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Fish Oil for Health and Happiness?

The Trifecta of Mental Health Supplements: Vitamin D, Probiotics & Fish Oil

This post is the last in a series of three in which we thoroughly explore the darlings of supplementation for mental health: vitamin D, probiotics and fish oil.  Read on to learn it all – the good, the bad and the ugly.

What’s all the fuss about fish?

I can’t argue that you are made up of fish the same way I could argue that you are made up of bacteria. But fish does contain special fatty acids that your brain needs to function at its best and it contains them in a form that you can’t get from just any fish oil supplement. It’s time to get snobby about what you feed your brain…and this article will tell you why! Your brain is made up of fatty acids in the forms of docosahexaenoic acid (DHA) and arachidonic acid (AA). Eicosapentaenoic acid (EPA) is another fatty acid that exists in the brain but is not present in large amounts [1]. Food sources of the omega-3 fatty acids DHA and EPA include fatty cold-water fish like salmon and tuna. Sources of arachidonic acid include eggs, beef and chicken. Food or supplements containing preformed fatty acids are important because your own ability to synthesize some of these is not that efficient [2].

Unfortunately, modern diets provide an unbalanced ratio of omega-6 (more pro-inflammatory or immune stimulatory) to omega-3 (more anti-inflammatory) fatty acids of over 10:1, whereas the optimal ratio has been suggested to be as low as 2:1 or 1:1 [3]. The high omega-6 content comes from a combination of factors, including the popularity of corn, sunflower, soybean, safflower, and cottonseed oils and the consumption of beef from cows fed corn [2,3]. While we do need some omega-6 fatty acids, balance is key. DHA, an omega-3 fatty acid, sticks around in our brain for about two and a half years [1]. Due to its role in neuronal membranes in the brain, it has been suggested that changes in dietary DHA could affect the structure of new neurons as they are being formed [1]. In addition, omega-3 fatty acids like DHA and EPA act on dopamine and serotonin systems, as well as regulating pathways of inflammation [4]. Conventional thought is that increasing the amount of omega-3 fatty acids in membranes affects AA-dependent signalling [4]. This is relevant because some drugs that activate dopamine receptors, for example, trigger AA-dependent signalling [4]. It is thought that SSRIs (a type of antidepressant drug) may use AA and its metabolites to effect their actions in the brain as well [4]. One lab-based study actually demonstrated that long-term EPA (but not DHA) supplementation increased the release of AA from membranes, possibly by preventing re-uptake of AA into the membrane [4]. This suggests an inhibitory activity of EPA on enzymes such as lysophospholipid acyltransferase (LPAT) or fatty acid CoA ligase (FACL) which would allow for that re-uptake [4]. Less AA in the membranes means more AA is available for the signalling reactions including those affecting dopamine and serotonin systems [4]. There is also a newer set of compounds that can be made from EPA and DHA and these are called resolvins. We don’t know a lot about the E- and D-series resolvins yet, but we do know that they are involved in decreasing inflammation in the brain [4]. This may be another mechanism by which EPA and DHA supplementation could exert an effect on mental health.

Seafood Consumption

Countries with higher rates of fish or seafood consumption have lower rates of major depressive disorders, postpartum depression, and bipolar disorders in addition to better outcomes for patients with schizophrenia [2]. This idea does not go undisputed, as other researchers suggest it is the amount of sugar we eat that is at fault, and that fish consumption has no significant effect on the mental health disorders [5]. Truly both are important. You can’t feed yourself an epic fish dinner, polish it off with a bag full of leftover Hallowe’en candy and expect them to somehow balance out to a neutral effect.

Fatty Acid Status Screening

It seems most likely that fatty acid status does have something to do with mental health. Interestingly, suicidal ideation is correlated with low fatty acid intake and fatty acid status can provide an indicator for future suicidal attempts in patients with depression [2]. A study performed at a psychiatric inpatient facility in Cincinnati actually screened patients on admission to determine their fatty acid status. Most of these patients (75% of them!) had a whole blood fatty acid composition of less than or equal to 4% EPA and DHA [2]. For the sake of comparison, only 25% of a healthy population would have levels of EPA and DHA that low [2]. While the study shows rates of deficiencies, it is not clear if supplementation was helpful in this population or not. In all the case vignettes provided, changes were made to the patient’s medications aside from fish oil supplementation, and so the patient’s improvements cannot be attributed solely to the fish oil. You may be familiar with a link between medications that lower cholesterol and risk for suicide. What else does this affect? Lowering cholesterol levels also affects concentrations of polyunsaturated fatty acids. When studied, blood levels of polyunsaturated fatty acid levels are the strongest predictors of 5-HIIA levels in the cerebrospinal fluid (CSF) [6]. 5-HIIA is a metabolite of serotonin and low CSF levels are associated with both suicide and violence [6].

Seasonal Variation in Omega-3 Fatty Acids

Did you know that there is seasonal variation in omega-3 fatty acid levels in your blood? Part of this could be from seasonal variation in diet. EPA, DHA and AA all vary with the seasons, being significantly lower in the winter (December to March) [7]. When extrapolating this data to previous data on suicide rates, it was discovered that there was no significant correlation between EPA, DHA or AA and violent or nonviolent suicide [7]. However, there was a significant correlation between a change in these parameters, especially the change in EPA, and violent suicide [7]. In simpler terms, as EPA levels drop the suicide risk increases. It is the drop itself, rather than the actual level that was correlated with suicide risk. This is an important point to consider because studies looking at a static point in time with regards to omega-3 fatty acids levels (as most do) may miss this correlation with suicide risk. Indeed, a review of the literature reveals conflicting results on the association between levels of various omega-3 fatty acids and suicide risk [8].

Considerations in Research on Omega-3 Supplementation

When examining this research, there are several other important factors to consider along with the studies’ results:

Which fatty acids and fatty acid ratios were studied? Some studies use just EPA, others use just DHA, some use different ratios of EPA and DHA, while yet others combine these with some of the key omega-6 fatty acids as well. This makes studies difficult to compare.

What type of omega-3 fatty acid supplement (fish oil, cod liver oil, krill oil and salmon oil, etc) was used?

Fish oil supplement or actual fish intake? Fish oil supplements contain DHA in free form, whereas actual fish contains DHA in a phospholipid form which may be more beneficial for people whose ability to uptake the free DHA into the brain is impaired.9

Do patients included in the studies actually have a clinical diagnosis of the studied condition, and how severe are their symptoms?

Are omega-3 deficiencies found in these populations because of the disease process, or because of behavioural changes that result from the disease process?

Do omega-3 fatty acid deficiencies create problems during development that cannot be corrected with supplementation later on in life, even if that supplementation corrected the fatty acid status [2]?

How long was the study? Based on animal studies of omega-3 deficiency, at least 8 weeks are needed to change brain composition [10]. It is expected that omega-3 supplementation in human clinical trials would also take several weeks or months to see an effect [10]. In the meantime, the slow onset of effect could cause participants to believe they are in a placebo group, and these beliefs may trigger thoughts and behaviours that affect outcomes [10].

How do you disguise fish oil? Last but not least, it is challenging to create a placebo for fish oil, because fish oil can be pretty gross and smelly [10]

Despite these drawbacks, omega-3 intake in the form of fish oil supplementation or fish in the diet has been a huge topic in the mental health research and is commonly used clinically. The following discussion will cover the efficacy of fish oil in:

Traumatic brain injuries and chronic neurodegenerative diseases

Memory and cognition

PTSD

Depression

Postpartum Depression

Manic-Depressive Disorder

Attention Deficit Hyperactivity Disorder

Autism

Anxiety

Schizophrenia

Feel free to skip to the sections that most interest you!

Traumatic Brain Injuries and Chronic Neurodegenerative Diseases

In the right form, dose and duration, a little bit of stress like exercise can be beneficial. This is a concept known as “hormesis”, or in this case “neurohormesis”. It is how some dietary phytochemicals acting as pro-oxidants actually have a neuroprotective effect by stimulating an antioxidant response in the brain [11]. But in chronic neurodegenerative diseases oxidative stress gets out of control and we end up with excess oxidative stress and programmed cell death [11]. Lipid metabolism is important in traumatic brain injuries, Alzheimer’s disease, Parkinson’s disease, stroke and many other brain disorders. Our brains are pretty delicate when it comes to oxidative stress. Our neuron membranes and our neurotransmitters are easily oxidized and the incredible output of mitochondria in our brain means lots of reactive waste products [11]. Now what protects the fatty acids in fish oil from being oxidized? These are delicate structures just like our neurons’ membranes. One form of omega-3 supplementation being studied in more detail is krill oil. Krill oil is special because it contains the antioxidant astaxanthin within it and this can protect those fatty acids. The first time I heard about astaxanthin was in an undergraduate biology class. It was intriguing to think that this was what was responsible for the pink colouring of flamingos, salmon and lobster. It would be curious if our hair or skin also turned pink if we ate a lot of salmon!

The therapeutic components of krill oil have good bioavailability because the fatty acids are part of phospholipids and can cross the blood-brain barrier [11]. Animal studies demonstrate that salmon oil and krill oil supplementation result in higher brain DHA than fish oil supplementation [11]. DHA in phospholipid form (such as acquired when you eat and metabolize actual fish) might be particularly helpful for those with Alzheimer’s disease because it can get into the brain through different mechanisms than free DHA [9]. The way free DHA accesses the brain is impaired in people with the APOE4 gene that is linked to Alzheimer’s disease [9]. Getting that DHA into the brain helps prevent the tau tangles and amyloid-beta plaque characteristic of the disease [9]. This sounds pretty good in theory. But where are the clinical trials for effectiveness of omega 3 supplementation in traumatic brain injury or neurodegenerative disease? Definitely scarce in the last few years. There has been one clinical trial of omega-3 (from flaxseed oil, which is not quite the same as fish oil in omega-3 content) combined with vitamin E supplementation in Parkinson’s disease. This trial saw a decrease in disease rating over 12 weeks along with improvements in insulin sensitivity and inflammation [12]. The lack of studies is frustrating because despite theoretical benefits, quite promising animal studies and potential effects based on research in other disease states we just don’t have human clinical trials to support this approach. There are two case studies on this topic. One provides a word of caution on fish oil supplementation and the other provides a glimmer of hope. First, the word of caution. Fish oil can dramatically increase the INR in people taking anticoagulant medications like warfarin. INR is a measure that is used to determine correct dosing of warfarin and if it gets too high you’ll have an increased bleeding risk. Why mention this as part of the trauma and neurodegenerative disease section? Because elderly populations are going to have a greater likelihood both of experiencing those conditions and of being on an anticoagulant.

The published case was an 83-year old male who was admitted to the ER with head trauma as the result of a motor vehicle accident [13]. He was on several medications, including warfarin. He was also taking fish oil supplements, possibly because he also had a diagnosis of dementia. The initial CT scan showed a left-sided subdural hematoma (brain bleed) and the patient was given therapies to reduce the effects of warfarin and help stop the bleeding [13]. Despite this, the INR kept creeping up [13]. The brain bleed got bigger and bigger and the patient ended up passing away later that day [13]. This patient was in an accident but given the age you might also consider the risk of traumatic brain injury from falls, especially in the elderly. If a patient is at risk for falling and hitting his head, should we supplement with fish oil? This is where each individual case needs to be considered in terms of dosing and risks and benefits. The other case is much more optimistic. This was the case of a teenager involved in a motor vehicle accident who had such a severe TBI that it was supposed to be lethal [14]. Omega-3 fatty acids were added to his enteral feedings on day 3 [14]. On day ten, the patient started receiving 15 ml twice per day of Nordic Naturals Ultimate Omega consisting of over 9g EPA and over 6g DHA per day [14]. The patient went from being in what the physicians thought would be a permanent vegetative state to a specialized rehabilitation institute on day 24 [14]. Four months after the injury he was able to go home [14]. Two years later he has difficulties with speech, balance and use of the left side of his body but is otherwise doing well [14]. That’s an incredible improvement. This highlights the importance of timing and dosage as well as the potential of omega-3 supplementation as a therapy.

