will suffer, including mental health.
If Daily Essential Nutrients doesn’t seem to be working for you, poor gut health may be standing in the way. Because getting our gut healthy is so important for so many people, we’ve formulated specific products to help with this:
Answer: You know Olive Leaf Extract is working when you start having temporary flu-like symptoms, which means the yeast is dying and releasing chemicals that produce what is called a Herxheimer’s Reaction. This is why we recommend that at first, you should take no more than 1 capsule per day of Olive Leaf Extract. When you no longer feel flu-like symptoms from taking 1 capsule per day, take 2 capsules. Eventually, if you can take 6 capsules per day without experiencing flu-like symptoms, your yeast should be well-controlled.
Answer: Many people’s diets supply plenty of food for the yeast to thrive on and not nearly enough fiber for the good bacteria that compete with yeast. Many people find that when they stop taking Olive Leaf Extract, their yeast symptoms return. These people often choose to continue taking an anti-yeast product on a regular basis. We recommend changing to a different type of anti-yeast product every few months to prevent the yeast from adjusting to a single product. A few options (besides Olive Leaf Extract) include colloidal silver, oil of oregano, garlic, and caprylic acid.
Answer: Some people have reported that taking colloidal silver by mouth can eradicate yeast issues and produce only a mild die-off reaction. Our customers have also reported that regardless of which yeast treatment they use, taking oral vitamin C can quickly help to reduce their flu-like yeast die-off symptoms – often within 20 minutes. If taking 2 grams of vitamin C doesn’t help, take 2 more grams 30 minutes later, and repeat this until you find relief.
If your body isn’t accustomed to taking this much vitamin C, it can cause temporary gastrointestinal upset, but you may find it’s worth it if you get quick relief from your unpleasant flu-like symptoms. Drinking plenty of water while you’re taking yeast treatments can also help minimize die-off symptoms.
Answer: Antibiotics (especially oral antibiotics) have a very direct effect on gut microflora and therefore on gut health. They kill much of the beneficial bacteria in the digestive tract that facilitates digestion. Because food breakdown is compromised, you are unable to get the normal amount of nutrients from your food - increasing the risk for deficiency. This explains why people taking antibiotics almost always see an increase in their mental health symptoms. We have learned that an increase of 50% in the dose of Daily Essential Nutrients immediately before, during, and for two to three weeks following antibiotic use compensates for the decrease in absorption and works to prevent a return of symptoms.
Another fact of antibiotic use is that it dramatically increases the risk of a severe yeast flare-up in the gut and the potential of that to spread to the bloodstream and internal parts of the body. Antibiotic use negatively impacts gut bacteria that keeps yeast in check while doing nothing to deter yeast growth – thus the potential for a flare-up! To counteract this tendency we recommend simply taking an effective antifungal product to check the yeast while you are taking the antibiotic and for a few weeks after, (Nistatin or Oil of Oregano, for example). Our Olive Leaf Extract also has a powerful antifungal effect.
After running the course of antibiotic treatment, it is wise to help restore the compromised digestive process by taking live bacterial cultures for a number of weeks to re-establish healthy levels of beneficial bacteria in the gut. Our Greens & Probiotics product is formulated to do this most effectively.
As a side note, we have found intravenous antibiotics to cause fewer of these concerns simply because they are not released directly into the digestive tract and therefore have a diminished effect on gut microflora.
Answer: The short answer is yes – if you follow the guidelines we give! We encourage all individuals who are currently taking medications to work closely with their doctor, because all medication levels should be monitored while using Daily Essential Nutrients. The main reason is that people who take Daily Essential Nutrients have a reduced need for most medications over time – especially psychiatric medications. As the nutrients begin to normalize body chemistry, people feel over-medicated until they reduce their psychiatric medication doses.
Answer: It depends what medication you’re taking. Anyone taking a medication together with Daily Essential Nutrients should go to www.RxList.com, search for each drug they are taking, and assess how many of the drug’s side effects they are experiencing. Side effects are listed in the “Side Effects and Drug Interactions” section for each drug. For example, Abilify (aripiprazole) can cause side effects that can include nausea, vomiting, constipation, headache, dizziness, akathisia, anxiety, insomnia, and restlessness. If you were taking Abilify and began to feel an increase in any of these symptoms over time, you would know that you’re over-medicated.
Doctors and researchers have found that when people are taking Daily Essential Nutrients, the best overall outcome is almost always achieved when all psychiatric medications are completely removed.
Answer: Health professionals who are familiar with Daily Essential Nutrients will recommend that you reduce your medications gradually when you start feeling over-medication symptoms. For most medications, we recommend reducing by no more than 1/8th at a time. After a reduction, monitor your symptoms and drug side effects carefully. It is important to work with a healthcare professional through this important transition time.
Answer: In general, you can expect that when you reduce your medications, you will experience an effect opposite to what you felt when you started taking the medication. So if a medication helps you sleep, you could experience the opposite when you reduce it by 1/8th – difficulty getting to sleep. When you reduce by 1/8th, these withdrawal symptoms should be tolerable and short-lived.
