The Basics of ADHD in Adults

ADHD is the most common psychiatric disorder of childhood. It is classified as a neurodevelopmental disorder that may persist from childhood into adulthood. In childhood, it is associated with inattention, hyperactivity, and impulsivity. Symptoms often change as a person gets older and are associated with an increased risk of developing depression, anxiety, and substance abuse. However, recent studies have challenged the idea that every adult with ADHD had it as a child. The results of those studies show the following. First of all, ADHD often goes unrecognized throughout childhood. Secondly, families may help children develop good compensation strategies. The conclusions, therefore, remain that, indeed, ADHD in adults is still considered a continuation from childhood.

Attention-Deficit/Hyperactivity Disorder (ADHD) is often a disabling condition in adults. As just noted, a significant portion of patients is not diagnosed during childhood, as diagnosis of the syndrome can be complex, especially when other psychiatric conditions are also associated. As undiagnosed ADHD patients age, they are presenting to memory clinics with attentional and executive disorders. Neuropsychological examinations of these undiagnosed ADHD patients often reveal atypical cognitive profiles that complicate the usual diagnostic procedures for ADHD and increase the risk of misdiagnosis. Therefore, first and foremost, it is recommended that any explorations of cognitive and/or behavioral disorders in adults should systematically screen for ADHD. Let’s now explore adult ADHD symptoms, usual remedies, and then functional alternatives.

• Is it possible for Adults to Develop ADHD out-of-the-blue?
• What are Adult ADHD Symptoms?
• Typical Medical Treatment for ADHD in Adults
• How do the medications work?
• What’s the problem, then?
• Cortisol
• Cortisol part deux
• The gut-brain axis
• Fixing the ravages of high cortisol
• Repairing the gut lining
• Repairing the Microbiome
• Behavioral and supplemental interventions
• The cool stuff: peptides
• Miscellaneous “other”

Can Adults Develop ADHD?

Adults can have ADHD, of course.  About 4% to 5% of U.S. adults have it. But surprisingly, few adults get diagnosed or treated for it. Instead, they often end up being evaluated at memory care centers, as noted above.

Who develops adult ADHD? Every adult who has ADHD has probably had it as a child. Some may have been diagnosed and known it. However, some adults may not have been diagnosed when they were younger and only find out later in life due to having “life issues” crop up, which will be discussed below.

While many children with ADHD do outgrow it, about 60% still have it as adults. Adult ADHD affects men and women equally. Many questions of late-onset ADHD remain incompletely answered, and further research is necessary to understand better and explain the etiology and development of this late-onset disorder. One very important thing we are noticing, and reporting: CIRS patients all have difficulty concentrating and often come to me on Adderall.

What are Adult ADHD Symptoms?

If you have adult ADHD, you might have difficulty with the following:

• Ability to concentrate and focus on tasks
• Task organization
• Following directions
• Remembering information
• Finishing work on time or deadline

If you have ADHD, you may have trouble with one or more of the following:

• Anxiety
• Mood swings
• Procrastination
• Poor organization skills
• Low tolerance for frustration
• Trouble concentrating when reading
• Chronic lateness and forgetfulness
• Impulsiveness
• Depression
• Chronic boredom
• Depression
• Trouble controlling anger
• Low self-esteem
• Substance abuse or addiction
• Low motivation

What is the Typical Medical Treatment for ADHD in Adults?

In a word: Stimulants! Adults with ADHD have usually been prescribed stimulant medications. As a result, studies demonstrate that about two-thirds of adults with ADHD have big improvements in their symptoms, at least at first.

Typical medications used include:

• Amphetamine/dextroamphetamine (Adderall, Adderall XR)
• Lisdexamfetamine (Vyvanse)
• Methylphenidate (Ritalin, Concerta, Metadate, Daytrana, Quillivant XR, and Methylin)
• Dextroamphetamine (Dexedrine)
• Dexmethylphenidate (Focalin)

Studies suggest that these drugs improve (the happy brain chemical)- dopamine transmission by increasing its levels in the striatal region of the brain. Researchers have found that most amphetamines promote dopamine release, while Ritalin blocks the transporters that remove dopamine, keeping levels up. Ritalin also seems to improve norepinephrine transmission as well. This is all well in good, but amphetamines stimulate the adrenal glands to produce more and more cortisol over the long term. So-what’s wrong with that? Plenty.

Let’s Talk about Cortisol

Cortisol modulates many of the changes that occur in the body in response to stress. These include things like blood sugar levels and blood pressure. Cortisol has firm control over proper immune responses. It has anti-inflammatory activity. It also activates our entire nervous system by being coupled with adrenaline (epinephrine) release. As a result, it has a role in sleep, mood, energy, anxiety levels, and more. Short term, it acts in a beneficial way to help us through stressful situations. However, long-term adrenal stimulation by amphetamines causes persistently elevated cortisol levels, which definitely can become a problem. Here’s why.

