Category: Research

Interview by Sheldon Baker

 

David Perlmutter, MD, is a Board-Certified Neurologist and six-time New York Times bestselling author whose work focuses on the intersection of neurology, nutrition, and brain health. A Fellow of the American College of Nutrition, he serves on its Board of Directors and on the Editorial Board of the Journal of Alzheimer’s Disease. His books, including the #1 bestseller Grain Brain, have been published in 32 languages and sold over a million copies. Dr. Perlmutter lectures globally at leading institutions and has been featured on major media outlets including 20/20, CNN, The Today Show, and Oprah. His contributions have earned him numerous national and international awards for clinical innovation and leadership. His upcoming book, Brain Defenders, focuses on the pivotal role of microglia, the brain’s immune cells, in protecting, repairing, and reprogramming the brain for lifelong resilience.

Brain Defenders reveals the powerful story of your brain’s immune guardians (microglia), and how lifestyle choices can turn them into either fierce protectors or hidden saboteurs. The book directly challenges the notion that we now have meaningful treatments for diseases like Parkinson’s and Alzheimer’s. Despite FDA approval for drugs that reduce beta-amyloid, the book reveals that these drugs are not impactful and actually profoundly dangerous. Packed with cutting-edge science and practical steps, Brain Defenders helps readers take charge of their long-term brain health and unlock lasting cognitive vitality.

 

Sheldon Baker is an InnoVision contributing editor. His freelance editorial content can also be found in several lifestyle publications, and as CEO of Baker Dillon Group LLC, he has created numerous brand marketing communications and public relations campaigns for health and wellness organizations. Contact him at [email protected].

 

Integrative Medicine: A Clinician’s Journal (IMCJ):  In your new book Brain Defenders, you argue that we’ve been targeting the wrong thing in Alzheimer’s disease.

 

David Perlmutter, MD: For sure.

 

IMCJ: What is the core fallacy behind the amyloid based treatment model?

 

Dr. Perlmutter: I think that it’s quite obvious that the model gained so much traction in the late 1980s because there was this need, I believe, to find a single cause. Alzheimer’s is not a disease characterized by a single cause or single event. There are multiple issues that lead to a good brain going bad. And I feel to be fair, the reason there’s always been emphasis on looking for single cause, is it lends itself then to what’s called monotherapy. If we could identify a single cause related to Alzheimer’s disease then we might target a therapy at that single cause and next thing you know we have a blockbuster. The amyloid hypothesis was really based on flawed and doctored research. That is what’s public knowledge now. Ultimately, the therapies that were an outgrowth of that hypothesis haven’t worked. The idea that we could rid the brain of beta amyloid using monoclonal antibodies has been proven to be true. And yet, the effect on the disease course is almost none whatsoever in the face of potential death from the medications, or at least a significant risk of developing a potentially threatening side effect like ARIA which is amyloid-related imaging abnormalities. It basically means developing changes on your MRI scan that are either indicative of brain hemorrhages or areas of swelling.

 

IMCJ: Where do we go from here or in other words, the next steps to treatment?

 

Dr. Perlmutter: The risk-benefit ratio of what has evolved out of the FDA approval of this medication, which is really at this time, the go-to approach for the treatment of Alzheimer’s disease is, to be kind, lacking and unfair. We recognize now that a certain number of Alzheimer’s patients do accumulate beta-amyloid in their brains. We also recognize that it’s fairly common. But it is a consequence and not the cause. We certainly see the evidence of individuals developing aggressive Alzheimer’s with no appreciable beta amyloid in their brains. Similarly, we see evidence of individuals who are randomly tested as part of research and have quite a bit of beta amyloid accumulating in their brains and yet are cognitively quite intact. These findings really cause us to call to question the whole amyloid hypothesis. And now, in the past several years, we recognize that there is a lot going on upstream of the accumulation of beta amyloid, that really represents mechanistically what is involved fundamentally in terms of the pathogenesis of that disease. Interestingly, this shift in immune functionality in the brain that we are talking about is seen to be involved across the spectrum of neurodegenerative conditions. So, it’s really quite an exciting development in neuroscience and neurology that we see such a global mechanism now being involved across the array of neurodegenerative conditions.

 

IMCJ: You also say that Alzheimer’s is not primarily a disease of plaques and tangles, but of misdirected immunity. So how do microglial cells reframe the entire conversation?

 

Dr. Perlmutter: What we’re now recognizing with research is becoming very exciting and captivating. Over the past five years it has been the central role of the brain’s immune system, the microglial cells, in really dictating the destiny of the brain. The changes in the function of the brain’s immune system by microglial cells is very much upstream of the accumulation of both phosphorylated tau and the accumulation of beta amyloid. So, these are proximate events that we have to pay attention to. Our microglial cells in the best of times exist in their M2M2 phenotype. What does that mean? It means that these microglial cells can shift in their phenotype and their function. In the M2 supportive phenotype, they’re nurturing neurons, enhancing synapse stability, and are shoring up the blood-brain barrier. They’re really on our side.

 

IMCJ: At the end of the day, the key to supporting a good brain lies in the microglial cells.

 

Dr. Perlmutter: Simplistically, the microglial cells can shift to being M1 configuration, or phenotype, and as such, can become the evil twin. They can become threatening so they can become destabilizing in the brain such that neurons are no longer nurtured, but synapses are. In fact, destroyed and the blood-brain barrier becomes less functional and more permeable allowing ingress of threatening issues into the brain which would normally have been excluded. This shift from the supportive to the threatening microglial cells is fundamental to what makes a good brain go bad. This shift is characterized by a profound shift in the metabolism of these microglial immune cells in the brain. When they’re in their M2-supportive configuration their mitochondria and energy production is top notch. They’re producing energy through oxidative phosphorylation meaning that in the presence of oxygen they are utilizing glucose to create the energy currency of life in humans called ATP. This is a very efficient process. When this is threatened by any number of issues that we will discuss, this shift in their metabolism changes immune function in the brain and is characterized by their shift from supportive M2 to destructive M1. This marries two seemingly disparate ideas, that is the idea of immunity and the idea of metabolism into a term that we call immunometabolism. A beautiful dance between metabolic function in these cells and their function as the arbiters of immunity. But what is so empowering about this understanding, and is fundamental, is that the metabolism of the microglial cells mirrors the metabolism of the entire body.

Why is that empowering? It’s empowering because when we engage lifestyle factors to improve our body’s metabolism we are directly targeting our microglial cell’s metabolism and helping nudge them to be more supportive and less destructive. When they are destructive they are digesting away our vital synapses, our connections between neurons that form our neural networks and allow us to have the sophisticated cognitive experience that we all enjoy. It is the loss of synapses that most characterizes the Alzheimer’s brain, not the accumulation of beta amyloid. The loss of synapses means the loss of connection at a cellular level and at a social level as it relates to this disease. The reason we use the term immunometabolism is to ultimately drive home the point that we, through our lifestyle choices, are the arbiters of our systemic metabolism, and as a consequence, the arbiters of the metabolism of our microglial cells, and determine whether they will be supportive or the evil twin.

 

IMCJ: What does the science show about the triggers of dietary, metabolic, or environmental that shift microglial into a destructive pro-inflammatory state?

 

Dr. Perlmutter: The incredible number of threats to the microglial polarization, or the shift from supportive to destructive, seems to be expanding daily. We certainly know that changes in our body’s metabolism directly target our microglial cells. When, for example, our blood sugar is elevated, we create glycated proteins to which this excess sugar can bind. People are familiar with that because hemoglobin A1C is a glycated protein, in this case hemoglobin that is measured as an indication of average blood sugar, and many people seem to be aware of that. But let’s be clear, hemoglobin is certainly not the only protein in our bodies that becomes glycated. It’s a rampant event when blood sugar is elevated. There are receptors called RAGE receptors on the microglial cells. Receptors for advanced glycosylated end products, and they respond to proteins when they are modified by binding sugar when blood sugar is elevated and help to morph these supportive microglial cells into being destructive. So, the rage receptor is one of the powerful inroads to make this happen, and interestingly, as well as importantly, Beta amyloid binds to that receptor. So, that creates a vicious cycle whereby increasing the activity of the M1 destructive microglial cells increase in beta amyloid, because it limits the way that our immune system would normally have phagocytized or destroyed and gotten rid of this beta amyloid. That process is compromised as our immune cells shift from being friend to being foe.

