Natural Medicine Journal Podcast

Natural Medicine Journal's interviews with thought-leaders in the field of natural and integrative medicine dig deep into the most important topics in the field. Whether it's a one-on-one with top researchers in integrative medicine or a conversation with a practitioner about treating hard-to-tackle conditions, each episode promises to provide trusted, cutting-edge, evidence-based knowledge about natural medicine that you won't find anywhere else.
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Oct 23, 2018

In this podcast episode, we speak with Ross Pelton, RRh, CCN, about the variety of mechanisms of action that probiotics have when it comes to reducing cancer risk. Pelton also talks about colon cancer, H. pylori, and probiotic safety and dosage. Finally, he describes how to support a healthy microbiome with a healthy lifestyle.

(Approximate listening time is 32 minutes)

About the Expert

Ross Pelton, RPh, CCN, is Essential Formula's director of science, in addition to being a practicing pharmacist, clinical nutritionist, and health educator in Southern Oregon. Pelton earned his bachelor of science in pharmacy from the University of Wisconsin. A certified clinical nutritionist, Pelton was named as one of the Top 50 Most Influential Pharmacists in the United States by American Druggist magazine for his work in natural medicine. Pelton teaches continuing education programs for healthcare professionals to use natural medicine and integrate it into their practices. He also has authored numerous books, including The Drug-Induced Nutrient Depletion Handbook, which is a gold-standard reference book for health practitioners.

About the Sponsor

Essential Formulas Incorporated (EFI) was established in 2000 as the sole US distributor of world-renowned microbiologist Dr. Iichiroh Ohhira’s award-winning probiotic dietary supplements and skin care products. Always an innovator, EFI introduced REG’ACTIV in 2015, containing ME-3, a probiotic catalyst that produces the “master’” oxidant glutathione inside the body's cells. A family-owned and operated business, EFI was founded on the philosophy of providing high-quality preventative, supportive, and comprehensive pro-health products for the entire family. EFI continues to flourish and grow through a strong company and product integrity and the knowledge that they’re providing scientifically proven products that positively impact the health and well-being of their customers.


Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today, our topic is reducing cancer risk with probiotics. Before we begin, I'd like to thank the sponsor of this interview who is Essential Formulas Incorporated. My guest is integrative pharmacist and nutritionist Ross Pelton who is an expert on the topic of probiotics and health. Ross, thank you so much for joining me.

Ross Pelton, RPh, CCN: Hi, Karolyn. It's really nice to be with you. I enjoy our conversations.

Gazella: Yes. Now, first of all, how does the scientific literature stack up when it comes to probiotics and cancer prevention? Are there published human clinical trials?

Pelton: Well there's really not a lot of human clinical trials, but there's really quite a bit of research that has been conducted looking at cancer with probiotics. Human clinical trials are lacking, but there's a lot of work that has been done, cell culture studies and animal studies. There's a lot of work being done in this area. We just don't have the longterm human clinical trials which are very expensive to do. I think there's a lot to talk about because we've got substantial studies that have been published on the relationship between probiotics and cancer.

Gazella: Right. So I'd like to begin by having you give us an overview of exactly how probiotics influence the microbiota to reduce cancer risk. Now, there are several mechanisms of action. So go ahead and fill us in.

Pelton: Sure. Well some of your probiotics produce compounds that have antioxidant activity. Some of them have anti-inflammatory activity. They help to regulate detoxification. A lot of these functions are due to the fact that your probiotic bacteria produce secondary compounds or secondary metabolites that are called postbiotic metabolites. This is really the new frontier in microbiome science, starting to learn more about the compounds that your probiotic bacteria produce when they digest and ferment the food that you give them. Remember, these compounds have anticancer activity or protectant mechanisms that help protect against cancer.

Gazella: So I'd like to focus on these mechanisms of action as they relate to reducing risk of cancer. So let's begin with a more well-known mechanism and that is, as you mentioned, probiotics influence immunity. Describe what the scientific literature tells us about probiotics and the immune system.

Pelton: Well we know that 70% to 80% of the cells in your immune system reside in the gut. So it's really critical to have a healthy microbiome, a healthy gastrointestinal tract because that is the bulk of your immune system cells. One thing a lot of people don't realize is in the first 6 months of life, the primary function of your probiotic bacteria is to train your immune system. So it's really critical that kids get a good start in life with a vaginal delivery and adequate breastfeeding and for kids that don't, that's a compromised immune system. The gut is the seat of the immune system, and your probiotic bacteria are what trains the immune system.

Gazella: So now, what about maybe a little less known activity which is, as you mentioned, the antioxidant potential of probiotics? This may not be on the radar of some practitioners. Describe this mechanism of action.

Pelton: Sure. We know that free radical damage causes DNA damage and can increase your cancer risk. In a highly inflammatory condition in the gastrointestinal tract, there's a lot of free radicals being produced and a number of your probiotic bacteria have antioxidant activity and they also produce compounds that have antioxidant activity. There's 2 things going on here. Some of the bacteria themselves are antioxidants, but more importantly, they produce compounds that have direct antioxidant activity. In that respect, they're reducing free radical damage and reducing cancer risk especially for colon cancer which is a site of a lot of the free radical activity in a highly inflamed colon.

Gazella: Yeah. We're going to definitely talk about colon cancer, but now, when it comes to this influence on immunity and antioxidant potential, are there research studies in vivo or in vitro studies indicating probiotics, which probiotics can help with immunity and antioxidant potential?

Pelton: Sure. There's both some of the lactic acid-producing bacteria, Lactobacillus strains, and also some of the Bifidobacteria, bacteria that reside primarily in the large intestine and colon. One of the classes of antioxidants that they produce, they're called exopolysaccharides. That's a big word for people, but it just means that there are chains of sugars that the bacteria produce and then they excrete them and they have antioxidant activity. So this is just one of the mechanisms of action by which both Lactobacillus and Bifidobacteria are able to produce antioxidant compounds that reduce cancer risks.

Gazella: So the research tells us that probiotics can influence gene expression. Tell us how this impacts cancer risk reduction.

Pelton: Well various different strains of probiotic bacteria can influence gene expression. They can influence apoptosis, which is the rate of cell death. They can influence metastasis. They can influence cancer stem cells. They can up-regulate tumor suppressor genes. So a number of different ways that probiotic bacteria and the compounds that they produce, these postbiotic metabolites can influence gene expression which ultimately is going to influence cancer risks.

Gazella: So now, there's a significant amount of evidence and research showing that toxins can increase risk of cancer. What role do probiotics play in neutralizing some of these toxins or in supporting the detoxification of some of these toxins?

Pelton: Sure. This is actually a pretty broad category. There's a lot of different ways that probiotics can have detoxification capabilities. Some strains of bacteria can detoxify or decrease the absorption of a cancer risk factor called bisphenol A. There's a lot of studies on that substance now that show that it increases cancer risk. This is a compound that's in a lot of products that are on the market, especially baby products.

Some strains detoxify some of the agricultural pesticides. One of the Essential Formulas' products, Reg'Activ, contains a strain of bacteria called Lactobacillus fermentum ME3, and that strain of bacteria up-regulates a group of enzymes called paraoxonase enzymes. Those enzymes directly detoxify things like organophosphates, which are one of the commonly used pesticides in the agricultural industry.

Other strains can directly bind some of the heavy metal toxins like mercury and lead and cadmium. They also decrease the absorption of these heavy metal toxins when they bind them up so they don't get absorbed into your system. They get excreted. Some strains actually metabolize cancer-causing food preservatives like sodium nitrate, and Bifidobacteria are able to degrade and detoxify a very serious compound called perchlorate. We get exposed to perchlorate from fertilizers in the environment and a lot of that in the agricultural industry.

Heterocyclic amines are frequently caused by cooking meat at high temperatures. So our middle America, meat and potato people, they're out there with their barbecues and they're producing these heterocyclic amines. Some of the Lactobacillus organisms reduce the toxicity from heterocyclic amines. That's just a number of the different ways that your probiotic bacteria function as detoxifying agents in the gastrointestinal tract.

Gazella: Yeah. It's a long, impressive list. Now, I want to get back to the ME3 that you mentioned. Are there scientific studies on that particular-

Pelton: There are.

Gazella: ... strain, the ME3?

Pelton: It is a really, really fascinating topic because Lactobacillus fermentum ME3 synthesizes glutathione. Glutathione is the master regulator of your detoxification throughout your system and every cell produces glutathione, but it's hard to boost your levels of glutathione because, when you take it orally, it gets oxidized, it gets broken down and destroyed so you don't absorb it. But now we've got a strain of bacteria, this Lactobacillus fermentum ME3, where the bacteria actually synthesize glutathione.

Yes, we have human clinical trials showing that the antioxidant activity of glutathione produced by the ME3 probiotic bacteria will reduce levels of oxidized LDL cholesterol so you're reducing your cardiovascular risk, and it does a good job of increasing detoxification throughout your whole body. The human clinical trial, people taking ME3 had an astounding 49% increase in the ratio between oxidized glutathione to reduced glutathione with the reduced glutathione is the active form. A 49% increase in the ratio of the reduced to oxidized glutathione is a huge, huge meaningful marker.

This is really a revolution in healthcare and medicine to be able to boost your glutathione levels on a regular basis because, as I mentioned, glutathione regulates your detoxification. It's also called the master antioxidant and probably protects more of your body than all the other antioxidants combined. This is one area that is just really astounding both in terms of antioxidant protection and detoxification capabilities.

Gazella: That's great. So I'd like to switch gears and I'd like to talk about specific cancers. When I think about probiotics and cancer, I often think about colon cancer. You mentioned that previously. What role can probiotics play in reducing the risk of colon cancer?

Pelton: Well there's a number of ways that this can happen. Pathological bacteria will convert bile acids into secondary metabolites that promote cancer. When you have the proper acid-base balance in the GI tract, there's a dramatic reduction in the conversion of these bile acids into the more cancer-causing secondary metabolites. So maintaining the proper acid-base balance, which is what the probiotic bacteria do when they produce things like short-chain fatty acids and organic acids and nucleic acids, they create the proper acid-base balance which reduces the conversion of bile acids into secondary cancer-causing metabolites.

Your probiotics can also inhibit the activity of carcinogenic enzymes. They suppress growth of bacteria that produce enzymes that deconjugate carcinogens. What I mean by that is that a lot of carcinogens get bound up and they're supposed to be excreted when you have bowel movements, but if you don't have good elimination and so things stay in the colon too long, those cancer-causing things that are bound up can get released and reabsorbed. So probiotics can actually suppress the growth of bacteria that produce these enzymes that are deconjugating these carcinogens. Good bacteria are actually keeping these carcinogenic byproducts bound up so they get eliminated from your body.

Gazella: Well speaking of bacteria, it's widely known that there's a connection between H. pyloriand cancer. Can you describe that connection and tell us how probiotics can help prevent or even reverse H. pylori?

Pelton: Sure. That's another big topic because now that H. pylori has been discovered and understood, we realize it's the primary cause of stomach cancer and cancers in the upper small intestine. This is an interesting bacteria. It's got kind of a corkscrew tail on it, and it can just burrow its way into the lining in the stomach or the lining in the small intestine. When that happens, you've got a hole in your intestinal wall. Then you get the acids and the digestive enzymes leaking through, creating inflammation, and you end up with a higher incidence of cancer.

If you have a good, healthy microbiome and adequate numbers of your good bacteria, you suppress the growth or the overgrowth of H. pylori. There's a little bit of a controversy about whether people should try to totally eradicate H. pylori. Some people, some of ... Martin Blaser is one of the leading scientists that's exploring this and saying maybe we shouldn't totally eliminate H. pylori, but people that have H. pylori overgrowth certainly do have increased risk to gastric cancer and small intestinal cancers. It's having a good microbiome and adequate numbers of your good bacteria that will keep the H. pylori in check and not get overgrown so you reduce your cancer risk.

Gazella: What are some of the symptoms of H. pylori overgrowth? I mean how does a doctor recognize this in their patient population?

Pelton: Well as I described, the bacteria has this corkscrew tail that burrows through the unprotected mucus lining in your stomach or your small intestine. When you get that hole in the lining, you've got an ulcer. It's painful. Your digestive acids, your stomach acid, and your bile acids and small intestine. Then they go through the mucus membrane which is your protective barrier, and they come into direct contact with the cells that line your GI tract. When that mucus protective layer is breached, then those acids contact those cells that line the GI tract and it's painful. You've got an ulcer and you say "Oh, man. This is sore." So people actually oftentimes stop eating because every time they eat, they get more digestive juices in that ulcerative location. You need to heal that ulcer. Getting rid of H. pylori is one thing, but you also have to take time to heal the ulcer.

Gazella: Yeah, that makes a lot of sense. Now so far, we talked about colon cancer, stomach, upper GI. Are there any other cancers when it comes to using probiotics? I mean do you pretty much recommend probiotics as a risk reduction strategy across the board?

Pelton: I do because your immune system is so directly related to cancer risk factors. A lot of people don't realize that probiotics have an effect outside the intestinal tract. We now know that things like short-chain fatty acids get absorbed into your system and can actually reduce the risks of liver cancer. It's a whole body effect. These bacteria are not just a local effect in the gastrointestinal tract. I kind of use the analogy of Mission Control at NASA where those computers are controlling your space flights. Well your probiotics and the postbiotic metabolites in your small intestines and your colon are really Mission Control for all health-regulating effects in your whole body.

There's a new study that I wanted to share with you, Karolyn, published just recently in a journal called Oncotarget. It's a cancer journal. It says cancer killers in the human gut microbiota. One of the things they're reporting here is that they identify intestinal bacteria that exhibit potent antimalignancy activities on a broad range of solid cancers and leukemia. So this is a relatively new paper just published in July of 2017, identifying that postbiotic metabolites and your probiotic bacteria are helping to reduce both solid cancer tumors and leukemia. It's just an exciting new report giving more emphasis on the anticancer capabilities of your probiotic bacteria.

Gazella: Yeah. I think this area of research is going to just really explode. Now, a lot of patients go into their doctor's office and they say "Oh, well I'm fine. I don't need a probiotic supplement because I eat yogurt everyday," or something like that. How easy or difficult is it to get the probiotics we need from diet alone?

Pelton: It depends on what you mean by diet. If people are eating fermented foods, that's a really good source of probiotic bacteria, but most people aren't eating sauerkraut and kimchi and tempe and things like that. Most foods don't have probiotic bacteria. People think about yogurt, but commercial yogurts have a lot of sugar which actually promotes the growth of your pathological bacteria and yeast like candida. So commercial yogurts are generally not a good idea either in terms of just not getting a good source of probiotic bacteria. You're really working against the health of your gastrointestinal tract and your microbiome.

If people produce their own yogurts, there are some good ones. Yes. But you're really not getting a diverse level of bacteria in yogurt, and a healthy microbiome is a diverse microbiomes which means you want to get a lot of different types of strains of bacteria. The best way to do that is to consume a diet that has many different types of fiber-rich foods, especially the multicolored vegetables. That's the number one food source for your bacteria.

Gazella: Right. We have to feed those good bacteria.

Pelton: That's right.

Gazella: So now, you represent a specific type of probiotic, the Dr. Ohhira's brand. Why do you recommend that specific brand of probiotic?

Pelton: Well I'm glad you asked that. I'm the scientific director of Essential Formulas, and Dr. Ohhira's Probiotics is our primary product line. Dr. Ohhira's Probiotics are made differently than every other probiotic in the world. In fact, it's kind of confusing, but Dr. Ohhira's Probiotics is really not primarily a probiotic. It is primarily a fermented food.

The Dr. Ohhira's Probiotics are produced in a fermentation production system. We have large fermentation vats in a warehouse, and we start with 12 strains of probiotic bacteria. Then at seasonally appropriate times throughout the year, we shred and harvest dozens of different types of organically-grown foods. There's fruits and vegetables and mushrooms and seaweeds. Then the bacteria get to digest and ferment these foods for 3 years before the product is finished.

During that fermentation process, the bacteria are breaking down the foods and producing this wide range of compounds that we now refer to as postbiotic metabolites. As I mentioned earlier, these are the master health-regulating compounds in our system. So Dr. Ohhira's Probiotics have been tested and we find out there are over 400 postbiotic metabolites in Dr. Ohhira's Probiotics. We are not primarily just delivering probiotic bacteria. We're delivering over 400 of these postbiotic metabolites that rapidly create change in the GI tract. You rapidly reduce inflammation, rebalance the acid-base level, promote the growth of healthy new cells that line the GI tract, cell signaling and gut-brain communication directly with postbiotic metabolites.

We get what we call rapid microbiome restoration or rapid microbiome repair. Other companies are just giving you bacteria in a capsule. That's kind of like a starter culture. Those bacteria haven't done any work yet. Our bacteria have been working for 3 years producing postbiotic metabolites by the time you ingest them. That's the big difference. Dr. Ohhira's Probiotics is different than every single other probiotic in the world. The new science in the microbiome, the new frontier in microbiome science is starting to realize that it's these postbiotic metabolites that have the master health regulatory effects in the gastrointestinal tract and health-regulating effects for the entire body. So by directly delivering this postbiotic metabolites, we get rapid improvement in the microbiome in the gastrointestinal tract for people who take Dr. Ohhira's Probiotics.

Gazella: Now, I know this particular product does not have to be refrigerated. Why is that?

Pelton: Well these bacteria learn to thrive and survive at room temperature during the 3 years of fermentation. They don't need to be refrigerated, which makes them very user-friendly. Also they are in a patented capsule that stays hard in the harsh acid environment in the stomach. Then it preferentially releases the contents in the small intestine. So it doesn't make any difference if you take it with food or on an empty stomach. Any way you take it, just the main thing is 2 capsules once a day. Get Dr. Ohhira's in on a regular basis and you'll be maintaining a healthy microbiome.

Gazella: Yeah. I'd like to talk a little bit about dosage because honestly it seems like you can ask 3 different experts about dosage and they'll give you 3 different answers. When it comes to dosage specific to cancer prevention, is that the 2 caps per day? What does that deliver in terms of CFUs or different strains for that two caps per day?

Pelton: Well 2 capsules a day is the recommended dosage. One thing we emphasize, we're not concerned about how many million or how many billion bacteria we have. There's a numbers game that is really a misconception by people when we're talking about probiotics that they call the bacteria that are available CFU which stands for colony forming units. It really means just the number of viable bacteria, but people have a misconception that more is better. They say "Mine has 30 billion. Mine has 50 billion. Oh, mine's got 100 billion." They think more is better.

One of the most critical factors in a healthy microbiome is balance. If you take massive doses even as a healthy strain of bacteria, you're not working in favor of balance. You're actually working against creating balance in the microbiome. So it's not important to have high strains of, high dosages and high numbers. It's better to have a multistrain probiotic, a lot of different strains but at lower dosage levels.

I really talk in my lectures and seminars against the high-dose probiotics. I'm not saying they're never appropriate. A product like VSL3, which is a prescription probiotic, I think it has 112 billion bacteria per dose. Those people have some good research and have documented benefits from their high-dose probiotic, but I don't think high-dose probiotics are appropriate on a longterm maintenance basis. You want to strive for balance and diversity.

Gazella: Yes, I would agree with that. How many strains are in the Dr. Ohhira's product?

Pelton: Dr. Ohhira's has 12 strains. We start out with 12 strains in the manufacturing process. We are a multistrain probiotic. I'm not sure, but Dr. Ohhira may have been the first scientist in the world to understand the concept and the importance of a multistrain probiotic because he created Dr. Ohhira's Probiotics 30 years ago.

Gazella: Yeah. So let's talk a little bit about safety. When it comes to cancer prevention, are probiotics safe for the majority of patients or is there any patient or group of patients who should not take probiotics to help reduce cancer risk?

Pelton: No, everybody should take probiotics. One of the most important things for health is a healthy microbiome. We now understand that a healthy microbiome is the foundation of health. I think it's important for everybody to realize that supporting and maintaining a healthy microbiome is a critical factor for health regulation. There's no contraindications.

I do want to mention briefly, Karolyn, there are 2 studies that were recently published in the journal Cell that have gained a great deal of publicity because they cast doubt on the effectiveness of probiotics. The scientists who conducted these studies stated that their results suggested probiotics are almost useless. There's been a lot of pushback after the publication of these studies. It turns out there was some methodological shortcomings in the way they set up their studies, and there were a very low number of people. I think there was only 8 to 12 people in these studies.

What's more disturbing is that it has been learned that the scientists that conducted these studies, they have a personalized approach to probiotics that they promote in their studies. Turns out that they have a vested interest. They have financial interest in this company that's promoting this personalized approach. So it's a very serious flaw and their conclusions should not be generalized of the whole field of probiotics. Allowing studies to be published in which the authors state that probiotics are almost useless is really grossly misleading and a disservice to the general public.

Gazella: Yes, I would agree. Now, I often like to ask experts to grab their crystal ball and look into the future. In your case, I'd like to have you tell us what you'd like to see happen when it comes to probiotic or postbiotic metabolite research in the future. What do you want to see happen as we go into this next phase? Because I'll tell you, there's a lot of exciting stuff happening. There's a lot of different directions we could go into.

Pelton: You're absolutely right. It is a very exciting field and rapidly evolving. As I've talked about these postbiotic metabolites, the compounds that your probiotic bacteria produce, in the future, we will learn a great deal more about the health-regulating effects of these compounds that your bacteria produce and we'll learn more about which strains of bacteria are more effective at producing some of these health-regulating postbiotic metabolites.

I think in the future, we'll probably make a great deal of inroads and progress in designing personalized probiotic programs for people. We'll be able to assess your own innate microbiome and be able to know more accurately how to promote and enhance the growth of your own innate what we call your probiotic fingerprint, the bacterial population that you've developed early in life. I think we'll get into more of a personalized microbiome and personalized approach to probiotics to help promote health in individuals.

