Mental Wellness Supplement Research

Earlier this month (Sept 10), I saw an interesting headline on one of my newsfeeds:

“The Science Is Mixed on Taking Supplements for Mental Health, Research Review Finds”

Having studied the effect of supplements on mental wellness for more than 20 years, you can imagine that my curiosity was peaked?!?!

My highlights of the article appear below and the full article in the online magazine Gizmodo is here = https://gizmodo.com/the-science-is-mixed-on-taking-supplements-for-mental-h-1838014070

A new large review of the scientific evidence suggests that most dietary supplements don’t do much to help people suffering from mental health disorders.

(NOTE – if you actually read the full study – which I highlight for you below – you’ll see that “most dietary supplements” refers most often to studies of single-nutrient vitamins like folate – which you might expect is unlikely to have much benefit on its own against major depression?)

Supplements are often touted as something like a shortcut to a healthy body and mind, though evidence for that rosy view is lacking. Researchers in Australia took a deep dive into the medical literature to see what they could find about supplements and mental health.

Their review, published in the journal World Psychiatry, is a meta-analysis of 33 other meta-analyses published since 2012, which looked at randomized, controlled clinical trials of people taking supplements to treat symptoms of depression and other mental illnesses. All told, the trials included more than 10,000 patients, who often took the supplements alongside standard treatments. These supplements included vitamin B9, otherwise known as folic acid, omega 3 fatty acids, minerals like zinc or magnesium, and amino acids like N‐acetylcysteine (NAC) and glycine.

They ultimately found that supplements were safe to take and not likely to interfere with existing psychiatric medications. But many of the interventions tested, such as taking magnesium for depression or folic acid for schizophrenia, didn’t have significant evidence for their benefits. In other cases, such as taking NAC for depression symptoms, the evidence was positive but based on very small trials.

That said, there were situations where the positive evidence was compelling and merited further study, the authors said.

This was most apparent with taking omega-3s to supplement treatment for major depression; they might also have a small effect on relieving symptoms of ADHD. Some decent evidence showed that NAC could boost the benefits of standard treatments for mood disorders and schizophrenia. And there was also evidence that taking methylfolate—the byproduct of folic acid that our bodies actually use—could be useful as an add-on treatment for schizophrenia and depression. Methylfolate is already offered as a prescription medical food for people with treatment-resistant depression who are deficient in it.

“Although the majority of nutritional supplements assessed did not significantly improve mental health outcomes beyond control conditions, some of them did provide efficacious adjunctive treatment for specific mental disorders under certain conditions,” the authors wrote.

The findings, mixed as they are, should be seen in a positive light, according to study author Joseph Firth, a senior research fellow at Western Sydney University’s National Institute of Complementary Medicine.

“While there has been a longstanding interest in the use of nutrient supplements in the treatment of mental illness, the topic is often quite polarizing, and surrounded by either over-hyped claims or undue cynicism,” Firth said in a statement released by the university. “This mass of data has allowed us to investigate the benefits and safety of various different nutrients for mental health conditions—on a larger scale than what has ever been possible before.”

In addition to quantifying how effective some supplements can be for certain groups, Firth and his team said, there needs to be work done on figuring out why exactly they’re helpful.

People who have major depression, for instance, are sometimes deficient in methylfolate—often due to a genetic mutation that makes it hard for them to convert folic acid to methylfolate. Without enough methylfolate, these people are then less able to produce serotonin and other neurotransmitters important for proper mental functioning. There might very well be similar explanations for why the lack of certain nutrients is crucial to the development of mental illness in some people.

These explanations could also involve the gut microbiome—the teeming microbial environment that lines our digestive system. The gut has garnered more and more attention for its role in our physical and mental health in recent years, since it “talks” regularly with our brain. And many researchers now believe that the microbiome needs to be balanced for this line of communication to be healthy. For the time being, the authors noted though, there’s less evidence looking into whether probiotics and prebiotics—supplements loaded with “good bacteria”—can effectively help people with mental illness.

It’s also important to caution that anyone taking supplements should ideally consult their doctor first, since some can interfere with certain medications or medical tests. Experts generally recommend that people stick to single-ingredient supplements (rather than multivitamins), since those are less likely to contain useless, undisclosed, or potentially dangerous ingredients.