What happens with long-term high cortisol?

Cortisol helps us deal with stress by shutting down “unnecessary functions,” like reproduction and the immune system, to allow the body to direct its energy towards dealing with the stressor. These functions are supposed to be short-lived to deal with the stress. However, our modern lives are full of stress, and when stress is chronic or caused by amphetamines, this becomes a problem.

Cortisol partially shuts down the immune system when levels are high. It interferes with T-cell (a type of white cell) production and function, making your body more susceptible to pathogens like viruses, bacteria, and fungi. Ever notice how people who are constantly under stress are also always getting sick? This is why.

Cortisol also affects your muscles and bones. Cortisol is “catabolic.” It inhibits the uptake of amino acids into muscle cells, making it impossible to fuel muscle cells. It also inhibits bone formation and decreases intestinal calcium absorption. So when cortisol is high, there’s minimal to no bone growth and little muscle growth going on. And yes, there’s more when you have long-term high cortisol levels.

Adults with ADHD tend to have BDNF levels on the low side of normal for reasons still unknown. BDNF is “brain cell food,” so it’s important to continue neurogenesis throughout our lifetimes. Add high cortisol to the mix, and first, we see gut hyperpermeability. Why? High cortisol can cause the breakdown of your GI lining. It does this by slowing down both GI motility (peristalsis) and the process of digestion. When this happens, some people experience reflux, or “heartburn,” while others have absolutely no symptoms. Blood flow then decreases to all of the digestive organs. This results in a higher concentration of toxic metabolites, which then whittle away at your gut lining.

We then see a breach in the gut-brain barrier, the slow-down of conversion of neural stem cells into neurons, and the further lowering of BDNF needed for that process to happen. Cortisol has even been shown to be a direct neurotoxin!  The result=impaired cognitive performance in terms of memory, executive functioning, speed of thought, and so on. It usually all starts with a little “brain fog.”  More about the gut-brain barrier next.

In addition, we see dampened thyroid function, blood sugar imbalances,  insomnia, osteoporosis, blood pressure elevations, lowered immune function, and universally- increased abdominal fat. 

What happens to the gut-brain axis?

Much recent research shows that changes in gut microbiota could affect the brain’s cognitive, behavioral, and basically- all physiological functions. Although the exact mechanism of the connectivity of the gut-brain axis has not yet been elucidated, the evidence shows that gut microbiota plays an important role by producing immune factors, hormones, and metabolites that influence brain functioning.

Stress, meaning high cortisol, can significantly impact the microbiota-gut-brain axis. Recent studies have implicated the gut microbiota in many brain conditions, including anxiety, autism, Alzheimer’s disease, schizophrenia, and Parkinson’s disease. In addition, ongoing research implicates diseases such as obesity, heart disease, and diabetes.

Fixing the Effects of High Cortisol

When we finally stop someone’s amphetamines, we still have the carnage caused (often) by years of taking them with resultant years of high cortisol levels. We know cortisol is a direct neurotoxin, likely being a risk factor for Alzheimer’s disease. We know all of the things mentioned above. However, when we’re talking about the root cause of Ulcerative colitis, Crohn’s disease, or any autoimmune disease for that matter, we see the direct effect high cortisol has on the gut. As previously mentioned, sustained high cortisol can be the sole reason for having a leaky gut. But for adult ADHD symptoms controlled by the “traditional drugs” discussed previously, it often requires someone to actually experience cognitive changes to bring them to a doctor such as myself. So what do we do?

First, we lower high cortisol levels. Adrenal (herbal) adaptogens, glandulars, liposomal GABA, and certain aromatherapy oils are proven to lower cortisol levels. Stress-reducing techniques such as “vagal breathing,” meditation, and yoga are great practices to maintain overall health as well as lower cortisol levels. Finally, just activating your hypoglossal nerve (the nerve to the tongue and vocal cords) and, therefore, your adjacent vagal nerve to tone down your sympathetic nervous system will help. All you need to do is gargle, sing or do vocal exercises. We also always need to fix the gut lining and the microbiome. Here’s how we do it.

Heal the gut 

The pentadecapeptide BPC-157  (Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val) has been demonstrated to counteract peritonitis, and heal upper intestinal lesions, heal colitis lesions and seal up a hyperpermeable gut lining.

Gastric pentadecapeptide BPC 157, now found to be effective in the upper and lower GI tract, is remarkably free of side effects, as are the other peptides being used in functional medicine. More about peptides to follow.

