I have noticed a growing number of companies offering to measure nutrient levels and then offering a personalized treatment approach to address deficiencies identified. I have also been sent individual blood results from members of the public and asked whether the results can be used to direct the best treatment. Others contact me and tell me their nutrient levels are “normal” so their doctor told them there was no need for additional nutrients.

It is a reasonable question because there are many studies that suggest that people with psychological problems such as ADHD have lower levels of nutrients in their blood relative to the nonclinical population. What we don’t know is whether it is necessary to be deficient in order to benefit from additional nutrients than what you can get out of your diet.

So what does the research say?

Our lab at the University of Canterbury in New Zealand is one of a few that has specifically investigated whether nutrient levels are predictive of response to a broad spectrum micronutrient intervention. It is important to note that not many labs take this approach, that is giving a combination of nutrients together and then assess treatment response. Many researchers make the assumption that one must be deficient to benefit from nutrients, and therefore select people for the deficiency and only treat them. We treat everyone, regardless of identified deficiency, and then assess whether the deficiency predicts who will respond and who won’t.

Overall, our research shows that the effect, if there is one, is weak, and certainly not useful at an individual level as a good predictor of treatment outcome.

Here is what we did: We assessed some key nutrients pre-treatment via serum/plasma. We measured vitamin B12, vitamin D, zinc, copper, folate, ferritin, potassium, sodium, calcium, and homocysteine. We have looked at two data sets – an adult study and a child study, both comparing vitamins/minerals to placebo in the treatment of symptoms associated with ADHD.

Findings from the adult ADHD trial:

Participants improved significantly on all outcome measures after exposure to the micronutrients for 8 weeks; 61% were identified as responders.

But, there was no relationship between baseline functioning and baseline nutrient levels. This was a bit surprising given that studies have identified deficiencies in magnesium, zinc and iron in children with ADHD. Surprisingly, we didn’t find that these nutrient levels were highly correlated with ADHD symptoms.

Very few predictors were identified. We found that greater pre-treatment with ferritin predicted who would be an ADHD responder. We wondered if those with higher ferritin had higher inflammation and therefore responded more rapidly to the treatment as the micronutrients may have improved inflammation.

Lower pre-treatment vitamin D predicted greater change on a measure of mood. This finding is not unexpected as low vitamin D levels have been associated with low mood. Pre-treatment copper gave us a signal, but it was weak and mixed.

Micronutrient supplementsIt is important to note that while there were these small signals, there were still many people with normal levels of these nutrients who benefitted from the nutrient approach, only there were fewer relative to those with vitamin D and copper deficiencies.

No other relationships between baseline nutrient levels and treatment response were identified. In other words, zinc, iron and vitamin B12 pre-treatment did not predict who would benefit and who would not. Further, there were no specific demographic variables (age, socio-economic status, gender, marital status, education) which contraindicated micronutrient treatment for ADHD in adults.

Findings from the child trial:

We identified that 49% of the children responded to the micronutrient intervention. Substantial nutrient deficiencies pre-treatment were observed only for vitamin D (13%) and copper (15%), otherwise most children entered the trial with nutrient levels falling within expected ranges. Lower pre-treatment folate and B12 levels, being female, greater severity of symptoms and co-occurring disorders pre-treatment, more pregnancy complications and fewer birth problems were identified as possible predictors of greater improvement for some but not all outcome measures although predictive values of all of them were weak. Lower IQ and higher BMI predicted greater improvement in aggression.

It is important to note that levels of folate pre-treatment for ADHD responders was within the normal reference range for folate (>8nmol/L). In other words, the blood tests did not identify responders as deficient in folate, just lower relative to non-responders. Note though, that there were many children with higher B12 and folate who did benefit from the nutrient treatment. No other relationships between pre-treatment nutrient levels and treatment response were identified.

It is also important to point out that across two studies, replication did not occur and any findings we did observe were incredibly modest. As such, they could not be used at an individual level to reliably identify who might benefit from this treatment approach. We see this as good news as it means people don’t have to feel they need to get expensive testing done before trying nutrients. The bad news is that the search is still on to figure out why some people respond and some don’t.

Although not reported in these trials, we have also looked at the predictive value of nutrient levels recorded from hair samples and similarly, the levels were also not overly helpful at predicting treatment response.

Do nutrient levels have to change for benefit to occur?

Now this is a tricky question. But we have now published a study looking at this very question, that is, whether change in a nutrient biomarker is correlated with improvement in mental health. Our overall findings were that they were not.

I think this type of question stems from research in medicine such as physicians tracking cholesterol levels in order to determine whether they are associated with the progression of disease (such as incidence of stroke). Change in cholesterol levels are used to estimate risk for future cardiovascular events.