Gazella: When you think about cancer specifically and reducing cancer risk, I mean now obviously, it's estimated that 1 in 2 men and 1 in 3 women will develop cancer in their lifetime. I mean this is now reaching near epidemic proportions. How critical is it that we look at things like probiotics when it comes to reducing cancer risk?

Pelton: Well again, I go back to the immune system. It's absolutely essential that people have a healthy microbiome so that they have a healthy immune system. This is really where it starts. Your gastrointestinal tract and your microbiome are literally the foundation of your health for everything that happens. It is the number 1 thing that people need to be aware of and it's not just the microbiome.

As we mentioned earlier, you have to learn how to feed your probiotic bacteria well. This is another key message of mine. This is why diet is so important because you're not eating just for yourself. You're eating to feed 100 trillion guests. It's a pretty big party that's going on down there. Every time you eat, you have to realize that you're feeding your microbiome, and your microbiome is the center and the foundation of your health and your immune system and your anticancer activity. So people need to realize how important it is on a regular basis to eat a wide range of different types of fiber-rich foods, especially the multicolored vegetables, because a more diverse fiber-rich diet will promote the growth of a more diverse microbiome which means your bacteria will produce a wider range of these health-regulating postbiotic metabolites and you will be a healthier person with a stronger immune system.

There's a recent study that was just published that shows that, reports that people that consume more probiotics take less antibiotics. That's just another insight into probiotics being able to support your immune system. So these people using probiotics more have a stronger immune system. They have less need over time for antibiotics.

Gazella: Yeah. That antibiotic issue, that's something that we ... That could be whole other topic for us.

Pelton: It's a big one.

Gazella: But as an integrative pharmacist, you share a philosophy with our listeners who are, most of them are integrative practitioners. It's not just about giving a pill and calling it a day. It's a very comprehensive approach, and I like the fact that you focus so heavily on diet and using a healthy diet to feed the probiotics and the bacteria and that you use probiotics hand-in-hand with that comprehensive lifestyle approach which I'm assuming, beyond diet, you counsel people to exercise and get enough sleep and those other lifestyle factors as well.

Pelton: Absolutely. Those are critical factors. There are studies now that show that your probiotic bacteria respond to exercise. Exercise needs to be emphasized. So it's diet and exercise, lifestyle. All these healthy things go into creating and maintaining a healthy individual and having a healthy aging process. It's not just probiotics and it's not just diet as you mentioned. It's exercise and sleep and learning how to avoid environmental toxins. There's lots of things that go into it.

Gazella: Right. Treat your microbiome well and it will serve you for a long time to come.

Pelton: It will work for you. Absolutely.

Gazella: Well great. Well Ross, this has been very informational as per usual. I want to thank you for joining me. Once again, I'd like to thank Essential Formulas Incorporated for sponsoring this topic. Thanks so much, Ross. Have a great day.

Pelton: Nice to be with you, Karolyn. Always enjoy speaking with you.

Oct 9, 2018

In this podcast, we take a guided journey with noted professor and neuroscientist, Jane Foster, PhD, as she explains how animal models have elucidated the complexities of the gut-brain axis and role of gut microbes in mood and mental wellbeing. From a sound scientific footing, we join practicing psychiatrist, Scot Bay, MD, as he shares his experience with the integration of a mood-targeted probiotic blend in challenging cases and complex therapeutic interventions.

Approximate listening time: 35 minutes.

About the Experts

Scot Bay, MD

Scot Bay, MD, is board certified in adult psychiatry. He was educated at the University of Rochester and New York Medical College. He completed his residency in psychiatry at St Vincent’s Hospital in New York City. Bay specializes in the evaluation and management of mood, anxiety, and thought disorders and has special interests and expertise in psychopharmacology. He has extensive experience with numerous psychiatric medications and has lectured all over the Southeast regarding practical and innovative uses of psychiatric medications.

Jane Foster

Jane Foster, PhD, joined the McMaster University faculty in 2003. She holds a research appointment with the University Health Network in Toronto, Ontario, Canada, as well as a scientific position with St Michael’s Hospital.

Foster is an active researcher with 2 translational networks, The Province of Ontario Neurodevelopment Disorders Network (POND) and the Canadian Biomarker Integration Network in Depression (CAN-BIND). Her research focuses on the role of immune-brain and gut-brain interactions on neurodevelopment, behavior, and brain function.

About Klaire Labs

Klaire Labs

Since 1969, Klaire Labs™ has been dedicated to developing clean, efficacious nutritional supplements to ensure optimal outcomes for the most sensitive individuals. It is this dedication to purity, potency, and performance that has guided the development of our legacy formulations including the highest selling professionally distributed probiotic brand in the United States, Ther-Biotic, as well as our novel, indication-targeted probiotic products such as Target gb-X™ (gut brain axis) and Target b2™ (breast and baby).


Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today, we will be discussing the gut/brain axis as it relates to mood and mental health. I have 2 experts joining me today, researcher Dr Jane Foster and clinician Dr Scot Bay. Before we begin, I'd like to thank the sponsor of this interview who is Klaire Labs.

Gazella: Dr Foster, I'd like to start with you and then I'll switch gears and get a clinical perspective from Dr Bay. Dr Foster, how does the human microbiota communicate with the brain?

Jane Foster, PhD: The human microbiota actually covers all of the surface of our bodies. However today I'm going to talk mostly about gut microbiota. That's a key component of the gut/brain axis. There are several pathways of communication between gut microbes and the brain. Neural connections are very important. In particular, the vagus nerve, which is a bi-directional nerve that can communicate from the gut to the brain but also from the brain to the body, that includes communication with the immune system and the gut, has a well-established role as a communication pathway between the gut and the brain.

The enteric nervous system, which is the mini-nervous system that wraps the gastrointestinal tract, responds to signals from microbiota in the lumen of your gut, and this influences both the host physiology at the level of the gut but also communications with the central nervous system.

These neural pathways are important, but there's also humoral pathways that are important. We know, and we have for a long time, that the brain can influence gut function and microbiota through the production of hormones such as cortisol. The interaction between stress and our microbiota is actually where a lot of the work that currently goes on started. But in the past decade we've been learning a lot more about how microbiota participate in bottom-up communication through the immune system and through other systems. But by influencing immune cells themselves or by influencing the immune molecules produced by the peripheral immune system such as cytokines and other molecules, the microbiota can influence this immune cascade signal to the brain.

One of the big areas of interest in the field is metabolism. Gut microbiota influence metabolism through the composition and function of gut has been shown to influence things like tryptophan metabolism bot locally and across the body, which may influence mood through modulation of central serotonergic systems.

And finally if we think about the microbes themselves, microbes can produce neurotransmitters and their lack of molecules. Although the role of microbiota-produced neurotransmitters might just be in the local area of the gut between microbes themselves and some of the gut tissue, there's a big interest in understanding how these might influence microbiota brain communication. Microbes also ferment dietary fiber, and through this fermentation they produce short-chain fatty acids including things like acetate, butyrate, and propionate. These short-chain fatty acids are important for crosstalk between microbiota themselves and promote healthy gut physiology.

Some of the evidence suggests that short-chain fatty acids can communicate beyond the gut, and in the case of propionate it's very important in the portal vein system and communication with the liver. In the case of acetate there's evidence that it can systemically communicate to the brain.

Gazella: That's fascinating. Why is it so important for us to understand this complex communication that's taking place?

Foster: Evidence from both pre-clinical studies and clinical studies supports a role for the microbiota-brain axis in these communication pathways in both physical and mental health. From the mental health perspective there's several potential benefits for understanding these connections. First, there's a great interest in the potential use of interventions that may target the microbiome, such as probiotics or prebiotics, but also diet and exercise and how these interventions might improve mental health.

Second, understanding the molecules and some of the signal transception pathways that mediate microbe/host or host/microbe interaction may actually provide novel targets for drug development outside of these microbiota-related therapies.

And finally one of the most interesting things from my perspective is the remarkable interpersonal differences in microbiota composition such that in fact between you and I our differences are in the range of 90% at the level of our microbiota composition. And such it seems that each person's microbiota is their own. This feature is really interesting when we think about heterogeneity and psychiatric illnesses or mental health in general. As the field moves toward more precision medicine approaches where we really do need to identify biomarkers that will help understand how individual biological differences might influencing what treatment might be best for each person.

Gazella: You mentioned the research. Can you describe some of the more significant studies that indicate how microbes influence brain function and mood?

Foster: Yeah. The foundation for our understanding of how microbiota influence brain function and mood has really come from a long history of animal studies that manipulated microbiota both in early life and in adulthood to show how connections between microbiota and behavior exist and also in these studies identify key signaling systems in the brain that are influenced by the microbiome but include things like our stress circuitry, our fear circuitry, systems that influence anxiety and depressive like behavior.

One of the ways that people have taken this animal work and started to think about are these systems actually operating in people has been to actually do the fecal transplant experiments where they've actually taken fecal samples from depressed patients and put them in rodents and demonstrated that rodents that received that depressed fecal sample actually have an increase in depressive-like behaviors and in sometimes anxiety-like behaviors.

That just supports this connection between microbes and the behavior, but a small collection of studies so far has also examined the composition of that microbiota in healthy and depressed individuals and shown that there are actually differences in the microbiota composition in depressed individuals when compared to healthy volunteers. A few of these studies have actually taken that a little bit farther and showed a direct association between specific taxa and clinical symptoms and disease severity.

If I can just highlight a couple of things about that that really are interesting and the sort of observations that I think will move the field forward. In a study by Chang in 2015 and colleagues, they shed a reduction in a very abundant bacteria called faecalibacterium. A reduction here was associated with an increased severity in depression. What's interesting about that is this is it's an abundant bacteria in healthy adults and a major producer of that short-chain fatty acid I mentioned butyrate. A reduction in this bacterial taxa has also been reported in other studies in depression but also in individuals with gut functional disorders. Suggesting this link between gut dysfunction and mood could be related to some of these key taxa.

If I can just tell you one more study that really links the bacteria to the brain is the work that comes of Kirsten Tillisch's group and Emeran Mayer's group at UCLA where they've shown some key taxa in healthy individuals are actually associated with brain connectivity using both DPI and structural imaging and then have also shown that the same taxa might actually be involved in emotional response using functional imaging. These sort of studies really do start to connect specific bacteria to brain function and behavior.

Gazella: Yeah. I think it's fascinating. When we're trying to target a microbiome to change the composition, you mentioned that there are some key factors that can influence gut health and therefore hopefully influence brain health. You mentioned probiotics, prebiotics, diet, lifestyle. Can you tell us some more specifics about how we can influence this gut/brain axis connection?

Foster: There are several factors that influence the composition and the function of gut microbiota. There's a lot of interest in the field to determine how both genetics and the environment and that interface influence the microbiome and how those interactions might influence both physical and mental health. A key factor that influences the microbiome is genetics. There's a whole series of twin studies that provide evidence for a role for host genetics or the DNA that we inherit influencing your microbiome.

The first evidence that showed this was this observation that monozygotic twins that have exactly the same DNA have more similar microbiomes than dizygotic twins but not perfectly matched suggesting that while genetics is an important role other things might also be important. There's extensive literature both in animals and in humans that looks at the importance of genetics but also highlights the influence of these other environmental factors. Some of those are important to consider in mental health.

Age, for example, influences microbiota composition and function. Our relationship with our microbiomes happens very early in life as we travel down the vaginal tract and are colonized by the bacteria. The dynamic changes that occur in early life really do influence all sorts of health outcomes, including risk of particular allergic responses, but also potentially mental health. Age-related changes that occur later in life also could have a direct impact on gut health and brain health.

Another big factor to consider is diet. There's a direct impact of diet on gut health and brain health but also understanding which specific taxa are influenced by the diet and how the related molecules and signaling systems that influence the interaction between diet, microbiome, and mental health really has to be addressed in a very systematic way.

The final factor, I think, that we all know about and pay attention to are the impacts of drugs on the microbiome, the most obvious being antibiotics. There's one large epidemiological study that suggests exposure to antibiotics increases risks of anxiety and depressive disorders, but recent evidence actually shows that both antibiotics and non-antibiotic drugs have direct effect on microbiota composition. The impact of the influence of these different drugs on the microbiome and how that bottom-up mechanisms might influence the side effects or the direct action of drugs is very important.

Gazella: What about probiotics? You mentioned prebiotics and probiotics. What role can they play in influencing the microbiome and then influencing mood and brain function?

Foster: There's enormous public and scientific interest in probiotics and other psychobiotics as you mentioned such as prebiotics but also naturally fermented foods, which have been around for a long time, to improve mental health. There is extensive preclinical literature that demonstrates benefits of probiotics in mood and brain function. Interestingly within this literature even when it's a challenge in an animal model that has nothing to do with mental health outcomes, the addition of a probiotic tends to improve some of the emotion-related behavior such as anxiety-like behaviors in these animal models.

The first evidence to support microbes can influence and probiotics specifically can influence brain function came from a whole series of probiotic studies in healthy adults. These studies administered probiotic cocktails or single probiotics to healthy individuals for a period of usually a month or longer. The benefits included things like reduced inflammation, reduced stress hormones, and improved anxiety and depressive measure, and that's in healthy individuals.

A key report in this area that actually launched some of the interest of Dr Bay who we're going to speak to later was a randomized control trial conducted by Laura Steenbergen and colleagues in the Netherlands that showed that this particular probiotic cocktail, Ecologic BARRIER, which is now in the US as Target gb-X, reduced cognitive reactivity to sad mood and reduced ruminative thoughts in those healthy individuals, suggesting again this link between microbes and a benefit on mood. But there's only been to date maybe 1 or 2 but 1 particular randomized control trial by Akkasheh and colleagues in 2016 that showed probiotics administration in depressed subjects reduced depressive scores and was accompanied by reduced inflammation and reduced serum insulin.

The field is certainly supporting the hope for therapies such as probiotics and prebiotics influencing mood.

Gazella: Perfect. Your last question Dr Foster. When it comes to gut/brain research, what would you like to see emphasized in the future? What more do we need to learn? I would imagine it's a long list.

Foster: I have a long list, and in fact the interesting thing about this field is its multidisciplinary nature and that as a neuroscientist in the field I also get the great advantage of associating with microbiologists who have never considered mental health in their research. I think this crosstalk between these different disorders helps us try to define what is a healthy microbiome, which is actually a critical step of the field right now, before we can figure out how alterations in the microbiome influence illness, whether it be physical illness or mental illness.

One of the things that I think is needed from a research perspective is actually, particularly in mental health, it's some longitudinal studies so that we can understand how dynamics of the microbiome and perhaps perturbations of it over time influence mental health. And also we need more studies examining the microbiome in psychiatric populations, paying attention to some of these individual differences that we know are emerging that might influence the gut/brain axis's impact on mental health.

If I go back to an earlier comment I made, if we think about the field in general and the researchers that have advanced some of our technology, the field's really very interested in functional readouts of the microbiota-host interactions. A lot of studies have looked at the composition of the microbiome. Knowing who's there is just the first step along the path of understanding how these communication pathways impact health. In particular, people are now using shotgun metagenomics to get a more comprehensive profile of what the functions of the microbiome are using genomics to look at the genes that are being expressed and metabolomics in both fecal, urine, and plasma samples to understand what the functional outcome of these different taxa have within our whole system.

This is a great advantage to psychiatry because depression and anxiety are really very heterogenous disorders. Understanding how the microbiome and the related signaling systems are linked though, clinical presentations of these disorders is important. What might be very important is understanding using these sophisticated tools, how individual differences in these microbiome readouts or proxies for the microbiome can identify a microbiota-brain signature that might actually allow us to cater treatments to individuals based on their own microbiome and their own depression or anxiety symptom profile. That way the trial-and-error component of treating individuals with psychiatric illness may be improved.

Gazella: Yeah. That's a great goal, and it's going to be exciting to watch this area of study as it evolves.

Okay, Dr Bay, it's now your turn. Dr Bay, much of your work has focused on psychopharmacology. What prompted your interest in the gut/brain axis?

Scot Bay, MD: I've always been looking through the literature for new and interesting developments in the field both to stay current on the latest developments in case you care but also because I had a weekly mental health–related podcast for many years and I was looking for new and interesting topics to discuss on that. Over the past several years I've been seeing more and more articles documenting research studies about the effects of probiotics in mood and also as Dr Foster mentioned even the effects of certain fermented foods in things like anxiety and also depression. That really struck a chord with me because I've always observed that there's a lot of promorbidity between states of anxiety and depression and gastrointestinal disorders. And again Dr Foster very elegantly laid out how the gut and brain are connected, so that always made perfect sense to me that people who have mental health problems are likely as not to have also gastrointestinal issues. It's just one of many ways I think that mental health problems affect the body physically.

People with depression but also especially with anxiety almost always have some kind of somatic or physical symptoms that are a manifestation of their disorder. Having gastrointestinal-related symptoms is a very common manifestation of the things that we psychiatrists treat on a daily basis, the depression, anxiety, and other adverse mood states.

Gazella: What type of GI issues are you seeing in your practice in people who have mental health issues?

Bay: Things like irritable bowel syndrome, which could either be prime persistent constipation or diarrhea or switching from one to the other, bad reflux, gastroesophageal reflux disease, and also other just non-specific functional bowel complaints that may not have a particular diagnosis associated with them but nonetheless affect people's gastrointestinal functioning.

Gazella: That is an interesting connection between mental health issues and the GI issues. Were there others that you wanted to mention?

Bay: Gastroparesis is another one. It's commonly associated with certain medical conditions especially diabetes but can also be affected by mood. And then there's also the other consideration being many psychotropic medications can affect motility of the intestines, so there's that consideration as well.

Gazella: I'd like to talk a little bit about treatment resistance because you have been focusing on psychopharmacology. How common is the issue of treatment resistance, and why is that such a challenge for many clinicians?

Bay: Right. I would say the treatment-resistant patients, in other words people who I guess by some definition had failed trials of 4 or more psychotropic medications, this is a very difficult problem because when you have people who don't respond to the normal typical treatments, it's very difficult to get them any symptomatic relief whatsoever. There's only a limited number of treatment alternatives to consider. The other part to that is when people wind up seeing psychiatrists, they've often cycled through several treatments already through their primary care physician. There are too few psychiatrists, so people often don't start their treatment of their mental health problems with us. It's usually started with primary care, so by the time they get to see us they've already struggled to not get any relief with the treatments they've been getting. It's even more difficult by the time that they see us.

The way I see it, we have patients who have their experience of their illness and all of them are as unique as their individual DNA, but the illnesses that we treat are not so unspecific that any treatment would be effective. For example, if someone has a bacterial infection it's very cut and dried. You send it for a culture. You know exactly what antibiotics will or will not kill it. You pretty much know what results you're going to get when you give the patient the treatment.

But when it comes to psychiatric problems, we just don't have a way of knowing in advance what treatments will work or not. When people don't respond to several treatments, that unfortunately indicates often a guarded prognosis. Another reason why I'm always looking around for other additional ways to help people who don't respond to the standard psychiatric medication treatments.

Gazella: That makes a lot of sense. I'd like to switch gears a little bit and talk about probiotics specifically. What are the clinical applications of using probiotics in patients who have mood issues like depression, anxiety, or other mental health disorders?

Bay: So far what I've been doing is adding this to the regimen of medications that I have my patients on. Initially what I did was to have people add the probiotic who were already on medication but still having symptoms to see if it would do two things, address their gastrointestinal symptoms and also bring about further improvement in mood.

When I first started doing this I had a limited supply of Ecologic BARRIER, which is the version made by the original manufacturer in Netherlands, Winclove. The company was kind enough to shoot me some samples. Initially since I had a limited supply I was just saying let me try this out on the people who are really bad off, maybe chronic, severe, treatment-resistant conditions, very complex regimens of medications, or polypharmacy and see how they respond because they're the people most in need of relief. Sure enough they all saw at least slight improvements in mood, and in many cases very rapid relief from their gastrointestinal symptoms.

But since the product is now available in the States and has been for quite some time under the name Target gb-X, I'm expanding that to people who are not necessarily only treatment-resistant as far as their depression and/or anxiety to people who aren't necessarily on complex regimens of medication with polypharmacy, even who may not necessarily have co-morbid gastrointestinal symptoms to see how this would help people.

I often get the question as far as another potential applications, I'm not getting support yet, but when I've discussed this with other clinicians I get the question, "Have you ever tried to give this to people to help them get off their psychiatric medication?" I haven't because initially the issue is helping people feel better who are only getting partial relief from their medication. But that's definitely something I plan to explore in the future.

Gazella: I definitely want to talk about some of your specific patient outcomes, but first can you please tell us the name again of the product and also tell us why you chose that particular product because there are a lot of probiotic products out there. Tell us the name of the product and why you chose this one.

Bay: Right. It's called Target gb-X, and it was originally only available through the original manufacturer in the Netherlands, Winclove. The reason I chose it going back to my always scanning for articles in the mental health field and looking for new developments and seeing the literature about probiotics, the study that Dr Foster mentioned earlier by Dr Steenbergen, that really caught my eye. This is what really, I think, initiated my getting involved in using probiotics in my clinical practice. As Dr Foster explained, Dr Steenbergen and her colleagues found that this particular probiotic helped reduce cognitive reactivity to sad mood and the aggressive negative ruminative thinking that is common in states of major depression even though in the study there were healthy adults, not depressed.

That really caught my eye when I saw the article about that study. I said to myself, "Wow. If this probiotic will do that, I need to get some of that and get some of my patients on it because so many of my patients are dealing with symptoms like that." I reached out to Winclove. They were kind enough to respond very readily and quickly. Kind enough to ship me some samples, and when I saw the results in my patients, that's when I realized that this could be very helpful.

To get back to your question why this one, the main reason is that because I saw the research study documenting that this particular one had benefits for those types of symptoms that I commonly see in my patients. But then also looking at the specific species that are contained in this particular probiotic, Bifidum bacterium species is one of them, and also Winclove really dialed down to not the specific subspecies in terms of which bacteria they included in their product. I have seen other studies besides Dr Steenbergen's in the literature mentioning probiotics that contained Bifidum bacterium species as far as helping with mood.

