Chapter 15

CONTRIBUTING CAUSE

Food, Fasting, and Your Gut

What we eat, when we eat, and how much we eat have direct effects on metabolism and mitochondria. Everyone knows that diet plays a role in obesity, diabetes, and cardiovascular disease. What most people might not know is that diet also has profound effects on mental health and the brain.

This field is massive. Tens of thousands of research articles and countless textbooks have explored the effects of diet on metabolism and mitochondria. Most of this research has focused on obesity, diabetes, cardiovascular disease, Alzheimer’s disease, aging, and longevity. Although these researchers don’t usually see the connection with mental health, by now, I hope you do.

The connections go far beyond correlations. They overlap at the level of neural circuits in the brain and, of course, the entire network of metabolism and mitochondria within the human body. For example, the neural circuits that drive appetite and eating behaviors have also been directly implicated in addiction to tobacco, alcohol, and heroin.¹ That’s not too surprising to most people. What might be more surprising is that the neural circuits for loneliness overlap directly with the neural circuits that warn of starvation.² This study, published in Nature, showed that chronic social isolation in the fruit fly led to increased eating and decreased sleep. A “social” problem led to changes in appetite and sleep. When the researchers artificially stimulated the neural circuit for social isolation, it caused the flies to eat more and sleep less. Another study identified specific GABA and serotonin neural circuits that were directly involved in obesity and anxiety and depression.³ One neural circuit plays a role in how much you weigh and how you feel.

Some people call this field nutritional psychiatry, one that looks at the role of diet in mental health. Personally, I feel this is too narrow. It’s more than how diet affects brain function. It’s also about how our mental states affect our metabolism, which can impact appetite and feeding behavior, which can affect overall health. It’s a bidirectional relationship. Metabolic affects mental, and mental affects metabolic.

As I said, this field is massive. I can’t possibly do it justice in one chapter. Nonetheless, I will give you a tiny taste (see what I did there?) of how this field relates to mental health by running through several food-related topics and tracing how they act as contributing causes under the brain energy theory.

Vitamins and Nutrients

One of the easiest places to start is with vitamins and nutrients. Several vitamin deficiencies are known to cause mental and neurological disorders. Correcting these vitamin deficiencies can sometimes completely solve the problem. Along with hormonal imbalances, vitamin deficiencies are one of the few examples in psychiatry where there is a clearly identified problem with a simple treatment.

Three of the best-known vitamin deficiencies that can result in mental and neurological symptoms include thiamine, folate, and vitamin B12. These vitamins should be routinely checked in patients with psychiatric and neurological disorders because if they are low, there is a clear treatment for them. What do these vitamins do? They are all required for energy metabolism within mitochondria. If a person is deficient in these vitamins, they will have impaired energy production within mitochondria, aka mitochondrial dysfunction.

True to the theory of brain energy, the symptoms associated with these deficiencies are widespread and include most diagnostic categories. There are many physical symptoms as well as mental symptoms. The mental ones include depression, apathy, loss of appetite, irritability, confusion, memory impairment, sleep disturbances, fatigue, hallucinations, and delusions, to name just some of them. Deficiencies in these vitamins in pregnant women can also result in developmental abnormalities in their children, highlighting the role of mitochondria in development.

There are many other vitamins and nutrients that can easily be connected to mitochondria and metabolism, but I’ll move on. As I said, this field is massive.

Food Quality

Our food supply has changed dramatically in the last fifty years. Plants have been genetically modified. Cattle, pigs, and chickens are pumped with antibiotics and growth hormones to make them fatter. Processed foods are filled with artificial ingredients and often devoid of nutrition, including fiber, vitamins, minerals, and phytonutrients. Understanding the effects of all these hormones and chemicals on human metabolism is far from clear, but research suggests they do have an impact.

Junk food is often described as “junk” not only because it lacks important nutrients, but also because it usually contains highly processed and unnatural ingredients, which have been linked to poor metabolic health. We have all heard arguments about which ingredients are bad for us. Some blame fat; others blame carbohydrates; still others blame animal-sourced products. The controversies are endless. I’ll walk through three examples of dietary factors that have been directly linked to mitochondrial function and both metabolic and mental health.

