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A UNIFIED APPROACH TO UNDERSTANDING AND TREATING Inflammation to minimize ADDICTION AND PSYCHIATRIC DISEASE

The longest article on this site-apologies

  

For many decades, the medical establishment has focused on neurotransmitters as the causes of psychiatric disease.  Neurotransmitters are chemicals that help neurons communicate with each other.  We know that drugs that stabilize serotonin or norepinephrine have relieved depression and anxiety. We know that drugs of abuse work through the dopamine and the opioid systems. The focus of treatment has classically been to concentrate on these systems to determine how to get the best patient outcomes. This approach has led to benefits for many patients, but many others have poor treatment outcomes. 


Basic science research is now suggesting that this focus has been too narrow. Neurons are only one type of brain cell; we have many different types of cells in our brain. There are the cells that form a barrier between the brain and the rest of the body. There are others that provide nutrition to the neurons and help with impulse conduction. However, most relevant for this discussion, there are immune cells called Astrocytes and microglia. These immune cells are responsible for keeping the environment clean of debris and fighting invaders (if heaven forbid- an infection or bleed was occurring).  They are also known to prune some of the temporary nerve connections that constantly form which encode our daily experience into short term memory. Such pruning, which often occurs in sleep, will keep the numbers of connections at a manageable level and optimize brain function. 


These immune cells typically maintain a baseline level of activity- not too much and not too little. However, a variety of insults, unrelated to infection or injury, can increase their activity- a process known as neuroinflammation. The reason this happens is related to the generalized nature of these cells. Each cell maintains its own area, so a single cell must respond to a wide variety of insults. Instead of receptors that react with a specific chemical, they contain a family of receptors (called toll-like receptors) which react with many different chemicals. Of these, toll-like receptor #4 has been found to be to most important and is involved with inflammation of the brain in a variety of neurological and psychiatric disorders. These include addiction, depression, anxiety, neuropathy and Alzheimer’s disease. Toll-like 4 activity also contributes to arterial plaque formation throughout the body which can lead to heart attack or stroke. It is also involved in causing arthritis and other rheumatology disorders. 


During neuroinflammation, the inflammatory agents released by the immune cells will change the biology of the nerve cells which change the levels of various neurotransmitters. Glutamate and dopamine levels rise while GABA and serotonin levels fall


In the short term, this is a benefit. These changes allow for greater focus, faster reaction and more learning. However, too much glutamate results in microscopic cell damage and death; after prolonged immune activation, there may be large scale damage. In addition to damage, increased glutamate levels cause depression, irritability, anxiety and several other psychological symptoms. The other neurotransmitter abnormalities contribute to these symptoms. Chronic pain will be magnified and perpetuated.


During times of stress, illness and injury, neuroinflammation increases. However, it turns out that opioids, stimulants, and alcohol, and other controlled substances, also stimulate toll-like receptors and increase neuroinflammation. This also allows glutamate to accumulate, causing the symptoms mentioned above. In this way, the effects of chronic drug use are often opposite from the immediate effects of use. For example, chronic opioid use will increases pain impulse conduction, leading to more suffering.


Many people disagree that psychiatric and addiction diseases are mainly biological processes. They point out that PTSD and stressful childhood experiences lead to many problems.  I am often asked how these problems can be due to cell abnormalities when life experiences are integral in developing these diseases. However, when one understands how emotionally stressful experiences affect the brain, one realizes it is a different process leading to the same end-result. When there is intense stimulation from stressful events, the neurons secrete a variety of stress chemicals (such as fractaline, dynorphin and the neuro-hormone CRF). These chemicals subsequently increase the activity of inflammatory cells and eventually lead to dysfunction of the neurons. In other words, emotional experiences are translated into abnormal neuron function.


The Hippocampus is an important area of the brain to consider and has recently become a focus in addiction research. It is the area most responsible for memory and has been extensively researched in Alzheimer’s disease and other disorders of memory. However, it turns out to have profound effects on many other functions of the brain and has an essential role in the biology of depression, bipolar disease and addiction. 