That's really why I said this probiotic seems to have the species that I've seen in literature can help with psychiatric symptoms and there's a study to back up that it treats symptoms that are common in depressed patients. That's why I said this one definitely has value as far as helping psychiatric patients.

Gazella: Yeah. It's always good to use the exact product that was used in the study. I think that's a really important factor. Before I get to the outcomes of your patients, it seems like dosing is always challenging. Do you dose the same with all of your patients and what dose do you typically prescribe to your mental health patients.

Bay: Right. The dose that's recommended by the manufacturer is the one that I typically prescribe, which is one sachet it's called, really just a packet of powder, in several ounces of tepid or lukewarm water once a day on an empty stomach. On occasion, I have suggested to patients that if they did not respond to one packet a day to try one packet twice a day. I've made that recommendation in the case of people who have especially severe gastrointestinal symptoms as well as mood symptoms or in people who they only had a very modest response to one packet a day or maybe not much of a response. But the vast majority of the patients that I've had try the Target gb-X have only been taking it once a day, and they have found that very effective.

Gazella: Okay, perfect. Describe some of the outcomes you've achieved in your practice using this particular probiotic.

Bay: In the original case series that I did when, again, I only had the samples shipped from the Netherlands, there were about 8 patients. They all had very rapid and thorough relief from their gastrointestinal symptoms such as irritable bowel syndrome symptoms, whether that was constipation or diarrhea. One older lady had this chronic severe diarrhea despite being on 2 antidepressants that are notorious for causing constipation. That was especially puzzling, but on the probiotic her diarrhea stopped.

I had another male patient with just very, very severe treatment resistant depression. He had tried multiple antidepressants of all different classes of drugs. No relief whatsoever, and he was only able to tolerate a very low dose of a much older generation antidepressant. But also he had chronic, severe, unremitting diarrhea. This man literally wore out his gastroenterologist's office and was not able to get any relief from it. The diarrhea stopped almost immediately upon staring the probiotic. That was amazing, and he was quite surprised, too.

These are the types of outcomes that I've seen as far as the GI symptoms. As far as mood symptoms, they were not as immediate or as dramatic, but usually after months, sometimes after 2 months, patients were able to look back and say you know what, I do think my mood is at least somewhat better than it was before I added this. It definitely has been successful as far as bringing about improvement in mood symptoms as well as improvement in gastrointestinal symptoms.

Gazella: Yeah, that's great. This as been a lot of great info, and once again I would like to thank the sponsor of this interview who is Klaire Labs. And I would like to thank you Dr Foster and you Dr Bay for joining me today.

Foster: Thanks very much, Karolyn.

Bay: Yes, you're very welcome. Thank you. It's been a pleasure.

Gazella: All right. Have a great day.

Sep 5, 2018

In this interview, Ross Pelton, RPh, PhD, CCN, describes the new science associated with postbiotic metabolites and their impact on health. Listeners will also discover what postbiotic metabolites are and why they are so important to the human microbiome.

About the Expert

Ross Pelton, RPh, PhD, CCN, is Essential Formula's director of science, in additino to being a practicing pharmacist, clinical nutritionist, and health educator in Southern Oregon. Pelton earned his bachelor of science in pharmacy from the University of Wisconsin and received his PhD in psychology and holistic Health from the University for Humanistic Studies in San Diego, California. A certified clinical nutritionist, Pelton was named as one of the Top 50 Most Influential Pharmacists in the United States by American Druggist magazine for his work in natural medicine. Pelton teaches continuing education programs for healthcare professionals to use natural medicine and integrate it into their practices. He also has authored numerous books, including The Drug-Induced Nutrient Depletion Handbook, which is a gold-standard reference book for health practitioners.

About the Sponsor

Essential Formulas

Essential Formulas Incorporated (EFI) was established in 2000 as the sole US distributor of world-renowned microbiologist Dr Iichiroh Ohhira’s award-winning probiotic dietary supplements and skin care products. Always an innovator, EFI introduced REG’ACTIV in 2015, containing ME-3, a probiotic catalyst that produces the “master’” oxidant glutathione inside the body's cells. A family-owned and operated business, EFI was founded on the philosophy of providing high-quality preventative, supportive, and comprehensive pro-health products for the entire family. EFI continues to flourish and grow through a strong company and product integrity and the knowledge that they’re providing scientifically proven products that positively impact the health and well-being of their customers.


Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today, we have a fascinating topic. We'll be talking about post-biotic metabolites with probiotic expert Dr Ross Pelton who is also an integrative pharmacist. Before we begin, I'd like to thank the sponsor of this interview who is Essential Formulas Incorporated. Dr Pelton, thank you so much for joining me.

Ross Pelton, RPh, PhD, CCN: Hi, Karolyn. It's nice to be with you.

Gazella: Well the research regarding the human microbiome is really exploding. Why is this so significant?

Pelton: Well I like to give people a little historical overview which I think gives us an understanding of how and why this incredible acceleration of research into the microbiome has taken place. I'd like to go back to the Human Genome Project. It took 13 years and billions of dollars to sequence the first human genome. After sequencing the human genome, one of the primary goals of that whole scientific endeavor, they thought once they sequenced the human genome we would be able to get cures for many of our chronic degenerative diseases.

That primary goal of the Human Genome Project was a total failure. We did not get any cures for human diseases from the Human Genome Project, but one important thing that we did get was the development of incredible technology and incredible equipment that allowed for much faster and much cheaper sequencing of genomes. That's when scientists started to use this new technology to sequence the genomes of bacteria in the human gastrointestinal tract. They were astounded with what they found, this whole massive population of organisms in the human gastrointestinal tract. Fortunately, our government then went on to fund the Human Microbiome Project. The funding for the Human Microbiome Project coupled with the incredible technology developed in the Human Genome Project allowed scientists to make tremendous progress in exploring and identifying many of the different species and strains of bacteria in the human microbiome.

Now, a little historical overview. Bacteria were discovered several hundred years ago, and scientists like Louis Pasteur had a major impact on the development of microbiology and the study of bacteria. But Louis Pasteur was responsible for the gene ... Excuse me. The germ theory of disease. He solved most of the serious diseases of his time. He developed vaccines for them and taught people how to avoid them or limit their problems. He was a global rock star in his lifetime because he solved most of the common diseases of his time. It would be similar if one person today solved Alzheimer's disease and cancer and diabetes and autism or something. It's amazing what he did, but he set in motion this germ theory of disease. For a couple of centuries, most people had the concept that germs or bacteria were bad. They're causing disease and we need to eradicate them.

Well another thing that happened along the way is that the only way scientists could study bacteria was extract them from the body, put them on what's called a Petri dish on an auger plate that allows the bacteria to grow, and then they watched them and observed it. A couple hundred years, that's the only way we could study bacteria, but we've recently learned that over 99% of your bacteria are anaerobic which means they can't stand oxygen. For a couple of hundred years, scientists would extract bacteria, put it in the lab to look at it, but it would get exposed to oxygen and die. For several hundred years, we could not study over 99% of the bacteria in our microbiome, but the development of this incredible technology from the Human Genome Project allowed scientists to start to dive into this new area and sequence the genomes of the bacteria and start to learn what they are and how they function. That's what started to kind of explode the research into the human genome, the human microbiome.

Also a very interesting thing happened. There's a thing that I refer to as the genome complexity conundrum. This is a fact that, when the human genome was sequenced, we found out that humans have about 23000 genes which is significantly less than scientists thought they would find, but the conundrum is that the common rice plant has around 45000 genes. Scientists are scratching their heads. How could we as evolved beings as we are have only 23000 genes and the common rice plant has over twice as many genes as we do? The answer to this conundrum is the fact that, although we only have 23000 genes, the bacteria in our microbiome have millions of genes. In fact, over 99% of the DNA in your body is the DNA of your bacteria.

This starts to open up an understanding of how important it is to create and maintain a healthy population of these bacteria in your microbiome so that they are doing good work for you. Because if you have pathological bacteria, their DNA and their genes are creating bad compounds that cause inflammation and poison you and create all sorts of diseases. This ... We're starting to understand why it is so important to create and maintain a healthy microbiome because your bacteria in your gastrointestinal tract are controlling and regulating vast amounts of your health.

Gazella: Well I have-

Pelton: It's kind of a little overview for starters.

Gazella: Yeah. I have to say I love that historical perspective because it provides the perfect backdrop for today's conversation. Thank you. It was very thorough.

Pelton: Sure.

Gazella: Now today, I'd like to focus on post-biotic metabolites because, as you have referred to in your recent presentation, this really is a new frontier in probiotic science. Remind us. What are post-biotic metabolites?

Pelton: This is another fascinating area, Karolyn. It's just starting to be explored, but it's extremely important when it comes to microbiome science. [inaudible 00:06:39] say in my lectures and seminars the reason probiotic bacteria is important is because of the work they do. The work that they do is that their metabolic processes digest the food that you give them and break it down and, in turn, their metabolic processes produce a wide range of compounds that we're referring to as post-biotic metabolites. What's really important for people to understand is it's these compounds that the bacteria produce that regulate vast amounts of your health, not the bacteria themselves.

We're shifting our focus a little bit from putting all our research efforts and all of our money into just identifying and naming different strains of bacteria. Now, we're starting to realize it's probably more important to identify what are the compounds that these bacteria produce, what are the health regulatory effects of these compounds, which strains of bacteria are more efficient and more effective at producing some of these compounds. That's the new frontier in microbiome science. Two months ago, I gave a presentation at the International Probiotic Association's annual convention in Miami. The title of my presentation was Post-biotic Metabolites: The New Frontier in Microbiome Science. This is what we're starting to explore and understand now.

Gazella: Yeah. It sees like it's taking this science ... It's giving it a whole new level of complexity. Let's talk a little bit about practical things like what functions do these metabolites serve as it relates to the human microbiome and health in general.

Pelton: Sure. That's a good segue here. I'm emphasizing these post-biotic metabolites. What do they do? Well they have a vast number of functions, and in fact, a very highly respected author and scientist in the microbiome arena—his name is Dr Emeran Mayer—wrote a book called The Mind-Gut Connection. In his book, he tells us that your bacteria with their millions of genes will digest your food and produce hundreds of thousands of metabolites. We're just beginning to understand what all these metabolites, these post-biotic metabolites are. Some of their functions, they have antiinflammatory activity. They adjust the acid-base balance in the GI tract. They have cell signaling capabilities. They have detoxification capabilities. They can directly fight and kill pathological bacteria. There's just a wide range of functions.

Let me just mention one major class of these post-biotic metabolites. They're called short-chain fatty acids. This is a class of really important post-biotic metabolites produced by your probiotic bacteria. Since they're acids, short-chain fatty acids, they're weak acids, but they create the proper and optimal acid-base balance in the gastrointestinal tract. The optimal acid-base balance is just slightly acidic, but when people have dysbiosis ... That's the term for different types of gastrointestinal problems or you have gas or bloating or diarrhea or constipation or inflammation or pain or whatever. Dysbiosis is the term for these general conditions. When people have dysbiosis or gastrointestinal problems, the acid-base balance goes anywhere from 10 to 100 times too alkaline. If you're going to get the GI tract back to good health, you have to bring it from it's alkalinity back down to its slightly acidic condition, and these short-chain fatty acids produced by the probiotic bacteria readjust and create that optimal slightly acidic acid-base balance.

Short-chain fatty acids also have antiinflammatory activity. If you have dysbiosis and gut problems, you've got inflammation. They'll help to dampen that inflammatory fire. Also another really important part of this in the story with the short-chain fatty acids is the fact that the cells that line your gastrointestinal tract have the most rapid rate of turnover of any cell in the human body. People don't realize this. Most people don't, but you create a whole new digestive tract every 6 to 10 days. It takes an enormous amount of energy for the body to continually generate these new cells in the lining of the gastrointestinal tract, and you do not get the energy to produce these new cells from your blood supply. The energy comes from short-chain fatty acids like butyric acid that are produced by your probiotic bacteria, these post-biotic metabolites.

These are just some of the ways one class of post-biotic metabolites, the short-chain fatty acids, contribute to a wide range of health-related things related to your gastrointestinal tract.

Gazella: Now, can you expand a little bit more on the mechanisms of action and how these metabolites kind of work on our behalf? I mean the short-chain fatty acids is a great example.

Pelton: Sure. Again, there's a wide range of these different compounds, and so there's different mechanisms depending on what post-biotic metabolite the particular strain of bacteria are producing. This gives me a chance to emphasize a really important point, Karolyn. A healthy microbiome is a widely diverse microbiome. By diversity, I mean a lot of different types of probiotic bacteria. It's not enough just to have high numbers but only a few different types. You want to have lower numbers but a wide range of different types of bacteria. If you have diversity of bacteria, you'll have a lot more bacteria producing different types of health regulatory compounds, and the way to create a diverse microbiome is to consume a diverse diet.

You have to consume a wide range of different high-fiber foods because these are the foods that your bacteria require. The fibers in multi-colored vegetables especially, that's the number one food group for your probiotic bacteria. Then there's also multi-colored vegetables and various other types of foods that are high in fiber, but our human body cannot digest these fibers. They go through your system into your colon, your large intestine, and that's where your probiotic bacteria start to digest them. That's the food for your probiotic bacteria. Yes, it's important to take probiotics, but you have to learn how to feed your probiotic bacteria well. If you don't, they will not thrive and survive.

Here's a couple of examples of some other mechanisms and how they work on our behalf. Some probiotic bacteria produce a wide range of compounds called antimicrobial peptides. Scientists just abbreviate these as AMPs, but antimicrobial peptides are very small amino acid chains or I describe them as small fragments of proteins. They specifically have antibiotic effects, but they have a narrow range of effectiveness. They are only damaging to pathological bacteria. They don't harm your good bacteria whereas prescription antibiotics are called broad-spectrum. They kill everything, your good and your bad, but the natural antibiotics produced by your microbiome and your probiotic bacteria as antimicrobial peptides are only going to function or be active against pathologic organisms. It's an important part of your immune system. These natural antibiotics being produced in a healthy microbiome are sometimes suppressing the growth of any bad bacteria that happen to be resident in your gut.

Another example, there's lactobacillus fermentum ME-3. It's a very unique strain of probiotic bacteria that synthesizes glutathione. Glutathione is a post-biotic metabolite of that particular strain of probiotic bacteria. I could go on and on. There are many different types of post-biotic metabolites. Just a couple of general classes, your probiotic bacteria are little chemical manufacturing plants. They make all the B vitamins and Vitamin K and some of the critical amino acids. They make some of our most important nutrients. That's really a source of some of our nutrition. That's a little overview of some of the things and some of the ways that some of these other post-biotic metabolites are helping us.

Gazella: Yeah. Those are some great examples. I have to say, when I knew that I was going to talk to you about this topic, I jumped online to do a literature search and I was actually quite surprised at the amount of research specifically about post-biotic metabolites. Can you tell us about some of the more recent studies that you have enjoyed reading about in the scientific literature?

Pelton: Sure. Well I'm very excited having learned that a strain of bacteria called lactobacillus fermentum ME-3 can produce glutathione. Glutathione is one of the most important compounds in the human body. We call it the master antioxidant. It's produced in every cell in your body, and glutathione probably protects more of your body than all the other antioxidants combined. Glutathione also is the master regulator of all your detoxification. Being able to boost your glutathione levels by taking a strain of probiotic bacteria everyday is really a breakthrough in health and medicine. That's a pretty unique, new understanding of one particular strain of probiotic bacteria.

Another thing that's very exciting to me is that, last year in Japan, there was some independent research done on Dr Ohhira's Probiotics which is a brand of probiotics that's produced in a fermentation process that's different than all other types of probiotics on the market. The fermentation process used in the production of Dr Ohhira's Probiotics allows the final product to contain over 400 post-biotic metabolites. This is a real interesting, new viewpoint and insight into how probiotic bacteria work where you've got a probiotic, Dr Ohhira's Probiotic by brand name, that's produced in a multi-year fermentation process -- and I'll explain that in just a moment -- but the end product contains 400 of these post-biotic metabolites.

Let me explain this fermentation process and how these post-biotic metabolites are produced. We start out with big fermentation vats in a sterile warehouse. They start out with 12 strains of probiotic bacteria. Then they, at seasonally appropriate times, harvest and shred dozens of different types of organically grown foods: mushrooms, vegetables, seaweeds, fruits, and so forth. Then the bacteria get to grow and digest and ferment these foods for 3 years before the product is ready for encapsulation. During that 3-year fermentation process the bacteria in those fermentation vats are breaking down the food and producing this wide range of post-biotic metabolites.

With Dr Ohhira's Probiotics, we are not so much impressed by the probiotic bacteria we're delivering. We're really focusing on the delivery of these post-biotic metabolites. We get what we call rapid microbiome restoration because we're not just supplying somebody with bacteria in a capsule. We're directly delivering these post-biotic metabolites. Other companies that supply probiotics, you have a capsule with bacteria in it. Those bacteria haven't done any work yet. It's like a starter culture. When you take those bacteria, they have to go into your system, start to try to find the proper foods that they need so that their metabolic processes can begin to start to produce some of these post-biotic metabolites that are responsible for improving the health of the gastrointestinal tract.

But with Dr Ohhira's, we're directly putting in over 400 post-biotic metabolites. We quickly readjust the acid-base balance and suppress inflammation and start to heal the leaky gut or intestinal permeability problems and have some detoxification capabilities and start to work against some of the allergies that might be present in the GI tract. It's a very fast, rapid way of addressing gastrointestinal problems.

Gazella: Yeah. I'll disclose to our listeners that I actually have been taking the Dr Ohhira brand of probiotics for a lot of years actually now. I have been impressed with the product. You're telling me something very, very new though. I had no idea about the 400 post-biotic metabolites and this delivery of all these post-biotic metabolites. I've always loved the fermentation process and all the organic foods that are put in there in a 3-year period, and there's just so much that I love about the product. This kind of adds a new level of complexity to this particular product. I'd like to stay on the Dr Ohhira product just because I always like to clarify dosages and ... Now, how many strains, again, are in the Dr Ohhira product?

Pelton: There's 12 strains that we use to start the process, but again, I want to kind of emphasize that our product is really what we call a complete microbiome product because it doesn't just have probiotic bacteria. It's got probiotic bacteria plus some of the prebiotic food supply that was present in the fermentation process, and most importantly, it's got this wide range of post-biotic metabolites.

We just redesigned the packaging for Dr Ohhira's Probiotics, and on the new package, there are 3 different arrows that go in a circular direction. The 3 individual areas, the words inside the arrows say probiotics, prebiotics, and post-biotics. The post-biotic arrow is right front and center on the package. We're trying to emphasize to people the importance of this topic of post-biotic metabolites and Dr Ohhira's specifically delivering post-biotic metabolites. There is no other probiotic in the world that we know of that is produced in this multi-year fermentation process that allows the direct delivery of post-biotic metabolites.

Gazella: So as a result, do you dose this differently than you would a typical probiotic? Am I able to maybe use less? How do you handle the dosing of this?

Pelton: Sure. The recommended dosage is 2 capsules daily. I'll give just a little recommendation on some other uses of it. If people have food poisoning and it's very common when people travel, get some bad food, and get sick pretty quickly, then I advise them to bite and squeeze the contents out of Dr Ohhira's and swallow it that way because the capsule in Dr Ohhira's is a patented delivery system where the capsule actually stays hard in the harsh acid environment in the stomach and then it becomes porous in the more alkaline pH in the small intestine. So it preferentially releases the contents in the small intestine. But if you've got food poisoning, if you've got bad bacteria directly in your stomach, you want to bite the capsules, squeeze the contents out so it gets directly into your stomach and start to fight the bacteria locally in the stomach. I have people who chew 5 to 10 capsules and do it every 20 or 30 minutes, and it clears food poisoning out very quickly for most people.

Another thing to emphasize is that, in the fermentation process, the bacteria learn to grow and thrive and survive at room temperature. Dr Ohhira's does not need to be refrigerated. That's a very nice user-friendly part of Dr Ohhira's. Also because of this patented capsule design, you don't have to worry about food. It can be empty stomach, can be with meals, after meals, makes no difference. Main thing is everyday get them in. If I'm working with somebody that has Crohn's disease or colitis or irritable bowel syndrome, some of these really serious GI problems, I personally suggest they try taking 5 to 10 capsules daily, maybe 5 capsules twice a day for a period of 10 days or longer until you start to get improvement because you want to power these post-biotic metabolites and start to accelerate the change.

Some relatively new information, SIBO is a condition that is getting a lot more press these days, becoming more recognized as a fairly widespread condition. SIBO stands for small intestinal bacterial overgrowth where you have bad bacteria that normally reside in the colon, but they backed up into the small intestine and then they digest foods there. They're in the wrong location in the GI tract. They produce a lot of gas and bloating and diarrhea. So a lot of people with SIBO can't tolerate probiotics, but with Dr Ohhira's Probiotics, we're not primarily delivering probiotic bacteria. We're delivering the post-biotic metabolites. Many people on SIBO will find that Dr Ohhira's is very helpful.

Gazella: Interesting. An interesting note too, it doesn't taste bad. I've actually opened up the capsule and put it on a little part of my gum.

Pelton: I'm glad you brought that up, Karolyn, because that's another recommendation I make. There are a couple of dentists that make this recommendation, and I myself do it personally. Several nights a week at bedtime, I will take one capsule and bite it in my mouth and squeeze the contents out and swish it around in my mouth before swallowing it. This helps support a healthy oral microbiome. It helps to suppress gingivitis and periodontal disease and things like that. We're not calling it a treatment for these conditions. You're just trying to support the health of your oral cavity and a good healthy oral microbiome.