Trans fatty acids (TFAs) are man-made, processed fats that were originally marketed as a healthier alternative to saturated fats. We were told that “healthy vegetable shortening” was far better than lard. For years, TFAs were ubiquitous in the US food supply. Tragically, it turns out that they are in fact toxic to human health, and they have now been banned in the US. Their use has been associated with increased risk of cardiovascular disease, depression, behavioral aggression, irritability, and Alzheimer’s disease.⁴ Although the exact mechanisms are still unclear, one animal study tried to figure it out by assessing what impact TFAs might have on rats and their babies.⁵ Researchers gave pregnant and lactating rats either TFAs or soybean/fish oil with their diets. When the baby rats were born, they got a normal diet without TFAs. At sixty days, the babies from the mothers who got TFAs showed greater anxiety, higher levels of ROS, greater inflammation, and reduced glucocorticoid receptors in the hippocampus. This one study demonstrates how several things I’ve discussed so far are all interconnected. A single factor in a mother’s diet ended up affecting her children’s anxiety, mitochondrial function, inflammation, and glucocorticoid receptor levels, which plays a role in the stress response. Wow! Luckily, these have been banned in the US as of 2018, but could something like this account for the higher rates of depression and anxiety in the youth of America? I described how parents can transmit a vulnerability to mental illness from their own trauma history. What this research suggests is that if your mother ate trans fats while she was pregnant with you, it is possible that this might play a role in your metabolic health.

Sometimes, junk food isn’t called junk because of the “bad” things in it, but instead because of the “good” things that it doesn’t contain. Let’s look at fiber. As you likely know, fiber is found in fruits, vegetables, and whole grains and is highly recommended these days. Most experts are certain that it plays a beneficial role in metabolic health and aging. Some studies suggest that it also plays a role in mental health. High levels of adherence to the Mediterranean diet, which includes lots of fruits, vegetables, whole grains, and olive oil, has been associated with lower rates of depression and cognitive impairment.⁶ One of the biggest benefits of fiber is its conversion by microbes in the gut into butyrate, a short-chain fatty acid. Butyrate, in turn, serves as a primary fuel source for the mitochondria in gut cells (colonocytes). It also plays a role in liver cells. One research group found that butyrate directly changes mitochondrial function, efficiency, and dynamics (fusion/fission), and that these changes directly impact insulin resistance, fat accumulation in the liver, and overall metabolism.⁷ There are strong connections between the gut and the brain that I’ll get to shortly, but interestingly, butyrate itself appears to directly play a role in sleep! And even more fascinating is that the mechanism appears to be located in the liver or the vein going to the liver (portal vein). Researchers studied mice to work this all out.⁸ They injected butyrate into their guts or their portal veins and found that the mice slept 50 to 70 percent more. When they injected butyrate into other parts of their bodies, it did nothing for sleep. Another research study found that butyrate decreases neuroinflammation in aging mice, something that might protect against Alzheimer’s disease.⁹

Sometimes, it’s not about one specific ingredient. Instead, it might have more to do with how much we eat. Junk food can be addictive, at least for some of us. We all know the saying, “You can’t eat just one.” Is overeating the problem? This can lead to high levels of insulin and blood glucose, especially in people with insulin resistance. I already told you how insulin resistance is related to mental disorders and mitochondria. Does high blood glucose play a more direct role? Some research suggests that it does.

One study in diabetic rats found that high levels of glucose directly impaired mitochondria, as measured by decreased ATP production, increased oxidative stress, and decreased antioxidant capacities, and that all of this likely damages neurons.¹⁰

Another study looked at human endothelial cells (cells that line arteries) to see if high glucose levels affect their mitochondrial function. They found that it does. Although it didn’t change baseline energy production, when the cells were stressed, those exposed to high levels of glucose had impaired ability to produce more energy. Again, a paradox. More glucose, or fuel, led to lower levels of ATP.¹¹

Another study looked at twenty people with diabetes to see what impact high blood glucose had on their mood and brain function.¹² They used a clamp technology to artificially control blood glucose and exposed all the people to both normal and high glucose levels. High glucose led to impairment in processing speed, memory, and attention, and also led to reduced energy levels, increased sadness, and anxiety. This research suggests that if people with insulin resistance overeat comfort foods, it might actually cause them to feel sad and anxious and have cognitive impairment.