Answer: Because the transition away from medications is sometimes tricky, we recommend a few nutritional tools that can significantly help many people with their drug withdrawal symptoms. We often recommend our Hardy Nutritionals® Free-form Aminos product for individuals looking for some relief from medication withdrawal. The essential amino acids in Free-form Aminos help to bind the medications up and get them out of the body, helping to reduce withdrawal symptoms. To help manage the remaining anxiety-related symptoms we recommend our Hardy Nutritionals® Inositol Powder which helps to calm the physical symptoms of stress and anxiety.
Many use Phosphatidyl Choline to slow racing thoughts and address other troubling symptoms resulting from elevated mood.
Some have also found that higher doses of vitamin C can help manage drug withdrawal symptoms as well. Give us a call if you have questions about any of these products or look them up in our Store.
Answer: The most important thing you can do is to gain an understanding on the over-medication and withdrawal symptoms specific to your drug(s) so that you can successfully taper off your medications. We can't stress enough how important it is to visit RxList.com and research the "Side Effects & Drug Interactions" of each medication you are taking (or have taken recently).
This journey can feel a bit rocky at times, but educating yourself will help immensely to make your way smoother. Always remember that many others have travelled this road before you and that they have found a very fulfilling and productive life after mental illness by providing their bodies with the nourishing essential nutrients they need.
Reducing medications in the right way is essential to your success when you are taking Daily Essential Nutrients.
Based on published research, our own extensive experience, and feedback from healthcare professionals who have worked with thousands of people like you, we have compiled detailed clinical reference materials to help your doctor understand how to help you transition safely from psychiatric medications to Daily Essential Nutrients.
We have helped thousands successfully introduce our nutrients to their diets and simultaneously wean off their medications. We are happy to answer any questions you or your health professional might have about this.
You or your doctor are welcome to reach us toll free in the USA or Canada at 1-855-955-1110. For overseas or international calls use 1-587-271-1110. We are open from Monday to Friday 9:00 am to 5:00 pm Mountain Standard Time (MST). We look forward to hearing from you.
Answer: At Hardy Nutritionals™, we’re focused on helping individuals achieve real-life results. Extensive scientific research at more than a dozen universities and medical clinics around the world has shown that the equivalent of this dosage delivers the most consistent results and marked improvements in both adults and children. This research has included careful safety monitoring which showed no safety concerns at the equivalent of the 12 capsule per day dosage.
Answer: Daily Essential Nutrients is more bulky than other multivitamin-mineral products for several reasons:
Answer: Daily Essential Nutrients is specially formulated to meet the needs of individuals who have higher than average genetic needs for certain vitamins. We've been careful to ensure that all these vitamin levels are safe according to vitamin safety levels established by the US Institute of Medicine and other scientific authorities on nutrient safety.
Answer: That depends. Be sure to tell your doctor about all the supplements you’re taking. Certain supplements may interfere with Daily Essential Nutrients.
For more information on taking additional supplements while taking Daily Essential Nutrients, see Section 8.4 Supplements in the Clinical Reference for Healthcare Professionals.
Answer: Yes, it's okay to take additional iron if your doctor recommends it.
Answer: Most likely. However, as Daily Essential Nutrients is introduced into your diet you will likely experience increased drug side effects. When this happens, talk with your doctor about gradually reducing or eliminating your psychiatric medications. Here’s how you can prepare for your doctor visits:
Answer: Yes. However, your doctor will need to adjust the dosages of any heart medications (like warfarin) that interact with vitamin K.
For additional information on taking anti-coagulant medications with Daily Essential Nutrients see Section 4.2 Drug Interactions in the Clinical Reference for Healthcare Professionals.
Answer: Most likely. However, it's important for your doctor to monitor all of your medication doses while you're taking Daily Essential Nutrients. Taking nutrients might change your medication needs.
For additional information on taking other medications with Daily Essential Nutrients see Section 8.2 Non-psychiatric medications in the Clinical Reference for Healthcare Professionals.
Answer: If you have a special medical condition, we recommend that you consult with your physician before using Daily Essential Nutrients.
Answer: Yes. Tell your doctor if you’re experiencing gut problems like constipation or diarrhea. You’ll need to get your gut healthy to benefit the most from Daily Essential Nutrients.
For additional information on gut health, see Section 8.5 Gastrointestinal Problems in the Clinical Reference for Healthcare Professionals.
Answer: Hardy Nutritionals® products outperform other supplements for at least four reasons:
Answer: NutraTek™ proprietary technology micronizes and pre-combines every mineral in the formula with natural organic molecules, creating a chelation complex which greatly enhances each nutrient’s usefulness to the body.* Learn more.
Answer: NutraTek™ mineral delivery technology goes beyond amino acid chelation. It mimics nature by using natural organic molecules. This allows essential elements to even more efficiently cross the blood-brain barrier, enter cells, and optimize nutrient levels.* Learn more.
Answer: Research shows that most people fall short of getting the recommended daily amount of multiple nutrients from food alone. Since the body’s wellness is limited by the most deficient nutrient, a superior formula will not leave any essential nutrient lacking. The Daily Essential Nutrients formulation contains many more active ingredients (at effective levels) than other multivitamin-mineral formulations in order to address all insufficiencies of essential minerals and vitamins in the body.* Learn more.