Gazella: Yeah, absolutely. Probiotic supplementation and probiotic science has really come a long way. There was a time when we thought that all you had to do is eat a little yogurt and you're good to go. Then there was the exciting research regarding prebiotics and synbiotics. Now, there's this topic of post-biotic metabolites. What does the future hold when it comes to this exciting area of study that seems to be moving quite rapidly?

Pelton: Well I think the future is in post-biotic metabolites because ... In fact, even pharmaceutical companies, drug company industry is starting to look at post-biotic metabolites and realizing that there's potential for them to develop new drugs on these naturally occurring compounds that are produced by your probiotic bacteria. These are compounds that are natural to the human body. It's not like they're putting a foreign chemical into your body.

As I mentioned earlier, Dr Mayer, in his book The Mind-Gut Connection. He's telling us that your probiotic bacteria produce hundreds of thousands of metabolites. I think the future will be less emphasis on just trying to name and identify strains of bacteria, but learn more about what are the compounds, what are the post-biotic metabolites that these bacteria make, what are the health regulatory effects of these compounds, which bacteria are more efficient at producing these compounds.

I think that's really the new area, new era, new frontier of microbiome research. It really is very exciting because we're really starting to understand that the microbiome is the foundation of your health at all levels. There's a physician by the name of Alessio Fasano who discovered the primary cause of leaky gut and intestinal permeability which happens when you have inflammation, it opens up your tight junctions in your GI tract and allows toxic things to leak into your system. Dr Fasano says that 2 main causes of inflammation and leaky gut are gluten and bad bacteria. I recommend that everybody be on a gluten-free diet. Then we need to clean the gut up.

I did a presentation a month ago at the American Association of Antiaging Medicine Conference, and my topic was Natural Therapies for ADD and ADHD. One of my primary messages is scientists are looking for the answers for autism and ADD and ADHD in the brain. Don't look in the brain. The answer is in the gut. We have to heal the gut and heal this intestinal permeability problem because if you have leaky gut, you have leaky brain. We mean your blood-brain barrier is leaky and some of these toxins are getting into your brain. You have gut inflammation. You have brain inflammation.

We have to focus on the gut, and one of the most serious worldwide health dilemmas right now is the rapid rise in antibiotic-resistant bacteria. Many of the people listening to this probably are familiar with MRSA, methicillin-resistant Staph aureus. There's hardly any antibiotics that are effective against it anymore. Now, we've got antibiotic-resistant [inaudible 00:29:33] and antibiotic-resistant tuberculosis on the rise. We have to understand that we have to reduce our reliance on antibiotics and increase our reliance on good bacteria. We need more bugs, not drugs.

The rise of antibiotic-resistant bacteria is a global health crisis, and you don't want to have a weak immune system and wait until you get sick because scientists are talking about a post-antibiotic era where antibiotics are not going to be effective anymore. We won't be able to have Cesarean births and we won't be able to have our appendix out or our teeth cleaned because, if you get an infection, you're dead. The answer to the problem is to have a good healthy diet with lots of fiber-rich foods to create a diverse microbiome which gives you a healthy immune system. That's the way to stay away from all these antibiotic prescriptions. That's my little rant on that topic.

Gazella: No. It makes a lot of sense. I have to say that human microbiome research is fascinating and so important. This new research on post-biotic metabolites resulting from probiotics just really adds a lot to the conversation that we need to have about -- excuse me -- the human microbiome. Don't you agree?

Pelton: I agree totally. I think this is the next level of understanding of how and why the microbiome is important and gives people a little bit more insight into why it's so important to learn how to create and maintain a healthy microbiome so you can have many different types of bacteria producing all these health regulatory post-biotic metabolites so that, in turn, you will have a healthy immune system.

Gazella: Absolutely. Well this has been a great interview with a lot of great, important information. Once again, I'd like to thank the sponsor of this interview who is Essential Formulas Incorporated. Thank you, Dr Pelton, for joining me today.

Pelton: My pleasure. Nice to be with you, Karolyn.

Gazella: Have a great day.

Pelton: You bet. Bye-bye.

Aug 14, 2018

This paper is part of NMJ's 2018 Microbiome Special Issue. Download the full issue here.

In this interview, naturopathic physician and probiotic expert Donald Brown, ND, discusses the role of probiotics in supporting the gut microbiome. Brown also describes the mechanisms of action and clinical applications of probiotics, as well as strains, dosages and potential contraindications.

About the Expert

Donald Brown

Donald J. Brown, ND, is one of the leading authorities in the USA on the safety and efficacy of dietary supplements, evidence-based herbal medicine, and probiotics. Brown currently serves as the director of Natural Product Research Consultants (NPRC) in Seattle. He is a member of the Advisory Board of the American Botanical Council (ABC) and the Editorial Board of The Integrative Medicine Alert. He was a member of the Board of Directors for the International Probiotics Association (2008-2010) and its Scientific Advisory Board (2006-2008). He has also previously served as an advisor to the Office of Dietary Supplements at the National Institutes of Health. Brown is the author of Herbal Prescriptions for Health and Healing (Lotus Press, 2002) and was a contributor to The Natural Pharmacy (Prima Publishing, 2006), the A-Z Guide to Drug-Herb-Vitamin Interactions (Prima Publishing, 2006), and The Textbook of Natural Medicine (Churchill Livingstone, 2006).

About the Sponsor

Allergy Research Group

Founded in 1979 by molecular geneticist Stephen Levine, PhD, Allergy Research Group® is one of the very first truly hypoallergenic nutritional supplement companies. For nearly 40 years Allergy Research Group® has been a leading innovator and educator in the natural products industry. Our dedication to the latest research about cutting-edge nutritional supplements continues to this day.

Our purpose is to provide customers with products they can use to improve their patients’ quality of life, through scientific based innovation, purity of ingredients, education and outstanding service.

ARG is proud to be a sponsor of the Clinical Education LinkedIn Forum, a closed peer-to-peer group on LinkedIn where healthcare professionals can ask clinical questions and receive evidence-based and clinical-based responses by experts in their field.

Visit for more information & to sign up for free!

Visit for more information on ARG and our products.


Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today we are exploring the impact that probiotics can have on the gut microbiome. Before we begin, I'd like to thank the sponsor of this topic who is Allergy Research Group.

My guest is naturopathic physician and a leading probiotic expert, Dr. Donald Brown. Dr. Brown, thank you so much for joining me.

Donald J. Brown, ND: Hi Karolyn. It's a pleasure to talk to you. It's been a long time.

Gazella: I know.

Brown: How are you?

Gazella: I'm doing great. I know. This is like old times. And you know, before we dig into this topic, I have to tell you that I am just fascinated by the human microbiome, and it seems like the research in this area has really exploded. Why is that?

Brown: Well, I think, again, it's ironic as a naturopath talking about it because we've always talked about the impact that the intestinal tract has on health in general. Immune health, skin health, so forth and so on, and I think that what's happened is that particularly probiotic research has led us to realize that there's these microbes on our body. And we have a tendency in probiotics to focus on bacteria, but what's exploding in this area is that we have resident microbes that are viral microbes. We have fungal microbes that are natural inhabitants of our body.

So looking at this, we're really talking about 40 trillion microbes, predominantly bacteria, and sort of the balance that we have with these microbes which are part of our body. And it's funny because the research [inaudible 00:01:54] dramatic, and we have 10 times more microbes on us and in us, mainly in us, than we have cells. And the new data is really indicating that that's not the case; it's about 1.3 to 1.

So people who get itchy when they think that they have more bacteria on them than cells, it's not quite as dramatic as we thought. Again, I think it gets back to the fact that we're recognizing the fact that these things play such an interesting part in our health and our wellness, and when it tips in the wrong direction, our illness too. So expanding it out so we're not just looking at the microbes in the GI tract, but the microbes in other parts of our body as well.

Gazella: Yeah, I think that's really some of the most interesting parts of this research is that it does expand beyond the intestinal tract. So as it relates to the human microbiome, remind us of the mechanisms of actions that probiotics have. How and why do probiotics even work?

Brown: Well, probiotics ... When you think about the GI tract, the analogy I like to use, especially when I'm talking to the public ... talking to healthcare professionals here ... is it's sort of like a busy parking lot. And you have organisms that are health promoting, and then you have organisms that are potential pathogens, and they're looking for parking spots. Remember that bacteria ... viruses are the same way ... have to adhere to cells to be able to be either health promoting or disease promoting.

So that's one of the first things that probiotics are doing is they're competing for spots. And once they actually set up house, they then start creating a micro-environment that is inhospitable to potential pathogens, producing things that are anti ... compounds that are antimicrobial. They alter the pH slightly to make it inhospitable for these microbes and really create a situation where, "Hey, this is our home. This is our neighborhood, and you're not welcome here" kind of a thing.

The other thing that should resonate with most of the doctors on the phone is the whole idea of leaky gut and intestinal barrier function, too. It's one of the things that probiotics do once they set up house is they're also helping to produce mucin and to sort of keep those tight junctions in the intestinal tract, the cells healthy and intact. And that's very, very important.

The other thing that they do is they also, in the colon, are producing short-chain fatty acids which are associated with reducing risk of cancer as we age. Production of short-chain fatty acids act to help with digestive health as well. And then one of the really interesting things that's really been discovered over the last, I would say, eight to 10 years, is that when these little bacteria actually bind, they're communicating through the intestinal wall with what are called dendritic cells which are funny-looking, little, sort of odd-looking starfish type things that send little feelers up through the ... into the epithelial cells. And the probiotics are actually communicating with them to sort of modulate the immune system. So they produce a little bit more of this, produce a little less of this. Inflammatory responses are also modulated through it.

And then the last thing and one of the really, really interesting things right now is we're beginning to realize that the intestinal tract is communicating with the brain. So the gut-brain axis is what that's called, and we know that stress, for instance, can actually negatively impact the probiotics in the GI tract, the healthy bacteria in the GI tract, and in turn, through the vagal nerve going up to the hypothalamic-pituitary axis, actually modulates that response.

So we're now finding out that probiotics may actually be involved in ... I'm sure you've done interviews where you talk about the HPA axis and stress response. We're now finding out that the GI tract is very, very directly involved in that. So it could be negatively impacted by stress but can also positively impact the HPA axis, which is a whole new mechanism of action which is wild.

So we've got gut health, digestive health. We have immune health based on responses with the GI tract. Now we're finding out that there's actually effects on mood, stress response, that sort of thing. And that's not even covering the female genitourinary tract which has its whole population of probiotics that are positively affecting genitourinary tract health as well, so it's big. It's a vast influence on the body.

Gazella: Yeah. There is a lot going on here with probiotics. I think that's why I like the topic so much because there's just so much to talk about.

So when we're looking at the scientific literature and the research, what conditions have the most compelling research in terms of improved outcomes? I realize that this may be a pretty long list, given the mechanisms that you've just described, but take us through that list from a research perspective.

Well, I think what I like to do is I like to start with the things that are accepted by the larger medical community. And one of those is the fact that we've known for a long time that probiotics have a positive effect on prevention of antibiotic-associated diarrhea. So I would put that probably at the top of the list of, hey, if I'm in a room and I've got people who are skeptical of alternative medicine, integrative medicine, that's always a good starting point because we have really solid data that antibiotics definitely are good at preventing that.

My background is in pediatrics, and I think another area that has sort of reached a critical mass is actually ... it's fascinating ... is the prevention of atopic dermatitis in children who are potentially at risk. The studies started ... First one was in the Lancet in early 2000s, and basically the studies are looking at mom particularly but also whoever the partner is, and risk of ... that have a background of atopic diseases, allergic diseases, and actually starting to give mom probiotics during the second half of her last trimester. And then once the baby is born, if mom's nursing, continuing to give the probiotics to the mom until she stops. And then, anyway, it varies on the study, but usually then the infant starts to take the probiotics.

What they're finding is that it's reducing the incidence of atopic dermatitis by about 50%. That's amazing to me because if you look at sort of tracking the use of the antibiotics in children on a graph and you look at the increase in atopic diseases, so you're looking at eczema, atopic dermatitis. You look at asthma. They track almost exactly if you look at from 25 years ago to now, they track almost exactly. And also cesarean births contributing to that as well where the microbiome, so that's really fascinating to me.

I would say the other area, sort of shifting gears, that I think has reached a critical mass is also adjunctive use of probiotics in female genitourinary tract health. So treatment using standard treatments for things like bacterial vaginosis would probably be the top area, but also prevention of recurrence of urinary tract infections.

We're, particularly in the bacterial vaginosis area, I think really reaching a point where we have enough data to sort of suggest that, hey, using these things really can help with prevention. And then I would probably put the last one, as we move into the immune system and we really have reached a critical amount of data. Not a lot of pediatric data but adult data now that suggests that routine use of probiotics seems to reduce the incidence of upper respiratory tract infections. So, again, I could go on and on and on.

Gazella: Right. Yeah.

Brown: There's a lot of stuff. There's a lot of stuff that's emerging and that we're sort of on the edge.

But one of the things I think the listeners need to know about is the fact that I think we like to think about alternatives too, but one of the great things about probiotics is that adjunctive use. Obviously it's antibiotics, but Helicobacter pylori, for instance. The standard treatment of that is very rough on people. Recurrence rates are really high, so one of the themes that I always like to talk about when I talk in my lectures to healthcare professionals is that remember that a lot of the treatments that we use for ... Let's take urinary tract infections. E coli are really good at setting up what are called biofilms that are these little bits like taking a Visqueen sheet and putting it over themselves so that you can get to use the antibiotics. You can get to the ones that are not underneath the protective shield, but the ones that are under there don't get affected.

So one of the things that probiotics are great about is going in and helping to break up that biofilm and actually make standard treatment perform better, and then continuing to use the probiotics actually reduce recurrence rates. So, and there's reduced recurrence rates, and there's a whole litany of examples of areas where if we use probiotics. I mentioned helicobacter pylori but also UTI's, bacterial vaginosis, where probiotics actually help the treatment go better, outcomes are better, and then really reduces recurrence rates.

Gazella: Yeah. That's such a good point and you know, you mentioned antibiotics and how they disrupt gut flora and how probiotics can help reverse that dysbiosis. Are there other medications that kind of do the same thing as antibiotics where they disrupt that gut microbiota diversity and that probiotics may be able to help reverse that?

Brown: We're thinking that some of the more aggressive inflammatories that people take may have an affect. That's still sort of in the early phases. One of the early ones, interesting ones that there's still a limited amount of data, but I actually reviewed it, was a study with a proton pump inhibitor, so things that we're using for reflex and that sort of thing, having a very negative effect on the microbiome. So, we're sort of still in the early stages of learning what specific drugs and the effects are. Obviously antibiotics would the be the easiest case study, because we can actually look at the what affects. They've done studies with people who are getting the triple therapy for helicobacter pylori and realizing that during that therapy, the healthy bacteria in the G.I. tract can be reduced by as much as 80%. If we use probiotics, during that treatment, it reduces that to 40 to 50% and then if we continue to use it after, people tend to bounce back quicker. There are other drugs that we know are beginning to emerge that have negative effects, but stay tuned on that one.

Gazella: Right. Right. Now, let's switch gears and talk little bit about strains, because I know that that's a hot topic. So, specifically for the conditions that you mentioned in helping to restore gut microbiota that's been disrupted by medications like you were just talking about, what are the more common strains used for these types of clinical applications?

If you don't mind my backing that up, I am very, very disturbed when I hear people lecturing who say that strains don't matter. I go to a lot of international conferences. I sit on committees that set standards, international standards for probiotics and it is something that experts who know a lot more about this area than I do are upset about, because there are people out there who are saying that it's species specific and strains don't matter. I beg to differ.

I think that it's very, very important that health care professionals realize that, particularly health care professionals realize that ... and Karolyn, you've known me for a long time. We've done interviews about [bontanical 00:16:20] medicine that I'm an evidenced based person. I like to see the ... particularly if we're talking about treating a condition. And so when we go from species level where there's very little research to strain level, we emerge into an area where we know what the dosage was, that was used in the study. Particularly when we talk about pediatrics, we talked about people who might be immune compromised. We talked about older folks like myself. It's important also to ... safety is pertinent too and that's one of the areas that is a little bit of a red flag for me with the whole probiotic area. Particularly on the commercial side where we have this race to do all these different things and some of the species level stuff that's being sold has not been clinically studied.

And so, very, very important that people realize that some of the standards that go around a strain or viability is the lack of bacillus or the bifidobacterium strain that you're using shown to be viable. Does it actually adhere in the intestine is one of the things that we now have the ... within the persons body, but we now have technology that can actually show that these things sort of do adhere, and how long they adhere, and how long they stick around.

Another thing that's really important that I've given many lectures to health care professionals is they don't think about is that we also don't want these strains, what's called trans located, we don't want them to go from the intestine to the blood stream. And they're having case studies. There was a paper published a number of years ago on people who were really severely immune compromised where the probiotic that was being ... it was a specific strain actually trans located into the blood stream and caused sepsis. People then had to be treated with very aggressive antibiotics. So, we don't want them to go from the intestinal tract into the blood stream.

Another one that's [inaudible 00:18:39] ... we're talking about antibiotics, I always chuckle when I remiss on this one is also we realized that hey, probiotics are good for people who are taking antibiotics, but we also want to be sure that the probiotics strain has been tested for not blocking the ability of the antibiotic to do it's job. So, it's called antibiotic resistance. And it can be transferable. They have run into organisms that we think are probiotics that actually have a negative effect on an antibiotic doing it's job, so that's important.

I already talked about safety and efficacy. I'm all about that. A silly one that I just want to toss in that's talked about internationally, that I still bump into in the U.S. more so than in other areas is the fact when we talk about being a probiotic supplement, we want to look at the label, and we want to be sure that these stability, or the shelf life of the product is actually been proven to the time expiration. There are still a lot of probiotic products that are sold in the United States that actually declare their potency at the time of manufacture, which is like, well okay, but I have a vitamin C product. They told me the potency when it was manufactured, but it says it has a two year shelf life. Have they actually tested that? Has that actually been proven? And so, remember, these are living organisms. Very, very important that stability or shelf life be proven for these as part of the choice of picking a supplement. 

Gazella: Well, I was just going to say, do you have some go to strains that you like to focus on when it comes to recommending probiotics?

Brown: I think there's a lot of them right now, actually. That's another area where we could probably go on and on about. There are what I like to call legacy strains that have been around for a while that have a lot of research on them that have ... and we also understand their mechanism of action really well. The one that people probably know the most is lactobacillus GG, which is a rhamnosus strain that was discovered by a couple of guys in Boston. I always like it when they give their own name to the strains. It was Gorbach and Goldin I think were their names, so they named it lactobacillus GG. But anyway, that one has been around for a long time. A lot of really, really excellent research. Some of the bifidobacterium strains from Japan from [Morinaga 00:21:24] is the name of the company, have a lot of research, particularly in the pediatric area. Been around really since the ... lactobacillus GG, since the early '60's, the Morinaga [inaudible 00:21:38] really since the '50's. The Japanese were doing isolation in human studies long before we were doing them here in the U.S.

Brown: Another one that I really like is lactobacillus acidophilus DDS-1. It's an interesting strain that was discovered by a guy named Dr. [Shahani 00:21:56]. By the way, all of these strains that we're talking about are derived from humans. These are human derived strains and this one was actually discovered and isolated first in 1959. And like the lactobacillus GG and some of the Morinaga strains has a lot of clinical research. It also ... in vitro research that shows that it adheres, that it survives. And then human trials, actually looking at it's ability to treat things like travelers diarrhea, prevent antibiotic associated diarrhea, those sorts of things.

When I look at products, I always look at what's the indication? What's been studied? There's commercial strains the lactobacillus, I'm sorry rhamnosus HN001, for instance, in the atopic dermatitis prevention area that has phenomenal studies. And so there are a number of strains out there that have reached that critical point of whether its specific to one condition or have been looked at in other areas that have really excellent data. And again, being somebody whose background was in pediatrics, I'm always also looking at what's your safety data as well. That would be an example of a few strains that I think have really excellent data.

Gazella: Yeah. That's good. And you know, not that long ago, we were seeing maybe just one or two species, one or two strains. Now we're seeing multi species, multi strains in these formulations, sometimes six, nine, twelve different species or strains in one formulation. Is that a good thing?

Brown: Sometimes it's a commercial thing. Here's my theory and I could easily be misproven [inaudible 00:23:58], but or unproven. Are you misproven or unproven? Which-

Gazella: I'm not sure.

Brown: Called out for my lack of proof. My answer to that, when I get asked that, and it's more common when I'm lecturing to the public or to managers of supplement sections is that probably for wellness purposes. So if I'm taking a probiotic or if I'm a doctor and I'm recommending a probiotic supplement to be taken daily, I probably would use something that's a little bit more of a multi strain. Sort of a balance between the lactobacilli family and the bifidobacterium family. That's a sort of my go to. And as you get into the senior population, seniors have a tendency to have a drop in the bifido. That's probably dietary related, because fiber and that sorts of things, they like to feed on ... They're probably eating less fiber in their diet.

But anyway. Having a balance of a number of strains, is there a magical number of strains? I don't think so at this point. I don't think anybody's proven that. I think the difficulty ... what I say to people is, is that when you shift, it's much easier to talk about a single strain or a combination of a couple strains. You know, in irritable bowel syndrome, inflammatory bowel disease, BSL-3 has eight different strains in it. I mean, that's a lot of strains. It's been around for a long time. They use very high doses, but its easier to look at disease endpoints when we do a clinical trials, because we have very clear outcomes that we're looking for compared to what's a placebo, for instance, Wellness studies are really hard to do, so I don't know that there's an easy answer to your question because I don't know if the company after I ... know a lot of them, and some of them have a lot of ... have deep pockets. I don't know who's gonna do a wellness study that shows that, "Hey, if you do this many strains at this potency, that it works better than if you only do one strain at this potency, or if you do nothing." 'Cause those are expensive studies to do.