Finally, a meta-analysis of forty-six studies that included over 98,000 participants who did not yet have diabetes looked at levels of blood glucose to see if this increased risk for brain changes related to Alzheimer’s disease. The researchers found that higher levels of blood glucose increased risk for higher levels of amyloid and brain shrinkage.¹³

Could elevated blood glucose account for the higher rates of depression and Alzheimer’s disease in people with diabetes? All of this research suggests that it might play a role.

But wait . . . it’s another feedback loop! It turns out mitochondria play a direct role in controlling glucose levels. A study published in Cell found that mitochondria in the cells of the ventromedial nucleus of the hypothalamus (VMH), an area of the brain known to regulate glucose levels throughout the body, were critical in this regulation.¹⁴ Their fission with each other and their levels of ROS directly control glucose levels throughout the body. So, if these mitochondria aren’t functioning properly, glucose regulation will be off. This, in turn, might cause sadness, anxiety, and increase the likelihood of developing Alzheimer’s disease.

Obesity

Obesity is a complex topic. Most people think of it as a problem of overeating—people are eating more calories than they are burning. But “eating more calories than they are burning” has two parts. Sometimes people are eating too much food—in that case the question is why they are eating too much. But the second part of the equation is burning calories. Some people who struggle with obesity can eat very little and still fail to lose weight. Therefore, a better question is this: Why are those who are obese storing so much fat and/or not burning it? The reality is that almost everyone overeats on occasion. Think of Thanksgiving. Those who are thin can feel stuffed even into the next day. This drives them to eat less. Or their metabolism increases to burn off the excess calories. Either way, they go on being thin. Obese people don’t have the same responses. In fact, sometimes, when obese people lose weight, their metabolism plummets. It fights their efforts to lose weight.

These are complex topics. I’m not going to try to address them here. Instead, my goal is to highlight that obesity does play a role in metabolism and mitochondrial function, and mitochondria play a role in obesity. These things, in turn, are all related to mental health.

I’ve mentioned that loneliness, anxiety, depression, and sleep share some neural circuits with appetite and feeding behaviors. What would happen to someone if these neural circuits were hyperexcitable? Well, that person would feel depressed, anxious, inappropriately lonely, have trouble sleeping, and would overeat. Do you know anyone like that? I can tell you that I’ve met many people exactly like this in my career as a psychiatrist.

Both obesity and mental disorders are associated with mitochondrial dysfunction. When people have both, these conditions can make each other worse. Mental disorders can lead to even more weight gain. Obesity can lead to even more depression, anxiety, and bipolar symptoms. One study looked at bipolar patients, some who were obese and others who weren’t, and found that the obese patients had more depressive episodes than the thin ones.¹⁵ Obesity itself was playing a role in their mood symptoms.

One way to understand some of this is through insulin. I’ve already shared some information about insulin, mitochondrial function, and brain function. People with obesity usually have insulin resistance, in both their bodies and brains. One group of researchers specifically looked to see if mitochondrial dysfunction is playing a role, and sure enough, they found signs of mitochondrial impairment in both the brains and livers of insulin-resistant rats.¹⁶

Insulin resistance takes on a life of its own, though. The pancreas responds to insulin resistance by pumping out more insulin. If a little isn’t working, then send out a lot. That helps! But the problem is that higher levels of insulin usually make insulin resistance even worse over time. They drive hunger and weight gain. And one of the problems with higher and higher levels of insulin is that insulin resistance alone inhibits mitochondrial biogenesis, compounding the metabolic problem.¹⁷

In the brain, insulin plays a direct role in how mitochondria respond to stress. When insulin signaling is working fine, mitochondria respond to stress effectively. One way to stress mitochondria in mice is to feed them a high-fat diet (HFD), which usually leads to obesity. Researchers studied mice with insulin resistance being fed an HFD and found impairment in the stress response in mitochondria.¹⁸ When they gave the mice intranasal insulin, the mitochondria responded normally again, and interestingly, the mice gained less weight. So, helping mitochondria function properly helped the mice deal more effectively with the HFD.