Memory and Cognition

What about memory and cognition? We have some observational data demonstrating a correlation between fish oil supplementation and maintaining good cognitive function with age [15]. However, there are a lot of drawbacks to this type of study. The people who took fish oil supplements also took other supplements and quite likely put more effort into health promoting behaviours in other areas of their life. Taking a fish oil supplement cannot be isolated as the cause of their good cognitive function.

Clinical trials on supplementation with omega-3 fatty acids seems to help some people with dementia but not others [1]. This may be related to the type of dementia experienced or it may be the result of the doses or form used [1,16]. Those with intracellular A-beta oligomer-associated AD responded better to DHA supplementation and Rhonda Patrick suggests a phospholipid form specifically (krill oil or actual fish consumption) will have superior benefits for those with the APOE4 gene [1,9]. Overall, a Cochrane review found that there isn’t currently enough evidence to support the effectiveness of omega-3 supplements in mild to moderate Alzheimer’s disease [17]. What about supplementation earlier in life? There is one study that was completed last year on the effects of krill oil supplementation in adolescents on learning and cognition [18]. The results haven’t been published yet, but it will be interesting to see if it makes a difference. It’s important to remember that no matter how well you supplement, diet still matters. A particularly relevant point in the context of omega-3 supplementation is that omega-3 intake in the presence of dietary fructose appears to have a negative effect on learning and memory [19]. You can’t expect your supplements to do all the work in keeping you healthy!

PTSD

For Post-Traumatic Stress Disorder (PTSD), there is a focus in the research on how to prevent fear memories from forming related to whatever event triggered the onset of PTSD. It takes a period of time before our fleeting thoughts and experiences become more long-term memories and it is during this time that we want to intervene. Theoretically, during a traumatic event, a large amount of stress hormones are released which causes fear memories to be remembered more than they should [20].

The areas of the brain involved processing these fear memories include the hippocampus, amygdala and medial prefrontal cortex [20]. We can potentially get fear memories to move out of the hippocampus if we stimulate hippocampal neurogenesis early after the traumatic event has occurred [20]. Increasing hippocampal neurogenesis can be useful aside from PTSD, in that it is also linked to improvements in cognition and mood [20]. How do we increase hippocampal neurogenesis? It has been proposed that omega-3 supplementation could be beneficial for those with newly acquired PTSD by upregulating brain-derived neurotrophic factor (BDNF) and stimulating new neurons to grow in the hippocampus, an area of the brain involved in fear responses and fear memory [1,20]. Indeed, in one small pilot trial, patients given omega-3 supplementation in the form of 1470 mg DHA and 147 mg EPA every day for two weeks had a much lower Clinician-Administered PTSD Scale score [20]. Of the patients given the omega-3 supplementation, only one went on to develop PTSD. In the responders there was an increase in serum BDNF, which was not seen in the one patient who did not respond [20]. Follow-up studies with larger groups of participants did not find a difference in Clinician-Administered PTSD Scale scores compared to placebo [21,22]. However one study did find that the omega-3 supplementation group experienced decreased heart rates [21]. The authors suggested this might be a result of increased activity of the vagus nerve [21].

You may be familiar with the effects of exercise on neurogenesis and cognition in general. Combining both exercise and DHA supplementation seems to have greater effects on the brain than exercise alone [20]. Therapies combining supplementation with lifestyle interventions are harder to study but might be more clinically useful in the real-world.

Depression

As with many diseases that have increased in prevalence and incidence in modern society, changes in diet quality also impact depression. Resulting imbalances in omega-6 to omega-3 content in the foods we eat have led to the investigation of omega-3 supplementation as a therapeutic strategy for mood disorders [4]. 
 Of earlier studies, lower doses (1 gram per day) of EPA resulted in better improvement of depressive symptoms than higher doses (such as 2 grams or 4 grams per day) [4]. This effect was seen as early as four weeks [4]. Although significant compared to the placebo, the results were not dramatic [4]. Other studies have found beneficial effects from supplementing with 2 grams of EPA per day [4]. The recommended dosage is typically 1–2 g of an EPA/DHA combination, preferably at a ratio of 3:2 or higher [23]. A high EPA content appears more helpful than a high DHA content for depressive symptoms and this is suspected to be due to EPA working better as an anti-inflammatory [1,4]. However, the authors of one review paper suggest caution in discounting DHA altogether, because trials comparing DHA and EPA are lacking and EPA alone is not effective as a single therapy [4].

A randomized, double-blind, placebo-controlled trial of omega-3 supplementation in an elderly population specifically found no effect on mental well-being at 26 weeks for high (1800 mg) or low (400 mg) dose supplementation [24]. Although, 1800 mg might still be considered a low dose by some physicians, this study is valuable because of its design. The follow-up at 26 weeks should be long enough to take into account long-term changes in, for example, membrane structure. The randomized, double-blind, placebo-controlled aspect of it helps us to determine that whatever effects were present were not due to patient expectations upon receiving a supplement.

A thorough review of studies up to 2015 also comes to the conclusion that supplementation with omega-3 fatty acids has a small effect at best on depressive symptoms, and that based on the evidence so far this effect is not clinically significant compared to placebo [25].

In a newer study on treatment-resistant depression, omega-3 supplementation was quite helpful after four weeks but the number of patients in the study was small, so the finding needs repeating [23]. Clearly, there is a lot of discrepancy over the effectiveness of omega-3 supplementation. So why are we so drawn to using it still? These negative studies could indicate that it really isn’t effective, but they could also indicate that we aren’t studying the right things. For example, severity of depression or different underlying causes for depression.

One group of researchers decided to address this. Considering the multiple pathophysiological processes behind depressive symptoms, they not only studied a group of participants who met criteria for depression, they also obtained information on inflammation markers in these participants. They found no significant difference between the treatment group and the placebo group overall [26]. However, something very interesting emerged when looking at those markers of inflammation. In participants with at least one marker for high inflammation, there was a significant difference for EPA-rich supplementation (about 1 g EPA per day) over both placebo or DHA-rich supplementation [26]. After eight weeks, these participants had improved by eleven points on the HAM-D-17, a scale commonly used to assess depressive symptoms [26]. The total number you can score on this scale is 52 (9 items scored from 0-4 and 8 items scored from 0-2). A drop by eleven points is a considerable improvement. Participants without high markers for inflammation had a better response to placebo or to the DHA-rich supplementation than to the EPA-rich supplementation [26]. Remission rates in this study looked like the following: [26]

The researchers also found that looking at a combination of inflammatory markers was more helpful than looking at any single marker [26]. The markers they used included plasma hs-CRP, IL-1ra, IL-6, adiponectin (low levels indicating inflammation), and leptin. Obese participants, especially obese women, were the most likely to have high levels of inflammation in this group [26]. This study gives us a new perspective on omega-3 fatty acid supplementation in patients with depression. We can look at inflammatory markers in patients to help us assess whether or not they might be a good candidate for omega-3 supplementation.

There are several reasons that individualizing treatment like this is important. The one that comes to mind most readily is simply that quality (and trust me, quality is very important!) omega-3 supplements can get expensive, so you want to make sure that it is actually giving you benefit. Information like this helps identify which patients will benefit most from omega-3 supplementation. You might speculate from this that using lifestyle interventions to reduce inflammation might remove the need for supplementation down the road.

On the flip side, it also helps identify which patients are not likely to benefit from supplementation. Importantly, if you take a closer look at the numbers above or the paper itself, you will see that patients with low levels of inflammation actually got worse on EPA-rich supplementation than they did on placebo [26]. Not only was the supplementation not helpful, it appeared to be harmful! In addition, without looking closer at the causes behind an individual’s depressive symptoms we could miss other important contributing factors whether that’s inflammation, infection, anemia, social factors, etc. It would be great to see a replication of this study, or to see more studies that seek to examine underlying mechanisms for the depressive symptoms in relation to the experimental supplementation. Can we disregard DHA in the context of depression completely? Likely not, although most studies suggest effects with EPA-rich supplementation. White matter in the brain has been seen to change with 6 weeks of omega-3 supplementation in association with increasing percent DHA levels [27]. This was only seen in those with a diagnosis of major depressive disorder (compared to healthy controls) and only in those that improved with the supplementation [27]. How do we make sense of this information if we just went through a study that suggested EPA-rich supplementation was the way to go? Well the authors of the white matter changes study suggest that EPA helps DHA to get into the brain more easily which would explain why EPA-rich supplementation is more helpful than DHA-rich supplementation but white matter changes in the brain correlate with increases in DHA levels [27]. Now say you have a patient with depression who has elevated markers of inflammation and you want to try omega-3 supplementation with a high EPA to DHA ratio. How much supplementation is needed? While most studies use 1-2 g EPA per day, a fairly recent study in children suggests bodyweight makes a considerable difference in how supplementation affects blood levels of these fatty acids [28]. Not only that, but heavier children/adolescents in which levels increased to a smaller degree saw better improvement in mood [28]. The authors propose more research on dosing and metabolism should be conducted, and the possibility of a U-shaped curve explored [28]. A U-shaped curve is like what we’ve seen for vitamin D supplementation where too little is associated with poor health outcomes but too much is also associated with poor health outcomes. More studies need to be done to elucidate the “Goldilocks” range for omega-3 fatty acids. However, what is another possible reason the overweight group saw greater improvements? Inflammation. As the other study we discussed found out, there was greater inflammation in obese participants and participants with inflammation were the ones who benefited most from omega-3 supplementation. Clearly, there are still many questions to answer in this area but this is exciting progress.

Postpartum Depression

Postpartum depression is another area for which omega-3 supplementation is attractive. Supplementing with fish oil during and after pregnancy may be a safer option than some of the pharmaceuticals that could be used for depression [4]. Unfortunately, studies in this area either have not been promising and/or are very small [4,29–31]. For example, a study in 2013 randomly assigned 118 women (determined to be at risk for depression) in early pregnancy to receive either a EPA dominant fish oil, a DHA dominant fish oil or a soy oil placebo [29]. A depression inventory was taken at enrollment, 26-28 weeks, 34-36 weeks and then 6-8 weeks postpartum. Serum (blood) levels of EPA or DHA increased with supplementation [29]. However, neither EPA nor DHA supplementation prevented depressive symptoms [29]. In 2014, a slightly smaller study of 80 pregnant (over 20 weeks) women with mild depression found supplementation with 1 gram of omega-3 fatty acids (composition unspecified) for 6 weeks to be significantly more effective than placebo in reducing scores on a Beck Depression Inventory [32]. It’s hard to reconcile these conflicting results without knowing more about the makeup of the supplementation used. Another study taking into account long-term effects of diet on pregnancy and child development found that women who consumed no fish during pregnancy were more likely to have depressive and anxiety symptoms [33]. It’s possible that actual fish consumption has benefits over fish oil supplementation for this purpose.

Interestingly, DHA-rich fish oil supplementation has been seen to result in longer gestation lengths, significantly higher birthweight, and significantly higher Apgar scores [29]. In contrast, in another study the association between actual fish consumption and gestation and birth weight disappear when adjusting for factors like child’s sex, maternal smoking, maternal age, maternal education and number of other children [33]. This doesn’t mean supplementation or actual fish consumption is useless in this population, but we are lacking information on subgroups of the population which might benefit. For example, markers of inflammation or other mechanisms behind the depressive symptoms which could indicate the use of omega-3 supplementation as helpful. There are too many causes behind depressive symptoms to expect one supplement to provide a cure-all.

Aside from maternal depression, there may be other reasons for supplementing during pregnancy. One example would be the apparent effect of fish consumption or fish oil during pregnancy and breastfeeding on the child’s visual development [33]. It also appears to have an association with the child’s prosocial behaviour and fine motor skills development [33].