Re-Balancing your Disturbed Microbiome 

By definition, when you have gut hyperpermeability, you have more “toxic bacteria” than “healthy bacteria” populating your GI tract.  Use prebiotic fiber to feed the good bacteria and (if you are not in a “mold and mycotoxin situation” a little bit of “good yeast” (Saccharomyces boulardii) to begin to re-create a healthy gut microbiome. If you like un-ripe bananas, they make great prebiotic fiber. Other foods include asparagus, Jerusalem artichokes, red onions, and naturally fermented (not pickled) foods such as sauerkraut.

When your gut lining is coming together-usually the 2 to 3-week mark, add probiotics. Historically, we have recommended 50 to 100 billion probiotic CFU’s per day. A mixture (in your main probiotic) of Lactobacillus species and Bifidobacterium species is probably fine. Still, even more evidence supports the use of sporulating probiotics for an even better microbiome. These probiotics are species of Bacillus with b. subtilis and b. coagulans being the most studied. Start as low as 5 billion and increasing to as many as 25 billion CFU’s daily (best done under a doctor’s supervision if you have GI symptoms). But now that you’re weaning from ADHD stimulants, what do you do?

Food, Exercise, Sleep, Therapy, and Supplements 

Studies have associated poor attention and worsened  ADHD symptoms with diets full of the unhealthy things we tell you not to eat, such as refined sugar and fried foods. In addition, artificial food colorings and the preservative-sodium-benzoate may worsen ADHD-hyperactivity in children but otherwise hasn’t been studied for other effects or in adults.

According to some good clinical evidence, regular exercise may reduce adult ADHD symptoms. And I don’t believe I need to tell you that poor sleep quality impairs attention and other cognitive functions, worsening ADHD symptoms.

Cognitive-behavioral therapy has been shown to improve ADHD symptoms in adults. In addition, mindfulness-based therapies improved ADHD symptoms in multiple studies, mostly in adults as well.

Supplements that might be useful: ADHD patients tend to have lower magnesium levels than average, with the caveat that most of us not on MG supplementation are a bit deficient. At any rate, in two clinical trials, magnesium supplementation did indeed improve adult ADHD symptoms. Similarly, there is a higher prevalence of vitamin D deficiency in ADHD patients, and studies suggest that supplementation is helpful. Finally, fish oil supplementation appears to be quite promising, is anti-inflammatory, and is usually a good “health practice” anyway.

L-Tyrosine: This amino acid is being discussed separately because the data supports its use in adults with ADHD. A review of 15 clinical trials concluded that L-tyrosine (a dopamine precursor) boosts attention and cognitive performance in stressful and demanding situations in normal adults. These were not trials done with adult ADHD symptoms, but the extrapolation of that data to patients with ADHD has resulted in numerous clinical reports of the same benefits. There is less data on SAMe (S-adenosyl-L-methionine), but one study indeed suggested that it might be a useful way to increase dopamine and norepinephrine.

Peptides 

Peptides are small chains of amino acids that make up proteins and are available in every part of your body. Because peptides can be found in any part of the body, they each have particular functions. They act as messengers, signaling specific glands and proteins into performing specific tasks. These; essentially bioidentical substances have been isolated and replicated for use by Functional Medicine doctors. Since they are bioidentical, there are no side effects. They are an amazing addition to our arsenal of treatments, and there happen to be three that are quite useful for adult ADHD symptoms.

Heptapeptide Semax: (Met-Glu-His-Phe-Pro-Gly-Pro) 

Semax is considered a brain-enhancing or “nootropic” peptide due to its ability to increase BDNF:brain-derived neurotrophic factor, nick-named “brain fertilizer,” since it is the largest (neurotrophic) stimulator of neurogenesis. In addition, Semax has also been found to be a potent enkephalinase inhibitor. In other words, the enzyme that destroys the natural painkillers and anti-anxiety brain chemicals called enkephalins is blocked by Semax, which has been independently proven to reduce anxiety and, therefore, likely decrease cortisol. In addition, several studies demonstrate its ability to cause the brain to release both serotonin and dopamine, enhancing feelings of well-being and, more-than-likely (due to the dopamine boost) attentiveness.

The heptapeptide Semax is an analog of the N-terminal fragment (4-10) of ACTH (adrenocorticotropic hormone) but is absent any hormonal activity. However, it has been found to stimulate memory and attention in rodents and humans after intranasal application. In addition, evidence from animal studies reveals that Semax augments the effects of psychostimulants on central dopamine release.

As noted above, it stimulates central brain-derived neurotrophic factor (BDNF) synthesis. In addition, Semax is thought to improve selective attention and modulate brain development. Since ADHD is likely to be a neurodevelopmental disorder with disturbance in both dopamine and BDNF function production, it is proposed by many neuroscientists that Semax may have excellent therapeutic potential in ADHD. In Russia, this peptide is used as a common alternative for drug therapy for children with ADHD. In addition, functional doctors in the U.S. prescribe it for mood issues, adult ADHD symptoms, cognitive and pain issues.

