June 17, 2013

An Interview With Dr. Mike Morea – Doctor of Chiropractic, Bodybuilding Champion, and Believer in Integrated Supplements

IFPA Pro North American Overall Champion Dr. Mike MoreaFor years, we at Integrated Supplements have been educating the masses on the true nature of the health food and nutritional supplement industries.  We’ve repeatedly shown that many of the most heavily-marketed health foods and supplements may not be quite as healthy as they’re made out to be.  In fact, many of the nutritional products currently marketed towards athletes and fitness enthusiasts may be no healthier than the junk foods they’re supposedly meant to replace.

Unlike most supplement companies that seem to promote dozens of unnecessary (and even potentially harmful) products, our philosophy has always been to offer a select few high-quality nutritional supplements – while emphasizing the importance of  integrating them into a healthy diet and intelligent exercise program.

That’s why it’s so exciting for us to see the Integrated Supplements philosophy in action.

Several years ago, we received a call from Dr. Mike Morea – founder and namesake of the Morea Chiropractic Wellness Center located in Fruitport, Michigan.  Dr. Morea had read some of our articles on IntegratedSupplements.com and noticed many parallels between the Integrated Supplements philosophy and his own.  After discussing the details of exactly why we formulate our products the way we do, Dr. Morea decided to make Integrated Supplements products available to his chiropractic patients.  

As it turned out, Dr. Morea was not only a medical professional with a keen eye for quality, but was, himself, an accomplished natural bodybuilder and fitness enthusiast.  Unlike many bodybuilders these days, Dr. Morea knew full well that he didn’t need to sacrifice his health to be a great athlete.  He knew as well that only quality foods and supplements build quality physiques.  So, both personally and professionally, Integrated Supplements were a perfect fit.      

After adding the full array of Integrated Supplements products to his regime, Dr. Morea was able to reach new levels of muscularity and leanness, allowing him to earn natural bodybuilding professional status at the 2013 NANBF Natural Southern States Classic as well as an overall first place finish at the 2013 IFPA Pro North American bodybuilding championships earlier this year – at 43 years of age, no less.

Dr. Morea’s success is especially exciting to us at Integrated Supplements.  It reinforces what we’ve been saying all along: with a little hard work and dedication, we really can forestall the ravages of aging and reach our full potential at any age.   The good doctor truly is the Integrated Supplements philosophy in action.

Dr. Morea and Integrated Supplements are both dedicated to education as well, and, along those lines, we recently conducted a question and answer session to gain insight into the universal principles driving his success.  We discussed the many unrecognized benefits of chiropractic care, how the quality of what goes into our body influences our health and athletic success, and how limiting beliefs so often hold people back from reaching their full potential.


Integrated Supplements: As a chiropractor, you require expert knowledge of the muscular and neurological systems of the body.  As a bodybuilder, you’ve no doubt gained practical experience as to how the body responds to even the most subtle changes in diet and exercise.  How does your bodybuilding experience influence the type advice you give your patients, and how does your chiropractic expertise influence your success as a bodybuilder?

Dr. Morea: First as a “Doctor” of Chiropractic, the word Doctor in Latin means to be a teacher.  We have to give good advice that we ourselves would follow and do follow.  As a bodybuilder, my experience has helped out in many ways.  First, our patients here at Morea Chiropractic know that when I give advice it is genuine and is something that I am not just promoting, but actually doing and living.  Being a lifetime natural drug-free athlete has allowed me to truly know about living a drug-free lifestyle, not just in regards to not taking steroids, but also taking other unnecessary medications. As a bodybuilder, when it comes to nutrition and supplementation, it is easy for me to give information that has not only been researched extensively, but also that I have done in regards to brands and foods that have worked for me as well.  So many times advice is given because it is standard of practice.  I feel that each person has an athlete inside of them and it is up to me to give them advice that is true and tried.  When it comes to exercise and stretching, I have to realize that if I am not willing to do it, they shouldn’t either – so we keep our recommendations simple, to easily fit into their busy schedules and lifestyles.

 As a chiropractor, I have had a fascination with biochemistry and physiology.  It is a given that all chiropractors have extensive training in the structure of the body.  After all, that is what we work with every day.  However, nutrition has really peaked my interest, as well as the effect that lifestyle plays in my patient’s overall quality of life.   It is this fascination with body chemistry and incorporating whole foods into my diet that I believe has allowed me to become a champion bodybuilder.  I have attended seminars around the country taught by chiropractors who have shaped my thoughts on human nutrition including Dr. Dan Murphy and Dr. James Chestnut.  Both of these researched chiropractors have hammered home the points of a whole-food diet with the elimination of the omega-6 fats and a healthy omega-6-to-omega-3 ratio.  Since eliminating almost all processed carbohydrates and increasing my fruit and vegetable content, I have eliminated a tremendous amount of inflammation in my body. 

I have also incorporated many of the Integrated Supplements products including the Whey Protein Isolate, Bio-Available Magnesium, and the Fiber Balance.  This has allowed me to add over 6 pounds of muscle in the past two years, and feel overall energized.  As a chiropractor, I have done the research and have eliminated all cheap protein concentrates loaded with artificial chemicals, and added Green Detox and another greens product to alkalize my body tissues. 

I have also researched the best training protocols for natural athletes incorporating changing rep ranges, time between sets, and different exercises.  Every week is different than the one before and this also benefits my soft tissue and joints as I am not doing the same repetitive movements week-in and week-out that can lead to a tremendous amount of scar tissue in the body.  I also, over the last few years, started to study weight loss and realized, ideally, a very slow loss of weight would lead to the least amount of muscle loss and subsequently, the least amount of strength lost – which means a tremendous amount when you are trying to preserve that precious muscle tissue. 

As a chiropractor, I also had the best care possible for my body as well: regular adjustments to keep my body functioning optimally and every other week massages to allow greater recuperation and blood flow for recovery.  Just like I document patient notes meticulously, I did the same with my nutrition and workouts.  Every day over the last two years, I knew how much food I was getting and exactly what workouts I did, as well as the reps and weights.  This allowed me to track precisely if I needed to make any changes.  I felt that my chiropractic knowledge and experience helped me tremendously against guys many years younger, and am grateful for this experience.

Integrated Supplements: A lot of people probably still think of chiropractic care as something they only need if they’ve suffered an injury, or if they’ve developed a problem such as chronic back pain.  The typical overweight person with elevated cholesterol/triglycerides, pre-diabetes, and 20+ pounds to lose, however, may not immediately consider chiropractic care for their issues.  What would you want this person to know about the benefits of chiropractic care in general, and about your services in particular?

Dr. Morea: You’re right.  Unfortunately, we as chiropractors have not done such a good job of educating the public about what we really do.  Yes, we are good at helping relieve a lot of acute and chronic conditions like migraine headaches, neck pain, sciatica, shoulder pain, etc., but most people don’t realize what chiropractic even works with.  It is the nerve system.  Unfortunately, our “why” does not get explained really well.  Why would someone who has chronic health conditions see a back pain doctor for their problems?  I get this question a lot actually.  What we need to understand in regards to our health is that every health related problem that we have has a cause or reason behind it.  If we have high blood pressure, or elevated triglycerides, or LDL’s, or even back pain, there is a reason.  We have been taught that the problem is the symptom; but it’s merely the manifestation of the problem.  The true problem is the cause.  And that cause more often than not is our lifestyle choices. When I have a patient who wants to get off some medications, or even just reduce them, it is important for them to realize that we need to look at what got them there to start.  Just blindly trying to get their blood pressure decreased or cholesterol lowered without educating them to what caused it to increase in the first place is the same thing that the Medical doctors do with prescription medication.  It is my job as a chiropractor to show them ways – naturally with food choices, supplementation, and exercise – to decrease a symptom.  And, as I start making changes to their nerve system by realigning vertebrae that connect with their vital organs, they will often say, “Wow this is a miracle.”  And I tell them what I believe, and that is the truth.

Integrated Supplements: So many people blame age and hormonal/metabolic slowdown as the factor responsible for their poor health, expanding waistlines, and deconditioned physiques. Their implicit assumption is that the human body is just designed to start to wear out after only a couple of decades.  But you, and so many other over-40 bodybuilders, simply prove this assumption wrong in every conceivable way – your level of bodyfat is remarkably low, your level of muscle mass is high, and, as natural bodybuilders, you’ve got to work with what nature gave you in the hormonal department. Obviously, you never could have achieved this success if you believed that your body began an inevitable decline after your 30th birthday.  What, do you believe, are some other limiting beliefs that may be holding people back from reaching their full potential – and how do you address these limiting beliefs with your patients?

Dr. Morea: Some other really common limiting beliefs are “It’s genetics, Doc.”   I will often see people my age (43) and younger letting me know that their bad knees, or weight problem, or arthritis, is related to their mom and dad passing it on to them.  They have been told this by their doctor who, in turn, took care of their parents who had the same condition. By association, this could seem very true on the outside.  Upon further review, we find out in the case history that they eat the same foods as their parents ate; processed carbohydrates and too many trans fat foods.  They exercise even less than their parents because more of them have sedentary jobs, and they get continued reinforcement in drug ads and television commercials about the next miracle pill that will save them.  If we believe that old age and disease is related to our genetic lineage then we have an easy way out.  This limiting factor must be broken, and self-responsibility taught, for us to make true strides.  Once we show each of our patients that their lifestyle is what is causing their ill woes, we can move forward.  For those that don’t want to believe this, their reliance on pain pills and surgeries continue to occur.  Another limiting belief is that the body is not self-healing.  In chiropractic, we truly believe in the body’s incredible ability to heal itself.  Think about it: what happens when we have a cut?  Do we have to intervene?  Most of the time no – the body repairs itself through natural clotting mechanisms – white blood cells help invade the area, and within a week or so the body has done what it is supposed to have done.  For most things that go on in the body, we have a built in homeostasis that regulates us and keeps us in great shape.  As I get patients to understand with greater clarity the power animating their body, they start to take more responsibility in keeping it in shape.


Integrated Supplements: In your practice, you offer a full gamut of health solutions including nutritional and exercise consultations, supplements (including Integrated Supplements), massage, and yoga –  in addition to traditional chiropractic services.  I think it’s important for people to recognize that you can help them make meaningful improvements to their health precisely because you address the many different aspects of health in a natural and sustainable way.  How would you contrast your approach to that of other chiropractors?

Dr. Morea: As a chiropractic doctor, there are different schools of thought on how to take care of the patient.  There are some who try to be everything to everyone, there are some who only work with the spine and don’t want anything to do with supplement or exercise suggestions, and there are those who only work with nutrition and don’t adjust the spine at all.  Having had severe back pain back in my early 20’s, I found a chiropractor who just adjusted, and it worked great for me for the few visits before I attended chiropractic school.  When I got to Life University, the chiropractic college I attended, that is when I knew that there were many other approaches out there.  So with that being said, with the 11 years now being in practice, I have recognized, more than ever, the importance of coaching my patients, and giving real lifestyle advice that they can apply today and start getting results.  Every other week, we have our WOW talk, our wellness orientation workshop, that discusses chiropractic care, lifestyle stressors, exercise, supplements that almost every American is deficient in, with emphasis on whole food that is simple yet so effective in combatting many of today’s major illnesses.  We also discuss the importance of creating simple habits that can been implemented right away – whether it is to create more abundant energy, to drop 15-20 pounds, or to just break away from the myriad of medications they are currently on.  So I believe overall that besides walking the talk, I give patients plenty of opportunity for understanding and application that they can use right away.

Integrated Supplements: Traditional physicians often take a lot of heat from the natural-health and chiropractic communities for over-relying on pharmaceuticals to treat problems (e.g., overweight, obesity, diabetes) which respond well to dietary and lifestyle changes.  But in fact, traditional physicians often implore their patients to improve their diet and exercise more.  The problem is that, more often than not, their patients simply don’t do it (at least not with any meaningful consistency).  Why do you think so many people struggle to consistently implement even the most basic diet and exercise strategies, and what approaches have you taken to make diet and exercise a more permanent part of your patients’ lives?

Dr. Morea: The major challenge is that there is no accountability when they see their primary care health doctor.  It is so easy to say to a patient, “eat more fruits and vegetables” – and most people already know that anyway, and they already know they need to lose weight.  Why do they continue to struggle and yet some make it look so easy?  The answer is that the majority of patients go to their doctor only when they are sick, or have some type of symptom.  Maybe their blood pressure is high, maybe their energy is low, maybe they have had some other recent scare.  When they do their follow up appointment with their doctor, it is to check usually some diagnostic value whether it is blood pressure, a cholesterol reading, or an MRI.  And occasionally, on those follow up visits, the doctor will ask if they have lost weight or started eating better.  But that is not good enough.  There has to be more one-on-one support with the patient on a more regular and consistent basis to make true change.  In my office, follow up appointments are much more regular, sometimes in the beginning up to three times a week, and we do regular reexaminations where we get to ask questions related to changes in their diet, changes in their medications, and what exercise have they started.  Many times, we will get patients that truly start a lifestyle approach to eating better and we address the common foods to eat, the ones to stay away from, and even how many times they should be eating in the day.  We get to follow up with them on how often they are doing the recommended stretches, exercises, etc.  So, by checking them regularly and holding them accountable, they feel more motivated to continue with those positive action steps that have helped them along the way.

Integrated Supplements: At Integrated Supplements, our philosophy has always been that there’s really no such thing as “sports nutrition.”  There’s really just human nutrition.  Athletes and bodybuilders may need different amounts of nutrients than the average person, but the same overall nutritional principles apply to pretty much everyone.  This is why our product line contains effective “sports nutrition” staples like Whey Protein Isolate and Creatine, but also products such as Fiber Balance, Green Detox, and Bio-Available Magnesium which fill the most important nutritional gaps encountered by athletes and non-athletes alike.  What particular benefits do you feel green foods, fiber, and magnesium have for bodybuilding?

Dr. Morea: As a chiropractor and bodybuilder, I have been able to witness on myself and my patients the deficiency in greens, fiber, and minerals.  The problem is obvious to anyone who studies nutrition, and that is that most of us take in way too many processed foods that contribute to the very acidic bodies that we have.  Ask how many people get at least 5-7 servings of fruits and vegetables a day, and one hand in ten may go up.  That is why we need a greens product in our diets.  We are just not getting enough and this addition helps alkalize our systems which helps out with chronic inflammation and lowers our acidity which helps out with our bone density.  When we are very acidic our bloodstream uses minerals from our bone to neutralize it; good for the blood, very bad for our bones.  Obviously, fiber at the recommended amount of 30-35 grams a day is also not being gotten because of our lack of whole food nutrition.  The addition of fiber in our diets help our digestive tract tremendously and, as bodybuilders, this can help with allowing our bodies to become more regular as many of us stick to the same basic foods.  Fiber in addition can help out with keeping our sugar levels more sustained and that is always a good thing when it comes to weight loss and sugar metabolism issues.  I include both Green Detox and Fiber Balance every morning in my diet.  And finally Magnesium!  Of all the minerals as a chiropractor and bodybuilder that I see deficient it is Magnesium.  Once again this mineral is so deficient because we are not getting it through whole foods and the soil today is depleted of this vital mineral.  Since magnesium is found in many green foods, including seaweed, spinach, turnip greens, and spirulina, you can see why we may not be taking in enough of this incredible mineral.  As a chiropractor, I have seen magnesium deficiency lead to muscle weakness, insomnia, anxiety, phobias, brain fog, and even suicidal thoughts.  Magnesium is important for a good mood and helping stabilize blood pressure.  I have seen deficiencies in magnesium even lead to cardiac and blood sugar issues – so as an athlete looking to maximize their muscle potential and sugar usage, magnesium supplementation is a must.

Integrated Supplements: In almost two decades in the supplement and nutrition business, I’ve encountered thousands of people who want to take supplements to improve their health or physiques. Very rarely, however, do I encounter people who have actually sat down and calculated their overall nutritional intake for any period of time to see which nutrients their diets may be lacking.  Bodybuilders are better than most, although they often have a tendency to calculate their protein intake and not much else.  Most people I’ve met (bodybuilders included) often have almost no idea what their caloric intake is – never mind their intake of vitamins, minerals, fiber, fatty acids, and fatty acid ratios.  I think not having this knowledge really holds a lot of people back from reaching their full potential.  Can you share with our readers how important nutritional tracking is to your success as a bodybuilder?  Were you ever surprised to find that what you thought was a healthy diet was actually missing a few nutrients that you then needed to supplement?

Dr. Morea: First of all, that is a great question.  My bodybuilding knowledge in the last 20 years has come a long way.  When I first began competing back when I was in my early 20’s, I would eat the same 4-5 foods every day and wonder why I was so burned out and exhausted.  At that time I included quite a few processed carbohydrates, like bagels, as long as it fit in my protein, carbohydrate, and fat macros.  Little did I realize the importance of a lot of green leafy vegetables and the colorful array of other vegetables out there as well.  At that time, it was not uncommon for me to have a lot of muscle cramping and fatigue too, as I was definitely deficient in a lot of the minerals greens give us.  When I won my natural pro bodybuilding card this year, I was definitely getting a much broader group of foods including fish, some lean steak and grass fed beef, healthy cage free eggs, and a small amount of organic peanut butter in my diet to supply my healthy fats while eliminating almost all omega-6 fats.  I also included every night a huge salad with a mixture of dark green lettuce, different color peppers, tomatoes, and low fat cottage cheese.

For me, I have always tracked my protein, carbohydrates, and fat and knew exactly how much I was getting each day.  This past year, however, I made it a point to include the Green Detox and an array of colorful healthy vegetables in addition to the healthy fats and I believe this was by far the best I ever looked on stage and the best I ever felt. I owe that to my increased knowledge of eating whole foods and just being part of my lifestyle and not just a diet.  One month after my IFPA Pro North American bodybuilding win, I am still incorporating the same nutrition that allowed me to take home the first place award and my first overall pro card win at 43 years old!

Integrated Supplements: To me, one of the most frustrating things about bodybuilding is that it has the potential to be the single most health-promoting activity in which a person can engage, but, in actual practice, many would-be bodybuilders aren’t particularly healthy.  It’s very common, for example, to see bodybuilders who, though muscular, still carry quite a bit of extra body fat year round.

And while bodybuilders often give lip service to the value of fresh, nutritious, “real” food, too many of them don’t practice what they preach.  In fact, processed “junk” foods have become intertwined into the very fabric of bodybuilding nutrition.  At Integrated Supplements, we’ve written many times about the true nature of things like whey protein concentrate, casein powder, protein and energy bars, so-called “good” fats, ready-to-drink protein shakes, and artificial sweeteners.  Judging by the evidence in the scientific literature, these are the sorts of foods and ingredients that even a marginally health-conscious person would probably seek to avoid, and yet these ingredients are all staples in products marketed towards bodybuilders and other fitness enthusiasts.

That’s why it’s so refreshing to see a successful bodybuilder like yourself who knows the value of natural, high-quality products like ours.  We’ve always said that serious bodybuilders don’t fill their bodies with junk, and you’re living proof of that.  Can you tell us how you came to place such an emphasis on natural, high-quality supplements and how you think such products helped you in your recent bodybuilding efforts?