When I was in school, I was told that the adult brain did not regenerate neurons. This has been shown to be wrong, especially regarding the hippocampus. When healthy, 2% of hippocampal cells are less than 1 year old. This is true even in seniors. This is how we can continue to encode new memory. New nerve formation is reduced in Alzheimer’s, other memory loss disorders, depression, anxiety and addiction. As a result, the hippocampus becomes measurably smaller. 


The hippocampus has roles other than memory recall. We use our memory to exploit the environment and to help us make decisions. Emotions such as fear, pleasure and attraction are often assigned to various items (a yummy piece of cake, a scary dark street) to help us evaluate our memories faster and make decisions quickly (if not always optimally). In ways that we do not quite understand, the hippocampus helps match emotion to memory. That is why its’ abnormal size and/or function are so important to consider in depression and anxiety disorders. This abnormal function may turn out to be the primary cause of many of these disorders. 


Motivation is another area that is affected by inflammation and hippocampal dysfunction. Our behavior is motivated by two separate systems in the brain. One system is mainly involved in mindful, carefully planned behavior. It contains the hippocampus, and several other areas, connecting to the frontal cortex (responsible for executive decision making) and then on to the anterior striate cortex. The anterior striate cortex is responsible for keeping us focused on a goal and motivating behaviors to accomplish that goal.  This is a complex system with many, many connections and this complexity makes it more susceptible to damage.   When these circuits are damaged, the motivation for conscious, planned behavior is reduced. Damage to the hippocampus affects the entire circuit. One consequence of damage to this system is that our brains rely more on a second, simpler, system for motivation. This other pathway bypasses the hippocampus and executive areas.  It is a much shorter path with far fewer nerve connections. It works as a direct line between our senses and the posterior striate cortex.  It leads to more automatic behavior. (i.e. moving our foot to the brake when we hear or see something unexpected as we drive.) Thus, we react more quickly to environmental triggers and seemingly without conscious thought. This automatic behavior is not always the best option. We may find ourselves behaving in inappropriate ways without knowing why and seemingly, even unaware of out behavior. Drug cravings and addictive behaviors operate through this second pathway; impulsivity is increased.


Therefore, optimizing hippocampal health as well as minimizing neuroinflammation will improve mood and memory while reducing addictive cravings and impulsivity. How do we do this?


It turns out that the doctors were already treating inflammation and hippocampal atrophy even though we did not realize we were doing so. Most anti-depressants have anti-inflammatory activity. Studies that showed successful treatment with anti-depressants, also showed reduced inflammation, increased hippocampal size and increased neuron formation. These benefits may be as important, if not more important, than any effects they have on serotonin and norepinephrine levels. Anti-psychotics and mood stabilizers have also been found to be anti-inflammatory. It is interesting to note that neurons take three months to go from stem cells to fully integrated mature cells. Is it a coincidence that this is also the same amount of time it takes to see full benefits from many psychiatric medications? Could hippocampal health be the final step in these benefits? 

There are a variety of other drugs, both prescribed and over-the-counter, which have anti-inflammatory benefit. They will be reviewed later.  However, it is important to realize that since we can now target neuroinflammation, we have many more interventions to combat these problems. 


Drugs of abuse including most opioids, alcohol, nicotine, cocaine and amphetamines increase neuroinflammation and are associated with a smaller hippocampus.  Highly processed carbs and various unhealthy lifestyles do this as well. Marijuana’s effects are more complex. THC and Cannabidiol are the two most significant chemicals in marijuana.  THC increases neuroinflammation while cannabidiol does not and may be anti-inflammatory.  Suboxone has several pro-inflammatory actions but it reduces withdrawal in opioid dependent patients. By preventing withdrawal, it reduces levels of stress hormones which in turn reduce inflammation.   Opioid blockers like naloxone and naltrexone are anti-inflammatory


Sedatives are not as well studied but result in reduced integration of stem cells into the brain and a smaller hippocampus. Thus, they prevent many of the benefits derived from anti-depressants. They can lead to depression, anxiety, memory issues and increased pain.