Cerebrolysin  

This peptide is widely used in Europe and Russia but not approved in the U.S. However, it has been studied for many years and is a go-to for adult ADHD in other countries. Numerous studies show that this peptide increases cognitive functioning and attention with decreased impulsivity in children and adults with ADHD.

Dihexa    

Dihexa is a peptide derived from angiotensin IV-a metabolite of the potent, naturally occurring vasoconstrictor angiotensin II.  Angiotensin IV  has been shown to enhance acquisition, consolidation, and recall of memory and learning in animal models.  What’s more, the peptide Dihexa has been determined to be seven orders of magnitude more potent than BDNF. Thus, you first read about BDNF as the potent neurogenesis stimulant, but there’s more to it than simply being a cognitive enhancer.

Brain-derived neurotrophic factor is the most dominant neurotrophin in the CNS (central nervous system). It plays a crucial role in physiological brain functions via its two independent receptors: tropomyosin-related kinase B (TrkB) and p75. These two activities are critical during neurodevelopment. In addition, the disrupting of BDNF signaling has been documented in many neuropsychological diseases, including ADHD.

Dihexa is a first-in-class compound that is orally active, penetrates the blood-brain barrier, increases BDNF, improves memory consolidation and retrieval as well as concentration and neural processing speed.

Miscellaneous Functional Medicine tools 

Deserving of more than an honorable mention is functional medication likely to be helpful with adult ADHD symptoms. While definitive research is pending, the logic is compelling for the following.

Oral nicotinamide mononucleotide supplementation increases intracellular NAD+ concentrations, improving mitochondrial biogenesis and ATP (mitochondrial energy) output. It is well known that the brain has an enormous supply of mitochondria, so mitochondrial enhancement should, in theory, benefit all brain functions.

The peptide selank increases BDNF and decreases levels of anxiety by increasing concentrations of GABA in the brain. Due to the importance of BDNF enhancement and, in some cases, lowering anxiety to ameliorate adult ADHD symptoms, it makes sense to utilize this peptide. But, again, data is pending on these two measures.

Mitochondria are the key to energy and health -Important update: I can now get NAD+ troches for you! 

Before I dive right into a discussion about mitochondria, I’d like to ask you why you are reading this article? If you are looking for improved health and longevity, this article will give you lots of actionable information. However, if you have been feeling ill, with fatigue being a prominent component of whatever is wrong, you need Functional Medical care. You can’t “fix fatiguing illness” yourself. That’s all I’m going to say about that; now I’ll get into the topic you came for: how to boost and why to boost your mitochondrial function. Mitochondria are involved in many vital processes in human cells, including energy production, fatty-acid oxidation, and the Tricarboxylic Acid (TCA) cycle, calcium signaling, apoptosis (cellular death), and heat production. However to simplify things let’s talk about energy and longevity which is what their function translates to for practical purposes. And to help this occur, we can review the health practices, along with the best supplements to improve mitochondrial function.

• Why do we want well-functioning mitochondria?
• What happens when mitochondria malfunction?
• What about mitochondrial function and aging in general?
• Mitochondria boosting health practices
• Mitochondrial specific exercise
• CoQ10
• Alpha lipoic acid
•  PQQ
• L-carnitine
• D-ribose
• Phospholipids
• NAD
• Miscellaneous supplements
• Final words

But before we begin, I’d like to give every one of my readers “patient access” to my Designs-For-Health account so that if you want to purchase supplements, you’ll receive a 15% discount from their Amazon price. Here is their website: https://www.designsforhealth.com/ and then my practitioner code is: kimcrawford, allowing you to create a un and pw for your own account. You’re welcome! In addition, mitochondria reproduce and put out more of their “good stuff” when you lower sympathetic nervous system activity. Here’s the best and easiest way to do VNS to accomplish that goal quickly.  Feel free to use and share my patient code: DrKim25 for a $25 discount on the best thing you’ll buy this year.

Mitochondria: Why do we care?

First, let’s discuss the “energy part.” Mitochondria produce Adenosine Triphosphate (ATP). In the cell, the energy in the form of ATP is produced in two ways: in the cytosol as a product of glycolysis and in the mitochondria as a product of oxidative phosphorylation. The substrates, in the form of fatty acids and pyruvate, are oxidized via fatty acid β-oxidation and the TCA cycle, respectively. The Nicotinamide Adenine Dinucleotide (NADH) and flavin adenine dinucleotide (FADH₂) produced by these reactions are used by the electron transport chain to generate ATP. Just remember from this complex discussion of energy production that you need ATP and you need NAD+/NADH to make that ATP, so you feel as if you have enough energy.