Gazella: Yeah. Totally. And I'm gonna ask you another unfair question, and it's regarding dosage. You know that can be somewhat controversial, still debatable. How do you dose probiotics or recommend ... What's your philosophy on the dosage?

Brown: Well, I always start with what is the clinical. If I'm treating a specific condition and I'm using an evidence-based strain I dose it at the dose. And it's interesting, 'cause there's extremes and that's one of the issues when we look at meta-analyses that have been done, so stuff like say, not only was there this cacophony of strains that were used, going from one strain to five strains. That sort of thing. But the dose, the potency and we measure the potency of probiotics, what are called colony forming units so we talk about milligrams or gram amounts of these things. So I always try to look up with what the research showed.

Again, leading back to wellness and sort of, regular use. I have a patient who's take a multi-vitamin, who's taking fish oil every day and I say, "Hey, one of the things you should think about is keeping your intestinal tract healthy and probiotics are gonna contribute to that, keeping your immune system healthy." I don't have an easy answer for that.

I typically use multi-strains and I'll probably usually go in the 10 to 50 billion CFU per day. Is that correct? Is there clinical data to back that up? The answer is no, I don't know for sure. But that's sort of how I think.

The one thing that I can tell you is that I remember a client who decided to go high potency and high potency is definitely [inaudible 00:28:23] was like 25 billion CFUs per instance, it was like a shot across the balance. It was 12 years ago. And I'm freaking out because [inaudible 00:28:33]. You can't go run 5 billion CFUs per day or people gonna be having a [inaudible 00:28:41] reaction or getting thrown out of dinner parties 'cause they're farting and having to go to the bathroom all the time.

So what I can tell you is that we have enough data now in healthy people that if we go to, even, 100 billion CFUs per day that we're not seeing any adverse effects. We're usually with this ... How much of that is actually ... adhering how much of it is actually having an impact versus 40 billion, 50 billion or even 10 billion for that instance. So that's another one that's gonna be interesting to see how that evolves. There's obviously, particularly on the retail side in this race to see who can come out with the highest potency with most strains and we'll see how that goes.

Gazella: Right, yeah. Well, I think that was a difficult question and you answered it brilliantly. So now it seems like many probiotics on the market are actually synbiotics because they combine pro and prebiotics. Now, what's your view about this combination and why are more companies going in that direction? And am I right, are companies going in this direction?

Brown: Well, here's my criticism of that and I like synbiotics. I think the whole concept is an interesting one. On the retail commercial sense, it's been difficult for consumers to wrap their head around a probiotic and then also there's this concept called prebiotics and then again for people who are listening, a prebiotic is basically something that acts as a food for probiotics to feed on and grow and encourage growth even on their own.

The issue that I have with a lot of products that combine probiotics and prebiotics, whether it's FOS, GOS, XOS now is another one that's used. Now these are basically complex sugars. Really, for all intents and purposes, kind of fibers. All of the FDAs now said that they are probably not gonna qualify to make the cut.

The problem is that if you look at the studies on the prebiotics, the dosages are way higher than what you're gonna put into a capsule.

There are some probiotic products that I've seen that have ... that are powders or that are in the sachets where you can actually get the prebiotic up to a dose that actually has any meaningful effect clinically.

So remember with prebiotics, we're rack out a low of a gram and many of the studies were as high as 10 to 15 grams. So again, really important to sort of ... And I know this is a challenge for people who are in clinical practice because they're trying to treat some patients with what they think is the best, but it's really an issue of, again, getting back to sort of ... Does the company make an attempt to sort of match up the dosage of the prebiotic that actually showed an effect, a positive effect on probiotics? And that's a challenge. That your delivery yet [inaudible 00:31:50] in capsules, it's under dose. You don't get enough of the prebiotic.

Gazella: Yeah, that's really interesting because I was not aware of that. So, that's a good heads up there. Now you talked about safety, but are there any contraindications that clinicians should be aware of? Direct contraindications that says, "This patient should not be on probiotics"?

Brown: The area that I'm most cautious about ... I used to think it was premature infants, very low growth weight infants, but there's been enough research. When you ask, probably why the other thing too, that would be our [inaudible 00:32:24] list of things that have really reached critical masses, prevention of what's called Necrotizing Enterocolitis and in very low growth rate entrance ... fascinating and it worked. It's basically saving lives is what we are talking about. The death rate from that is quite high. So used to saying, "Hey, these kids are born ... GI tracts not really developed." That's a potentially dangerous use in that population.

The answer to that is "No, actually. It's actually good." I would still continue to encourage on healthcare professionals to be very selective in strains that they use in people ... HIV positive, AIDS, people with really severe immune deficiencies. Cancer patients who ... technically more advanced cancer. Be very selective and try to get to the best of their possibility, look at the data and say, "Okay, this is strain that actually was used in that population and works." That would not ... Those two populations are ... that collection of population severely immunocompromised people is not one that I could, probably just use any probiotic supplement. Particularly multi-strain, high potency without doing any sort of research.

I'm very selective and usually do one strain or two strains in that population that I feel have enough safety data.

Gazella: Yeah, that's good advice. Anything else that you'd like to add on the topic of probiotics for listeners that you'd like to leave them with?

Brown: Again, I just think that it very, very important to first and foremost, and I'm repeating myself. First and foremost look at if you're using it for specific use. We didn't even get into female genital urinary tract health nursing. Really amazing stuff going on in that area. Your oral use of probiotics to actually, finding that they're populating in the vagina and that you're getting significant effects, which is amazing. We used to think you'd have to use everything with ... through a vaginal, pessary type of an effect. So that's it.

I think again, trying as much as possible to deal with companies that are trying to ... that are working with strain suppliers or strain suppliers that are manufacturing products for them that are looking at the essentials that we talked about at the beginning. It's really, really important to me. And also again, trying to insist that companies refer back to the data on specific strains as opposed to just saying "It doesn't matter, you can use anything you want." I'm horrified when I go to professional lectures and I hear ... For instance, medical doctor getting up and saying that it's [inaudible 00:35:14]. So it goes against every thing that is accepted in the probiotic world. So, again, a lot of white noise in this area. Healthcare professionals are going to be as susceptible to it as consumers are but that's a couple of areas where I think you can sort of cut through that and try to get to what really has been shown to be effective and safe.

Gazella: Yeah. I mean, it's a big topic for sure. We're going to have you back to dig in a little bit more deeply on some of these topics, but I want to thank you for definitely shedding some light on this important topic, and helping us get through it. And I'd also like to once again thank the sponsor of this topic, who is Allergy Research Group. So Dr. Brown, thank you again for giving us all this wonderful information and I hope you have an awesome day.

Brown: Thank you Karolyn.

Aug 14, 2018

This paper is part of NMJ's 2018 Microbiome Special Issue. Download the full issue here.

In this interview Natural Medicine Journal's editor-in-chief, Tina Kaczor, ND, FABNO, and Steven Sandberg-Lewis, ND, DHANP, discuss the integral role of the gut microbiota in mood and cognition. A review of how the gut and brain communicate through both the nerves and gut microbial metabolites is discussed. They also talk about how intestinal permeability and brain permeability are associated and what you can do about it. As a naturopathic clinician with over 40 years' experience, Sandberg-Lewis shares some clinically useful pearls along the way. 

About the Expert

Steven Sandberg-Lewis

Steven Sandberg-Lewis, ND, DHANP, has been practicing since 1978, teaches gastroenterology at National University of Natural Medicine and has a private practice at 8Hearts Health and Wellness in Portland, Oregon. He lectures, presents webinars and interviews on issues of digestive health.

He is the author of the medical textbook Functional Gastroenterology: Assessing and Addressing the Causes of Functional Digestive Disorders, Second Edition, 2017. His column Functional Gastroenterology Bolus appears regularly in the Townsend Letter.

Within gastroenterology, Sandberg-Lewis has special interest and expertise in inflammatory bowel disease, irritable bowel syndrome, small intestine bacterial overgrowth (SIBO), hiatal hernia, gastroesophageal and bile reflux (GERD), biliary dyskinesia, and chronic states of nausea and vomiting. He lives in Portland with his wife, Kayle. His interests include mandolin, guitar, writing, and lecturing.


Tina Kaczor, ND, FABNO: Hello, I'm Tina Kaczor with the Natural Medicine Journal. I'm speaking today with Dr. Steven Sandberg-Lewis and our topic is the gut-brain axis. Dr. Sandberg-Lewis has been a practicing clinician for over 40 years now and he is the author of Functional Gastroenterology: Assessing the Causes of Functional Gastrointestinal Disorders, and that has come out in a second edition as of March 2017. He's also adjunct full professor at the National University of Natural Medicine. Dr. Sandberg-Lewis, thank you so much for joining me today.

Steven Sandberg-Lewis, ND, DHANP: You're welcome.

Kaczor: Alright, so I think our talk about the gut-brain axis is extremely timely because of the media attention now given to the bacteria and the effect of our microbiome on our physical ailments and I think it's beginning to look at how it effects the brain both cognition and mood as well.

And so, what I'd like to do is really start at the beginning and can you just give us a quick overview of what exactly do we mean when we talk about the gut-brain axis?

Sandberg-Lewis: Yeah, naturopathic medicine seems to always be at least 30 years ahead of the rest of medicine. We've been talking about this a long time but now we have a lot of research to back up what we talk about. So, the gut-brain axis probably has many more players than we're aware of but the ones we know about are, of course, the microbiota, a lot of people call that the 'microbiome'. But it's the bugs. About 100 trillion of them and they are, of course, not just in the colon but in the small bowel, in the stomach, which is not sterile and the oral and esophageal areas.

The true meaning of microbiome is the genome of the gut floor which has way more, at least 100X more genes than the human genome, which is 26,000. And when you put the two together, you call it the 'holobiome', which is the human genes and the microbial gene. But really, you need to do that because they interplay so much and the bugs really control our genome so intensely.

Then there's that whole genetic piece then there's all the, what we call the metabolon. What the bugs and the enteric cells make, all their metabolic products and that includes secretory IGA, short chain fatty acids, lipooligosaccharide, bacterial hormones and neurotransmitters and cytocinesis. We can talk about all those kind of details.

And then of course there's the enteric nervous system speaking to the vagus and the vagus speaking back. And there's the HPA axis and then there's the immune system and the gut. So, it's huge. It's so much talk it's deafening crosstalk.

Kaczor: It is interesting and one of the pleasures, I think, I've been practicing nearly 20 years and I know that you've been practicing over 40 eyras so, it's quite a long time to watch the evolution of thought processes in medicine as well as the population at large.

And in some of the folk medicine even, naturopathic medicine, but good old folk medicine, an apple a day and staying regular and keeping the bowels moving, it's amazing how that comes back at us and now we're talking about it in scientific terms which is fascinating to watch the pendulum swing.

Okay so, when we talk about how they communicate, you gave a little overview of some of the ways, when you mention the vagus system, what do you mean exactly?

Sandberg-Lewis: On every new patient, I like to have them open their mouth, stick out their tongue, take a look at their palatal arch and their uvula and then have them say 'ah'. When they phonate, we've all done this, check the vagus nerve. The place you can check the vagus nerve directly is there in the palate because the levator palatini muscles on either side raise the palate when you say 'ah' and when you phonate.

So, I'd like to see both arches go up symmetrically and not an asymmetrical rod. Occasionally you see nothing. The patient says 'ah', nothing happens. There's no palatal rise and you can have them do it over and over and nothing happens. So, that's a sign that the vagus isn't really firing the way it's supposed to and there are lots of ways to try and improve vegul tone. But that's a good thing to know about your patient.

The next thing is the vagus nerve gets sensory information from the enteric nervous system and the neuroendocrine cells in the gut as well as the epithelial cells. It gets input in actually 90% they assume, 90% of the crosstalk is from the enteric nervous system to the Brian through the vagus.

So, it's mostly the gut talking to the Brian and then the brain through the vagus talks back about 10% of the time. So, there's direct transmission through the nerves and then there's all the cytocinesis and other factors and neuro peptides that also speak through the humoral method.

Kaczor: So, what you're saying is the gut itself is sending signals through the vagus nerve to the central nervous system and effecting what exactly?

Sandberg-Lewis: So, yeah. It's pretty interesting what the gut is interested in talking about. Yeah, you wonder, what does my gut have to say? What does it care about? So, what the gut is saying, the 90% of impulse is going from the gut to the brain, it's talking about the shape and the consistency of the bowless of food moving through and scraping up against the ... rubbing up against the mucosa. The sheering forces of the bowless against the mucosa. That's stimulating serotonin locally but there's also this ... That's what the gut's interested in. Is, what kind of food is it, what's the shape, what's the consistency and what does it feel like as it rubs against the enteric cells?

This seems to stimulate taste receptors on the antero endocrine cells that are scattered throughout the mucosa and give information about the composition of the food, there's, again, there's all these neuro peptides and hormones, GI hormones that are released as well. But directly through the vagus nerve, we think it's mostly the gut talking about it's scratchiness of the food and the size and the consistency and the kind of food.

Kaczor: Okay. And I have to clarify for my own self, when you say 'taste receptors', you're going beyond the tongue? Is that what I hear you saying? Is this "taste receptors" that you say along the GI tract, how does that work?

Sandberg-Lewis: Air quotes, well, our genius in our midst, Paul [Calmens 00:08:18], he's been telling me for years that there are taste receptors throughout the entire gut. And especially most pronounced is the bitter, bitter receptors. And I've tried to go into the research and find out what exactly they do. We don't know a lot about what they do but we know that bitter receptors are not just in the tongue and the mouth, they're throughout the whole gut and they seem to trigger the release when they're stimulated. They trigger the release of ghrelin and glucagon peptide one which have to do with blood sugar balance and hunger and my guess is, Flip Wilson used to say, "The devil made me do it" when he did something that he thought was nasty.

But I really think that in many ways, the GI flora and the food that we eat interact to create cravings so that the body can get what it needs. And if you get more ghrelin, you get hungrier. And certain other, like GLP, maybe you're gonna create more sugar.

It's really important, of course, to eat food ... I think this is why Indies think it's so important to eat foods that's close to nature because once you get these synthetically modified foods or their consistency and their flavor and their compositions is altered, it probably throws off these natural mechanisms that tell us when to eat, when not to eat, when our blood sugar is fine, when it needs to go up or down. So, these are really finely tuned things.

Kaczor: Yeah, it's interesting in context, again, of traditional medicines because it automatically makes me think of Ayurvedic medicine and other traditional practices that naturally balance the flavors on the plate, that's a big part of making sure each meal is healthy in that tradition. So, let's talk about the microbiotas some more.

You mentioned briefly that its metabolites are part of the talk between the gut and the brain, can you elaborate on that?

Sandberg-Lewis: Yeah. First of all, I wanted to mention that the metabolic byproducts, the products of the microbiota, it's huge, it's huge. And Emerson Mayor's book, the gut-brain connection, he makes a quote that 40% of the metabolites in human blood are derived from gut flora, which blew my mind completely.

And so, I said, "Where is he getting that?" And I looked, I found it in two or three different articles. And so, to me, that means 40% of our blood chemistry is derived from the intestinal flora. And that makes sense since there are at least 10-to-1 more of them than there is of us in terms of cells. But I never really put that together.

So, there's these metabolites in our blood derived from the flora that do fine tuning of eating behavior, mod, blood glucose, digestive secretion, absorption, motility, just it's mind blowing. It's so important and it makes sense. You can understand that when you go ahead and even just take a broad spectrum antibiotic, we know that greatly increases the risk of kids and even adults, getting inflammatory bowl disease, especially Crohn's.

Just so many effects on immunity and the balance within the body if we knock down the bacteria or alter them or decrease their diversity. So, pretty important, pretty major stuff that everybody's been messing around with since the 1920s and '30s with antibiotics.

Kaczor: Mm-hmm (affirmative). Yeah and you mention a metabolite that caught my attention because I think it's at least in our naturopathic circles, we're paying a lot of attention to the role of that lipopolysaccaride and the LPS, for short. Can you talk a little bit about that? Because I feel like that's, as far as I can see, getting a bit of attention these days in how the gut and brain effect one another.

Sandberg-Lewis: Yeah well, I'm glad it's getting attention, it deserves it. You know, every physician knows about LPS in one particular way and that is, it is the cause of septic shock. It kills people if the LPS is high enough. What we don't usually hear about and we're starting to get more and more research on is, what about physiological levels of LPS when it's not super high?

Sandberg-Lewis: LPS is used in research, they inject it into lab animals to activate the NF kappa B pathway of inflammation and there's a tremendous amount of it. These are from the gram-negatives. The gram-positives also have an inflammatory precursor like this, which is the peptidoglycan. But, mostly we talk about the gram-negative because it's so potent and there were a million copies or so of LPS in each gram-negative microbe and it's not just something that gets emitted when the bug dies, it's also just when it's replicating or if you take an antibiotic and weaken it a little bit, they don't have to die to give off LPS.

And it's thought that in the adult human gut, you have up to a gram of LPS, a thousand milligrams at any one time. So, it's a major player. There's a lot of it and it can trigger the Zonulin pathway, which leads to intestinal permeability, hyperpermeability, which we know is related to autoimmunity and allergies.

Obese humans have up to a three fold increase in LPS compared to lean and maybe some of that also dove tails with the fact that obese adipose tissue has 10X as many macrofacies. So, you got a lot of esocine activity, a lot of TNF alpha.

Kaczor: Mm-hmm (affirmative).

Sandberg-Lewis: And different types of enteric flora have different amounts of LPS. Or even different potentiates. So, antero bacter are thought to have some of the most potent LPS that can be up to 1,000X more potent than some of the other gram-negative bacteria.

So, this is a major toxin, it's a major provoker of inflammation and pre radical activity in all kinds of changes.

Kaczor: So, how does LPS effect the brain directly? Since, I hear what you're saying and I know even in experimental animals LPS is a common way to reliably instill an inflammatory process in a lab animal. So, it's clearly a very potent, inflammatory molecule. How does it effect the brain?

Sandberg-Lewis: So, the bacteria, we get some bacteria trans locating into the blood but they usually get called out after they travel through the portal vein to the liver by the cooper cells. At least if the liver's working well. You're not gonna have a lot of bacteria in the blood but the bacteria can still effect the central nervous system, even if they don't cross the blood brain barrier and never even get there.

First of all, one mechanism is that LPS and the inflammatory cytocinesis that it induces include interleukin one, interleukin six and I mentioned TNF alpha and they can actually up regulate the transcription of these cytocinesis in certain discrete areas of the brain.

And then one of the things that happens with that is, within the brain you get an up regulation of indoleamine dioxygenase, which is that enzyme that converts tryptophan to kynurenine and that can move further to quinolinic acid, which is neurodegenerative. Although, there's quinolinic acid, which is also has a positive effect.

So, depending on how it goes through the pathways, you can have neuro degeneration up regulated. And studies show that depression, anxiety and insomnia can issue from high levels of quinolinic acid. So, there's that.

There's also cognitive deficits and in my book, very important, is increased visceral sensitivity. All the functional disorders of the GI tract, there is increased visceral sensitivity meaning, people perceive their own motility and movement within the gut as pain or strong discomfort. And man, those patients are strong to treat because if you start to activate their GI tract and get it moving again after it's been atonic for years, then they're complaining that they're up all night with abdominal pain. And that's a tough one, we're trying to learn more about how to deal with visceral hypersensitivity.

But, it's thought that LPS is one of the things that triggers that too.

Kaczor: So, I have a two part question. I guess, in our clinical assessment of LPS, is there a means, I mean, I know that we could do testing for small intestine bacteria overgrowth through breath testing but, is there any blood test, I guess is what I'm thinking? Can you tack on any blood test to gauge LPS levels and the second part of this question is, what do we do about it?

I suppose treating the gut in a totality dysbiosis present, is the short answer. Any clinical pearls are certainly welcome.

Sandberg-Lewis: Yeah. So, you can, this is available, you can measure LPS. You can measure LPS binding protein, I believe as well. And you can, in your patients, you can, of course, measure zonulin, which gets up regulated by LPS. So, yeah. By all means, start experimenting with that and then see if you can get the levels down.

Now, yeah. I'm known for spearheading along with some other really busy physicians and researchers. The treatment and in our case, more the natural treatment, of small intestine bacterial overgrowth, you just can't get away from it. It's so key to, we used to say, "Death begins in the colon" when I was in school in the 1970s and now, I think it makes sense to say, "Disfunction and autoimmunity begins in the small intestine". It's just associated with so much and that includes neurodegenerative diseases, like Parkinson's as well.

A practical thing, yeah. Learn how to test for, interpret and treat ... Use your testing and learn how to treat SIBO. Both the hydrogen, methane and hydrogen sulfide types. And don't throw out the yeast with it either because they often go together and get that metabolite base 40% of the blood. Get it into a functional mode instead of a dysfunctional mode.

Kaczor: Mm-hmm (affirmative). Mm-hmm (affirmative). Yeah. And I know, I will say that, you lecture and write a lot on the clinical aspects of this. So, anyone who wants further information can certainly start Googling you and find lots and lots to followup on. I do want to ask another question because this issue that we are in for the Natural Medicine Journal this month is a special on the microbiota and the microbiome. How do probiotics specially effect the gut-brain axis?

Sandberg-Lewis: I don't know that we have enough yet to really have a great answer. Although, there are some docs out there that really have a strong handle on the strain specific effects of probiotics and people like Jason Hawrelak who is a ND and teaches at Western States and practices in Australia, he has totally got that covered. So, I would highly recommend looking at his website Jason Hawrelak, Hawrelak. But I mean, we know that there are studies that show that fermented foods significantly reduce anxiety, especially social anxiety.

And there's a lot more research going on on strains, specific things that show that there are specific effects on anxiety and depression. But it's still really early so, I can't say I have a really good picture of that. When people ask me about probiotics, I usually say, "I don't know anything about probiotics". They don't believe me but, yeah.