Another research group also looked at the role of mitochondria in brain cells of mice given an HFD.¹⁹ They found that microglial cells were causing brain inflammation in response to the HFD. This occurred before the mice gained any weight. When they looked further to see what was driving the changes in the microglial cells, they found that it was mitochondria. There was an increase in a specific mitochondrial protein, UCP2, that was driving changes in mitochondrial dynamics (movement, fusion, and fission). When the researchers deleted this protein, the mice no longer had brain inflammation, and shockingly, did not develop obesity even though they continued to have access to the high-fat diet. Instead, these mice ended up eating less and were burning more calories. This study suggests that mitochondria are, in fact, key players in how the brain and body respond to high-calorie foods. Two other studies published in Cell confirm a direct role of mitochondria in brain cells in the regulation of feeding behaviors, obesity, and leptin resistance.²⁰

When I first read this study, I was confused. The researchers clearly demonstrated a direct role of mitochondria in both brain inflammation and subsequent obesity. However, they interfered with what the mitochondria were normally doing. So, one way to look at this study is to think that the microglial mitochondria were dysfunctional and the researchers prevented them from making a mistake. Another way to look at it is that these mitochondria were receiving erroneous signals from somewhere else in the body, maybe the gut microbiome, or gut cells, or the liver. Or maybe it was due to insulin resistance, as I described earlier. But another distinct possibility is that the mitochondria were doing exactly what they are programmed to do; they may have been looking out for the long-term health of the organism. At this point, we don’t know what the correct response should be to a toxic diet. Maybe obesity is a better survival strategy when consuming toxic foods. We can’t be certain that preventing the inflammation and obesity in this case would lead to better health outcomes or longevity, but I suppose that study would be easy enough to do. As you can see, it’s complicated. And then again . . . it’s not. If you want to prevent obesity in mice, don’t feed them the toxic diet.

Just for the record, the “high-fat diet” can also contain other unhealthy ingredients, such as sucrose—it’s often the evil combination that is so fattening. I mention this because I will soon be discussing a different type of high-fat diet that usually results in weight loss and lower levels of inflammation, so it’s not the fat, per se.

Fasting, Starvation, and Eating Disorders

Fasting is going without food. For any amount of time, really. We all fast when we sleep. That’s why breakfast has its name—it’s breaking a fast. Fasting for longer periods of time results in many changes to metabolism and mitochondria. Interestingly, it can also have profound, beneficial effects on the human body. To most people, this is surprising. We usually think about our bodies needing food and nutrients. We’ve all heard that we need three square meals a day. Some of us have been told to eat six or eight times throughout the day. We need to keep fueling our bodies. We need the energy.

For infants, this is unequivocally true—most need feedings every two hours. For children who are growing, this can be true as well. But for adults, there is now a tremendous amount of science to suggest that eating all the time actually harms health.

Fasting prompts the body to be frugal and encourages autophagy, which has tremendous healing potential. The body hunkers down and makes do with what it has. It’s time to tap those fat stores. We all know that can be good. But there’s more to the story than that. Each and every cell responds, and mitochondria are right there to direct things. They immediately change shape. They elongate themselves, fuse with each other, and form long tubular networks.²¹ What ensues is a spring-cleaning, if you will. The cells identify old and defective proteins and cell parts. They are the first to go in a massive recycling campaign. These proteins and parts are shuttled to lysosomes for degradation. These nutrients are then recycled; some get used for energy, while others might be used for new, essential proteins and cell parts. The cells are looking for anything and everything that is expendable in a carefully orchestrated reboot.

So, what about the cells’ mitochondria? Are they also getting destroyed? Well, the defective ones are, as mitophagy also gets activated during this process. But the healthy mitochondria are now working with each other in the long tubular networks. They keep up the pace of ATP production during this process, and these networks protect them from being recycled. When the person eats again, the cell parts that got destroyed get replaced. These replacement parts are new and healthy, and they often include some new mitochondria!