In the mental health world, at best, they are weakly correlated with improvement in symptoms and probably not that helpful. We investigated whether changes in serum nutrient levels mediate clinical response to a micronutrient intervention for ADHD. Data were compiled from two ADHD trials (8-10 weeks), one in adults (n = 53) and one in children (n = 38). Seven outcomes included change in ADHD symptoms, mood, overall functioning (all clinician-rated) as well as response status. Change in serum/plasma nutrient levels (vitamins B12 and D, folate, ferritin, iron, zinc, and copper) were considered putative mediators.

We found that a decrease in ferritin and an increase in copper were weakly associated with greater likelihood of being identified as an ADHD responder; none of the other nutrient biomarkers served as mediators. Perhaps we need to look to see if other tissue (like hair or microbiome samples) might be more useful. Monitoring these biomarkers is unlikely helpful in understanding clinical response to a broad-spectrum micronutrient approach.

Blood levels don’t necessarily tell us what is going on in the brain and what nutrients are being used and what isn’t being used. We didn’t look at ALL nutrients so it may be we missed an important biomarker. It may be ratios are more important. But next time a professional is keen to track nutrient levels as a proxy for response, perhaps be a bit sceptical about whether the data support such testing.

Is the term deficiency accurate?

The term “deficiency”, as is often used in the ADHD literature when discussing nutrient levels, may be problematic. Although research shows that the ADHD group mean nutrient levels are often below control group means, the ADHD means are typically still falling within the normal reference range, potentially challenging the use of the term “nutrient deficiency” when attempting to investigate causes of ADHD and in relation to predicting response to nutrients. Given that reference ranges are generally defined as the set of values that 95 percent of the normal population falls within, this does not necessarily mean that these ranges are best equipped to identify what is required for optimal health for any particular individual.

Had functional ranges (the range used to assess risk for disease before the disease develops) been used in these studies, many more would have been identified with “deficiencies”. An important hypothesis which requires further investigation is that some individuals may have suboptimal nutrition for brain health despite having nutrient levels within the reference range. In other words, they might have a nutrient deficiency relative to their metabolic needs rather than relative to general population levels.

It is exciting that the EAT2BeNice consortium (NewBrainNutrition) will be looking at nutrient levels alongside other biomarkers so we can confirm whether these results are replicable. Hopefully some of the other biomarkers will prove more useful at predicting treatment response. Afterall, it is a valid clinical question to wonder – when a treatment works, who does it work for and why? These types of data inform clinical practice and can help the consumer decide whether you should go for that expensive testing, or not bother. At this stage, I wouldn’t bother.

References

  1. Rucklidge JJ, Johnstone JM, Gorman B, Boggis A, Frampton CM. Moderators of treatment response in adults with ADHD treated with a vitamin-mineral supplement. Prog Neuropsychopharmacol Biol Psychiatry. 2014;50:163-71.
  2. Rucklidge JJ, Eggleston MJF, Darling K, Stevens A, Kennedy M, Frampton CM. Can we predict treatment response in children with ADHD to a vitamin-mineral supplement? An investigation into pre-treatment nutrient serum levels, MTHFR status, clinical correlates and demographic variables. Prog Neuropsychopharmacol Biol Psychiatry. 2018.
  3. Rucklidge JJ, Eggleston MJF, Boggis A, Darling K, et al. Do Changes in Blood Nutrient Levels Mediate Treatment Response in Children and Adults With ADHD Consuming a Vitamin–Mineral Supplement? Journal of Attention Disorders. 2019. 0:1087054719886363.

 

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When we are under high stress, we can often reach for foods that are “comforting” (like cookies, donuts, cake, pastries, and chocolate bars), but these foods may not be the best choice for feeding your brain under stressful and demanding circumstances. Comfort foods are often calorie-rich but nutrient-poor.

Further, under high stress (and it doesn’t actually matter what has caused the high stress, whether it be a natural disaster like an earthquake or fire, or witnessing something really traumatic), the reactions our body goes through can be quite similar. We release adrenaline. This is part of our natural alarm response system.

Adrenaline is an essential neurotransmitter that is released as part of the fight-flight response. It enables our body to get us to safety, shut down non-essential functions, and make sure the muscles needed for fight or flight get activated. Cortisol, a hormone, is also essential for the alarm system to function optimally.

Unfortunately, over extended periods of time, the alarm system can go into over-drive, and this is one factor that can lead to re-experiencing memories, flashbacks, hypervigilance, being on edge all the time, feeling anxious and panicky when reminded of the traumatic event, struggling with sleeping and having nightmares.

Making neurotransmitters and hormones requires micronutrients, which are numerous kinds of vitamins and minerals. This is a well-established scientific fact. Micronutrients like zinc, calcium, magnesium, iron, and niacin are all essential for making neurotransmitter chemicals for the brain and the body. If your body is depleted of these nutrients, then either it won’t have sufficient nutrients to make these essential chemicals, or it will redirect all resources to the fight or flight response (as it is so vital for survival) and there won’t be much left for ensuring optimal brain function to do things like concentrate, regulate moods and sleep.

Consequently, as micronutrients get depleted at a high rate during times of stress, we need to replenish them in greater quantity from our food (and perhaps other sources).

Where can we get these micronutrients from?

