The Integrative Medicine Approach to Mental Wellbeing Biochemistry

The Integrative Medicine Approach to Mental Wellbeing: Biochemistry

By George Gillson MD PhD CCFP

At EvolveWell, the theme for October is Mental Wellbeing.  In this post I want to talk about an integrative medicine approach to helping patients who might be troubled by lower-grade, less intrusive complaints of depression, mood swings, and anxiety. I think the goal is to help all patients be as mentally resilient as possible. Mental illness includes persistent severe depression, profound anxiety, pronounced mood swings between depression and agitation/mania, post-traumatic stress disorder, losing touch with reality (delusions, paranoia, auditory hallucinations). These conditions all interfere markedly with daily life and require appropriate consultation and prescription medication.

Everyone has bad days, and sometimes bed weeks. We can all be moody and anxious at times.  What can we do to keep those times to a minimum?

A crude analogy would be to consider a computer with hardware and software. Can seeking out and addressing faulty/failing/malnourished biochemical pathways, i.e. “hardware”, help change our mental state?  Can we change our moods/mental state, despite biochemical issues, by “running a different program”, by thinking different thoughts and/or adopting a spiritual practice?

I would say the answer is a qualified “yes” to both questions. I’ll stick to the biochemical/hardware approach here and talk about the “changing the software” approach next time.

Sleep and Exercise

I`ll talk about depression to start but don’t worry (!): I won’t forget about anxiety. Sleep and exercise are the low-hanging fruit, things that you can get more of without it costing you much. A common thread joining those two is brain-derived neurotrophic factor (BDNF), a protein which is neurotrophic: it helps the brain to preserve and grow new connections between neurons (great for memory!) and regulates sleep architecture (Rahmani 2020).  A deficiency of BDNF is associated with increased depression and anxiety. If you’re not exercising at all, any increase in activity can make a difference (Schuch 2019). If you’re somewhat active, increasing the intensity and duration of activity can be helpful, as exercise increases BDNF. So does regularly getting enough sleep.

This brings me to Obstructive Sleep Apnea (OSA) in which the tongue relaxes in sleep, transiently but repeatedly blocking the airway, cutting the oxygen level in the blood/brain and inducing a disruptive startle response. OSA is often, but not always, associated with snoring. A sleeping partner may relate that you stop breathing during sleep without snoring. OSA is associated with depression (Kerner 2016, van Wyk 2020). If you are struggling with depression, waking up some mornings feeling depressed for no good reason, awakening with headaches or brain fog/slowed mental processing speed, then you need to be assessed for OSA by a Sleep Medicine specialist.

Brain Inflammation

We are now aware that depression can be associated with inflammation in the brain (Troubat 2021). OSA worsens brain inflammation. Conversely, exercise is able to promote increases in anti-inflammatory and anti-oxidant enzymes, along with increasing BDNF, as mentioned (Schuch 2019). IL-6 is a signaling molecule involved in inflammation; elevated serum IL-6 is associated with depression and OSA (Campos-Rodriguez 2021). Lots of things can increase IL-6 but it might be helpful to know your level if you struggle on and off with depression. It is a readily available test often ordered by Integrative Health practitioners.

Since we’re talking about brain inflammation, I need to mention the association of depression to low-grade head trauma such as concussion. Even seemingly-mild trauma can trigger significant brain inflammation in a surprising number of individuals. A study by Stein et al indicated that Major Depression and Post-Traumatic Stress Disorder were present in about 20% of study subjects. Please be sure to mention any history of head trauma to your Integrative Health practitioner if you have concerns about your mental wellbeing.

The foregoing discussion of BDNF and brain inflammation leads nicely into a discussion of the possible role of EPA, an Omega-3 fatty acid found in fish oil, in mitigation of depression. EPA is anti-inflammatory and appears to be a promising supplement to target low mood although the official verdict is still out (Appleton 2021, Deacon 2017, Liao 2021, Okereke 2021). Wide variation in dose may lead to inconclusive results in meta-analyses of the research. EvolveWell offers dried bloodspot fingerprick testing of essential fatty acids. I feel that if you are taking fish oil for any reason, it`s mandatory to get tested as the quality and absorption of fatty acids is hugely variable from product to product and person to person.