Additionally, any medical condition associated with increased body inflammation will increase neuroinflammation. Such conditions include chronic infection including dental issues, poor control of diabetes, arthritic disorders and many others. 


I was stunned to learn that a multi pronged approach using lifestyle, drugs and supplements increased memory in more than 90% of patients suffering from mild Alzheimer’s. Not only did they demonstrate improved memory, but many had measurable increases in the size of their hippocampus. I wondered why I had not heard about these studies. Perhaps, it is because the studies are recent, involve less than 20 patients, and require adherence to many lifestyle changes. There is no miracle cure by taking a pill or two. Many previous studies intervened with only a single factor or two. The results have been disappointing since many patients are deficient in several aspects of their lifestyle or nutritional status. Fixing only one aspect may not produce significant results since the remaining deficiencies reduce or prevent any improvement. 


My conclusion is that reducing neuroinflammation and optimizing hippocampal function are important parts of addiction treatment as well as overall neurologic health. It may be equal to or even more important than treating imbalances in the neuro-receptors and neurotransmitters. Interventions to optimize this process should have a profound effect on patient lives and the ability to stay drug free. 


INTERVENTIONS TO PREVENT AND/OR TREAT PSYCHOLOGICAL DISEASE


In the ensuing part of this discussion, I will delineate some of the interventions that can be done. It is not necessary to do all aspects of the program; even in the successful studies, few of the patients did all, but doing many could improve neurological and emotional function and prevent deterioration in the future. In the interest of being honest, the studies were done in patients suffering from mild Alzheimer’s disease so the effects on emotional and addictive disorders are often not studied but inferred. This seems reasonable as all three types of disease have similar pathology, overlapping symptoms and anatomic findings. The same interventions in the lab show similar results no matter what the disease state is. Therefore, I predict that regimens that work with Alzheimer’s will benefit all disease states. It addition, there may also be positive benefits with diabetes, cardiovascular disease and many other diseases. 


Many of the recommendations will be like those you have heard often in the past regarding healthy living. Please believe me when I say I am not a “holistic” doctor, I have never recommended vitamin therapies in the past and have always been skeptical when the term anti-oxidant is thrown around. Nevertheless, the recommendations that follow are based on published medical and /or basic lab studies published in established journals. If I am extrapolating, I will clearly let you know.


Personally, I am trying to maintain the program myself- with more and less compliant days. No one is perfect- but the more one does, the more one benefits.


Lifestyle recommendations:


The lifestyle changes are often based on what occurred in a pre-societal state. 


We had less access to carbs and none to processed carbs; we might eat once daily or less; and we were more active. All this resulted in less glucose (sugar) in the blood. Our bodies switched to ketones as a fuel source. Unfortunately, the dietary choices available to us today can result in a lot of sugar delivered to the brain even in the absence of diabetes. The sugar can only be broken down at a certain rate- when too much is delivered, problems occur. Sugar turns to lactic acid which lowers the PH of the cells. (FYI-Lactic acid is what gives us a burn when we lift weights.) Free radicals also increase. These changes lead to abnormally functioning cells and stunted neuron growth. Studies have also shown that high intake of processed carbs and diabetes is associated with a smaller hippocampus. Therefore, we want to minimize our carbohydrate load.


Since infection and cell injury involve disrupted cell membranes and release of fat molecules, certain fat molecules are natural stimulants (or blockers) of the toll-like receptors. This is one reason highly fatty foods and trans-fat intake cause health problems. Diets containing Omega 3s, which reduce this activity, are healthier. 

Constant foraging for food was necessary (no refrigerators in the town of Bedrock) and this required that we remember our environment and learn the locations of food. We moved at a modest pace but for long periods of times. Therefore, movement became a signal for our brains to focus and learn. This stimulated development of the new neurons.