Now, that accumulation of beta-amyloid then further causes shift in these microglial cells from M2 supportive to M1 destructive by binding to that receptor, the receptor for advanced glycated end products, or the RAGE receptor. Microglial cells are exquisitely sensitive to the chemical mediators of inflammation called cytokines. These can be produced within the brain, but they can actually enter the brain from anywhere in the body, meaning inflammation can be anywhere in the body and cause the microglial cells to turn their backs on us and shift to their threatening M1 phenotype. This is a very interesting idea because now, we have a good explanation as to why there’s such a powerful relationship between the microbiome, changes in the gut microbiome, dysbiosis, and inflammatory diseases of the bowel, for example, and risk for neurodegenerative conditions, like Alzheimer’s, Parkinson’s, and even multiple sclerosis. It is because these shifts lead to increased permeability of the gut, or so-called leaky gut. The amplification of the production of these inflammatory cytokines in the body, making their way to the brain, and then shifting these microglial cells from M2 supportive to M1 supportive are destructive. We need desperately to preserve our brain defenders. The brain defenders being these supportive M2 microglia. When cytokines approach these M2 microglia, it shifts them away from being supportive.

A powerful source of the production of inflammatory cytokines in the brain are the M1 microglial cells. In other words, once we shift the microglial cells away from being our brain defenders to the M1 phenotype it dramatically amplifies inflammation in the brain.

Neuroinflammation is the cornerstone of what makes a good brain go bad. The destruction of the brain as a consequence of neuroinflammation has been talked about in the context of Alzheimer’s for decades. But what we’ve created now is by shifting our microglial cells away from being supportive to being destructive, there’s an increase in the very chemicals that are continuing this process. Those inflammatory cytokines then target neighboring supportive M2 microglia and shift them like zombies into being destructive. So, it spreads through the brain like a cancer. This is quite powerful.

 

IMCJ: But is there a way to shift from M1 to M2?

 

Dr. Perlmutter: I’ll answer that question in just a moment because we’ll get there. Let me finish my previous point.

This understanding of the spreading of the shift of these microglial cells now helps us understand why events earlier in life set into motion a progressive decline. An example is CTE, chronic traumatic encephalopathy in people who engage in events that threaten brain trauma like professional football players. They’re retired from football, are diagnosed with chronic traumatic encephalopathy, and they continue to decline long after they’ve retired from the inciting event. It’s a feed-forward process.

We know that exposure to various toxins in the environment, including PM2.5 particles in the environment increase of inflammation including herbicides, or heavy metals that we are exposed to. The question then arises, and here’s a great lead-in for your question, if that’s the case, then what can we possibly do?

To shift these M1 microglial cells back to being supportive we can absolutely do that. I think job one is recognizing what I mentioned earlier, and that is that the metabolism which dictates the configuration of our microglial cells is mirrored by our body’s metabolism. So, job one is to get our metabolic house in order and reduce the metabolic mayhem that so characterizes more than 90% of American adults at this time.

 

IMCJ: As I often say, you’re only as healthy as your gut.

 

Dr. Perlmutter: We live in a country where we have 40 million adults suffering from full-on diabetes. When you add in prediabetes that’s 80 to 90 million. That’s a huge metabolic insult on the body, and certainly on the brain itself, through the mechanisms that I just described as it relates to polarization of our microglial cells. We know that if you are, in fact, a type 2 diabetic that your risk of becoming an Alzheimer’s patient may be as much as quadrupled. So, the issue then is to regain metabolic health, and that will nudge our microglial cells back to being supportive. How do we do that? Well, there are countless ways, including more exercise, getting better sleep, and socialization, a ketogenic diet, or a more ketogenic diet, a less inflammatory diet, reducing our consumption of ultra-processed foods are key. We recognize now that more than 60% of the calories consumed by American adults are derived from foods that are pro-inflammatory and lead to microglial polarization. It’s no wonder that we’re seeing the increase so drastically of these neurodegenerative conditions. More so, at least on a percentage basis, as it relates to Parkinson’s, than as it relates to Alzheimer’s, though Alzheimer’s is certainly continuing to spread, like a pandemic.

 

IMCJ: But as you state we need a multifaceted approach.

 

Dr. Perlmutter: Yes, but diet is certainly job one, but there’s a multi-factor approach with exercise, ensuring we’re getting adequate sleep, metricizing these issues, and the value, the duration, and the quality of our sleep, or being more aggressive with understanding our blood sugars, not just what our fasting blood sugar might be. Once a year getting a better idea as to what our fasting blood sugar is moment to moment for example, or using a continuous glucose monitor, or even less aggressively, checking not just our fasting blood sugars but fasting too. Checking our insulin level as well, as a powerful insight into where we are on the scale of the harbinger for prediabetes, which is insulin resistance. These are important things that we can do to rein in our metabolism, things that I think many people are familiar with. But beyond that, I touched upon earlier the notion that our exposure to various toxins is certainly threatening through a number of mechanisms. Toxins can bind to specific receptors on the microglial cells and shift them away from being supportive.

 

IMCJ: Our polluted, toxic air is everywhere.

 

Dr. Perlmutter: I recently took a trip to Egypt and used an app just to get a sense as to what the level of air pollution was day by day in Cairo and in Luxor, other cities that we visited. It was astounding to me the level of air pollution that we were experiencing. What recourse do we have? We requested an air purifier in our room. We also used PM, rather N95 masks whenever we were outside. I don’t know what kind of social statement that makes, but PM2.5s are directly threatening to the brain. People who are exposed to higher levels of PM2.5s have a significantly increased risk for Alzheimer’s disease, a disease for which there is no pharmaceutical fix.

I feel it’s certainly valuable for us to assess our level of toxicity by doing blood tests that look at heavy metals, and what our exposure to these particulate matters that are in the air that we breathe, these threatening PM2.5s. The idea of actually measuring air quality, which we can do at home, or with various apps we can use, I describe in the book.

 

IMCJ: Of course, it’s not just the air we breathe that’s harmful to our brain.

 

Dr. Perlmutter: People who become diabetic have such a risk that I just explained earlier. These are modifiable factors in our lives. We know that there’s an increased risk of polarization of our microglial cells when we’ve experienced head trauma. What is the response? The response is to wear a seatbelt and use a helmet when you’re involved in any activity that could threaten your brain, be it bicycling or riding a motorcycle, a horse, doing snowboarding or snow skiing. Any issue that could potentially increase your risk of head trauma needs to be taken care of. There are many issues we have significant control over that can help us keep our microglial cells in their M2-supportive configuration. One thing, a very sophisticated tool, that I often talk about that can be employed to determine risk of microglial polarization is simply a tape measure. A tape measure around the belly and around the hips determines your waist-to-hip ratio. The higher that is translates to a higher risk of Alzheimer’s and other metabolic issues and certainly translates to risk of Alzheimer’s as well. We know that increased amounts of body fat, depending of course on its distribution, correlates with increased inflammation.

Getting back to the mechanism we talked about earlier, the U.S. obesity rate is pegged right now at around 40-45%, with about 16% of Americans being diagnosed or categorized with extreme obesity. We used to say the standard American diet became the Western diet. It’s now the global diet. The global diet is highly processed, pro-inflammatory, and dramatically increasing the risk of both obesity and diabetes worldwide. Anticipated that by 2035, we’re going to have 1.5 billion adults categorized as being obese on our planet. Let’s be clear, Alzheimer’s is not a disease that suddenly begins in our 60s and 70s, when we start to manifest the clinical manifestations like we don’t remember why we went into a room, the Wi-Fi code, or our grandchildren’s names. The seeds are sown In terms of our metabolic dysfunction in our 20s, 30s, and 40s, I’m hopeful that this message can land on those individuals, because that’s when we can begin to implement such changes targeting brain protection by reducing metabolic mayhem, and reining in overweight and obesity. Childhood obesity in America was 5% in the 1970s. It jumped to 20%. There was a four-fold increase by 2018 and continues to increase. Children who are obese become adolescents who are obese, teenagers who are obese, and kids in their 20s, 30s, and 40s carry that legacy and ultimately are setting the stage for declining brain function and everything else that goes along with metabolic dysfunction. These are inroads to what happens to our microglial cells just through the lens of what we can do from a lifestyle perspective. We can engage in things such as a variety of nutritional supplements that specifically target metabolism and therefore target the microglial cells.