Below is a terrific Medical-grade brand of EPA/DHA I`ve been taking for years. I might note that to optimize my ratio of inflammatory to anti-inflammatory essential fatty acids, I needed to test.

Medical grade brand of EPA DHA

In case you were wondering, I didn`t forget BDNF! Read on.

Nutritional (Low-Dose) Lithium

At least five years ago, I read a book on the benefits of lithium for the brain, by James Greenblatt MD. Lithium isn’t consistently present in any one food to any great extent, so it’s not widely talked about. Most people get it from their drinking water and many localities don’t have much lithium in the water supply. In places where the groundwater is naturally high in lithium there is low incidence of depression, suicide and violent crimes. Who knew? Dr. Greenblatt advocates taking low-dose lithium orotate in amounts ranging from 5 to 20 mg once daily, for mood improvement and mental clarity. Come to find out that along with exercise and sleep, lithium increases BDNF. It has been referred to as an exercise-mimetic for its beneficial effects on the brain.

Nutritional (Low-Dose) Lithium

I was surprised at the large number of current (at time of writing) literature citations in the book regarding the safety and beneficial effects of low-dose lithium (aka Nutritional lithium). Note that lithium is used in Conventional Medicine for treatment of bipolar affective disorder at daily doses of hundreds of milligrams, with attendant side effects and risk of serious toxicity. If someone tells you that low-dose lithium is toxic, they are misinformed. Talk to your Integrative Health practitioner about lithium orotate as it isn’t available over the counter.

The Gut-Brain Axis

So. There’s not much lithium in food. But what about the overall influence of food on mood and behaviour?  This is a vast topic whose surface I can only skim but the relationship between brain function, the food we consume and the bacteria that live in our colons (the “microbiota-gut-brain axis”) is being intensively studied (Valles-Colomer 2019, Zalar 2018).

The food you eat can influence the bacteria who, in turn, send chemical messages (metabolites, cytokine signaling molecules, peptides, hormones) directly to the brain.  These chemical messages also influence nerve signals sent to the brain by peripheral neurons. These messages can be positive or negative.  For example, butyrate, a small bacterial metabolite, can be produced in your gut when you eat certain high-fibre foods. Low butyrate is associated with depression and poor cognitive performance (Stilling 2016). Diets such as the Mediterranean Diet which, among other things, can boost butyrate levels, has been shown to be effective in mitigating depression.

Foods can also influence the brain through the immune system, by provoking inflammatory immune responses in the gut that may be mirrored in the brain: this is the so-called “leaky gut, leaky brain” hypothesis (Obrenovich 2018).

For decades, Integrative Medicine laboratories have been offering testing to detect antibodies to many common (and not-so-common) foods that may be circulating in your blood at higher than average levels, indicating a sensitization of the immune system to those foods. This type of testing has been used at the EvolveWell clinic since inception and is widely used here and overseas. High levels of these antibodies have been shown by others to be related to conditions such as migraines, irritable bowel syndrome and inflammatory bowel disease.

In a small study, the highest food antibody levels were seen in patients with depression versus patients with irritable bowel syndrome and versus controls although this needs to be verified in larger studies (Karakula-Juchnowicz 2018). It also remains to be determined whether elimination diets based on removal of food antibody testing are helpful in mitigating depression. In my opinion, this type of testing is certainly worth consideration as part of the Integrative Medicine approach to depression.

Another frequently overlooked immune-related contributor to both anxiety and depression is sensitivity to gluten with or without the gastrointestinal manifestations of celiac disease (Losurdo 2018). Over the years, various patients presenting at EvolveWell with both anxiety and depression were subsequently found to have celiac disease. Their symptoms improved following the adoption of a gluten-free diet.  Patients whose celiac blood testing is negative may still find that their mental health improves with a gluten-free diet.