Answer: The U.S. Institute of Medicine states that an imbalance in the intake of two or more nutrients can have a diverse array of adverse health effects. The ratios among ingredients in our formulations are carefully set to avoid the risks of nutrient imbalance. This compensates for deficiencies and excesses in individual diets. Balance is never achieved by supplementing only a few elements.* Learn more.
Answer: Taking Daily Essential Nutrients can prevent health problems by ensuring that you get the essential nutrients your body needs.* For example, Daily Essential Nutrients qualifies for nearly 50 different preventative health claims in Canada, a country with one of the most progressive natural health product regulations in the world.
Answer: Yes. For example, in Canada Daily Essential Nutrients qualifies for the following claims related to metabolism*:
Answer: Yes. For example, in Canada Daily Essential Nutrients qualifies for the following claims related to skin and tissue health*:
Answer: Yes. For example, in Canada, Daily Essential Nutrients qualifies for the following claims related to growth and development*:
Answer: Yes. For example, in Canada Daily Essential Nutrients qualifies for the following claims related to preventing vitamin deficiencies*:
Answer: Yes. For example, in Canada, Daily Essential Nutrients qualifies for the following claims related to preventing mineral deficiencies*:
Answer: Yes. Many nutrients play a role in the structure and function of the brain. An impressive amount of research has revealed the powerful influence of high quality essential nutrients on the brain, affecting every aspect of function from mood to body systems and intellectual capacity.* Learn more.
Answer: Yes. The proprietary mineral blend in Daily Essential Nutrients has been extensively studied by independent researchers and refined in clinical practice for over 15 years. Its impressive effects on stress and mood have been published in medical journals around the world.* Learn more.
Answer: No. Daily Essential Nutrients supplies essential vitamins, minerals, and other nutrients, but your body needs more than this to stay healthy. Fruits, vegetables, and whole grains also contain fiber, antioxidants and phytochemicals which help keep you healthy.* Learn more.
Answer: Supplementing with vitamins and minerals can save money through prevention. There’s no question that healthier people incur fewer healthcare costs. They are also more active, more productive, and they enjoy a higher quality of life. In a recent analysis, world-respected economists concluded that supplementing essential nutrients yielded tremendously high benefits compared to costs.* Learn more.
Answer: In general, it’s safer to take Daily Essential Nutrients than not to take it!* Those taking medications and those with special medical needs should consult with a physician before use. Learn more.
Answer: Yes. There’s no danger in this. However, we recommend that you split your daily dose of Daily Essential Nutrients into 3 doses in order to increase absorption and ensure that your body has the nutrients it needs throughout the day.*
Answer: Yes. Daily Essential Nutrients contains riboflavin (vitamin B2), which can make your urine more intense in color.
Answer: No, there is no safety concern. However, we can’t guarantee that all the ingredients listed on the label will have their original potency beyond the expiration date.
Answer: Daily Essential Nutrients may contain an insignificant amount of lactose. Lactose intolerant individuals have been able to tolerate small quantities of lactose. Consult a physician if you have any questions.
Answer: Daily Essential Nutrients may contain an insignificant amount of gluten. Although we do not add any gluten to our products, we cannot guarantee that all raw materials are 100% gluten-free.
Answer: No, Daily Essential Nutrients contains no caffeine or any natural sources of caffeine.
Answer: Daily Essential Nutrients is backed by over 35 years of applied nutritional science. The proprietary mineral blend in Daily Essential Nutrients has been extensively studied by independent researchers and refined in clinical practice for over 15 years. Through this test of time, it has produced never-before-seen results that have been published around the world in medical journals.* Learn more.
Answer: Hardy Nutritionals™ is committed to bringing you high quality products. In order to bring you products that meet our high standards, we use a manufacturing facility in the United States that maintains rigorous Good Manufacturing Practice (GMP) standards. Our facility is registered with and inspected by the FDA, the Department of Health and Human Services, and by NSF international. NSF international is a third-party not-for-profit company that provides GMP audits, safety audits, and certifications for a wide range of consumer products. These standards, along with our commitment to quality, are why you can depend on the quality, potency and purity of our products. Learn more.
Answer: Good Manufacturing Practices (GMPs) help to safeguard the health of the consumer as well as ensure high quality products in accordance with dietary supplement regulations. GMP involves testing of products during the manufacturing process to ensure that ingredients are uncontaminated and in the correct amounts (as indicated on the product label), and that the expiration date is based on real and accelerated stability measurements. Learn more.
Answer: Yes. The Society of Obstetricians and Gynaecologists recommends that women with no personal health risks take a daily multivitamin with folic acid at least 12 weeks before conception, throughout pregnancy, and 4 to 6 weeks postpartum or as long as breastfeeding continues. Daily Essential Nutrients meets the daily needs of women who are pregnant or breastfeeding.*
Answer: Daily Essential Nutrients provides calcium, vitamin D, and many more essential nutrients to help meet a breastfeeding woman’s needs. Because breastfed babies rely wholly upon their mother for nutritional support, mothers need not only additional calories, but extra vitamins and minerals. By continuing to take Daily Essential Nutrients, both mother and baby will receive the nutritional support that is so important for a healthy postpartum experience.*
Answer: Menstruation increases nutrient needs. If symptoms worsen during this time, increasing your dosage of Daily Essential Nutrients may help. For more information, see Section 8.8.1 Menstrual cycle in the Clinical Reference for Healthcare Professionals.