In addition, as social animals, communicating with one another helped survival. Therefore, talking and listening also is stimulation for the neurons to mature. If we managed to communicate and walk at the same time, this was especially potent stimulation.


The above leads to the following recommendations:


1-Minimize sugar in blood and encourage switch to ketones for energy


1a-Minimize processed carbohydrates (breads, pasta as these will result in a glucose load. Use high protein diets when possible.

1b- avoid saturated fats as these stimulate the toll like receptor

1c-try a Mediterranean diet (without the pastries in the AM however) - This is a diet consisting of increased olive oil, legumes, unrefined cereals, fruits and nuts, and vegetables, moderate to high consumption of fish, restrained consumption of dairy products, modest red wine consumption, and low consumption of non-fish meat and non-fish meat products. This diet will also provide more Omega-3 trans-fats. I will review this issue more. 

1d-Encourage a 12 hour fast- as often as every day if possible. -  Ketones will dominate as a fuel source by the end of that time. It requires 4-5 hours not eating before and/or after 7-8 hours of sleep.  Drinking clear sugar free fluids is allowed. Some people even try a 16 hour fast but I cannot find any study that shows that the longer fast is more beneficial than 12 hours.

1e- Avoid artificial sweeteners- These change the environment in the intestines allowing for overgrowth of specific bacterial species. The metabolic waste products of these bacteria are absorbed to some extent and this increases our resistance to Insulin. The result is higher blood sugars.


2-Avoid illicit and certain prescription drugs


2a- All opioids, cocaine, alcohol, and nicotine increase neuroinflammation via different mechanisms. Marijuana has two major chemicals that are actively studied. THC, which is the intoxicant and addictive component, increases neuroinflammation. Cannabidiol, which has more medical potential, seems to be anti-inflammatory. Suboxone stimulates inflammation in some ways and inhibits it in other ways.  This makes the effects of marijuana and Suboxone on inflammation harder to predict. Sedatives are harmful via inhibiting hippocampal growth without increasing neuroinflammation.  

2b- Avoid drug withdrawal - If you are prescribed controlled medications- withdrawal (even mild withdrawal) will increase stress hormone activity. This will increase neuroinflammation.

2c- Use antibiotics only when you are strongly suspected of having a bacterial infection. Antibiotics kill healthy bacteria in the gut, allowing overgrowth of less healthy species. The metabolic waste products of the replacement bacteria are absorbed and increase tendencies for high bloods sugar. Bronchitis almost never needs antibiotics. Neither do most cases of sinusitis.

2d- Minimize use of stomach acid reducing medications as this interferes with certain vitamin and mineral absorption and may allow abnormal bacteria to populate the gut.


3-Exercise- 


Any physical activity will make our brain focused and active. On a cellular and subconscious level, it thinks we are foraging for food and will need to exploit the environment. When we forage, the brain needs to retrieve old memories and save new ones.  Therefore, any activity stimulates brain growth, especially in the hippocampus. 

The exercise does not have to be strenuous. One study showed benefit even though the average pulse during exercise was about 60% of the maximum heart rate for 30-60 minutes. (Maximum heart rate is calculated as 220- age). Therefore, the target heart rate in a 50-year-old would be about 105 and about 95 in a 70-year-old.)  Walking, or other aerobic activities, at a mild to moderate level is fine. Yoga seems to be beneficial. Just trying not to sit down helps.  The more often this is done, the better.  


Studies have looked at more intense exercise regimens, but it is unclear whether there is an incremental benefit with more intense intensity. It is to be noted that while maximum effort exercise may improve our strength and/or stamina, it also gets stress hormones flowing. This interferes with neurological function. An important concept is “Eustress” which essentially states that mild stress is beneficial while severe stress is detrimental to neurological activity. 