 

IMCJ: Which supplements do you suggest?

 

Dr. Perlmutter: Some are relatively new on the scene, like rosmarinic acid and dihydroxymiracetin. We know that things like Coenzyme Q10, and one of my favorites being creatine monohydrate, or creatine hydrochloride are helpful. We’ve seen recent interventional trials using creatine monohydrate that targets mitochondrial function and is central to the polarization of the microglial cells. A recent study, actually an interventional trial, showed significant change in early Alzheimer’s patients who received a dosage of 10 grams twice a day of creatine monohydrate. It’s inexpensive and tasteless, and I’ve not seen any side effects from the use of this nutritional supplement. So, why wouldn’t anybody take it? Other things to consider are interventions like using Urolithin A, the new player on the block called spermidine, a type of oil that increases what we call mitophagy, or the body’s natural ability to rid itself of defective mitochondria paving the way for replacement with more functional mitochondria. That’s where the money is in terms of shifting our microglial cells to being supportive. It’s targeting their mitochondrial function. I’ve been very impressed with the research on Himalayan tartary buckwheat in terms of its ability to bring about epigenetic changes associated with reduction in inflammation and various aging parameters as well as favorable impact on metabolism. Now, we can get more advanced with respect to our interventions and use things like hyperbaric oxygen therapy where we oxygenate the body. We increase blood flow and we allow the growth of new blood vessels through hyperbaric oxygen therapy through its activation of something called hypoxia-inducible factor 1-alpha. It amplifies something called VEGF, vascular endothelial growth factor, which improves blood supply.

 

IMCJ: Beyond supplements, what role is technology bringing to the forefront?

 

Dr. Perlmutter: Exciting technology is a background rhythm, a symphony that is played and we call it gamma oscillation. It’s a beautiful sinusoidal curve that characterizes a normal, healthy, functioning brain with age. With a deterioration of the brain and deterioration of its functionality, this background rhythmicity gets threatened and we get a bit of cacophony. We’re now using the metaphor of an orchestra. There’s no longer a conductor, and people are not playing instruments in a way of synchrony, and creating this beautiful outflow, and the sound that characterizes a normally functioning brain. A forward-thinking researcher, Dr. Li-Wei Tsai at MIT discovered that. When you evaluate the Alzheimer’s rodent model, the APP plus a rodent model that develops cognitive decline and all the pathological changes that we see in Alzheimer’s, there’s a decay of the gamma oscillation in the background, as expected, as there is in mammals across the board. But what Dr. Tsai noted was when these laboratory animals were exposed to a particular frequency of flashing light, 40 times per second, not 20 or 80. There was a significant change in the background rhythm with restoration of this gamma oscillation.

The next thing we would want to know, taking this a little further, is in addition to the restoration of the gamma oscillation in the background Dr. Tsai noted, a significant reduction in the accumulation of beta amyloid 1-40, as well as beta amyloid 1-42 in multiple areas of the brain in those animals exposed to a simple flashing light at 40 Hz, thinking that the rodent studies are interesting, but how does that play out for humans? In 2024, she conducted a study on humans which included 76 subjects. It was a six month interventional trial with a sham group as well that didn’t get 40Hz light but was exposed to the delivery of light through the same goggles, but they didn’t know if they were getting 40Hz light or not. The group receiving the 40 Hz treatment demonstrated a significant reduction in their cognitive decline as evaluated on two scales. First, it was Alzheimer’s. A standard evaluation of Alzheimer’s disease, and also an Alzheimer’s disease assessment score that focused specifically on how individuals are able to perform their activities of daily living, like self-care, bathing, feeding, and other types of things. The difference between the sham group and the intervention group was breathtaking, especially in the context of how patients decline versus control when they are given the so-called Alzheimer’s drug that targets beta amyloid. This was incomparable with respect to the results of the beta amyloid interventional studies and much more significant leveling off of their decline in terms of their amyloid load and their function which is really where the money is.

A bigger study is underway now, and these individuals are receiving not just a flashing light at 40 Hz but also listening to a sound at 40Hz as well, and the results are spectacular so far through this ongoing trial. We’re hoping that it will be approved soon. There are companies, and there’s one called Optoceutics that already makes a 40Hz light available to consumers. I have one and this technology is targeting our microglial cells. The original research demonstrated more than anything else in the rodents was not only an increase of microglial cells, but specifically an increase of the M2 supportive microglial cells, simply by shining a light in their eyes at a particular frequency.

I’m very taken by the simplicity and the elegance of this intervention. There’s no downside that has been observed. I think that people who might have issues with flashing lights, photo-induced epilepsy for example, may not be able to avail themselves of this therapy. It’s a very small number of people, but I feel it is something to be considered.

 

IMCJ: Like I always say advancements in technology are great when it works as intended to do.

 

Dr. Perlmutter: Well, then let me just go to another place. One of the most profound interventions we’ve ever seen developed to target metabolism has been the GLP-1 agonist drugs. The way these drugs are improving metabolism, as we know, were originally developed for the treatment of diabetes, now are used globally for the treatment of overweight and obesity. But what research demonstrates is that, at least in diabetes, they have a profound effect on improving mitochondrial function. That’s something to be aware of. In April 2024, in the New England Journal of Medicine, a published study, an interventional trial, included 156 patients. It was a one-year study, giving part of the group a placebo, and the other receiving, lixisenatide, a GLP-1 agonist drug. These people were evaluated after the trial with what is called the Unified Parkinson’s Disease Rating Scale. It’s a standardized scale used to determine functionality or degree of compromise in the Parkinson’s patient. Parkinson’s patients decline over time. It’s incessant. These medications that are used in the treatment of Parkinson’s today do not target Parkinson’s disease, they only target Parkinson’s symptoms, and they’re certainly useful. There are medications for tremor and rigidity. It’s an integral part of what my practice utilizes, or utilized, for the treatment of Parkinson’s disease. It allows us to keep patients functional, but in the background, the disease continues to threaten their brains and they further decline. Mainstream treatment is focused on treating the smoke and ignoring the fire.

What the study demonstrated was that, as expected, the group receiving the placebo declined over the course of one year significantly in terms of the Unified Parkinson’s Disease Rating Scale (UPDRS). The intervention group astoundingly not only stabilized but demonstrated a slight improvement with the utilization of an intervention, in this case, a GLP-1 agonist drug, that targeted their metabolism, and their mitochondrial function. As a result, I’m very excited about the future. Yes, I am sure there will be risks for long-term usage of GLP-1 agonist drugs. There are those that are already described. Do individuals seem to rebound with reference to their diabetes and weight gain after they stop these drugs? Yes, of course they do and I’m aware of that. But I think there’s some incredibly valuable information here saying at the very least that when we target metabolism it is good for the brain in people who have neurodegenerative conditions because it shifts their microglial cells back to being supportive.

 

IMCJ: Just to confirm, I think you said early lifestyle intervention is more powerful than any late-stage drug.

 

Dr. Perlmutter: Oh, I like that, and yes you could say that. That’s actually a great quote, Sheldon. I was going say young Sheldon, but that’s already taken.

 

IMCJ: Thank you and yes it has. If you could distill Brain Defenders into one message about taking control of your range destiny what would it be?

 

Dr. Perlmutter: Simply, that it’s time that we recognize the paradigm that has been presented to us. It’s one of being passive, a patient, and being at the mercy of treatments that are developed. I think the most important message is that we should recognize that we can absolutely take control today and be the architects of our brain’s destiny.