Dr. Morea: When I competed two years ago, I overheard a guy who was 43 years old say this was the best he ever looked and he owed that to getting rid of all the artificial sweeteners and other pre-workout products that he used to take.  At the time I was taking all the major brands that you see in Supplement Warehouse and Bodybuilding.com.  I started looking into them and found that every one of them had an artificial sweetener in them whether it was aspartame or sucralose. I also found that almost every one of them was not pure; they almost all had a protein concentrate listed in their ingredients.  Then one day after my contest was over, I ran into an old friend that had a smaller gym and he told me about a new protein he was selling that tasted great, had no artificial ingredients, and was a pure protein isolate.  I was directed to your website, started reading the articles and the philosophy of Integrated Supplements, and decided first to try your whey protein out.  I was pleasantly surprised that I was taking something so pure that tasted so good.  And it had a totally different effect on my digestive system.  When I used to take some of the cheaper products, I always had an uneasy stomach and just attributed that at the time to being on a contest diet.  After I started taking the Integrated Whey Protein Isolate, I had no bloating, no stomach discomfort, and no uneasiness.  That is when I began promoting Integrated and invited some of my friends to try it out as well.  No doubt, I felt better and knew that I was not putting junk into my system; no artificial ingredients, no cheap fillers, and truly a product that was being absorbed to help the muscles recover as quickly as possible.

And then I started analyzing my pre-work out products and recognized that I was actually creating free radicals by taking in these NO products.  That was the last thing I wanted to do as a natural bodybuilder trying to live the best life I could.  I am clearly interested in eating as many healthy whole foods that I could, to have as many natural antioxidants in my system to help encounter those free radicals, and to turn back the clock on the aging process.  I got rid of the pre-work out products, started taking some extra caffeine before my work out with some simple sugars and felt much better.  Since then, I have been taking the Herbal Energy and feel that I am alert but not wired and that has made a difference. I also have always taken creatine and now use exclusively the Creapure Creatine carried by Integrated Supplements as well.  I do five grams before my workout, 5 grams during, and 5 grams after my workout.  And finally I believe that upping my greens with my salad and lots of veggies, and taking Green Detox has helped out with my inflammation tremendously and allowed me to stay injury free.  I take your magnesium every day and this was the first bodybuilding contest that I did not have a Charlie horse in my calves when I was posing.  Obviously, increasing my magnesium levels was paramount to my muscles feeling less tight and overall stronger.  I continue to use Integrated Supplement products and will continue to endorse them as I feel that you stand behind what you believe and you understand the difference between hype and truth.  Thank You!

Integrated Supplements: It's our pleasure, Dr. Mike.  Keep up the great work!

Those interested in Dr Morea’s services can visit the website for Morea Chiropractic Wellness Center.






April 04, 2013

What's Wrong With Nitric Oxide - Part 3


Ask a cardiologist about the effects of nitric oxide, and there’s a good chance you’ll hear about the chemical’s role in dilating blood vessels, lowering blood pressure, and supporting cardiovascular health.

Ask a neurologist about nitric oxide, and you’ll likely to hear about the widespread cellular damage this chemical can cause, and how an excess of nitric oxide in the brain is now thought to be a major contributing factor to degenerative neurological diseases like Alzheimer’s disease, Parkinson’s disease, and ALS.

And, ask an oncologist for yet a third opinion, and you may hear about nitric oxide’s role in either suppressing tumor growth – as a potent tumor–killing agent of the immune system; or, conversely, its role in stimulating tumor growth by triggering angiogenesis, the formation of the new blood vessels tumors need to survive.

So, clearly, nitric oxide has many varied effects within our bodies – some beneficial, and some very harmful. This is the fundamental reason why so many attempts to manipulate nitric oxide levels, either pharmacologically or nutritionally, have met with failure.

As relates to the cardiovascular system, for example, it was initially thought that increasing nitric oxide levels would be the key to correcting what was simplistically assumed to be a “deficiency” of nitric oxide in cardiovascular disease. But this approach is quickly being abandoned, as a myriad of unforeseen (and sometimes fatal) side effects have accompanied nitric oxide–boosting therapies.

Of course, some nutritional supplement companies, and some health practitioners (whose products and recommendations lag decades behind the actual research) continue to recommend that we indiscriminately increase our nitric oxide levels with various nitric oxide–boosting concoctions. But the flaws inherent in such an approach are now well–documented, even if not yet well–publicized.

In light of what we now know about the often harmful effects of nitric oxide, it seems that we’ll want to do everything we can, not merely to increase nitric oxide levels, but to keep nitric oxide production under tight control throughout the body.

A Brief Review

When produced, nitric oxide rapidly reacts with a chemical called superoxide, to form a particularly damaging chemical called peroxynitrite. It’s now believed that this process is largely to blame for many of the harmful effects of nitric oxide.

When nitric oxide–boosting therapies are employed – like the use of the amino acid precursor to nitric oxide, arginine – or the nitric oxide pro–drug, nitroglycerin, the production of peroxynitrite increases right along with nitric oxide itself. And the result has often been a short–term benefit, marred by longer–term harm.

Recent research has found, however, that we may be able to give our nitric oxide metabolism a nutritional “tune–up,” without increasing our burden of harmful nitric oxide byproducts. The answer lies not in “boosting” nitric oxide, but in supplying our body with the nutrients needed to metabolize nitric oxide safely and efficiently.

In the last Integrated Supplements Newletter, we looked at nutritional factors like folic acid, Vitamin B6, and Vitamin B12 which may reduce homocysteine and simultaneously protect the fragile nitric oxide cofactor, called tetrahydrobiopterin.

We saw how antioxidant nutrients like Vitamin E, Vitamin C, selenium, and whey protein isolate may help to reduce the oxidative stress which constantly threatens nitric oxide metabolism.

We even saw how cocoa flavonols and creatine monohydrate may exert especially beneficial effects on nitric oxide metabolism.

Building on these strategies, we’ll now look at other nutritional factors which will help support proper nitric oxide metabolism in the cardiovascular system and beyond.

This Is Your Brain on Nitric Oxide

In the late 1980’s, an iconic public service announcement on television depicted a frying egg, while an actor sternly warned an entire generation of impressionable Americans, “This is your brain on drugs.” And while this PSA offered a powerful visual metaphor of the effects certain drugs can have on brain function, it may serve us well to look a little deeper into the molecular biology of the matter.

It turns out that much of the toxicity associated with neuro–active drugs is ultimately due to the actions of nitric oxide. In fact, the chemical inhibition of the enzymes which produce nitric oxide has been shown to abolish the toxicity associated with both methamphetamine and cocaine.

Study Link – Nitric oxide (NO) synthase inhibitors abolish cocaine–induced toxicity in mice.

Quote from the above study:

Repeated administration of cocaine (45 mg/kg/day) for 7 days to Swiss–Webster mice resulted in a progressive increase in the convulsive response to cocaine and augmentation in lethality rate. Pretreatment with the nitric oxide (NO) synthase inhibitors, L–NAME (100 mg/kg/day) or NO–Arg (25 mg/kg/day), prior to cocaine administration completely abolished the sensitization to the convulsive and lethal responses to cocaine. These findings suggest a role for NO in cocaine–induced toxicity.

Study Link – Role of nitric oxide in methamphetamine neurotoxicity : Protection by 7–nitroindazole, an inhibitor of neuronal nitric oxide synthase.

Quote from the above study:

These findings indicate a role for nitric oxide in methamphetamine–induced neurotoxicity and also suggest that blockade of NOS may be beneficial for the management of Parkinson's disease.

And you don’t have to be a drug–user to be susceptible to the neurotoxic effects of nitric oxide. The damage caused by nitric oxide and its metabolites has been very strongly linked with age–related brain degeneration, and disorders such as Parkinson’s disease, ALS, and Alzheimer’s disease.

Study Link – Nitric oxide neurotoxicity.

Quote from the above study:

NO has many roles in the central nervous system as a messenger molecule, however, when generated in excess NO can be neurotoxic. Excess NO is in part responsible for glutamate neurotoxicity in primary neuronal cell culture and in animal models of stroke. It is likely that most of the neurotoxic actions of NO are mediated by peroxynitrite (ONOO−), the reaction product from NO and superoxide anion.

Study Link – Widespread Peroxynitrite–Mediated Damage in Alzheimer's Disease.

Quote from the above study:

These findings provide strong evidence that peroxynitrite is involved in oxidative damage of Alzheimer's disease.

Studies have found, as well, that mice bred to be deficient in one of the nitric oxide–producing enzymes had decreased mortality, and were significantly protected from many of the manifestations of Alzheimer’s disease:

Study Link – Protection from Alzheimer's–like disease in the mouse by genetic ablation of inducible nitric oxide synthase.

Quote from the above study:

Deficiency of iNOS substantially protected the AD–like mice from premature mortality, cerebral plaque formation, increased ß–amyloid levels, protein tyrosine nitration, astrocytosis, and microgliosis. Thus, iNOS seems to be a major instigator of ß–amyloid deposition and disease progression. Inhibition of iNOS may be a therapeutic option in AD.

And, in addition to degenerative brain diseases, nitric oxide has also been implicated in other neurological disorders such as migraine headaches:

Study Link – Nitric oxide is a key molecule in migraine and other vascular headaches.

Study Link – Nitric oxide–induced headache in patients with chronic tension–type headache.

Study Link – Nitric oxide supersensitivity: a possible molecular mechanism of migraine pain.

The following study even found that those with migraine headaches may be at increased risk of developing Alzheimer’s disease later in life. The common role of nitric oxide in each disorder helps to explain why.

Study Link – Risk factors for Alzheimer's disease: a population–based, longitudinal study in Manitoba, Canada.

Quote from the above study:

The association of AD with a history of migraines and occupational exposure to defoliants/fumigants is of particular interest because these are biologically plausible risk factors.

Nitric oxide is even suspected to play a major role in the development of the chronic ringing in the ears known as tinnitus:

Study Link – The NO/ONOO– cycle as the etiological mechanism of tinnitus.

Study Link – Pharmacological models for inner ear therapy with emphasis on nitric oxide.

At first glance, it may seem ironic that nitric oxide, a compound deemed so beneficial for cardiovascular health, could be so universally maligned for its harmful role in neurological health.

But of course, we now know that there is much more to nitric oxide metabolism than was once assumed. Though a certain amount of nitric oxide is necessary for cardiovascular function, any excess can be decidedly harmful. As we’ll see, the same general principles (ensuring the proper metabolism of nitric oxide) apply when addressing nitric oxide metabolism in the brain and in the neurological system.

Nitric Oxide – Inflammatory Chemical

One of the ways in which nitric oxide can be produced in the body is via an enzyme known as inducible nitric oxide synthase (iNOS). Immune cells, called macrophages, contain iNOS, and can produce nitric oxide to destroy invading viruses or bacteria, or under other conditions of stress and trauma. This means that nitric oxide is an integral part of our bodies’ immune system and inflammatory response, but it also means that the production of nitric oxide by macrophages can very easily spiral out of control.

Unlike endothelial nitric oxide synthase (eNOS, the form of nitric oxide synthase which produces NO in the blood vessels), iNOS can churn out massive amounts of nitric oxide virtually non–stop. This excess nitric oxide (and the metabolites produced from it) can be particularly harmful to the delicate, lipid–rich structures of the brain. And, as we now know, inflammation and tissue damages often proceeds in a vicious downward spiral, perpetuating even more tissue damage and inflammation. This is a major reason why nitric oxide production needs to be kept under control in conditions of stress, aging, and disease.

As we mentioned in previous issues of the Integrated Supplements Newsletter, we ideally want any inflammatory response of our immune system to be “short and sweet” – sufficient enough to deal with the stress at hand, but not excessive enough to cause a self–perpetuating spiral of tissue destruction.

Reducing Inflammation Safely

It’s now widely accepted that all degenerative diseases share the common thread of excessive and uncontrolled inflammation – including the over–production of nitric oxide. But, for as many anti–inflammatory foods, drugs, and supplements as we have at our disposal, reducing systemic inflammation safely still takes a bit of biochemical know–how.

For instance, it’s well–documented that some “anti–inflammatory” strategies may ultimately be destined to do more harm than good. The dangerous side effects associated with the wildly popular COX–2 inhibitor medication, Vioxx® are a chilling reminder of this; and, in the May 2008 edition of the Integrated Supplements Newsletter, we saw how even many of the “anti–inflammatory” fats often recommended by the health–food and nutritional supplement crowd (omega–3s, for example) may predispose us to tissue fragility and destruction when consumed in excess.

On the other hand, when we attempt to reduce inflammation in a physiologically sound manner, we’ll find that the pieces of the puzzle fit together in such a way as to actually give us far–reaching health benefits.

As relates to nitric oxide, we’ll find that some nutritional substances can serve to reduce the excess production of inflammatory nitric oxide produced by the immune system, while at the same time improving the bioavailability of the nitric oxide produced within the cardiovascular system. The most important nutrient offering such a two–pronged benefit is likely to be the often overlooked mineral, magnesium.

Magnesium and Nitric Oxide

According to data from the United States Department of Agriculture, a full 68% of Americans fail to consume the minimum recommended amount of magnesium each day; and a stunning body of scientific evidence indicates that very few nutritional deficiencies are as widespread, or as deadly, as magnesium deficiency.

Many people know that the electrolyte mineral, magnesium, is involved in “electrical” functions of the body like the heartbeat, and nerve impulses, but very few people realize that the presence of a magnesium deficiency leads to an absolutely massive increase in various markers of systemic inflammation.

The list of biological substances increased in the body when magnesium is deficient reads like a “who’s–who” of inflammatory chemicals. C–reactive protein, substance P, cytokines, prostaglandins, histamine, and of course, nitric oxide all become elevated when magnesium levels are sub–optimal.

Study Link – The nerve–heart connection in the pro–oxidant response to Mg–deficiency.

Quote from the above study:

In rodent models of dietary MgD [magnesim deficiency], a significant rise in circulating levels of proinflammatory neuropeptides such as substance P (SP) and calcitonin gene–related peptide among others, was observed within days (1–7) of initiating the Mg–restricted diet, and implicated a neurogenic trigger for the subsequent inflammatory events; this early "neurogenic inflammation" phase may be mediated in part, by the Mg–gated N–methyl–D–aspartate (NMDA) receptor/channel complex. Deregulation of the NMDA receptor may trigger the abrupt release of neuronal SP from the sensory–motor C–fibers to promote the subsequent pro–inflammatory changes: elevations in circulating inflammatory cells, inflammatory cytokines, histamine, and PGE(2) levels, as well as formation of nitric oxide, reactive oxygen species, lipid peroxidation products, and depletion of key endogenous antioxidants. Concurrent elevations of tissue CD14, a high affinity receptor for lipopolyssacharide, suggest that intestinal permeability may be compromised leading to endotoxemia. If exposure to these early (1–3 weeks MgD) inflammatory/pro–oxidant events becomes prolonged, this might lead to impaired cardiac function, and when co–existing with other pathologies, may enhance the risk of developing chronic heart failure.

And, as relates specifically to nitric oxide, it’s interesting to note that magnesium deficiency has the effect of increasing the “inflammatory” nitric oxide (produced by iNOS), rather than the cardioprotective type produced by eNOS (called constitutive NOS in the following study):

Study Link – Magnesium deficiency in rats induces a rise in plasma nitric oxide.

Quote from the above study:

Magnesium deficiency in rats leads to an oxidative stress involving an increased production of radical oxygen species. The present study was designed to examine the effect of experimental magnesium deficiency on plasma nitric oxide (NO) level and nitric oxide synthases (NOS) activities in rats. The data show that the concentration of NO is markedly increased in plasma of magnesium–deficient rats. This rise in plasma NO results from activation of inducible nitric oxide synthase (iNOS) rather than of the constitutive form (cNOS) of the enzyme. These data are in agreement with previous observations indicating that inflammation occurs during magnesium–deficiency and provide an additional cause of oxidative lesions through formation of peroxynitrite from nitric oxide and superoxide anion.

Study Link – Magnesium–deficient medium enhances NO production in alveolar macrophages isolated from rats.

Quote from the above study:

These results suggest that Mg(2+) deficiency enhances NO production via iNOS by alveolar macrophages.

And knowing that nitric oxide is largely responsible for much of the brain deterioration of Alzheimer’s, it’s interesting to find that there may be a direct correlation between magnesium status and the progression of the disease. The following study found that as magnesium status worsened so too did the progression of Alzheimer’s disease as evidenced by falling scores on cognitive tests:

Study Link – Serum magnesium level and clinical deterioration in Alzheimer's disease.

Quote from the above study:

Our data suggest that there is a relationship between serum Mg levels and the degree of Alzheimer's disease and that the determination of the Mg level at various stages may provide valuable information in further understanding the progression and treatment of Alzheimer's disease.

Because of the multiple roles magnesium plays in reducing systemic inflammation and excessive nitric oxide production, a lack of magnesium can exert effects at every level of biological functioning. As evidence, the widespread magnesium deficiency caused by our modern diet is known to be a major factor in the increasing prevalence of all degenerative diseases of aging, including not only brain diseases, but heart disease, diabetes and cancer as well.

And considering the fact that so few individual foods contain high amounts of magnesium (and the fact that multivitamins never contain sufficient amounts) it’s safe to say that a stand–alone magnesium product is often the single most important nutritional supplement a health–conscious person can take. But, even magnesium alone may not be enough to fully rectify a magnesium deficiency. Other nutritional factors, such as selenium, potassium, vitamin B6, and vitamin D, are also needed for proper magnesium absorption and metabolism.

Study Link – The multifaceted and widespread pathology of magnesium deficiency.

Quote from the above study:

Unfortunately, Mg absorption and elimination depend on a very large number of variables, at least one of which often goes awry, leading to a Mg deficiency that can present with many signs and symptoms. Mg absorption requires plenty of Mg in the diet, [selenium], parathyroid hormone (PTH) and vitamins B6 and D.

Curcumin and Nitric Oxide

In addition to correcting outright nutritional deficiencies, there are many other steps we can take to reduce the inflammatory over–production of nitric oxide.

It seems that nature, in her infinite wisdom, has supplied us with many plant–based anti–inflammatory substances which may impart particularly powerful effects when it comes to scavenging nitric oxide. One of the most notable of such substances is the yellow/orange pigment from turmeric, called curcumin.

Turmeric, a member of the ginger family, is a spice which has been long–used in Indian and Chinese cuisine, and respective systems of medicine. Recent research has uncovered that many of the health–promoting benefits traditionally associated with turmeric may be attributable specifically to curcumin; and interestingly, we find that curcumin may act as a powerful scavenger of nitric oxide.

Study Link – Nitric oxide scavenging by curcuminoids.

Quote from the above study:

The results indicate curcumin to be a scavenger of nitric oxide. Because this compound is implicated in inflammation and cancer, the therapeutic properties of curcumin against these conditions might be at least partly explained by its free–radical scavenging properties, including those toward nitric oxide.

And, although some research indicates that curcumin may be poorly absorbed, there’s reason to believe that curcumin and turmeric may exert their health–benefits despite this fact. Even though turmeric contains only about 3% curcumin at the most, and curcumin is likely to be poorly absorbed, preliminary studies conducted in India (where turmeric is very widely used in cooking) have shown some of the lowest levels of Alzheimer’s disease ever recorded – results which held true for both rural and urban communities:

Study Link – Incidence of Alzheimer's disease in a rural community in India: the Indo–US study.

Quote from the above study:

These are the first AD incidence rates to be reported from the Indian subcontinent, and they appear to be among the lowest ever reported. However, the relatively short duration of follow–up, cultural factors, and other potential confounders suggest caution in interpreting this finding.

Study Link – Prevalence of dementia in an urban Indian population.

Quote from the above study:

In the population surveyed, the prevalence of AD and other dementias is less than that reported from developed countries but similar to results of other studies in India.

If these results have anything to do with turmeric consumption, the chances are good that most of us can benefit from simply adding more turmeric–rich meals to our diet. Curcumin extracts do exist as nutritional supplements, but they are very costly relative to the very inexpensive spice, turmeric.

And research indicates that we can find many other inexpensive ways to reduce the inflammatory effects of nitric oxide as close as the local grocery store. Antioxidant compounds in (green and black) tea, coffee, red wine, cocoa, and pomegranate have all been shown to protect against the inflammatory over–production of nitric oxide.