Manic-Depressive Disorder

While omega-3 supplementation does not seem to affect manic symptoms, research suggests there may be some benefit for the depressive symptoms in manic-depressive disorder [4]. One randomized controlled trial in particular found a positive effect for omega-3 supplementation in bipolar I disorder [34]. This is an important finding because treating depressive symptoms without triggering manic episodes can be a tricky balancing act [4].

However, considering these studies overall, the effect on depressive symptoms was quite small and omega-3 supplementation may not be the most useful intervention. A meta-analysis of randomized controlled studies published prior to May 2015 found five studies on omega-3 supplementation in manic-depressive disorder with only two reporting a significant positive result over placebo [35]. This review suggested that although omega-3 supplementation didn’t have a significant effect, anti-inflammatories in general might be helpful in depressive symptoms of manic-depressive disorder, with promise specifically for N-acetylcysteine [35]. When we see a link between omega-3/omega-6 status in a particular patient population but they don’t seem to improve with diet change or supplementation we can also investigate whether there is an actual physiological issue in how that nutrient is absorbed or used. One fatty acid breakdown product is known to be lower in patients with manic-depressive disorder [36]. This product normally stops the production of hydrogen peroxide in thyroid cells. However, the implications or relevance of this finding is unknown [36].

Attention Deficit Hyperactivity Disorder

It is thought that ADHD may partly arise from a diet that isn’t balanced in the types of fatty acids that we need, and elevated omega-6 to omega-3 ratios have been found in this population [4,37]. However, in earlier reviews covering research on essential fatty acid supplementation for ADHD, no trials demonstrated any impressive effect [4,23,38]. These studies used DHA, DHA/EPA mixtures or mixtures of both essential omega-3 and omega-6 fatty acids [4]. More recently, there have been two randomized, controlled trials with positive effect. One compared Ritalin, omega-3 supplementation and placebo in a double-blind trial in children (average age of 8 years old) [39]. The researchers found that omega-3 and Ritalin were both effective in reducing symptom scores in children with hyperactivity-impulsivity or combined type but neither were effective in attention deficit disorder [39]. The omega-3 supplement was dosed at 1 gram once per day and Ritalin was 0.3-1 mg/kg three times per day. Unfortunately, the publication seemed unclear as to how long the intervention lasted. The methods state the omega-3 supplement was given for three days, which seems odd if the Ritalin was used continuously throughout the study. A similar study in male adolescents found no benefit after 12 weeks of omega-3 and omega-6 supplementation but the amount of omega-3 they used was very low [40]. What if we combine EPA/DHA with something that will allow the omega-3 fatty acids better access to the brain? There is a prescription medical food called Vayarin available specifically for ADHD that does just that. This product combines a small amount of EPA and DHA with phosphatidylserine, which allows the omega-3 fatty acids to get to the brain. The phosphatidylserine also has effects of its own, including improvements in memory and stress. This combination has been studied in a double-blind placebo-controlled trial, but the results weren’t exactly astounding. Although symptom scores significantly improved in the group of children receiving the phosphatidylserine-omega-3 combination, their scores overall were not all that better than those of the children in the placebo group [41]. The study evaluated results with a teacher rating scale, a parent rating scale and a child health scale. If scrutinized further, there was a significant reduction (seen only in male participants) in the DSM-Inattentive subscale score of a teacher rating for those receiving the experimental treatment compared to those receiving placebo [41]. But this is only one subscale of one of three rating scales used! It also appeared that a subgroup of the initial set of participants who displayed more severe hyperactive and impulsive behaviour experienced greater improvement compared to the placebo group [41]. This analysis occurred after study completion and needs repeating to determine if there really is a beneficial effect in a particular subgroup of children with certain characteristics. A different study found that the combination of phosphatidylserine and EPA/DHA actually did have a beneficial effect [42]. Why the difference? This study used a different measure – a computerized test of inattention. It also used a smaller set of participants. Because of the discrepancies in how the symptoms were measured it is hard to compare the two studies’ results. This study stands out in that it found improvements in inattention, whereas the other studies we’ve discussed that show any positive effect mainly demonstrated a positive effect in impulsivity or hyperactivity. It was also odd to note that this study combined the fish oil or EPA/DHA/phosphatidylserine combination into a chocolate paste that the children were to consume! Hard to imagine what that would taste like! It also seems that omega-3 fatty acid supplementation could improve inattention in boys without ADHD as well as with ADHD [43]. These researchers combined the omega-3 fatty acids with margarine. What will they think of next? Omega-3-enriched donuts??!

On the topic of food, just last year a study was published on the effect of fish intake on attention in adolescents. This is interesting because whole foods or a good diet can provide benefits beyond that of an isolated supplement. In this case, fish intake had a slight benefit over meat or fish oil supplementation on attention [44]. The effect was small due to compliance issues but gives direction for future research in this area.

Autism Spectrum Disorders (ASD)

Neuroinflammation is a major contributor to autism spectrum disorders. This includes imbalances of omega-3 fatty acids, which contribute to the regulation of neuroinflammation, synaptic plasticity, the activity of the microglia that provide an immune system in the brain and even affect the gut microbiome [45]. The effects of omega-3 fatty acid deficiency on the gut microbiome are especially fascinating in the context of ASD because omega-3 deficiency is associated with dysbiosis, whereas omega-3 supplementation is associated with decreased LPS (a toxin produced by bacteria) and decreased gut permeability [45]. Maybe it’s not the brain we need to be looking at in these studies, but the gut!

This imbalance in omega-3 fatty acids in ASD could be attributed to either genetics (such as abnormalities in Fabp7 gene expression) or nutrition [45]. Children with autism spectrum disorders have been found to consume fewer foods containing omega-3 fatty acids like DHA, [45] and this quandary of picky eating and poor nutrient intake is something I also highlighted in the previous post on Vitamin D. Low DHA in these kids is associated with elevations in anti-myelin basic protein antibodies [45]. Studies in patients also display increased phospholipase A2, an enzyme that is very important to fatty acid metabolism. This enzyme’s activity is reduced by supplementing EPA [45,46]. Rodent models of autism spectrum disorders demonstrate the detrimental effects of omega-3 depletion on changing neurotransmitter systems in the brain [45]. They also show promising effects of supplementation on social interactions, anxiety, memory repetitive behaviours and other facets of ASD [45]. However, review of human research on essential fatty acid supplementation for ASD reveals a lack of rigorous trials demonstrating an impressive or significant effect over placebo, despite a trend towards benefit [23,47–50]. One of the negative trials was quite small, and participants were between 18 and 40 years old [51]. This is problematic, as supplementation by that age may not be able to reverse the effects of deficiencies during prenatal or childhood development. Another study focused on children aged 2 to 5 years old but again, did not find significant benefit of supplementation [52]. There is controversy over the optimal amount of omega-6 vs omega-3 fatty acids we need at different developmental stages [53]. After all, omega-6 is still an important fatty acid. For example, when we depress arachidonic acid by giving omega-3 supplementation, some research has associated this with poor growth in preterm infants [53]. Yet fish consumption during pregnancy is associated with better developmental scores in infants at 18 months [54]. This doesn’t necessarily mean it doesn’t work at all in ASD, but we don’t have enough data to determine which subsets of patients it would work for, if at all. For example, there is genetic variability in fatty acid metabolism and we don’t know much about this variability in the context of ASD [45].

Anxiety

There are few early studies on omega-3 supplementation for anxiety. One of the more curious findings of early research was that supplementing with a combination of EPA/DHA for a couple of months decreased levels of catecholamines compared to placebo [4]. Catecholamines include adrenaline, noradrenaline and dopamine. Although fish oil supplementation is not generally associated with adverse events, and there is some support for fish oil being helpful for anxiety, there is one interesting case where high-EPA fish oil supplementation had some unwanted effects. For this patient, the supplementation was very helpful in reducing depressive symptoms, but after several years of use he began to experience severe anxiety and insomnia [55]. These symptoms subsided when he ran out of fish oil, and then returned after he started taking it again [55]. This may be an anomaly, but there does happen to be a larger study on fish consumption and anxiety and depression that could shed some light on this finding. In the larger trial, fish intake was helpful for anxiety and depression…but only up to a certain point [56]. Higher intakes of fish seemed to lean towards increased rates of mental disorders [56]. This finding didn’t quite reach statistical significance; nevertheless it is something worth considering. Again, we have that possibility of a U-shaped curve we discussed previously in the section on “Depression”. The authors proposed mercury content as one potential reason for creating a higher risk with increased consumption [56]. This seems unlikely as the fish we commonly consume is higher in selenium then mercury and this should provide a protective effect against the mercury.

Schizophrenia

A curious finding in patients with schizophrenia is that these patients have been seen to undergo a resolution of symptoms during periods of high fever…only to relapse once the fever subsides. Years ago, Horrobin made a connection between fever and phospholipid metabolism and suggested that if something as simple as a fever can reverse symptoms, it is possible that schizophrenia could result from a minor biochemical problem and be resolved with minor changes. Omega-3 supplementation could be considered as one such minor change. It’s thought that in a fever, the fever provides a sink for excess arachidonic acid – and by supplementing with EPA, we create a similar effect by adjusting the ratio of AA to EPA without having to use a fever to do so.

There are several other associations between essential fatty acids and schizophrenia. One is the Fabp7 gene. This gene plays a role in our ability to take in and use fatty acids and problems with this family of genes can result in impaired sensorimotor gating function [1]. It’s not only involved in schizophrenia, but increased expression of this gene has been seen in autism spectrum disorders [45]. Another is caspase-3, an enzyme involved in the loss of brain tissue in schizophrenia [23]. This enzyme can be inhibited by the omega-3 fatty acid EPA [23]. What does all this mean for a patient with schizophrenia? Let’s start with an optimistic outlook and then dive in with a more critical perspective. There is a rather remarkable case report of a 31-year old male diagnosed with schizophrenia at the age of 28 [57,58]. At the time of the study he was not on antipsychotic medication. He showed remarkable improvement on both positive and negative symptom scales two months from the start of treatment with 2 grams of EPA per day [57,58]. At six months from the start of treatment his positive symptom scores had dropped from 46 to 4 and his negative symptoms scores had dropped from 16 to 3 [57,58]. Changes on imaging revealed decreases in ventricular size with treatment [57,58]. This case is very exciting because it shows how such a small change can make a very dramatic change to a patient’s life. However, there are many variables involved in complex conditions such as schizophrenia, and given the multifactorial nature of many such psychiatric conditions, these results may not be seen in all or even very many patients.