I think on a broader scale I write these books for empowerment. For individuals to read these books and see the other side of what we just talked about, that here’s a whole different way of understanding of what can be done as it relates to your brain’s destiny, and as opposed to being passive versus proactive. I think your quote just now was great. And that’s been my mission across every book I’ve ever written. This is book number 16. I’m very taken by this book for a number of reasons. First, because it really brings together everything I’ve done. It explains why a high-carbohydrate diet that we described in Grain Brain ultimately threatens the brain. It’s through the polarization of the microglial cells. It explains what I described in Brain Maker that focused on the relationship between changes in the microbiome and brain degeneration. Again, through the mechanism of inflammation, and how that polarizes our microglial cells. It explains what I wrote about with our son, Austin in the book Brainwash that looked at our disconnection from others and isolation. It relates to risk for brain degeneration, because we know that when we are isolated like that we experience less production of oxytocin. I talk about it in this new book. And oxytocin fundamentally signals our microglial cells to remain supportive. Think about that.  The hormone of love is received by our nurturing microglial cells and keeps them doing their job. How profound. We’re all aware of the research demonstrating that people decline very quickly, cognitively, when they’re socially isolated. A key component is community and was one of the things that was seen in the Blue Zones research. Also having a purpose and socialization. People kind of underplay those things thinking that they don’t have anywhere near the traction of a ketogenic diet that’s rich in fiber, or getting a good night’s sleep and exercise, things I mentioned earlier. But not true. These are profound inroads to better brain health and now we understand mechanistically why they work.

Everything has come together in Brain Defenders, and it’s what I’ve been interested in for the past 40 years. I’m also very taken by the fact that here we are, a little over four months prior to publication, and the book has already been bought by 15 countries around the world and translated in 15 other languages. That’s very exciting because I love my message becoming global. It just shows that there’s real interest in this and moving away from being the passive patient to becoming the participant. It’s also a recognition and I can see that it’s happening globally, thus very exciting.

 

Vanessa Gourdine, PsyD, APN-C, IFMCP

 

Abstract

The incidence of mental health disorders increased by about 40% from 2019 to 2023. The incidence of mental health disorders continues to escalate while the outcomes remain poor. The outcomes of psychopharmacology are mildly to moderately effective and rarely, if ever, result in a cure. The expectation is a lifetime use of medication for symptomatic management. The following case is an example of an integrative mind-body approach that may lead to an actual cure of psychiatric conditions when focused on neuroinflammation and not solely on neurotransmitters. The current case involves a young man who had been hospitalized seven times within seven years and treated with multiple attempts at various combinations of polypharmacy, resulting in similar outcomes and more hospitalizations. He sought a functional medicine approach due to the poor outcomes with conventional treatment. Subsequently, he was admitted to our outpatient facility utilizing a multi-systems model of an in-depth mind-body assessment. The treatment was based on inflammatory markers likely triggered by multiple toxin exposures, aimed at eliminating the sources of inflammation and introducing lifestyle and diet modifications to support detoxification. The outcomes obtained were extraordinary, with a total remission of all symptoms up to and including a post-treatment two-year follow-up assessment. This suggests that our approach to creating health outcomes needs to be personalized and integrative of both mind and body to achieve the best outcomes. The case presents an alternative approach to conventional treatment involving polypharmacy and psychiatric hospitalizations.

 

Keywords

Functional Medicine, Schizophrenia, Complement C4, Neuroinflammation Depression, Case Report

 

Vanessa Gourdine, PsyD, APN-C, IFMCP; The Functional Medicine Centers for Personalized Care, LLC; Paramus, New Jersey, United States.

 

Corresponding author: Vanessa Gourdine, PsyD, APN-C, IFMCP   

E-mail: [email protected]        

 

 

Introduction

The incidence of mental health disorders rose 40% from 2019 to 2023.¹ The outcomes for psychotherapies and pharmacotherapies remain poor.² Current treatments of psychiatric disorders remain focused on neurotransmitters and ignore any other potential causes of changes in brain function. Much research is based on the theory that the blood-brain barrier (BBB) is largely impenetrable; however, there is evidence to the contrary, especially for inflammatory immune cells.³ Consequently, if inflammatory cells can enter the brain, then what are the effects? The research on the effects of neuroinflammation and the result of such inflammation point to the association with psychiatric symptoms of depression, schizophrenia, bipolar disorder, and others.^4-6 Researchers also suggest that dietary habits can significantly influence inflammation, having a positive effect on both the body and brain. Several studies describe the positive influence of a diet consisting of anti-inflammatory foods on depression.^7,8

There are connections between the microbiome and the brain. There are microbes in the gut that trigger inflammation, and that inflammation can become chronic. Chronic inflammation is known to cause changes in the brain, and these changes are linked to psychiatric diagnoses. Dysbiosis is defined as an imbalance of the commensal bacteria that are essential for the healthy production of neurotransmitters, as well as the barrier between the gut and the gut-brain axis. The gut bacteria, such as Escherichia, Enterococcus, and Streptococcus, are serotonin-producing microbes. Bifidobacterium and Lactobacillus are GABA-producing (gamma-aminobutyric acid), while Bacillus and Serratia are dopamine producers from the amino acids that synthesize their respective hormones and neurotransmitters in the microbiome. These are examples of microbes in the gut that comprise the microbiome. When there are imbalances in the population of these respective commensal bacteria, the condition is referred to as dysbiosis of the microbiome. Dysbiosis leads to systemic changes in the various pathways alluded to above.^9,10

There are many sources of inflammation. A common source is the diet. Foods high in sugar content, as well as ultra-processed foods containing various chemicals, such as emulsifiers, can lead to higher levels of inflammation. The environment is another major source of inflammatory chemicals, such as pesticides, BPA (bisphenol A) from plastics, PFAS (polyfluoroalkyl substances), and glyphosate, which is an endocrine disruptor. These are only a few examples of the various toxins in our environment to which we are exposed daily.

Thus, a personalized food plan is not only an essential part of the intervention to limit the sources of inflammation but also to decrease inflammation by providing foods known to have high anti-oxidant properties.

The first step is to test and identify the specific toxins, given that testing vast numbers of toxins can be challenging. The treatment intervention is based on the identified toxins, followed by the detoxification process. The sources of inflammation can be the gut’s microbiome,^2,3,9 or other organs.^11,12 The intervention is based on examining the effects of inflammation. The impact of various toxins on different parts of the brain and neurochemistry varies widely. This may help explain the variability of symptoms for the same diagnosis and the variability in results upon using the same medications for the same diagnosis.

This study discusses the adoption of an integrative mind-body approach to treat psychiatric conditions, focusing on neuroinflammation and not solely on neurotransmitters. The treatment in this case study began with a focus on dietary sources of inflammation. An anti-inflammatory diet with support for detoxification pathways can lead to substantial improvement in the symptoms associated with schizophrenia and depression.

 

Initial Assessment

The patient was 37 years old at the time he presented to the practice for treatment and had stopped all medications due to a lack of benefit and side effects commonly associated with psychiatric medicines. He presented with a multitude of symptoms and a very long history of psychiatric hospitalizations and medications that began at the age of 30. He reported that he had been diagnosed with Schizophrenia, Bipolar Disorder II, and Major Depression, and had been admitted to psychiatric hospitals seven times in seven years, before his admission to this practice. He stated that he had no mental health issues before age 30. He was arrested for a violent crime he did not commit in his early 20s and was exonerated. Despite experiencing the trauma of the arrest and the trial, he denied having any specific mental health issues or post-traumatic stress disorder (PTSD) symptoms from the arrest. He stated that he started painting for a living soon after.

His occupation as a painter involved daily exposure to different chemicals. As reported, he did not use protective gear while working. Based on his report of exposure to toxins during his 20s and a report of developing psychiatric symptoms in his 30s, the symptoms were severe and repetitive despite ongoing conventional interventions with anti-psychotic and anti-depressant medications.

The patient described symptoms consistent with a thought disorder, a common symptom of schizophrenia. He would lose track of his thoughts. He struggled with focus and concentration while performing ordinary tasks.