Answer: Research shows that we are at risk of being deficient in many essential nutrients at once. The broad spectrum of essential nutrients in Daily Essential Nutrients is critical to prevent metabolic inadequacies and many related health problems.* Learn more.
Answer: Vitamins are carbon-based organic compounds. The human body makes many of its own organic compounds; however, vitamins are required from the diet in small amounts because the body does not make them. Vitamins are used to synthesize substances involved in body functions, such as hormones and neurotransmitters. Learn more.
Answer: Vitamins are needed for normal growth and development and are essential for the healthy maintenance of cells, tissues, and organs. Vitamins enable cells to efficiently use chemical energy provided by food, and to help process the proteins, carbohydrates, and fats required for metabolic function. Although requirements seem small, these molecules are absolutely essential in a healthy diet as deficiency can cause severe problems. Daily Essential Nutrients contains all 13 essential vitamins known to sustain optimal vitality for the body.* Learn more.
Answer: Minerals are inorganic chemical elements that are required from the diet because the body cannot produce them. Minerals are typically from the various families of metals listed in the periodic table. Minerals usually carry a positive electric charge which allows them to act as electrolytes, as co-factors, or as active centers in catalytic enzymes. Learn more.
Answer: Minerals are needed for normal growth and development and for the healthy maintenance of cells, tissues, and organs. Minerals enable cells to efficiently use vitamins and other chemical nutrients provided by food for structure and function in the body. Without minerals, there would be no osmotic balance, no electrical impulses in nerve cells, no oxygen transport, and no large-scale structures (like bones). Although requirements differ between certain minerals, they are absolutely essential in a healthy diet as deficiency can cause severe problems. Daily Essential Nutrients contains 17 essential and trace minerals to sustain optimal function for the body.* Learn more.
Answer: The Dietary Reference Intakes (DRIs) are used for planning and assessing diets for healthy people. They expand on the Recommended Dietary Allowances (RDAs) which have been published since 1941 by the US National Academy of Sciences. The DRIs comprise a set of six nutrient-based reference values:
Answer: The recommended dietary allowance (RDA) is the minimum daily amount of a vitamin or mineral expected to prevent deficiency in most people. However, getting the RDA each day doesn’t necessarily mean that you will be optimally healthy. The US Institute of Medicine states that intake at the level of the RDA is not expected to be enough for individuals previously undernourished, nor is it adequate for disease states marked by increased requirements. The levels of vitamins and minerals in Daily Essential Nutrients are carefully formulated to supply a safe and optimal level of each nutrient in conjunction with a healthy diet. Learn more.
Answer: If sufficient scientific evidence is not available to calculate an Estimated Average Requirement (EAR), a reference intake called an Adequate Intake (AI) is provided instead of an RDA. The AI is a value based on experimentally derived intake levels or approximations of observed mean (average) nutrient intakes by a group (or groups) of healthy people.
Answer: The Estimated Average Requirement (EAR) is the daily intake value that is estimated to meet the requirement in half of the apparently healthy individuals in a life stage or gender group.
Answer: The Tolerable Upper Intake Level (UL) is the highest level of daily nutrient intake that is likely to pose no risk of adverse health effects for almost all individuals in the specified life stage group.
Answer: When possible, the Tolerable Upper Intake Level (UL) is based on a no-observed-adverse-effect level (NOAEL), which is the highest intake (or experimental oral dose) of a nutrient at which no adverse effects have been observed in the individuals studied.
Answer: If there are no adequate data demonstrating a no-observed-adverse-effect level (NOAEL), then a lowest-observed-adverse-effect level (LOAEL) may be used. A LOAEL is the lowest intake (or experimental oral dose) at which an adverse effect has been identified.
Magnesium stearate has come under some very negative scrutiny of late. There are numerous statements which indicate that magnesium stearate is bad for you, magnesium stearate harms the immune system, and that quality supplements do not contain magnesium stearate.
These strongly worded positions lacked adequate references and the few that provided references cited one primary source, which will be reviewed in this comprehensive examination. Statements like these can be very concerning and we determined to find where they were coming from. What we found was that none of the comments had any cogency or authority.
Stearic Acid and Magnesium Stearate
Stearic acid is one of the most common saturated fatty acids found in nature and occurs in many animal and vegetable fats and oils. Cocoa butter and shea butter have the highest stearic acid content at 28–45%. 
Magnesium stearate 
Magnesium stearate is used as a lubricant in the manufacture of medical and supplemental tablets, capsules and powders. Studies have shown that magnesium stearate may affect the release time of the active ingredients in tablets, etc., but that it does not reduce the overall bioavailability of those ingredients. [4,5]
The few milligrams of magnesium stearate in a supplement capsule represent 0.069% of the average daily dietary intake of stearic acid. In other words, based on average daily intake, 99.83% of stearic acid comes from all the other foods we eat every day, even the “healthy” foods.
Making dietary supplements in a high quality way is far more complex than most people realize. There are several variables involved with nutrients that affect flowing and sticking. These include particle size of the ingredient, moisture content, chemical nature, solubility, and cohesive nature. These factors vary based on the ingredients in any product and become more complex as the number of different ingredients in the product increases. We use USP grade stearates derived from vegetable sources.
Did you know?