My highlights are below from the full research study in the journal World Psychiatry on which this article is based = https://onlinelibrary.wiley.com/doi/full/10.1002/wps.20672

The efficacy and safety of nutrient supplements in the treatment of mental disorders: a meta‐review of meta‐analyses of randomized controlled trials

Joseph Firth  Scott B. Teasdale  Kelly Allott  Dan Siskind Wolfgang Marx  Jack Cotter  Nicola Veronese Felipe Schuch  Lee Smith Marco Solmi  André F. Carvalho  Davy Vancampfort  Michael Berk Brendon Stubbs  Jerome Sarris

First published: 09 September 2019 https://doi.org/10.1002/wps.20672

Abstract

The role of nutrition in mental health is becoming increasingly acknowledged. Along with dietary intake, nutrition can also be obtained from “nutrient supplements”, such as polyunsaturated fatty acids (PUFAs), vitamins, minerals, antioxidants, amino acids and pre/probiotic supplements. Recently, a large number of meta‐analyses have emerged examining nutrient supplements in the treatment of mental disorders. To produce a meta‐review of this top‐tier evidence, we identified, synthesized and appraised all meta‐analyses of randomized controlled trials (RCTs) reporting on the efficacy and safety of nutrient supplements in common and severe mental disorders. Our systematic search identified 33 meta‐analyses of placebo‐controlled RCTs, with primary analyses including outcome data from 10,951 individuals. The strongest evidence was found for PUFAs (particularly as eicosapentaenoic acid) as an adjunctive treatment for depression. More nascent evidence suggested that PUFAs may also be beneficial for attention‐deficit/hyperactivity disorder, whereas there was no evidence for schizophrenia. Folate‐based supplements were widely researched as adjunctive treatments for depression and schizophrenia, with positive effects from RCTs of high‐dose methylfolate in major depressive disorder. There was emergent evidence for N‐acetylcysteine as a useful adjunctive treatment in mood disorders and schizophrenia. All nutrient supplements had good safety profiles, with no evidence of serious adverse effects or contraindications with psychiatric medications. In conclusion, clinicians should be informed of the nutrient supplements with established efficacy for certain conditions (such as eicosapentaenoic acid in depression), but also made aware of those currently lacking evidentiary support. Future research should aim to determine which individuals may benefit most from evidence‐based supplements, to further elucidate the underlying mechanisms.

Abundant evidence now suggests that people with mental disorders typically have an excess consumption of high‐fat and high‐sugar foods, alongside inadequate intake of nutrient‐dense foods, compared to the general population1-5. The relationship between poor diet and mental illness appears to persist even when controlling for other factors which could explain the association, such as social deprivation or obesity, and is not explained by reverse causation1, 6.

Furthermore, although the metabolic and hormonal side effects of psychotropic medications can affect food intake7, 8, inadequate nutrition appears to be present even prior to psychiatric diagnoses. For instance, in depression, it seems that poor diet precedes and acts as a risk factor for illness onset6, 9, 10. Similarly, in psychotic disorders, various nutritional deficits are evident even prior to antipsychotic treatment11.

The importance of diet for maintaining physical health is widely accepted, due to the clear impact of dietary risk factors on cardiometabolic diseases, cancer and premature mortality12, 13. In parallel, the potential impact of diet on mental disorders is increasingly acknowledged14, 15. However, along with regular food intake, nutrients can also be consumed in supplement form16. Supplements are typically used in attempts to: a) complement an inadequate diet (or low measured plasma levels of a nutrient) to achieve recommended nutrient intakes/levels; b) administer specific nutrients at greater doses than those found in a typical diet, for putative physiological benefits; c) provide nutrients in more bioavailable forms for individuals with genetic differences, or relevant health issues, which may result in poor nutrient absorption. Supplements can be synthetically manufactured or directly food‐derived, typically including substances such as vitamins (e.g., folic acid, vitamin D), dietary minerals (e.g., zinc, magnesium), pre/probiotics (from specific strains of gut bacteria), polyunsaturated fatty acids, PUFAs (typically as omega‐3 fish oils), or amino acids (e.g., N‐acetylcysteine, glycine).

Currently, there is an increased academic and clinical interest in the role of nutrient supplements for the treatment of various mental disorders14-16. This growth of research is partly attributable to our evolving understanding of the neurobiological underpinnings of mental illness, which implicates certain nutrients as a potential adjunctive treatment for a variety of reasons25.

First, recent clinical research has found that many mental disorders are associated with heightened levels of central and peripheral markers of oxidative stress and inflammation26-29, and an association has been reported between the efficacy of both pharmacological and lifestyle interventions for mental illness and changes in these biomarkers30, 31. Thus, the antioxidant and anti‐inflammatory properties of certain nutrient supplements (such as N‐acetylcysteine32 and omega‐3 fish oils33) indicates that these could be beneficial in the treatment of psychiatric conditions caused or exacerbated by heightened inflammation and oxidative stress.

Second, there are now extensive data from large‐scale studies showing that psychotic and mood disorders are associated with significantly reduced serum levels of essential nutrients, including zinc34, 35, folate36, 37 and vitamin D38, 39. Since these deficits appear to be related to treatment response and clinical outcomes in these populations11, 34, 40, there is a possibility that nutrient supplementation could improve outcomes.

Third, there is nascent (but growing) evidence that mental disorders may be linked to dysfunction of the gut microbiome41, 42. As gut bacteria can be modified through micronutrients and pre/probiotics43, 44, this suggests that some pre/probiotic supplements may serve as potentially useful novel therapeutic optionsworthy of further investigation45, 46.