In addition to the symptoms consistent with schizophrenia, he had physical symptoms that were consistent with inflammation. He reported difficulty falling asleep, a symptom associated with changes in brain chemistry, interfering with his ability to relax and produce the neurochemistry consistent with sound sleep.

He reported muscle and joint pain along with spasms and stiffness. He believed he had multiple food intolerances based on his experience of gastrointestinal discomfort from lactose, gluten, eggs, and yeast.

He had chronic sinusitis. He described hair loss and chronic fatigue. The clinical picture was consistent with inflammation, and the symptoms were overlooked when classifying a patient as schizophrenic. If the symptoms did not fit the diagnosis of schizophrenia, they were usually overlooked, and therefore not considered in the overall presentation that would press the need for an in-depth insight into the root causes. At the core of the Functional Medicine process, by definition, is to do a deep dive analysis of the root causes.

 

Medical, Family, and Psychosocial History

He reported his medical history of multiple hospitalizations, totaling 7 psychiatric admissions. He had an MRI of the spine following a car accident, and there were no abnormalities. A CT scan of the brain performed several years before admission to this practice revealed negative findings. Traditional medical tests did not find any underlying causes for his symptoms.

He underwent various medical evaluations before admission to the practice, which revealed negative findings. He had a tonsillectomy as a very young child. In December 2021, he tested positive for COVID-19 and treated himself with vitamins and fasting. He stated that his COVID-19 symptoms were headaches and confusion.

His family history included a father with multiple food sensitivities, celiac disease, eczema, asthma, and cancer. He reported that his sister was diagnosed with major depression and bipolar disorder, inflammatory bowel disease (IBD), and food allergies. The extended family history was reportedly positive for autoimmune diseases, cancer, and psychiatric disorders. Neither parent has a diagnosed psychiatric disorder. Both sets of grandparents lived until their late 80s and 90s and were not diagnosed with psychiatric disorders.

 

Prior Interventions and Outcomes

He was treated with different psychotropic medications. They were combined at times, and he reported he struggled to recall all the medications. He recalled the more recent ones: Zyprexa, Abilify, Risperidone, Olanzapine, and Haldol. He stated that medications created “terrible side effects” and that he could not tolerate most medications.

The outcomes of using multiple medications and changing dosages were described by the patient as not helping his condition. The side effects from the many medications at times made him feel worse, resulting in more hospitalizations, with the outcome of combining a different set of medicines. The result was an ongoing and repetitive cycle of the same ineffective outcomes with polypharmacy and hospitalizations.

 

Clinical Findings

He was exposed to multiple chemicals in his occupation. He described that the paints used were usually oil-based with xylene. He did not wear a mask or gloves while working for a decade with these toxic exposures. He reported having mold in his home, and based on the mold toxin report from the labs listed below, there were clear indications of chronic exposure.

His height and weight were 5’11”, 170 lbs, and his waist circumference was 37 inches. Blood pressure was 124/72. He did not not drink alcohol or use recreational drugs. He made attempts to exercise several times per week with aerobics and strength building, but stated that experiences of soreness and inflammation curtailed the frequency. On a scale of 1-10, he rated his psychosocial stressors as 7 for work and health, and below 5 for all other aspects of family, social life, and finances.

He reported practicing meditation, breathing, and prayer for supportive calming activities. He stated he has difficulty falling asleep and usually sleeps between 6 to 7 hours. He mentioned that he never feels rested or energized. He reported a low tolerance for other identifiable toxins, such as processed foods, cigarette smoke, perfumes, industrial chemicals, and pesticides, in particular. He stated that over the years, he has been exposed to glyphosate in non-organic foods and xylene in his occupation as a painter.

The Functional Medicine approach requires an in-depth assessment of various systems using the Matrix, which includes the antecedents, triggers, and mediators. Exercise, nutrition, stress levels, sleep, and relationships, along with the physiological and clinical imbalances listed below, are part of the Functional Medicine Matrix, which was the model used to assess the patient’s functioning. The identified disrupted systems in the matrix for this patient culminated in a series of complex symptoms that ultimately impacted the brain and mental functioning.

It is rare to have a case of a physical malady that is not accompanied by mental symptoms and vice versa. The Functional Medicine approach requires a focus on systems with an eye towards core causes. In this case, it began with assessing exposure to possible toxins disrupting the functioning of various metabolic systems.

The Functional Medicine assessments of clinical imbalances in the matrix are listed below. The descriptions of clinical imbalances are based on the major systems within the brain and body. By reviewing the symptoms and linking them to the physiological processes, the analysis guides the practitioner in creating a holistic picture encompassing the symptoms and the interacting metabolic processes associated.

Clinical and Physiological Imbalances 

Assimilation, Respiration, Digestion, and Microbiome. Symptoms were consistent with assimilation issues, such as an imbalanced microbiome, adding to overall poor metabolic balance. The patient reported signs of food intolerance, leading to digestive problems. There were no signs of respiratory symptoms.

Defense and Repair. There were signs of systemic inflammation, such as bloating, indigestion, fatigue upon exertion, and joint and muscle pain.

Structural, Musculoskeletal, and Cell Integrity: He reportedly experienced musculoskeletal stress with spasms and pain.

Communication, Endocrine, and Neurotransmitters. He had signs of imbalanced hormones and neurotransmitters, as indicated by brain chemistry-related issues, with reports of psychosis.  There were neuroendocrine imbalances as indicated by sleep issues, hair loss, concerns about cognition, and reports of difficulty sustaining focus and persistent brain fog.

Transport, Cardiovascular, Heme, Lymph. There were no signs of poor transport.

Biotransformation, Elimination, Bowel, Kidney, Methylation, and Cell Matter Waste. There were probable methylation issues. Given dysbiosis and the inability to tolerate a variety of foods that assist with the production of essential nutrients, there were likely issues with biotransformation.

Energy, Mitochondrial Functioning, and Nutrient Formation of ATP (Adenosine Triphosphate). There was a likely buildup of toxins caused by poor detoxification. Toxins impact mitochondrial functioning, culminating in lower ATP production. Consequently, this reduces the energy supplied to all cells, causing fatigue and chronic daytime sleepiness.

Lifestyle Factors: Sleep, Relaxation, Exercise, Nutrition, Stress, and Relationships. He practiced some relaxation and careful nutritional choices by occasionally eliminating a few intolerant foods such as sugar and gluten. He exercised occasionally.

Mental, Emotional, and Spiritual. He reported good spiritual practices with meditation and prayer.

 

Diagnostic Assessment

The assessment began with a discussion of the toxins causing inflammation and oxidative stress. In this case, the environmental sources were several, including the exposure to oil-based paints daily, mold in the home, and non-organic and processed food sources.  He was exposed to multiple chemicals in his occupation, including the use of oil-based paints and the chemicals used in the paint. He reported that paint includes at least one known chemical toxin, xylene. He did not wear a mask or gloves while working for at least a decade with these toxic exposures.

Based on his report of symptoms, it was decided to test for markers of inflammation, environmental toxins, and gut microbiome. Lab tests for IgG mold toxins were included in the standard tests, along with C4a, a marker for inflammation associated with inflammatory responses to infections, autoimmune disorders, chronic fatigue, and/or tissue injury. The Biome FX test was administered to assess the status of the microbiome, a major contributor to inflammatory conditions and communication along the gut-brain axis (Tables 1 and 2).