As proof of concept, one study looks at sedentary seniors and subjected half of them to the above exercise regimen. At one year, the exercise group had a 2% increase in size of their hippocampus vs. a 1-2 % decrease in the normal care group.  They had better scores on cognitive testing as well.


4-Social Interaction/Involvement- Communication has always been important for our survival, whether it is to 

determine our place in our social group, cooperate on a hunt or something else. Verbal stimulation is important because it seems to stimulate our brains to exploit the environment; it has been shown to stimulate memory.  

As examples, Alzheimer’s disease is less pronounced in those who set personal goals and remain involved in social activities. Unfortunately- these findings only demonstrate an association- not cause and effect. Someone could argue that those with less cognitive impairment have greater social involvement as opposed to greater level of social involvement leading to less impairment. However, I have seen many people, symptomatic when alone at home, make significant improvements after beginning a community outreach program and interacting with others. In addition, animal studies demonstrated that stimulating environments spurred nerve growth in the hippocampus and reduced addiction tendencies.  By extension of what we know, this should also benefit those with depression and other psychiatric disease as isolation and social withdrawal play such a prominent role in their disease presentation. Perhaps this is one of the reasons why the social interaction from counseling and 12 step groups are so helpful.

The combination of exercise and social interaction (such as walking with other people) is likely to be particularly effective. Therefore, it is important to push yourself into community and social activities. It will help heal your brain. Meditation should also be helpful, but it is not well studied.


5-Sleep


It used to be thought that sleep issues were only symptoms of a variety of illnesses including pain, 

depression and memory issues. Now it appears that sleep may be a major factor, if not the main factor, in making these diseases worse. New memories and learning are associated with new synapse formation and build-up of certain chemicals. These chemicals need to remain in an optimal range. For instance, consider beta-amyloid:  too much leads to Alzheimer’s disease but too little impairs learning. Some memories are minor (did I lock the door?) and others are more important. During sleep, the synapses formed for minor memories are pruned while others are strengthened and toxic molecules that build up during the day are more efficiently removed. This allows the brain to continue optimal function the following day. An increase in toxic chemicals will spur inflammation inhibiting memory, mood and pain control.


It has been shown that sleep deprivation leads to increased levels of stress hormone and increased levels of inflammatory chemical c/w with inflammatory cell activation. Melatonin, a sleep related hormone with potent anti-inflammatory affects, will get released at the wrong time and will be less effective


The recommended duration is 7 hours for most adults though some may do as okay with six and others may need more. It is important to try to sleep at the same time each day, expose ourselves to sunlight when we awaken, avoid too much electronic light in the bedroom and make sure we don’t have sleep apnea.


6-Prescription Medication to Help


This section of my program is based on generalizing from my clinical practice and certain readings I have done. It is rather speculative, but I believe relevant in many patient types. Many psychiatric medications have been found to have direct anti-inflammatory effects.  This is in addition to their long-appreciated effects on serotonin, nor-epinephrine and/or dopamine levels.  Their clinical benefits have long been attributed to these neurotransmitter effects; however, the additional roles they have in reducing inflammation and hippocampal growth, may be as important, if not more important, in relieving psychiatric illness. I want to emphasize that the use of the following medications as anti-inflammatories is not FDA recognized. Also, studies demonstrating clinically relevant benefits are often small and not well controlled. Any apparent results may have other explanations. 


6A- Naltrexone- My experiences with naltrexone were instrumental in changing how I view these issues. As I learned that opioids increased the activity of inflammatory cells, I learned that naltrexone blocked this via several mechanisms. I learned that patients, prescribed naltrexone for weight loss, had a significant reduction in pain. I reasoned it was due to its effect on inflammation (although there are other mechanisms at play as well). Subsequently, many other patient types have consistently gotten pain relief, whether they had misused drugs in the past.

Published studies showed its benefit in fibromyalgia and auto-immune disease.  It is being studied as an anti-depressant.  I have found it helpful for pain caused by sciatica and other types of neuropathy. The dosages used in published studies are not commercially available; however, commercial naltrexone is also effective. 