According to USDA National Health and Nutrition Examination Survey (NHANES 2001-2002) the average intake of stearic acid is 5.7 g/day (8.1% of total fat) for women and 8.2 g/day (8.4% of total fat) for men from all dietary sources. 
Stearic acid, or stearate, intake is second only to palmitic acid which accounts for 54.2% of saturated fatty acids (SFAs) (5.8% of total calories) for females and 54.5% of SFAs (6.0% of total calories) for males. 
· In 95% lean ground beef, 37% of the saturated fat is stearic acid. 
· One cup of Brazil nuts contains 8.305g of stearate (38.7% of SFAs). 
· One cup of cashew nuts, dry roasted no salt, contains 4.072 g of stearate. 
· One tablespoon of olive oil contains 0.264 g (264 mg) of stearate. 
Generally Recognized as Safe
- Food and Drug Administration
FDA's GRAS (generally recognized as safe) Substances (SCOGS) review states, "There is no evidence in the available information on ... magnesium stearate ... that demonstrates, or suggests reasonable grounds to suspect, a hazard to the public when they are used at levels that are now current and in the manner now practiced, or which might reasonably be expected in the future." 
- World Health Organization
Magnesium stearate has been the subject of study by the Joint FAO/WHO Expert Committee on Food Additives and industry manufacturers for over forty years. The 80th meeting of the Expert Committee was held in Rome, Italy and the technical report was published in 2016. In their report they summarized the history of the review of magnesium stearate.
“At the seventeenth meeting (in 1973), the Committee evaluated salts of palmitic and stearic acids and established ADIs “not limited”, with notes that palmitic and stearic acids are normal products of the metabolism of fats and that their metabolic fate is well established. Provided that the contribution of cations such as magnesium does not add excessively to the normal body load, there would be no need to consider the use of these substances in any different light to that of dietary fatty acids.”
“At its twenty-ninth meeting (in 1985), the Committee was of the opinion that “ADIs for ionizable salts should be based on previously accepted recommendations for the constituent cations and anions”. The Committee listed ADIs for a number of combinations of cations and anions, including those of magnesium stearate and magnesium palmitate (ADI “not specified”). The Committee was concerned that dietary exposure resulting from the use of magnesium salts as food additives may have a laxative effect. The Committee stated that fatty acids are normal constituents of coconut oil, butter and other edible oils and that they do not represent a toxicological problem. As the Committee had no information on the manufacture or use of the food-grade materials at that time, an ADI for magnesium stearate was not established.”
“In 2010, at the Forty-second Session of CCFA, the deletion of magnesium salts of fatty acids from the INS had been proposed. The International Alliance of Dietary/Food Supplement Associations offered technological justification for the use of this additive.”
The Committee “at its Forty-third Session in 2011 assigned the new INS number 470(iii) to magnesium stearate and asked the Committee to conduct a safety assessment, assess dietary exposure and set specifications for magnesium stearate”
“At its forty-ninth meeting (in 1997), the Committee evaluated the safety of palmitic acid and stearic acid when used as flavouring agents and concluded that they would not present a safety concern under the proposed conditions of use.”
“At its seventy-sixth meeting (in 2012), the Committee established an ADI “not specified” for a number of magnesium-containing food additives and recommended that total dietary exposure to magnesium from food additives and other sources in the diet should be assessed. This was in the context of the evaluation of magnesium dihydrogen diphosphate, in which the estimated chronic dietary exposure to magnesium from the proposed uses was up to twice the background exposures from food previously noted by the Committee and may be in the region of the minimum laxative effective dose. For the present evaluation, a range of published studies together with three reports on genotoxicity testing of magnesium stearate were submitted to the Committee.”
For the current 2015-2016 evaluation, a range of published studies together with three reports on genotoxicity testing of magnesium stearate were submitted to the Committee. The Committee concluded that there are no differences in the evaluation of the toxicity of magnesium stearate compared with other magnesium salts and confirmed the ADI* “not specified” for magnesium salts of stearic and palmitic acids.
*ADI (Allocation of Acceptable Daily Intakes) ‘not specified’ is a FAO-WHO term for a substance with very low toxicity for which no safe upper-limit of intake is established, or deemed necessary, on the basis of available biochemical, chemical, and toxicological data. 
Stearic Acid may have Health Benefits
In a systematic review  and a meta-analysis of 60 controlled trials  in humans the data clearly (referenced back to 1957) indicate that stearic acid (or its conjugate base stearate) has no effect on cholesterol levels compared to other long-chain saturated fatty acids. In fact the authors of the 2010 systematic review concluded that “LDL cholesterol decreased as dietary stearic acid increased in a statistically significant dose-response relation.”
Researchers from the Netherlands even evaluated hydrogenated linoleic acid (to produce stearic acid) and found that there was no difference in the serum lipid profiles compared to “natural” stearic acid. 
Molecular basis for the immunosuppressive action of stearic acid on T cells
The common reference used to demonstrate harm caused by magnesium stearate was published in 1990. The experiment entitled “Molecular basis for the immunosuppressive action of stearic acid on T cells”  is research that many people have used as evidence that magnesium stearate is harmful to human T cells.
It is clear that anyone referring to this study to claim magnesium stearate is toxic to humans hasn’t actually read it.
