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The Underlying Drivers of Anxiety + Depression & Natural Remedies To Try

Your Go-To Guide To The Wonderful World Of Tea Dr. Will Cole

Recently, I spoke with a new patient who was struggling with debilitating anxiety, depression, brain fog, and fatigue. She’s in her mid-30s and can’t even get out of bed some days because her life is so wrecked by health problems which all seem to be brain-related.

Over the past few years, she’s seen dozens of doctors and specialists. All of her labs and tests came back “normal,” so she was given antidepressants and anti-anxiety medications. Yet, she knew instinctively that something was wrong that wasn’t being addressed. This brought her to a webcam consultation with me, from across the country.

Why am I telling you this? Because this is no isolated incident. This patient is just one of many I’ve seen over the years experiencing similar unexplained symptoms, who have not found answers from conventional medicine.

Brain issues are an epidemic. Depression is the leading cause of disability worldwide, and anxiety disorders affect more than 40 million Americans. Many people spend years not knowing why they’re suffering. As a functional medicine practitioner, I have to ask, why? Why this catastrophic rise in brain problems? At last, science may have uncovered an answer that could explain the one common factor among many of these otherwise highly differentiated cases: an inflammatory-immune response in the brain.

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FUNCTIONAL MEDICINE FOR PEOPLE AROUND THE WORLD

The Rise of Autoimmune Brain Problems

Autoimmune conditions themselves have also grown to epidemic proportions in our lifetime, affecting an estimated 50 million Americans. Today there are close to 100 recognized autoimmune diseases, with 40 more disease processes likely having an autoimmune component, and I predict that we will uncover more still.

Autoimmune disease attacks the body’s own tissues in an overzealous attempt to slay invaders like viruses or bacteria, and frequently attack specific areas of the body – the brain included.

Millions of people’s immune systems are attacking their brain and nervous tissue, and this particular problem is drastically under-diagnosed. Autoimmune brain diseases like multiple sclerosis, Parkinson’s, Alzheimer’s, and autism are affecting people now more than ever before in human history. Even Celiac disease, so often considered a GI disease, can be strictly neurological in its symptoms, leading to severe anxiety disorders and other brain problems.

So what gives? Fascinating new research is looking at how inflammation can damage the brain’s protective blood-brain barrier (1) (BBB) and possibly lead to brain problems such as what is now often referred to as neurological autoimmunity.

This inflammation activates the brain’s immune microglia cells, which can trigger an inflammatory-autoimmune response. In other words, people’s immune systems might be attacking their brain and nervous tissue in response to inflammation that could have started somewhere else entirely, such as in the gut.

How is depression related to inflammation?

So what does depression have to do with inflammation? As it turns out, a lot. Inflammation has the potential to trigger depression, exacerbate it, and even be the root cause. As the authors of a study (2) published in Frontiers in Immunology wrote: “While many factors play a role in the development of depression and fatigue, both have been associated with increased inflammatory activation of the immune system affecting both the periphery and the central nervous system (CNS).” In the same study, they explain that antidepressants have been shown to decrease inflammation, and higher levels of inflammation at baseline is often a predictor of how well depression treatments will work.

Pretty shocking, right?

Even more, research has also shown (3) that depression is more common in patients with autoimmune diseases compared to other chronic conditions — even chronic degenerative diseases —  which can likely be explained by what they have in common: chronic inflammation.

How is anxiety related to inflammation?

According to the National Alliance on Mental Illness, anxiety disorders, which range from generalized anxiety and social anxiety to post traumatic stress disorders, affect more than 40 million Americans. Depression was the first mental health condition to be related to inflammation, but due to the similarities between anxiety and depression — and the fact that they often occur together — anxiety was not far behind.

Research has shown that anxiety symptoms are correlated with increased levels of inflammatory cytokines, which are inflammatory substances secreted by immune cells. Higher levels of inflammation have also been observed in patients with PTSD, panic disorders, and generalized anxiety disorder. Other studies, like one published in Behavioral Neuroscience (4), showed that people with lupus have higher levels of anxiety due to inflammation in the brain.

