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February 4 - April 8, 2025
cortisol, insulin, estrogen, and thyroid hormone—in
Cortisol plays an important role in the stress response. High levels have been associated with all the metabolic disorders and numerous mental symptoms, including anxiety, fear, depression, mania, psychosis, and cognitive impairment. High levels in utero affect fetal development and play a role in epigenetics,
Cortisol always begins in mitochondria, which have the enzyme that initiates its production.
strong bidirectional relationships between diabetes and mental disorders.
mitochondria are important regulators of insulin production and secretion. Mitochondria are involved in glucose metabolism and sensing how much glucose is available. They ramp up production and secretion of insulin as needed.1
Mitochondria are known to play a significant role in both types 1 and 2 diabetes, with some experts speculating that mitochondrial dysfunction may be the primary cause.
Insulin itself stimulates mitochondria to produce more ATP and also stimulates mitochondrial biogenesis, as measured in muscle tissue.3 However, when researchers did this study in people with type 2 diabetes, these effects were blunted or absent.
insulin resistance can be both a cause and a consequence of mitochondrial dysfunction.
Insulin receptors are located throughout the brain, and they are involved in regulating whole-body metabolism, appetite, reproductive functions, liver functions, fat stores, and body temperature. Brain insulin also modulates neurotransmitter activity and mitochondrial function within brain cells. Changes in insulin signaling have been associated with impairment of neuronal function and synapse formation.
insulin alone can increase GABA activity.
insulin resistance can occur in the brain. When it does, it can result in mitochondrial dysfunction, which can then lead to neurotransmitter imbalances, which can then lead to overactivity and underactivity of neurons.
The brains of the people with psychosis had insulin resistance compared to the healthy controls, but the normal siblings also showed signs of insulin resistance, suggesting that insulin resistance might be a risk factor that runs in families. These researchers went on to find differences in mitochondrial function between the patients with psychosis and their normal siblings. This all suggests that insulin resistance might come first, which then leads to mitochondrial dysfunction, which then leads to psychosis.
Children who had persistently high insulin levels (a sign of insulin resistance) beginning at age nine were five times more likely to be at risk for psychosis, meaning that they were showing at least some worrisome signs, and they were three times more likely to already be diagnosed with bipolar disorder or schizophrenia by the time they turned twenty-four. This study clearly demonstrated that insulin resistance comes first, then psychosis.
“type 3 diabetes.” Strong evidence has emerged that the brains of people with Alzheimer’s disease are not getting enough energy from glucose due to insulin resistance, and that this results in mitochondrial dysfunction.
Clinicians would inject patients with large doses of insulin until they went into a coma. This process was repeated a few times per week. Most reports from that era suggested that it was a highly effective treatment, at least for some people. At one point, it was the most widely used treatment for psychosis and severe depression in the Western world.
Early results were promising. A pilot trial of intranasal insulin in 105 participants with mild cognitive impairment or Alzheimer’s disease showed maintenance of cognitive abilities and improved brain glucose metabolism as measured by PET imaging over four months.
Estrogen has profound effects on metabolism. It is known to play an important role in mental health, obesity, diabetes, and cardiovascular disease. It also impacts brain metabolism directly and has widespread effects on mood, cognition, and other brain functions. Mitochondria make estrogen.
Mitochondria also contain estrogen receptors.
for women diagnosed with other mental disorders, symptoms can also fluctuate like clockwork around their periods. This goes for all mental symptoms—depression, anxiety, bipolar symptoms, psychotic symptoms, concentration problems, etc.—true to the theory of brain energy. As I discussed earlier, women are twice as likely to develop depression as men.
blood loss from menstruation results in the loss of metabolic resources, such as iron, which can also take a metabolic toll.
The nutrients and metabolic resources that it takes to create a child are enormous. This leaves women’s bodies metabolically vulnerable. If you think about it, pregnancy comes with increased risks for both metabolic and mental disorders—weight
Women who had depression prior to menopause are five times more likely to become depressed around the time of menopause. Brain energy metabolism decreases broadly.
After menopause, women are known to be at elevated risk for developing Alzheimer’s disease compared to men. In some women, these brain metabolism abnormalities can correct themselves over time, but in others, they appear to become permanent, likely putting these women at increased risk for mental disorders and Alzheimer’s disease.
These pills usually contain both estrogen and progesterone. They sometimes have adverse mood effects, but ironically, are also sometimes used to treat mood symptoms, such as PMDD. So, it can be confusing: Do they help, or do they hurt? In the end, there are likely differences between women, with some experiencing benefits and others experiencing adverse effects.
Thyroid hormone is known as the master regulator of metabolism. As far as researchers can tell, it acts on every cell in the human body. Thyroid hormone increases metabolism, revving up mitochondria. It plays a profound role in growth, development, temperature regulation, and the function of every organ, especially the brain. When people have too much or too little thyroid hormone, problems are almost always evident.
Thyroid hormone, either directly or indirectly, stimulates mitochondria to produce ATP or heat.