Study Link – Protection against nitric oxide toxicity by tea.

Study Link – The coffee diterpene kahweol suppress the inducible nitric oxide synthase expression in macrophages.

Study Link – Synergy between ethanol and grape polyphenols, quercetin, and resveratrol, in the inhibition of the inducible nitric oxide synthase pathway

Study Link – Effects of an aqueous extract of cocoa on nitric oxide production of macrophages activated by lipopolysaccharide and interferon–gamma.

Study Link – Pomegranate juice protects nitric oxide against oxidative destruction and enhances the biological actions of nitric oxide.

As we’ve seen in this series of articles, nitric oxide metabolism can be more than a bit complicated. And despite a frenzy of conflicting nitric oxide research, we’ve seen the unfortunate tendency of both the medical community and the nutritional supplement industry to “jump the gun”, and rush to market products based upon dangerous misinterpretations of the scientific evidence.

But, yet again, only as we look deeper into the research, does the big picture become clear. Only then can we address fundamental biological imbalances, and not merely symptoms or biological markers.

And again, we see that carefully–chosen, time–tested natural foods and nutrients offer us the greatest long–term benefit – with little to no risk. The nutrients and foods mentioned in this series of articles are the substances the human body has always needed to support health, but they are often the substances most conspicuously lacking from our modern food supply.

In the final analysis, nitric oxide is just another example of a biological chemical whose actions can seem baffling and paradoxical when we forget to look first to nature for the answers. Only when we remember our role as a part of nature, will the pieces of the puzzle fall neatly into place.

About Us: At Integrated Supplements, our goal is to bring you the wellness information and products you need to live your life to the fullest. We are dedicated to producing the highest–quality, all–natural nutritional supplements; and to educating the world on the health promoting power of proper nutrition. You can find out more by visiting: www.IntegratedSupplements.com


These statements have not been evaluated by the FDA. No Integrated Supplements product is intended to diagnose, treat, cure or prevent any disease.


What's Wrong With Nitric Oxide - Part 2


Given the sometimes overwhelming complexity of biological systems, there’s an almost unavoidable tendency, even among top researchers, and medical professionals, to simplify matters by labeling certain biochemicals simplistically as either “good” or “bad.”

But rarely in biology do substances wear only black or white hats. More realistically, we find that certain substances produced within the body exert protective roles in some situations, but in other situations, when regulatory and stabilizing systems fail, these same substances may be harmful if produced in excess, or metabolized inefficiently. In other words, in an ironic twist of fate, many biological molecules have the tendency to exacerbate the very bodily damage they were initially produced to protect against.

As an example, many researchers believe that the cholesterol which leads to the production of atherosclerotic plaque in the arteries is initially a protective substance. The thinking is, that as a vital component of cellular structure, cholesterol is drawn to the artery to “patch up” microscopic injuries in the arterial wall. It’s only when various cell–signaling and inflammatory systems go awry, however, that cholesterol is altered from a protective to a pathological molecule, eventually resulting in the build–up of the cholesterol–laden plaque associated with heart disease.

Another example of such a two–faced biological chemical is the gaseous signaling molecule, nitric oxide.

Produced as a protective molecule under periods of stress and trauma, nitric oxide is most well–known as a substance integral for the proper dilation of blood vessels. The blood vessels of people with cardiovascular disease, high blood pressure, insulin resistance, and diabetes are almost always dangerously resistant to the vasodilating effects of nitric oxide; and as such, strategies to increase nitric oxide levels and to restore proper nitric oxide signaling in these patients represent a major focus of current nutritional and pharmaceutical intervention.

But so far, the results of such strategies have failed to deliver much in the way of meaningful benefit – and some have even proven deadly. Such puzzling outcomes speak to the dual nature of nitric oxide, as well as the intricate complexity of its metabolism.

As the big picture of nitric oxide becomes clearer, we now know that while a deficiency of nitric oxide function is strongly implicated in cardiovascular disorders, an excess of nitric oxide, and inefficient nitric oxide metabolism, are known to exacerbate the vascular damage associated with heart disease. Nitric oxide and its metabolites also play particularly crucial roles in the spread of cancer, and the development of degenerative brain disorders like Alzheimer’s and Parkinson’s disease.

In recent years, many companies within the nutritional supplement industry have offered up “nitric oxide–boosting” formulas containing amino acid precursors of nitric oxide such as arginine and citrulline. The marketing behind such products obviously focuses on the supposedly “good” roles of nitric oxide, but the research that exists indicates that such products may possess the potential to do serious harm in certain populations, or if taken over extended periods of time.

So, rather than simply finding ways of “boosting” or suppressing nitric oxide levels to treat or prevent different disorders, our goal will be to find nutritional and lifestyle strategies to modulate nitric oxide production, ensuring proper, healthy, nitric oxide signaling and metabolism in all tissues of the body for a lifetime.

To do this requires that we first take a look at the biological “assembly line” responsible for the production of nitric oxide. Though complicated at first, we’ll find that the answers we seek can be found only by a glimpse into the inner workings of our molecular biochemistry.

The Nitric Oxide Synthases

It’s well–known that our body produces nitric oxide (NO) from the amino acid arginine, and that the production of nitric oxide from arginine is catalyzed by a group of enzymes known as nitric oxide synthases (NOS). At least three (major) types of NOS exist, each classified by the types of tissues and cells in which they are found (the fact that nitric oxide can be produced by several different enzymes, and can be used for many different biological reactions, may be our first clue as to why NO may be beneficial in some instances, and harmful in others).

Endothelial nitric oxide synthase, or eNOS, can be found in the lining of the blood vessels, called the endothelium. The nitric oxide produced by eNOS triggers vasodilation, and is an important factor in regulating blood pressure. Endothelial nitric oxide further supports cardiovascular health by inhibiting the “stickiness” of blood cells called platelets, and preventing platelets from adhering to the endothelium – an early phenomenon in the development of atherosclerosis. It has been noted that all known or suspected risk factors for cardiovascular disease – including high cholesterol, high blood pressure, high homocysteine, high triglycerides, and smoking – involve the reduced bioavailability of nitric oxide within the endothelium.

Neuronal nitric oxide, or nNOS, is found in neurons in the brain and nervous system. The nitric oxide produced by nNOS acts as a neurotransmitter and signaling molecule, and, in precise amounts, may play a role in memory and learning. Disorders of nitric oxide production by nNOS, on the other hand, may play a role in many neurological diseases like Parkinson’s and Alzheimer’s.

Inducible nitric oxide, or iNOS, is produced by cells of the immune system called macrophages. Our immune system makes use of the nitric oxide’s toxic free radical–generating capacity to kill invading pathogens like viruses and bacteria. But unlike eNOS and nNOS, which produce nitric oxide on demand for seconds, or minutes at the most, iNOS is able to chronically stimulate the production of nitric oxide for hours or even days.

Although nitric oxide is a potential free radical regardless of where and how it’s produced, nitric oxide produced by the immune system (in macrophages via iNOS) may be particularly apt to inflict dangerous collateral damage to the tissues with which it comes in contact. As the name inducible nitric oxide synthase indicates, the activity of iNOS is greatly increased under conditions of stress or trauma. It’s now thought that many of the potentially harmful effects of NO may be due to the excess nitric oxide produced from iNOS in the macrophages.

In this edition of the Integrated Supplements Newsletter, we’ll begin by focusing on nitric oxide’s role in the cardiovascular system. We’ll see precisely why trying to “boost” nitric oxide levels via the indiscriminate intake of nitric oxide precursors isn’t advisable. Instead, we’ll find that nitric oxide modulation is akin to performing a tune–up on a high–performance engine, and that we’ll need to make subtle, calculated adjustments to keep our nitric oxide metabolism running smoothly. Given what is now known about nitric oxide (but which many supplement companies continue to ignore), we’ll develop a unique strategy to ensure the proper, healthy, production and metabolism of nitric oxide within the cardiovascular system.

NO and the Cardiovascular System

In recent decades, research has made it clear that all known cardiovascular risk factors (including elevated cholesterol, elevated triglycerides, elevated homocysteine, and smoking) impair nitric oxide metabolism. As such, it’s now well–accepted that disorders of nitric oxide activity underlie the development of cardiovascular disease. Decreased bioavailability of NO is not only a direct cause of the “silent killer” known as high blood pressure (as blood vessels dilate under the influence of NO), but faulty NO signaling can also lead to cell adhesion, proliferation, and ultimately, to the acceleration of arteriosclerotic lesions within the endothelium. Impaired nitric oxide activity has also been associated with insulin resistance and diabetes, and some researchers believe that nitric oxide may be the molecular key to the well–established link between diabetes and cardiovascular disease.

Study Link – Is type 2 diabetes mellitus a vascular disease (atheroscleropathy) with hyperglycemia a late manifestation? The role of NOS, NO, and redox stress.

Quote from the above study:

Cardiovascular disease accounts for at least 85 percent of deaths for those patients with type 2 diabetes mellitus (T2DM). Additionally, 75 percent of these deaths are due to ischemic heart disease. . . The vulnerable three arms of the eNOS reaction responsible for the generation of eNO is discussed in relation to the hypothesis: (1) The L–arginine substrate. (2) The eNOS enzyme. (3) The BH4 cofactor.

In the early days of nitric oxide research (which wasn’t all that long ago), scientists logically assumed that the nitric oxide precursor, the amino acid arginine, when added to the diet, would increase levels of nitric oxide. They therefore reasoned that supplying the body with large amounts of arginine would likely restore proper vascular function (including vasodilation). This hypothesis was often validated in animal studies, and even in some short–term human studies:

Study Link – Oral L–arginine improves endothelium–dependent dilation in hypercholesterolemic young adults.

Quote from the above study:

After oral L–arginine, plasma L–arginine levels rose from 115+/–103 to 231+/–125 micromol/liter (P<0.001), and [ endothelium–dependent dilation] improved from 1.7+/–1.3 to 5.6+/–3.0% (P<0.001).

But as longer–term studies on supplemental arginine began to be conducted in patients with pre–existing heart disease, a seemingly strange trend began to emerge. In many of these studies, the patients taking arginine often fared notably worse than those not taking the amino acid. One important trial even had to be stopped prematurely because of an increase in death in the group taking arginine supplements:

Study Link – L–Arginine Therapy in Acute Myocardial Infarction The Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial.

Quote from the above study:

6 participants (8.6%) in the L–arginine group died during the 6–month study period vs none in the placebo group (P = .01). Because of the safety concerns, the data and safety monitoring committee closed enrollment. . . L–Arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L–Arginine should not be recommended following acute myocardial infarction.

Study Link – L–Arginine Supplementation in Peripheral Arterial Disease – No Benefit and Possible Harm

Quote form the above study:

Although absolute claudication distance improved in both L–arginine– and placebo–treated patients, the improvement in the L–arginine–treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024). . . As opposed to its short–term administration, long–term administration of L–arginine is not useful in patients with intermittent claudication and PAD.

Study Link – Dietary Supplementation With L–Arginine Fails to Restore Endothelial Function in Forearm Resistance Arteries of Patients With Severe Heart Failure.

Study Link – Oral L–Arginine in Patients With Coronary Artery Disease on Medical Management.

Quote from the above study:

Oral L–arginine therapy does not improve NO bioavailability in CAD patients on appropriate medical management and thus may not benefit this group of patients.

In retrospect, it’s not surprising that adding additional arginine to the diet of people with cardiovascular disease often produced negative results. The reason is that, whatever the underlying causes of nitric oxide dysfunction in heart disease, one thing’s for certain – it is NOT due to an arginine deficiency (as arginine is abundantly supplied in the vast majority of diets).

It’s likely that individuals with pre–existing heart disease (or a tendency towards heart disease) suffer from disorders involving several of the enzymes and cofactors which are needed to convert arginine into nitric oxide efficiently. In other words, if nitric oxide production is faulty, then adding arginine to the diet is destined to make matters worse in the long–run, as was found in the above studies. It’s highly likely that overwhelming the nitric oxide–producing system with supplemental doses of arginine may actually impair nitric oxide production, and lead to the production of other, more harmful substances – even in healthy people (we’ll see exactly how this phenomenon takes place later).

ADMA – The First Clue

As supplementing the diet with additional arginine produced many unpredictable and harmful effects, researchers began to wonder what factors could be responsible for impairing nitric oxide production in those suffering from cardiovascular disease and diabetes. One current suspect is an arginine analog called asymmetrical dimethyl arginine, or ADMA, for short. Acting as arginine’s “evil twin”, so to speak, ADMA can “tie up” nitric oxide synthase enzymes and can significantly inhibit NO production. People with heart disease and diabetes almost always exhibit very high levels of ADMA, and ADMA has proven to be a very strong independent risk factor for cardiovascular disease and insulin resistance:

Study Link – Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine.

Quote from the above study:

In an analysis of men who did not smoke, those who were in the highest quartile for ADMA (>0.62 μ mol/L) had a 3.9–fold (95% CI 1.25–12.3, p=0.02) increase in risk of acute coronary events compared with the other quartiles. Our findings suggest that ADMA is a predictor of acute coronary events.

Elevated ADMA levels have even been implicated in erectile dysfunction, a finding which isn’t terribly surprising considering the role of nitric oxide and vasodilation in facilitating the erectile response. Given how important proper NO metabolism is to cardiovascular health, researchers now believe that erectile dysfunction may be among the earliest physical manifestations of heart disease:

Study Link – Elevation of asymmetrical dimethylarginine (ADMA) and coronary artery disease in men with erectile dysfunction.

Quote from the above study:

As elevation of ADMA has been found to be associated with many risk factors for both CAD [coronary artery disease] and ED [erectile dysfunction], our data provide further strong evidence for the close interrelation of CAD and ED. Determination of ADMA may help to identify underlying cardiovascular disease in men with ED.

Where Does ADMA Come From?

In simple terms, ADMA is a byproduct of protein metabolism. Healthy people are usually able to metabolize and eliminate it properly, but in aging and disease, ADMA levels tend to rise. Because kidney disease patients excrete protein metabolites like ADMA less efficiently than healthy individuals, ADMA levels are known to be particularly high in those with kidney disease. And because ADMA is able to increase heart disease risk by interfering with NO production, an elevated ADMA level has been proposed to be the key “non–traditional” risk factor for heart disease in those with kidney disease. In other words, even kidney patients with normal cholesterol, blood pressure, and triglycerides are still very much prone to heart disease simply because of their elevated levels of ADMA.

In patients with heart disease and/or diabetes, but without overt kidney disease, it’s a little more difficult to say exactly why ADMA levels are almost invariably elevated. We do know, however, that the enzyme which breaks down ADMA, called dimethylarginine dimethylaminohy­drolase, or DDAH, is known to be particu­larly susceptible to oxidative damage in­flicted by known cardiovascular toxins like oxidized cholesterol, oxidized polyun­saturated fatty acids, and homocysteine.

For many months now, we at Integrated Supplements have been warning you of the dangers of oxidized cholesterol – found in many processed cholesterol–containing foods and powders, or produced in the body under conditions of oxidative stress. Researchers have recently shown that oxidized cholesterol caused a much greater elevation in ADMA levels than native, unoxidized cholesterol, due to oxidized cholesterol’s (oxLDL) unique ability to impair DDAH function.

Study Link – Novel Mechanism for Endothelial Dysfunction. Dysregulation of Dimethylarginine Dimethylaminohydrolase.

Quote from the above study:

The addition of oxLDL or TNF–a to ECV304 significantly increased the level of ADMA in the conditioned medium. The effect of oxLDL or TNF–a was not due to a change in DDAH expression but rather to the reduction of DDAH activity.

And the following study showed that a lipid peroxidation product produced from the omega–6 fat linoleic acid, called 4–HNE, significantly impaired nitric oxide production by interfering with DDAH activity. The effect was only partially reversed by arginine, but completely reversed by supplying increased amounts of DDAH along with antioxidants:

Study Link – Role of DDAH–1 in lipid peroxidation product–mediated inhibition of endothelial NO generation.

Quote from the above study:

We show that the lipid hydroperoxide degradation product 4–hydroxy–2–nonenal (4–HNE) causes a dose–dependent decrease in NO generation from bovine aortic endothelial cells, accompanied by a decrease in DDAH enzyme activity. The inhibitory effects of 4–HNE (50 µM) on endothelial NO production were partially reversed with L–Arg supplementation (1 mM). Overexpression of human DDAH–1 along with antioxidant supplementation completely restored endothelial NO production following exposure to 4–HNE (50 µM). These results demonstrate a critical role for the endogenous methylarginines in the pathogenesis of endothelial dysfunction. Because lipid hydroperoxides and their degradation products are known to be involved in atherosclerosis, modulation of DDAH and methylarginines may serve as a novel therapeutic target in the treatment of cardiovascular disorders associated with oxidative stress.

Study Link – Lipid peroxidation and nitric oxide inactivation in postmenopausal women.

Quote from the above study:

NO inactivation and the increase in lipid peroxidation may contribute to endothelial dysfunction and to the greater risk for atherosclerosis in postmenopausal women.

And, illustrating just how far–reaching the effects of lipid peroxide–induced disruption of nitric oxide metabolism can be, patients suffering from major depression have been shown to exhibit elevated levels of 4–HNE, decreased activity of DDAH and subsequently, increased levels of ADMA, and decreased plasma nitric oxide.

Study Link – Increased (E)–4–hydroxy–2–nonenal and asymmetric dimethylarginine concentrations and decreased nitric oxide concentrations in the plasma of patients with major depression. 

Quote from the above study:

There is an increase in circulating HNE in major depression. HNE inactivates the cysteine residue in the active site of endothelial DDAH leading to the accumulation of ADMA in the circulation. The ADMA then decreases the production of eNOS. This could reduce the amount of NO diffusing from cerebral blood vessels to nearby neurons and influence the release of neurotransmitters. ADMA also constricts cerebral blood vessels and may contribute to the decreased regional perfusion in major depression. The accumulation of ADMA could explain the increased risk of CHD in major depression. The preservation of DDAH activity and the reduction of ADMA accumulation may represent a novel therapeutic approach to the treatment of major depression.

In the above study, we also find that the potent cellular antioxidant glutathione was able to significantly reduce the level of lipid peroxides and protect the damage inflicted on the DDAH enzyme:

The effects of HNE on DDAH activity were significantly attenuated by the addition of glutathione (P<0.0001).

Taken together, these studies give us good reason to believe that the fundamental disorder of nitric oxide bioavailability seen in aging and disease is due to oxidative stress – particularly oxidative stress driven by products of lipid peroxidation (i.e. oxidized fat and cholesterol).

And researchers in the field are beginning to come to this same conclusion:

Article Link – When the endothelium cannot say ‘NO’ anymore.

Quote from the above article:

The mechanism by which ADMA is elevated in some patients may relate to oxidative stress. ADMA is inactivated by an enzyme named dimethylarginine dimethylaminohydrolase (DDAH); most investigators agree that DDAH plays an important role in the regulation of ADMA levels. DDAH activity is downregulated by oxidative stress, as it is associated with high cholesterol, high glucose, and high homocysteine levels. In these settings, accumulation of ADMA can be prevented by addition of antioxidants in experimental models. Inhibition of DDAH, in turn, leads to elevated ADMA levels, which in turn promote further generation of oxidants, possibly by uncoupling NO synthase. This vicious circle provides an integrative explanation for the interrelation between lack of NO, excess of oxygen–derived free radicals, and progression of vascular lesion formation.

A Nutritional Plan of Attack

To lower our level of oxidative stress, reducing our intake of oxidized cholesterol (from cholesterol–containing powders like powdered eggs, powdered cheese, and whey protein concentrate), as well as dramatically reducing our intake of dietary polyunsaturated fatty acids (omega–6– and omega–3–containing fats) is the only reasonable place to start. In addition, it is likely prudent to supplement with known inhibitors of lipid peroxidation, like Vitamin E, coenzyme Q10 and lipoic acid.