Before we jump into clinical trials on omega-3 supplementation for schizophrenia, let’s first consider omega-3 intake across populations from more of a bird’s eye view. Schizophrenia is actually milder in some populations, and it has been found that as the ratio of essential fatty acids to other fats in the diet increase, the severity of schizophrenia decreases [59]. It has been argued that it is impossible for omega-3 supplementation to prove beneficial to the wide range of mental health conditions discussed in this post because these conditions involve different types of activity in different neurotransmitter systems of the brain [4]. Since omega-3 fatty acids have an effect on these neurotransmitter systems, researchers don’t know how they can be beneficial for both (for example) mood disorders and schizophrenia, which result in different neurotransmitter functioning [4]. Schizophrenia is typically associated with excess in the neurotransmitter dopamine. Deficiencies in omega-3 fatty acids in utero are actually associated with less dopamine, less dopamine receptors, and increased dopamine breakdown [4]. These findings imply that omega-3 supplementation could be helpful for mood and anxiety disorders, but would increase dopamine and make schizophrenia worse [4]! Conversely, a different animal model found that omega-3 deficiencies were associated with increased dopamine activity [4]. The authors suggest that decreased dopamine may make the dopamine receptors more sensitive to the dopamine that becomes available [4]. These findings are difficult to extrapolate to human patient populations, but clinical trials of supplementation in mood disorders support an effect of increasing both serotonin and dopamine activity [4]. A review of clinical trials up to 2007 concluded that results of EPA and other omega-3 supplementation for schizophrenia were inconsistent and that supplementation likely had no clinical utility [4]. More recent clinical trials on omega 3 supplementation have shown beneficial effects on both positive and negative symptoms, but suggest that supplementation is best used as a preventative measure in high-risk groups or first episode psychosis populations [60–62]. One trial showed rather remarkable results in a young population experiencing subthreshold psychotic states. These participants were given omega-3 supplementation for 12 weeks and this reduced their risk of progressing to psychotic disorders at both 12 months and at seven years later compared to the placebo group [60–62]. Of young people with ultra-high risk for psychosis, more severe baseline negative symptoms and higher erythrocyte (red blood cell) alpha-linolenic acid levels predicted improvement with omega-3 supplementation [61]. Studies like this, although small, allow us to further refine which patients this intervention would be best suited for. A longer trial of omega-3 supplementation in first-episode psychosis also demonstrated a benefit [63]. Not all studies show benefit. One trial demonstrated no benefit over placebo, but participants in this trial were allowed to take additional non-antipsychotic medications (such as antidepressants or benzodiazepines) and cognitive behavioural case management as needed [64]. Supporting this effect specific to first-episode psychosis or high-risk patient populations, a study on lipid profiles between first-episode, chronic unmedicated and healthy participants revealed that low levels of omega-3 fatty acids were present in the first-episode group only [65]. It is thought that this deficiency is characteristic of early schizophrenia, and antipsychotic treatment was seen to correct the fatty acid levels in the first episode patients [65]. In addition, patients taking EPA have been found to need lower doses of antipsychotic medication and to have fewer extrapyramidal side effects than those taking antipsychotics plus a placebo [66]. This was an interesting study that is hard to interpret in a standard fashion because adding in the medications provides confound in the interpretation of the results. On the other hand, it does demonstrate a more practical scenario as in real life patients are likely going to be on a variety of antipsychotic medications and dosages, and it is useful to see how omega-3 supplementation may affect outcomes for this group. In contrast, omega-3 supplementation may worsen symptoms in chronic schizophrenia or after discontinuation of antipsychotic medication [67]. One possible explanation for this is that the omega-3 supplementation cannot counteract progressive gray matter loss later in the disease process [67]. Other discrepancies in effectiveness on a case by case basis may be the result of different biological subtypes [67]. Other studies have started exploring combinations of omega-3 and antioxidant supplementation [68,59].

Final Thoughts

Overall, the answer to whether fish oil supplementation is helpful in mental health conditions is a rather unhelpful: it depends. We don’t have enough evidence to demonstrate a clear positive effect in the case of traumatic brain injury, dementia, autism spectrum disorders or anxiety. We haven’t fully elucidated when or if it is helpful in PTSD, manic-depressive disorder or ADHD. We are just starting to understand how certain subsets of depressed patients could benefit (namely those with inflammation behind their depressive symptoms) or how it might be a useful preventative for those at increased risk for psychotic disorders.

While we are making progress in this area, more investigation needs to be done to identify subsets of patients that will benefit, that will not benefit or that might experience a detrimental effect. Supplementation can be useful to speed up progress for a patient, but it should not be used as a band-aid and the exact type of supplementation (fish oil vs cod liver oil vs krill oil etc) should be chosen thoughtfully. Lifestyle factors are important to consider, and the root cause of the problem should be sought. And, last but not least, don’t forget fish can also be consumed as a food rather than a supplement!

Further Reading

For any nerds out there I highly recommend this paper for a more thorough look at how vitamin D and omega-3 fatty acids affect serotonin synthesis and the implications for mental health.

Patrick, R. P. & Ames, B. N. Vitamin D and the omega-3 fatty acids control serotonin synthesis and action, part 2: relevance for ADHD, bipolar disorder, schizophrenia, and impulsive behavior. FASEB J. 29, 2207–2222 (2015).

And learn more about other common mental health supplements by checking out these posts on vitamin D and probiotics!

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Do probiotics improve your mental health?

The Trifecta of Mental Health Supplements: Vitamin D, Probiotics & Fish Oil

This post is the second in a series of three in which we will thoroughly explore the darlings of supplementation for mental health: vitamin D, probiotics and fish oil.  Read on to learn it all – the good, the bad and the ugly. Do probiotics improve your mental health? The answer may surprise you. It’s common knowledge that you should supplement with probiotics if taking an antibiotic, right? Probiotics are recommended to improve a number of symptoms, especially those surrounding gut dysbiosis (an imbalance of good and bad bacteria and other small creatures that live in your gut). People feel like they are supposed to be on a probiotic for general health and I’ve seen them express guilt if they admit to forgetting to take it. We often think of supplements as harmless at worst and beneficial at best. Research over the years has demonstrated time and time again just how flawed this logic is. As one example, check out my discussion on the use of fish oil in non-inflammatory depression, which will be included in the next blog post in this series. My good friend Dr. Burke recently alerted me to a new study that is poised to make us all re-think our use of probiotics. This ground-breaking study suggests probiotic supplementation after antibiotic use may actually be worse than not taking anything [1]. How is this relevant to mental health? Oh, so many reasons!! First, let me explain this study and its implications for the use of probiotics. This study was carried out on both mice and healthy humans. The fact that it was also done in humans makes it all the more relevant to clinical practise. These brave healthy human volunteers were given standard doses of ciprofloxacin and metronidazole for seven days. At the end of the antibiotics, tests were run to determine how the antibiotics changed the gut microbiota.

Side note, please picture this idyllic scenario: You head to a research lab where you poop a minimum of 350 grams of poop for someone. Then they add some nice glycerol and stuff and freeze it. Next, after hearing all your life about the benefits of your healthy gut bacteria, you agree to take a course of antibiotics that will take that advantage away from you. Seven days later you sit smelling lovely fecal fumes waft through the lab as they thaw it for thirty minutes. Next, they draw your old bacteria up into a syringe and then inject it into your jejunum…WHO WANTS TO SIGN UP??? I have to applaud these volunteers for their contributions to science and the betterment of society.

After this, the participants were divided into three groups. One supplemented with probiotics, one was given an autologous fecal microbiota transplant (basically given their own healthy stool back again) and the other did nothing but “watch and wait”. They found that in a healthy gut, the resident microbiota provide resistance against the colonization of the probiotic bacteria [1]. When you impair your normal gut bacteria with something like antibiotics, then the probiotic bacteria are better able to colonize [1]. It sounds good right? You take away bacteria with an antibiotic and then you replace the bacteria. It turns out this is actually detrimental in some ways. While it is still possible that taking the probiotic prevents other pathogens from taking up residence while your normal flora is away, we don’t know this for sure. Plus, this study demonstrated that having those probiotic flora make a home in your gut actually prevents your own bacteria from replenishing themselves and results in continued dysbiosis as long as five months after stopping the probiotics [1]. How do they do this? The probiotic bacteria secrete antimicrobial agents that inhibit your own bacteria from growing. They also increase inflammatory mediators [1]. The people in the fecal microbiota transplant group were treated with their own healthy pre-antibiotic stool. This group saw the greatest improvements and saw their gut microbiome restored to health as soon as one day [1]!

Those who just “watched and waited” and did not receive any treatment or supplementation after the course of antibiotics saw better improvements than the probiotic group but not quite as good as the fecal microbiota transplant group [1]. These results are pretty astounding because the current general consensus is to take your probiotics if you take antibiotics. Now perhaps there are benefits to taking probiotics if you do not have dysbiosis – but is that how they are being used? Not always. However, this paper also highlights the promise of fecal microbiota transplants as a future therapeutic strategy.

Antidepressants and Your Gut Flora

You’ve probably heard that we’re facing a bit of an antibiotic-resistant infection crisis. These infections are set to become a leading cause of death by 2050 [2]. We focus a lot of effort on promoting more judicious use of antibiotics (and botanical antimicrobials!) in order to prevent this problem but is it only antibiotics that are the culprits?

Turns out, there are non-antibiotic drugs that could also be contributing to this rise in antibiotic resistance. One example is the popular antidepressant fluoxetine (also known as Prozac). This is no small matter, as there are concerns over the amount of fluoxetine accumulating in our environment in addition to its impacts on those who actually ingest it as a prescription medication [3]. The amount of prescription medications ending up in our environment and the ramifications of this was a top concern for doctors and other health professionals at the Academy for Integrative Health and Medicine conference when I last presented there. Earlier this year, a group of researchers demonstrated that E. coli subjected to various doses of fluoxetine underwent greater rates of mutations [3]. This allowed the bacteria to gain resistance (potentially via increased efflux pumps) to a range of antibiotics, including amoxicillin, chloramphenicol, tetracycline, fluoroquinolones, and aminoglycosides [3]. Not only were these bacteria becoming resistant to the antibiotics tested one by one, they also exhibited resistance to multiple antibiotics [3]. The consequences of this are that if you are taking an antidepressant medication like fluoxetine and you acquire an infection, it may be more difficult for you to eradicate that infection. Of course, this is a simplification and the investigation of this should also be done in humans. However, it is worth consideration and we should explore what other non-antibiotic drugs could also be contributing to antibiotic-resistance. There is another possibility. Perhaps some of these antidepressants or antipsychotics or whatever other psychiatric medication a person is taking have an effect because they affect the person’s microbiome. An example that comes to mind would be Toxoplasma gondii infections in schizophrenia and the effect of some antipsychotic medications on that particular parasite.

“Psychobiotics”

There are numerous associations between mental health conditions and dysbiosis. Antibiotics are one way to approach this. But what about probiotics? In these conditions, can we positively influence our mental wellbeing by taking probiotics, or as they are becoming known for this purpose, “psychobiotics”? There are a plethora of animal studies on this topic, but let’s focus in on human studies for this discussion. Animal studies are great for telling us what not to do in humans or for telling us what would be worth investigating further. Human studies help us know what to do in humans. If we begin at the beginning, research suggests our microbiome begins developing before we are even born. The transfer of bacteria from mother to child is associated with multiple health outcomes, affecting the immune system and the integrity of the blood-brain barrier as two examples [4]. Then, the time periods in which we develop our gut microbiota from infancy to an adult’s composition coincide with early life and adolescent periods of synaptogenesis and pruning in the brain [4]. Our gut talks to our brain through the vagus nerve, the immune system, microbial metabolites (like short-chain fatty acids), neuropeptides, hormones and cortisol [4]. We can see how there are many players in this game, and for optimal gut and brain health we need them to work as a team. Without getting too technical, I do want to mention one pathway in particular. This is the pathway in which tryptophan is metabolized. Tryptophan can be made into inflammatory metabolites or into neuroprotective metabolites. This pathway is influenced by bacteria, the immune system and the HPA axis, etc.

Tryptophan can also be made into serotonin and this occurs in two ways. One enzyme occurs in the body and pineal gland and is inhibited by vitamin D. During the day, when you are getting exposure to sunlight and making vitamin D (in an ideal scenario), this vitamin D keeps your pineal gland from making serotonin. The serotonin is then not there to be made into melatonin and put you to sleep at the wrong time of day. The other enzyme occurs in the brain, and is stimulated by vitamin D. This keeps serotonin levels in the brain higher during the day. If our gut bacteria maintain some control over our tryptophan metabolism and in producing neuroactive metabolites we can see just one of the ways in which these bacteria can affect our mental state. Bacteria are important, but how and when do we tap into this resource?

When are probiotics useful?

To examine this question, we need to understand the effects of probiotic supplementation in the different types of scenarios we are looking at. We could have a patient who:

Has antibiotic-related changes in microbiome. This is the situation we discussed at the beginning of this article.

Has dysbiosis that has not yet been addressed by antibiotics.

Has dysbiosis and a psychiatric condition.

Has no dysbiosis but has a psychiatric condition.

Is healthy and has no dysbiosis or psychiatric condition.

Okay, maybe reading that gives you a bit of a headache but those are some of our options. As we’ve seen from the newly published study I mentioned at the beginning – just because we know the microbiome is affected doesn’t mean probiotics provide the solution. And they aren’t necessarily the antidote we thought they were for antibiotic-induced changes. This is why we really need to take a closer look and understand when exactly they are useful.