However, if people go without food for too long, at some point, it turns into starvation. The body mounts a defense strategy. It lowers metabolism broadly to conserve energy. Heart rate slows. Body temperature declines. People become sluggish, irritable, unmotivated, distractible, obsessed with food, and somewhat depressed. Paradoxically, symptoms of hypomania can emerge within the first week or two of starvation. This is likely an adaptive strategy to give the starving person enough energy, motivation, and confidence to get food, no matter what.

As I’m sure you know, this is not good. It’s life-threatening. Cells begin to malfunction and die off. Organs are struggling, and this includes the brain. The list of mental symptoms and diagnoses includes depression, irritability, insomnia, mania, eating disorders, confusion, memory disturbances, hallucinations, and delusions.

Perhaps the best evidence for the mental effects of starvation come from the famous Minnesota Starvation Experiment, in which thirty-six healthy men were subjected to semi-starvation diets (half their normal daily calories) for twenty-four weeks, and then received twenty weeks of “rehabilitation.” The men lost significant amounts of weight and showed signs of slowed metabolism. They experienced wide-ranging and sometimes severe mental symptoms, including depression, anxiety, fatigue, poor concentration, and obsessions with food. Some became transiently hypomanic. Interestingly, it was during the refeeding period that some had the most difficulty. Depression got worse in some of them. Others began binging and purging. Some developed body image concerns. One man cut off three fingers. This study is often used today to understand some of the symptoms of anorexia and bulimia. Starvation itself can cause mental symptoms.²²

This leads to a discussion of eating disorders.

For some people, an eating disorder can start through societal pressure to lose weight and be thin. Young, female ballet dancers are an obvious example. Many young women who dance are told in no uncertain terms that they must be thin to compete. There is tremendous pressure to lose weight. For the girls and women who follow these recommendations, they can put themselves into starvation. This can start the vicious cycle of metabolic disturbances that impact brain function. The parts of the brain that control feeding behaviors are impacted, but so are the parts of the brain that interpret how they perceive their bodies. They can develop severe distortions in body image, thinking they are fat when they are truly emaciated. This sometimes verges on delusional, because the way they perceive themselves can be so far removed from how they really look. Researchers looked at a mouse model of anorexia to see if, in fact, there is mitochondrial impairment in the brain, and sure enough, they found oxidative stress and impairment of specific parts of mitochondria within the hypothalamus.²³ A study of forty women, half with anorexia and the other half without, found mitochondrial dysfunction in the white blood cells of those with anorexia.²⁴

However, other people can develop an eating disorder because of a preexisting vulnerability. Eating behaviors impact metabolism, whether it’s overeating or undereating. For some, this can result in short-term, rewarding feelings.

Binge eating can make some people feel better because it provides more insulin and glucose to struggling brain cells, and it stimulates the reward centers in the brain. This may be the quickest and easiest way to overcome insulin resistance—eat a lot of sugar. Unfortunately, as I just discussed, this makes matter worse over time. For others, restricting eating can improve mood because it can provide stress hormones or ketones (you’ll hear more about these soon) that can be helpful to struggling brain cells. These two extremes of overeating and undereating can both produce rewarding experiences in different people. So, for people with preexisting mental disorders who are already struggling, changing eating behaviors can be appealing. For some, it can become a way of life, even if it causes health problems. This likely explains why people with all mental disorders are more likely to develop an eating disorder. They are looking for ways to feel better.

The Gut-Brain Axis and the Microbiome

Over the past few decades, a growing body of research suggests that our intestinal tract plays an important role in both metabolic and mental health. Many signals get sent from the digestive tract to the brain, and vice versa. There appear to be many mechanisms by which this communication occurs. I’ll briefly look at a few of them.

First, it has become increasingly clear that the trillions of bacteria, fungi, and viruses in our guts play an important role in human health, especially obesity, diabetes, and cardiovascular disease. For example, animal studies have shown that gut microbes can affect weight. In one study, researchers found that the microbiome in obese mice extracts more nutrients and calories from food than in thin mice. When this obese microbiome is transferred to thin mice, the thin mice gain weight.²⁵

There is also increasing evidence for the role of the gut microbiome in mental disorders. Animal models and small human trials have shown that the gut microbiome appears to play a role in depression, anxiety, autism, schizophrenia, bipolar disorder, and eating disorders. There is also evidence for the role of the gut microbiome in epilepsy and neurodegenerative disorders.