Kaczor: So, is it accurate to say that you advocate the whole foods diet, plenty of prebiotics in the form of fibers and resistant starches and things like that and then trust that if that is done well and consistently and then, of course if there is other treatments to kill undesirable bacteria etc. but complimenting ... I mean, the way to encourage the good bacteria is to give the prebiotics more in your view?

Sandberg-Lewis: Well, the problem is a lot of my patients, because they have overgrowth, they can't tolerate prebiotics and fiber. So, when I first start working with them, we can't really use those things except very specific types. We know that partially hydrolyzed program seems to be actually beneficial for people who have overgrowth, sometimes used along with rifaximin in treatment of hydrogen SIBO and it increases the effectiveness of that.

But, there's some GOS's that that may also be well tolerated. But that's a problem in the beginning because if you have overgrowth and then you feed them with a prebiotic, then it just increases symptoms and problems. So, it's a fine balance, it's a fine balance. But, yeah. I really encourage my patients to eat whatever fermented foods, probiotic foods that they tolerate.

So, we use lactose-free, fermented dairy products, we use pickled items like kimchi or sauerkraut, the real stuff not the fake stuff. The refrigerated kind. Or homemade. And things like that. I think all traditional groups of people around the world have their own probiotic foods. Some of them pretty hard to even relate to, like haggis in ... where is that? Scotland. Where they eat the goat stomach that's fermented. Fish and rotten fish in the northern areas of Europe.

There are some really interesting things you'd think, "Why the hell would people ever invent that food?" But these things have tremendous fermentative capabilities. And one thing that I'm sure NDs understand this but it comes up a lot with patients asking, they'll say, "So, you don't want me to eat any fermented food, right? Because I already have ... You want me on a low fermentation diet". And I say to them, "Well, no that's not what I want you to do". Unless you have a histamine sensitivity and you can't handle foods that are fermented, I want you to use those things because if you eat a high fermentation diet that has carbohydrates that are easily fermented, that produces gases. Hydrogen, carbon dioxide, maybe ethanol, methane, hydrogen sulfide in the gut and causes distention and pain and changes the stools and can cause bloating.

But if you eat a food that is a fermented food, the gases have already come off into the atmosphere in the process of fermentation and now you're just getting all the bacteria and the great metabolites without the gas that causes the symptoms. I think that's an important differentiation.

Kaczor: Well, yeah that's a great way to put it. To help them and us understand it a little bit. One last question, we'll end on a fun question, when you hear the term 'gut reaction to something', because we're talking about the gut-brain axis and someone says, "I used my gut" or gut instinct, gut reaction, what do you think?

Sandberg-Lewis: Well, I'll bet physicians with different backgrounds have different ways of interpreting that but clearly if 90% of the input in the gut-brain axis is coming from the gut and if you think about it, if virtually every neuro peptide and GI hormone that's produced in the gut effects insulin and blood sugar and we know the brain suffers within minutes from blood sugar that's too low whereas the other organs may not care for quite some time and oxygen as well, of course, to the brain within three minutes.

There are major effects on life and death related emotions that take place when the gut is feeling like something is wrong and it's gonna make more jittery molecules instead of more serotonin and gaba.

And that's gonna have very rapid effects on the mood and on the functioning of the person's nervous system.

Kaczor: Mm-hmm (affirmative). Alright well, I sure do appreciate the time you took to talk to us today about this. It is a huge topic and I am excited, as a naturopath that everything is coming back to a source, the GI tract, I mean and we've always been taught that we have to remedy the gut and get that in order before we can really keep someone in an optimal health state.

So, sometimes that's harder than others and I do appreciate the time it took to enlighten us today with the gut-brain axis and it look forward to talking to you probably in the realm of gastroenterology again in the future.

Sandberg-Lewis: Great, let's do it.

Kaczor: Alright, take care.

Sandberg-Lewis: Alright, bye.

May 15, 2018

In this interview, naturopathic physician Carrie Decker, ND, describes some of the actions she takes with patients to help reduce the risk of developing dementia and cognitive decline. Her integrative approach includes nutritional and lifestyle assessment, assessment for common risk factors or other potential exposures, and nutritional supplementation to meet her patients' individual needs.

About the Expert

Carrie Decker, ND, is a certified Naturopathic Doctor, graduating with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Decker sees patients at her office in Portland as well as remotely, with a focus on gastrointestinal disease, mood imbalances, eating disorders, autoimmune disease, and chronic fatigue. Prior to becoming a naturopathic physician, Decker was an engineer, and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectively. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Decker supports Allergy Research Group as a member of their education and product development team.

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Allergy Research Group

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Karolyn Gazella: Hello, I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today we're talking about maintaining healthy brain function with naturopathic physician, Dr. Carrie Decker. Before we begin, I'd like to thank the sponsor of this podcast who is Allergy Research Group. Dr. Decker, thank you so much for joining me.

Carrie Decker: Thanks Karolyn, I'm glad I'm able to be with you today.

Gazella: So we're going to start by having you remind us of the medical definition of dementia, and then tell us how common these conditions are.

Decker: Yeah, so dementia basically is the mental decline and associative changes in memory, mood and even personality which can occur from an acute incident, such as a vascular event or head injury, or be the progressive changes we see with conditions such as Alzheimer's and Parkinson's Disease, or even alcoholism. There are other less common causes of dementia as well.

Not surprisingly, many of these conditions can overlap, particularly vascular and Alzheimer's dementia. The main difference with vasculars and Alzheimer's dementia, is that with a vascular event there will be a more sudden decline and then a fairly stable period compared to the typical slow decline of Alzheimer's disease. With a vascular event you might see a sudden change in personality, mood, language or even motor symptoms. Personality, mood and motor changes also may occur with Alzheimer's disease, but are generally in the later stages and occur gradually.

Vascular or stroke related dementia accounts for 10 to 20% of dementia in the US and Europe. And the most common type of stroke is ischemic stroke which represents roughly 80% of all strokes in the US. There actually is a region in the US known as the stroke belt in the Southeast, which I was unaware of. Multiple studies have found a higher incidents of stroke in this region. Even in well characterized populations such as healthy male physicians and patients born there. There are many subcategories of ischemic stroke and, of course, all are associated with conditions such as a clot or vessel disease which leads to obstruction and reduced blood flow. And with this oxygen, the nutrients to a focal region of the brain.

With a hemorrhagic stroke, which is often associated with hypertension and trauma, blood leaks into the brain and locally increases pressure in the surrounding region. Changes with a hemorrhagic stroke may occur somewhat gradually over minutes or hours, where the intracerebral hemorrhage are very suddenly with a subarachnoid hemorrhage.

Clinically, the course of events helps to diagnose which type of stroke someone had, but brain and vascular imaging is required for diagnoses. Incidents of cognitive impairment in dementia after stroke ranges from six to 32% which becomes clouded with factors contributing to other types of dementia the longer the patient is followed.

Alzheimer's dementia is most common type of dementia. In the age specific incidents ranges from less than 1% in an individual 65 to 70 years of age, to as high as 8% in individuals 85 years in age and older. Early onset Alzheimer and dementia can occur in individuals as young as 30, however this is far less common and usually genetically related or many misdiagnoses and other conditions which can cause cognitive changes.

Gazella: Perfect. So what I'd like to do, is I'd like to focus on Alzheimer's a little bit, because it is the most common form of dementia as you mentioned. So what are some of the hallmark changes that take place in the brain, that can indicate Alzheimer's has set in?

Decker: So all this again is pretty gradual, but the key things that occur in the brain with Alzheimer's dementia, which many people ... the physicians out there, at least will remember from cramming for pathology tests, are extra cellular deposits to amyloid beta peptides near fibrillary degeneration and associated tangles and neuritic plaques.

These are not specifically seen with imaging, but analysis techniques and tracers are constantly being developed that can help us see these changes more specifically. Additional biomarkers that assess for changes in markers related to tau and amyloid beta in the cerebral spinal fluid are also being developed to help determine the risk of cognitive decline and assess for Alzheimer's disease, but are not yet recommended for routine diagnostic purposes.

Brain imaging with an MRI is indicated in the evaluation of dementia and is capable of identifying alternative diagnoses such as the cerebral vascular types of events. Contrast may be used, excuse me, to help visualize the regions of vascular compromise or even an altered blood-brain barrier.

Structural changes seen in an MRI with Alzheimer's dementia include general and focal atrophy, as well as white matter lesions; however, these findings are non-specific.

The most characteristic finding with Alzheimer's disease is reduced hippocampal volume, or medial lobe atrophy, which must be evaluated relative to one's age, as a decrease in volume is normal with aging, as well.

At times, there might be a dramatic reduction in hippocampal volume of over 40%. Positron Emission Tomography, which is commonly called a PET scan, with amyloid tracers can help us determine if there's an amyloid burden on the brain and this helps rule out the likelihood of Alzheimer's dementia if they're not found. But, it's not diagnostic if they are found, because you still have to rule out other types of pathology.

Gazella: Okay, perfect. Now what are some of the symptoms of Alzheimer's disease?

Decker: As most people ... even an untrained non-professional would know, the cognitive impairment is one of the most common signs that we see. Especially, initially, with Alzheimer's dementia. But it may be accompanied by executive disfunction and visual spatial impairments.

Executive disfunction may manifest as difficulties in things like problem solving, multi-tasking, and abstract reasoning. Visual spatial impairment can manifest as changes with difficulties with reading, discriminating form and color, perceiving contrast, and detecting motion.

For the most part, these deficits and changes manifest insidiously.

The memory changes with Alzheimer's dementia involve significant deficits and declarative episodic memory, that is the memory of events occurring at particular time and place, which relies heavily on the hippocampal function.

Memories for recent events are also impaired early in Alzheimer's disease, whereas the ability to recall something that's mentally rehearsed, like an address, is kind of spared early on.

Longer term memories, which have been consolidated and in essence kind of rehearsed over years, are also spared because they don't rely on the hippocampal function. The deficits in immediate recall of rehearsed items, as well as semantic memory, the knowledge and facts we accumulate through our lives, gradually develop with time.

Procedural memory, like knowing how to tie your shoes, can become affected in the later stages. Generally, the earlier changes are described overall, as recent memory impairment. Kind of avoid confusion and language that's often over a patient or caregiver's level of understanding.

Also, with this we might see neuropsychiatric changes, particularly in the mid to late stages of the disease. This can include apathy or depression, irritability or related disengagement.

More severe behavioral disturbances, such as aggression, wandering, and psychosis or hallucinations, also can be seen but really should be evaluated for further other possible causes, such as infection or medication-related toxicity, which is also more common in the elderly.

It is not uncommon for patients to underestimate their deficits and offer alibis or explanations for them when they're pointed out, which kind of contributes to some of the mood-related symptoms, such as irritability for people.

Loss of insight also occurs with time. And, interestingly, those with more insight into their condition are more depressed. While those with less insight are more likely to become agitated, experience psychotic features or perform actions like leaving the house, wandering in their pajamas. Which, if someone had the insight, they were less likely to do.

Seizures may also occur in 10 to 20% of individuals in the later stations of Alzheimer's disease. The seizure type isn't so much a motor one, it's more of a focal non-motor seizure which manifests with impaired awareness, confusing amnesia spells, unexplained emotions, and experience of a metallic taste.

Sleep disturbances are also common with Alzheimer's disease and may occur early in the disease process. This includes the fragmented sleep. It also may manifest as longer sleep. Sleep time generally decreases by 30 minutes per decade, starting at mid-life. So some sleep changes are also normal with aging. Poor sleep also happens to be a risk factor for cognitive decline and dementia, which is important to note.

Gazella: Yeah, it's a devastating diagnosis, there's no question about it. And today we're talking about reducing risk. How do we even know that's possible?

Decker: Whenever I think about risk for any type of disease, I think about, "Well, what are the risk factors?" And if we can associate it with a risk factor, if we deal with those risk factors then we're reducing your risk.

So, from the Alzheimer's disease, specifically risk factors are hypertension, dyslipidemia, and altered glucose metabolism. Each, of course, is treatable. Individuals who are physically active have a reduced incidence risk of Alzheimer's disease and cognitive decline. Exercise, of course, also reduces the risk of these other things; the hypertension, dyslipidemia, and hyperglycemia. So we really can't say enough about that.

Long-term use of certain medications, such as benzodiazepines, anticholinergics, antihistamines, opioids, and proton pump inhibitors, may be associated with increased risk of Alzheimer's disease. So working with patients to discontinue these, if not needed, may really benefit brain health.

Exposure to environmental pollutants, including air pollution, second-hand smoke, or pesticides may put someone at increased risk for Alzheimer's disease.

Chronic infections, such as Lyme disease, also may put someone at risk for developing dementia. That can be mistaken for Alzheimer's disease, but the inflammatory aspect of any type of chronic condition also may play into something that may later manifest as Alzheimer's.

Cigarette smoking contributes to cardiovascular disease and hypertension, both of which are risk factors for Alzheimer's disease.

The high-sugar diet, of course, contributes to the development of diabetes and hyperinsulinemia, which increases the risk of Alzheimer's.

Excessive alcohol use contributes to dementia in its own right and affects memory acutely. Chronic use of alcohol in excess also contributes to hyperglycemia and the nutritional deficiencies, which may also be contributing factors to longer-term memory problems, as well as Alzheimer's.

So, with so many things that are risk factors that are associated with Alzheimer's disease, correcting them inevitably reduced the risk. And then when we start to eliminate many of these factors that are known risk factors for Alzheimer's disease, or at least associated with it, the reduction in risk, of course, compounds as well.

Genetically, there are definitely some things that we're unable to change, per se, but we can still influence the phenotype by addressing environment, nutritional, and other factors which impact it.

Gazella: Well, that's great. And I would like to talk about nutrition and specific diet. You mentioned high-sugar diet as being a possible risk factor. When it comes to reducing risk, what do you like to emphasize and why?

Decker: For me, really that's one of the biggest places to start. Reducing the high intake of high glycemic foods, like the breads, pastas, desserts and sugary snacks, often is one of the first changes that most people need to make.

So often, people are grabbing these things for a quick energy fix because they're easy. And they also come with a blood sugar spike and then a blood sugar crash. Good brain food really includes foods that provide the essential vitamins and minerals, proteins, and healthy fats. Eating a diet that has lots of color, and not the artificial variety, helps people to take in the necessary vitamins and minerals, as well as many other phytonutrients found in fruits and vegetables.

Nuts like walnuts, which provide healthy fats, protein, Vitamin E, as well as other nutrients and salmon, which provides a lot of Omega-3 fatty acids, are particularly good things to routinely include in the diet.

A higher total intake of Omega-3 fatty acids, particularly DHA, is associated with a reduced risk of Alzheimer's disease. DHA helps reduce the amyloid beta peptide accumulation, as well as oxidative damage, which also is a contributor to Alzheimer's.

One more part of that, when you dial really into the diet more, on an individual basis there might be other things that come up, things like the food sensitivities, the allergies, different types of things that cause inflammation. And for some sensitive people, even things that are high in histamine might be something to reduce. Histamine is an inflammatory mediator, which released from basophils and mast cells in the body, like when we have an allergic response, but it's also found in certain [inaudible 00:11:40] like fermented meats and wine. People can become more sensitive to foods like this when the lining of the gut is damaged, or if they have certain genetics related to the breakdown of histamine. Histamine increases the blood-brain barrier permeability, which can contribute to neuroinflammation and neurodegeneration.

Gluten absolutely should be out of the diet for people with celiac disease, as it's been determined in this population, specifically, to contribute to cognitive impairment, as well as nutritional deficiencies. But, not only them, the people who are not affected by celiac disease also can have an inflammatory response and with this foggy thinking, however we don't have research that I'm aware of that specifically connects it with Alzheimer's yet.

Gazella: Okay, so it sounds like a really solid anti-inflammatory diet. In addition to diet, you mentioned exercise. You mentioned sleep. But what other lifestyle factors are critical to look at when it comes to reducing risk of dementia in the patient population?

Decker: Yeah, like I said, exercise is one of those things that just is important for so many aspects of metabolic health, but also has other ways that it improves cognitive function. It's something that supports the levels of brain-derived neurotrophic factor in the body. We shorten that up, calling it BDNF. And that improves neurogenesis and cognitive pathways in the brain. Exercise also has been shown to increase hippocampal and total brain volume, which we already talked about as being something that happens with Alzheimer's disease.

Cognitive stimulating also benefits cognition, and that's been shown in studies. Just something people talk about. So whether this includes reading a book, playing a game of cards, or learning a new musical instrument or other skill, it's important to include.

Eliminating smoking and excessive alcohol intake also should be a part of a dementia protocol. But, also general health promoting advice.

Healthy sleep is important for cognitive function and preventing dementia. So working with lifestyle to make adaptations, such as new blue light or other stimulating things at least an hour before bed might come into play with people if the sleep is poor.

Gazella: So Let's talk a little bit more specifically about nutritional factors and how they might contribute to cognitive decline in Alzheimer's disease.

Decker: Nutritionally, deficiencies or lower levels of certain vitamins, minerals, or other essential nutrients have been shown to be associated with Alzheimer's disease. This includes the B vitamins; B-12 and folate, Zinc, Vitamin D, as well as tocophorols, and tocotrienols. Lower levels of CoQ10, which our body produces, have also been shown in some studies to be associated with an increased risk of dementia.

I believe it's critically important to start with the necessary nutrients, such as these, because their impact in the body extends far beyond just the brain.

Zinc has a critical function in the brain and lack of zinc can cause neuronal death. Low zinc levels are associated with a poor ability to smell and depression. So if these symptoms are also mentioned, screening should be considered.

Homocysteine levels have been observed to be significantly higher in patients with Alzheimer's disease and also can be deficiencies in the B vitamins; folate, B-12, or riboflavin. Homocysteine elevation also is commonly seen in cardiovascular disease and depression. So if these are also an issue for a patient, and even if not really, this should also be considered.

Vitamin D access in your [inaudible 00:14:45] hormone and also impacts genetic expression. Vitamin D levels should be at least 30 nanograms per milliliters and I would recommend even higher, really around 50 nanograms per milliliters. Low levels of vitamin D are also often seen with cardiovascular disease and should be a part of screening for that.

Tocophorols, tocotrienols, and CoQ10, they're all fat-soluble, neuroprotective antioxidants and they're also cardio-protective. They support not only a healthy brain, but they reduce the risk of cholesterol oxidation and they support health vessel function, which can help reduce the risk of the vascular dementia, which we talked about earlier as well

Gazella: What about other botanicals or natural substances? Are there any others that have evidence supporting cognitive function and helping reducing risk?

Decker: Yeah. There's so many that I kind of got into thinking about some of them and there's way too many to discuss. But, I'm looking at ... I wanted to talk about some of them with the biggest evidence that I've seen.

So because inflammation plays a role with Alzheimer's disease, we talked about that with diet. Some different therapies, which can help reduce inflammation like oxidative shots, can be helpful. But some other mechanism-like things like essential fatty acids also may improve dementia.

When we talk about managing inflammation with natural substances, curcumin, the active compound found in tumeric is often at the top of the list. And it comes into play here, too. Curcumin has been shown to improve working memory, attention, and reduce cognitive decline in healthy elderly patients. Curcumin has clinical evidence it helps reduce depression, as well. Which, again, is common with Alzheimer's disease.

Mechanistically, it has been shown to reduce oxidative stress and accumulation of the beta amyloid plaques, at the same time reducing our increasing levels of protective antioxidants, such as superoxide dismutase.

Of course, making sure the curcumin is bioavailable is very important. The best data I've seen comparing a lot of the [inaudible 00:16:35] curcumin preparation suggests that the best bioavailable can be obtained with a molecular dispersion process that then answers the water solubility and dispersion of fat-soluble ingredients, like curcumin.

With this type of preparation, it's been shown to be even six times higher absorption than the more commonly used curcumin phytosome that's found in many supplements.

Another one that has a lot of evidence behind it is Huperzine A. Huperzine A is an extract from the club moss and it acts as an acytlcholinesterase inhibitor, which also happens to be one of the mechanisms of many drugs which address dementia. Huperzine A also may help reduce dementia by regulating production of beta amyloid precursor protein, protecting the cells from oxidative stress, mitochondrial disfunction, as well as damage associated with glutamate induced toxicity.

Glutamate's an excitatory neurotransmitter in the brain, and when in excess, it promotes some of this neuroinflammation and neurodegeneration that we see with a lot of chronic nervous system diseases.

There've been multiple randomized, placebo-controlled trials looking at the impact that Huperzine A has on both Alzheimer's disease, as well as vascular demential. It's been shown to significantly improve cognitive function in patients with mild to moderate vascular dementia and significantly improve cognition, mood, and activities of daily living scores in patients with mild to moderate Alzheimer's disease.

The benefits of Huperzine A have also benefits in other populations with findings of enhanced memory and learning in adolescence and improved recovery in elderly patients from general anesthesia.

Ginkgo Biloba has been studied in many clinical trials, as well as in the studying of dementia. As a botanical, we always think of it as being this go-to for supporting microcirculation, kind of in the fingertips, the toes, the eyes, the kidneys, but the brain is also a part of that. Ginkgo's protective, in part, due to its antioxidant effects and supports circulation in the small vessels by reducing platelet activation and aggregation, as well as stimulating the release of endothelium-derived relaxation factor.

In double-blind, randomized, placebo-controlled studies in patients with mild cognitive impairment, Ginkgo has been shown to improve cognitive function and reduce dementia conversion rate, improving episodic memory and even improving activity challenged gait, which is something that can be an issue with people with dementia.

In a double-blind, randomized, placebo-controlled study in patients with mild to moderate Alzheimer's or vascular dementia who also had the neuropsychiatric aspect of that, Ginkgo was shown to significantly improve cognition, neuropsychiatric symptoms, functional abilities, and the quality of life in patients, as well as their caregivers.