If you suspect chronic inflammation may be at the root of your anxiety and/or depression, you can take my Inflammation Spectrum Quiz to see just how much inflammation is impacting your wellness.

The Anxiety/Depression and Autoimmune Connection

In order to be diagnosed with most autoimmune diseases, there must first be evidence that the immune system has destroyed a significant amount of tissue – in this case, the brain or nervous system tissue. Yet, autoimmune disease starts long before conditions are sufficient for an official diagnoses. Typically it progresses along an autoimmune spectrum in this order:

  1. Silent Autoimmunity: Labs show up with positive antibodies, but there are no noticeable symptoms.
  2. Autoimmune Reactivity: There are positive antibody labs and some symptoms, but no radical tissue destruction.
  3. Autoimmune Disease: There is enough body destruction to warrant an official diagnosis.

The patient I mentioned earlier is like the countless other people on the autoimmune spectrum: Not sick enough to be labeled with an autoimmune disease, but demonstrating symptoms that interfere with her life and function.

Why aren’t we catching these diseases sooner? Brain destruction should never be taken lightly. Research has shown (5) that depression and anxiety are more common in patients with autoimmune diseases than chronic degenerative conditions, likely due to the direct effect of inflammatory cytokines on the central nervous system. Further, someone with one autoimmune disease has a higher chance of suffering an immune system attack on another system, such as the brain. This is called polyautoimmunity. (6) For example, one study (7) looking at lupus found higher rates of anxiety due to inflammation in the brain.

Keep in mind these studies are using people already diagnosed with an autoimmune disease. Just think about all of those undiagnosed in stage 2 of autoimmune reactivity, and what is likely going on inside their bodies and brains!

Functional medicine practitioners don’t believe in waiting until someone’s health declines enough to be labeled with a disease and matched with a corresponding drug. Instead, autoimmune reactivity should be ruled out first, or caught as early as possible. I suggest thinking about this now. For example, you may want to consider autoimmune reactivity as the culprit in your health symptoms if:

  • You have a family history of autoimmune conditions
  • You have a family history of mental health problems
  • You’ve been diagnosed with an autoimmune disease
  • You’re not improving with medications or behavioral therapy

If you suspect autoimmune reactivity might be leading to depression or anxiety issues now or in your future, here are a few interventions you can take right now:

1. Ask your doctor about having these five tests done:

  • Autoimmune Reactivity Brain Labs: These blood labs can look for raised antibodies, including GAD antibodies, which attack the enzyme used to make the calming neurotransmitter GABA.
  • Microbiome Labs: Your gut is your “second brain,” where 95% of your “happy” neurotransmitter called serotonin is made. Leaky gut syndrome and SIBO, or small intestinal bacteria overgrowth, are both associated with many autoimmune brain conditions because they can lead to leaky brain.
  • Wheat and Gluten Testing: A comprehensive look at gluten intolerance includes looking at antibodies to transglutaminase 6 (TG6). These are rarely tested in a mainstream medical setting, and yet some studies show they can damage neurological tissue. A functional medicine doctor can order these tests for you.
  • Food-Immune Reactivity Labs: Sugar and dairy are common food triggers for autoimmunity, but I’ve also seen the healthiest plant foods be immunoreactive in some patients. The diet that works for one person may not be right for you – and labs can help cut through the autoimmune food confusion.
  • Predictive Autoimmunity Labs: Elevated antibodies against the adrenal glands are another contributing factor to depression and anxiety. This lab looks for this particular issue, and can also discover undiagnosed autoimmune thyroid problems like, Hashimoto’s or Graves’ which can also trigger depression or anxiety issues. Knowing your antibodies can give you insight into why you feel the way you do.

2. Look into natural autoimmune medicines.

Studies suggest that optimizing vitamin D (8) and intracellular glutathione (9) levels with supplementation can help support Regulatory T Cells to balance the immune system, and TH-3 activity, which suppresses autoimmunity. Other natural options include supplementing with curcumin (10) and resveratrol, (11) two powerful natural anti-inflammatories, and TH-17 cells in autoimmune cases.