If you’re still wondering if consuming bacteria can really impact your brain that significantly, consider this study in healthy female volunteers. These women drank two portions of fermented milk per day for four weeks and then underwent brain imaging. Compared to the two control groups, those who had taken the fermented milk as instructed had decreased emotional responsiveness and sensory network activity [5]. While the mechanisms and relevance of this outside of the research lab remains to be elucidated, the fact that differences could be seen on imaging is thought-provoking. Let’s examine some specific situations in which probiotics might be used. If you don’t see a particular mental health condition on here that you expected, don’t be surprised! There are actually a very limited number of human trials in this area. The doses for most of these studies are around 1 billion colony forming units (CFUs), with some using up to 6 or 20 billion CFUs. For each of these I will mention what type of probiotic intervention was made because there is a huge variety of options. Imagine if I said all pets are the same – you will have the same experience from having a pet fish as you will from having a pet dog. Bizarre, right? Picture trying to take your pet fish for a walk! Bifidobacterium and Lactobacillus or whatever type of bacteria you’re looking into may all seem the same – just tiny creatures we can’t see without a microscope. While they may share similarities, it’s unrealistic to expect them to be exactly the same. That’s why we pay attention to the type of probiotic these studies are using.

Probiotics for Stress

Our understanding of the microbiota in relationship to stress is built on a large number of animal studies with relatively few human studies or clinical trials [6]. One small study of 22 healthy male volunteers demonstrated a significant reduction in cortisol output in response to stress after four weeks of supplementing with the probiotic Bifidobacterium longum 1714 [7]. They also demonstrated slightly lower ratings of perceived stress and better performance on a learning task [7]. Interestingly, although the probiotics did result in better outcomes on the learning task than the placebo, there was still a pretty good relative change from baseline with the placebo [7]! What is one area in which we could really use a little stress reduction and cognitive improvement? Medical school! This next study investigated the effect of fermented milk (containing Lactobacillus casei strain Shirota) on stress in medical students about to take a nationwide exam [8]. This was also a small trial, consisting of 47 students (half to placebo and half to treatment groups). They drank a probiotic milk or a placebo milk every day for 8 weeks up until the day before their examination. The researchers measured a lot of objective markers, like cortisol levels but although there was some statistically significant difference between placebo and probiotic at certain timepoints, the changes were small enough that a clinical relevance is not clearly demonstrated. In addition, the groups had pretty big differences in some of these markers at baseline, which skews comparisons. One finding from this study that warrants further attention was that as the exam drew closer, the students taking the probiotic experienced fewer physical symptoms like diarrhea, constipation, abdominal pain, runny nose or change in temperature [8]. Similar results were found in a small study using L. helveticus R0052 and B. longum R0175 for 30 days in healthy volunteers. This study found no significant change in 24 hour urinary free cortisol between the probiotic and placebo groups (although it did decrease over time in the probiotic group), but did find that the probiotic reduced scores of somatisation, depression, anger-hostility, self-blame and anxiety [9]. Another study of healthy male volunteers found no effect of the probiotic Lactobacillus rhamnosus JB-1 on stress [10]. These studies all look at healthy volunteers. We need to know more about the effects of probiotics in a population with more severe clinical symptoms, such as severe anxiety. After all, as demonstrated in the study I was so excited about at the beginning of this article – there are differences in how probiotics respond to a healthy vs dysbiotic gut. Who’s to say that the gut flora are necessarily healthy in someone with severe anxiety? Could probiotics have different effects on someone who has both anxiety and dysbiosis compared to someone with only anxiety? Much more to learn! As an interesting note on this topic, our bacteria can also make GABA for us from glutamate in our gut. Increases in gastrointestinal GABA levels are associated with increased GABA in our central nervous system [11]. This is a neurotransmitter we associate with reducing anxiety. What hormone can help us with our stress? Does oxytocin sound familiar? This is the “love” hormone that is most commonly associated with uterine contractions during labour, breastfeeding, maternal care and social bonding but is also responsible for a number of other roles throughout our bodies. One very thorough review of the literature (consisting mainly of animal studies) suggests we may be able to boost our endogenous oxytocin production through the use of the probiotic L. reuteri [12]. That’s one powerful little creature!

Probiotics for Depression

In my talk at the Ancestral Health Symposium this year, I discussed the importance of social connection in addressing depression. One of the papers on this topic brought up the consideration that we are not only isolated from people, we are becoming more isolated from our “old friends”, our microbial companions [13]. Handwashing, sanitation, washing our food etc have reduced the exposure we have to microbes. Of course, some of this is an incredible improvement towards our wellbeing. However, those little bugs also help train our immune system and decrease pro-inflammatory signalling [13]. It has even been suggested that losing tolerance for these little guys can cause inappropriate immune responses to “psychosocial” antigens such as interpersonal rejection [13]. Inappropriate immune responses interfere with our ability to handle rejection, conflict, or even tolerate our imperfections as well [13]. Fascinating. These are all relevant in the context of depression of an inflammatory nature.

Antidepressants, Antibiotics and Depression

We’ve already discussed the connection between SSRI antidepressants and creating resistant bacteria. SSRIs are one way to influence serotonin levels, but would supporting healthy gut flora through prebiotics or by supplementing with probiotics be a better way to improve serotonin levels without creating antibiotic-resistant bacteria? Or could they improve depressive symptoms by some other mechanism? Interestingly, one of the first drugs used as an antidepressant was a drug used to treat tuberculosis [14]. Since then, we’ve realized that many types of antidepressants including MAOIs, TCAs, SSRIs and even ketamine have antimicrobial effects [14]. Coincidence? These drugs exert antidepressant effects via other mechanisms too, but this antimicrobial activity is intriguing and could certainly be a contributing factor. This also opens up the question: which antibiotics could also have antidepressant effects? One such drug that has been used with some success in the literature is minocycline at a dose of 150 mg for 6 weeks [15]. Patients with Major Depressive Disorder (MDD) have been documented to have lower levels of Bifidobacterium and Lactobacillus [16]. Some of these patients have also been reported to be taking a probiotic but to have even lower Bifidobacterium counts than their fellow patients who were not taking probiotics [16]. It is possible that these patients took those probiotics because of a GI concern in the first place, and that their microbiota were already compromised relative to the other patients [16]. Interestingly, those consuming fermented milk had increased levels of Bifidobacterium. This association was seen in patients, but not controls [16]. What do the trials on probiotics demonstrate? There are actually a few small trials in this area. First let’s examine this from the perspective of prevention.

Preventing Depression

When healthy participants are given probiotic supplementation (containing B. bifidum W23, B. lactis W52, L. acidophilus W37, L. brevis W63, L. casei W56, L. salivarius W24 and L. lactis W19 and W58) for four weeks they see significant improvements in their cognitive reactivity [17]. Cognitive reactivity is how we respond to a sad mood and is associated with increased vulnerability to depression. More specifically, they saw improvements in aggressive and ruminative responses to sad mood [17]. From a prevention standpoint, this is very relevant because ruminative thoughts can trigger a depressive episode and aggression can lead to suicidal ideation and attempt [17].

Major Depressive Disorder

How does this play out in a population of patients who already have depression? A small study in 2015 examined the use of L. acidophilus, L. casei, and Bifidobacterium bifidum in patients with a diagnosis of Major Depressive Disorder. After taking the probiotic for 8 weeks, scores of depressive symptoms significantly improved, along with improvements in insulin, hs-CRP (a marker of inflammation) and glutathione (an antioxidant) [18].

The Use of Prebiotics

Could we get this same result by taking a prebiotic to feed our existing bacteria instead of by taking a probiotic containing bacteria? The answer appears to be “no”. When a group of patients with MDD were assigned to receive either probiotic, prebiotic or placebo for two months, the probiotic group had a significant improvement in depressive symptoms scores while the placebo and prebiotic groups did not [19]. The probiotic used was a combination of L. helveticus R0052 and B. longum R0175.

Treatment Resistant Depression

These patients had all been on antidepressants for a minimum of three months prior to the trial start date [19]. What about patients for whom antidepressants aren’t helping their depressive symptoms? A small but hopeful pilot trial suggests that adding on magnesium orotate (800 mg twice daily) and a probiotic (L. acidophilus, B. bifidum, S. thermophiles) to these patients (still on their SSRIs) may be helpful [20]. After eight weeks of supplementation, 75% of these patients had significantly improved depressive symptoms and quality of life [20]. Further studies using a control group or multiple groups to compare magnesium and probiotics on their own versus in combination would be enlightening. The results of these studies suggest probiotics may be helpful for prevention or as an adjunctive treatment in depressive disorders, but not so much as a primary intervention.

Postpartum Depression

Postpartum depression is one condition in which primary interventions or preventative methods that don’t involve pharmaceuticals are particularly appealing. Research on the use of Lactobacillus rhamnosus HN001 during pregnancy has found significant reductions in anxiety and depression scores postpartum compared to placebo [21]. The average symptoms scores were significantly different between the probiotic and placebo groups, but the very small difference in these scores may not be clinically relevant overall. There was no significant difference in the number of participants meeting cut-off scores for depression, although the difference in the number of participants meeting cut-off scores for anxiety was significantly lower in the probiotic group [21].

Probiotics for Childhood Disorders

A small study investigated the long-term effects of probiotic supplementation in infants. Here is something remarkable: 17% of children in the placebo group were diagnosed with ADHD or Asperger syndrome (AS) by the age of 13 years. Guess how many were diagnosed in the probiotic supplementation (Lactobacillus rhamnosus GG) group? None [22]. Not one. This is a smaller study, however this could be a pretty powerful intervention if supplementation in the first 6 months of life can have such incredible effects long-term. Those who later developed AS or ADHD did have lower levels of Bifidobacterium at a young age, but there were not differences in the composition of the gut microbiome between those with and without AS or ADHD by 13 years of age [22]. Bifidobacterium is a species of bacteria associated with decreasing anxiety-like behaviour in animal studies, as well as promoting healthy gut linings [22]. It’s possible that this intervention is best suited towards use during a specific window of a child’s development. Other disorders that pop up in childhood are the autism spectrum disorders (ASD). These too are associated with gut microbiota: increased GI symptoms and dysbiosis are more common in kids with ASD and antibiotics have been seen to help ASD symptoms [23]. Probiotics (Lactobacillus plantarum WCFS1 in one trial and S. boulardii in another) have also helped with autistic symptom scores and gastrointestinal symptoms in a couple of trials and supplementation is associated with decreased markers of inflammation [24]. There is a very exciting trial in progress which will enlighten us on how preschoolers with ASD respond to probiotic vs placebo therapy over 6 months. This study also takes into account differences between patients with comorbid GI symptoms and those without comorbid GI symptoms [25]. For those who aren’t too squeamish, there is actually some interesting research into parasite eggs (Trichuris suis to be specific) improving symptoms in patients with autism (both kids and adults) [24]. This parasite is found in pig gastrointestinal tracts. The proposed mechanism for this is the parasite eggs help to train the immune system to behave in a more appropriate manner [24]. For those who really aren’t squeamish let’s go into one of the most exciting and promising studies in the literature on the topic of ASD and probiotics! This is a microbiota transplant study and were the results ever impressive [26]! This study had 18 children between the age of 7 and 17 years old (the FDA put restrictions on the researchers using any younger children) who had a diagnosis of ASD and also had gastrointestinal symptoms. Age-matched children without ASD were used as a control who did not undergo any study interventions. First, the researchers gave each child in the experimental group a 14 day course of the antibiotic vancomycin (oral). On the 12th day of that they also began on Prilosec. Next they took MoviPrep to clean out pretty much whatever was left in their gut. This was followed by a one day fast. Then the fun part: Standardized Human Gut Microbiota therapy! This wasn’t done with actual fecal matter but it was done with standardized human gut bacteria originally obtained from the stool of healthy donors. The resulting material was kept cool at the Arizona State University which really makes me wonder how far down the hallway those freezers were from the lab I was at there! The microbiota transplant therapy was given over ten weeks, with researchers studying the children for an additional 8 weeks after that intervention. Apparently, you can order this therapy in many ways. You can have it with chocolate milk, a milk substitute, juice or, if you really don’t feel like drinking it you can have it as an enema! So many options friends! The participants received a lower oral dose of the gut microbiota therapy for several weeks after that initial larger dose. There ended up being no significant difference between those who received the microbiota transplant orally or rectally. The treatments were well tolerated [26]. At completion of therapy, only two of the participants did not respond with improved gastrointestinal symptoms (defined as at least a 50% reduction in the Gastrointestinal Symptom Rating Scale). Along with improvements in GI symptoms, participants experienced significant improvements in ASD-related symptoms, and this was maintained at the 8-week post-intervention mark [26]. This includes things like improvement in social skills, mood, activity levels, speech and communication and daily living skills. Developmental age scores had not yet caught up with chronological age scores at the end of the study, but participants did make strides towards closing that gap by about 1.4 developmental years [26]. The researchers suggest that the results are promising but we need to do additional research to check that the results couldn’t be achieved by vancomycin alone. I would agree but, based on the newer study of healthy adults receiving antibiotics and then FMT, probiotics or nothing that I mentioned earlier, my guess is that the microbiota transplant would still have better therapeutic value than vancomycin alone.