As noted, the above study on nitric oxide and depression showed that the cellular antioxidant, glutathione, significantly reduced the harmful effects of HNE on DDAH, so a supplement of undenatured whey protein isolate (which contains the “building blocks” of glutathione) along with the mineral selenium (also important for glutathione production) are likely to be very helpful as well.

Note: For more information on the role of lipids in oxidative stress, see the November and December 2007 issues of the Integrated Supplements Newsletter.

Homocysteine and Nitric Oxide

In addition to byproducts produced from unsaturated fat and cholesterol, the protein–derived substance, homocysteine, has also been shown to be an important contributor to the burden of oxidative stress. Homocysteine is an amino acid produced in high amounts due to the inefficient metabolism of the amino acid methionine, and elevated homocysteine levels have increasingly been implicated as a major heart disease risk factor in recent decades. If homocysteine does, in fact, cause an elevation in ADMA (and a subsequent decrease in NO production), as is shown in the following study, this would clearly lend molecular–level support to the homocysteine hypothesis of heart disease.

Study Link – Homocysteine Impairs the Nitric Oxide Synthase Pathway Role of Asymmetric Dimethylarginine.

Quote from the above study:

Homocysteine post–translationally inhibits DDAH enzyme activity, causing ADMA to accumulate and inhibit nitric oxide synthesis. This may explain the known effect of homocysteine to impair endothelium–mediated nitric oxide–dependent vasodilatation.

Vitamins B6, B12, and folic acid can reliably reduce homocysteine, which seems to be an important piece of the puzzle given what we now know about homocysteine’s role in impairing nitric oxide production. Folic acid in particular may play several roles in ensuring proper nitric oxide metabolism (more on this later).

And as we look beyond ADMA and DDAH, deeper into the various pathways involved in nitric oxide metabolism, we begin to see yet again, that oxidative stress is the common thread responsible for disrupting all of them.

Nitric Oxide, Superoxide, and Peroxynitrite

As we outlined in the previous Integrated Supplements Newsletter, nitric oxide, being a gaseous chemical, often doesn’t stick around long once it’s produced. Nitric oxide is known to rapidly react with the free radical superoxide (O2–), producing the powerful oxidant, peroxynitrite (OONO–) (remember that oxidizing chemicals like superoxide and peroxynitrite are potent molecular–level drivers of oxidative stress).

Researchers now believe that much of the cellular damage associated with cardiovascular disease (and other diseases in which nitric oxide plays a major role) involves the over–production of superoxide and peroxynitrite from faulty nitric oxide metabolism. In fact, much of the reason that nitric oxide levels are low in cardiovascular disease is because, under conditions of oxidative stress, arginine is converted to these harmful oxidants instead of nitric oxide – yet another reason why supplying additional arginine to the body is wrought with potential danger.

Article Link – Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly.

Quote from the above article:

The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO–). Nitric oxide is the only biological molecule produced in high enough concentrations to out–compete superoxide dismutase for superoxide.

As we’ve seen, the oxidative stress of aging and disease can damage the fragile enzyme DDAH, causing nitric oxide’s “evil twin,” ADMA to become elevated. ADMA competes with arginine for NOS and causes a reduction in nitric oxide production.

But this isn’t even the only way in which oxidative stress can impair nitric oxide production. The synthesis of nitric oxide from NOS requires a cofactor called tetrahydrobiopterin, or BH4, for short. When BH4 is damaged under conditions of oxidative stress (i.e. when it is oxidized), NOS then converts arginine directly to superoxide, and ultimately to the harmful reducing agent, peroxynitrite. Scientists call this effect an uncoupling effect, as damage to BH4 is able to uncouple, or divert arginine synthesis away from nitric oxide and towards superoxide and peroxynitrite. In a vicious downward spiral, peroxynitrite causes the oxidation of even more BH4, and the synthesis of nitric oxide is then even further impaired.

Study Link – Oxidation of Tetrahydrobiopterin by Peroxynitrite: Implications for Vascular Endothelial Function.

Quote from the above study:

Nitric oxide and superoxide react rapidly to form peroxynitrite, which may be the reactive species responsible for many of the toxic effects of nitric oxide. Here we show that BH4 is a primary target for peroxynitrite–catalyzed oxidation because at pH 7.4, physiologically relevant concentrations of BH4 are oxidized rapidly by low concentrations of peroxynitrite. . . Thus, abnormally low levels of BH4 can promote a cycle of its own destruction mediated by nitric oxide synthase–dependent formation of peroxynitrite. This mechanism might contribute to vascular endothelial dysfunction induced by oxidative stress.

Not surprisingly then, damage to tetrahydrobiopterin has been shown to cause all of the cardiovascular risk factors associated with impaired nitric oxide bioavailability; and repairing or preventing damage to tetrahydrobiopterin represents a key strategy in restoring healthy nitric oxide production.

As an example, while it’s common knowledge that high cholesterol levels represent a threat to cardiovascular health (especially when coupled with an environment of oxidative stress, in which significant amounts of cholesterol are prone to oxidation), few people realize that (oxidized) cholesterol may do cardiovascular damage largely through its ability to damage tetrahydrobiopterin, and thus, healthy nitric oxide production. Infused tetrahydrobiopterin has been shown to counter this effect and restore endothelial function in patients with high cholesterol:

Study Link– Tetrahydrobiopterin restores endothelial function in hypercholesterolemia.

Quote from the above study:

In hypercholesterolemia, impaired nitric oxide activity has been associated with increased nitric oxide degradation by oxygen radicals. Deficiency of tetrahydrobiopterin, an essential cofactor of nitric oxide synthase, causes both impaired nitric oxide activity and increased oxygen radical formation. . . this study demonstrates restoration of endothelial dysfunction by tetrahydrobiopterin suppletion in hypercholesterolemic patients.

It’s also been shown that other cardiovascular risk factors, like smoking, may do their damage by impairing tetrahydrobiopterin function as well:

Study Link – Tetrahydrobiopterin Improves Endothelium–Dependent Vasodilation in Chronic Smokers Evidence for a Dysfunctional Nitric Oxide Synthase.

Quote from the above study:

These data support the concept that in addition to the free radical burden of cigarette smoke, a dysfunctional [eNOS] due to BH4 depletion may contribute at least in part to endothelial dysfunction in chronic smokers.

And while we can’t realistically inject ourselves with tetrahydrobiopterin as was done in the above studies, there may be several nutritional strategies which will allow us to optimize the function of tetrahydrobiopterin within our bodies.

Supplementation with the well–known antioxidant, vitamin C, has been shown to protect tetrahydrobiopterin from oxidation, and to restore proper NOS activity:

Study Link – Long–Term Vitamin C Treatment Increases Vascular Tetrahydrobiopterin Levels and Nitric Oxide Synthase Activity.

Quote from the above study:

In vivo, beneficial effect of vitamin C on vascular endothelial function appears to be mediated in part by protection of tetrahydrobiopterin and restoration of eNOS enzymatic activity.

Nitrate Tolerance – More Clues on The Importance of Tetrahydrobiopterin

The nitric oxide–boosting drug, nitroglycerin, has been used for over a century as a vasodilator in coronary artery disease, but a troubling phenomenon, called nitrate tolerance, almost invariably arises with the drug’s long–term use. Researchers have wondered for years why it is that nitroglycerin quickly loses its efficacy, and many theories have been proposed to explain this occurrence. The most likely scenario appears to be that nitroglycerin gradually increases the formation of reactive oxygen species (or, ROS – the molecular–level drivers of oxidative stress) by impairing the bioavailability of tetrahydrobiopterin. Two of the ROS produced in the development of nitrate tolerance are the aforementioned superoxide and peroxynitrite radicals, which, as we’ve seen, further impair nitric oxide production in a vicious downward spiral. Ironically, considering the fact that nitrate drugs are so commonly used as short–term treatments for heart disease symptoms, nitric oxide drugs are known to increase mortality in those with existing heart disease; and the production of superoxide and peroxynitrite from nitric oxide helps to explain why:

Study Link – Long–term nitrate use may be deleterious in ischemic heart disease: A study using the databases from two large–scale postinfarction studies. Multicenter Myocardial Ischemia Research Group.

Quote from the above study:

The Cox analyses with all the variables retained revealed that nitrates were associated with a significantly increased mortality risk (MSMI: hazard ratio 3.78, P =.011; MDPIT: hazard ratio 1.61, P =.019) in patients who had recovered from an acute coronary event. . . These analyses raise concern about the potential adverse effects of long–acting nitrate therapy in chronic coronary disease.

It’s worth noting, too, that the phenomenon of nitrate tolerance – where a nitric oxide boosting substance “works” in the short–term, but is harmful in the long–term – parallels many of the same surprisingly harmful effects noticed in long–term studies where arginine was administered as a nitric oxide precursor. Many nitric oxide–boosting products are often “cycled,” or taken for relatively short periods of time, with a subsequent “layoff” of arbitrary duration. But, if these products “stop working” with continued use (as empirical evidence indicates is indeed the case), it’s fair to assume that the arginine they contain is no longer being converted to nitric oxide efficiently, and is instead being converted into harmful superoxide and peroxynitrite. No supplement company can say with any certainty precisely when this toxic phenomenon begins, or whether “cycling” the product makes it less harmful in the long–term. Thus it’s probably safe to say that the more a person consumes supplemental arginine or nitric oxide–boosting supplements (cycled or not), the greater the potential harm he or she is doing to his or her body.

But, of course, even those of us not consuming nitrate drugs or nitric oxide–boosting supplements can still learn a valuable lesson from what is now known about nitrate tolerance.

If progressive damage to tetrahydrobiopterin (both by nitric oxide itself and its ROS metabolites) is responsible for nitrate tolerance, then many of the same strategies which help to prevent nitrate tolerance may do so by protecting tetrahydrobiopterin (which is our goal as well). Studies show that this is, in fact, the case.

Vitamin C has been used with success to attenuate nitrate tolerance:

Study Link – Randomized, double–blind, placebo–controlled study of the preventive effect of supplemental oral vitamin C on attenuation of development of nitrate tolerance.

Quote from the above study:

These results indicate that combination therapy with vitamin C is potentially useful for preventing the development of nitrate tolerance.

And folic acid, a nutrient which may be able to “pinch hit” for tetrahydrobiopterin, has been shown to prevent nitroglycerin–induced nitrate tolerance as well:

Study Link – Folic Acid Prevents Nitroglycerin–Induced Nitric Oxide Synthase Dysfunction and Nitrate Tolerance.

Quote from the above study:

Our data demonstrate that supplemental folic acid prevents both nitric oxide synthase dysfunction induced by continuous [nitroglycerin] and nitrate tolerance in the arterial circulation of healthy volunteers. We hypothesize that the reduced bioavailability of tetrahydrobiopterin is involved in the pathogenesis of both phenomena. Our results confirm the view that oxidative stress contributes to nitrate tolerance.

And, beyond its role in nitrate tolerance, we find several unique roles of folic acid in ensuring proper NO production and cardiovascular health. The active form of folic acid, known as 5–methyltetrahydrofolate, has been shown to prevent the vascular disruption caused by high cholesterol:

Study Link – 5–Methyltetrahydrofolate, the Active Form of Folic Acid, Restores Endothelial Function in Familial Hypercholesterolemia.

Quote from the above study:

These results show that the active form of folic acid restores in vivo endothelial function in FH. It is suggested from our in vitro experiments that this effect is due to reduced catabolism of NO.

Folic acid is also known to play a role in reducing levels of the previously–mentioned cardiovascular toxin, homocysteine. And homocysteine has been shown to inhibit tetrahydrobiopterin functioning:

Study Link – Homocysteine induces oxidative stress by uncoupling of no synthase activity through reduction of tetrahydrobiopterin.

Quote from the above study:

The results show that the oxidative stress and inhibition of NO release induced by homocysteine depend on eNOS uncoupling due to reduction of intracellular tetrahydrobiopterin availability.

Tetrahydrobiopterin and Depression

It’s also interesting to note that, in addition to its role in producing nitric oxide, tetrahydrobiopterin is also a known co–factor in the production of the neurotransmitters noradrenalin, serotonin, and dopamine.

We saw previously how lipid peroxides can impair proper nitric oxide production; and we referenced studies in which depressed patients were shown to exhibit elevated lipid peroxide levels and decreased nitric oxide levels in their plasma.

Other studies show that reduced availability of tetrahydrobiopterin may not only impair nitric oxide production, but also the production of important brain chemicals (called monoamines in the quote below) in depression.

Study Link – The role of pterins in depression and the effects of antidepressive therapy.

Quote from the above study:

As a raised N:B ratio implies failure to convert neopterin to biopterin, it is possible that reduced availability of tetrahydrobiopterin, the essential cofactor for the formation of noradrenaline, serotonin and dopamine, may exert rate–limiting control over the synthesis of monoamines implicated in the pathogenesis of depressive illness.

Add to this the fact that depression is very strongly correlated with the development of heart disease:

Study Link – Depression as a predictor for coronary heart disease. A review and meta–analysis.

Quote from the above study:

It is concluded that depression predicts the development of [coronary heart disease] in initially healthy people. The stronger effect size for clinical depression compared to depressive mood points out that there might be a dose–response relationship between depression and [coronary heart disease].

And it’s tempting to theorize that disorders of tetrahydrobiopterin function, leading to both impaired nitric oxide function, and impaired neurotransmitter synthesis, may act as a common biological thread tying together both heart disease and depression.

Unlike the symptoms of heart disease, the burden of psychological depression often manifests during the first three or four decades of life – so even young people who are not often concerned with their heart disease risks should still take note of the research presented here. And considering that psychological depression is not only a major health challenge in and of itself, but is also a clear warning sign of impending cardiovascular disease, we can clearly see how valuable integrated and biologically sound nutritional strategies are if we can indeed combat both disorders simultaneously.

As is so common in biology, addressing fundamental defects and nutrient imbalances on a cellular and molecular level, imparts a beneficial “ripple effect” throughout the entire body, whereas treating merely symptoms (with pharmaceuticals, and the “wrong” nutrients) often leads to a whole host of negative side effects.

Further Neutralizing ROS

Many of the nutrients we’ve already mentioned have potent antioxidant and cell–protective effects, and synergistically, these nutrients work together to ensure proper nitric oxide production at each step of the biological “assembly line.”

To Review:

Nutrients to prevent lipid peroxidation and to lower ADMA by preventing oxidative damage to DDAH:

• Vitamin E

• Lipoic Acid

• Whey Protein Isolate

• Selenium

Nutrients for lowering homocysteine levels:

• Folic Acid

• Vitamin B–6

• Vitamin B–12

• Trimethylglycine

Nutrients for protecting tetrahydrobiopterin

• Vitamin C

• Folic Acid

And in addition to these nutrients, several others may play important roles in ensuring healthy nitric oxide metabolism within the cardiovascular system and beyond. Plant chemicals like polyphenols and flavanols (found in such foods as tea, wine, and chocolate), may be able to scavenge superoxide and peroxynitrite radicals, potentially neutralizing these reactive oxygen species before they can trigger NOS uncoupling and the downward spiral of faulty nitric oxide metabolism.

Of course, even though polyphenols are able to quickly deactivate ROS in vitro (in a test tube), there’s still some debate as to how well these plant chemicals do so within our bodies. Our livers usually do an excellent job of “deactivating” these “foreign” chemicals before they reach the bloodstream, and surprisingly few polyphenols actually reach general circulation. It’s been proposed that either these polyphenols stimulate our own antioxidant systems (like those involving glutathione), or that the polyphenol conjugates (conjugation, or the “attachment” of one substance to another in order to improve elimination, is what the liver does to detoxify such compounds) may have antioxidant effects in and of themselves.

For more info, see:

Study Link – How should we assess the effects of exposure to dietary polyphenols in vitro?

But whatever their mechanisms of action, some plant chemicals appear to have remarkable effects on nitric oxide production in vivo (in the body) when consumed orally. The flavanols (a type of polyphenol) in unprocessed cocoa, for example, have been shown to significantly lower blood pressure via nitric oxide–mediated action.

Study Link – Flavanol–rich cocoa induces nitric–oxide–dependent vasodilation in healthy humans.

Quote from the above study:

In healthy humans, flavanol–rich cocoa induced vasodilation via activation of the nitric oxide system, providing a plausible mechanism for the protection that flavanol–rich foods induce against coronary events.

And subsequent studies by the same researchers showed that older individuals had a greater response to cocoa flavanols than younger individuals – indicating that the flavanols may be able to partly correct the decline in nitric oxide function which occurs in aging.

Study Link – Aging and vascular responses to flavanol–rich cocoa.

Quote from the above study:

Flavanol–rich cocoa enhanced several measures of endothelial function to a greater degree among older than younger healthy subjects. Our data suggest that the NO–dependent vascular effects of flavanol–rich cocoa may be greater among older people, in whom endothelial function is more disturbed.

And besides various plant polyphenols, and the vitamins we’ve already mentioned, another, more “non–traditional” antioxidant may have the unique ability to protect against the free radical damage associated with nitric oxide.

Creatine and Cardiovascular Health

Though it’s often though of only as a sports supplement useful for enhancing muscle size and strength, the high energy molecule, creatine (which, unlike some polyphenols, is very well–absorbed) has been shown to scavenge both superoxide and peroxynitrite – the molecules largely responsible for nitric oxide–induced damage.

Study Link – Direct Antioxidant Properties of Creatine.

Quote from the above study:

. . .creatine displayed a significant ability to remove [superoxide] and [peroxynitrite] when compared with controls. . . To our knowledge, this is the first evidence that creatine has the potential to act as a direct antioxidant against aqueous radical and reactive species ions.

We looked briefly at the role homocysteine plays in inhibiting DDAH, and tetrahydrobiopterin – two cofactors required for proper nitric oxide production. So, logically, lowering homocysteine will be an important part of ensuring proper nitric oxide metabolism and cardiovascular health. It’s known that the neutralization of homocysteine requires a chemical process called methylation, and that substances which donate methyl groups (CH3), such as betaine (TMG), SAMe, and choline – all available as dietary supplements – have been shown to lower homocysteine levels.

Because creatine can produce energy substrates quickly, without the metabolic demands of breaking down glucose or fatty acids for fuel, creatine can be thought of as an “emergency” energy molecule. As such, creatine is in very high demand by the most metabolically active tissues like the muscles, brain, and heart (even in non–athletes).

But the production of creatine within the body just so happens to “use up” methyl groups at an astonishingly high rate. It turns out that taking “pre–formed” creatine as a supplement (meaning, that our body doesn’t have to go through the metabolic steps of making it) spares the valuable methyl groups which would otherwise be used for creatine production – methyl groups which can then be used to neutralize homocysteine. And this effect is more than mere biological speculation – oral creatine supplements have, in fact, been shown to lower homocysteine levels significantly:

Study Link – Oral creatine supplements lower plasma homocysteine concentrations in humans.

Quote from the above study:

After four weeks of creatine supplements, [total plasma homocysteine] in [the experimental group] changed by an average of –0.9 micromol/L (range: –1.8 to 0.0), compared to an average change of +0.2 micromol/L in C (range: –0.6 to 0.9) during the same four weeks. The difference in the changes in [total plasma homocysteine] between the two groups was statistically significant (p < 0.01). CONCLUSION: Creatine supplements may be an effective adjunct to vitamin supplements for lowering [total plasma homocysteine].

Given that we must reduce the burden of superoxide, peroxynitrite, and homocysteine in order to ensure proper nitric oxide metabolism within the cardiovascular system, daily supplementation with pure creatine monohydrate probably represents one of the most physiologically sound ways to achieve all of these goals simultaneously – all the while supplying a vital energy substrate to the metabolically active cells of the muscle, brain, and heart.