I’ve mentioned Nicotinamide (aka Niacinamide) several times now, in previous posts. It’s good for joint mobility, osteoarthritis, excess callus formation, elevated cholesterol, just to name a few. Beneficial effects on mood were noted by William Kaufman, MD, PhD throughout the 1940’s and 1950’s (Kaufman 1955). Supplementation with nicotinamide may prevent conversion of tryptophan to kynurenine, a potentially inflammatory metabolite, thereby increasing the availability of serotonin, the feel-good neurotransmitter (Oxenkrug 2010).

Hormones and Mental Wellbeing: Vitamin D, Sex Steroids

I know you’re wondering why Vitamin D is lumped in together with the sex steroids estradiol, testosterone and progesterone. This is because I couldn’t figure out where else to talk about it. Also, the active form of Vitamin D is indubitably a hormone and is also derived from cholesterol, so it deserves to rub shoulders with the other steroid hormones.

I’m citing two example studies on Vitamin D supplementation and depression which will illustrate an important concept. One was a one-year placebo-controlled study in individuals aged 60 to 80 years receiving 1200 IU/day Vitamin D3 (de Koning 2019). The results showed no effect on clinically relevant depressive symptoms. The accepted way to follow Vitamin D3 supplementation is via measurement of 25-hydroxyvitamin D3 (25OHVD) in serum. The average 25OHVD level after 6 months of supplementation was 85 nmol/L ranging up to 100 nmol/L.

The other study was an 8-week study of younger, mildly- to moderately-depressed patients (mostly females) who received 50000 IU Vitamin D3 every two weeks (approximately 3500 IU/day). On average, they experienced a significant improvement in mood. The mean 25OHVD  level at 8 weeks was 128 nmol/L ranging up to 150 nmol/L in some patients.

Potential confounders aside, the lesson here is that Vitamin D3 supplementation can help mood but dosing matters and needs to be guided by testing. While 80 nmol/L is cited as the conventional target level for 25OHVD, Integrative Medicine practitioners typically aim for 125 to 175 nmol/L to support optimal wellbeing including mental wellbeing.

I’ve covered a lot of ground to this point but I’ve left one of the most important aspects of mental wellbeing to last and that is balancing of sex hormones (estradiol, testosterone, progesterone) along with the adrenal hormones cortisol and DHEA. Like food and mood, the literature on this topic is vast and can’t easily be summarized here.

Women are prone to mood issues (anxiety and depression) in the postpartum period, during the luteal phase in cycling women, during the premenopausal years (when estrogens levels can be high and fluctuate erratically accompanied by low/absent progesterone) and during/after the menopause transition when estrogens and progesterone are waning. Testosterone wanes in males with aging and with development of abdominal obesity, accompanied by depression and anxiety. Elevated cortisol levels associated with any kind of stress can wreak havoc on hormone balance. Low cortisol levels can be associated with fearfulness and anxiety. In short, the balance of sex steroids and adrenal steroids can have a huge influence on mental wellbeing.

I am making these observations based on years of experience and reading of the literature. My laboratory, Rocky Mountain Analytical, offered hormone testing (saliva and urine) for almost twenty years. I consulted with hundreds of Integrative Health Practitioners along the way regarding their patient’s hormone test results. My wife, Jeanette Queen, RN, NP, MSc, clinician/owner of EvolveWell, has been using saliva, urine and serum hormone testing on patients for almost twenty years. I speak for us both when I say that proper assessment and balancing of hormones can be life-changing and can certainly ameliorate depression and anxiety. Note that although they are not steroid hormones, thyroid hormones also play a key role and need to be included in the overall approach.

Often, it’s not enough to simply address biochemistry. Gaining an understanding of how past life events have made us who we are today can be invaluable. If we haven’t been in optimum mental shape for a while, we can tend to adopt habits of thinking and beliefs about ourselves and how the world works that might also need changing. Maybe we need help to change lifestyle patterns that got us into trouble in the first place.

As I mentioned in the introduction, “changing the programming” is the other powerful approach to mental wellbeing.  Just me for the next post when I’ll talk about the role of counselling.

George Gillson MD PhD

Author: George Gillson, MD, PHD, CCFP
EvolveWell Medical Director


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