Answer: Nutrient-dense foods; real food, not ultra-processed foods.
Compare a banana to a cookie; one obtains far more of these micronutrients (like potassium, magnesium, folate) that are required for brain function from a banana. Eating kale chips over potato chips would also provide more nutrients. Reaching for a carrot stick and dipping it in hummus would be better for your brain than gorging down a commercial meat pie (although meat pies can be healthy if they contain lots of vegetables too). Choosing nuts and seeds over pretzels would also give you better brain food.

Overall, to cope well with stress your goal should be to increase intake of plant food and food high in nutrient density while still getting adequate protein, fats and carbs. Fish is a great source of protein and of essential fatty acids, which are also vital for brain function. In eating these types of foods, you would be shifting your diet from a Western type of diet (ultra-processed, high in sugar) to a Mediterranean-style diet (high in fruits and veggies, fish, nuts, healthy fats and low in processed foods).

Therefore, stop counting calories and start focussing on nutrients, especially nutrients that are good for your brain!

Would this be sufficient to sooth the over-activated alarm system in a situation of high and chronic stress? Possibly, although some people might need more nutrients than what they can get out of their diet, even if it is a healthy one. There are many reasons for this, some of which reflect reduced nutrient density in modern foods, some of which are due to our own specific genetic make-up, and some have to do with the health of our microbiome (the millions of helpful bacteria that live inside us, especially in our gut).

If you do need to consume more nutrients than what you can source from your diet, or you are struggling with cooking due to your particular circumstances and the stresses you are experiencing, or you are time poor because of family or work demands, what do you take in terms of a supplement? Research from the Mental Health and Nutrition Lab in Christchurch, NZ found that following the Christchurch earthquakes as well as other research on stressed communities shows that B vitamins, in particular, can be helpful. A recently published meta-analysis confirmed the positive effect of B vitamins on reducing stress. In addition, some may find a reduction of intrusive thoughts require additional minerals as well.

Nutrition resources for psychologists and mental health professionals working with people struggling with anxiety post-trauma:

When working with people struggling with stress/anxiety, research shows that it is essential that their diet includes foods that are nutrient-dense. This means being aware of foods that are high in vitamins and minerals as well as being a good source of fats, proteins and carbohydrates.

You can ask some simple questions:

  • How many times a week do you eat fast food meals or snacks?
  • How many regular fizzy drinks do you drink each day?
  • Snacks? Favourite Foods? Problem Foods?
  • Any restrictions? Allergies? Aversions?
  • How many servings of fruit do you eat each day?
  • How many servings of vegetables do you eat each day?
  • How often do you eat red meat (good source of iron, folate)?
  • Do you eat fish? (good to know if they are vegan, vegetarian, or gluten-free)

These questions can start the conversation to find out if they are eating nutrient dense foods.

Here are some basic tips:

  1. Start with whole foods diet approach including good fats, nuts, seeds, fish, a modest amount of meat, vegetables, fruit, whole grains
  2. Shifting towards eating “real” as opposed to processed foods naturally eliminates unnecessary food additives such as artificial colours, flavours, sweeteners and preservatives that do not add nutritional value and may contribute to psychiatric symptoms in some people
  3. Limit sugar intake (sugar is everywhere in processed foods, energy/fizzy drinks – encourage clients to look at labels to spot the hidden sugar)
  4. watch caffeine and alcohol intake doesn’t creep up
  5. Eat a good solid nutrient-dense breakfast: e.g., omelette with vegetables, muesli (oats, nuts, raisins) with milk, yogurt, fresh fruit
  6. If your client is struggling with cooking or a change in diet is not working enough to reduce psychological symptoms, you can consider suggesting supplements as there has been a lot of research on them. If suggesting supplements, stick to the data and published research, the best research is on adding additional B vitamins (like Blackmores or Berocca). For more information please email the Mental Health and Nutrition Research Group: mentalhealthnutrition@canterbury.ac.nz

Here are some useful resources:

A recent radio interview about dietary patterns and stress: https://www.radionz.co.nz/national/programmes/nights/audio/2018687489/nutrition-during-times-of-stress-and-trauma

Harvard Medical School has put together lots of resources on healthy eating, including the healthy eating plate: www.health.harvard.edu/staying-healthy/healthy-eating-plate

The Helfimed trial was a successful trial that showed the benefit of assisting people suffering from depression to nudge over to a more Mediterranean-based diet. They have lots of recipes on their website: http://helfimed.org/cgi-sys/suspendedpage.cgi

The Mood and Food Centre in Melbourne often blogs on diet-related topics. Check out their website: http://foodandmoodcentre.com.au/

Dr Drew Ramsey has some excellent resources on eating well on a budget: https://drewramseymd.com/uncategorized/brain-food-budget/

There are lots of great resources at this site: https://www.getselfhelp.co.uk/freedownloads.htm

Books that we have enjoyed reading on nutrition and mental health that do have some scientific basis to their recommendations:

  • Brain Changer – Prof Felice Jacka
  • Finally Focused – Dr James Greenblatt
  • The Mad Diet – Suzanne Lockhart
  • The anti-anxiety food solution –Trudy Scott
  • What the FAT? – Prof Grant Schofield (also includes recipes)

Rachel Kelly has devised a cookbook directly focused on eating foods that will contain nutrients help you feel mentally better:

https://www.rachel-kelly.net/books-apps/

How to eat well on a budget:
From the British Dietetic Association: A healthy diet can be more expensive than a diet made up of more refined foods. Fish, fruit and vegetables can be particularly pricey. However, by cutting down on sugary drinks and snacks, takeaways and alcohol, you can save money to be spent on healthier items. Take care to buy only as much as you know you can use within the next few days to reduce waste. You can also cut your costs by taking advantage of special promotions and by shopping at market stalls which are often cheaper than supermarkets.

If you live alone you could save money by splitting purchases with friends (larger pack sizes are usually cheaper) or by cooking several portions of a dish and freezing some of them. This also saves fuel and saves you the effort of preparing meals every day. Frozen fruit and vegetables are often cheaper than fresh produce and are usually just as good nutritionally (with no wastage). Fresh fruit and vegetables are usually cheapest when they are in season.

Also, research from Australia has shown that a Mediterranean style diet was cheaper than a poor quality diet.

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What is vitamin B1 (thiamine)?

Thiamine, which is also known as vitamin B1, is an essential micronutrient, which is required for metabolism, enzymatic processes and conduction of nerve signals. All living organisms use thiamine, but it can be made only in bacteria, fungi and plants. In humans, gastrointestinal microbiota also produces thiamine, but not enough for the organism functioning. Thus, we, as well as other animals must obtain vitamin B1 from the diet.

Thiamine deficiency

Deficiency of thiamine can affect the cardiovascular, nervous and immune systems. A severe and chronic form is known as beriberi. Wet beriberi affects cardiovascular system resulting in tachycardia, high arterial and venous pressures, leg swelling. Dry beriberi affects nervous system resulting in impairment of sensory, motor and reflex functions and altered mental status. Worldwide thiamine deficiency is most widely reported in populations where primary food source are polished rice and grains. In Western countries, it most commonly affects people suffering from alcoholism or chronic illness. Thiamine deficiency in patients with alcohol use disorder often lead to Kosakoff syndrome, a chronic disease with severe memory loss and learning problems.

Food sources of thiamine

It is very easy to add foods rich with thiamine to the diet. Food sources of thiamine include beef, pork, eggs, liver, nuts, oats, oranges, seeds, legumes and yeast. Such foods as rice, pasta, breads, cereals and flour are often fortified with vitamin B1 as the processing involved in creating these products removes thiamine. Thiamine supplements and medications are available on market to treat or prevent thiamine deficiency. Remarkably, B1 is well tolerated and has almost no side effects.

Bioavailable analogues of Thiamine

Analogues of vitamin B1, such as benfotiamine or dibenzoyl thiamine, have improved bioavailability, due to their higher lipid solubility, which facilitate permeation in cell membranes. As a result, they provide higher levels of thiamine in muscle, brain and liver. This can be the reason of their higher effectiveness.

Thiamine as medication

Thiamine was the first of the water-soluble vitamins to be discovered, and since early 20th century it was extensively studied. Most commonly thiamine supplementation is used to treat syndromes associated with severe thiamine deficiency and during pregnancy and lactating due to increased need for this vitamin. Rapid recovery can occur within hours if thiamine is given intravenously. If concentrated thiamine supplements are not available, diets rich with thiamine will also lead to recovery, though at a slower rate.

New properties of thiamine

Recently, other important roles of thiamine including the regulation of oxidative stress were discovered [1]. As emotional stress is associated with oxidative stress in the brain, it was hypothesized that thiamine can counteract negative effects of the stress. And indeed, in studies on mice thiamine precluded negative changes in mood and emotionality, as well as neuroinflammation and oxidative stress caused by stress [2,3]. It also ameliorated cellular proliferation and neurogenesis in the hippocampus under stress conditions. In agreement with animal studies, vitamin B1 was also able to ameliorate symptoms of major depressive disorder in patients [4] or work stress-related mood swings [5].

Thus, thiamine was shown as a promising treatment for the depressive-like changes and excessive aggression, caused by stress. Hopefully, new studies on thiamine will be conducted in the nearest future to show novel properties of this vitamin.

 

References

[1]      L. Bettendorff, P. Wins, Biological functions of thiamine derivatives: Focus on non-coenzyme roles, OA Biochem. 1 (2013).

[2]      N. Markova, N. Bazhenova, D.C. Anthony, J. Vignisse, A. Svistunov, K.-P. Lesch, L. Bettendorff, T. Strekalova, Thiamine and benfotiamine improve cognition and ameliorate GSK-3β-associated stress-induced behaviours in mice, Prog. Neuro-Psychopharmacology Biol. Psychiatry. 75 (2017) 148–156.