The Top Anxiety Triggers

I’ve dealt with anxiety in the past, so I will be the first to agree with you that it really sucks. This comprehensive (if I do say so myself) list is a combination of some of the most common physiological anxiety triggers and aggravators. All health issues – mental health included – are most of the time multifactorial. Every piece of the anxiety puzzle is unique. The factors on this list are interconnected because your body is brilliantly interconnected as well.

1. Caffeine

Let me introduce you to your caffeine gene, CYP1A2. This little guy has the final say on how you handle tea, coffee, or any other form of caffeine. People with the fast metabolizer version of this gene get tons of cool health benefits from coffee and tea, but people who have the slow metabolizer gene can be feeding anxiety with each sip of coffee.

2. Sugar

The sweet stuff is fuel for the anxiety fire. In fact, many studies have shown (12) that the more sugar you eat (specifically the refined kind), the worse (13) your anxiety can be. And research (14) has found that high levels of serotonin are, in fact, making anxiety levels worse. And guess what also raises serotonin levels? Yep, you guessed correctly. Sugar.

So, if you struggle with anxiety every time you eat sugar you are contributing to the neurochemical reaction of anxiety and further perpetuating your dependence on prescription drugs.

And it all can be traced back to your microbiome. The correct balance of bacteria in your microbiome is responsible for exactly how healthy you are. You can either feed good bacteria or bad bacteria by the foods you choose to eat. Sugar is the perfect fuel for all types of bad bacteria including yeast overgrowths such as Candida.

Studies have shown (15) that lower levels of beneficial bacteria, Bifidobacterium longum and Lactobacillus helveticus are found in those struggling with anxiety.

Then, there's blood sugar. When you consume too much sugar it can lead to blood sugar spikes, imbalances, and insulin resistance and when your blood sugar is on a roller-coaster it throws off you’re your hypothalamic-pituitary-adrenal axis (HPA axis) which is responsible for releasing your stress hormone cortisol. Your “fight or flight” response that happens when you are stressed or anxious is due to an increased stream of cortisol. Because of this constant up and down your body never really gets a chance to calm down which further perpetuates the feelings of anxiety.

It’s been shown (16) that diets mainly comprised of sugar and high glucose foods raise anxiety but by switching to a low-sugar diet can drastically lower anxiety after just 4 weeks!

3. 5HT2A receptor activation

The brain stem hypothalamus, and prefrontal regions of the brain have what is called 5HT2A receptor sites. Activation of these sites can be linked to depression, anxiety, and chronic fatigue. Stress and other items on this list, can trigger 5HT2A activation.

4. Irregular menstrual cycles

In my anxiety patients, I often see underlying hormonal imbalances during different times of their cycle, especially before menstruation when there is an imbalance between progesterone, estrogen metabolites, and cortisol – all of which can fuel anxiety.

5. HPA-axis dysfunction

Your brain-adrenal communication line is what is known as the hypothalamic-pituitary-adrenal axis, or HPA-axis for short. This is often one of the top contributing factors to anxiety. What is commonly known as “adrenal fatigue” is actually a brain-based issue. Bringing balance back to HPA-axis function can take time but is crucial in order to overcome anxiety.

6. Thyroid problems

Each cell in your body has a thyroid receptor site – meaning, if your thyroid isn’t working well, then nothing is. Underlying thyroid pathway problems like autoimmune thyroid (Grave’s or Hashimoto’s disease) or thyroid conversion issues can be contributing to anxiety.

7. Alcohol

Alcohol can often be used as a way to curb anxiety but that is far from a good idea. Research has shown that alcohol consumption is associated (17) with a worsening of anxiety disorders over time. Studies have also shown (18) that drinking alcohol can rewire the brain and contribute to feelings of anxiety.

8. High LPS

Research often refers to your gut as your “second brain.” Your gut and brain were formed from the same fetal tissue while in the womb and are inextricably linked for the rest of your life by the gut-brain axis. Gut problems like “leaky gut syndrome” are associated with anxiety and other brain problems. This can happen because of increased levels of lipopolysaccharides (LPS) – bacterial endotoxins located on gram-negative bacteria in the microbiome. When your gut lining is compromised they are able to pass into the bloodstream and contribute to anxiety and other health problems.