Proper mitochondrial functioning is crucial for every nucleated cell in a body. A number of diseases are characterized by dysfunction of muscular or neural systems or metabolic reactions. All these diseases and pathophysiological conditions are developed against a specific genetic background, together with environmental factors.

Mitochondria produce energy as ATP (adenosine triphosphate), which your body then uses to fuel your daily activities. Some cells have more mitochondria than others. Your brain, muscles, and heart cells are full of mitochondria. Putting diseases and aging to the side: you want your mitochondria working at full strength to keep your energy levels up, your brain sharp, and your muscles and heart at their peak performance. The creation of new mitochondria (mitochondrial biogenesis) is needed for optimal aging, which we now call our healthspan. Not to be repetitive, but always remember this is mandatory to keep your energy levels at a peak. It’s also a part of what’s needed to protect you from oxidative stress. As you would predict, mitochondrial dysfunction tanks your energy and contributes to numerous physical ailments.

Mitochondrial Dysfunction and Disease

Mitochondrial dysfunction, characterized by a loss of efficiency in the synthesis of ATP, is a characteristic of aging and, essentially, of all chronic diseases. Loss of function in mitochondria can result in excess fatigue and even other symptoms in just about every chronic disease you can imagine.  These conditions include neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease, and Amyotrophic Lateral Sclerosis.

Metabolic syndrome, heart disease, and diabetes are all associated with mitochondrial dysfunction. Metabolic syndrome is a group of conditions that combine hypertension, hyperglycemia, abdominal obesity, and abnormal cholesterol or triglyceride levels. Metabolic syndrome greatly increases the risk of cardiovascular disease, stroke, and Type two diabetes. There are numerous reports mentioning mitochondrial dysfunction and lower oxidative capacity in patients with Type two diabetes compared with healthy individuals.

The cardiovascular system strongly depends on mitochondrial function. Cardiomyocytes (heart cells) have very high mitochondrial content in order to produce the necessary ATP, and mitochondrial dysfunction inevitably leads to the development of cardiovascular diseases.

There is now increasing evidence of mitochondrial dysfunction in Alzheimer’s Disease, Parkinson’s Disease, Huntington’s disease, and Amyotrophic lateral sclerosis. Even some psychiatric conditions, such as autism spectrum disorders, schizophrenia, and bipolar mood disorders, are included.

In addition, mitochondrial dysfunction plays a significant role in the inflammatory response in acute human pathologies. Systemic Inflammatory Response Syndrome (SIRS) is a pathological state with a systemic immune reaction to severe damage, including ischemia, acute pancreatitis, trauma, and sepsis.

Autoimmune diseases such as rheumatoid arthritis, Crohn’s disease, and systemic lupus erythematosus are all characterized by mitochondrial failure. Of course, truly fatiguing illnesses, such as CIRS (mycotoxin and mold illness and Chronic Lyme), Chronic fatigue syndrome, fibromyalgia, and Gulf War Syndrome have mitochondrial near-failure as a prominent component. Lastly, as you might predict, cancer and chronic infections round out the list of disorders. If you have any one of these disorders, you will need to improve your mitochondrial health and function in order to recover.

Mitochondria and Aging

A number of age-related processes (e.g., “normal aging of the brain”) are associated with mitochondrial dysfunction, so most of the popular aging theories take this into account. The mitochondrial theory of aging posits that the accumulation of damage to mitochondria DNA promotes the process of cellular aging of both humans and animals. The theory claims that there is a  vicious cycle involving the accumulation of damage in mitochondrial DNA, which then leads to more oxidative damage due to defects in the mitochondrial respiratory chain. Let’s say that this theory is true. What, then can we do to save our precious mitochondria and therefore slow the aging in our cells and help prevent diseases?

Mitochondrial health practices

Eating an anti-inflammatory diet is one of the easiest ways to improve mitochondrial function. Polyphenol-rich foods such as blueberries, red and purple foods (e.g. raspberries and purple cabbage), and many fresh green foods are high in healthy mitochondrial-boosting polyphenols. Using intermittent fasting methods such as timed eating and intermittently “going keto” are also mitochondrial boosters.

Heat shock proteins produced by extreme cold or extreme heat are great for your mitochondria. Cold exposure is an easy way to give your mitochondria a boost. Studies have demonstrated benefits with “ice jackets”, facial submersion, and ice baths. Even cryotherapy tanks! And “ice swimming.”  Based on what I personally find tolerable and affordable, you can get enough of a boost by doing the following. At the end of your daily hot shower, just turn the temperature to cold for 30 seconds. It is mostly quite invigorating!

