TCPR: You’ve studied micronutrients in ADHD and other psychiatric disorders. What are micronutrients?
Dr. Rucklidge: They are small nutrients—vitamins, minerals, and amino acids—that are essential for your brain to function optimally. They include cofactors like B6, zinc, and magnesium that are involved in the synthesis of neurotransmitters and hormones. Patients take them in pills that contain a broad spectrum of these nutrients. Some are available by prescription, like EnLyte, and others are over the counter, like EMPowerplus or Daily Essential Nutrients. So you might see patients who are taking them already.

TCPR: How are these different from multivitamins?
Dr. Rucklidge: When people think of multivitamins, they think of over-the-counter pills for general health and well-being. What we have studied is quite different. Micronutrients are much more substantial in their doses and breadth of ingredients, which is how they exert a therapeutic effect (see “Micronutrients Discussed by Dr. Rucklidge” table on page 5).

TCPR: What did you see in the ADHD studies?
Dr. Rucklidge: We’ve done two randomized, placebo-controlled trials in ADHD, one in children (n = 93) and one in adults (n = 80). None of them were taking medications for ADHD, and we treated them with either a micronutrient formula or placebo. The specific formulas we used were EMPowerplus in the adult study and Daily Essential Nutrients in the child study. In the children, we saw improvement in emotional regulation, aggression, inattention, and general functioning after 10 weeks. Compared to placebo, the micronutrients had a moderate effect size, and benefits were observed across patient, parent, teacher, and clinician report. In the adult trial, we saw improvements in the patient-rated and observer-rated symptoms, but the clinician-rated measures were only positive on the Global Assessment of Functioning (GAF), which speaks to what these micronutrients are doing. They are not specific treatments for ADHD. Rather, they have a broader effect on mental health (Rucklidge JJ et al, J Child Psychol Psychiatry 2018;59(3):232–246; Rucklidge JJ et al, Br J Psychiatry 2014;204:306–315).

TCPR: Do you see micronutrients as treatments for specific disorders? Or do they improve mental health more broadly in the way that social supports, exercise, and good sleep do?
Dr. Rucklidge: I think they are improving mental health more broadly. They seem to have similar effects regardless of the population that was studied. To sum up dozens of controlled studies, I’d say that micronutrients help emotional dysregulation.

TCPR: What does emotional dysregulation look like in real life?
Dr. Rucklidge: Volatile, irritable, anxious, reactive. People with emotional dysregulation might meet criteria for different disorders in the DSM. You’re walking on eggshells with them because their mood can change so quickly. They might be aggressive; it might express itself in temper tantrums in children. You might end up with a lot of anxiety as a consequence of being emotionally dysregulated. We see all those symptoms improve with micronutrients, and we see related improvements in patients’ ability to self-regulate. They sleep better, are better able to cope with stress, and—anecdotally—are less likely to turn to alcohol, drugs, or cigarettes.

TCPR: So micronutrients may help nonspecific symptoms, but they were also studied in specific populations. Which populations have they been studied in?
Dr. Rucklidge: There are randomized controlled trials in juvenile delinquents, school children, healthy adults, and prisoners that generally confirm this effect on emotional regulation. There are two studies in autism where micronutrients improved hyperactivity, tantrums, and receptive language (Adams JB et al, BMC Pediatr 2011;11:111). We don’t have positive studies in bipolar disorder and schizophrenia, although a few specific nutrients have positive results in those populations, mainly omega-3s, N-acetylcysteine, vitamin D, and B vitamins (Balanzá Martínez V, Actas Esp Psiquiatr 2017;45:16–25; Fusar-Poli L et al, J Affect Disord 2019;252:334–349).

TCPR: Are there positive studies in depression?
Dr. Rucklidge: Yes, there is one on EnLyte, a branded micronutrient that has been cleared by the FDA as a medical food. EnLyte contains zinc, methylfolate, and B vitamins. In that study, it was the depressive symptoms themselves that improved, and the effect size was large (0.9). Importantly, the study only enrolled depressed patients with abnormalities at the methylenetetrahydrofolate reductase (MTHFR) gene, which is involved in folate metabolism. The study was large (n = 330), double blinded, and placebo controlled (Mech AW and Farah A, J Clin Psychiatry 2016;77(5):668–671). We are currently conducting a large randomized controlled trial of Daily Essential Nutrients in depression.

TCPR: Which age groups have the best response?
Dr. Rucklidge: There doesn’t seem to be an age effect. In our ADHD studies, we saw pretty much the same effects in adults and children. Older people also do well on micronutrients. So far, we don’t really know who is going to respond. We’ve looked into biomarkers like the MTHFR gene, inflammatory markers, and even direct serum measurements of vitamins and other micronutrients. But none of these reliably predict response.

TCPR: So you don’t need to have a micronutrient deficiency for these to work?
Dr. Rucklidge: Well, at least not from the point of view of the clinical measures we’ve looked at. We’ve measured levels that are commonly available, like B12, folate, copper, zinc, and vitamin D. In our research, people who have a deficiency in those nutrients are just as likely to respond as those who have normal levels. But there’s a caveat there. Lab tests only tell us about population averages. They don’t tell us if an individual’s levels are meeting the person’s needs. Someone might have a greater need for zinc, for example, because of genetic differences. Another person might have “low” levels that are plenty sufficient for that person’s needs. I’m being a little speculative here as we don’t have enough research to prove that (Rucklidge JJ et al, Prog Neuropsychopharmacol Biol Psychiatry 2014;50:163–171).