9. Inflammation

NFkB is another inflammatory bad guy that is associated with anxiety. People with lower levels of NFkB often have lower rates (19) of anxiety as well. We are continuing to find more and more research that inflammation is a huge factor in depression, anxiety, fatigue, and brain fog. There is actually a whole field of research known as the cytokine model of cognitive function on how inflammation messes with our brains.

10. Viral infections

Multiple studies (20) have found links (21) between mental health issues like anxiety with Epstein-Barr virus (EBV) (22) and cytomegalovirus (CMV).

11. Lyme disease

Sadly, Lyme disease is reaching epidemic proportions. Neurological symptoms, like anxiety, are one of the most chronic symptoms that I see in people dealing with chronic Lyme disease.

12. Methylation impairments

Methylation is your body’s biochemical superhighway that makes our brain, gut, and hormones run optimally. People with methylation impairments such as the MTHFR gene mutation, have a higher risk for GABA/glutamine imbalance, low lithium levels, and high homocysteine inflammation which is a recipe for anxiety. But there is good news! You can do a lot to mitigate risk factors.

13. Food intolerances

It all comes down to the food that you eat – or don’t eat. Clinically, I have found that just by removing a patient’s particular food sensitivity like gluten or dairy, it reduces or even eliminates their anxiety.

14. Blood sugar problems

Blood glucose balance is essential for brain health. If your blood sugar goes up and down, it is anything but fun. Thankfully, you can do a lot to naturally balance your blood sugar.

15. Nutrient deficiencies

Your body needs each vitamin and mineral for a specific purpose. When I run labs for patients dealing with anxiety I look for low levels of vitamin D, magnesium, and lithium which are all linked to anxiety.

Any of these factors, or a combination of some of these, can be responsible for your anxiety. Luckily, it can be beneficial to take the time to get accurate testing and work with a functional medicine practitioner to get to the root cause of your anxiety. My hope is that you’ll find some relief in no time!

Natural Tools To Overcome Depression

Depression affects over 300 million people (23) worldwide. A proper balance of chemicals in your brain, such as norepinephrine, dopamine, and serotonin, are needed for proper mood stabilization. Norepinephrine is responsible for how well we deal with stress, serotonin is the biggest player in regulating our mood, and dopamine acts as our pleasure chemical allowing us to enjoy life.

Anti-depressants can be very helpful and in some cases, lifesaving, when it comes to treating depression. However, when used on a consistent basis it can become an issue. Medications end up treating symptoms rather than the underlying cause. It becomes a situation of disease management rather than healing. And what happens when the medication comes with a whole list of side effects all their own? Weight gain, lowered sex drive, fatigue, and suicidal thoughts are all potential problems can go along with taking an antidepressant.

The majority of antidepressants are designed to increase serotonin levels which are lower in cases of depression. Thankfully, there are many ways to naturally increase these neurotransmitters and start to heal the reasons behind why serotonin is low to begin with.

1. Heal your “second brain.”

Your brain health is directly correlated to the status of your gut health. These two systems form from the same fetal tissue and continue their connection through the gut-brain axis for the rest of your life. The two proteins occludin and zonulin control the permeability of both the blood-brain barrier and gut lining. When there is increased permeability your immune system has to work in overdrive to fight off invaders which leads to chronic inflammation.

Depression has been linked (24) to imbalances in the beneficial bacteria Bifidobacterium and Lactobacillus. A daily probiotic with these two strains is a great way to boost your microbiome health. Including fermented foods such as sauerkraut and kimchi in your diet will also up the beneficial bacteria in your gut.

2. Go keto.

The ketogenic diet is abuzz in the health world. The diet consists of high-fat, moderate protein, and low carbohydrates. The whole goal is to turn your body into a fat burner instead of a sugar burner by relying on ketones produced from fat for energy rather than glucose. About 60% of your brain is made of fat and 25% of your body’s total cholesterol is found in the brain. It makes sense that in order to support optimal brain health you would want to feed your brain exactly what it is made of. It’s no surprise then that research shows (25) ketogenic diets to have similar effects to antidepressants. Even just adding more healthy fats into your diet, such as wild-caught fish, can greatly improve (26) symptoms of depression.