Probiotics for Psychosis

There are many factors involved in complex conditions like psychotic disorders. And yes, this actually does include the gut bacteria (surprise). What is the connection here? First, there is an association between gastrointestinal inflammation and first episode psychosis or schizophrenia [27]. Secondly, there is a difference in fecal microbiota composition between patients with first episode psychosis (and without chronic GI disease or celiac disease) and healthy controls. While healthy controls had higher levels of Bacteroides and Ruminococcaceae, the patients had higher levels of Bifidobacteria and Lactobacillus [27]. This particular study was too small to reach a significant difference on this account, but the number of bacteria were correlated with higher amounts of negative symptoms and lower functioning [27]. Of the limited number of patients in this study, those who had microbiota compositions more similar to the healthy controls had a 70% remission rate at one year compared to 28% in the patients whose microbiota compositions were more different from the healthy controls [27]. Most of the patients in this study were already on antipsychotics. Duration of antipsychotic treatment was not noted to correlate with bacterial numbers in this study. However, this is an important consideration since some antipsychotic medications are known to have antimicrobial or antiparasitic effects [28–32]. We need to further consider if this contributes to positive therapeutic effects or if it contributes to negative side effects of antipsychotics. It is curious that Lactobacillus in particular were associated with poorer outcomes, as this is a common type of bacteria used in probiotics and has some animal research supporting that it decreases anxiety and depression. This is further support for a push to better define which “bug” we need to support for which health condition. There is a study that did use Lactobacillus (specifically, they used Lactobacillus rhamnosus GG and Bifidobacterium animalis subsp. lactis Bb12) in patients with schizophrenia. The patients took this probiotic each day for 14 weeks. Researchers in this study were most interested in how probiotic treatment would affect Candida albicans antibodies. C. albicans is a type of yeast and in preliminary analyses, these researchers had noticed that many in their group of patients had elevated levels of antibodies towards this yeast. This was typically seen along with GI symptoms like trouble having bowel movements. Having elevated C. albicans antibodies was significantly associated with more positive symptoms in male patients [33]. Curiously, the probiotic had no effect on levels of antibodies in female patients compared to placebo but the probiotic did have a significant effect on reducing antibody levels in male patients [33]! This is suggested to be due to the increased susceptibility to genitourinary Candida infections in female patients, which may not have the same effect on mental health as a GI Candida infection [33]. This means that the elevation in antibodies that we see in the female patients in this study may not be as related to their symptom scores or to their gut microbiome. Taking a probiotic also helped improve positive symptoms in male patients both with and without antibodies [33]. No improvements were seen in positive and negative symptoms in another study of probiotic use in patients with schizophrenia, but this study did not take into consideration other health variables such as C. albicans antibodies [34]. As I’ve mentioned before, there are so many ways in which symptoms of mental health conditions can arise, and it is very important for future studies to elucidate specific subsets of patients that may or may not benefit from a particular intervention. Studies on probiotic supplementation for psychotic disorders are clearly very limited, but what about diet-based interventions? I discussed the relevance of gluten-free diets for a subset of patients with schizophrenia in my Ancestral Health Symposium presentation on Schizophrenia and Evolution. Another diet that has been suggested for those with schizophrenia who do not have celiac disease or non-celiac gluten sensitivity is the Mediterranean Diet [35]. This is a diet that provides fiber, otherwise known as a feast for your gut bugs! Here is something to consider with interventions focused on “prebiotics” like this. Prebiotics feed all your bacteria, not just the good bacteria. If you start out with a bunch of dysbiosis, you may not want to feed that. What happens when we use this dietary intervention in patients with schizophrenia? Do we really want to promote a dysbiotic set-up? There are no clinical trials on this yet, but it would be interesting to see not only how this affects psychiatric symptoms but also how it affects metabolic markers for patients with schizophrenia.

Probiotics for Dementia

Probiotics whether in the form of food, supplement or fecal microbiota transplant have been proposed as a future treatment for Alzheimer’s Disease [11]. Now, I’m not aware of any human clinical studies in this particular area but I want to bring up something curious. It seems that serotonin plays a role in amyloid-beta plaque production [36]. Treatment with SSRI’s reduces the production of amyloid-beta proteins in the brain, suggesting that increasing serotonin levels might help reduce risk [36]. Remember that lovely tryptophan and serotonin pathway? Well our gut bacteria affect our serotonin production and taking care of our gut might be an important step towards reducing risk as well [11].

Final Thoughts

Overall some of the most exciting findings were those for the childhood conditions of Asperger’s syndrome, ADHD and autism. Future research that elaborates on the role of microbiota transfer therapies rather than simply probiotic supplementation could be very helpful. When we think about our microbiome and our mental health, we often consider what we’ve talked about in this article: antibiotic use, probiotic use, microbiota transplants, food. There are a couple of other important influences on our beneficial microbes. One is our circadian rhythm. Disrupted circadian rhythms can really mess with our poor little bacteria [37]. Circadian rhythms can be disrupted when we don’t sleep enough or at the right times, or if we don’t get enough exposure to daylight. Consider the fact that seasonal changes in gut microbiota in bears help them adjust their energy output for activity or for hibernation [12]. These microbes act like a timekeeper for the bears. This fluctuation is thought to occur via seasonal changes in light and diet [12].

The other influence is nature. Our environment is full of microbes [37]! Plants, dirt, air…these are microbial “supplements” that our ancestors were exposed to on a regular basis. Next time you step outside and take a deep breath just think of how many microbes you’re getting! Did you know that your omega-3 fatty acid status is also important for a healthy microbiome [38]? Be sure to check back in a couple weeks for the next post in this Trifecta of Mental Health Supplements series: fish oil and mental health!

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Is Vitamin D Actually Helpful for your Mental Health?

The Trifecta of Mental Health Supplements: Vitamin D, Probiotics & Fish Oil

This post is the first in a series of three in which we will thoroughly explore the darlings of supplementation for mental health: vitamin D, probiotics and fish oil.  Read on to learn it all – the good, the bad and the ugly.

Whether it’s a mood disorder, an eating disorder, schizophrenia, autism, or even the adverse effects from earthquakes (yes, it’s been studied!) there is something promising enough about vitamin D that makes us ask:

Will vitamin D help me/my child feel better?

The first consideration to make when examining studies on vitamin D is that we can have low levels of vitamin D for a number of reasons aside from inadequate sun exposure.  

In looking at mental illness we have to remember to see the patient as a whole person.  This is not just about the brain.  This could be about inflammation, anemia, gut dysbiosis, thyroid dysfunction…and supplementing with vitamin D, while making lab values look better or possibly improving symptoms, may completely miss the root cause of the problem.  

In addition to that, did you know that getting your vitamin D from a supplement will not give you the same benefits as getting your vitamin D from the sun? 

Naturally the next question is:

Are there some scenarios in which boosting vitamin D through supplementation may be an appropriate consideration?

For this question, we’ll focus on several mental health conditions with links to low vitamin D levels and the outcomes of supplementation in each of these conditions.  This post covers schizophrenia, depression, autism, eating disorders and ADHD �� if you’re primarily interested in just one of these conditions please feel free to scroll down to the appropriate topic.

Schizophrenia

Early Life Vitamin D Status

During the earliest years of our lives, there is potential for vitamin D deficiency due to the lack of vitamin D in breast milk.  Interestingly, vitamin D deficient rats will produce offspring that have changes in brain structure eerily similar to the changes we see in schizophrenia [1].  In humans, there does not seem to be a link between prenatal vitamin D levels and psychotic episodes [2], but there is some relationship between childhood vitamin D deficiency and the later development of schizophrenia [3].  

As one would therefore expect, vitamin D supplementation during infancy has long ago been linked to a reduced risk of schizophrenia in males [3,4].  However, correlational study, where the two variables of vitamin D supplementation and the development of schizophrenia are studied as they naturally occur without intervention, is slightly problematic.   This type of study cannot rule out other factors that would influence both schizophrenia risk and vitamin D status.  These factors include nutrition, toxicant exposure, socioeconomic status, and other lifestyle factors.   

What is perhaps most fascinating is one study that actually found a correlation between higher levels (in addition to lower levels) of vitamin D as an infant and psychosis [3]!  More is not always better!

Vitamin D and the Onset of Psychotic Symptoms

Once we get into adolescence and young adulthood, we see that lower bioavailable vitamin D correlates to the severity of patients’ symptoms in their first episode of psychosis [5].   

There are conflicting reports on vitamin D status depending on whether patients are in a first episode of psychosis (which also affects how long they have been on medication), if they have had schizophrenia for a longer period of time, and how their vitamin D levels were measured.

The overall consensus is that those with schizophrenia have significantly lower total vitamin D levels than healthy populations [6,7].   

Once a treatment regimen of antipsychotic drugs begins, serum levels of vitamin D will likely deteriorate further, as these drugs interfere with vitamin D synthesis and contribute to obesity.  Other factors playing a role in vitamin D status are decreased sun exposure (either through withdrawal from activities or through psychiatric hospitalization), poor nutrition and malabsorption issues. 

Is Supplementation the Answer?

With all the data on low vitamin D levels in patients with schizophrenia, many claim that we need to establish appropriate vitamin D supplementation protocols for this group of people.  Yet the existence of such trials (on vitamin D3 supplementation specifically) remains almost nonexistent.

One trial that used 600,000 IU of vitamin D over two treatments found improvement in negative symptoms (blunted emotions, poor rapport, apathy, etc) at three months but the correlation did not reach levels of significance [8].  

This trend is important to note, even if it was not significant.  The little research that has been done may not be terribly promising but perhaps we are studying the wrong patient population.  Could there be a subset of patients that would respond to vitamin D supplementation?  

It is possible that there are some patients that would benefit more from supplementation than others, and this study was not designed to account for differences in proline dehydrogenase or COMT.  You’ll see why these are important in the next section.

Too little vitamin D, or too much proline?

Now consider this: the trial that used 600,000 IU found an improvement in negative symptoms.  Negative symptoms also happen to be correlated with high proline levels [9].  Coincidence? Likely not.  One of the areas of greatest genetic risk for schizophrenia involves the enzyme proline dehydrogenase, an enzyme that breaks down proline.  Vitamin D is involved in the expression of proline dehydrogenase.  When vitamin D is suboptimal, proline levels can increase because this enzyme isn’t functioning at its best.  It makes sense that giving vitamin D could upregulate expression of proline dehydrogenase and decrease proline levels, impacting negative symptoms specifically.

Elevated proline levels may be a better predictor of schizophrenia risk than actual vitamin D insufficiency itself, as it can account for one third of the relationship between schizophrenia and low vitamin D [10].  

Perhaps vitamin D supplementation to stimulate increased expression of proline dehydrogenase would be beneficial for the quarter of schizophrenia patients estimated to have hyperprolinemia (so long as there is not a loss of function for that enzyme) [10].  