[3]      A. Gorlova, D. Pavlov, D.C. Anthony, E.D. Ponomarev, M. Sambon, A. Proshin, I. Shafarevich, D. Babaevskaya, K.-P. Lesсh, L. Bettendorff, T. Strekalova, Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice, Neuropharmacology. (2019).

[4]      A. Ghaleiha, H. Davari, L. Jahangard, M. Haghighi, M. Ahmadpanah, M.A. Seifrabie, H. Bajoghli, E. Holsboer-Trachsler, S. Brand, Adjuvant thiamine improved standard treatment in patients with major depressive disorder: results from a randomized, double-blind, and placebo-controlled clinical trial, Eur. Arch. Psychiatry Clin. Neurosci. 266 (2016) 695–702.

[5]      C. Stough, A. Scholey, J. Lloyd, J. Spong, S. Myers, L.A. Downey, The effect of 90 day administration of a high dose vitamin B-complex on work stress, Hum. Psychopharmacol. Clin. Exp. 26 (2011) 470–476.

 

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Children with ADHD who keep taking micronutrients over one year are mostly in remission in their symptoms with no side effects

The results from a University of Canterbury (UC) study into the longer term effects of micronutrients on ADHD symptoms in children was recently published in the Journal of Child and Adolescent Psychopharmacology.  

This study was led by Dr Kathryn Darling at the Mental Health and Nutrition Lab in Christchurch (under the supervision of Eat2BeNice Scientist Julia Rucklidge) and looked at the long-term effects of a broad-spectrum micronutrient (vitamins and minerals) in attention-deficit/hyperactivity disorder (ADHD) treatment.

Eighty-four of the 93 children who entered a 10-week randomised controlled trial (micronutrients versus placebo), followed by a 10 week phase of all children taking micronutrients, then completed follow-up assessments after 12 months. This allowed us to gather valuable information about what happens when people choose to stay on or come off the micronutrient treatment.

The study showed that children who benefit in the short term from taking a broad-spectrum vitamin/mineral formula maintain those benefits or continue to improve when they keep taking it longer term, without side effects.

Continued micronutrient treatment was associated with improvements in ADHD symptoms which were similar to, or greater than, those associated with stimulant medication. Unlike stimulant medications, micronutrients were associated with improvements, rather than worsening, in mood and anxiety. This indicates that micronutrients can be a serious treatment option for those who choose not to take medications. Micronutrients may be especially helpful for children with ADHD who also have difficulties with mood or anxiety.

Other key findings from this research:

  • Those who continued to take micronutrients did not have any ongoing side effects.
  • Children who continued to take micronutrients and children who changed to medications (like methylphenidate/Ritalin/Concerta) either stayed well or continued to show improvement in ADHD symptoms at 12-month follow-up assessment, while those who stopped treatment altogether did not.
  • Children who switched from micronutrients to medications like methylphenidate/Ritalin were more likely to have problems with mood or anxiety at the 12-month follow-up assessment, which were worse than at the end of the micronutrient trial. After the end of the trial, mood and anxiety symptoms had generally continued to improve for the children who stayed on micronutrients, and mostly stayed the same for those who stopped treatment.
  • The most common reasons people stopped taking micronutrients were the cost and number of pills to swallow.
  • Based on dominant treatment, more of those who stayed on trial micronutrients (84%) were identified as “Much” or “Very Much” improved overall relative to baseline functioning, compared to 50% of those who switched to psychiatric medications and only 21% of those who discontinued treatment. Fifteen (79%) of those still taking micronutrients, 8 (42%) of those using medications, and 7 (23%) of those who discontinued treatment were considered in remission based on parent-reported ADHD. Those who stayed on micronutrients were more likely to have failed medication treatment in the past.

It is important to note that these findings are reporting on group averages, so the effect of micronutrients or other treatments for any specific child may have been different. People do respond differently to any form of treatment – perhaps they benefited across all areas of functioning or perhaps had no benefit at all.

This study is limited due to its naturalistic observational status but allows us to evaluate effectiveness in the real world. No funds were received from the manufacturer of the micronutrients.

If you want to know more about the micronutrients we studied, email mentalhealthnutrition@canterbury.ac.nz

 

Reference:

Darling, K. A., Eggleston, M. J., Retallick-Brown, H., & Rucklidge, J. J. (2019). Mineral-Vitamin Treatment Associated with Remission in Attention-Deficit/Hyperactivity Disorder Symptoms and Related Problems: 1-Year Naturalistic Outcomes of a 10-Week Randomized Placebo-Controlled Trial. Journal of child and adolescent psychopharmacology.

https://doi.org/10.1089/cap.2019.0036

 

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This week, my lab at the University of Canterbury published the first investigation1 into whether a mineral-vitamin supplement could change the bacteria in the microbiome of children with ADHD. Our preliminary data, based on our sample of 17 kids (half of whom were given micronutrients and half were given placebo for 10 weeks), hints at increased diversity and changes in the types of bacteria contained in the microbiome of the children exposed to the micronutrients. This type of study starts to moves us beyond the efforts to show that micronutrients benefit some people with psychiatric symptoms, and towards figuring out why they might exert their influence. So what does this mean?