 

Table 1. Timeline of Patient Diagnosed with Schizophrenia: Symptoms of Auditory Hallucinations, Thought Disorder, 7 Hospitalizations in 7 Years, Mixed Psychiatric Polypharmacy with No Resolution

 

Date	Assessment Findings	Diagnostic Tests	Test Results	Therapeutic Interventions
6-2022 Time of Admission	Mind-body assessment with a history of multiple hospitalizations; no relief from medications. Symptoms of hallucinations, thought disorder, feeling unwell, poor sleep	Prior Lab tests and hospitalizations yielded no significant results according to patient reports.  He requested an MTHFR gene test. The Medical Symptom Questionnaire (MSQ) is 62.	At the time of admission, the patient reported that general physical examinations yielded no significant findings in prior test results or PCP visits.	Before arriving at this practice, there were various medications of Haldol, Abilify, Zyprexa, Risperdal, Olanzapine, and others that he could not recall. He had Self-prescribed Niacin, zinc, Omega 3, Vitamin C, Saw Palmetto, L-Arginine, and NAC.
7-2022	Symptoms are still present from the time of admission to this practice.	Standard labs, CBC, CMP, Biome FX, Great Plains OAT (organic acid test) ordered to identify the presence of inflammation and toxins; Cyrex tests for BBB, pathogens, and autoimmune. MTHFR genetic single-nucleotide polymorphism (SNP).	CBC, CMP negative, C4a elevated 4541, OAT test found elevated arabinose, oxalic acid indicating Aspergillus, Candida and Penicillium toxins. His elevated Pyroglutamic acid was a sign of glutathione depletion and dysbiosis. Cyrex tests for pathogen and BBB were negative, but positive for autoimmune intrinsic factor. Lab results indicated toxins from mold and high levels of inflammation. He was positive for IgG to Candida, IgE to wheat, soy, and peanuts. OAT for catecholamines were positive with high levels of HVA/VMA ratio. MTHFR negative. Elevated B vitamins Nicotinamide 640, Nicotinic acid 8 and B12 1791.	The initial plan was designed to eliminate toxin exposure and IgE and IgG foods, to lower inflammation (see plan in table below).
An antioxidant diet is personalized based on food choices and the elimination of food intolerances and food allergies.
9-2022	Initial post-treatment follow-up indicated mild improvement across all symptoms that were present at the time of admission.	Clinical Interview consisted of an assessment of food diary, the report of symptoms, and MSE (mental status exam).	Follow up with patient regarding compliance with the personalized food plan indicated moderate compliance with occasional use of intolerant foods, based on the review of his food diary.	See The Prescribed Plan NAC, L-Glutathione, Glucomannan, Chlorella, L. plantarum C88, Magnesium, L-Theanine, GABA, Methylated B vitamins, CoQ10, S Boulardii and Nystatin
11-2022	Significant improvement in mental health and physical health.	Assessment based on clinical interview and rating scale of symptoms. Health counseling provided.	Clinical assessment indicated very good adherence to the plan.	Continue with plan
Lifestyle changes include change of career; daily exercise; good adherence to anti-oxidant diet and supplements
2-2023	Sustained improvement in symptoms and overall health	Repeat of standard labs to assess overall health and inflammation.	Standard labs of CBC, CMP were all negative. C4a was down from 4546 to 917, and Candida from 0.71 to 0.59.	Continue with the plan as prescribed.  Nystatin prescription was terminated.
12-2023	He reported feeling well for the first time in a long time. A normal sleep pattern is described.	Repeat of standard labs to assess inflammation markers. MSE, clinical interview, and rating scale reviewed.	Results were all within normal limits. Candida results went lower from 0.59 to 0.21	Supplements were discontinued except for D3, B complex, and CoQ10. Magnesium, L-Theanine, and GABA were continued if desired.
2-2024	Reports continued good mental and physical health.	Clinical interview and rating scale completed.  Standard labs repeated	MSQ 34; catecholamines and VMA are within normal limits for neurotransmitters.	He continued with lifestyle changes and food plan: avoid toxins, eat organic, and continue with exercise. Continued with Vitamin D3, B complex 2-3× per week, and daily CoQ10.
6-2024 Telemedicine follow-up at two years after treatment ended, with good results ongoing. No medications, no psychiatric symptoms, no hospitalizations. MSQ was a 6 down from the prior score of 34.

 

 

Abbreviations: ATP, Adenosine Triphosphate; BBB, Blood-Brain Barrier; C4a, Complement Component 4a; CBC, Complete Blood Count; CMP, Comprehensive Metabolic Panel; CNS, Central Nervous System; GABA, Gamma Amino Butyric Acid; HVA/VMA, Homovanillic Acid and Vanillylmandelic Acid; MSE, Mental Status Exam; MSQ, Medical Symptom Questionnaire; MTHFR, Methylenetetrahydrofolate reductase; NAC, N-Acetyl Cysteine; OAT, Organic Acid Test; SNP, Single Nucleotide Polymorphism

Table 2. Reference Ranges for Various Labs: The Results are Pre-Treatment and Patient’s Results are in Parentheses

 

Reference ranges for positive lab results for Labcorp and the subject’s results are listed in parentheses.	C4a 0.0-650 ng/mL (4541 ng/ml)	IgE <0.10 KU/L Candida albicans (0.71-0.59-0.21), wheat (0.59), peanut (2.44), and soybean (0.44)	IgG food intolerances 0.0-1.9 ug/ml (multiple food intolerances all above 4.0 were eliminated)
Great Plains Reference ranges are mmol/mol creatinine	3-Methylglutaric 0.02-0.38 (0.68), Arabinose <20 (32), 3-Oxoglutaric <11 (28), HPHPA <102 (119), Hydroxyphenalacetic 0.03-0.47 (0.74), HVA/VMA Ratio 0.32-1.4 (2.4), Vitamin B5 <5.4 (12)	Pyroglutamic 5.7-25 (33), 2-Hydroxybutyric <1.2 (2.6)	Orotic <0.46 (0.84), 2-Hydroxyhippuric <0.86 (0.89)
Reference Ranges for Biome FX	Microbiome Index 30-40 (27.45), Resistome 8-10 (7.3), Diversity Alpha/Beta 8-10 (5.71) (4.83)
Cyrex uses the ELISA Index, and results are in standard deviations	Intrinsic Factor 0.0-2.5 (>3.70)

 

 

 

He completed routine labs on 7/26/2022, and his CBC and CMP were normal. The thyroid was normal. Vitamin D was low normal at 40. Lyme and ANA were negative. He had elevated B vitamins, believing that he had a methylenetetrahydrofolate reductase or MTHFR SNP, as he was supplementing regularly with B vitamins (Rugby brand 500mg of Niacin and a methylated B complex from Pure Encapsulations) for about 8 months. The results of the MTHFR test were negative, showing no active SNPs for these genes. Wheat allergy was positive. C4a was elevated at 4541 ng/ml with a reference range of 152.0-1559.4 ng/ml.

The following labs were chosen to elucidate inflammation, infections, dysbiosis, and sources of toxins. There were positive findings across the categories except for infections.

The results of the Great Plains Laboratory Organic Acids testⁱ indicated that he has high levels of 3-Oxoglutaric and Arabinose at 0.8 and 32, respectively. Both indicate high levels of yeast overgrowth with a likely impact on the gut microbiome. Elevations of 3-Oxoglutaric acid indicated not only yeast overgrowth but may be due to metal and/or ammonia toxicity, causing disruptions in the Krebs Cycle. The result of 2-hydroxyphenylacetic acid at 119 was additional evidence of dysbiosis. High levels of HPHPA or (3-(3-hydroxyphenyl)-3-hydroxypropionic acid) are present when byproducts of Clostridium bacteria combine with typical metabolites. The presence of this molecule will result in high levels of dopamine metabolite of HVA, which he had at 2.2, exceeding the normal range, thereby creating an imbalance in the ratio of HVA/VMA at 2.4, with an upper limit of 1.4. This imbalance in the ratio is associated with behavioral and gastrointestinal symptoms, including depression, autism, schizophrenia, aggression, seizures, OCD, and hyperactivity.

He had high levels of Oxalic acid at 118, which was likely the cause of joint and muscle pain. He had high levels of 3-methylglutaric acid, which is a mitochondrial marker that may indicate mitochondrial dysfunction. Great Plains Laboratory reports that a symptom of methylglutaric acid elevation is muscle spasms, as the patient reported having spasms. A resource for interpreting the Organic Acid test is listed in the footnotes under Mosaic Diagnostics, a laboratory that purchased Great Plains in 2023.