3. Intermittent fast.

Going without food for periods of time can help to reduce (27) inflammation. This can be especially helpful since depression is considered a neuroinflammatory condition. If you want to learn more about the different ways to fast check out my article on the subject.

4. Boost your neurotransmitters.

There are certain activities that boost neurotransmitters. For example, ever heard of runners’ high? There’s a reason for that saying – physical activity releases endorphins to give you that elated feeling even if you just completed the hardest workout of your life. Listening to music you love, learning a new skill, (28) or indulging in aromatherapy can all be fun ways to hack your way to happiness.

5. Hygge it up.

Stress can be implicated in almost every health problem and depression is no exception. As a functional medicine practitioner I often see a correlation between the onset of patients symptoms after a period of intense stress. When you are stressed, your brain tells your adrenal glands to release cortisol and adrenaline. But if you aren’t able to calm down, your body doesn’t get a break and it can even change the structure of your brain and increase inflammation (29) which leads to depression. (30) So take a break from whatever is stressing you and set aside some Danish-inspired hygge to practice self-care and zen out.

6. Correct nutrient deficiencies.

The correct amount of specific nutrients is required for your body to run efficiently. A lack of B vitamins is the most common issue I see associated with depression. Methylation is your body’s biochemical superhighway and is responsible for making your feel-good neurotransmitters. In order to have properly functioning methylation you need B vitamins. In fact, it has been shown (31) that antidepressants don’t always work as effectively if folate is low.

7. Engage in light therapy.

Have you ever experienced the winter blues? This is due to a lack of sunshine which increases serotonin and decreases vitamin D. While you can get vitamin D in through diet and supplementation, sunshine is the most bioavailable. Bundle up and take advantage of sunny days any sunny days and enjoy the different winter scenery on a walk! But, if the thought of even being out in the cold gives you goosbumps, light therapy boxes are another option. They have been shown to reduce (32) depression symptoms by mimicking the sun.

8. Talk to someone.

Cognitive behavior therapy (CBT) was originally developed to treat depression and is still considered one of the most effective types (33) of therapy for depression. The whole idea is to improve negative emotions by changing destructive thoughts and behaviors through developing personal coping strategies for each person. In many cases, it can actually be just as effective as medication!

9. Supplement with St. John’s wort.

The power of St. John’s wort has caught on in Germany. This natural herb is used and recommended more often than Prozac and other antidepressants by doctors! Long-term studies have supported its ability to stabilize mood but more research (34) needs to be done to better determine just how effective it is.

Foods That Help Alleviate Depression + Calm Anxiety

In many cases, underlying deficiencies could also be contributing to depression and anxiety. Food can help address these and can also ease symptoms as you work to rebalance your system. These 13 can help address the common underlying dysfunctions that contribute to anxiety disorders, and give you a little symptom relief, too:

1. Oysters.

This superfood of the sea is a great way to balance the proper trace mineral ratio to help manage your stress levels. Research has correlated (35) an imbalance of zinc to copper, or more specifically, increased copper and decreased zinc – with symptoms of anxiety. That’s likely because this trace mineral ratio is responsible for proper neurotransmitter function as well as adaptation to stress.

I run trace mineral labs for my patients to see if this is a factor in their case. If it is, it’s time to enjoy some oysters on the half shell because they are packed with zinc! You’ll get even more benefit if you avoid grains and legumes, which contain phytic acid, an anti-nutrient that can bind to zinc and block its absorption.

2. Chamomile Tea.

The ultimate calming tea, chamomile is an easy and delicious anti-anxiety medicine. This soothing, mild tea was shown (36) to significantly decrease anxiety symptoms in just a few weeks of regular use.

3. Rooibos Tea.

Another powerful stress-busting tea is rooibos, or African red bush tea. This delicious red tea can infuse your day with a natural sense of calm. Researchers are investigating how rooibos tea may work by having a balancing effect (37) on cortisol, the body’s main stress hormone.