The researchers were specifically looking to determine the mechanism by which stearic acid (stearate) causes T cell suppression in mice, but in order for the experiment to work the scientists had to remove the immune cells from mice. The T cells then had to be incubated on rabbit anti-mouse immunoglobulins in order to be isolated and purified. The lymphocytes were cultured in medium containing 0.2% NaHCO3, penicillin, streptomycin and 5% fetal bovine serum.
The T cells were then stimulated with phytohaemagglutinin or with lipopolysaccharide. These are plant and bacterial factors that start the process of activating the T cells (mitosis).
At this point stearic acid combined with bovine serum albumin and diatomaceous earth (80-90% silica, 2-4% aluminum oxide, and 0.5-2% iron oxide) were added to the T cells. The T cells began to incorporate stearate into their membranes which resulted in inactivation of the T cell. B cells, also from mice, examined in the same way had no issues because they have an enzyme that desaturates the stearate molecule.
Yes, this experiment worked in mouse T cells. However, it had to be done in a petri dish (in vitro) to create the environment where it could happen. To quote directly from the authors; “If the effects of 18:0 (stearate) on T cells could be retained in vivo (in the living organism), the fatty acid could effectively and rapidly immunosuppress cell-mediated responses, but without the serious side-effects of cyclosporin.” In other words, the effect is not observed in the living mouse.
The researches were trying to see if there was a way that stearate could be used as a potential immune suppressing drug, but could only get it to work in conditions far removed from normal physiological conditions. Human T lymphocytes have a desaturase enzyme unlike the mouse T cell.  This means that human T cells can modify stearate by enzymatic desaturation and cannot be inactivated by stearate consumption.
 Beare-Rogers, J.; Dieffenbacher, A.; Holm, J.V. (2001). "Lexicon of lipid nutrition (IUPAC Technical Report)". Pure and Applied Chemistry 73 (4): 685–744.
 D. Søndergaarda, O. Meyera and G. Würtzena (1980). "Magnesium stearate given peroprally to rats. A short term study". Toxicology 17 (1): 51–55. doi:10.1016/0300-483X(80)90026-8. PMID 7434368
 "Magnesium stearate" by Edgar181 - Own work. Licensed under Public Domain via Wikimedia Commons - http://commons.wikimedia.org/wiki/File:Magnesium_stearate.png#/media/File:Magnesium_stearate.png
 Alija Uzunović, Edina Vranić; "Effect Of Magnesium Stearate Concentration On Dissolution Properties Of Ranitidine Hydrochloride Coated Tablets"; Bosnian Journal Of Basic Medical Sciences, 2007, 7(3): 279-283.
 Natalie D. Eddington, Muhammad Ashraf, Larry L. Augsburger, James L. Leslie, Michael J. Fossler, Lawrence J. Lesko, Vinod P. Shah, Gurvinder Singh Rekhi; "Identification of Formulation and Manufacturing Variables That Influence In Vitro Dissolution and In Vivo Bioavailability of Propranolol Hydrochloride Tablets"; Pharmaceutical Development and Technology, Volume 3, Issue 4 November 1998 , pages 535–547.
 U.S. Department of Agriculture, Agricultural Research Service. What We Eat in America, NHANES 2001-2002, individuals 2 years and over (excluding breast-fed children). Nutrient Intakes: Mean Amount Consumed Per Individual, One Day.
 U.S. Department of Agriculture, Agricultural Research Service, 2006. USDA Nutrient Database for Standard Reference, Release 19.
 U.S. Department of Agriculture, Agricultural Research Service, 2014. USDA National Nutrient Database for Standard Reference. Release 27.
 FDA's SCOGS Database; Report No. 60; ID Code: 557-04-0; http://www.accessdata.fda.gov/scripts/fcn/fcnDetailNavigation.cfm?rpt=scogsListing&id=198
 Hunter JE, Zhang J, Kris-Etherton PM. Cardiovascular disease risk of dietary stearic acid compared with trans, other saturated, and unsaturated fatty acids: a systematic review. Am J Clin Nutr. 2010 Jan;91(1):46-63. Review. PubMed PMID: 19939984.
 Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr. 2003 May;77(5):1146-55. PubMed PMID: 12716665.
 Zock PL, Katan MB. Hydrogenation alternatives: effects of trans fatty acids and stearic acid versus linoleic acid on serum lipids and lipoproteins in humans. J Lipid Res. 1992 Mar;33(3):399-410. PubMed PMID: 1569387.
 Tebbey PW, Buttke TM. Molecular basis for the immunosuppressive action of stearic acid on T cells. Immunology. 1990 Jul;70(3):379-84. Erratum in: Immunology 1990 Oct;71(2):306.
 Anel A, Naval J, González B, Uriel J, Piñeiro A. Fatty acid metabolism in human lymphocytes. II. Activation of fatty acid desaturase-elongase systems during blastic transformation. Biochim Biophys Acta. 1990 Jun 14;1044(3):332-9.
Titanium dioxide is the naturally occurring oxide of titanium, chemical formula TiO2. It is used to provide whiteness and opacity to foods and medicines, and in our case, the veggie capsule.
The US Code of Federal Regulations Title 21 (revised April 2014) states;
(c) Uses and restrictions. The color additive titanium dioxide may be safely used for coloring foods generally, subject to the following restrictions:
(1) The quantity of titanium dioxide does not exceed 1 percent by weight of the food.