First off, what is the microbiome?

The gut microbiome is defined as the trillions of microbes that inhabit the human digestive tract. In additional to playing a crucial role in digesting food, they also play pivotal roles in immune and metabolic functioning, gene expression, as well as playing a role in the expression of psychiatric symptoms through the gut-brain connection.2 We also know that they generate essential vitamins. When our microbiome gets into a state of dysbiosis (microbial imbalance), in addition to the physical symptoms like reflux, poor digestion, pain, constipation and/or diarrhoea, it is thought that dysbiosis can also lead to increased permeability of the gut wall, increased production of endotoxins, increased inflammation and decreased nutrient synthesis.

How do we learn about what bacteria are within and on us?

Research on the human microbiome has grown exponentially in the past decade. However, it was only recently that we could fairly cheaply quantify and describe the bugs contained within us. 16S rRNA sequencing (the technology we used) is a key methodology in identifying bacterial populations and allows scientists to easily and reliably characterize complex bacterial communities.3 This methodology is a simple and effective alternative to microbial culture, and provides detailed information about the various species of bacteria that are contained within our microbiome. The sequencing gives information on bacterial diversity, as well as details about the specific family (e.g., Bifidobacteriaceae), genus (e.g., Bifidobacterium), and species (e.g., Bifidobacterium Longom).

What about the microbiome of kids with ADHD?

What scientists are now wondering is whether people who suffer from specific psychiatric symptoms, like those associated with ADHD, have a different bacterial composition than those who don’t have these symptoms and whether these differences can help us understand the severity of the symptoms. In other words, is it possible that our bugs can make us impulsive? And if so, if we changed the bugs, can we become less impulsive?

There isn’t a huge literature exploring this topic in ADHD. Preliminary studies suggest that antibiotics in the first 6 months of life may increase risk of ADHD symptoms at 11 years of age,4 although this finding hasn’t been replicated.5 Another study found that the Phylum Actinobacteria is overrepresented in ADHD compared with controls.6 Other research suggests that reduced alpha diversity may exist in young patients with ADHD, specifically that boys with ADHD had more Bacteroidaceae relative to controls, with the species Neisseriaceae identified as a particularly promising ADHD-associated candidate.7 Although this finding of reduced alpha diversity was not observed in treatment-naïve children with ADHD, Jiang and colleagues noted that the more an individual had the species Faecalibacterium, the lower their ADHD severity.8

Overall, there are intriguing signals but the signals are not always replicating. Much more research with larger samples is needed to try to determine if there are reliable bacterial biomarkers. We also need to parse out the effect of diet, medications, age, ethnicity and gender on the results that have been reported. Further, we don’t know whether these differences are causal or a result of ADHD or completely irrelevant to the expression of the symptoms.

We still don’t know if changing the relative amount of a bacteria can change psychiatric symptoms. We know that diet manipulation can change levels of bacteria but whether those changes in bacteria are necessary for improvement in psychological states requires much more research.

So what did we find?

Looking at the microbiome over a short period of time with a small sample is challenging. There is such diversity in the bacteria within us and between us that it is a challenge to explore changes and also whether changes are meaningful. But we did observe some intriguing effects:

  1. The observed taxonomic units (OTU), a measure of community richness, significantly increased in treatment group but not in placebo group. We think this is a good thing.
  2. We observed significant greater decrease in abundance of genus Bifidobacterium from phylum Actinobacteria in active versus placebo and that the more it decreased, the more the ADHD symptom scores dropped. If Bifodobacterium is contributing to the symptoms of ADHD, this is a good thing.
  3. We also observed a significant positive correlation between Actinobacterium abundance and Clinician ADHD IV-RS rating scale before the intervention was introduced, which suggests that Actinobacterium may play a role in the expression of ADHD.

What does this mean?

The small sample makes it difficult to generalize from this study. However, these novel results provide a basis for future research on the biological connection between ADHD, diet and the microbiome. Previous research from our lab has shown that micronutrients do exert some positive effects on ADHD and associated symptoms.9 10 These findings suggest that micronutrient treatment may result in a more diverse microbiome which may in turn, have a positive effect on brain health.

What next?

The field of the microbiome is literally exploding with new studies out every day. The focus currently is trying to find ways to manipulate the microbiome for positive response. This has mainly been explored through either adding in bacteria (in the form of probiotics or psychobiotics if targeting psychological symptoms), diet manipulation, or more recently, fecal microbiota transplants. I do worry a bit that this search for the magic-bullet bacteria that causes distress may turn out to be as disappointing as the search was for candidate genes, but it is worth some effort to figure out if this is an important lead.