In fact, it’s probably safe to say that although creatine is remarkably effective for increasing strength and energy production in athletes, those who have avoided taking creatine monohydrate because of its stigma as a mere “bodybuilding” supplement are likely to be missing out on one of the most remarkably health–promoting substances within the entire realm of nutritional supplementation.

And similarly, many people who currently think that they are taking creatine may not be. In recent years, many different types of creatine have been introduced to the nutritional supplement market, each claiming offer benefits above and beyond creatine monohydrate. In recent studies, however, two of the most heavily promoted “new” creatines, creatine ethyl ester, and a brand of “buffered” creatine, have both been shown to be vastly inferior to creatine monohydrate. In direct opposition to the marketing claims of these newfangled creatines, both creatine ethyl ester, and so–called buffered creatines have been shown to degrade into the useless byproduct creatinine much more readily than does creatine monohydrate.

Exposing the lies and misinformation surrounding creatine is best left for another newsletter, but for now, it’s important to realize that the full benefits of creatine, for cardiovascular health, or athletic improvement, can be obtained only through supplementation with pure creatine monohydrate.

The Cardiovascular System – Just The Beginning

Faulty nitric oxide metabolism has been implicated as a common denominator in various degenerative diseases including not only heart disease, but also such disorders as Alzheimer’s disease and cancer.

Fortunately, many of the dietary and supplement strategies we’ve covered here will also serve us well as we examine the effects of nitric oxide not directly related to the cardiovascular system. In the next Integrated Supplements Newsletter, we’ll take a look at nitric oxide’s role in other systems of the body, and in other disorders associated with aging. As we put all of the pieces of the nitric oxide puzzle together, the big picture of nitric oxide will begin to come into even clearer focus.

About Us: At Integrated Supplements, our goal is to bring you the wellness information and products you need to live your life to the fullest. We are dedicated to producing the highest–quality, all–natural nutritional supplements; and to educating the world on the health promoting power of proper nutrition. You can find out more by visiting: www.IntegratedSupplements.com


These statements have not been evaluated by the FDA. No Integrated Supplements product is intended to diagnose, treat, cure or prevent any disease.


What's Wrong With Nitric Oxide - Part 1


Recently, a group of surgeons performing a bowel resection operation on a young man were alarmed to notice the patient bleeding profusely during the surgery. In a frantic attempt to save the patient’s life, as one standard procedure after another failed to normalize the bleeding, the surgeons were eventually forced to perform a full blood transfusion. Though the operation was eventually a success, the physicians were perplexed, as, according to the patient’s records, he wasn’t consuming any medications which could account for such massive and life–threatening bleeding.

But, with a little biological sleuthing, it was soon found that the patient had been taking a very popular nitric oxide–boosting nutritional supplement sold as an “energy and performance igniter” for bodybuilding training. It turned out that the product contained not only various nitric oxide precursors, but several herbal nitric oxide–boosting ingredients which also happen to be potent blood thinners.

The above situation, relayed to us by one of the surgeons performing the operation, is an extreme but telling example of the dangers of accepting the nutritional supplement industry’s hype at face value. In recent years some supplement companies – especially companies specializing in bodybuilding supplements – have been able to convince their customers that there are benefits to be gained by increasing the body’s levels of the vasoactive chemical, nitric oxide. Yet, in an industry never known to let safety concerns stand in the way of profit, any mention of the potential short and long–term side effects of increasing ones nitric oxide levels has been conspicuously absent.

As a vasodilator, or, substance which dilates blood vessels, nitric oxide is known to influence blood flow as well as nutrient and oxygen delivery to cells; and some companies have speculated that increasing nitric oxide to supraphysiological levels, may result in greater increases in nutrient delivery to working muscles, and a subsequent increase in muscle growth.

Nitric oxide–boosting supplements have also been widely promoted for increasing the muscular “pump” – the localized inflammatory swelling of muscle – which is especially evident during weight training.

But the physiology of the blood vessels and blood flow (what scientists call hemodynamics) is infinitely more complicated than many within the supplement industry would have you believe. Despite the impression you may get from reading bodybuilding and fitness magazines, the study of nitric oxide as a biological chemical is still in its infancy, and looking at the existing scientific literature will give any rational, intelligent person reason to think twice about attempting to increase nitric oxide levels. Although nitric oxide is an important signaling molecule essential for life, there’s also reason to believe that purposefully stimulating its production is wrought with both short–term and long–term risks.

In this edition of the Integrated Supplements Newsletter, we’ll set the record straight on what is really known about the biological role of nitric oxide – in particular, we’ll look at its effects on vasodilation, blood flow, blood vessel integrity, bleeding, hemorrhage, septic shock, energy metabolism, exercise performance, and oxidative stress. And in part two of this series, we’ll look at the long–term effects of nitric oxide over a lifetime, and we’ll examine the integral role of nitric oxide plays as an accelerator of aging and degenerative disease.

Nitric Oxide – From Humble Beginnings

In 1867, Alfred Nobel (for whom the Nobel Prize is named), received a patent for an invention which stabilized the highly explosive chemical, nitroglycerin, by combining it with silica. The resulting malleable paste allowed the explosive power of nitroglycerine to be harnessed and controlled, and proved useful in such endeavors as mining and drilling. His invention was, of course, called dynamite.

And, in an odd coincidence, during the latter part of his life, Nobel’s physician prescribed nitroglycerin as treatment for the noted industrialist’s heart disease. Nobel, however, refused to take it, knowing from experience that the chemical caused him headaches. It would take nearly 100 years for science to discover that the factor responsible for both nitroglycerins’ role in reducing symptoms of heart disease, and Nobel’s headaches, was a vasodilating chemical called nitric oxide.

During the mid 1980’s it was discovered that nitric oxide (NO) was the mysterious biological substance which caused the dilation of blood vessels – a particularly shocking revelation considering that this gaseous chemical had previously been known as a mere industrial pollutant.

And in 1998, the Nobel Prize for medicine was awarded to a group of scientists who discovered that nitric oxide played major roles as an endogenous signaling molecule in the vascular, nervous, and immune systems of the human body. Since that time, research into the complex biological role of nitric has exploded, but still a relative newcomer to the biological scene, many questions remain as to the varied functions of this enigmatic molecule.

At first glance, much of the existing research on nitric oxide makes the chemical seem beneficial – it can indeed lower blood pressure by causing a dilation of the blood vessels, which is precisely what has made NO–boosting drugs like nitroglycerin beneficial for cardiovascular patients suffering from angina.

But as nitric oxide research has progressed, the two–faced nature of nitric oxide has begun to come to light. Some studies have surfaced indicating that certain nitric oxide–increasing therapies may have serious and potentially deadly drawbacks. In 2006, a particularly notable study using the common nitric oxide–boosting nutrient, l–arginine, in heart disease patients had to be stopped due to a dramatic increase in death in the treatment group.

Study Link – L–Arginine Therapy in Acute Myocardial Infarction – The Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) Randomized Clinical Trial.

Quote from the above study:

Because of the safety concerns, the data and safety monitoring committee closed enrollment. . . L–Arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L–Arginine should not be recommended following acute myocardial infarction.

And subsequent research has served to dampen the initial enthusiasm for nitric oxide–boosting therapies even further. As with most chemicals which signal cellular stress, nitric oxide can be beneficial or harmful depending upon the amount released, and the energetic state of the cells with which it comes in contact. While, in some contexts, nitric oxide may be a chemical signal for vasodilation, cell growth and adaptation, an excess of nitric oxide has been shown to cause cellular fatigue, cellular damage, and even cellular death.

So, clearly in biology, nothing is as simple as it at first seems, and this appears to be especially true of nitric oxide. As a highly reactive and potentially damaging chemical, the effects of nitric oxide have proven incredibly difficult to predict. As more studies have emerged indicating that nitric oxide–boosting nutrients may be harmful in some treatment groups, many researchers now believe that, in certain circumstances, we should actually take steps to decrease our production of nitric oxide, not increase it.

Study Link – L–Arginine Supplementation in Peripheral Arterial Disease – No Benefit and Possible Harm.

Quote form the above study:

Although absolute claudication distance improved in both L–arginine– and placebo–treated patients, the improvement in the L–arginine–treated group was significantly less than that in the placebo group (28.3% versus 11.5%; P=0.024). . . As opposed to its short–term administration, long–term administration of L–arginine is not useful in patients with intermittent claudication and PAD.

Study Link – Effects of chronic treatment with L–arginine on atherosclerosis in apoE knockout and apoE/inducible NO synthase double–knockout mice.

Quote from the above study:

This raises the possibility that L–arginine supplementation may paradoxically contribute to, rather than reduce, lesion formation by mechanisms that involve lipid oxidation, peroxynitrite formation, and NOS uncoupling.

But, even though the work of world–renowned biologists and chemists clearly shows that nitric oxide is a double edged–sword whose benefits have yet to be harnessed without risk, we need only to open the pages of any bodybuilding or fitness magazine to witness the reckless hucksters of the supplement industry touting products specifically designed to dramatically increase our nitric oxide levels. If their past track record is any indication, we can expect these companies to largely ignore the growing body of research which paints nitric oxide, and nitric oxide–boosting nutrients in a negative light, simply because such research doesn’t help them sell products.

The Products and Their Claims

The advertising for nitric oxide–boosting products in the bodybuilding realm usually centers around claims of increased blood flow to muscles, better nutrient delivery, enhanced “pumps” while training, and overall, an increase in muscular size and strength.

NO–boosting products are also sold as aids to erectile function, and (despite the above–listed studies) to support cardiovascular health. Whatever the claim or target demographic, the underlying mechanism for these products revolves around the same basic biological function – the ability of nitric oxide to dilate blood vessels.

Most nitric oxide–boosting products are formulated with various types of arginine – the amino acid from which nitric oxide is produced in the body. And although simple l–arginine supplements have been available for decades, as studies on the biological role of nitric oxide began to fill medical journals, certain enterprising individuals within the supplement industry decided to blow the dust off of this amino acid, and re–introduce it to the bodybuilding world in the form of novel arginine–containing salts like arginine alpha–ketoglutarate (AAKG) – possibly the most common ingredient in the current group of nitric oxide boosting supplements.

Because both arginine, and ketoglutarate are known to increase arginine levels in the body, it’s reasonable to believe that AAKG may increase arginine levels (and subsequently, nitric oxide) to a greater extent than l–arginine alone. But given the scientific–sounding jargon of many supplement advertisements, many people are surprised to learn that little to no research has been performed on AAKG in relation to nitric oxide levels. And as we have seen, even some studies which look at the effects of orally administered l–arginine (a relatively modest NO–booster at best), still give us reason for concern.

Dozens of other ingredients are often added to nitric oxide–boosting products including other salts of arginine as well as citrulline, an amino acid which is converted to arginine in vivo (in the body). And complicating matters even further is the common presence of compounds (especially blood thinning nutrients and herbs) which can potentially amplify the vascular effects of arginine and its metabolites. Because of this, the risk of excessive and pathological bleeding and hemorrhage is a very real concern even with the short–term usage of some nitric oxide–boosting products. But before we get too far ahead of ourselves, a little perspective on the true biological roll of nitric oxide is probably in order.

A Little Perspective on NO

Because the literature on nitric oxide is often conflicting, it’s important to sketch a bird’s eye view of its function within the body. Those attempting to sell you nitric oxide–boosting formulas often have a tendency to cherry pick the literature, showing you only studies (if they reference valid studies at all), which support their claims in limited contexts. For example, nitric oxide, as the supplement industry has so widely advertised, does indeed cause dilation of blood vessels. And this vasodilation may increase blood flow and allow the cells to temporarily produce energy more efficiently (with less oxygen consumption) under periods of stress.

But it’s important to always remember that the production of nitric oxide, and the dilation of blood vessels, is a defensive response of the body to stressful stimuli. As with all defensive responses, if the body lacks the ability to “shut off” the response, the response self–perpetuates, and the overall effects will be damaging and sometimes deadly. It’s crucial to recognize this fact, because there is often the mistaken belief that biological functions which can be harmful are under “tight control,” and that it’s nearly impossible to harm oneself with mere nutrients or nutritional supplements. But in the presence of certain stressors, we find that a great amount of damage can be done before the body is able to restore balance. As an example, we can see the quintessential illustration of the self–perpetuating nature of the nitric oxide stress response in the phenomena of sepsis and septic shock.

In the previous issue of the Integrated Supplements Newsletter, we saw how the presence of a “leaky gut” can allow bacteria and bacterial components called endotoxin to enter the bloodstream from the intestines, causing chronic systemic inflammation.

When such translocation of bacteria from the intestines into the bloodstream is significant, the condition is called sepsis, or what is often known in layman’s terms as blood poisoning. One of the bodies’ primary responses to sepsis is an increase in the production of nitric oxide. In the very short term, NO can dilate blood vessels and increase nutrient delivery to cells possibly allowing them to counter the stress by increasing their energy production. Very quickly, however, the hypotension (low blood pressure) caused by NO can lead to the exact opposite phenomenon –a dangerous decrease in blood flow to vital organs like the brain and kidneys, and an overall reduction in protective energy production throughout the body.

The vasodilating effects of NO are so strong in septic shock, that the blood vessels remain dilated despite the body’s best efforts to normalize them with vasoconstricting agents like adrenaline. The heart frantically attempts to compensate for the lowered blood pressure by pumping blood at an accelerated rate, but often, to no avail. As the heart soon weakens, blood pressure drops even further, causing blood vessels to leak, leading to bleeding (especially in the lungs, causing difficulty breathing), hemorrhage, cardiac failure, and often, death.

In relation to the surgery patient we mentioned in the introduction, and noting nitric oxide’s fundamental role in this chain of events, we see why none of the surgeons’ interventions worked to stop the young man’s bleeding and hypotension, until they supplied his body with more blood via a transfusion – sufficiently increasing blood volume (and therefore, pressure) and oxygen delivery to stop the bleeding and save his life.

Nitric oxide is so fundamental to the vicious chain of events in sepsis, that strategies for combating sepsis now often involve therapies aimed at dramatically reducing the production of nitric oxide.

Study Link – Nitric oxide in the pathogenesis of sepsis.

Quote from the above study:

In sepsis and septic shock, inflammatory mediators result in the production of increased concentrations of nitric oxide (NO) from the enzymatic breakdown of the amino acid L–arginine. The increased amounts of NO are responsible for changes in vasomotor tone, decreased vasopressor responsiveness, and decreased myocardial function, characteristic of septic insult. Therapeutic strategies designed to reduce the concentration of NO by inhibiting the action of the nitric oxide synthase enzyme, or by scavenging the excess NO, offer the potential to treat directly the vasomotor abnormalities and myocardial depression seen in sepsis and other inflammatory states.

Study Link – Circulatory failure in septic shock. Nitric oxide: too much of a good thing?

Quote from the above study:

One of the characteristic features of septic shock is profound hypotension caused by a decrease in peripheral vascular resistance. This hypotension is unusually resistant to both volume replacement and vasoconstrictor agents.

And it’s important to remember as well, that nitric oxide doesn’t just affect the blood vessels. Cells of the immune system and the nervous system also synthesize nitric oxide, and cumulatively, the nitric oxide produced by various cells can cause massive tissue damage via NO’s free radical–generating capacity.

A quote from the same study:

. . . production of large quantities of nitric oxide leads not only to haemodynamic instability but also to widespread production of nitric oxide–based free radicals which have the potential to cause considerable damage to tissues. Evidence from clinical studies supports this.

So, let’s get it straight right from the beginning: nitric oxide is an inflammatory chemical, which is produced in response to stress, injury, and trauma. Like other inflammatory chemicals, nitric oxide has a role in normal human physiology, but an excess of it, or prolonged stimulation of it is decidedly harmful. Nitric oxide synergizes with and stimulates other inflammatory chemicals, including prostaglandins, and cytokines. NO reduces blood pressure and oxygen utilization, increases lactic acid production, impairs mitochondrial energy production, promotes excitotoxicity, and causes (either directly or indirectly) various types of cell death.

And knowing that nitric oxide is able to overwhelm the body’s hemodynamic regulatory systems should make us think twice about consuming large amounts of arginine, or other nitric oxide precursors or boosters. An abundance of nitric oxide precursors in the body could make even everyday stresses (like workouts) harmful and, in rare cases, even catastrophic.

For example, it’s known that exercise weakens intestinal barrier function, and causes bacteria and endotoxin to be absorbed. Sepsis and exercise share so many inflammatory factors in common, that intense exercise has even been proposed as a model for studying sepsis.

Study Link – Sepsis and mechanisms of inflammatory response: is exercise a good model?

Study Link – Are similar inflammatory factors involved in strenuous exercise and sepsis?

Study Link – Strenuous exercise causes systemic endotoxemia.

Quote from the above study:

Eighteen triathletes were studied before and immediately after competing in an ultradistance triathlon. Their mean plasma lipopolysaccharide (LPS) concentrations increased from 0.081 to 0.294 ng/ml (P less than 0.001), and their mean plasma anti–LPS immunoglobulin G (IgG) concentrations decreased from 67.63 to 38.99 micrograms/ml (P less than 0.001).

So, we should be aware that in exercise, and in sepsis, the same principles of nitric oxide metabolism apply – the difference is merely one of degree. This, of course, is a fact which is conspicuously absent from the advertising of nitric oxide–boosting supplements, but it’s an important fact to recognize if we are to accurately assess the risks associated with these products.

Nitric Oxide and Peroxynitrite – General Toxic Effects

But it’s not simply the vasodilating effects of NO which may prove harmful in excess. As alluded to above, nitric oxide and its metabolites are also able to produce massive amounts of free radical damage – damage which has been shown to be toxic to the well–known “power plants” of the cells, the mitochondria.

As the science of biology advances, mitochondrial function is turning out to be the key to the mysteries of aging and degenerative disease. If you take nothing else from this article, let it be this:

Maintaining healthy mitochondria – mitochondria which are undamaged physically, and which produce energy efficiently – is the key to a long, energetic, happy, and disease–free life.

The energy produced by our mitochondria creates a “force field” of protection around the cell, allowing it to grow, adapt, and survive various stressors. Think of your cells as being constantly protected by an invisible electric fence, the power for which is supplied by the mitochondria – cut the power (damage or poison the mitochondria), and the cell becomes susceptible and increasingly vulnerable to all sorts of cellular stressors. The cells lose the ability to “fight back” and can no longer grow stronger and more resilient in response to stress – eventually they simply wave the white flag of defeat in response to any threat which comes along. Poison enough of these power plants and you accelerate your descent into aging, depression, atrophy, and degenerative disease.

One of the keys to the generally toxic effects of nitric oxide on the mitochondria is the NO derivative, called peroxynitrite (ONOO –). Being a gas, and a free radical, nitric oxide doesn’t stick around long once it’s produced. It rapidly reacts with surrounding molecules, especially the free radical superoxide, producing the particularly harmful oxidizing and nitrating agent, peroxynitrite.

On a cellular level, both NO and peroxynitrite have been shown to decimate mitochondrial function.

In fact, the following study and quote show clearly that NO and peroxynitrite impair mitochondrial function in almost every conceivable way – inhibiting multiple mitochondrial enzymes, chewing up antioxidants, damaging proteins, spilling redox–active iron, as well as causing lipid peroxidation, cell swelling, calcium release, and membrane permeability (all direct precursors to cell death).

Study Link – Nitric oxide and mitochondrial respiration.