Far-infrared saunas are another way to generate heat shock proteins.  An FIR is a great investment in your health, as it is also a great way to do a bit of a detox.

Meditation and yoga also boost your mitochondrial output.

Ten minutes of direct sunlight is great for a burst of mitochondrial activity. Conversely, most data suggest that fluorescent lighting puts a damper on ATP production and mitochondrial biogenesis. The data is rather murky when it comes to EMFs, blue-blocking glasses, and so on, but it’s something to watch, as there seems to be some correlation between better health and less high-level EMF exposure, as well as less blue light exposure.

Exercising For Mitochondrial Health

Many types of exercise are mitochondria-healthy. Walking is great. Running is great. Weight training is great. Yet, the very best type of exercise for your mitochondria is high-intensity interval training. This doesn’t need to be complicated, but do get medical clearance if this is a new activity for you. Do you know how to do a burpee? Do burpees until you’re short of breath. Then catch your breath and do it again. Repeat this a total of 6 times if you can, less if you can’t.

You can do HIIT outside, too of course. If you have access to a track, great! If not, use a treadmill if you’re inside or run in your neighborhood if you’re outside. Sprint one lap. Or half of a lap. Whatever gets you short of breath. Then, walk until you catch your breath and you can even lie down on your back for faster autonomic neurological adaptation for up to 90 seconds if you need that long to catch your breath. I do this in our lap pool and it’s far more fun than simply “swimming laps” to me.

Now, let’s discuss the best supplements to improve mitochondrial function.

The best supplements to improve mitochondrial function

I see people perk right up within (literally) 24 hours of proper mitochondrial supplementation. If someone has a chronic and/or fatiguing illness or are just suffering from age-related mitochondrial failure, supplementation absolutely works. It sure beats energy drinks which end up causing adrenal issues and potentiating energy problems.

Here are the mitochondrial supplements that have been studied and proven effective.

Co-Q 10

CoQ10 is an essential electron carrier in the mitochondrial respiratory chain. In other (more complex) words, CoQ10 passes electrons between NADH-ubiquinone oxidoreductase,  succinate-ubiquinone oxidoreductase, or succinate-cytochrome C oxidoreductase. You can now just forget you read that and rub your eyes. Basically, CoQ10 can be found in both oxidized (ubiquinone) and reduced (ubiquinol) forms, and the conversion between these oxidized and reduced states allows it to act as a cofactor of enzymatic reactions via the transfer of electrons.

CoQ₁₀ is a critical part of the mitochondrial oxidative phosphorylation system. Over ten well-done studies show that supplementation with this vitamin-like antioxidant compound in individuals with reduced CoQ₁₀ levels results in increased energy production and reduced fatigue. The most dramatic results are in those individuals with degenerative diseases. Here are some examples.

In studies using Alzheimer’s disease models, CoQ₁₀ administration significantly delays brain atrophy and characteristic β-amyloid plaquing. In a 4 month clinical study on around 100 Alzheimer’s patients who took an oral mixture of vitamins E, C, CoQ₁₀, and α-lipoic acid, the group receiving supplementation showed significant reductions in oxidative stress markers and subsequent DNA damage.

Individuals with Parkinson’s disease tend to show increased levels of oxidized (and by definition: damaged) CoQ_10.  They also have significant increases in markers of oxidative stress and damage in their brains, which is partially reversible with CoQ₁₀ administration.

One last important clinical note: recall that the heart is filled with mitochondria which are partially powered by CoQ_10. If you are taking a statin drug, please be aware that they deplete your body of CoQ10, so supplementation is a must.

Alpha-lipoic acid

ALA is a potent fat and water-soluble antioxidant vitamin. It is also a metal chelator (helping to remove iron, copper, mercury, and other heavy metals). It is also a fairly decent anti-inflammatory supplement. Clinically, α-lipoic acid has been used mostly to help treat complications associated with diabetes such as neuropathies and vascular (blood vessel)  complications. It also improves cognitive (brain) and mitochondrial function, adding to the evidence linking oxidative damage to mitochondria and cognition. The use of α-lipoic acid for chronic fatigue syndrome (CFIDS) has not yet been studied in controlled clinical trials. However, it is widely used in “fatigue regimens” (200-600 mg) as a way to both support mitochondrial function and reduce oxidative stress.

Despite its various potentials, the therapeutic efficacy of ALA is reduced due to its “pharmacokinetic profile”. Data shows that ALA has a short half-life and bioavailability (only about 30%) due to degradation in the liver and chemical instability in the stomach. The R isomer of ALA (R-lipoic acid) shows better pharmacokinetic parameters, including increased bioavailability as compared to the S isomer, ALA. Translated: just use R lipoic acid or a double dose of alpha lipoic acid for approximately the same results.

