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!Read More
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). You may feel like you are supposed to be on a probiotic for general health and I’ve seen others express guilt if 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 .
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 practice. 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 . When you impair your normal gut bacteria with something like antibiotics, then the probiotic bacteria are better able to colonize .
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 .
How do they do this? The probiotic bacteria secrete antimicrobial agents that inhibit your own bacteria from growing. They also increase inflammatory mediators .
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 !
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 .
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 .
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 . 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 . This allowed the bacteria to gain resistance (potentially via increased efflux pumps) to a range of antibiotics, including amoxicillin, chloramphenicol, tetracycline, fluoroquinolones, and aminoglycosides . Not only were these bacteria becoming resistant to the antibiotics tested one by one, they also exhibited resistance to multiple antibiotics .
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.
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 . 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 .
Our gut talks to our brain through the vagus nerve, the immune system, microbial metabolites (like short-chain fatty acids), neuropeptides, hormones and cortisol . 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 . 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 .
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 . They also demonstrated slightly lower ratings of perceived stress and better performance on a learning task . 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 !
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 .
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 .
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 . Another study of healthy male volunteers found no effect of the probiotic Lactobacillus rhamnosus JB-1 on stress .
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 . 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 . 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 . 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 . It has even been suggested that losing tolerance for these little guys can cause inappropriate immune responses to “psychosocial” antigens such as interpersonal rejection . Inappropriate immune responses interfere with our ability to handle rejection, conflict, or even tolerate our imperfections as well . 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 . Since then, we’ve realized that many types of antidepressants including MAOIs, TCAs, SSRIs and even ketamine have antimicrobial effects . 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 .
Patients with Major Depressive Disorder (MDD) have been documented to have lower levels of Bifidobacterium and Lactobacillus . 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 . 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 . Interestingly, those consuming fermented milk had increased levels of Bifidobacterium. This association was seen in patients, but not controls .
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.
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 . 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 . 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 .
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) .
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 . 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 . 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 . After eight weeks of supplementation, 75% of these patients had significantly improved depressive symptoms and quality of life . 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 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 . 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 .
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 . 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 . Bifidobacterium is a species of bacteria associated with decreasing anxiety-like behaviour in animal studies, as well as promoting healthy gut linings . 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 . 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 .
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 .
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) . 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 .
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 !
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 .
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 . 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 .
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 . 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 . 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 .
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 .
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 .
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 ! 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 . 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 .
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 . 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 . 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 . 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 . Treatment with SSRI’s reduces the production of amyloid-beta proteins in the brain, suggesting that increasing serotonin levels might help reduce risk . 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 .
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 . 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 . These microbes act like a timekeeper for the bears. This fluctuation is thought to occur via seasonal changes in light and diet .
The other influence is nature. Our environment is full of microbes ! 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 ? 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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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.
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 . In humans, there does not seem to be a link between prenatal vitamin D levels and psychotic episodes , but there is some relationship between childhood vitamin D deficiency and the later development of schizophrenia .
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 ! 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 .
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 .
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 . 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 .
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) .
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 . 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 . 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 . In addition, gender can influence COMT activity through testosterone (increasing activity) and estrogen . Cannabis use and childhood maltreatment also interact with the COMT genotype and psychosis risk .
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 . However, adding vitamin D actually reduced survival in the animal model ! It is thought that vitamin D suppresses the necessary immune response for controlling early infection .
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.
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 . 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 . 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 .
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 . 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.
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 .
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 .
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 .
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 .
While one study found improvement in autism scores with the use of vitamin D supplementation, the trial did not include a control group . 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 . 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 . 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 .
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 . The second was a smaller study, and found no effect of vitamin D supplementation over five months .
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 . 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 . 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.
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 . This effect was seen with female children, but was not significant for male children .
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 .
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 .
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 . 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 . 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 .
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 . There are additional concerns with recommending exercise in this patient population, one of which would be the potential for appetite suppression .
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 . 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 .
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 .
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 . 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.
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.
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