4. Full-Fat Kefir.

With more than 100 million neurons, your gut’s health is essential to manage anxiety. In functional medicine, the gut is considered the “second brain” because it’s home to 95% of your “feel good” hormone serotonin, and bacterial imbalances (38) in your gut can alter brain chemistry. Kefir, an ancient fermented dairy drink, might just be the most powerful source of probiotics ever! It also has fat soluble vitamins A, D, and K2, all important for brain health.

5. Turkey.

It may be a cliché that people are tired after Thanksgiving dinner, but there is a reason – it’s the tryptophan in the turkey. Tryptophan is a precursor to the neurotransmitter serotonin, which helps you to feel calm. Especially when it comes in the form of meat, tryptophan has been shown (39) to reduce the incidence of anxiety disorders.

6. Turmeric.

This exotic spice is also an anti-inflammatory powerhouse and because of this, can be a profound mood-booster. Curcuminoids, the antioxidants in turmeric, have a neuroprotective quality and were shown in a randomized controlled trial (40) to be an effective option for major depressive disorder, which is often closely linked to anxiety disorders.

7. Organ Meats.

Organ meats are some of the best sources of nutrients for beating anxiety, such as zinc and vitamin D. They also contain copious amounts of choline, (41) needed for the synthesis of the neurotransmitter acetylcholine. Liver is also abundant in B vitamins, which we all need for methylation, a metabolic process in the body that is responsible for proper synthesis of neurotransmitters (42) that regulate mood. If you aren’t vegetarian and are willing to go there, organ meats can really boost your nutrient intake, especially if you have an MTHFR mutation and elevated homocysteine levels (I test these in my patients to ensure optimal neurotransmitter metabolism and methylation).

8. Avocados.

This superfruit (not all fruits are sweet) is great for supporting brain health and easing anxiety. They contain potassium, which helps naturally lower blood pressure, and also beneficial B vitamins and monounsaturated fats that we all need for both neurotransmitter and brain health.

9. Dark Chocolate.

Vindicated! Science has confirmed that chocolate really does boost your mood. A randomized, placebo-controlled trial (43) published in the Journal of Psychopharmacology revealed that people who drank a dark chocolate drink, equal to about 1.5 ounces of dark chocolate per day, reported feeling calmer than those who did not.

10. Asparagus.

Low levels of folic acid are linked (44) to neurotransmitter impairment, which can lead to anxiety, and a 5.3-ounce serving of asparagus provides 60% of the recommended daily allowance for folic acid! Asparagus is also sulfur-rich and contains moderate amounts of potassium, which can lower blood pressure.

11. Adaptogenic Herbs.

Adaptogenic herbs like ashwagandha, rhodiola, and holy basil are some of the tools I use to optimize brain-adrenal function in patients. One common hormonal signaling pathway dysfunction I find in patients struggling with anxiety disorders is the brain-adrenal axis. This hypothalamic-pituitary-adrenal (HPA) axis is part of your sympathetic “fight-or-flight” response and can play a role in adrenal fatigue. Stress hormones, like cortisol, can cause (45) serotonin receptors to become less sensitive to activation.

12. Leafy Greens.

Plant foods like Swiss chard and spinach are rich in magnesium, the natural “chill pill,” which also helps regulate (46) the brain-adrenal axis, so if you struggle with stress and anxiety increase the greens!

13. Fatty Meat.

Omega-3 fats have been shown (47) to decrease anxiety, likely due to their pacifying effect on inflammation. Omega-rich foods like Alaskan salmon and grass-fed beef can help decrease inflammation and help cortisol and adrenaline from spiking.

If you want to learn more about your own health case please check out our free health evaluation. We offer webcam as well as in-person consultations for people across the country and around the world.

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Dr. Will Cole, IFMCP, DNM, DC, leading functional medicine expert, consults people around the world via webcam and locally in Pittsburgh. He received his doctorate from Southern California University of Health Sciences and post doctorate education and training in functional medicine and clinical nutrition. He specializes in clinically researching underlying factors of chronic disease and customizing a functional medicine approach for thyroid issues, autoimmune conditions, hormonal imbalances, digestive disorders, and brain problems. Dr. Cole was named one of the top 50 functional medicine and integrative doctors in the nation and is the best selling author of Ketotarian and The Inflammation Spectrum.

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