PQQ

Pyrroloquinoline quinone (PQQ) is contained in fruits and vegetables such as kiwi fruit and green peppers. It has received a lot of research attention in the past several years. PQQ can reduce reactive oxygen species (ROS) levels and improve the apoptosis (death) of tumor cells. PQQ protects tissues by regulating the redox (electron transfer) reaction. Moreover, PQQ protects overall tissue function by improving the mitochondrial function of the liver, neurons, and other important tissues. It can also reduce atrophy in mouse skeletal muscles.

PQQ decreases oxidative stress (production of ROS) and inflammation which, by definition, will protect mitochondria. It also increases mitochondrial biogenesis, which is the formation of new, young-acting mitochondria. It is neuroprotective, too. Here’s how. Recall that you have read about GABA versus glutamate or inhibitory (relaxing) versus excitatory (too stimulating) neurotransmitter activity. We want more GABA than glutamate, plain and simple. Too much glutamate damages brain cells. PQQ protects neurons by preventing the long-term over-activation of the glutamate (NMDA) receptors, which results in toxic excitotoxicity of neurons. This over-stimulation of brain cells is associated with many neurodegenerative diseases and seizure disorders.

Recall again that you have the largest concentration of mitochondria in your brain, heart, and skeletal muscles. The brain “wins” pound for pound by a little edge, which is why you feel tired after using your brain all day. With this in mind, remember that when we protect the brain, we’re protecting brain mitochondria. PQQ protects the brain (to a certain extent) against neurotoxicity induced by mercury and other potent toxins such as mold mycotoxins. Lastly, it too helps to prevent the accumulation of amyloid tau and beta proteins associated with Parkinson’s and Alzheimer’s diseases.

Acetyl-l-carnitine 

Acetyl-l-carnitine is a naturally occurring fatty acid transporting amino acids. L-carnitine supplementation has long been studied and then used in many mitochondrial dysfunction disorders. These disorders are also characterized by low concentrations of serum l-carnitine levels such as heart disease, diabetes, kidney disease, and overwhelming infections.

An important cellular longevity function of l-carnitine has been to increase the rate of mitochondrial oxidative phosphorylation (ATP production) that declines with age. A  study where old rats were fed acetyl-l-carnitine resulted in the reversal of age-related decreases in l-carnitine levels, an increase in fatty acid metabolism, and an increase in mitochondrial activity. Acetyl-l-carnitine also reverses the age-related decline in muscle mitochondria.

Clinical studies show that L-carnitine supplementation may also be useful in alleviating fatigue symptoms in hypothyroid patients, especially in those younger than 50 years and those who have hypothyroidism after thyroidectomy for thyroid cancer. Note: L-carnitine is the nomenclature used for many clinical studies, but due to l-carnitine’s ability to increase TMAO, experts suggest that all human supplementation be done with acetyl-l-carnitine.

D-ribose

We know that D-ribose has documented positive mitochondrial effects for those who are genetically d-ribose deficient. It’s a popular bodybuilding supplement which “hardcore” bodybuilders credit as being helpful with their muscular fatigue. Studies have looked at neurodegenerative diseases such as Multiple Sclerosis and ALS with promising results. Due to these studies, I decided to use it in a protocol on a dog named Charlie. Charlie is a very beloved and smart standard poodle, belonging to a favorite patient of mine. The patient (another M.D.) contacted me, quite distraught that his dog had received the diagnosis of degenerative myelopathy or “doggie ALS” as I  found upon doing some research. Charlie, it seemed, couldn’t get himself up off the floor. The same mitochondrial problem has been identified in both dogs and humans. So, I got to work on Charlie’s protocol.

I calculated doses of supplements based on Charlie’s 48-pound weight. I recommended a mitochondria-boosting ketogenic diet. Then I added ALA, ALC, CoQ₁₀, PQQ, and NAD (discussed below), as well as some d-ribose powder. I had my patient add some antioxidant powder to Charlie’s food, too. “Why not” I thought. My patient said that 24 hours after Charlie started his regimen, he was noticeably stronger, up and walking, and even playing! The patient’s Veterinarian was astounded and has gone on to use my protocol on other dogs. Now, let’s give an honorable mention to another concoction.

Phospholipids

Mixtures of probiotic, phospholipid, and antioxidant preparations have shown some clinical promise in fatiguing illness. This mixture is made using antioxidant powders, probiotics, and phosphatidylserine. The bulk of the studies have been with patients who have fibromyalgia and/or chronic fatigue syndrome (CFIDS).