Gut bacteria get first dibs on all the food we eat. They produce a variety of metabolites, neurotransmitters, and hormones that they secrete into our guts. These get absorbed into our bloodstream and can affect our metabolism and brain function.

A second way that signals get sent from the gut to the brain is through hormones and neuropeptides that are produced in the cells that line the intestinal tract. These, too, are known to travel throughout the body, including to the brain, and have widespread effects on metabolism and brain function.

Finally, the gut has an intricate nervous system unto itself that communicates directly with the brain and vice versa. The vagus nerve plays an important role in this communication. As I mentioned, about 90 percent of the body’s total serotonin is produced in the intestinal tract.

This field of the gut-brain axis and the microbiome can quickly become overwhelming when one begins to think about all the different microbes, metabolites, hormones, neurotransmitters, neuropeptides, and other factors involved. However, there is a clear connection between all these factors. They all relate to metabolism and mitochondria. There is evidence that gut microbes send signals directly to mitochondria in the cells lining the gut and immune cells. These signals have been shown to change mitochondrial metabolism, alter the barrier function of the gut cells, and can lead to inflammation.²⁶

Food, Fasting, and the Gut Microbiome as Treatments

There are at least eight different ways that dietary interventions can be helpful in addressing mental symptoms:²⁷

A comprehensive discussion of all these areas is beyond the scope of this book. Instead, I’ll discuss a few highlights.

Vitamins and Nutraceuticals

Addressing vitamin and nutritional deficiencies is important. However, taking twenty-plus vitamins and supplements is not the answer to most metabolic problems. Sometimes, excessive use of vitamins and supplements can actually cause metabolic problems. Healthy metabolism is about balance—not too much and not too little.

Many vitamins and supplements, or nutraceuticals, might play a role in improving mitochondrial function and production. The list of possibilities is long. It includes L-methylfolate, Vitamin B12, SAMe, N-acetylcysteine (NAC), L-tryptophan, zinc, magnesium, omega-3 fatty acids, nicotinamide riboside, alpha-lipoic acid, arginine, carnitine, citrulline, choline, co-enzyme Q10, creatine, folinic acid, niacin, riboflavin, thiamine, resveratrol, pterostilbene, and antioxidants.²⁸ It’s unlikely that all of these will be beneficial for all people, and by no means should anyone take all of these at the same time.

Here’s a great example to illustrate this caution. Researchers gave 180 patients with bipolar depression one of three treatments: (1) a “mitochondrial cocktail,” (2) NAC alone, or (3) placebo for sixteen weeks as an add-on to their existing treatments.²⁹ The mitochondrial cocktail included N-acetylcysteine, acetyl-L-carnitine, Co Q10, magnesium, calcium, vitamin D3, vitamin E, alpha-lipoic acid, vitamin A, biotin, thiamine, riboflavin, nicotinamide, calcium pantothenate, pyridoxine hydrochloride, folic acid, and vitamin B12. Wow! That’s a cocktail. And guess what they found? No difference in any of the groups.

Again, low levels of these vitamins and other factors may simply be a consequence of mitochondrial dysfunction, not the cause of it. If that’s the case, adding more may not solve the problem. And pills like this don’t automatically stimulate mitochondrial biogenesis or mitophagy. But dietary interventions, good sleep, stress reduction, removing mitochondrially impairing medications, and exercise can!

Diet and Fasting

I shared with you that people who adhere to the Mediterranean diet (MD) are less likely to develop depression. But for people who are already depressed, can adopting this diet improve symptoms? It appears that it can, at least for some people. One trial, cleverly called the SMILES trial, randomized sixty-seven people with major depression to groups that encouraged people to follow the MD or a social support group (the control group). Participants continued their existing treatments for depression (medications or therapy). After twelve weeks, 32 percent of the people in the MD group achieved remission compared with only 8 percent in the control group.³⁰ Is there any evidence that this is due to metabolism or mitochondria? Well, we have at least one study to call upon.