In healthy populations of middle-aged and older volunteers, Ginkgo has also been observed to positively impact memory, improving recall performance, as well as speed of processing abilities.

Lipids are also very important for the brain, which is not very surprising, as the brain is very fatty tissue. Brain cells are especially rich in phospholipid choline, which the body can synthesize from a substance called citicholine, also known as CDP choline. Citicholine and phospholipid choline both support the integrity and functionality of the neuronal membrane, as well as the mitochondria.

Citicholine provides choline, and enhances the synthesis of acetylcholine, the neurotransmitter that plays a significant role in memory and learning. Citicholine has been studied in multiple clinical trials with populations experiencing memory-related issues ranging from mild cognitive impairment to vascular dementia and Alzheimer's disease.

A Cochrane review assessed the effectively of citicholine in 14 double-blind, randomized, placebo-controlled trials in patients with cognitive impairment due to chronic cerebral disorders, which can include both the vascular and Alzheimer's disease and found that, in patients with cognitive impairment due to these disorders, that citicholine has positive effects on memory and behavior in at least short to medium term and they recommended that studies of longer duration be conducted. Significant improvements in mental performance have even been seen in patients with early-onset Alzheimer's disease treated with citicholine, as well.

In a population of patients with the apolipoprotein protein, E epsilon four allele, which increase the risk of dementia, including that of the early-onset dementia as well as vascular dementia, citicholine has been shown to significantly improve cognitive performance, also improving the parameters of cerebral blood profusion in brain bioelectrical activity patterns. In patients who had their first recent ischemic stroke, citicholine was shown to improve attention, executive function, temporal orientation, cognitive status, as well as quality of life, many of which often decline in this post-stroke period.

Lion's mane mushroom is another one that's worthy of mention in a discussion of dementia, as well as in the other changes that occur with aging. Lion's mane has a long history of traditional use for supporting nerve growth and we now know it induces the secretion of nerve growth factor. In recent randomized, double-blind, placebo-controlled studies, lion's mane has been shown to significantly increase cognitive function scores in patients with mild cognitive impairment, as well as reduce depression and anxiety.

In animal models, lion's mane has been shown to improve spatial short-term and visual recognition memory impairments induced by amyloid beta peptide.

Peripheral neuropathy is not uncommon at all in the aging population, whether it be due to diabetes, nutritional life deficiencies, or idiopathic in nature, and lion's mane can also be a benefit for this, because of the fact that it promotes nerve growth factor again. Lion's mane, like many of the medicinal mushrooms, also may have protective effects against certain forms of cancer.

Gazella: I was gonna say, there's a long list here.

Decker: I know. I just have to throw this last one in.

French maritime pine bark extract also is another one that's been the topic of several clinical studies related to cognitive function. Although, this one hasn't been studied in the population with Alzheimer's or the decline already, it's been studied in several different healthy population ... in different clinical studies. In population ages ranging from kids to older adults, even including 60 years in age and above, it was repeatedly shown to improve cognitive function, as well as additional memory retention, mental performance, and working memory in some of the studies.

And beyond cognitive function, it is also one of these that can positively impact blood pressure, cholesterol balance, blood sugar, and has positive impacts on these other diabetes-related microvasculature complications. So it's really excellent for use in individuals who also experience these other challenges.

Gazella: So that is a long list. You've identified lots of choices when it comes to nutrients and botanicals. Now, are there any safety issues or contraindications associated with this long list that you've just mentioned.

Decker: Yeah. Well for the nutrients, of course, some of them such as zinc and vitamin D are appropriate only if there's a deficiency. As an excess, they can cause problems. But, things like CoQ10, tocotrienols, and essential fatty acids are really very safe and are used in part to help reduce cardiovascular disease risk, as well.

The side effects that some people might experience with agents that help increase blood flow to the brain, like Ginkgo, is a slight headache. And, of course, if this occurs the dosage should be diminished or supplement discontinued if it doesn't subside.

Some people might find cognitive support formulas, and even things like CoQ10 and phospholipids alone, to be somewhat stimulating. Not like the jitters type of thing, life coffee, but feeling like a little supercharged. A little of this sounds positive. It can be really problematic if you're not able to do something with that energy or need to go to sleep.

I've also seen people have more vivid dreams when taking something like Huperzine A, and that tends to usually be more transient. But if it's troubling and doesn't dissipate with time, an alternate supplement should be selected.

I generally instruct people to start with low dose, especially if you using combinations of these nutrients, because they really can be very potent. Although some of the nutrients can be taken at night, I generally tell people to take anything that's intended to support cognitive function in the morning. Because we really want it to be something that helps us fly through the day and be as productive as we can be. But really, with all supplements, it is important to screen them with your doctor to make sure they don't have interactions with other medications you may be taking and to make sure they're something for you, individually, that is correct.

Gazella: Yeah, that makes a lot of sense. And, it occurs to me that you mentioned formulas for brain health ... probably a lot of these ingredients that you mentioned are used in combination to be more effective. So there's a synergistic effect. Is that accurate?

Decker: Yeah. Some things more than other. Different supplement companies put different combinations together and a lot of the companies look to the research, just like I'm talking about today, and see what might be appropriate to put together. When I work with things, I often use a B vitamin complex or other specific combinations meant to address homocysteine elevation, if that's an issue.

Essential fatty acids and moderate doses of vitamin E, if not part of the diet routinely, should also be included.

CoQ10, Vitamin E, and essential fatty acids - the fish oils, sometimes you can find those in combination because they're all a fatty substance. They often combine very well.

Vitamin D and zinc tend to be single nutrient therapies that people are on because we use them for all sorts of things, including immune support as well as mood. So those will be things, individually, people take.

Generally, if someone's healthy and not experiencing cognitive decline, that's kind of a good combination package of nutrients to just prevent the nutritional decline-related issues. But, some of the combinations ... I've seen a combination that has the lion's mane mushroom, the phospholipids, citicholine, as well as a substance called coffee fruit extract that really supports cognitive health quite well on both a short-term and long-term basis.

The coffee fruit extract, which contains less than 1% caffeine, has been shown in multiple studies to increase levels of brain drive neurotrophic factor, which I kind of talked a little bit about with exercise. The brain drive neurotrophic factor promotes neurogenesis and is naturally increased in the brain when someone's working on learning something.

I like the combination again, because it's so potent and it's something that someone feels the effects of in the day they take it, yet it has long-term benefits because of the fact that both lion's mane mushroom and coffee fruit extract have of promoting neurogenesis. It also contains American ginseng, and that in combination with the phospholipids, has a pretty dramatic on energy levels as well.

You know, we see a decline in energy with aging populations, which also can be an issue.

I've also found this combination to be really helpful with patients with depression, which makes sense. There's a common overlap with some of the things we talked about in many ways with depression. So you might want to consider it for that, as well.

Gazella: Yeah, sounds like a good combination. Well this has been packed full of great information, but I'm wondering if you have any other advice for practitioners who might be listening, who are trying to help protect cognition in their patients.

Decker: Yeah, and this one doesn't maybe fit in with everything I've been talking about, but I'm a naturopath and I think about things in a very whole-minded fashion ... and I live in Portland, so maybe that influences it as well, but I think it's really necessary to look at the impact of community and how being happy can really impact the overall health of our patients. Particularly in older patients, a lot of them might be alone and if they get stuck in grief ... say they have the passing of a loved one or so many people pass the more we age, and often that will be people in the family. A partner. A spouse. And that contributes to loneliness and these things don't really just eat away at the mood, but they bleed into the health in so many other ways.

Community really gives people life. It gives them purpose and meaning. And being active and finding community, which someone resonates with, really serves a far greater purpose than just being an event on their schedule. And with the elderly or aging population, whether this is a local community center, a church or some other group, it can really help people find a fulfillment and happiness and that goes far beyond just that. It improves the mood and the health of the brain, as well.

Gazella: Yeah, that's such an important point and I'm glad that we're ending with social support, because it has far reaching benefits. Well, once again, I would like to thank the sponsor of this topic, who is Allergy Research Group. And I'd like to thank you, Dr. Decker, for this wonderful information and joining me today.

Decker: Yeah, it was great to be able to do so.

Gazella: Well have a great day.

Decker: Thank you, you too.

May 15, 2018

In this interview with Natural Medicine Journal's publisher, Deborah Yurgelun-Todd, PhD, and Perry Renshaw, MD, PhD, MBA, discuss the research they are conducting at The University of Utah in the Neuroscience Department. They specifically describe research associated with the safety and efficacy of supplemental citicoline, as well as evaluate emerging research in this area.

Approximate listening time: 30 minutes

About the Experts

Deborah Yurgelun-Todd, PhD

Deborah Yurgelun-Todd, PhD, is director of the Neuroscience Initiative and a USTAR Professor of Psychiatry at the University of Utah School of Medicine. Her research focus is on identifying the neuropsychological and neurobiological bases of human behavior. Yurgelun-Todd is an expert in the application of structural and functional magnetic resonance imaging, the administration and analysis of neurocognitive tests, and the integration of the results obtained by these multiple modalities. She has examined the etiologic bases of neural models of dysfunction in psychiatric disorders including depression, bipolar illness, substance misuse, and schizophrenia. She is also recognized for applying imaging techniques to study cortical changes during development in healthy children and adolescents, and during treatment intervention in adult patients.


Perry Renshaw, MD, PhD

Perry Renshaw, MD, PhD, MBA, is a USTAR Professor of Psychiatry at the University of Utah School of Medicine and a Medical Director of the VISN 19 Mental Illness Research, Education and Clinical Center (MIRECC) at the Salt Lake City Veterans Affairs Medical Center. His training as a biophysicist and psychiatrist has led to a primary research interest in the use of multinuclear magnetic resonance spectroscopy (MRS) neuroimaging to identify changes in brain chemistry associated with psychiatric disorders and substance abuse. Current clinical trials are focused on the use of citicoline as a treatment for methamphetamine dependence, creatine as a treatment for depression, and uridine as a treatment for bipolar disorder. Renshaw’s recent work focuses on brain chemistry changes that may increase depression and suicide for people living at high altitudes.


Karolyn Gazella: Hello, I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today, I'm thrilled to be joined by two highly respected brain researchers from them University of Utah Neuroscience Department, Dr. Deborah Yurgelun-Todd and Dr. Perry Renshaw. Now, before we begin and dig into today's topic, I'd like to have each of you describe the focus of your research. So let's start with you, Dr. Yurgelun-Todd.

Deborah Yurgelun-Todd: Yeah. Well, my research is initially started to focus on cognitive function and the neuropsychological, or brain, pathways that mediate how we think and how we feel. And then I became very interested in the application of brain-imaging to help us understand exactly how those pathways worked and give us some insights into how the brain does things well, and how it does things less well.

Gazella: Perfect. Now, Dr. Renshaw, how about you? Can you please describe your research focus?

Renshaw: Well, sure. Well, I'm sort of confused soul. I'm a psychiatrist/biophysicist, and the way in which I merged these techniques together is to do brain-imaging studies that focus on, how is brain chemistry altered in, particularly, diseased states that psychiatrists might be interested in. And based on identifying unusual patterns in brain chemistry, my research group likes to focus on identification and development of novel treatment strategies. One of which is a molecule, I guess we'll be talking about today, CDP-choline or Cognizin.

Gazella: Perfect. And you're absolutely correct, I'd like to talk about citicoline in a lot more detail. Now, Dr. Yurgelun-Todd, why did you become interested in citicoline for the brain, and why did it catch your attention?

Yurgelun-Todd: Well, they've done some work looking at why the brain was not working very well in mood disorders, and why attention, in particular, was a problem in individuals who had depression and other mood disorders. And when citicoline was brought to my attention, there seemed to be interesting potential for that to alter attentional systems. So I became very excited at the possibility of that becoming a treatment for individuals who may not have optimal brain functioning.

Gazella: Perfect. I love the fact that attention actually is what caught your attention, so that's brilliant. That's brilliant. Now, Dr. Renshaw, what does the scientific literature tell us about the safety of citicoline, and are there any contrary indications or risks associated with its use orally?

Renshaw: You know, that's a great question because we have a really well established answer that citicoline has been used millions of times around the world. In some countries, particularly where they use it as an intravenous administration as a drug. In other countries like the US and Canada, it's a nutritional supplement.

We've done studies, or rather, Dr. Yurgelun-Todd has done studies looking at the effects of citicoline on adolescents and she can describe what she saw. But, by and large, you have to take a whole lot of citicoline before you notice anything adverse. And in the few instances where we've seen that, it's been people feeling like they've had too much Starbucks coffee and that goes away over about a half an hour.

Gazella: Yeah, and I would like to hear about the studies on children, Dr. Yurgelun-Todd. What does your research tell you about safety, especially in that population?

Yurgelun-Todd: It's very interesting because we, as I mentioned, I was interested in potential ways to improve thinking and so we decided we would look at the developing brain in individuals who were adolescent. And we found that when we supplemented with citicoline, they actually improved their attentional span and could do—and had some improvement in their psychomotor function as well. So this was in healthy adolescence, rather than anyone who actually had a documented impairment. The fact that you could see improvement in cognitive functioning and psychomotor functioning in healthy individuals without a documented impairment was actually quite remarkable.

The other thing that was remarkable was that the dosing was very low, and in fact, this was a new area to explore. How low could we dose and still see an effect on the brain? So we were quite enthusiastic about those finding and think they have important implications. With regard to safety, we also were very rigorous in the documenting potential side effects associated with the administration of citicoline and we really saw essentially no side effects in the side effects profile that we did document. Looked very similar to the placebo, in fact, was not statistically different between placebo and the treatment arm. So we were really reassured that even with the rigorous assessment for side effects, there was nothing that was documented in this trial.

What's really compelling, however, is that most treatments for cognitive changes or for any neurologic disorder, neuropsychiatric disorder do end up having side affect issues, some of them being more visceral, like stomach or headache or things like that, but also some of them actually diminishing your cognitive functioning. So this was rather remarkable that we could enhance cognitive functioning with no side effects.

Gazella: Yeah. I mean, it's good to hear that the safety profile is good. And I may want to come back on that topic of children, but Dr. Yurgelun-Todd, I'm going to stick with you here. There's a wide variety of brain functions and cognitive issues that have been researched associated with the use of citicoline, like focus, attention, dementia, and other issues. Which area, presently, has the strongest, and most compelling research?

Yurgelun-Todd: Well, that's a very interesting question because there's a biased based on what science you happen to love. I think some of the most compelling research has been associated with the fact that there's a repair mechanism associated with the administration of citicoline, that is, cellular biochemistry is actually altered and phospholipid synthesis is improved when you have an administration of citicoline, therefore, individuals who have neurological insults, such as strokes or mild traumatic brain injury, things like that can see rapid repair in their cells with citicoline administration. That is the area that's more involved in the patient or the real neurological insult area.

Within the healthy individual, I think the most compelling research really falls on two ends of the lifespan, that is the elderly or middle-age and above, and also then some of the work we talked about in adolescence, where both when your brain is growing rapidly and also when your brain is aging, it seems as if the supplement with Citicoline can make a substantial difference.

Gazella: Yeah, that's interesting. Now, Dr. Renshaw, there's preliminary research demonstrating that citicoline may be able to help with cocaine dependence and addictions. I find that pretty fascinating. How promising is that research, and do you see that as a viable application in the future?

Renshaw: Yeah. No, that's a great question. Citicoline, broadly speaking, has 2 effects. One that Dr. Yurgelun-Todd just touched on. Brain repairs is probably more well established and been investigated for probably 30 or 40 years. Our work, to a first approximation, looks at the effects of citicoline in terms of increasing the levels, brain levels, of neurotransmitters, particularly dopamine and norepinephrine in the brain.

When someone is using cocaine or methamphetamine, they often have a depletion of dopamine within their brain, as well as, in the case of methamphetamine, some damage related to decreases in blood flow. From that perspective, citicoline is almost a perfect fit in terms of what it can do an active user, increasing the level of dopamine in the brain, makes them feel, I think, more intact and, perhaps, less inclined to continue using drugs. And the brain repair mechanism because the mechanism on which stimulants cause brain damage is often related to ischemia. It's just a really good fit.

Where we're going now in this research, is that we've broadened our scope from cocaine to methamphetamine to stimulants that are used to treat ADHD. In fact, we are in the middle of finding a study supported by the National Institutes on Drug Abuse, we're working with in Salt Lake City and Seoul, South Korea. And what we're looking at is adolescents who are using stimulants, not necessarily as a drug of abuse, as a way to approve their attention, focus, and do better on very rigorous South Korean college entrance exams. Some estimates suggest that close to a quarter of all high school students in South Korea are taking stimulants, which is probably not good or the long-term outcome of which is not good. We think citicoline may be a way to help people feel better and get off the use of stimulants. Which is better avoided, unless you have a really good reason for continuing treatment with that class of medication.

Gazella: Yeah. That's actually one of the questions I was going to ask. When you're talking about using citicoline in healthy children, I was curious ... and Dr. Renshaw, I'll stick with you on this one ... I was curious, I have not read any studies using citicoline for children with ADHD, but I think what you're saying is you're evaluating whether or not this could be a viable alternative to the pharmaceuticals that are being used for ADHD. Is that what I'm hearing?

Renshaw: There's a real divide, at least in the United States, between things that are approved as natural products, nutritional supplements, and pharmaceutical agents. The natural product industry lives in fear of having their products considered to be drugs because the amount of testing, and safety monitoring, and efficacy, and evaluation that goes into getting something onto the market as a drug is really very expensive and onerous.

So for us, any research that we do, we have to have it paid for itself. It's been a lot easier to look at the use of citicoline in healthy populations, and certainly the sponsors of the work that we've done, which have been certain large natural product companies, who are much, much happier without us in approach. That's said, if I take off my sort of business man's hat and put on the scientific garb, what we believe is that, in fact, citicoline would likely have good effects for treating ADHD.

In Europe, it's been used as a drug to treat Parkinson's disease with good outcomes, and Parkinson's disease is, as you may know, is also a disorder associated with decreased dopamine in the brain. The ability to increase focus and attention is generally quite good. The difference between citicoline and the stimulant per se, is the effect of citicoline is to increase the brain's concentration of dopamine, that you're encouraging the brain to make dopamine when it otherwise might not do so. Stimulants just release dopamine from the brain and tend to deplete it, so they are very different mechanisms, and there's every reason to think that they'd both be affective. They probably have different safety profiles.

Gazella: That's fascinating. And Dr. Renshaw, I'm going to stay with you one more time. What about autism, autism spectrum? There's numerous conditions that are in that category. Any preliminary research in that or are we pretty much leaving that alone for now?

Renshaw: We haven't been involved in that research. There was a company we did some research with in the Boston area, that was very interested in a related compound from the treatment of autism. They got involved in a big patent dispute with the University of California in San Diego that was resolved in UCSD's favor. So I don't think there's ever been a trial. But, there certainly is a suggestion in the autism literature to treat with pyrimidines, as the effect of either cytidine or uridine on the brain might help some individuals with autism spectrum disorders, but I think in fairness, it's really quite preliminary and that we'd have to do studies to understand what the effects were likely to really be to a population.

Gazella: Yeah. That makes a lot of sense. Now, Dr. Yurgelun-Todd, I'd like to stay on this topic of exciting new research in the area of citicoline use. Another area of research that's pretty interesting, and could be significant, is the use of citicoline for appetite control. I mean, obviously we have an issue with obesity in this country. Is it too early to tell is this may be a promising application of citicoline in the future?

Yurgelun-Todd: You know, I don't think it is. We've noticed some years ago that in looking at the response to food cues, individuals who had received the supplementation of citicoline actually showed significant decreases in appetite and that this was related to dose of citicoline that they'd received. And the thing that was interesting about that data, was it wasn't just that the individual said, "Oh, I feel like I have a reduced appetite." They actually showed differences in the way their brain responded to the cues, such as food items, ice cream, donuts, things like that when they viewed them in the magnet.

So we had documentation that neural activation was altered in food-processing related areas of the brain, as well as having a decrease in appetite, which really suggests that there is some mediation of brain responses to appetitive cues, which is really one of the problems with obesity. And within weight control, that's just sort of having an over-reaction to these kinds of cues.

And thinking about it further, it didn't really surprise us because it goes back to what Dr. Renshaw just mentioned about the dopamine system, the dopamine system in addiction are part of the reward system in the brain and the ... although we initially focused on the impact of citicoline on cellular function and phospholipid metabolism, we recognized as we thought about it further, that the concentration of dopamine is being changed with the supplementation of citicoline as well. So we're changing neurotransmitter balance in the brain and that had a really positive affect in terms of response to food items. I don't know if Dr. Renshaw wants to comment.

Renshaw: No, I think that's right. When stimulants have been used for this purpose, in fact, that's why many of them were developed initially, but they sort of force the brain to release all the dopamine that it's already made. What we really like about citicoline or pyrimidines as a strategy for increasing brain dopamine is that A, it's really encouraging the brain to speed up synthesis, which is sort of what you'd like to do, and again from a safety perspective the latter approach should be much safer for individuals taking a supplement or another medication over time.

Yurgelun-Todd: To go back to your question on is it too soon. I don't think so because I think most studies that we hear about are really just using self-report and don't have the documentation of a brain response. You couldn't really fake a brain response in terms of metabolic activations, so that is a really, I think, robust piece of research that will support this as an appetite moderator.

Gazella: That's fascinating. Now, I want to stick with you, Dr. Yurgelun-Todd because I do want to go into dosage. But specific to appetite control, what was the dosage used?

Yurgelun-Todd: 2,000 milligrams in the study that we did. Although, we did not ... we've not had the opportunity to see how low we can go to have this effect. And this was in middle-aged individuals. So we were looking at people, 40 to 60 years old, and they were looking at the extent to which having a 6-week supplementation could impact the brain. And that's what we saw.

Gazella: And 2,000 milligrams, is that divided doses?

Yurgelun-Todd: Yes, it was. It was morning and evening.