The conclusive findings were markers were markers showing a need for detoxification. He had elevations across all markers for pyroglutamic acid, indicative of glutathione depletion at 33, with an upper limit of 25; a toxic exposure with elevations at 2.6, with a normal range below 1.2 for 2-hydroxybutyric acid, indicating the likelihood of toxic exposure and glutathione depletion in an attempt to detox. The elevation changes were most likely caused by his attempts to detox. Orotic acid is a sign of ammonia excess at 0.84, with normal levels below 0.46. The elevations of GI bacteria at 2-hydroxyhippuric acid are indicative of poor detoxification attempts. The elevations are likely caused by environmental toxins and molds, exacerbated by dysbiosis, and are the core causes for inflammation.

He completed the Biome FXⁱⁱ (see the link to the interpretation guide in the footnote). It indicated and confirmed the dysbiosis (with 27.45, while 40 is considered the healthy index, according to the reference provided by Biome FX). His diversity was low for both alpha and beta, which refers to the diversity of commensal bacteria. His resistome occurrence index was at 7.3 (10 indicates healthy). The keystone species were low across the board. He had low out-of-range functions for saccharolytic fermentation, butyrate production, acetate production, and GABA, a critical neurotransmitter to induce calming effects and relaxation, and assists with sensory processing. Indole plays a role in maintaining intestinal homeostasis and regulating the mucosal barrier function, which affects immune responses and the balance of beneficial and pathogenic bacteria within the gut, and this was found to be low. Indole influences the production of B vitamins: B2, B9, and B12, and despite having a negative MTHFR SNP, it may explain the low production of B vitamins, and the need for supplementation. Saccharolytic fermentation was so low at 145, with a healthy range between 535 and 1573. The fermentation process of the microbiome is essential to produce short-chain fatty acids. Low production in saccharolytic fermentation interferes with gut barrier function and health. The impaired gut barrier function directly affects the immune system, leading to inflammation and creating negative implications for the gut-brain axis.^10,13

He completed the Cyrexⁱⁱⁱ Autoimmune reactivity test, with elevated antibodies to intrinsic factor, indicating low production of B12. The Cyrex Pathogen Associated Immune reactivity screen for multiple pathogens was within the normal range. He completed the Cyrex Blood Brain Barrier Screen, and it too revealed a normal result for IgG, IgA, and IgM.

 

Interventions

The first step to lower inflammation is to eliminate the source. He did so by changing his occupation and cleaning his living environment of the mold. The patient independently researched how to eliminate mold, identified the sources in his home, and cleaned them according to standard protocols.

He was provided with an anti-inflammatory diet, which benefits people with mental disorders and neurodegenerative diseases.⁸ The diet included fruits, primarily berries, vegetables and leafy greens, whole grains, legumes, fatty fish rich in Omega 3, nuts (especially walnuts), olive oil, and fermented foods such as plant-based yogurts, and kimchi, to name a few sources to support low fermentation. The antioxidant diet, fiber, and bioactive compounds are known to modulate inflammation and improve gut health, along with neuroprotective properties. Examples included whole grains such as quinoa, black rice, black beans, kidney beans, pinto beans, green peas for legumes, and a variety of nuts including walnuts, pecans, flax seeds, chia seeds, and turkey, duck, salmon, sardines for proteins. For healthy fats, he was advised to consume olive and avocado oils. He was encouraged to eat a variety of vegetables with a focus on leafy greens, spinach, arugula, and all cruciferous vegetables.^7,8

He was advised against eating processed foods, sugar, and any of the foods on his laboratory list of intolerances. He eliminated the foods to which he was allergic. He will eat foods rich in prebiotic fibers and antioxidants to aid in the release of toxins. He was encouraged to drink from clean water sources. He was advised to hire a mold remediation company to assist with cleaning mold from his environment, which he declined due to the expense. He did choose to remediate on his own. He researched and adopted methods recommended by various internet sources and referenced respected sources, such as the Department of Health and the Environmental Protection Agency.

He attended our health counseling sessions, which were scheduled throughout his stay with our practice to provide assessments and follow-ups on compliance and outcomes to the treatment plan. He attended sessions on a monthly and sometimes bi-monthly basis with decreasing frequency until he reached the point of discharge in 2024. At the beginning, he was advised to work using an industrial-qualified mask and gloves, or to consider an alternative occupation. Eventually he did change his occupation. Part of our work together included psychoeducation and how to sustain behavior changes over time. He was educated on the role of the microbiome in the production of neurotransmitters and the proper functioning of the immune system. He was educated about the role of toxins and increasing markers of inflammation, and the symptoms of inflammation. He was informed about mold, Clostridia species, and Candida metabolites that act as toxins affecting inflammation, and especially how they cause issues in brain functioning, leading to psychiatric symptoms. The psychoeducation was helpful in compelling motivation and compliance with the plan.

The gut-brain axis involves many pathways, including but not limited to the autonomic and enteric nervous system, endocrine and the hypothalamic-pituitary-adrenal axis, the immune system, and the microbiota and their metabolites, some of which are toxins. Vitamins, neurotransmitters, bile acids and amino acids, and the short-chain fatty acids modulate many immune system pathways, which ultimately affect behavior, memory, and learning, leading to psychiatric and neurodegenerative disorders. Many researchers have shown that the inflammasome, which is the sensor that initiates the activation of the immune system, plays a role in anxiety, depression, and schizophrenia, to name a few psychiatric diagnoses. Furthermore, the activation of C4a from the inflammasome is linked to changes in the prefrontal cortex.^10,13 Functioning immune cells can enter the CNS (central nervous system) through the BBB, along with the molecules that can pass, such as bacterial products and their metabolites.^9,14,15 A bidirectional mechanism exists between the gut and the brain, sending signals from the microbiome to the brain, and this gut-brain axis is widely documented in several studies.^3,4,6,16,17

 

The Prescribed Plan

1. NAC (N-Acetyl Cysteine) 600 mg, L-Glutathione 375-750 mg (must be liposomal type for improved absorption) to address the elimination of toxins and resolve the low level of glutathione. Dosing was once daily.
2. Binders during detoxification, such as the fiber, Glucomannan 2 g, have shown efficacy in binding various mycotoxins, and fiber was taken daily up to 2 grams. Two tabs of Spore probiotics and prebiotics (of 4 billion CFU) were prescribed with a meal to support the microbial re-colonization in the gut and help produce the neuro-hormones and re-establish balance.
3.  Chlorella 2 ml is a heavy metal and aflatoxin binder.
4.   plantarum C88 10billion CFU. This strain works not only to bind to aflatoxins, but it also works by upregulating the antioxidant activity of glutathione S-transferase.
5. Magnesium 300 mg, L-Theanine 200 mg, and pharma GABA 100-300 mg to support calm and more restful sleep.
6. D3, 5000 IU daily for two weeks, thereafter 2000 IU daily (vitamin D3 is reputed to have many functions in various systems, including the effect of reducing inflammation and improving mental health).
7. Methylated B Complex to support the production of neuro-hormones.
8. CoQ10 500mg to support antioxidant activity.
9.   Boulardii 10 billion CFU and Nystatin RX 500 000 IU two tabs twice daily for yeast overgrowth (use for three months, test, then terminate or extend treatment based on results).

 

Follow-Up and Outcomes

Two to three months into the treatment plan (11-2022), he reported that he was feeling much better and had no acute symptoms of schizophrenia. A routine mental status was performed using questions and an internal checklist with symptoms rated from mild, moderate, to severe. He rated his symptoms of psychosis as none. He stated that he felt better physically and could focus and concentrate. He was no longer on any medication and had a complete remission of all his psychiatric and physical symptoms.

02/02/2023: He repeated lab tests, his C3a returned to normal, while his C4a decreased from 4546.8 to 917.8. He remains intolerant to many foods, likely the result of his poor gut health. He was allergic to wheat, peanuts, and soybeans. He was intolerant of Candida. The Candida albicans was lowered from 0.71 to 0.59 owing to the Nystatin treatment.

10-19-2023: He repeated the labs, and all parameters were within the normal range except for a slight elevation of alkaline phosphatase at 127 (44-121 IU/L). Candida was further lowered, from 0.59 to 0.21. Nystatin treatment was discontinued given the lower levels and positive outcomes.