6b-SSRIs- Both Celexa and Prozac have been found to reduce the inflammatory response. Celexa shows reduced dementia in psychiatric patients and in lab animals bred to develop Alzheimer’s disease. It lowers levels of the proteins that lead to Alzheimer’s disease. Hippocampal volume increases with treatment. I am unaware of any studies in which these drugs were studied to prevent neurodegeneration-so no one can say whether it is helpful. I am assuming it is. I use this personally as a preventive for dementia which runs in my family.

6C- Wellbutrin- There are few studies looking at Wellbutrin effects on inflammation. However, its use was associated with increased hippocampal size and decreased impulsivity.

6D- Lithium- This is one of the most powerful antioxidants we have. It works inside the cell by slowing processes crucial to maintaining inflammatory activity. This may be its main mechanism of benefit when treating bipolar disorder; bipolar disorder has been shown to be caused by poorly regulated energy and free radical production in the hippocampus. These same processes also contribute to Alzheimer’s and multiple other psychiatric and addiction disorders. If lithium could reduce this inflammation, dementia and other diseases could be eased.  

Several studies have been done to look at lithium’s benefit.  Two studies showed no benefit. Yet, 3-4 other studies showed positive effects such as a delay of mental decline, and/or increased hippocampal size.

Unfortunately, the dosage that is optimal for bipolar disorder treatment carries side effects. As an anti-inflammatory- much lower dosages can be used. Most of the studies used low levels of prescription lithium. Few side effects were noted (though patients should still be monitored).  Of note, one study using over-the-counter dosages also showed benefit.

6E- Minocycline- This is an antibiotic, typically used chronically to prevent acne.  It has been found to be anti-inflammatory. There have been reports of its’ ability to reduce exacerbations in Multiple Sclerosis. A recent study showed slower progression of disease although it did eventually progress. Another recent paper showed that it was useful of improving certain aspects of depression, when used as an adjunct to traditional medications. Use of it in lab animals is associated with decreased addictive behaviors.


7- Nutraceuticals


 This refers to the many vitamins and/or minerals that can be obtained without a prescription. There have been numerous studies looking at one agent or another as an anti-inflammatory. Although there are studies that show significant effects in the laboratory, clinical trials showing improvement are scarce.  Some mild benefits have been demonstrated but nothing to get excited about. This is the main reason that I have been skeptical of these types of interventions until recently. However, it is important to realize that people may suffer from several nutritional and lifestyle issues and that correcting only one factor may have only a limited benefit since their other issues prevent them from reaping the benefit of a single intervention. As part of a multi-interventional change, more significant improvements may be realized. This however is speculation and we must acknowledge that there is no overwhelming evidence that any of the following interventions help. Nevertheless, since there seems to be no harm to them; the only danger is wasting money.   

7a- Omega 3 monounsaturated fats- There is no question that various fats cause disease and it is increasingly understood that the activation of various inflammatory cells lies at the root of this action. The omega 3 fatty acids, however, seem to antagonize this activity and have shown to reduce activity of the toll-like receptors and the inflammation they cause.  When populations are studied, the presence of Omega 3 in the diet is associated with a reduced incidence of a wide variety of metabolic, cardiovascular and neurological disease. The problem with these observational studies is that people who use a lot of omega 3s tend to lead healthier lifestyles.  We do not know how much of the healthy outcomes is due to the omega 3 consumption.  Unfortunately, when used as an intervention (i.e.-when a group is prescribed the omega 3 and compared to a placebo group) the results are not very convincing. As I mentioned before, this may be due to other coexisting deficiencies preventing a benefit. This lack of strong benefit has led to the resistance by traditional medicine to recommend this intervention with a high degree of confidence. Yet, this makes the modest benefits we see even that much more impressive. I believe it is a beneficial supplement. 