NAD

NAD is now the big news, thanks largely to the research by Dr. David Sinclair and his best-selling book, “Lifespan.” Recall the mentions throughout this article about the conversion of NAD+ to NADH, and vice versa, as essential reactions in creating ATP. Recall that ATP is cranked out by mitochondria, and gives cells (and you) energy. Therefore NAD and its substrates are crucial for cellular energy, mitochondrial biogenesis and it turns out; cellular longevity. All that remains to be seen, is proof positive that one “form” of NAD is superior to another. Here are some of the data.

Oral NADH supplementation can reduce symptoms in patients with chronic fatigue. One study on patients with chronic fatigue syndrome treated participants with micro-encapsulated, oral NADH or a placebo for a month’s time. 8 of 26 study participants (about 1/3) responded positively with increased well-being and energy levels to the NADH compared with 2 of 26 (8%) in the placebo group.

This supplement also shows promise for neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases. The increase in measured NADPH levels correlates with a marker for aging: an increase in telomere length.

NAD will stimulate the SIRT1 pathway which is notably dysfunctional in those with metabolic syndrome, diabetes, and more. When you stimulate the SIRT1 pathway, you lower leptin levels, making it again possible to lose weight, improve blood sugar, cholesterol, and triglyceride levels, and in fact, all aspects of metabolic syndrome.

Taken orally, NMN (nicotinamide mononucleotide) is rapidly absorbed and converted to NAD+. In numerous studies, supplementation with NMN increases NAD+ biosynthesis, suppresses age-related fatty tissue inflammation, enhances insulin secretion and its action, improves overall mitochondrial function, and in the brain, it improves mitochondrial as well as neuronal function. In animal studies, it extends lifespan. In fact, NMN given to mice does quite a bit. Before I discuss NMN, let me give a shoutout to nicotinamide riboside- also converted to NAD+. As well as NMN? We don’t know, and the research continues. Meanwhile, we have a lot of data from mice studies.

Orally administered NMN is rapidly converted to NAD+ in mice. NMN has been shown to enhance energy metabolism and physical activity, suppress age-associated weight gain, improve insulin sensitivity and even improve ocular function. It improves mitochondrial metabolism and prevents age-related negative changes in gene expression. In mice bred to be obese or diabetic, NMN improved both the action and secretion of insulin.

NMN also protects the mouse heart from ischemia and/or reperfusion injury. It restores skeletal muscle mass in aging mice. Of special interest to those of us who treat many patients with brain issues, it has been shown to slow cognitive decline in a mouse model of Alzheimer’s disease, by improving the survival of neurons, improving energy metabolism, and reducing oxidative stress. It may also help maintain the integrity of the blood-brain barrier.

NMN also probably suppresses the increase in systemic inflammation associated with aging based on the studies which show that it lowers adipose tissue inflammation associated with age. In fact, surprisingly enough, older mice appear to be more responsive to NMN, in comparison with younger mice.

Some studies appear to suggest an increase in blood vessel formation called angiogenesis with artificially increased NAD levels for prolonged periods of time. This is why, despite the fact that I use a lot of NMN and intra-nasal NAD in my clinical practice, I have patients take intermittent breaks from it, and will do so until more data is available on this phenomenon.

Additional supplements with much promise

Studies are increasingly showing that mitochondrial illnesses are fueled by oxidative stress; implicating the use of antioxidants such as natural vitamin E and NAC (the precursor to glutathione) as well as glutathione as additional treatment considerations. We know that the sirtuin pathways are boosted by resveratrol and ECGC-green tea extract; implying mitochondrial benefit. Branched-chain amino acids, vitamin D, and creatine are all pro-mitochondrial health supplements as well, despite being poorly studied for this particular issue. Finally, there is emerging data for mitochondrial health with berberine, magnesium threonate, selenium, and even immune-boosting melatonin. B vitamins are likely involved as well. It appears that the more useful a supplement has been proven to be (vitamin D as a prime example), the less it is studied for other, more complete benefits.

Final words

In any good health regimen, you want to eat an anti-inflammatory diet and take a few supplements. It makes sense to take vitamin D and high antioxidant power supplements for many reasons, including mitochondrial health. At this juncture, if you are healthy and have specific goals in mind, you might choose, let’s say, some acetyl-n-carnitine if you are lifting weights, or some PQQ if you have a family history of neurodegenerative disease. And currently, if you have metabolic syndrome, SIRT pathway issues, or fatiguing illness, it seems prudent and helpful to take NMN and/or NAD intra-nasal spray. Yes, IV NAD is beneficial, but I am “not a fan” of this current craze of “drip bars” and feel that consumers are being, quite frankly, ripped off by this trend when alternative routes of administration can be utilized. Finally, if you’d like my opinion on what would be good for you, just ask me.