(2) It may not be used to color foods for which standards of identity have been promulgated under section 401 of the act unless added color is authorized by such standards.
(d) Labeling. The label of the color additive and any mixtures intended solely or in part for coloring purposes prepared therefrom shall conform to the requirements of 70.25 of this chapter.
(e) Exemption from certification. Certification of this color additive is not necessary for the protection of the public health and therefore batches thereof are exempt from the certification requirements of section 721(c) of the act. 
The most current evidence indicates that titanium dioxide is not toxic and is relatively inert in biological systems. [2,3,4] Nanoscale range particles have different physical properties and are not suitable as a pigment. Nanoscale titanium dioxide is not currently approved as a food additive.
Titanium dioxide content is less than or equal to 1% of the weight of the empty capsule. We use the titanium dioxide for one reason and that is because the raw materials we use can sometimes have varying shades of colour depending on harvesting, original moisture content etc. and it distresses individuals when the colour is different between batches, even if it does not change the nutritional content. We also regularly evaluate the state of the evidence for many ingredients and make changes or improvements accordingly.
There is a lot of recent press on titanium dioxide. It appears that origins of the carcinogenic findings come from a 2010 publication of the International Agency for Research on Cancer (IARC), a branch of the World Health Organization. 
The IARC found that all the human studies analyzed do not suggest an association between occupational exposure to titanium dioxide as it occurred in recent decades in Western Europe and North America and risk for cancer. There was no evidence of an exposure–response relationship.
In animal studies oral, subcutaneous and intraperitoneal administration did not produce a significant increase in the frequency of any type of tumor in mice or rats. Inhalation studies did show an increase in lung tumors in rats breathing fine titanium dioxide dust at a concentration of 250 mg/m3 for two years. That is equal to breathing in and average of 30 grams of the particulate over two years.
The IARC concluded;
“Cancer in Humans: There is inadequate evidence in humans for the carcinogenicity of titanium dioxide.
Cancer in experimental animals: There is sufficient evidence in experimental animals for the carcinogenicity of titanium dioxide.
Overall evaluation: Titanium dioxide is possibly carcinogenic to humans (Group 2B).”
There are four IARC classification groups. 
Group 1: carcinogenic to humans (currently – 118 agents). There is enough evidence to conclude that it can cause cancer in humans.
Group 2A: probably carcinogenic to humans (currently – 79 agents). There is strong evidence that it can cause cancer in humans, but at present it is not conclusive.
Group 2B: possibly carcinogenic to humans (currently – 290 agents). There is some evidence that it can cause cancer in humans but at present it is far from conclusive.
Group 3: not classifiable as to carcinogenicity in humans (currently – 501 agents). There is no evidence at present that it causes cancer in humans.
Group 4: probably not carcinogenic to humans (currently – 1 agent). There is strong evidence that it does not cause cancer in humans.
There are two items to point out. First, the conclusion that titanium dioxide is possibly carcinogenic to humans comes from experimental animals exposed to incredibly high doses of inhaled material. Ingestion, or eating, did not increase the frequency of any types of cancer.
It is almost like saying that rats died when breathing in water therefore water is possibly harmful to humans. The statement may be accurate but it is very ambiguous.
Second, the categories are all worded in such way that cancer is a certainty or a probability. This too is ambiguous.
To be fair if humans breathed in the equivalent amount of titanium dust we would likely get lung tumors also. The human equivalent would be 2.1 kg or 4.6 pounds over two years.
On October 26, 2015, the IARC reported that consumption of processed meat (e.g., bacon, ham, hot dogs, sausages) was a Class 1 carcinogen, and that red meat was a Class 2A carcinogen ("probably carcinogenic to humans"). 
Therefore based on their own criteria titanium dioxide carries less cancer risk than red meat and far less risk than processed meats.
 Skocaj M, Filipic M, Petkovic J, Novak S. Titanium dioxide in our everyday life; is it safe? Radiol Oncol. 2011 Dec;45(4):227-47.
 Ophus EM, Rode L, Gylseth B, Nicholson DG, Saeed K. Analysis of titanium pigments in human lung tissue. Scand J Work Environ Health. 1979 Sep;5(3):290-6.
 Lindenschmidt RC, Driscoll KE, Perkins MA, Higgins JM, Maurer JK, Belfiore KA. The comparison of a fibrogenic and two nonfibrogenic dusts by bronchoalveolar lavage. Toxicol Appl Pharmacol. 1990 Feb;102(2):268-81.
National Academy of Sciences, Food and Nutrition Board, Institute of Medicine published the Dietary Reference Intakes which includes this excerpt on the mineral nickel.
Nickel serves as a cofactor or structural component of specific metalloenzymes of various functions, including hydrolysis and redox reactions and gene expression (Andrews et al., 1988; Kim et al., 1991; Lancaster, 1988; Przybyla et al., 1992). Nickel also serves as a cofactor facilitating ferric iron absorption or metabolism (Nielsen, 1985). Nickel is an essential trace element in animals, as demonstrated by deficiency signs reported in several species. Rats deprived of nickel exhibit retarded growth, low hemoglobin concentrations (Schnegg and Kirchgessner, 1975), and impaired glucose metabolism (Nielsen, 1996). Nickel may interact with the vitamin B12- and folic-acid dependent pathway of methionine synthesis from homocysteine (Uthus and Poellot, 1996). 