Fish oil is rich in omega 3s. Eating more fish as well as certain types of legumes will be an excellent way to increase omega 3 intake. Vitamin store fish oil supplements are usually 1200 mg. This dosage, taken once daily, is commonly used in many studies. Some studies used higher doses. However, no study (to my knowledge) has compared dosages and shown that taking a higher dose has more benefit than 1200 mg; in fact, a single study that compared dosages showed less benefit with a higher dosage.

7b-lithium - Please see prior section for information. One study using over-the-counter dosages also showed benefits. 

7c-N-Acetyl Cysteine (NAC) - This is an amino acid that has been demonstrated to reduce addictive cravings as well as improve a variety of physical disorders. One mechanism underlying its anti-addictive properties is that it stabilizes (and potentially removes) glutamate in the synapse. This results in weakening of impulsive behavior as well as reduced neuron damage. In addition, cysteine often becomes depleted in certain populations. This results in decreased production of glutathione, a powerful anti-oxidant.  NAC improves glutathione levels and has shown clinical and laboratory benefits in several studies. Two pills (1200 mg) twice daily is an appropriate dose

7d – Alpha-lipoic acid- This increases the production of the natural anti-oxidants: glutathione and vitamin C. It has

demonstrated anti-inflammatory activity by reducing inflammatory molecules in multiple studies. Unfortunately- there are no clinical studies showing benefits as an anti-inflammatory; yet, I still think it is valuable. In diabetics, it has been shown to objectively improve nerve function and increase sugar uptake. It improves circulation issues even in non-diabetics. It also chelates metal and excess copper, iron, aluminum and/or mercury; these metals may contribute to cell degeneration

7E-St. John’s Wort - This has many anti-inflammatory activities, which may be why it shows benefit as an anti-depressant. Its use is likely redundant if used by those already on prescription anti-depressants.

7f- Encapsulated Juice Concentrate- I was surprised to find that adding this as a supplement (as opposed to adding fruit to the diet) showed benefit in a handful of studies. The benefit was mainly seen as a reduction of laboratory makers of inflammation; the studies did not look at clinical outcomes (although one small single study showed benefit). There is no risk, so I think this is reasonable to use with little clinically significant outcome. One brand of concentrate is Juiceplus but this is not clearly better or worse than brands

.

AT PRESENT, NOT WORTH USING for NEUROINFLAMMATION: 


Gingko Biloba Although improvements in mood, memory and thinking have been demonstrated in those with mild Alzheimer’s disease, the only two studies that looked at its usefulness for prevention failed to show benefit.  It is unclear if its use is redundant to those interventions already listed

Zinc - improves diabetes control but may increase neuroinflammation

NRF2- This is an enzyme crucial in biology as anti-inflammatory. However, there are no studies using OTC preparations showing benefit

Probiotics- though “bad bacteria” induce inflammation, I have not seen any studies showing significant benefit from these agents. 

Anti-oxidants-  It is easy for many substances to neutralize free radicals in a test tube. However, the notion that these same substances can enter the cells and protect the molecules inside is preposterous.  Intra-cellular molecules are in much higher concentration and are much more likely to react with the radicals than any “anti-oxidant” taken as a pill. This is in distinction to anti-inflammatory medications, which work by inducing the cell to increase the synthesis of the naturally occurring antioxidant molecules. In the latter case we are not taking the antioxidants per se- but inducing the cells to make more of them; this is a more diffuse, prolonged and significant effect. For example- to induce cells to make glutathione or Vitamin E may be helpful but taking glutathione or Vitamin E is not. 

Coconut oil (or other high triglyceride oil) - There have been some studies looking at triglyceride supplementation to increase ketones. This may be beneficial to some degree, but the dosing is unclear, extra calories unwanted and studies showing benefit are sparse. 

Coenzyme Q- This is useful in lab research. Human studies are pending. 

High ketone supplements - ketosis is helpful but add ketones to diet will not put you into clinical ketosis.  You must eliminate processed carbs

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