Eat2BeNice (New Brain Nutrition) plans to explore the role of the microbiome in multiple ways, including determining whether individuals with high impulsivity/compulsivity have a unique microbiome profile, whether targeted probiotics can improve impulsivity/compulsivity symptoms, and also whether improvement in impulsivity/compulsivity symptoms from diet manipulation and via the use of supplements can be explained via changes in the microbiome. Watch this space!

REFERENCES 

  1. Stevens AJ, Purcell RV, Darling KA, et al. Human gut microbiome changes during a 10 week Randomised Control Trial for micronutrient supplementation in children with attention deficit hyperactivity disorder. Sci Rep 2019;9(1):10128.
  2. Frye RE, Slattery J, MacFabe DF, et al. Approaches to studying and manipulating the enteric microbiome to improve autism symptoms. Microb Ecol Health Dis 2015;26:26878-78.
  3. Ames NJ, Ranucci A, Moriyama B, et al. The Human Microbiome and Understanding the 16S rRNA Gene in Translational Nursing Science. Nurs Res 2017;66(2):184-97.
  4. Slykerman RF, Coomarasamy C, Wickens K, et al. Exposure to antibiotics in the first 24 months of life and neurocognitive outcomes at 11 years of age. Psychopharmacology (Berl) 2019;236(5):1573-82.
  5. Axelsson PB, Clausen TD, Petersen AH, et al. Investigating the effects of cesarean delivery and antibiotic use in early childhood on risk of later attention deficit hyperactivity disorder. J Child Psychol Psychiatry 2019;60(2):151-59.
  6. Aarts E, Ederveen THA, Naaijen J, et al. Gut microbiome in ADHD and its relation to neural reward anticipation. PLoS One 2017;12(9):e0183509.
  7. Prehn-Kristensen A, Zimmermann A, Tittmann L, et al. Reduced microbiome alpha diversity in young patients with ADHD. PLoS One 2018;13(7):e0200728.
  8. Jiang HY, Zhou YY, Zhou GL, et al. Gut microbiota profiles in treatment-naive children with attention deficit hyperactivity disorder. Behav Brain Res 2018;347:408-13.
  9. Rucklidge JJ, Eggleston MJF, Johnstone JM, et al. Vitamin-mineral treatment improves aggression and emotional regulation in children with ADHD: a fully blinded, randomized, placebo-controlled trial. J Child Psychol Psychiatry 2018;59(3):232-46.
  10. Rucklidge JJ, Frampton CM, Gorman B, et al. Vitmain-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised palcebo-controlled trial. The British Journal of Psychiatry 2014;204:306-15.
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A team of Iranian researchers recently published a meta-analysis seeking to determine what, if any, association there may be between low Vitamin D levels and ADHD in children and adolescents.

Combining the results from thirteen studies with 10,334 participants, they found that youth with ADHD had “modest but significant” lower serum concentrations of 25-hydroxyvitamin D than normally developing children. The weighted mean difference was just under 7 nanograms per milliliter. The odds of obtaining such a result by chance would be less than one in a thousand (p < .001). There was little to no sign of publication bias. Between-study heterogeneity, however, was very high (I2 = 94).

Vitamin D and ADHDThese results suggest an association. But are low serum levels of Vitamin D a cause or effect of ADHD? Causation is vastly more difficult to establish than association. To begin to tease this out, the researchers identified four prospective studies that compared maternal Vitamin D levels with the subsequent development of ADHD symptoms in their children. Two of these used maternal serum levels, and two used umbilical cord serum levels. Together, these studies found that low maternal Vitamin D levels were associated with a 40% higher risk of ADHD in their children. Whether maternal serum or umbilical cord serum measurements were used had little or no effect on the outcome. Study heterogeneity was negligible. But the authors noted that this result “should be considered with caution” because it was heavily dependent on one of the prospective studies included in the analysis. All of which suggests a need for further prospective studies.

In the meantime, the authors suggest it would be prudent to increase sun exposure and Vitamin D supplementation given the prevalence of Vitamin D deficiency.

REFERENCES

Yadollah Khoshbakht, Reza Bidaki, and Amin Salehi-Abargouei, “Vitamin D Status and Attention Deficit Hyperactivity Disorder: A Systematic Review and Meta-Analysis of Observational Studies,” Advances in Nutrition, vol. 9, issue 1, p. 9-20 (2018).

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Mediterranean diet could prevent depression, new study finds” [CNN]; “Mediterranean diet ‘may help prevent depression‘” [BBC]. The publication of Lassale and her colleagues in the prestigious scientific journal Molecular Psychiatry on the association between Mediterranean Diet and depression, received a lot of attention in the media last week.

So, can diet really influence your mental health? The publication of Lassale shows that there are indications that what you eat is related to how you feel. But because this study is an observational study, we can’t conclude anything yet about causation. In other words, we don’t know yet whether eating healthy causes you to feel less depressed, or whether feeling depressed causes you to eat unhealthy.