Thyroid hormone is also known to stimulate mitochondrial biogenesis, increasing the total number of mitochondria in cells.20 It also induces mitophagy—the mitochondrial repair process.
Thyroid hormone has been used as a treatment for mental disorders for decades, even when people have normal levels.
commonly used in treatment-resistant depression and bipolar disorder. However, the field has not been able to explain how or why it works. The brain energy theory provides an obvious explanation. Not only does thyroid hormone increase metabolism immediately, but it also increases the health and number of mitochondria. When you increase the workforce, cells function better.
His normal doses of thyroid medication—enough to increase his hormone levels into the “healthy” range—had done nothing to improve his depression, but we decided to try high-dose thyroid hormone as a treatment. It made a huge difference! His levels of thyroid hormone were now abnormally high, so we had to keep an eye out for side effects, such as heart arrhythmias and osteoporosis. But overall, he tolerated it quite well, and it changed his life. His recurrent depressions were all but gone. After about ten years of treatment with a high-dose of thyroid hormone, he was able to decrease the dose
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Low-grade inflammation is often found in people with metabolic and mental disorders. Many speculate that neuroinflammation might be the root cause of at least some mental and neurological disorders.
When inflammatory cytokines get released, more blood flows to that area of the body, bringing with it oxygen, glucose, amino acids, and fats to be used in some way. The inflammation is “calling” for these resources, and the body is allocating energy and supplies. This can occur due to infections or injuries, or in response to old or dying cells. Inflammation can trigger the production of more immune cells and antibodies.
mental symptom like loneliness has been linked to higher rates of not just mental disorders but also cardiovascular disease, Alzheimer’s disease, and premature death.
people with runny noses (rhinitis) from something like hay fever are 86 percent more likely to develop depression.
children hospitalized for serious infections were 84 percent more likely to develop a subsequent mental disorder and 42 percent more likely to be prescribed a psychiatric medication.4 The biggest risk was within three months of the infection.
Inflammation and mitochondria are in a complex feedback loop. Mitochondria are involved in many aspects of the normal inflammatory response, turning it both on and off. Inflammation, in turn, can impair mitochondrial function. Furthermore, mitochondrial dysfunction, even from other causes, can lead to inflammation.
mitochondria appear to play a role in immune cell death when the time comes to turn off the immune response.6 If mitochondria are not functioning properly in these cells, there will be problems with inflammation and immune cell function. It can lead to either an overactive or underactive immune and inflammatory response. These have been observed in many mental and metabolic disorders.
tumor necrosis factor (TNF), an inflammatory cytokine, has been found to directly inhibit mitochondrial function.
interferon has been shown to directly suppress mitochondrial ATP production in some brain cells.9
One drug, interferon, can produce every symptom known to psychiatry. Why? Mitochondria.
Inflammation can also affect brain development. In a fetus or young child, the brain can develop abnormally due to inflammatory conditions. For example, pregnant women with infections are 80 percent more likely to have a child with autism.
Inflammation can also be a consequence of mitochondrial dysfunction. In addition to mitochondrial dysfunction in immune cells directly impacting the inflammatory and immune response, if mitochondria in other types of cells aren’t functioning properly, that can also lead to the chronic, low-grade inflammation that we see in many people with metabolic and mental disorders.
mitochondria themselves, or at least parts of them, are known to be powerful DAMPs.
The low-grade inflammation associated with all the mental and metabolic disorders is likely a consequence of widespread metabolic dysfunction. To address the problem, we need to understand what is causing the metabolic problems in the first place. This can include a wide variety of factors, like a poor diet, stress, hormonal problems, a lack of sleep, heavy use of alcohol or drugs, and other toxins.
there are many lifestyle factors that I already mentioned that can cause widespread metabolic dysfunction, which can then lead to chronic inflammation. Addressing these can play a powerful role in decreasing inflammation and addressing metabolic and mental disorders.
Without sleep, cells can fall into a state of disrepair and begin to malfunction. Sleep is part of the body’s overall metabolic strategy.
The SCN detects light from our eyes and generates hormonal and nervous system responses. These signals, in turn, influence the peripheral clocks in all the cells of the body by turning thousands of genes throughout the body on or off. The circadian rhythm is largely driven by two things—light and food. It gets synchronized to cycles of light or dark and feeding or fasting.
Sleep allows metabolic resources to be devoted to growth, maintenance, and repair functions.
Genetic studies have found an association between the clock genes and autism, bipolar disorder, schizophrenia, depression, anxiety, and substance use disorders.1 Long-term studies looking at people who don’t get enough sleep have found that they are more likely to develop all the metabolic disorders as well. It can lead to and exacerbate epilepsy and Alzheimer’s disease, too.
It’s well described that sleep problems are a common symptom of most mental disorders. What’s less well known is that sleep problems are also more common in people with obesity, diabetes, cardiovascular disease, Alzheimer’s disease, and epilepsy.