Researchers looked at monkeys (cynomolgus macaques) fed an MD versus a Western diet (standard American diet) for thirty months and then measured brain mitochondrial function, energy utilization patterns, and biomarkers such as insulin levels.³¹ They found diminished bioenergetic patterns between brain regions in the monkeys getting the Western diet, which correlated with levels of insulin and glucose. The mitochondria in the MD-fed animals maintained normal differences between brain regions, whereas the mitochondria in the Western-fed animals lost these normal distinctions. The brain areas affected are known to play a role in diabetes and Alzheimer’s disease.

There is also evidence that fasting, intermittent fasting (IF), and fasting-mimicking diets may play a role in treating mental disorders. They all result in the production of ketone bodies, which are made when fat is being used as an energy source. Fat gets turned into ketones. And, interestingly, this process occurs exclusively in mitochondria, yet another role for these magnificent organelles.

Ketones are an alternate source of energy to cells. They also serve as important metabolic signaling molecules, resulting in epigenetic changes. Ketones can be a rescue energy source to insulin-resistant brain cells. While glucose might have trouble getting into these cells, ketones can get inside pretty easily. Fasting also results in autophagy, as I’ve described. There are several versions of IF. Some restrict eating to eight to twelve hours per day. Others allow one meal a day. And others restrict nighttime eating.

We have evidence that IF improves mood and cognition, and protects neurons from damage in animal models of epilepsy and Alzheimer’s disease. One group of researchers set out to understand how and why.³² You’ll never guess what they found—it’s mitochondria! When researchers put mice on an IF routine, they found that the hippocampus, a brain region often involved in depression, anxiety, and memory disorders, was largely driving the improvements from IF. It appeared to be due primarily to higher levels of GABA activity, which reduced hyperexcitability. Then the researchers went further to understand what was causing this change in GABA activity. They removed sirtuin 3 from the mice in two different ways—recall that this protein is exclusive and essential to mitochondrial health. When they did this, all the benefits were lost. This clearly implicates mitochondria directly in the benefits of IF on brain health.

Another review article outlines many of the ways that IF is thought to promote brain health, including reducing oxidative stress and inflammation, improving mitophagy and mitochondrial biogenesis, increasing brain-derived neurotropic factor (BDNF), improving neuroplasticity, and promoting cellular stress resistance.³³ These are powerful healing interventions not currently available in a pill.

Fasting-mimicking diets can replicate the benefits of fasting for longer periods of time without the risk of starvation. The best-known example is the ketogenic diet. You likely recall that it was this diet and its profound impact on one of my patients that led me on this journey.

The story of the ketogenic diet begins with epilepsy. Since the time of Hippocrates, fasting was known to stop seizures and was used as a treatment in many cultures. With the advent of modern medicine, however, this was largely believed to be religious folklore and likely nonsense. That changed in the 1920s when a physician published a research article about fasting stopping seizures in a boy. The problem with fasting is that if it’s done too long, people die of starvation—not a very effective intervention. And when people start eating normally again, the seizures usually come right back. In 1921, Dr. Russell Wilder developed the ketogenic diet, a diet high in fat, moderate in protein, and low in carbohydrates, to address this challenge. His desire was to see if the diet could mimic the fasting state, but prevent starvation, to treat epilepsy. Lo and behold, it worked. The ketogenic diet reduced or stopped seizures in about 85 percent of the people who tried it. By the 1950s, it had fallen out of favor as a growing number of antiepileptic medications came to market. Taking a pill is much easier than doing this diet.

Unfortunately, about 30 percent of patients with epilepsy don’t improve with any of the pills we have to offer, so the ketogenic diet was resurrected in the 1970s at Johns Hopkins for use in treatment-resistant epilepsy. Clinical use of this diet has grown around the world since. Many clinical trials have shown efficacy, and a 2020 Cochrane Review (a gold-standard meta-analysis) concludes that children with treatment-resistant epilepsy who eat ketogenic diets are three times more likely to achieve seizure freedom and six times more likely to experience a 50 percent or greater reduction in seizures than children getting usual care.³⁴

The ketogenic diet is now the best-studied dietary intervention for its effects on the brain. Neurologists, neuroscientists, and pharmaceutical companies have been studying this diet for decades trying to better understand its anticonvulsant effects. It provides an alternate fuel source, which can be a lifeline to insulin-resistant brain cells. It also changes neurotransmitter levels, regulates calcium channels, decreases inflammation, improves the gut microbiome, increases overall metabolic rate, reduces insulin resistance itself, and most importantly, induces both mitophagy and mitochondrial biogenesis.³⁵ After people are on this diet for months or years, their cells have more healthy mitochondria. This can result in long-term healing. Many people can stop the diet after two to five years and remain well.