While this is an interesting consideration, more research is needed to evaluate vitamin D supplementation at an appropriate dosage, long enough follow-up interval, and in the context of proline levels, vitamin D levels, proline dehydrogenase functioning, and COMT mutations.

COMT mutations?  How does that affect proline?

You may be familiar with the COMT SNP rs4680 as the Worrier or Warrior SNP.  Those with homozygous A/A (or Met/Met) are simplistically referred to as the “worriers” and those with homozygous G/G (or Val/Val) as the “warriors”.  These don’t necessarily confer risks on their own in the context of schizophrenia, but they can interact with other variables to impact symptom severity and response to treatment.  COMT is responsible for an enzyme involved in catecholamine (for example, dopamine) inactivation.

Those with the Val/Val version of COMT have lower dopamine in the front of their brain (involved in decision making and executive functioning tasks) than those with the Met/Met version.  More dopamine may (theoretically) lead to cognitive rigidity and negative symptoms in schizophrenia.

If we combine Met/Met (i.e. slower dopamine inactivation and higher dopamine levels) with high proline levels we get significantly increased negative symptoms [9].  Here we have more proline leading to more dopamine without good enzyme activity for inactivating the excess dopamine.

High proline + Higher dopamine (Met/Met version)  increased negative symptom severity

If we combine Val/Val (more dopamine inactivation) with high proline levels we actually get lower negative symptoms [9].  Here we have more proline leading to more dopamine but with increased enzyme activity for inactivating dopamine.  In this case high proline may be helpful in keeping the increased COMT enzyme activity from dropping dopamine levels below their narrow functional range.

High proline + Lower dopamine (Val/Val version)  decreased negative symptom severity

Clearly, context matters in determining the effects of proline levels.  In some people, high proline may be protective while in others it is detrimental.  Drugs like Valproate that increase proline may have a beneficial effect on Val/Val patients by further increasing proline, while having negative effects on those who are Met/Met [9].  In addition, gender can influence COMT activity through testosterone (increasing activity) and estrogen [11].  Cannabis use and childhood maltreatment also interact with the COMT genotype and psychosis risk [12].

Could vitamin D supplementation be dangerous for infection-related psychosis?

Even if you decide to supplement vitamin D, and see the levels rise on your labs, that increased vitamin D may not be able to be used by the body.  Some infections, for example, cause vitamin D receptors to be downregulated, meaning the body can’t “see” that vitamin D.

How might this be problematic?  Well here’s an example specific to schizophrenia.  One infection associated with schizophrenia is Toxoplasma gondii, a miserable little parasite you can get from food.  

Work by one group of researchers suggests that treating cells with vitamin D could prevent the Toxoplasma from growing and spreading in a petri dish of cells [13].  However, adding vitamin D actually reduced survival in the animal model [14]!  It is thought that vitamin D suppresses the necessary immune response for controlling early infection [14].  

Supplementing yourself into acute toxoplasmosis could hardly be considered a helpful recommendation!

And that’s just one infection implicated in conditions like schizophrenia.  Others may also interfere with vitamin D and this is why we must be careful to address the root cause.

So far we’ve gone through one situation (hyperprolinemia) in which vitamin D may be beneficial with further study and one situation (Toxoplasma or other infection) in which vitamin D may be rather detrimental.   This point about finding the root cause of an illness really can’t be reiterated enough. 

Depression

While vitamin D supplementation trials in schizophrenia are few, there are numerous studies on vitamin D supplementation for depression.  However, after years of trials we still have mixed results [15–17], which, again, really highlights the need to assess the root cause.

What do vitamin D levels indicate about root cause?

There are many conditions that could contribute to depression and/or that could contribute to low serum vitamin D levels.  If vitamin D levels are already adequate, further supplementation may not improve symptoms of depression as other contributing factors are clearly at play.  

Now if vitamin D levels are low, supplementation may still not improve symptoms.  After all, vitamin D status can simply reflect an underlying pathology that will continue unchecked if supplementation is used as a band-aid approach without further investigation.

One way in which low vitamin D can contribute to depression is through increased calcium levels within cells [18].  These elevated calcium levels have a negative effect on GABAergic neurons (inhibitory neurons) and are associated with depression, as well as Alzheimer’s disease.  Vitamin D binds to the vitamin D receptor within cells and reduces this calcium by increasing processes involved in calcium homeostasis.  If vitamin D levels are low, we may have trouble controlling runaway calcium levels.

How effective is vitamin D supplementation in treating depression?

Unfortunately, many studies of vitamin D and depression do not use study populations of clinically severe depression, and the dosing and follow-up intervals are highly variable [16].  This poses a challenge in determining the effectiveness of the interventions.  

While vitamin D supplementation may be a widely accepted treatment in the clinical realm, its use is not so widely supported by the research world.  Existing data suggests little benefit in study populations overall, although supplementation may be of use for severely depressed patients specifically [17].  

It is also valuable to differentiate between youth populations and adult populations.  As one review pointed out, vitamin D deficiency could cause alterations early in life that supplementation in adulthood will be unable to correct [15].  It will be interesting to see the results of a newer trial focused on vitamin D supplementation in a pediatric and adolescent population presenting with both clinical depression and low vitamin D.

In the meantime, what do we do?  Well we can always focus on prevention and lifestyle.  Going outside and getting some sunshine provides a myriad of benefits that taking a supplement won’t give you.  

Autism

Behavioural effects on vitamin D levels

We mentioned earlier that low vitamin D could be a signal of other issues like inflammation and infection. In the case of autism spectrum disorders, low vitamin D levels may partly be due to behavioural changes affecting dietary vitamin D intake (picky eating) and sunshine exposure [15]. 

Associations with vitamin D and serotonin levels

However, vitamin D definitely has some important associations with serotonin, a neurotransmitter involved in social behaviours and reading other people’s emotional and social cues.  This association begins prenatally when adequate levels of vitamin D prevent the mother’s body from attacking her growing child.  A large number of pregnant women do not have sufficient levels of vitamin D [20,21].  The association continues as the baby’s brain grows and vitamin D is needed to activate the enzyme responsible for producing serotonin in the brain.

There are two enzymes used in serotonin production.  One is used in the brain and one is used in tissues outside of the brain.  Vitamin D promotes serotonin production in the brain and inhibits serotonin production outside of the brain.  Interestingly, serotonin produced via the enzyme used by gastrointestinal cells creates inflammation whereas the serotonin produced via the enzyme used by the gastrointestinal nervous system stimulates gastrointestinal motility [20].

Children with autism spectrum disorders have more activity of the enzyme for serotonin synthesis outside of the brain, and less activity of the enzyme used for serotonin synthesis inside the brain.  This is important because serotonin cannot cross the blood brain barrier and must be produced in the brain to be used in the brain.  Vitamin D is also important for the proper functioning of oxytocin and vasopressin, both of which are related to the behaviours seen in autism [20].

Effects of vitamin D supplementation

With the relationship to low vitamin D levels, one might expect supplementation to provide benefit.  Unfortunately there isn’t enough research to draw that conclusion at this point.  While vitamin D insufficiency has clear links to autism, we don’t actually know how beneficial supplementation would be [19].

While one study found improvement in autism scores with the use of vitamin D supplementation, the trial did not include a control group [22].  This questions how effective the supplementation actually was because another intervention trial found improvement in both a group of children who received vitamin D supplementation, as well as in the control group of children who did not receive supplementation [23].  This suggests two alternate explanations for the improvement found in the uncontrolled study: The possibility that the children given vitamin D could have improved anyways (without the supplementation), and the possibility of a placebo effect.

A more recent study also found improvement in autism scores but had a huge drop out rate and again, no placebo control [24].  This gives rise to concerns of healthy user bias, differences between the kids that remained in the study and those that wouldn’t or couldn’t cooperate, and biased reporting of improvements.  One interesting trend that can be taken from this study was a greater improvement in younger children (3 years old and younger) than older children [24].

These studies may have some promise, but don’t give a clear sense of effectiveness over placebo.  To ameliorate this problem, randomized, controlled trials of vitamin D supplementation in children with autism are needed.  Two such studies have been published in the last two years.

The first demonstrated that vitamin D supplementation (300 IU/kg/day with a max dose of 5000 IU/day) over four months was effective in improving scores of aberrant behaviour and social responsiveness [25].  The second was a smaller study, and found no effect of vitamin D supplementation over five months [26].  

What are some possible reasons for these conflicting results?

First of all, as a recent review points out, it is possible that vitamin D deficiency prenatally may have effects that cannot be countered by later supplementation [27].  In addition, autism spectrum disorders are multifactorial.  Not all of the children in the first study saw improvement with vitamin D supplementation, although most did [25,27].  While vitamin D may play a big role for one child, it may not be the proverbial straw that broke the camel’s back for another child.  In addition, it’s possible that a combination of therapies may be needed.  Vitamin D may not improve production of serotonin in the brain if there is not enough tryptophan to produce it from.  Trials using a combination of vitamin D and tryptophan supplementation may reveal completely different results.

That pesky COMT business makes another appearance

We explored the impact of proline levels and COMT polymorphisms in the context of schizophrenia, and given the similarities between schizophrenia and autism it shouldn’t be terribly shocking that these two variables play a role in autism as well.

High proline combined with a Met/Met genotype has been found to correlate to severity of symptoms in children with autism [28].  Understanding the relationships between proline, COMT and vitamin D, we can see how low levels of vitamin D could impact these children.

Less vitamin D  More proline More proline + More dopamine (Met/Met)  increased symptom severity

Regardless of debate around how effective supplementation is and the mechanism by which low vitamin D is linked to autism, addressing problems in natural routes of obtaining vitamin D may be a useful first step in removing obstacles to health.  Further studies that differentiate between supplementation in younger versus older children, that supplement vitamin D along with tryptophan, or that include evaluations of COMT and proline levels would also allow us to see which specific populations with autism could most benefit.

Eating Disorders

When it comes to eating disorders, an immediate consideration would be the role of vitamin D in bone health for a severely malnourished population.  However, let’s start from the very beginning.

Prenatal Vitamin D Status and Eating Disorders

Low maternal vitamin D levels (18.30-45.98 nmol/l) during the second trimester have been linked to twice the risk of a child developing an eating disorder by age 20 [29].  This effect was seen with female children, but was not significant for male children [29].

An interesting point regarding this finding is the different effects low vitamin D might have on the developing brain during different trimesters.  For example, this study examined vitamin D levels in the second trimester, but others studies have looked at the relationship between low vitamin D in the third trimester and disorders such as schizophrenia [29].

Vitamin D Deficiency in Eating Disorders

While vitamin D may be low prenatally, vitamin D and parathyroid hormone levels may actually be better in or comparable between adolescents with anorexia nervosa and healthy controls [30,31].  This could be partially due to the decreased fat available for storage of vitamin D and the higher amount of vitamin D remaining in circulation, the increased proportion who are supplementing with vitamin D and/or the fairly high compliance with supplementation in this group [30].

Bone Health in those with Eating Disorders

In those with eating disorders, such as anorexia nervosa, vitamin D deficiency is related to low bone mineral density in the spine, the hips and the legs [32].  Correcting this low bone mineral density in adolescence gives the best chances for improving bone health in adulthood, but although vitamin D supplementation is important, it is not enough by itself [32,33].  Some would even argue that low vitamin D levels are not actually a factor in anorexia-related bone loss [31].  This finding may depend on the particular patient population studied.

Poor bone health in adolescents is a challenging issue because treatments used for adults with osteoporosis are not necessarily effective in a younger population [32,33].  Gaining weight, transdermal estrogen and the return of menses have the strongest effect in improving bone mineral density, while SSRI use and oral contraceptives are detrimental [32,33].   It has been suggested that adequate vitamin D status is needed for weight gain to have the desired effect on bone health [34].