Additional research since the 2001 Institute of Medicine publication has shown several human enzymes function with or are activated by nickel.
The superoxide ion, (O2-) is generated in biological systems by reduction of molecular oxygen. It has an unpaired electron, so it behaves as a free radical. It is a powerful oxidising agent. These properties render the superoxide ion very toxic and are deployed to advantage by phagocytes to kill invading microorganisms. Otherwise, the superoxide ion must be destroyed before it does unwanted damage in a cell. The superoxide dismutase enzymes perform this function very efficiently. 
In biology this type of reaction is called a dismutation reaction. It involves both oxidation and reduction of superoxide ions. The superoxide dismutase group of enzymes, abbreviated as SOD, increase the rate of reaction to near the diffusion limited rate. The key to the action of these enzymes is a metal ion with variable oxidation state which can act as either an oxidizing agent or as a reducing agent. 
In human SOD the active metal is copper, as Cu2+ or Cu+, coordinated tetrahedrally by four histidine residues. This enzyme also contains zinc ions for stabilization and is activated by copper chaperone for superoxide dismutase (CCS). Other isozymes may contain iron, manganese or nickel. Ni-SOD is particularly interesting as it involves nickel (III), an unusual oxidation state for this element. The active site Ni geometry cycles from square planar Ni (II), with thiolate (Cys2 and Cys6) and backbone nitrogen (His1 and Cys2) ligands, to square pyramidal Ni (III) with an added axial His1 side chain ligand. 
Calcineurin is a protein phosphatase  consisting of a catalytic subunit, calcineurin A, which contains an active site dinuclear metal center, and a tightly associated, Ca (2+)-binding subunit, calcineurin B. This enzyme has a wide variety of biological responses including Ca (2+) and calmodulin* dependent signal transduction, lymphocyte activation, neuronal and muscle development, neurite outgrowth, and morphogenesis of vertebrate heart valves.  Research dating to the early 1980’s has identified that nickel is an activator of the calcineurin enzyme. [7-13]
*Calmodulin is a calcium binding protein that mediates many crucial processes such as inflammation, metabolism, apoptosis, smooth muscle contraction, intracellular movement, short-term and long-term memory, and the immune response. Calmodulin is expressed in many cell types and can have different subcellular locations, including the cytoplasm, within organelles, or associated with the plasma or organelle membranes. Many of the proteins that Calmodulin binds are unable to bind calcium themselves, and use Calmodulin as a calcium sensor and signal transducer.
 Food and Nutrition Board, Institute of Medicine. Dietary Reference Intakes: Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academy Press, Washington, D.C., 2001.
 Packer, L. (editor) (2002). Superoxide Dismutase: 349 (Methods in Enzymology). Academic Press. ISBN 0-12-182252-4.
 Heinrich, Peter; Georg Löffler; Petro E. Petrides (2006). Biochemie und Pathobiochemie (Springer-Lehrbuch) (German Edition). Berlin: Springer. pp. 123.
 Barondeau, D.P.; Kassmann C.J.; Bruns C.K.; Tainer J.A.; Getzoff E.D. (2004). "Nickel superoxide dismutase structure and mechanism". Biochemistry 43 (25): 8038–8047.
 Liu L, Zhang J, Yuan J, Dang Y, Yang C, Chen X, Xu J, Yu L. Characterization of a human regulatory subunit of protein phosphatase 3 gene (PPP3RL) expressed specifically in testis. Mol Biol Rep. 2005 Mar;32(1):41-5.
 Rusnak F, Mertz P. Calcineurin: form and function. Physiol Rev. 2000 Oct;80(4):1483-521. Review.
 King MM, Huang CY.; Activation of calcineurin by nickel ions. Biochem Biophys Res Commun. 1983 Aug 12;114(3):955-61.
 Raos N, Kasprzak KS.; Allosteric binding of nickel(II) to calmodulin. Fundam Appl Toxicol. 1989 Nov;13(4):816-22.
 Mukai H, Ito A, Kishima K, Kuno T, Tanaka C.; Calmodulin antagonists differentiate between Ni(2+)- and Mn(2+)-stimulated phosphatase activity of calcineurin. J Biochem (Tokyo). 1991 Sep;110(3):402-6.
 Pallen CJ, Wang JH.; Stoichiometry and dynamic interaction of metal ion activators with calcineurin phosphatase. J Biol Chem. 1986 Dec 5;261(34):16115-20.
 Matsui H, Pallen CJ, Adachi AM, Wang JH, Lam PH.; Demonstration of different metal ion-induced calcineurin conformations using a monoclonal antibody. J Biol Chem. 1985 Apr 10;260(7):4174-9.
 Mancinella A.; Nickel, an essential trace element. Metabolic, clinical and therapeutic
Considerations. Clin Ter. 1991 Aug 15-31;138(3-4):159-65.
 Pallen CJ, Wang JH.; Regulation of calcineurin by metal ions. Mechanism of activation by Ni2+ and an enhanced response to Ca2+/calmodulin. J Biol Chem. 1984 May 25;259(10):6134-41.