Quote from the above study:

Nitric oxide (NO) and its derivative peroxynitrite (ONOO−) inhibit mitochondrial respiration by distinct mechanisms. Low (nanomolar) concentrations of NO specifically inhibit cytochrome oxidase in competition with oxygen, and this inhibition is fully reversible when NO is removed. Higher concentrations of NO can inhibit the other respiratory chain complexes, probably by nitrosylating or oxidising protein thiols and removing iron from the iron–sulphur centres. Peroxynitrite causes irreversible inhibition of mitochondrial respiration and damage to a variety of mitochondrial components via oxidising reactions. Thus peroxynitrite inhibits or damages mitochondrial complexes I, II, IV and V, aconitase, creatine kinase, the mitochondrial membrane, mitochondrial DNA, superoxide dismutase, and induces mitochondrial swelling, depolarisation, calcium release and permeability transition. . . The NO inhibition of cytochrome oxidase may also be involved in the cytotoxicity of NO, and may cause increased oxygen radical production by mitochondria, which may in turn lead to the generation of peroxynitrite. Mitochondrial damage by peroxynitrite may mediate the cytotoxicity of NO, and may be involved in a variety of pathologies.

So, in layman’s terms, nitric oxide and peroxynitrite can act as agents of wholesale cellular destruction, choking the life out of our cells at the most fundamental level. And once the cell is weakened in this way, even “normal” stresses and stimulation can become deadly to the cell.

And such damaging effects on a cellular level are easy to extrapolate to a macroscopic level as in the role of NO and peroxynitrite in degenerative disease:

Study Link – Nitric oxide and peroxynitrite in health and disease.

Quote from the above study:

Since its early description as an endothelial–derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. . . In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorder.

Nitric Oxide, NMDA, and Chronic Fatigue

Given what we now know about nitric oxide’s effects on cellular energy production, it seems especially strange that various nitric oxide–boosting products are being touted as energy boosters and performance enhancers. Many of these products are spiked with caffeine or creatine, both of which may impart energizing effects, but one thing’s for certain – nitric oxide itself certainly does not lead to an increase in energy production. In fact, quite the opposite is true. Some researchers have actually implicated an excess of nitric oxide production as the central metabolic defect underlying the chronic fatigue syndrome.

Without the damage caused by nitric oxide, and the subsequent drain on cellular defenses, stimulation of the excitatory NMDA receptor may simply be a normal physiological event involved in such phenomenon as memory and learning. In the presence of nitric oxide, however, uncontrolled nervous excitation, and cell death may result from the very same stimulation. Nitric oxide has been shown to be a necessary co–factor in the toxic effects of NMDA stimulation by excitatory amino acids. We’ve seen in previous Integrated Supplements Newsletters that the stimulation of the NMDA receptor is often a self–perpetuating sequence which drains cellular energy to the point of cell death.

Study Link – Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.

Quote from the above study:

We show that the nitric oxide synthase inhibitors, N omega–nitro–L–arginine (EC50 = 20 microM) and N omega–monomethyl–L–arginine (EC50 = 170 microM), prevent neurotoxicity elicited by N–methyl–D–aspartate and related excitatory amino acids. This effect is competitively reversed by L–arginine. Depletion of the culture medium of arginine by arginase or arginine–free growth medium completely attenuates N–methyl–D–aspartate toxicity. . . These data establish that NO mediates the neurotoxicity of glutamate.

Individuals with excess production of nitric oxide may suffer from NMDA over–stimulation, and may be predisposed to chronic pain, fatigue, chemical sensitivity, and they may even be especially susceptible to the negative effects of excitotoxic food additives like MSG and the artificial sweetener, aspartame.

The following study found that the amino acid citrulline (a “byproduct” of arginine’s production of nitric oxide), is consistently elevated in chronic fatigue patients.

Study Link – Levels of Nitric Oxide Synthase Product Citrulline Are Elevated in Sera of Chronic Fatigue Syndrome Patients.

Quote from the above study:

Serum citrulline levels were found to be significantly elevated in CFS patients and, in addition, there was a trend towards higher levels in CFS patients with stronger symptoms. These results provide support for the view that nitric oxide synthase activity tends to be elevated in CFS patients, thus supporting a prediction of the elevated nitric oxide/peroxynitrite theory of CFS etiology.

And it has also been proposed that the link between chronic fatigue syndrome and other related disorders stems from an elevation in nitric oxide synthesis.

Study Link – Elevated Nitric Oxide/Peroxynitrite Mechanism for the Common Etiology of Multiple Chemical Sensitivity, Chronic Fatigue Syndrome, and Posttraumatic Stress Disorder.

In relation to chronic fatigue, it’s interesting to note that chronic fatigue patients often manifest low blood pressure. It’s usually assumed that this low blood pressure has much to do with adrenal exhaustion. The thinking is that the adrenal glands of chronic fatigue patients aren’t sufficiently producing the adrenaline needed for energy and proper blood vessel tone. But if chronic fatigue patients do indeed overproduce nitric oxide, the vasodilating effect of nitric oxide could be another cause of the low blood pressure often noted in these patients.

This possibility opens up multiple avenues for treatment, and not coincidentally, the researchers who implicate nitric oxide in these disorders recommend nutrients and drugs aimed specifically at scavenging nitric oxide, lowering NMDA activity, and restoring mitochondrial function.

For example, the energizing effect of vitamin B–12 is well known, but few people realize that this effect may be due to B–12’s ability to scavenge and deactivate nitric oxide.

Study Link – Cobalamin Used in Chronic Fatigue Syndrome Therapy Is a Nitric Oxide Scavenger.

Other nutrients which may improve energy production by minimizing NO/peroxynitrite–induced damage include Co–Q10, niacinamide, magnesium and vitamin C.

What About Antioxidants?

Noting that the stimulation of nitric oxide is well–known to induce cellular and tissue damage via the free radical activity of peroxynitrite, some sellers of nitric oxide–boosting supplements have taken to formulating their products with a sprinkling of various antioxidants, supposedly acting as some sort of “damage control.”

But while the inclusion of antioxidants in these products may be somewhat beneficial, it’s unclear to what extent these antioxidants actually help counter an “artificially elevated” nitric oxide level. As for now, the inclusion of antioxidants with nitric oxide boosters (like so much else in the nutritional supplement industry) amounts to little more than simply wishful speculation.

But, it’s worth noting that some antioxidants do have unique and potentially positive effects on nitric oxide metabolism, and they may be beneficial in keeping nitric oxide levels within a normal, healthy range – assuming we don’t overwhelm the system with nitric oxide precursors or boosters.

The potent thiol (sulfur–containing) antioxidant, lipoic acid, has been shown to increase nitric oxide–mediated vasodilation in disease states, but not in healthy subjects. This effect is likely a clue that the way to ensure proper, healthy, nitric oxide production lifelong is via reducing our levels of oxidative stress – not by increasing our intake of arginine and similar nitric oxide precursors.

Study Link – Beneficial effects of α – lipoic acid and ascorbic acid on endothelium–dependent, nitric oxide–mediated vasodilation in diabetic patients: relation to parameters of oxidative stress.

Quote from the above study:

The impairment of nitric oxide (NO)–mediated vasodilation in diabetes has been attributed to increased vascular oxidative stress. Lipoic acid has been shown to have substantial antioxidative properties. . . Lipoic acid improved NO–mediated vasodilation in diabetic patients, but not in controls.

It’s known that the nitric oxide response of the blood vessels decreases in aging and disease (meaning that diseased blood vessels don’t respond to nitric oxide by dilating as effectively as healthy blood vessels do), but if, as the above study indicates, oxidative stress (and not lack of arginine) is the cause of the faulty nitric oxide response, then reducing oxidative stress is the most logical and physiologically sound solution – this is why taking arginine supplements won’t necessarily help, and is likely to do more harm, as has been shown in various studies.

Excess Nitric Oxide – Concerns in Exercise

Even people with little biological knowledge seem to understand the simplistic notion that the stress of weight training causes “damage” to the muscle, which, under ideal conditions, the body responds to by growing larger, stronger, or more efficient. Nitric oxide release is a normal response to the stress of training, and the damage which is caused by nitric oxide may be a part of the “damage” of training which the body adapts to by growing larger or stronger.

It’s conceivable that, in otherwise healthy people, and in the short–term, one of the responses to the cellular assault inflicted by nitric oxide and its metabolites may be an increase in muscle growth as a protective measure – assuming other factors like nutrition and rest are accounted for properly. But people taking nitric oxide–boosting products should know full–well, and without any ambiguity, that they are doing further damage to the body, and adding to the stress of training with these products, and not simply “supplying more nutrients to the muscle” as is commonly implied in product advertising.

Similarly, as relates to the “pump” experienced during training, this effect may indeed be partly due to increased blood flow to the muscle, but tissue swelling is a well–known to be a response to tissue damage and fatigue – and is probably not due to the simple dilation of blood vessels. In this sense, because nitric oxide does cause tissue damage and mitochondrial damage (leading to the more rapid onset of muscular fatigue), it’s fair to say that NO may stimulate a “pump” during training. But the fact that muscular swelling during exercise is largely due to a localized (and potentially harmful) inflammatory response, and not simply to increased blood flow as is sometimes implied, means that the marketers of NO–boosting products are simply spinning the science to make their advertising copy seem pleasing to an uneducated clientele.

And noting that nitric oxide decreases energy production on a cellular level, it’s interesting to look at studies which have shown significant decreases in exercise performance when the NO–precursor, arginine, was ingested – especially in endurance sports.

The following study, which looked at the effects of arginine on several metabolic markers during and after a marathon, found that arginine supplementation led to an average finish time 23 minutes longer than predicted.

Study Link – The effect of arginine or glycine supplementation on gastrointestinal function, muscle injury, serum amino acid concentrations and performance during a marathon run.

Arginine supplementation tends to fare a bit better in strength sports, but we can’t necessarily attribute this effect solely to nitric oxide. There are simply far too many metabolic fates for arginine besides NO to make such an assumption valid. Arginine, for example is a precursor to the well–known performance enhancer creatine, increased production of which could easily account for any marginal increases in strength or performance noted with arginine supplementation.

But, even in the highly “cosmetic” sport of bodybuilding, where a good pump is often just as important as improved performance, it’s hard to justify the use of nitric oxide supplements in light of the relevant research.

Unlike some unhealthy lifestyle habits, for which the repercussions manifest over decades, the negative effects of stimulating nitric oxide production can potentially be short–term and catastrophic. As we’ve seen, the threat of excessive bleeding and hemorrhage when nitric oxide is increased is very real.

Along these lines, a particularly strong warning should be made against the use of nitric oxide–boosting products for contact athletes such as football players, hockey players, and martial artists. The last thing these athletes want is high levels of nitric oxide and nitric oxide precursors running through their bloodstream during competition. If stimulated by contact, the over–production of nitric oxide could lead to excessive and uncontrollable bleeding.

The effect of nitric oxide–boosting drugs, such as nitroglycerine, on bleeding has been known for decades, and studies have shown that inhibiting the enzyme from which NO is produced, significantly shortens bleeding time.

Study Link – Effect of nitric oxide synthase inhibition on bleeding time in humans.

Quote from the above study:

These data show that systemic inhibition of NO production shortens [bleeding time] in humans.

And various other studies and reports have linked nitric oxide with excessive bleeding, cerebral hemorrhage, and hemorrhagic shock.

Study Link – Novel roles of nitric oxide in hemorrhagic shock.

Quote from the above study:

Thus, induced nitric oxide, in addition to being a "final common mediator" of hemorrhagic shock, is essential for the up–regulation of the inflammatory response in resuscitated hemorrhagic shock. Furthermore, a picture of a pathway is evolving that contributes to tissue damage both directly via the formation of peroxynitrite, with its associated toxicities, and indirectly through the amplification of the inflammatory response.

Study Link – Nitric Oxide Insufficiency, Platelet Activation, and Arterial Thrombosis

Quote from the above study:

We reported the case of a 29–year–old woman with a hypertensive crisis treated with [the nitric oxide–increasing drug] sodium nitroprusside for blood pressure control who sustained an intracerebral hemorrhage after being normotensive on therapy for 24 hours.

And, lest you think that nitric oxide–boosting nutritional supplements must somehow be safer than nitric oxide–boosting drugs, realize that the “witches’ brew” formulations of many nitric oxide–boosting supplements often contain dozens of vasoactive substances haphazardly thrown together – including shockingly potent blood–thinning agents in addition to arginine substrates.

One such blood–thinning ingredient is rutaecarperine from the herb called evodia rutaecarpa. On a molar basis, retaecarperine has been shown to prolong bleeding time twice as long as aspirin.

Study Link – Antithrombotic effect of rutaecarpine, an alkaloid isolated from Evodia rutaecarpa, on platelet plug formation in in vivo experiments.

Quote from the above study:

On a molar basis, rutaecarpine was approximately twofold more potent than aspirin at prolonging the occlusion [bleeding] time.

So, although the “blood–thinning” effect of nitric oxide and related substances is often simply assumed to be beneficial, such simply isn’t the case. Certainly, blood with an excessive tendency to clot is a risk factor for cardiovascular disease in the long–term, but, on the other side of the coin, blood which doesn’t clot sufficiently can be even more acutely dangerous in situations where bleeding is a possibility.

Very similarly, high blood pressure is a known risk factor for cardiovascular disease, but as we’ve seen, low blood pressure, as a result of excessive nitric oxide production, can often be deadly in certain stressful situations. Clearly, balance is the key, and nitric oxide stimulation can play a major role in upsetting this balance greatly – even in the short–term.

In part two of our series on nitric oxide, we’ll look at the long–term role nitric oxide plays in various degenerative diseases. But hopefully, the research we’ve presented here on the general and shorter–acting effects of NO is already sufficient enough to allow any rational person to look at nitric oxide–boosting products in a whole new light.

With their typical reckless abandon, and biological shortsightedness, the sellers of nitric oxide–boosting supplements are asking you to accept far more risk than you may realize, while offering you far fewer benefits than they promise. But, in many ways, with nitric oxide–boosting products, it’s the same formula we see far too often in this industry – wild baseless speculation, is backed by cherry picked research, and stunningly ignorant oversimplifications of complex biological processes are proffered as the latest in “cutting edge science.”

If you value your health, your longevity, your performance, your intellect, or even simply the money you’ve worked so hard for, you’ll let the current nitric oxide fad run its course – without becoming one of its casualties.

About Us: At Integrated Supplements, our goal is to bring you the wellness information and products you need to live your life to the fullest. We are dedicated to producing the highest–quality, all–natural nutritional supplements; and to educating the world on the health promoting power of proper nutrition. You can find out more by visiting: www.IntegratedSupplements.com


These statements have not been evaluated by the FDA. No Integrated Supplements product is intended to diagnose, treat, cure or prevent any disease.


March 27, 2013

Combatting Chronic Stress and Fatigue Part 2 – Dopamine, Addiction, and Exercise

HerbalEnergyBlogIngSupporting dopamine levels and metabolism is an important (though often unheralded) aspect of long-term health.  As we covered in Part 1 of this article series, dopamine plays an important role not only in improving our motivation, and mood, but also in supporting such things as weight loss, mobility, and sex drive.  We also saw how low levels of dopamine lead directly to high levels of the stress hormone prolactin, which may predispose to conditions as far-ranging as depression, bone loss, and cancer.

Dopamine and Addiction

As the major neurochemical driver of the brain’s reward system, dopamine is largely responsible for our strongest and most irresistible urges.  Researchers have understood for some time that the biology of addition is intimately related to dopamine metabolism.     

Not surprisingly, stimulatory drugs of abuse, like amphetamine and cocaine, are known to cause a dramatic increase in dopamine levels – especially in the mesolimbic and mesocortical pathways of the brain known to be associated with reward and addiction.

But even potentially-addictive “sedatives” like alcohol are also likely to exert their initially pleasurable effects via dopamine:

Study Link - Oral alcohol self-administration stimulates dopamine release in the rat nucleus accumbens: genetic and motivational determinants.

For some individuals, pleasant-tasting food (and even the anticipation of it) seems to trigger the dopaminergic system similarly to drugs of abuse:

Study Link - Dopamine-based reward circuitry responsivity, genetics, and overeating.

Quote from the above study:

Consumption of a pleasant meal in humans results in dopamine release in the dorsal striatum and the magnitude of release correlates with ratings of meal pleasantness (Small et al. 2003). Furthermore, brain dopamine release increases during the anticipation of food intake (Volkow et al. 2002).

Thus, in addiction we can see an extreme example of how dopamine can energize us, and imbue us with a single-minded focus and drive.  It’s largely dopamine that can make us nearly powerless to resist the substance (or behavior) our brain has learned to crave.

Obviously, however, drugs of abuse are not long-term solutions to supporting healthy dopamine levels or metabolism.  Ultimately, these drugs do significant damage to the very dopamine-producing systems we’re trying to support.  As these systems become more and more impaired by addictive substances, tolerance develops which necessitates higher-and- higher levels of the drug to achieve the desired effect.  Understanding how this dopaminergic destruction occurs, however, may give us meaningful insight into how to support the dopamine system successfully in the long-term.

Addictive Drugs and Brain Damage

Research has shown that the dopaminergic brain damage caused by alcohol, amphetamine, and cocaine seems to be a result of excessive signaling in the brain of the chemicals nitric oxide and glutamate.  More specifically, the gaseous chemical nitric oxide inhibits the activity of energy-producing mitochondria, and without the energy needed to respond, signaling of glutamate (a chemical needed for neurons to fire) is more apt to become toxic.  When this sort of cellular stimulation becomes deadly to the brain cell, the phenomenon is known as excitotoxicity – a factor involved in many brain-related and neurodegenerative diseases.   

Studies have found that inhibitors of nitric oxide production largely abolish the brain damage caused by amphetamine and cocaine:

Study Link – Nitric oxide (NO) synthase inhibitors abolish cocaine–induced toxicity in mice.

Quote from the above study:

Repeated administration of cocaine (45 mg/kg/day) for 7 days to Swiss–Webster mice resulted in a progressive increase in the convulsive response to cocaine and augmentation in lethality rate. Pretreatment with the nitric oxide (NO) synthase inhibitors, L–NAME (100 mg/kg/day) or NO–Arg (25 mg/kg/day), prior to cocaine administration completely abolished the sensitization to the convulsive and lethal responses to cocaine. These findings suggest a role for NO in cocaine–induced toxicity.

Study Link – Role of nitric oxide in methamphetamine neurotoxicity: Protection by 7–nitroindazole, an inhibitor of neuronal nitric oxide synthase.

Quote from the above study:

These findings indicate a role for nitric oxide in methamphetamine–induced neurotoxicity and also suggest that blockade of NOS may be beneficial for the management of Parkinson's disease.

Study Link - Alcohol, nitric oxide, and neurotoxicity: is there a connection?--a review.

Quote from the above study:

Chronic alcohol exposure is reported to increase glutamate-N-methyl-D-aspartate (NMDA) receptors and calcium ion channel activity, resulting in the neurotoxicity and seizure activity associated with alcohol withdrawal in certain persons. Recent information indicates that nitric oxide is responsible for the neurotoxicity associated with excessive glutamate stimulation of NMDA receptors. Thus, it is hypothesized that nitric oxide is involved in producing the neurotoxicity and cell disturbances associated with chronic alcohol exposure.

Note: We discussed glutamate and the N-methyl-D-aspartate (NMDA) receptor extensively in our series of articles on magnesium, as magnesium is a major factor necessary for inhibiting excessive glutamate stimulation of the NMDA receptor:

Article Link - Stress, Anxiety, Depression, and Magnesium Part 4 – Glutamate in Mood Disorders

We’ve also previously examined, at length, the true biological roles of nitric oxide, and the potential dangers of attempting to stimulate nitric oxide production:

Article Link – Nitric Oxide The Big Picture – Part 1

Noting that drugs of abuse damage the brain via nitric oxide and excitotoxic mechanisms, we can see why it’s probably prudent to avoid stimulant products, including many common pre-workout mixtures currently sold in the bodybuilding realm, which contain a combination of somewhat amphetamine-like stimulants (e.g., 1,3-dimethylamylamine),  nitric oxide precursors (e.g., arginine, citrulline), and potentially-excitotoxic amino acids (e.g., aspartic acid).