Those with anorexia not only have low bone mineral density, but they also have poor bone microarchitecture, providing another risk for fractures.  Interestingly enough, weight-bearing exercise does not seem to improve bone health in those with anorexia until after recovery [33].  There are additional concerns with recommending exercise in this patient population, one of which would be the potential for appetite suppression [35].

ADHD

Prenatal Vitamin D Levels

In attention deficit hyperactivity disorder we see again the importance of prenatal vitamin D levels.  Low prenatal vitamin D levels are associated with an increased risk for ADHD problem scores in toddlers while higher vitamin D levels are associated with a lower risk [36,37].  There are some discrepancies amongst studies of prenatal vitamin D levels and risk of ADHD symptoms depending on the ages studied and the symptom reports used.  Vitamin D alone is not the only risk factor [38].  Having a young mother, a mother with low or high BMI, a mother who smoked or drank alcohol during pregnancy, a parent with a psychiatric condition and being a male child are all factors associated with ADHD [36].

Vitamin D Levels in Childhood

Whether or not prenatal vitamin D levels are lower for children who go on to exhibit ADHD-like behaviours, we see that children with ADHD have significantly lower vitamin D levels than healthy children and maybe even lower than children with autism spectrum disorders [39,40].  Does this mean we should supplement with vitamin D?  Not necessarily, but it should call into question dietary and lifestyle factors that may have an influence on normalizing these levels [41].

Vitamin D Supplementation as a Complementary Therapy

Disregarding the reasons for low vitamin D for a moment, could it be that supplementing with vitamin D is useful in ADHD?  Vitamin D is needed for the production of serotonin, a neurotransmitter involved in behaviour, impulse control and decision-making.  Omega 3’s are also needed for optimal serotonin functioning and these will be discussed in a future post.  Low serotonin levels have also been implicated in autism spectrum disorders and schizophrenia.

If we have a particular situation (whether it be infection, inflammation etc) leading to low levels of vitamin D, we’re going to see a negative effect on serotonin production.  Supplementing with vitamin D would theoretically be useful in these cases because it would allow for enhanced serotonin production.  This may be beneficial in the short-term, while underlying causes are investigated and addressed if possible.  

Let’s look at vitamin D deficient children taking methylphenidate (Ritalin) for ADHD.  What happens when we add 2000 IU of vitamin D to their daily routine?  After two months, we may see some improvement in symptoms later in the day [42].  However, the effects of the pharmaceutical may overpower any strong effects of vitamin D and studies are needed to examine how much of an effect vitamin D supplementation would have on its own.

Final Thoughts

There may be severe cases (or other conditions) or subsets of patient populations where supplementation is useful.  These studies aren’t perfect, and until we have better trials, we don’t really know the effectiveness of vitamin D supplementation for schizophrenia, depression, eating disorders, ADHD or autism spectrum disorders.  Current research does not provide a ton of support for the use of vitamin D supplementation [for review see 16].

In particular, it would be great to see more research on specific subsets of patients, such as the combinations of schizophrenia with high proline levels, various conditions with screening for key infections that alter vitamin D status, depression at a severe level, and autism with different age groups.

As always, we do want to investigate the root cause of illness and long-term supplementation may not be the appropriate answer.  In fact, low vitamin D levels may be a very real indicator that something else is wrong.  

There is no dispute that vitamin D is critical for many aspects of health, or that it has associations with many mental health conditions.  The dispute is whether supplementation is useful or not.  Would we be better off attempting to remove obstacles to health (i.e. things that could be lowering our vitamin D levels) and increasing vitamin D through diet and sunshine?  And are there specific cases in which supplementation is helpful or needed?

In mental health there are times when acute measures are taken to effect change quickly and keep a patient safe, so it is important to investigate which supplements could be of use.  In addition, we must still consider the effect of vitamin D on the developing brain and the possibility that supplementation may have benefits prenatally or at an early age that it would not have later on in life.

Then again, is it really vitamin D levels that are the problem?  Because that’s a number we could change on paper, but why silence with supplementation a signal that the body needs help?  Will supplementation actually provide complete relief on its own?  Or can we use supplementation in the short-term while removing obstacles to health?  Tolle causum.  Tolle totum.  Treat the cause, treat the whole person.

Further Reading

Vitamin D: Chasing a myth? Nutritional Deficiencies: Could infection be the culprit? Vitamin D Supplements: What you miss out on

References

All images in this post are copyright of Beyond20Questions.

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The 2017 Integrative Medicine for Mental Health Conference

With each passing year full of conferences and seminars I gain new perspectives and solutions to the challenges we face in the field of medicine.  I also note trends from conference to conference on current concerns and emerging treatments.  As with most new concepts, it is good to approach some of these treatments with skepticism, but once I see the same treatment or concept mentioned several times in a row by different authorities in different realms of the health industry I sit up and take more notice.

My final conference of the year, the 2017 Integrative Medicine for Mental Health Conference further reinforced topics that were discussed in detail at the Ancestral Health Symposium earlier this year and at the Academy of Integrative Health and Medicine Conference at the end of last year.

Here are a handful of common takeaways I’ve gleaned throughout the year.    

1.    We live in a toxic world 2.    The uses of heat stress 3.    Mold and mycotoxins 4.    Too much bacteria, too many antibiotics 5.    Are your salads hurting you?  The role of oxalates

Life in a toxic world Toxicants are everywhere.  No wonder they keep showing up in conference presentations as well!  The effects of pollution were highly stressed at AIHM last year, popped up during AHS and were hammered home at IMMH.  This is a concern that we cannot afford to ignore, for the sake of both our planet and our personal health.  

The uses of heat stress Sitting through all these lectures on our current bombardment with toxicants would be a little depressing if we didn’t also have some form of solution.  If Billy Mitchell’s (The Robust Human) presentation at AHS piqued your curiosity about the use of sauna for detoxification, you would have also loved listening to Dr Genuis speak on the same topic at IMMH this year.  Stay tuned for Billy’s ebook on the use of sauna therapy!  

Mold and mycotoxins Most people are aware that mold in the house is not conducive to wellbeing.  The relationship between a moldy environment and poor health has been described in detail at multiple conferences this year.  But take a moment to consider how much mold you are eating!  This includes the blue-green fuzz on leftover bread but it also includes less obvious sources of mycotoxins such as nuts and cereal grains.  Related health concerns include memory loss, depression, anxiety and insomnia.  If that sounds like you, it may be time to give your diet a tune-up!  

Too much bacteria, too many antibiotics Just like houseguests, bacteria are great in the right amounts and the right places.   But the party is officially over when the guests accumulate beyond the capacity of your guest rooms and start taxing your resources.  This is a tricky situation.  Our poor lifestyles and overuse of antibiotics have led to a common situation in which people develop an intestinal overgrowth of bacteria or fungi.  To correct this, we then turn again to antibiotics.  Botanical medicines may provide an alternative route to conventional antibiotics, but these too must be used carefully.  To learn more about botanical medicine research, follow my research partner Guillermo Ruiz (3030 Strong) and I for our latest publications.  

Are your salads hurting you?  The role of oxalates Your body can take in oxalates, make oxalates and excrete oxalates.  What happens if you eat too many high oxalate foods (such as spinach, almonds, chocolate) or can’t process the oxalates appropriately?  A low oxalate diet was mentioned at both AHS and IMMH as a beneficial therapeutic intervention for unresponsive pain conditions, autism spectrum disorders, kidney disease and several others.  While oxalates may not be your specific problem, diet is an important consideration in achieving a state of wellbeing.

Next up is a series of posts on the trifecta of mental health supplements: vitamin D, fish oil and probiotics!  All are very popular, but are all of them effective?  Stay tuned to find out, the results may surprise you!

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The 2017 Ancestral Health Symposium

What I really love about PaleoF(x) and the Ancestral Health Symposium is the tremendous sense of community.  I have always encouraged my peers to attend these conferences for the fantastic networking opportunities in addition to the quality of the presentations. 

It was a huge privilege to be granted a chance to present on schizophrenia and evolution at AHS this year.  For those of you who have been asking me for the presentation recording, please check back here for it.  I will upload the presentation recording and associated article once they are available.  

If you couldn’t attend this year, here is a little taste of what you missed!  You can find these and other talks, including those by Robb Wolf, Chris Masterjohn, and other leaders of the paleo movement in addition to researchers such as Rand Akasheh on the Ancestral Health YouTube channel once they have been posted.  I hope I will see you there at AHS 2018!

Phyto-biological warfare: An evolutionary approach to botanical medicine

Heat stress as a tool in detoxification

Hunter-gatherer sleep: What can we learn?

How the ‘New Man’ inadvertently sabotages the first ancestral food

Innovative approach to health education

N of 1 experimentation

Primal Play!

Phyto-biological warfare: An evolutionary approach to botanical medicine Listen to a favourite and familiar story by my research partner Dr. Guillermo Ruiz of 30/30 Strong as he explores the good, the bad, and the ugly of the beautiful plants we use for making medicine.  These plants aren’t producing medicinal compounds just for us, so why are they producing them?  How do we benefit and what happens when we mess up?  

Heat stress as a tool in detoxification You may not spend a million hours (okay, maybe it isn’t quite a million hours) in a lab like I do, but chances are you are exposed to environmental toxicants in some way, shape or form throughout your daily life.  Billy Mitchell of The Robust Human presented a solution to this in the form of saunas and you will definitely want to keep an eye out for his upcoming ebook on how to implement heat stress in your detox routine!  

Hunter-gatherer sleep: What can we learn? This presentation by our friend Dan Pardi may challenge your assumptions on how much sleep we get in comparison to our ancestors.  Perhaps those of you who are still students and subscribing to ridiculous study hours aren’t too far off from your great-great-greats as far as sleep is concerned.  Listen in to learn more about ancestral sleeping habits and factors affecting optimal sleep.  You’ll also want to check out the newly launched HumanOS.me!  

How the ‘New Man’ inadvertently sabotages the first ancestral food Nick Mailer really has a gift for “mansplaining” in the most entertaining way possible the role of the modern male and the quest for gender equality in interfering with breastfeeding.  Easily one of the most humorous and refreshing talks at this year’s conference, you will definitely want to dig up the recording for this one.  

Innovative approach to health education I’m sure we’ve all made a fuss at some point in our school careers about how we felt we were being left out of what we actually wanted to be learning.  Well our friend Dr. Rob Abbott is doing something about it!  This year he presented an ebook he created for those who are interested in learning more about functional medicine, and the resources that are available on this topic.  If this sounds like the perfect resource for you, download the book here!  

N of 1 experimentation Aaron Blaisdell actually presented on a totally different topic, but I want to share with you another really cool project he’s involved in.  This is a website called Health Crowds, a place dedicated to gathering the results of N of 1 experiments.  Consider the huge potential here for both patients and physicians in discovering what works, what doesn’t and maybe some new ideas you would have never thought of trying!  

Primal Play If you haven’t met Darryl Edwards I must say you are missing out.  This is not your typical talk.  This is an everybody-get-up-and-move around-roll-on-the-floor-don’t-lose-your-balance-if-you’re-not-participating-I’m-going-to-notice kind of talk.  And a word of advice: don’t wear a dress and heels to these events.  That would be stupid.  I agree with Darryl Edwards on this one, being in a dress and heels was a poor excuse for not being able to participate.

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You saw how much fun we had at PaleoF(x)! Join us on our next adventure to the Ancestral Health Symposium 2017 in Seattle! I will be presenting on schizophrenia, Guillermo Ruiz will be sharing one of my favourite stories on carnivorous plants and Billy Mitchell will have a presentation on saunas! And of course, #cmj Chris Masterjohn will be there as well, and why would you miss out on that? Dan Pardi is bringing cassava cake. And have you met Allyson Chrystal yet? Add that to the list. There are so many reasons you should go.

Sign up with our discount code "AHSstrong" to receive $15 off your registration. Not only will you save money, but for every registration using this discount code we will be making a donation to Terros! Terros is a healthcare organization here in Arizona that provides crisis management, mental health, and addiction services to help build a healthier community!

I can't wait! See you there!