TCPR: What about side effects and risks?
Dr. Rucklidge: You might see stomachaches or headaches, but generally micronutrients are well tolerated and safe. In our controlled studies, we saw similar rates of side effects for placebo and micronutrients. We also have long-term extension studies, where micronutrients continued to be effective in 85% of patients and remained well tolerated (average follow-up 2.7 years). There are rare cases where a micronutrient may cause problems—for example, someone with hemochromatosis should not take iron, and a person with Wilson’s disease should not supplement with copper.

TCPR: If psychiatrists want to recommend micronutrients, how do they choose a product?
Dr. Rucklidge: Well, first let me say I have not received any money from companies that make these products, and I don’t endorse any particular brands. But I can tell you which brands have the most research behind them: Daily Essential Nutrients and EMPowerplus. Newer products are moving toward methylated vitamins, like methylfolate instead of folic acid, or methylated B12, which may be more effective for some patients. Daily Essential Nutrients are methylated, and EMPowerplus has a methylated version as well. (Ed. note: For more on methylated folate, see TCPR, August 2019.)

TCPR: Your recent studies have utilized Daily Essential Nutrients. Did you do those without any support from the manufacturer?
Dr. Rucklidge: The companies that make Daily Essential Nutrients and EMPowerplus seem to have a general policy that they’ll provide free pills and matching placebo for anyone who wants to do a study. They don’t ask any questions and play no role in the development of the studies. They have only one caveat: The study has to be approved by an ethics board. So that’s the extent of their involvement. The financial backing for this research has come from charitable donations, grants, and academic awards.

TCPR: Each of these products has 20–30 ingredients in them. How did the manufacturers decide on the ingredients?
Dr. Rucklidge: The original formulas were developed in the 1990s by families in Alberta, Canada. These parents were struggling with mental disorders in their children that didn’t respond to conventional treatments. So they looked in other directions, in this case farming. Farmers have known for centuries that when their animals get irritable and start biting each other, the animals’ irritability gets better when they’re fed a broad spectrum of nutrients. The families started from there and added individual nutrients into the mix that have positive studies for mental health, like inositol, choline, and N-acetylcysteine.

TCPR: There are good studies on those individual nutrients. What is the advantage to taking them all together in a micronutrient pill?
Dr. Rucklidge: The thinking is that no one nutrient is special. You need them all in combination. It’s the same reason that we need variety in our diets. We tested this idea out in a study of healthy adults who were impacted by a natural disaster. We compared micronutrients to a single nutrient (vitamin D) or a few nutrients (B-complex ­vitamins). It was a small randomized trial (n = 56) with no placebo. When compared to the other vitamins, improvements were significantly greater with the micronutrients on measures of anxiety and stress (Kaplan BJ et al, Psychiatry Res 2015;228(3):373–379).

Table: Micronutrients Discussed by Dr. Rucklidge

View as a full-size PDF.

TCPR: Was the goal to prevent PTSD with micronutrients?
Dr. Rucklidge: Yes. This was in the summer of 2013 when there was severe flooding in Alberta, New Zealand. A lot of things fall apart when a natural disaster strikes, including food and nutrition, so we thought that micronutrients might be particularly helpful in this setting. We’ve done similar interventions after the earthquakes in 2010 and the mosque shooting last spring. The results were positive, but unlike the flood study, they weren’t randomized.

TCPR: Are there other ingredients in these products besides minerals and vitamins?
Dr. Rucklidge: Over the years, manufacturers have added in small doses of ingredients that I wouldn’t classify as micronutrients, like ginkgo or grapeseed extract. Those are few in number and small in amount, but they do make it hard to say definitively that it’s the micronutrients that are making the difference.

TCPR: I understand that the “nutrient” in micronutrients refers to minerals, vitamins, and amino acids. What does “micro” mean?
Dr. Rucklidge: We call them “micro” nutrients because they are much smaller than macronutrients: fats, carbohydrates, and proteins. Micronutrients are part of a healthy diet, but much of the Western diet is depleted of micronutrients. For some, that doesn’t matter as much and it’s not going to affect their mental health, but other patients are more vulnerable.

TCPR: Could patients get the same benefits by changing their diet?
Dr. Rucklidge: Yes. Food is where I go first. I recommend a diet that is low in processed foods and high in fruits and vegetables and healthy fats from nuts, seeds, and fish. Sometimes that works, but there are reasons why dietary change might not work. One is environmental. Society favors food that grows quickly, and when plants grow fast, they don’t take up as many nutrients from the soil. We don’t remineralize the soil, and instead we use herbicides like Roundup that leach minerals. Then there’s storage and transport. Once an apple is picked from a tree, the nutrient content decreases, and continues to decrease as it is shipped. When the food arrives in our kitchen, we cook it, and that can further deplete the nutrients. Finally, differences in genetics and the gut microbiome influence how available those nutrients are in the body after the food is eaten.

TCPR: Thank you for your time, Dr. Rucklidge.