Fortunately, however, we don’t need to resort to potentially-harmful substances to get our dopamine fix – there are likely to be effective ways to enhance dopamine levels, while improving the structure and function of the dopamine systems of the brain.  One of the most powerful such practices is intense physical exercise.

Exercise and Dopamine

For many of us, it can sometimes be difficult to muster up the motivation needed to hit the gym.  After all, a skipped workout here and there probably won’t make all that much difference with regard to our muscle building or fat loss efforts in the long-term.  When a lack of motivation sets in, however, it may help to remember that some of the most powerful benefits of exercise may not even be physique-related at all.  Exercise is very well-documented to improve mood – often rivaling anti-depressant medications in this regard: 

Study Link - Effects of Exercise Training on Older Patients With Major Depression.

Quote from the above study:

An exercise training program may be considered an alternative to antidepressants for treatment of depression in older persons. Although antidepressants may facilitate a more rapid initial therapeutic response than exercise, after 16 weeks of treatment exercise was equally effective in reducing depression among patients with [major depressive disorder].

Knowing this, and with what we now know about dopamine’s mood-elevating effects, it’s not surprising to find that exercise may help to increase dopamine levels significantly:

Study Link - Regulation of brain function by exercise.

Quote from the above study:

Exercise leads to increased serum calcium levels, and the calcium is transported to the brain. This in turn enhances brain dopamine synthesis through a calmodulin-dependent system, and increased dopamine levels regulate various brain functions.

In part 1 of this series, we saw how low dopamine levels, and high levels of its antagonist, prolactin, may play a role in the development of learned helplessness and subsequent clinical depression.  Studies have found that exercise may be of particular benefit in combatting the long-term and unavoidable stress associated with learned helplessness:

Study Link - Exercise, learned helplessness, and the stress-resistant brain.

Quote from the above study:

Identifying the mechanisms by which exercise prevents learned helplessness could shed light on the complex neurobiology of depression and anxiety and potentially lead to novel strategies for the prevention of stress-related mood disorders.

While all types of physical activity are likely to have some mood-boosting benefits, it seems that resistance exercise may be of particular value when it comes to boosting dopamine levels:

Study Link - Physiologic responses to heavy-resistance exercise with very short rest periods.

Studies have found that bodybuilding-type training and powerlifting with short rest periods between sets may elicit an even greater dopamine response than aerobic-type training:

Study Link – Endocrine responses to resistance exercise

Quote from the above study:

Kraemer and co-workers observed significant increases in dopamine values following a high-intensity, low-rest bodybuilding type exercise protocol…Changes in catecholamine metabolism in response to resistance exercise appear to be primarily related to the force of muscular contraction, the amount of muscle tissue stimulated, and the frequency of force application (i.e., amount of rest between sets and repetitions).  Exercise protocols, which utilize multi-exercise and high intensity resistance exercise, produce catecholamine concentrations similar to heavy anaerobic sprint and cycle exercise, which are greater than those values reported consequent to aerobic activities.

Long-term exercise protocols have also been investigated as possible means to reduce prolactin levels.  As we’ve seen, elevated prolactin is associated with increased risk of cancer, and for this reason researchers have studied exercise in post-menopausal women as a possible means to reduce prolactin and subsequent breast cancer risk.

Some such studies have reported interesting findings.  Recent research from Harvard Medical School tested the effects of a 12-week exercise protocol on levels of various hormones, including prolactin.  The researchers found that women’s prolactin levels declined only when their level of fitness improved.  This could be taken to mean that exercise produces its full hormonal benefit only when it’s intense enough to stimulate meaningful biological changes.  In other words, just showing up likely isn’t enough.  In order to enhance our dopamine metabolism (and/or reduce prolactin) meaningfully, the exercise we engage in has to be intense enough to stimulate adaptive changes in the body:

Study Link - Effect of a 12-month randomized clinical trial of exercise on serum prolactin concentrations in postmenopausal women.

Quote from the above study:

Prolactin is associated with an increased risk of postmenopausal breast cancer; however, few modifiable factors are known to reduce prolactin concentrations. Therefore, we examined the effect of a 12-month moderate-intensity exercise intervention on serum prolactin concentrations as a secondary end point (primary end points were estrogens and androgens)… Exercisers whose VO(2)max changed by <5% had a 5% increase in prolactin concentrations, whereas those who increased their VO(2)max by 5% to 15% and >15% had a 11% (P = 0.03) and 7% (P = 0.01) decrease in prolactin concentrations, respectively. Although the exercise intervention had little effect on prolactin concentrations overall, increasing physical fitness was associated with reduced prolactin concentrations among postmenopausal women.

But, one naturally wonders, if exercise is so effective at boosting dopamine, why doesn’t exercise eventually have the same negative effects of so many other dopamine-boosting strategies?  Why do the positive effects of exercise seem to be sustained over time, while we rapidly build up a tolerance to the dopaminergic stimulation caused by drugs of abuse?

Part of the answer to these questions seems to involve the types of changes that take place in the brain in response to exercise.  Unlike most stimulants and drugs with abuse potential, exercise seems to stimulate the growth of dopamine-related neurons rather than destroying them.

Exercise and Neurogenesis

Though exercise can be stressful, and can stimulate the brain in ways that could be potentially excitotoxic (e.g., exercise increases glutamate transmission) exercise is usually found to impart beneficial effects on brain function and mood.  Exercise is also likely to be helpful in the long-term prevention of various neurological disorders.

One reason for this is that exercise may be a unique stimulator of adult neurogenesis – the growth of new neurons and synapses in the brain and nervous system.  While it was once thought that the number of brain cells we possess was fixed prenatally, it has since been found that some structures of the brain are able grow and adapt throughout life.  In fact, some of the brain structures with the greatest ability for neurogenesis (e.g., the dentate gyrus of the hippocampus) are directly related to mood, learning, and motivation.  It’s been proposed, for example, that the mood-elevating effects of antidepressants (and exercise) may be a result of neurogenesis in these brain structures:

Study Link - Dentate gyrus neurogenesis and depression.

Quote from the above study:

While an involvement of neurogenesis in the etiology of depression remains highly speculative, preclinical studies have revealed a novel and previously unrecognized role for hippocampal neurogenesis in mediating some of the behavioral effects of antidepressants. 

Brain-Derived Neurotrophic Factor – A Key to Neurogenesis 

A particularly important chemical driver of neurogenesis is called brain-derived neurotrophic factor, or, BDNF - a substance which exercise has been shown to increase:

Study Link - Exercise: a behavioral intervention to enhance brain health and plasticity.

Quote from the above study:

It is now clear that voluntary exercise can increase levels of brain-derived neurotrophic factor (BDNF) and other growth factors, stimulate neurogenesis, increase resistance to brain insult and improve learning and mental performance.

Researchers have found that depressed patients exhibit low levels of BDNF, and have proposed that anti-depressant medications may work fundamentally by increasing BDNF levels:

Study Link - Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants.

Quote from the above study:

Our study suggests that low BDNF levels may play a pivotal role in the pathophysiology of [major depressive disorder] and that antidepressants may increase BDNF in depressed patients.

BDNF seems to have a particularly notable effect on the dopaminergic neurons of the substantia nigra – a region of the brain associated with movement, learning, and reward:

Study Link - BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra.

Quote from the above study:

BDNF seems to be a trophic factor for mesencephalic dopaminergic neurons, increasing their survival, including that of neuronal cells which degenerate in Parkinson's disease.

In contrast to the effects of exercise, drugs of abuse seem to compromise levels of BDNF.  Alcoholics, for example, have been found to have decreased levels of BDNF, as have cocaine addicts:

Study Link - Decreased plasma brain-derived neurotrophic factor levels in patients with alcohol dependence.

Study Link - Brain-derived neurotrophic factor serum levels in cocaine-dependent patients during early abstinence.

Quote from the above study:

Significantly lower serum BDNF levels (p<.0001) were observed for cocaine-dependent patients at baseline compared to healthy controls.

And animal studies have found that amphetamine treatment reduces BDNF as well:

Study Link - Chronic amphetamine treatment reduces NGF and BDNF in the rat brain.

Exercise and Fatigue

As any workout enthusiast can attest, intense training can be physically exhausting.  As such, it may be difficult to see precisely how this sort of activity can be used to combat fatigue.  In the longer term, however, the neurogenic effects of exercise may actually build the very brain structures which support energy levels and alertness.  Personal trainers and others in the fitness realm have long claimed that, rather than being draining, like sapping the juice from a battery, exercise actually recharges us and gives us energy.  In light of current research, this stance seems to be more than just an occupational bias – there’s now significant evidence showing that they very well may be right. 

Some studies which have investigated the effects of exercise on the chronic-fatigue syndrome, have found that exercise caused an increase in functional work capacity and a decrease in fatigue.  When the anti-depressant medication, fluotexine, was also employed, the drug improved depression, but it didn’t produce the benefits of exercise on work capacity, fatigue, or health perception.

Study Link - Randomised, double-blind, placebo-controlled treatment trial of fluoxetine and graded exercise for chronic fatigue syndrome.

Quote from the above study:

Graded exercise produced improvements in functional work capacity and fatigue, while fluoxetine improved depression only.

So, though both drugs of abuse and exercise stimulate the dopamine centers of the brain, exercise safely delivers mood and brain-building benefits in both the short and long-term.  In fact, it’s hard to imagine any intervention which carries more long-term mind and body benefits than regular, intense exercise.  This research clearly shows that intense exercise isn’t just for athletes or the physique-conscious – it’s a must for any individual who prioritizes his or her long-term mental, emotional, cognitive, and physical health.

But exercise isn’t the only way to strengthen the brain’s dopamine system either - many natural substances may be able to do so as well.

In subsequent articles in this series, we’ll discuss several natural substances which may stimulate neurogenesis synergistically with exercise.  These substances may have particular benefits for mood, motivation, drive, cognitive health, and feelings of well-being.  Most importantly, like exercise, the brain-building effects of these substances are likely to make them safe, effective, and even health-promoting in the long-term.


March 21, 2013

Combatting Chronic Stress and Fatigue Part 1 - Dopamine and Prolactin

HerbalEnergyBlogIngThough fatigue is among the most common health complaints patients report to their physicians, the condition is almost never addressed as a serious health problem in and of itself.  If the fatigue can’t be attributed to another disorder, the patient is usually given the safe, but more often than not, ineffective recommendations to simply get more sleep, and to try and eat a healthy diet.

Often times, the fatigued person is then left on his or her own to navigate a seemingly endless array of “solutions” which could include such things as energy and coffee drinks, stimulant pills, decongestants, “pre-workout” mixtures, soft drinks, or nicotine-containing tobacco products. 

The safety and biological soundness of such stimulants, however, simply can’t be assessed in the short term.  In other words, while most people judge stimulants merely by how they feel when they take them, this doesn’t provide any meaningful perspective on how the substance exerts its effects, or whether it constitutes a long-term solution.  Some of the most powerful stimulants often lose their effectiveness rapidly, and worse yet, many could have significantly negative side effects with continued use.

But, on the other hand, we mustn’t fall into the trap of damning all stimulants outright as many natural health advocates sometimes do.  There’s compelling research showing that some stimulants and energy-enhancing compounds may actually improve overall health. 

Where so many of us are seeking sustainable long-term solutions for fatigue, it’s prudent to gain a better understanding of which energy-enhancing substances can also impart long-term health benefits, and which substances are best avoided.

Dopamine – A Key to Enhancing Mood, Supporting Weight Loss, and Improving Overall Health

In beginning to investigate which psycho-stimulants may actually offer health benefits, one’s attention is naturally drawn to the effects of the neurochemical, dopamine.

At ideal levels, dopamine is an important contributor to positive mood, focus, drive, and goal-directed behavior.  With adequate dopamine, we feel confident and alert, our decision making is healthy, and we’re content in the knowledge that we possess the power necessary to shape our world.

In our modern age, however, it’s common for chronic stress to greatly compromise our dopamine levels. Under the influence of sustained stress, which inhibits dopamine production, we may notice that we’re more easily fatigued and chronically tired.  Our sex drive and libido suffer, and activities which we once enjoyed may lose their appeal.  As our motivation and drive erode, we often find it a constant struggle to maintain any meaningful level of ambition.  Our social relationships may suffer as we become increasingly more despondent and withdrawn.  Ultimately, the effect of low dopamine is usually a particularly stubborn sense of fatigue, depression, and despair. 

Worse yet, chronically-low dopamine levels (or low dopamine signaling / receptor sensitivity) may cause us to gravitate towards substances and behaviors which can give us an immediate (though temporary) dopamine fix.  It’s especially interesting to note the association between low dopamine levels and addiction.  The “hedonistic” pleasures of life – food, recreational drugs, smoking, sex, gambling – all serve to give us a potent dopamine surge.  It seems that the psychological torment of low dopamine is often so unbearable, that we’ll do just about anything to counteract it – even if the behaviors are ultimately unhealthy or life threatening.

Dopamine, Chronic Stress, Learned Helplessness, and Depression

For decades, psychologists have noted that animals and humans subjected to chronic and inescapable stress eventually lose the motivation and drive to escape these conditions – even when the stress becomes no longer inescapable.  This phenomenon is called learned helplessness, and researchers have found that the condition offers a powerful insight into common mood disorders.  At the stage where animals and humans largely give up on avoiding their adverse conditions, their symptoms manifest as those remarkably similar to chronic clinical depression.

Landmark studies in the field clearly illustrate this concept.  The first of many studies on learned helplessness involved three groups of dogs.  Those in the first group were restrained in harnesses, but quickly released.  Dogs in the second group were restrained in harnesses and subsequently given electric shocks, which they could stop by pressing a lever (i.e., they had some control over their adverse environment).  Dogs in the third group were restrained in harnesses, and given electric shocks at random which they could not stop – i.e., the stress was inescapable.  While the dogs in the first two groups rapidly recovered with no ill effects, the dogs in the third group developed symptoms concomitant with clinical depression.

In the second part of the study, the same three groups of dogs were tested in an apparatus where they could easily escape an electric shock by jumping over a low partition.  While dogs from the first two groups did so, dogs from the third group lay down passively and accepted the electric shocks – though escape was physically as easy for them as it was for the other groups, these dogs had lost the will to even attempt to free themselves from their torment.

Subsequent research has confirmed and strengthened these initial findings, and interestingly, in humans, the effect may even be more pronounced.  Studies have found that humans are capable of “vicarious learning” through which people can learn to be helpless merely through observing others undergoing stressful and inescapable events.

Our fast-paced modern world, of course, offers no shortage of chronically stressful situations.  It’s been noted that today, we generally work longer hours for less real pay than previous generations did, and it’s easy imagine why so many people feel trapped and powerless in a system which offers fewer and fewer rewards for their expended effort.  In the realm of physical fitness, failure to stick with diet and exercise plans is well known to be the norm rather than the exception.  Such chronic and repeated failure can induce a sort of learned helplessness wherein a person gives up due to the feeling that their fitness goals are simply impossible to achieve.

Dopamine – The Drive Chemical

Studies investigating the hormonal and neurochemical aspects of learned helplessness have begun to offer some insight into the condition – especially as relates to the yin-and-yang relationship of the “drive” chemical dopamine, and its antagonist, the pituitary stress hormone, prolactin.

Primate studies have found that African green monkeys held in captivity experienced elevated cortisol levels (an acute stress hormone) for two days after capture, but while their cortisol levels eventually normalized, their levels of prolactin elevated steadily as their time in captivity increased:  

Study Link - Physiologic manifestations of stress from capture and restraint of free-ranging male African green monkeys (Cercopithecus aethiops).

Quote from the above study:

Mean prolactin concentration was significantly lower in the wild-caught monkeys on day 2 after capture, and the levels increased gradually to 45 days in captivity and was highest in monkeys that had been captive for 7 mo.

As such, prolactin could be seen as acting as a long-term stress hormone under prolonged periods of inescapable stress.  It’s not likely a coincidence that the symptoms of prolactin excess are exactly those which sap our drive, motivation, and zest for life:

Symptoms of Prolactin Excess:

Mood Changes / Depression Decreased Motivation
Low Libido / Impotence Hostility / Anxiety
Decreased Testosterone Infertility
Fatigue Lack of Drive

In biological circles at least, it’s well known that the chemical most responsible for keeping prolactin in check is dopamine.  In fact, dopamine is sometimes referred to by the alternate names, prolactin-inhibiting factor (PIF), prolactin-inhibiting hormone (PIH), or prolactostatin.  It’s no coincidence either, that the symptoms of low dopamine almost exactly mirror the symptoms of elevated prolactin.

Signs of Low Dopamine:

Inability to Love Lack of Ambition
Low Libido Withdrawal
Erectile Dysfunction Low Energy / Fatigue
Addictions Social Anxiety
Depression Lack of Remorse
Anhedonia — the inability to experience pleasure.  

Whereas healthy dopamine levels are associated with the opposite:

Signs of Healthy Dopamine Levels:

Feelings of well-being Sound Decision Making
Healthy Libido Realistic Expectations
Healthy Bonding Good Feelings Toward Others
Pleasure in Accomplishing Tasks Motivation
Energy and Vitality  

Prolactin and Cancer

The tandem of low dopamine and high prolactin levels likely affects not just our moods – but every aspect of our health.  In fact, prolactin and dopamine are two stress-related chemicals that may play a major role in helping to explain the association between chronic stress and somatic (bodily) diseases.  Prolactin, for example, has been found to play a role in stimulating the growth of hormone-sensitive cancers of the breast and prostate:

Study Link - Prolactin in breast and prostate cancer: molecular and genetic perspectives.

Conversely, dopamine has been shown to counter many of the effects of prolactin in breast and prostate cancer cells, and has been proposed as a potential therapeutic agent in the disorders:

Study Link - Dopamine stabilizes tumor blood vessels by up-regulating angiopoietin 1 expression in pericytes and Krüppel-like factor-2 expression in tumor endothelial cells.

Quote from the above study:

There is increasing evidence for a role of dopamine in the development of obesity. More specifically, dopaminergic hypofunction might lead to (over)compensatory food intake.

Low Dopamine / High Prolactin and Weight Gain

Similarly, excesses of prolactin are known to cause weight gain as well.  Classes of medications which increase prolactin levels (many by specifically antagonizing dopamine) are notorious for causing weight gain:

Study link - Body weight gain induced by antipsychotic drugs: mechanisms and management.

Quote from the above study:

…when [sulpiride] was administered to healthy men their weight gain was significant, and prolactin was found to be the only variable that correlated positively with the [body weight gain].

The weight gain which often accompanies smoking cessation may have more to do with dopamine than with mere changes in metabolic rate.  It seems that the dopamine fix afforded by nicotine is often replaced with the dopamine fix afforded by overeating.  It’s likely no coincidence, therefore, that the most successful medication for assisting smoking cessation without weight gain acts upon the dopaminergic system:

Study Link - Smoking cessation and weight gain.

… body weight gain at the end of treatment was significantly lower in the patients receiving bupropion or bupropion plus nicotine patch, compared with placebo.

Ultimately, the balance of dopamine and prolactin play a role throughout every aspect of our health including energy levels and fatigue, mood disorders, weight gain (and associated sequelae), neurodegenerative disease, bone loss, and cancer.

Knowing this, it seems prudent to investigate, not just ways to keep ourselves alert, but, at the same time, ways to mitigate the effects of chronic stress by supporting healthy dopamine metabolism.