DISCUSSION

The nutritional intervention with the strongest evidentiary support is omega‐3, in particular EPA. Multiple meta‐analyses have demonstrated that it has significant effects in people with depression, including high‐quality meta‐analyses with good confidence in findings as determined by AMSTAR‐264. Meta‐analytic data have shown that omega‐3 is effective when given adjunctively to antidepressants51, 64. As a monotherapy intervention, the data are less compelling for omega‐3, while DHA or DHA‐predominant formulas do not appear to show any obvious benefit in MDD51, 64.

Omega‐3 supplementation appears to be of greatest benefit when administered as high‐EPA formulas, as significant relationships between EPA dosage and effect sizes are also observed in high‐quality meta‐analyses of RCTs59, 64. Emergent data from RCTs further indicate that omega‐3 may be most beneficial for patients presenting with raised inflammatory markers83. The available meta‐analyses suggest that omega‐3 supplementation is not effective in patients with depression as a comorbidity to chronic physical conditions65, including cardiometabolic diseases, a finding which has been replicated in subsequent trials84. In light of current adverse event data, omega‐3 seems to represent a safe adjunctive treatment.

More research is needed concerning the efficacy of omega‐3 supplements in other mental health conditions. For instance, omega‐3 was indicated as potentially beneficial for children with ADHD, again with high EPA formulas conferring largest effects79. However, the negligible effect sizes after controlling for publication bias, along with the low review quality identified by AMSTAR‐2, reduces confidence in findings. Additionally, whereas the existing meta‐analytic data have found a lack of significant benefits in people with schizophrenia55, 59, subsequent trials in young people with first‐episode psychosis have reported more positive, though mixed, results85, 86, putatively ascribed to neuroprotective effects87, 88.

Adjunctive treatment with folate‐based supplements was found to significantly reduce symptoms of MDD and negative symptoms in schizophrenia54, 67. However, in both cases, AMSTAR‐2 ratings indicated low confidence in review findings, and positive overall effects in these meta‐analyses were driven largely by RCTs of high‐dose (15 mg/day) methylfolate. Methylfolate is readily absorbed, overcoming any genetic predispositions towards folic acid malabsorption, and successfully crossing the blood‐brain barrier89, 90. Indeed, a placebo‐controlled trial of methylfolate in schizophrenia reported significant increases in white matter within just 12 weeks, co‐occurring with a reduction in negative symptoms91.

Regarding other vitamins (such as vitamin E, C or D), minerals (zinc and magnesium) or inositol, there is currently a lack of compelling evidence supporting their efficacy for any mental disorder, although the emerging evidence concerning positive effects for vitamin D supplementation in major depression has to be mentioned.

N‐acetylcysteine may assist in treatment of schizophrenia, bipolar disorder and depression through decreasing oxidative stress and reducing glutamatergic dysfunction96, but has wider preclinical effects on mitochondria, apoptosis, neurogenesis and telomere lengthening of uncertain clinical significance.

The role of the gut microbiome in mental health is also a rapidly emerging field of research99. Gut microbiota differs significantly between people with mental disorders and healthy controls, and recent faecal transplant studies using germ‐free mice indicate that these differences could play a causal role in symptoms of mental illness41, 100, 101. Intervention trials that aim to investigate the effect of probiotic formulations on clinical outcomes in mental disorders are now beginning to emerge71. We included one recent meta‐analysis that evaluated the pooled effect of probiotic interventions on depressive symptoms: while the primary analysis reported no significant effect, the moderately large effect in the three included studies suggests that probiotics may be beneficial for those with a clinical diagnosis of depression rather than subclinical symptoms71. However, additional trials are required to replicate these results, to evaluate the long‐term safety of probiotic interventions, and to elucidate the optimal dosing regimen and the most effective prebiotic and probiotic strains102.

While improving dietary intake appears to have a clear role in increasing life expectancy and preventing chronic disease, there is currently a lack of studies evaluating this in people with mental disorders. Additionally, although recent meta‐analyses of RCTs have demonstrated that dietary improvement reduces symptoms of depression in the general population106, more well‐designed studies are needed to confirm the mental health benefits of dietary interventions for people with diagnosed psychiatric conditions25.

It is recognized that people with mental disorders commonly take nutritional supplements in combinations. In some instances, research has supported this approach, most commonly in the form of multivitamin/mineral combinations107. However, recent research in the area of depression has revealed that “more is not necessarily better” when it comes to complex formulations108. Of note, recent large mood disorder clinical trials have revealed that nutrient combinations may not have a more potent effect, and in some cases placebo has been more effective47, 108, 109.

In conclusion, there is now a vast body of research examining the efficacy of nutrient supplementation in people with mental disorders, with some nutrients now having demonstrated efficacy under specific conditions, and others with increasingly indicated potential. There is a great need to determine the mechanisms involved, along with examining the effects in specific populations such as young people and those in early stages of illness. A targeted approach is clearly warranted, which may manifest as biomarker‐guided treatment, based on key nutrient levels, inflammatory markers, and pharmacogenomics 83, 91, 110.

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