The research for the diet’s efficacy in treating mental health disorders is in the early stages. In my own work, I have seen people with severe, treatment-resistant psychotic disorders achieve full remission of their symptoms for long periods of time through a ketogenic diet.³⁶ You’ll hear about one at the end of this chapter. The effects of the diet in the first year are just like a medication. People need to remain on the diet religiously. They can’t stop it for “cheat days,” just like they can’t stop their medications for cheat days. All hell can break loose if they do. I should point out that it’s common to use epilepsy treatments in psychiatry. We use many of them for almost all types of mental disorders. So, in many ways, this is nothing new. It just happens to be a dietary intervention. There are several clinical trials for bipolar disorder and schizophrenia getting underway currently.

Alzheimer’s disease researchers looked at twenty-six patients who all got twelve weeks of the ketogenic diet and twelve weeks of a low-fat diet, separated by a ten-week washout period.³⁷ Participants did the diets in different orders and the assessments were blinded. At the end of the study, the researchers found that when people were on the ketogenic diet, they had improvement in daily function and quality of life. I should point out that this is one of the few studies to demonstrate improvement in symptoms of Alzheimer’s disease. Most studies, like the intranasal insulin studies I told you about, only prevent progression of the disease. They don’t reverse it. Obviously, this was a small trial that needs to be replicated in more people over longer periods of time, but the basic science certainly supports why and how this might be working.

There are many versions of the ketogenic diet, including ones for weight loss, diabetes management, and epilepsy, and they don’t always have the same effects. The foods can also be tailored to personal preferences, such as vegetarian, vegan, meat-only (the “carnivore diet”), or a diet with both animal and plant-sourced foods. Those with medical or mental disorders should only do this diet with medical supervision, as there are risks and side effects, and prescription medications usually need to be adjusted or stopped safely.

The Gut Microbiome

As mentioned, there is no question that the gut microbiome plays a role in mental and metabolic health. In terms of proven interventions, however, this field is in its infancy.

Here are four types of interventions to consider:

Summing Up

Success Story: Mildred—It’s Never Too Late!

Mildred had a horrible, abusive childhood. There is no doubt that she suffered from symptoms of PTSD, anxiety, and depression. At age seventeen, she was also diagnosed with schizophrenia. She began having daily hallucinations and delusions. She became chronically paranoid. Over the ensuing decades, she tried different antipsychotic and mood-stabilizing medications, but her symptoms continued. She could no longer care for herself and was assigned a court-appointed guardian. She was miserable. She tried to kill herself numerous times, once drinking a bottle of cleaning fluid. On top of her mental symptoms, she was obese, weighing 330 pounds.

At age seventy, after fifty-three years of being tormented and disabled by her schizophrenia, her doctor encouraged her to go to a weight-loss clinic at Duke University. They were using the ketogenic diet as a weight-loss method. She decided to give it a try. Within two weeks, not only did she begin to lose weight, she noticed significant improvement in her psychotic symptoms. She said that for the first time in years, she was able to hear the birds singing outside. The voices in her head were no longer drowning them out. Her mood was also improving, and she began to have hope. She was able to taper off all her psychiatric medications. Her symptoms went into full remission. She also lost 150 pounds and has kept it off to this day.

Now, thirteen years later, she remains symptom-free, off medication, and doesn’t see any mental health professionals. Having learned to take care of herself, she got rid of the guardian, too. When I last spoke with Mildred, she said she was happy and excited to be alive. She asked me to share her story with anyone and everyone willing to listen. She hopes that her story might help others escape the living hell that she had to endure for decades.

Stories like Mildred’s . . . just don’t happen in psychiatry. Even with the best traditional treatments that we have to offer, this is unheard of. Mildred’s story and the theory of brain energy say it is possible. It is a new day in the mental health field, one filled with hope for more stories like Mildred’s.