In subsequent articles, we’ll examine ways to foster healthy dopamine levels and proper dopamine signaling using certain “stimulants,” adaptogens, and activities. 


March 07, 2013

Like Us on Facebook, and Get Your Free Sample of Herbal Energy

HerbalEnergyBlogIngFor a limited time, we’re giving away free sample packets of our new Herbal Energy drink mix – we’ll even pay shipping!

To get yours, visit our facebook page here.

But hurry, free samples are only available while supplies last.

Looking for more info on Herbal Energy? Check out our Herbal Energy Product Page.

Rules and Regulations:

Free samples are available only to those over 18 years of age living in the continental United States.  Limit one sample per person.

WARNING: This product is for healthy adults 18 years of age or older.  This product is not to be used if you are using any prescription or over-the-counter medication, or if you have any pre-existing medical condition including (but not limited to): high or low blood pressure, cardiac arrhythmia, stroke, heart, liver, kidney or thyroid disease, seizure disorder, psychiatric disease, diabetes, prostate enlargement, or if you are taking a MAOI (Monoamine Oxidase Inhibitor).  This product is not for use by pregnant women, or women who may become pregnant. This product contains caffeine, and should not be taken by individuals wishing to eliminate caffeine from their diet.  Do not use in combination with other sources of caffeine or other stimulants.  Do not combine with alcohol.  Discontinue use and consult your health care practitioner if you experience any adverse reaction to this product.  Do not consume more than the recommended dose.  KEEP OUT OF REACH OF CHILDREN.


March 03, 2013

Ingredients in Herbal Energy – Damiana and Sexual Health

HerbalEnergyBlogIngThe use of damiana leaves (Turnera diffusa) as an aphrodisiac and sexual stimulant dates at least as far back as the ancient Mayan civilizations of Central America.  The writings of Spanish conquistadors in the 16th Century noted that the indigenous people they encountered in the new world often consumed a drink made from damiana as an aid to sexual potency.

And the Mayans weren’t alone in this practice.  Wherever damiana has grown throughout the world, similar uses of this flowering shrub have been noted in the historical and medicinal literature.  During the 18th and 19th Centuries in the Americas, European physicians learned of herbal remedies like damiana from Native Americans. Many of these physicians began practicing what was eventually known as eclectic medicine – a discipline incorporating both herbal and orthodox medical treatments.  One notable eclectic physician, Dr. Finley Ellingwood – albeit in dated and morally-pejorative language – wrote extensively on the restorative and sexually-stimulating effects of damiana in both men and women:

[Damiana is a] mild nerve tonic claimed to be valuable in the treatment of sexual impotence. Some of our physicians praise it highly for its influence in sexual neurasthenia, and it is said to correct frigidity in the female. It had long enjoyed a local reputation as a stimulant tonic of the sexual apparatus among the natives of Mexico, before it attracted the attention of the profession. Besides its peculiar action on the sexual appetite and function, it is a general tonic, somewhat cathartic and is slightly cholagogue. The midwives and women of loose morals of western Mexico also attribute emmenagogue properties to it.

Dr. Reid uses Damiana in all conditions where a general tonic is needed, especially if there be enfeeblement of the central nervous system.

In modern days, the use of damiana continues in the Americas, and has even spread to Europe where, in Germany, the herb is used to quell excess mental activity and nervous debility, and as a tonic for the hormonal and central nervous systems.

In Holland, damiana is renowned for its sexual-enhancing qualities and its positive effects on the reproductive organs. The British Herbal Pharmacopoeia even cites the use of damiana for "anxiety neurosis with a predominant sexual factor, depression, nervous dyspepsia, atonic constipation, and coital inadequacy."

As with many herbal remedies, clinical research has begun to substantiate many of the herb’s traditional uses.  We’ve already seen research supporting damiana’s adaptogenic and anxiety-reducing effects, and additional research lends some credibility to its use as an aphrodisiac and sexual tonic as well.

Researchers in both Italy and Mexico have conducted numerous studies showing that damiana helps to restore sexual function to “sexually exhausted” animals:

Study Link - Turnera diffusa Wild (Turneraceae) recovers sexual behavior in sexually exhausted males.

Study Link - Stimulating property of Turnera diffusa and Pfaffia paniculata extracts on the sexual-behavior of male rats.

Study Link - Stimulating property of Turnera diffusa and Pfaffia paniculata extracts on the sexual-behavior of male rats.

Study Link - Evaluation of Aphrodisiac Activity of Turnera aphrodisiaca

The above study even showed evidence that the long-term use of the herb improves its effectiveness:

Quote from the above study:

Male mice showed maximum aphrodisiac activity upon sub-acute administration of alkaloidal fraction. This observation infers that T. aphrodisiaca improves reproductive organs upon long term use.

Like most herbal remedies, damiana’s diverse biological effects can’t be attributed to a single constituent element.  The fact that damiana supports sexual health in males as well as females, is evidence that the herb likely imparts a multi-faceted and balancing effect upon the body.

For example, some of damiana’s pro-sexual effect may be attributable to its ability to facilitate the production of the vasodilator chemical, nitric oxide:

Study Link - Pro-sexual effects of Turnera diffusa Wild (Turneraceae) in male rats involves the nitric oxide pathway.

Additionally, components in damiana have been found to impart anti-aromatase (i.e, anti-estrogenic) activity:

Study Link - Anti-aromatase activity of the constituents from damiana (Turnera diffusa).

But a great deal of damiana’s effectiveness likely doesn’t involve improved circulation or hormonal metabolism.  The true key to the herb’s energizing, mood elevating, and pro-sexual activity may involve its ability to positively modulate the production and metabolism of important neurotransmitters.

A component of damiana known as apigenin has been found to activate monoamine transporters which may help to regulate neurotransmitter metabolism.  Apigenin may have the notable ability to facilitate the uptake of dopamine:

Study Link - Functional activation of monoamine transporters by luteolin and apigenin isolated from the fruit of Perilla frutescens (L.) Britt.

Apigenin has also been found to act as a ligand for the benzodiazepine receptor, which may explain damiana’s notable anxiety-reducing effect:

Study Link - Apigenin, a component of Matricaria recutita flowers, is a central benzodiazepine receptors-ligand with anxiolytic effects.

HerbalEnergyDamiana’s calming and restorative effect on the brain and nervous system shouldn’t be overlooked when investigating the herb’s role in sexual health.  Excessive stress is a well-documented destroyer of both desire and function in the sexual realm.  In our high-stress modern world, perhaps we would be well served to look to the rich wisdom of herbal traditions in begin to restore optimal function of both body and mind.

January 17, 2013

Polyunsaturated Fats in Pregnancy Influence Bodyfat of Children

PregnancyA recent study conducted at the University of Southampton found that pregnant women with higher plasma levels of omega-6 fatty acids have children with higher fat mass and greater risk of childhood obesity.

At age 4, and, after adjusting for several variables, children’s fat mass was found to be higher in those whose mothers had higher plasma omega-6 levels in pregnancy.  The mother’s omega-3 fatty acid levels showed no correlation with the children’s fat mass:

Study Link - Maternal Plasma Polyunsaturated Fatty Acid Status in Late Pregnancy Is Associated with Offspring Body Composition in Childhood.

Quote from the above study:

After adjustment for maternal factors and child factors including height and duration of breast-feeding, maternal plasma n-6 PUFA concentration positively predicted offspring fat mass at 4 yr (β = 0.14 SD/SD; P = 0.01) and 6 yr (β = 0.11 SD/SD; P = 0.04), but there was no association with offspring lean mass at either age (β = 0.005 SD/SD, P = 0.89; and β = 0.008 SD/SD, P = 0.81, respectively). Maternal plasma n-3 PUFA concentration was not associated with offspring fat mass at 4 yr (β = 0.057 SD/SD; P = 0.34) or 6 yr (β = 0.069 SD/SD; P = 0.21).

The researchers conducting the study noted that dietary restriction of omega-6 fatty acid by pregnant women may have positive effects on the body composition of their children.

Study author, Dr Rebecca Moon, was quoted as saying: “Obesity is a rising problem in this country and there have been very few studies of mother’s fatty acid levels during pregnancy and offspring fat mass. These results suggest that alterations to maternal diet during pregnancy to reduce n-6 PUFAs intake might have a beneficial effect on the body composition of the developing child.”

Omega-6 polyunsaturated fatty acids are found in many vegetable oils, nuts, and seeds, and are more common in the human diet than at any other time in history.  This study is one of the first of its kind in humans showing that polyunsaturated fatty acids may contribute to obesity from the pre-natal period and beyond.

The Low-PUFA Diet

At Integrated Supplements, we’ve written extensively on the metabolic disruption caused by polyunsaturated fatty acids (PUFAs), and we’ve long advocated a low-PUFA diet for weight control and optimal health.  In previous articles, we’ve cited animal studies which are in keeping with the role of maternal omega-6 polyunsaturated fatty acids in driving obesity in offspring.

In adulthood, fat cells can expand to hold more lipids, but the overall number of fat cells remains largely constant.  It's during gestation and early childhood that the quantity of the body's fat cells is largely determined.  Linoleic acid (an omega-6 polyunsaturated fatty acid) appears to stimulate the production of fat cells at this critical time in development, and animals exposed to large amounts of linoleic acid during gestation and lactation appear to be particularly prone to obesity:

Study Link – Arachidonic acid and prostacyclin signaling promote adipose tissue development: a human health concern?

Quote from the above study:

During the pregnancy–lactation period, mother mice were fed either a high–fat diet rich in linoleic acid, a precursor of arachidonic acid (LO diet), or the same isocaloric diet enriched in linoleic acid and alpha–linolenic acid (LO/LL diet). Body weight from weaning onwards, fat mass, epididymal fat pad weight, and adipocyte size at 8 weeks of age were higher with LO diet than with LO/LL diet. In contrast, prostacyclin receptor–deficient mice fed either diet were similar in this respect, indicating that the prostacyclin signaling contributes to adipose tissue development. These results raise the issue of the high content of linoleic acid of i) ingested lipids during pregnancy and lactation, and ii) formula milk and infant foods in relation to the epidemic of childhood obesity.

Similar evidence from animal studies suggests that the obesity–inducing effects of omega–6–rich oils may even increase across generations.  Animals fed vegetable oils produce offspring which are more apt to have both larger and more numerous fat cells and greater fat mass, even with no change in caloric intake.  Several generations of such feeding has been shown to result in offspring exhibiting marked obesity.  If even a similar phenomenon occurs in humans, this would go a long way towards explaining the rapidly increasing rate of obesity (especially childhood obesity) found in recent decades:

Study Link – A Western–like fat diet is sufficient to induce a gradual enhancement in fat mass over generations.

Quote from the above study:

Offspring showed, over four generations, a gradual enhancement in fat mass due to combined hyperplasia and hypertrophy with no change in food intake.

Study Link – Fatty acid composition as an early determinant of childhood obesity.

Quote from the above study:

…changes over decades in the fatty acid composition of dietary fats observed in breast milk and formula milk, i.e. a high increase in [linoleic acid] with slight or no change in [linolenic acid], may be responsible, at least in part, of the dramatic increase in the prevalence of childhood overweight and obesity.

The above studies can be found in our article:

A Diet For Long-Term Weight Control and Optimal Health Part 5 – The Role of Modern Fats in Heart Disease, Cancer, and Obesity

Polyunsaturated Fatty Acids – Major Players in the Obesity Epidemic  

Strangely, the role of polyunsaturated fats as major players in the obesity epidemic is rarely recognized.  Many are quick to indict sugars (especially uniquely modern variants such as high-fructose corn syrup) as major causative factors - but the role of sugars in the obesity epidemic likely pales in comparison to the role of polyunsaturated fats.  This stance is born out both by the data on food intake over the last several decades, and by the biochemical activities of both categories of food.  In other words, the increase in the intake of polyunsaturated fatty acids in the past several decades dwarfs the increase in the intake of sugar.  And, unlike sugar (which, assuming other nutrients are present, the body can metabolize efficiently), polyunsaturated fatty acids inhibit metabolism and cellular respiration by almost every conceivable mechanism – creating the ideal environment for the accumulation of bodyfat.

Limiting Polyunsaturated Fatty Acids

Limiting polyunsaturated fatty acid intake can obviously be somewhat difficult for people who aren’t familiar with the composition of foods.  Omega-6 fatty acids can be found in well-known “junk-foods” (e.g., almost all fried foods, and commercial baked goods), but significant amounts of them can also be found in foods which are often regarded as healthy.  This could include, for example, nuts, seeds, nut butters, flax, almond milk, etc.  Ultimately, rather than focusing on “good or “bad” foods, we advocate that the overall diet be constructed so as to contain approximately 2% of its calories from the polyunsaturated fatty acids.  We’ve written details on how to do that here:

A Diet For Long-Term Weight Control and Optimal Health Part 6 – Essential Fatty Acids and Metabolic Disruption

With a little practice, the low-PUFA diet is simple to construct and not nearly as restrictive as many other dietary philosophies.


December 22, 2012

Integrated Supplements Herbal Energy Now Available!

HerbalenergyblogIntegrated Supplements is proud to introduce Herbal Energy – an all-natural pre-workout and energy drink mix that really works!.

Herbal Energy is a naturally-flavored and naturally-sweetened blend of invigorating and nourishing herbs such as Catuaba, Damiana, Mucuna, and Yohimbe – all delivered in a great–tasting and refreshing drink mix. These herbs have been used by cultures for centuries to safely and naturally improve alertness, focus, mood, and even sexual energy and stamina*.

Whether you need a quick pick-me-up at work, or the energy to power through a tough workout, you’ll quickly be convinced that there's no energy product on the market that can compare to Herbal Energy – another breakthrough formula brought to you only by Integrated Supplements.


The ingredients in Herbal Energy were specifically chosen to support healthy levels of mood-elevating* and energy-enhancing* neurotransmitters – including, and especially, dopamine.


Healthy levels of dopamine may support:
  • A positive mood*
  • Energy levels*
  • A healthy sex drive*
  • Focus and goal-directed behavior*
  • Appetite control*


Herbal Energy Supplement Facts IntegratedHERLHeader Q. How is Herbal Energy different from other pre-workout drinks?

A. Because the energy–enhancing effect of most pre–workout supplements is almost completely due to simple caffeine, companies often feel the need to include many other seemingly "exotic" ingredients to make their product seem more complex and advanced. Thus, many pre-workout drinks are "witches-brew" formulations that contain dozens of unnecessary (and even potentially harmful) ingredients.

We took a different approach with Herbal Energy. We included several core ingredients which work synergistically to enhance the activity of brain chemicals involved in drive, focus, energy, stamina, positive mood, and sexual health*.

Along these lines, note that Herbal Energy does NOT contain:

• Arginine, Citrulline, or other common nitric-oxide boosters. We've written several articles on the dangers of trying to elevate nitric oxide with such substances.

• DMAA (1,3-dimethylamylamine) or other synthetic stimulants with questionable safety profiles and legal status.

• Unnecessary ingredients and fillers.

Q. How is Herbal Energy different from other energy drinks or energy shots?

A. Most energy drinks and energy shots are rather haphazard mixtures of caffeine along with a “sprinkling” of B vitamins, and a few other esoteric ingredients. For as flashy as energy drinks may seem, however, their energizing effect is often limited to the caffeine they contain.

And because of the costs involved in formulating and shipping liquids, it's not uncommon for energy drinks and shots to sell for several dollars per serving. As such, energy drinks and shots can become quite expensive over time.

Not only do we believe that Herbal Energy is a superior formulation relative to other energy drinks, but because of its convenient powdered form, it costs significantly less per serving than other energy drinks as well.

Q. Coffee seems to work fine as a quick "pick me up." Why should I consider Herbal Energy?

A. Coffee is an excellent drink with many documented health benefits. There are a few reasons, however, why people may want to consider Herbal Energy as an alternative:

Like regular use of energy drinks and shots, a daily coffee habit can become quite expensive over time. A serving of Herbal Energy is generally far less expensive than a serving of premium coffeehouse coffee, and may even be less expensive than many types of home-brewed coffee.

Though coffee can obviously be a pretty good pick-me-up, Herbal Energy is formulated specifically to support energy, alertness, mood, and even sex drive*. The energizing benefits of Herbal Energy simply surpass those of ordinary coffee.

Many people simply don’t like the taste of coffee, and prefer something more light and refreshing. Herbal Energy has a delicious raspberry lemonade flavor, is sugar free, and is made with only all-natural ingredients.

Herbal Energy is a concentrated drink mix you can take anywhere. The small micro-scoops are easy to pour into a standard 500ml (16.9 oz) bottle of water.

Q. Is Herbal Energy just, basically, caffeine?

A. Not at all. Though Herbal Energy contains 100 milligrams of natural caffeine per serving, the effects of Herbal Energy are far beyond those of other caffeine sources. The ingredients in Herbal Energy were all chosen to work synergistically to support the production and metabolism or brain chemicals involved in improved energy, alertness, drive, and mood*.

Even the organic acids (e.g., malic acid) used to give Herbal Energy a pleasantly tart taste, also function as a facilitators of cellular energy production. Because of the synergy of all the ingredients it contains, we believe that there's no product available today that enhances energy, alertness, and mood* as effectively as Herbal Energy.

Q. What are the ingredients in Herbal Energy?

A. Herbal Energy contains:

Mucuna (Mucuna pruriens Extract)
Mucuna pruriens is a tropical legume which has been used for hundreds of years in Ayurvedic medicine as a nervous-system tonic and aphrodisiac*. It is often used to elevate mood and to enhance sexual energy*. Mucuna is one of the few plant sources of l–dopa, a direct precursor to the "feel–good" brain chemical, dopamine.

Damiana Leaves (Turnera diffusa)
Damiana leaves have been used traditionally to enhance energy levels, mood, and both male and female sexual health*. Modern research has shown that Damiana may reduce anxiety and act as an adaptogen* – a substance which improves the body's ability to cope with stress.

Catuaba Bark (Trichilia catigua)
Catuaba is a Brazilian herb which has been used for centuries as an aphrodisiac, and to combat exhaustion and fatigue*. Though energizing, Catuaba is also reported to calm the nerves and reduce anxiety*. Modern research has shown that Catuaba may impart a mood-elevating effect through its actions on the "feel–good" brain chemical, dopamine*.

Yohimbe Bark Powder (Pausinystalia yohimbe)
The bark of the African Yohimbe tree has traditionally been used as an aphrodisiac and energy tonic*. These traditional uses are in keeping with modern research showing that substances in yohimbe may increase levels of energizing brain chemicals such as norepinephrine and dopamine*. Integrated Supplements Herbal Energy contains a small (but effective) dose of whole yohimbe bark powder – not a concentrated extract of yohimbe alkaloids like some yohimbe supplements. Though some concentrated yohimbe extracts can be overly stimulatory in high doses, the small dose of whole yohimbe bark in Herbal Energy is both safe and effective, and is likely to impart a pleasant energizing effect at the recommended dose.

Natural Caffeine
Integrated Supplements Herbal Energy contains 100 milligrams of natural caffeine per serving – approximately the amount in a cup of fresh coffee.

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  • The Best All-Natural Supplements
  • All–Natural Whey Protein Isolate
  • Whey Protein with No Artificial Sweeteners
  • Fiber Supplements
  • BioAvailable Magnesium Supplements
  • Creapure Creatine Monohydrate
  • Detox Supplements
  • Weight Loss Supplements
  • Muscle–Building Supplements
  • Anti–Aging Supplements
  • Kosher Supplements
  • Bodybuilding Supplements
No claims found on our web pages or in print have been evaluated by the Food and Drug Administration. These products are not intended to diagnose, treat, cure, or prevent any disease. No claim or opinion on these pages are intended to be, nor should be construed to be, medical advice. Please consult with a healthcare professional before starting any diet or exercise program.