Causal links between diet and mental health

Diet and mental healthThe researchers of the European consortium Eat2beNICE are investigating exactly this causal link. The way we do this is through clinical trials. In this way, we first let chance decide whether a person receives a particular diet or is part of the control group. Through this randomization we can be sure that the differences that we find between the two groups are really due to the dietary intervention that people received, because all other factors are the same between the two groups.

Specifically for the effects of the Mediterranean diet on behaviour, in the Eat2beNICE project we are using the information and measurements available from the PREDIMED-PLUS trial. In this study, we are looking specifically for the effect of a calorie-restricted Mediterranean diet, combined with physical activity, on several behavioral outcomes related with several psychiatric diseases of adults at high cardiovascular risk.

At the same time, we are conducting three other clinical trials:

  1. In Nijmegen (The Netherlands), we investigate the effects of a very strict, hypo-allergenic diet on behavioural problems in children with ADHD.
  2. We are investigating the effects of vitamin supplements in a clinical trial that will be conducted in Mannheim(Germany) and Groningen(The Netherlands).
  3. Researchers in Barcelona (Spain) and Frankfurt (Germany) are investigating the effects of probiotics (i.e. bacteria that are good for you) on mental health in adults that are highly impulsive and/or aggressive.

Through these studies we hope to be able to identify if these types of food improve mental health and in which circumstances. This can have big implications for psychiatry, where putting someone on a specific, personalised diet may be a way to improve treatment. Also, people who are at a risk for developing mental health problems may benefit from specific diets to reduce this risk. But before this can be put into action, we first need good scientific data on what really works.

How can food drive human behaviour?

A second aim of our large research consortium is to identify the mechanisms between nutrition and the way the brain works. We think that the bacteria that live in your gut play a large role in this, as they interact with other systems in your body, including your brain. So we are collecting poop samples of the people that are participating in our clinical trials to identify which bacteria are more or less common in our participants compared to the control population. We are also measuring our participants’ behaviour and we will scan their brains. We hope that this will help us understanding better why certain types of food can be beneficial for mental health, and why some others increase the risk for mental health problems. This too will help to elucidate, and understand, the causal links between food and behaviour.

In short, we are very thankful for the study of Lassale and her colleagues, for backing up the evidence that what you eat is related to how you feel and behave. Now there’s work for us to do to prove the causal and mechanistic links. We’ll keep you posted here!

 

Authors Jeanette Mostert and Alejandro Arias-Vasquez work at the department of Genetics at the Radboud University Medical Center in Nijmegen, The Netherlands. Alejandro Arias-Vasquez is the project coordinator of the Eat2beNICE project. Jeanette Mostert is the dissemination manager.

 

Further reading

Lassale C, Batty GD, Baghdadli A, Jacka F, Sánchez-Villegas A, Kivimäki M, Akbaraly T. Healthy dietary indices and risk of depressive outcomes: a systematic review and meta-analysis of observational studies. Mol Psychiatry. 2018 Sep 26. doi: 10.1038/s41380-018-0237-8.

 

Blog by Jordi Salas explaining the Lassale paper and the PREDIMED trial:
http://newbrainnutrition.com/category/nutrition/mediterranean-diet/

Blog by Jolanda van der Meer on hypo-allergenic diet (TRACE study): http://newbrainnutrition.com/adhd-and-food-elimination-diet/

Blog by Julia Rucklidge on trials with vitamin supplements: http://newbrainnutrition.com/micronutrients-and-mental-health/

Blog by Judit Cabana on the Gut-Brain axis: http://newbrainnutrition.com/the-gut-brain-axis-how-the-gut-relates-to-psychiatric-disorders/

 

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Vitamin B and ADHDThere is a well-documented relationship between dietary factors, health and human behavior. Severe malnutrition produces neurological and psychiatric symptoms. It is also assumed that dietary factors play a role in common mental disorders, such as ADHD, but this is less established and more difficult to investigate. A few studies have documented a beneficial effect of dietary interventions and vitamin supplements in ADHD in children and adults. To examine the nutritional status in ADHD, Landaas et al.(1) recently compared blood vitamin levels in 133 adult ADHD patients and 131 healthy controls. In the ADHD group there was a clear overrepresentation in the group with low levels of vitamins B2, B6 and B9.

It is yet unclear whether these vitamin levels are a) associated with ADHD symptoms, or b) whether they are the result of altered dietary intake, or c) metabolism in ADHD patients. However, it is possible that the differences reflect dietary habits that are different in a subgroup of ADHD patients and controls. Dietary habits are established early during life and may last into adulthood. It is possible that suboptimal dietary habits may precipitate, exacerbate or maintain symptoms of ADHD. More research in larger samples is obviously needed to clarify these issues. Over the next five years in our project, entitled “Effects of Nutrition and Lifestyle on Impulsive, Compulsive, and Externalizing behaviours,” we expect to gain much more insight into these connections.  We will share our findings with you.  Stay tuned!!

(1) BJPsych Open. 2016 Nov; 2(6): 377–384. Published online 2016 Dec 13. doi:  10.1192/bjpo.bp.116.003491
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5153567/ 

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