02/28/2024: All repeat labs using standard lab testing were within normal limits. CBC and CMP results were normal. His VMA 24-hour Urine test was within normal limits. C4a was lower at 651.8, proving that the treatment to lower inflammation was successful.

He was compliant with the food plan, medication, and supplements. All supplements were stopped six months after initiation, except for Vitamin D3, CoQ10, and Vitamin B complex. He continued using glucomannan, L-Theanine, and GABA as desired for a calming effect.

The assessment of his outcomes included the MSQ (Medical Symptom Questionnaire) and the MSE checklist, as well as clinical interviews to document his results. The Institute for Functional Medicine MSQ score lowered from 62 (6-2022) to 34 (9-2022), and further to 6 (6-2024), indicating a substantial decrease in symptoms over time, confirming the positive outcomes from the treatment approach.

He reported being adherent to the food plan and doing daily exercise at the gym. After the treatment plan, he was off all psychiatric medications, never hospitalized again for two years following the plan in 2022, and as evaluated in 2024. He reported positive outcomes because of the plan, and that he had never felt as healthy both mentally and physically. He did not experience any side effects from the treatment plan.

 

Discussion

The patient had losses in his life as an adolescent, and that, coupled with poor diet and lack of exercise routines, made it extremely challenging for his system to tolerate any major stressors. Additional antecedents were the family history of immune system dysfunction with autoimmune diseases and the likelihood that he, too, was genetically predisposed. As a young adult, he experienced a major stressor as he was involved in legal trouble, but was absolved of it, and his name was cleared. He described it as a very stressful event in his life, but it did not lead to any significant psychiatric symptoms. The major stressors in his life triggered a breakdown of many metabolic processes typical of chronic high levels of cortisol, such as neuroendocrine imbalances.

The series of traumatic events, coupled with a job in which he experienced an overload of toxins, led to deterioration. From a psychosocial viewpoint, he was not caring for himself during these high-stress episodes. His diet was not adequate or wholesome. The pattern of poor self-care led to chronic inflammation and poor gut health. The patterns included poor dietary choices and a lack of protective equipment to wear during exposure to toxic chemicals. These mediators fueled the ongoing downtrend in his health. His symptoms of chronic inflammation included weariness, fatigue, daytime sleepiness, irritability, and cognitive components, such as pain and disease activity.¹⁸

The lack of positive or sustained symptom relief from conventional approaches indicates that the traditional explanations for psychiatric disorders do not apply in this case, or likely in most cases, as symptoms are rarely, if ever, remitted to the extent that the recipient reports a return to “normalcy”.

An alternative approach to conventional treatment is examining the effects of toxins, which trigger inflammation that leads to changes in brain chemistry and functioning. He was exposed to toxins such as xylene and other unknown chemicals in oil-based paints during his job, and mold toxins in his home. Chronic inflammation from the toxins is a risk factor for mental health disorders.^14,19,20

Based on his history and assessment, it is likely that a build-up of toxins has interfered with the healthy functioning of various systems. The history of his losses and stressful events set into motion a shifting of metabolic processes from the baseline of optimal to borderline functioning. Precious metabolic resources were being used to maintain daily functioning. Since additional assaults occurred in the form of a toxin-laden job, he could no longer maintain daily functioning. He then entered the realm of traditional psychiatry with multiple biochemical interventions that did not produce any relief.

He was tested for dysbiosis, and the positive finding was associated with chronic inflammation. Dysbiosis not only leads to gastrointestinal disorders but also affects distal organs. Intestinal bacteria can affect the central nervous system. There exists a bidirectional network of signaling pathways along the gut-brain axis through multiple connections in the vagus nerve, the immune system, and bacterial metabolites and toxic products cause dysregulation of these pathways.³

Chronic low-level inflammation is a mediator of neuroinflammation. The chronic level of inflammation interferes with synapses in the brain, as immune cells are believed to do “pruning” of cells.¹⁰ The pruning of cells in the prefrontal cortex will lead to the common symptoms of schizophrenia, such as a decrease in logical and rational thinking and changes in sensory perception.

His case illustrates the need for a systems review of the possible causes of mental health and physical anomalies. When the mind is not well, neither is the body. When the body is in poor health, so is the brain/mind. The integrative and whole-brain-body systems approach provided a new path to explore. His career change, along with the introduction of detoxifying supportive supplements and an anti-inflammatory diet, improved the functioning of both mind and body. The focus on inflammation in this case is warranted, given the research findings of the impact of chronic inflammation on the production of various diseases, including depression, bipolar depression, anxiety-related disorders, and schizophrenia.¹⁴

The normal catecholamines test result of serotonin, epinephrine, dopamine, and Vanillylmandelic acid (VMA) raises the question whether mental health diagnoses are truly the result of varying levels of serotonin and/or dopamine or are the imbalances in neurohormones produced by other core triggers? If it is due only to specific neurotransmitter imbalances, then medications that solely focus on one or two neurotransmitters should work across the board. Instead, we find that there is some symptom relief for a few, but seldom without side effects.² This case study highlights the likelihood of other issues that need to be addressed to restore normal functioning of the brain and body. We should not ignore the high levels of inflammation that are common in every disease, and should have a plan to address it.

The therapeutic plan aimed to remove the sources of inflammation, namely the chemical toxins on the job, non-organic and processed foods, and mold. The treatment helped calm the state of inflammation, along with detoxifying glutathione and the precursor of NAC to support the ongoing production of natural glutathione and antioxidants in the form of CoQ10. Vitamin D3 is known to support the immune system, and B vitamins support metabolic processes throughout the body.
S. Boulardii and L. plantarum help regulate dysbiosis and restore a more stable gut-brain axis, thus improving mental health.¹¹ Fiber has many healthy supportive functions in the gut and acts as a binder of aflatoxins, which are another source of toxins produced by molds. Magnesium, L-Theanine, and GABA are known to promote calmness and help restore sleep, crucial for healthy brain functioning.²¹

The strengths of the case study are the length of the follow-up and having achieved the identified objectives, which were to seek a cure for his psychiatric symptoms without medication or hospitalization. The treatment itself was efficacious and required only simple changes in lifestyle (such as diet, exercise, and supplements prescribed to normalize metabolic processes) as opposed to the costly and ineffective treatments, including multiple hospitalizations and chronic use of psychiatric medications.

This study has a few limitations. Firstly, this is a single patient case study. Secondly, the mold infestation could not be documented with real data, except for reports associating higher levels of mold toxins with a downstream metabolite.

The positive aspect of the case study is that a well-supported model with a different approach is outlined, illustrating how the approach worked, supported with lab results, and achieved a reduction in inflammation. The approach not only achieved its goals but also supported overall health, since chronic inflammation is also associated with other illnesses.^18,19 The patient’s case clearly illustrates the track towards repeated failed outcomes for him with yearly or more frequent psychiatric hospitalizations and a multitude of medications that by themselves could and would lead to other metabolic anomalies. Additionally, an economic burden is associated with hospitalizations and chronic use of medications that do not lead to a cure.^1,2 The patient is functioning well, happy, and productive, without any additional costs for hospitalizations and medications.

 

Subject’s Perspective and Comment

Hello Dr. G,

After completing my treatment plan, I have had zero psychiatric hospitalizations, no use of psychiatric medications, and no return of any original symptoms.

I realized a total recovery in my mental and physical health. I realized a total improvement in my physical health by removing wheat and dairy from my diet, and on a scale of 1-5, how well I am doing and achieved my goals, I would give it a 5. Because of your treatment and the work you did, I have been able to identify that toxins are extremely dangerous for me, and I changed my line of work. In addition, I was able to solidify that I didn’t have a mental illness. I had medical issues that were masking themselves as mental illnesses.

 

Funding

The research received no funding of any kind

Ethics Statement

Informed consent was obtained from the subject.

Author Disclosure Statement

The authors declare that they have no competing interests.

Acknowledgements

The Case report followed the Care Guidelines. IFM Matrix, Clinical Imbalances used with Permission from the Institute for Functional Medicine (IFM), the global leader in functional medicine and a collaborator in the transformation of healthcare.

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