Gazella: Okay, perfect. Now, Dr. Renshaw, I want to dig a little bit deeper into this issue of dose. Now, does the dose of citicoline vary depending on the application or is there a consistent dosage range that is affective across most conditions?

Renshaw: That's a great question, and citicoline has a funny history that was used most extensively first in Europe. And there, after an injection of citicoline, they had a lot of trouble showing that there was any citicoline or cytidine in the bloodstream. When they went to oral ingestion, that became an even bigger problem. And it turns out, that the stomach plays tricks with citicoline, it turns the cytidine, that's part of it, into a molecule called uridine, which is the predominate pyrimidine in the human central nervous system. Because of that, it's been a wide spectrum on the views on how bioavailable, that is how much citicoline gets used by the body. It turns out that if you measure uridine, essentially all the citicoline is absorbed and gets distributed across the body, but it took a long time to figure that out. This was sorted out by a scientist at MIT, Richard Berkman, who's also studied citicoline extensively.

If you look at the clinical indications, a lot of the ones we look at, mood disorders, attention-deficit disorder, probably require lower doses. In the United States, the most recent trials have really looked at serious brain injury conditions, like stroke, and so there have been trials that are conducted with oral administration of citicoline to treat stroke. The problem there is that in the context of someone who's found out a real metabolic stress affecting the brain and the body, it just sort of absorbs things effectively from your stomach, plus you've got a problem with the area you want to impact has got decreased blood supply due to the stroke. And doses went up to something like four grams a day in those instances.

We've been ... most of our indications using somewhere between 500 and 2,000 milligrams of citicoline. The effects of citicoline last for about two, or three, or four hours just depending on the individual. So taking it twice a day works reasonably well. There is, for many normal people, a self-correcting mechanism, which if you're taking more than your body needs, you will feel anxious and jittery. That's relatively uncommon. Anyone taking less than 2,000 milligrams a day is unlikely to have side effects. This is obviously important in figuring out what to do. Studies in children, for example, as Dr. Yurgelun-Todd has done. Children come in a variety of shapes, sizes, and weights. It's probably going to be important to adjust the dose to reflect the weight of the child.

Gazella: Yeah. I think one of the fascinating things for me with citicoline, is that it does, in fact, have efficacy at what could be considered a fairly low dose, even as low as 250 milligrams. But even at 500 milligrams, that's a pretty low dose, and it's still showing affect, correct?

Renshaw: That's right. From that perspective, it's really important to recognize that one of the most established effects of citicoline is to speed up membrane synthesis, and this is true in every cell in the body, and we all travel around with CDP-choline in our cells. For that reason, because it's highly important in controlling this fundamental process, the body tends to keep the concentration of CDP-choline low. So that relatively low doses, especially for natural product, work much more effectively than is true of almost any other type of natural product. And again, we think that that has a lot to do with the fact that it's a really important regulatory control molecule within the body.

Gazella: Right. Now, Dr. Yurgelun-Todd, we've talked about a lot of different conditions, and application, and some pretty exciting emerging research associated with the oral use of citicoline. Out of all of that, what do you feel shows the most promise?

Yurgelun-Todd: I think I'm going to relate that to where I think there's a great deal of need. And that is in our children, and our adolescents, and young adults. And specifically, I think the fact that we can provide a very safe, minimally, essentially no side effect treatment to improve attention, and you touched on this earlier, I think is very significant. We've not done studies in ADHD or populations, such as a diagnosed ADHD population, but I'm quite sure that this would be a supplement that would make a significant difference for many of those and not have any long-term or short-term side effects. So I think that's a very important point.

The other thing that hasn't been as well explored, but I think is important, is the area of concussion or sports injury. Where, I believe, because of the data that we've seen in stroke, and in other neurologic disorders there's every reason to believe that citicoline could actually provide a preventative capacity, like in a sports drink or a bar, something to that effect, prior to concussion. And then also supplementation during the season could be very helpful. So I think that ... well, that hasn't been an area that we've focused on so much. I think given the attention now in the sports of our children and college students, that this would be an area that could be really important.

And then, of course, my original reason for wanting to get into this work, which is mood disorders. I think that we hadn't really capitalized on the impact of Cognizin on improving mood disorders. And I think there are many individual, particularly, in the perimenopausal age group who have found that this has been a very important supplement in their life and has helped them significantly in feeling that they can think more clearly and feel better overall. So those are my favorite areas to think about.

Gazella: Yeah. That concussion, that is really fascinating and it would be great if there could be some studies done there. Dr Renshaw, do you agree? Anything to add to that list?

Renshaw: Yeah. There's a substance abuse investigator at the University of Texas Southwestern in Dallas, Sherwood Brown, who did a study of the individuals who had both, cocaine dependence and bipolar disorder. And what he found was citicoline was actually much more effective in treating the bipolar disorder than the cocaine dependence in the patients that he was working with.

We have a colleague here in Utah, Doug Hondo, who looked at that and said, "Why would something like citicoline be effective in treating bipolar disorder?" And he's developed a theory that suggests that citicoline may have a really potent antisuicidal effect. And it shares, to an unbelievable degree, many of the same effects on the human brain that both lithium, which is known to antisuicidal and ketamine, which is the antidepressant for those of us in psychiatry. So he's about to begin a study looking at whether or not, and this has been funded by the Veterans Administration, Citicoline reduces suicidality with treatment for only the first week. This is very exciting, and is something that will get underway, it's a 4-year study, in a couple of weeks. And if that's really true, and you could get the same protective effect without having to take Lithium or Ketamine, both of which have pretty significant side effects, that would be a real advance. The compound that Doug will be using in the study is uridine, which is the major metabolite that citicoline provides through the body in [inaudible 00:25:19].

Gazella: Dr. Yurgelun-Todd, because we're talking about bi-polar mood disorders, a lot of these folks are on some heavy duty medications as Dr. Renshaw just mentioned. Do we know anything about interactions? I don't know that there's been any studies, but if somebody is on a Prozac, or an antidepressant, or some of these other, Lithium and whatnot, can citicoline be taken with that or is that a no-no?

Yurgelun-Todd: Thus far, I don't know of a clinical trial that examined that specific question, however, everything that we know about citicoline would suggest that because this is found in normal diets and is a part of the human body, that it would not have any interaction effect with the treatments that have been provided. So it should be perfectly safe.

Gazella: Yeah. That makes some logical sense.

Yurgelun-Todd: But with the caveat that we don't have that empirical data.

Gazella: Right. You're basing that on logic and mechanisms of action and ...

Yurgelun-Todd: Exactly.

Gazella: Now, Dr. Renshaw, I'm going to put you on the spot here, but this is your area of expertise, your background is with addiction. I would love to hear your thoughts on our present opioid epidemic. I realize that this is a huge topic. This might be an unfair question, but can you give us a snapshot from your perspective as a researcher with this type of expertise, what needs to happen to get this issue, this opioid epidemic under control?

Renshaw: Boy, if I knew the answer to that question, I'd have a really high profile job. We're very interested in addiction as you know, we live in the Rocky Mountain states, and so one of the things we study is, what happens when someone moves from a lower altitude to higher altitude, and what we find is that people often get more depressed and more anxious and, curiously, use more different kinds of drugs of abuse. So I guess you could say, flatten out the Rocky Mountains states, but that's not actually our strategy. We're looking for molecules like citicoline that may have an effect in changing brain chemistry in ways that are effective in treating some of these high altitude related conditions.

The fact that this is something you can do that changes the use of drugs across a broad variety of categories suggests that these may be molecules that are really valuable in treating a range of different addictive disorders, but clearly you've figured out by now, that I'm sort of waving my hands because I think there are a lot of very smart people who are struggling with the question of how do you prove the problems of opiate dependence in this country. And it's really shocking how we have a problem that's occurred over a short period of time.

Gazella: Right. We've covered it in the Natural Medicine Journal, so it's definitely in our radar as well. Now, I think we covered everything, but Dr. Yurgelun-Todd, is there any final thoughts that you'd like to add on this subject?

Yurgelun-Todd: Yeah, just one final thought, which is that I think that the impact of citicoline and particularly Cognizin citicoline has not been fully appreciated yet. It's come a long way since we began working with it and I think we've appreciated that it has multiple types of impact on the human brain and body, but I think we have even more potential to see it improve the quality of our lives. So I'm excited to continue working with it.

Gazella: Yeah. That's kind of why I wanted to focus on the emerging research because I think that that's very exciting, and I think that this can be a really positive clinical tool for healthcare practitioners. Dr. Renshaw, anything else to add to that?

Renshaw: Just one comment and then a tantalizing tidbit if you will, we can edit this out, I guess. But one of the things that we think is going be an important trend, is the combination of citicoline with other natural products as a way to boost its efficacy. And that's something that hasn't happened yet, but we have some combinations that we're exploring now. One of the things that Dr. Yurgelun-Todd didn't share with you, is she has, across 3 different studies, evidence that citicoline also improves complexion. It has effects on skin tone, which makes some sense when you think that both the brain and the skin are rapidly turning over cells. So that's an area that's a little bit outside our area of clinical expertise that merits investigation as well.

Gazella: Wow. Yeah, that is pretty interesting because that could then ... it could be a topical ingredient.

Yurgelun-Todd: Right. Exactly.

Renshaw: Exactly.

Gazella: Yeah. Wow. That's pretty interesting. Well, I want to thank you both for joining me. This has been fascinating and information-packed. I'm so pleased that you took time out of your schedule to join me today. And I hope you have an awesome day.

Yurgelun-Todd: Well, thank you so much. We were delighted to join you.

Renshaw: Yeah, you too, Karolyn.

May 2, 2018

In this podcast episode, we talk about cardiovascular labs with naturopathic cardiology expert, Daniel Chong, ND. Chong discusses the use of cholesterol panels and other tests he uses in practice. He dispels some common myths about how to interpret different lab results.


About the Expert

Daniel Chong, ND

Daniel Chong, ND, has been a licensed naturopathic physician, practicing in Portland, Oregon, since 2000 and focusing on risk assessment, prevention, and drug-free treatment strategies for cardiovascular disease and diabetes, as well as general healthy aging, and acute and chronic musculoskeletal injuries. Chong has also completed certificate training in cardio-metabolic medicine from the American Academy of Anti-Aging Medicine and is an active member of the Society for Heart Attack Prevention and Eradication (SHAPE). In addition to his clinical work, Chong serves as a clinical consultant for Boston Heart Diagnostics Lab.

Tina Kaczor, ND, FABNO: Hello I'm Tina Kaczor editor-in-chief at the Natural Medicine Journal. I'm speaking today with my friend and colleague Dr. Daniel Chong a naturopathic physician and specialist in cardiology specifically. Dr. Chong is a founder and lead consultant at as well as a consultant for the cardiology industry. Dan, thanks for joining me today.

Daniel Chong, ND: Hello Dr. Kaczor, it's nice to be here.

Kaczor: We have talked informally, and I thought this would be a great opportunity to talk specifically for our audience, about the use of cholesterol panels, and we'll go into specifically some breakdown of the usefulness of common cholesterol panels, and then break that out into more particular cardiology panels. There's a lot out there right now about whether cholesterol is or isn't even linked to heart disease, so let's just start at the beginning. Can you give us a little bit about the roots of the cholesterol theory? We'll branch off from there.

Chong: I can try. It definitely is a relatively long-standing theory now. As I understand it, the first thoughts as to whether or not cholesterol had anything to do with cardiovascular disease came in the early 1900s on animal research with rabbits, but at that point it was dismissed because people were still not clear whether or not you could make any correlations between findings in rabbits and extrapolate out to humans.

The major real focus on the connection between cholesterol and heart disease started more in the mid-1900s almost simultaneously in a way with Ancel Keys and the Framingham study, so they started around the same time. Ancel Keys was one of the first people to really make a point of saying, "We should really research this because we repeatedly are seeing this potential connection," and so he was one of the first people to really start trying to splice it out. Then, the Framingham study started simultaneously. They don't come out with any of their more definitive conclusions until a little later than him with that. That's where it all began as far as I understand it.

Kaczor: In the Framingham study specifically I know that there has been ... The broad interpretation in the professional world has been high cholesterol equals risk of heart disease, LDL being the "bad cholesterol," in general. Is there particular subpopulations that this is more true for? In other words, can we say if you are a 40 or 50 something-year-old male this is more true than if you're a 80-year-old male, or a female? Is there any way to delineate that with just looking at broad generic cholesterol levels, nothing too specific yet?

Chong: Hopefully, it will be answering your question by saying this, but to me one of the most fascinating pieces of information I heard come out of the Framingham study in particular is that over the course of however many years ... this was a statistic we heard about maybe five or so years ago. The Framingham study had been active for well over 50 years and they had well over 50 years of data on how many thousands of people, and the statement was made by the former director of the Framingham study, so it was certainly legitimate. Essentially what they said was, one of the key pieces of information that they saw in terms of the relationship between at least total cholesterol and cardiovascular disease was that it appeared as though if a person's total cholesterol was at or below 150 naturally, so throughout their lives without necessarily an intervention with a drug or whatever, just the people in the study who had naturally low cholesterol did not get heart disease period.

Of course, you can't then take that and make any truly definitive statements, but there is, in terms of a general viewpoint that was one of the things that came out. In other words, nobody with cholesterol under 150 naturally got a heart attack in their study. Again, there would still need to be more done to splice that out and figure out what exactly is going on there and why that is, but there's definitely something to be said. You can see the same exact type of finding if you look at epidemiological research on different cultures of people in history who did not get heart disease or got very little heart disease, all of those people regardless of where they were on the planet, what types of specific foods they were eating, even to some extent what their lifestyle was some of these people smoked, et cetera, the cultures of people who were known and found not to get cardiovascular disease all had cholesterol at or below 150.

Kaczor: You're talking about total cholesterol?

Chong: Correct.

Kaczor: Let's move over to talking about the bad cholesterol. LDL-

Chong: Can I pause you for one quick second?

Kaczor: Yeah.

Chong: Just to say one other thing about that. There's a lot of questions that would be immediately raised from those statements that I just made. One other way that I look at things is, and I know we'll get into it more, but cholesterol in of itself, I will say right from the beginning, has to be involved. It is not a worthless thing to measure, it is not something to just disregard and only focus on information. Time and again it has to be involved, technically it has to be involved. You can't make plaque without it, but it's just an important way to think about it. It's just whether or not it's the primary causative factor and we'll get into that.

Kaczor: Yeah, that's an important point. I don't see many people with total cholesterol below 150, but we'll put that aside. It's pretty uncommon. I don't know about other people. Let's break it down-

Chong: In modern times it absolutely it is.

Kaczor: Let's talk about LDL specifically and just start out with there's a lot of more specific labs that are looking at LDL particle size rather than total LDL. Just a brief primer, if you would, on the difference between LDL-

Chong: I like your emphasis on brief.

Kaczor: Yeah.

Chong: Sorry, go ahead.

Kaczor: On LDL calculated as it is in a common cholesterol panel and the particle size as it is measured by several different labs now.

Chong: I'll do two separate simple ways that I look at it. One is technically LDLC or "LDL cholesterol" measurements that are most commonly done in the average physicians' offices et cetera is technically measuring the mass or total amount of cholesterol being carried around on LDL molecules. Just as a reminder to people, these LDL molecules are protein-based particles that are essentially like cargo ships carrying around different substances, one of the main ones being cholesterol.

When you are getting an LDLC you are getting an estimate of the mass of the total amount of cholesterol being a carried around by all of the LDL particles in the system whereas, an LDLP is specifically getting a count of the LDL particles floating around in any one measurement of blood. From an analogy perspective it's like you're counting either the cargo that's being ... The Pacific Ocean has a certain amount of cargo ships out in it carrying cargo and LDLC is like, "Okay, what's the estimate of total cargo being carried around by all of those ships?" Whereas an LDLP would be like, "Okay, we're going to go into the ocean, we're going to count each one of those ships and see how many there are."

Depending on some different factors this is why you could theoretically ... Let's say a cargo ship could technically carry 100 pounds of cargo, you could technically have two ships carrying 200 total pounds of cargo or you could have 20 ships carrying 10 pounds of cargo each. In both cases the LDLC would be the same and yet one, there's 20 ships and the other there's two ships, if that makes sense. The reason why that's so important to make the distinction is that what we know now is that risk specifically goes up with ship count or particle count—not necessarily total mass or total cargo. If you have a way of identifying, "Aha, there is actually only two ships in this ocean versus 20," that can significantly impact risk level.

Kaczor: Looking at the LDLC, which is the calculated one, it may or may not correlate with cardiovascular disease is what I'm hearing you say, and LDLP we can use as a more specific correlation with cardiovascular disease.

Chong: Right, that is correct. In the grand scheme of things when we're also potentially considering other factors like inflammation, and oxidative stress, et cetera, it's still relative ... we're just talking about cholesterol-related markers and their impact on risk, so there are obviously ... I don't want to discount the fact there are other factors involved here, but when we're just talking about the cholesterol and its impact on future risk or not the particle count is what trumps everything. Again, just in the realm of the cholesterol markers.

Just for an example, there's a research study I've seen where they looked at 16-year survival, from year 0 to 16 and measured LDLP and LDLC in each person. This is a very large study, and what they saw is a distinct difference between particle count and future event risk for cardiovascular disease. In other words, you had a distinct increase or higher rate of survival in people who have low particle counts regardless of what their LDLC or mass was. Whereas the people with worse outcomes all had high particles even though some of them technically had low LDLCs or low amount of total mass or cargo.

Kaczor: It's been-

Chong: It's been clearly seen that there's a distinct difference. It's also important to mention here, it is unfortunately true that there are some people out there who are still saying, "If I have large puffy LDL (i.e., my LDL particles are loaded with a lot of cargo per particle) and yet not necessarily ..." If you have a high LDLC, but all of your LDLs are large and puffy, and you also have a high LDL particle count you will still have an increased risk. There are some people out there who are under the misconception that if LDL particles are large and fluffy or large and puffy enough they can't cause problems, that's totally inaccurate. Bottom line, when we're talking about LDL, particle count trumps everything.

Kaczor: Let's move on to HDL. That's really good points on the LDL because I do know that the size and the type, the fluffy or the dense, that idea is very much part of the verbiage that patients use when they come through the door-

Chong: I'm sorry, I will say one other thing quickly about that. I don't mean to say that it's worthless to check LDL particle size because it's still true that LDL particle size, the smaller the particles the higher the potential is for future risk, but it's not just because of the mechanism itself. It's like just because there is a strong relation between what causes LDL particle sizes small and what causes cardiovascular disease. As an example, typically people with poor insulin sensitivity, or insulin resistance, diabetes, et cetera tend to have smaller particles, so it's still important to look at particle size because it does add to the predictive value of the test you're running. I don't mean to say that it's worthless or anything like that, you just can't say, "If my particles are large and puffy, I don't care how many there are."

Kaczor: Got you. Okay. Let's go back and just come back to HDL, the high density lipoproteins. This we don't harp on as much, the drugs aren't targeted towards it as much. We tend to know that higher is better. How do you use HDL in your interpretations?

Chong: One of the reasons why the drugs aren't targeted as much is because they keep trying and failing. Pretty much every study that's ever been done on a drug that it raises HDL shows that they clearly work and then oftentimes the people die sooner, so they have to stop. The bottom line is it's not a cut and dry direct simple relationship where the higher the HDL the better necessarily. Especially if you make a change in somebody, so like diet, lifestyle, et cetera, and their HDL goes up it is absolutely not a guarantee that they are getting better or that they are more cardio protected than they were beforehand. It might be the case, but it's not a certainty.

From that perspective, at least personally, when I'm looking at HDL I'm always looking at the whole picture. If I see a relatively low HDL and yet this person might happen to be one of these lifelong naturally low in total cholesterol, naturally low in LDL people I'm not as concerned about that low HDL as I am in somebody who has really high LDL, really high total cholesterol, insulin resistance, et cetera, and they have low HDL. There's a definite difference.

Those two people might both have the same HDL number, but one is way more concerning than the other one, and it just has to do with the role of these particles, these molecules, and what are they doing for us? If you really simplify it down HDL does a lot of complicated things, we still don't even know everything that it does, but definitely one of its main job is reverse cholesterol transport where it's helping to remove excessive cholesterol deposited in the periphery so to speak. I like to look at it as a garbage truck or a garbage collector. It is very true that if you do have a lot of "garbage" in the system, you have a high total cholesterol, a high LDL there's lots of cargo, or garbage, or whatever you want to call it being shipped outward you would hope to see the body responding to that by increasing garbage truck count to pick up the extras.

You commonly see that on people who go onto low-carbohydrate, high-fat diets. Oftentimes you will see, hopefully, an elevation in HDL as the body is literally just adapting to the additional load on the system that you're putting on it. It does not, however ... Unfortunately, you can't take that response and then conclude that the low-carbohydrate diets are cardioprotective because they cause HDL to go up. It's not that cut and dry, it's more just that the body is responding and having to increase its HDL to adapt and make up for the extra amount of cholesterol in the system, if that makes sense.

It's quite complicated. You do see HDL go up for that reason. The other thing is sometimes you'll see high HDL in somebody who's got disease, especially if they're inflamed or they have chronic inflammation. In those situations, in all likelihood, what's going on is that inflammation is known to hinder HDL function. The body always trying to adapt, always doing the best that it can to deal with the cards it's being dealt, if it has poorly functioning HDL it's going to spit out more of them in an effort to continue doing the job that needs to be done. If the HDL are dysfunctional as a result of oxidative stress, inflammation, et cetera in the system if the person has the capability you may sometimes see HDL production go up or HDL number go up on the person's lab because each one is not working as well as it should.

Kaczor: That's an interesting idea, that it's a reaction.

Chong: Absolutely. It's a fluid, functional system. Again, people just think, "Oh, HDL went up, that's good," or whatever. It's not like that. You have to think about why is the body doing that? What is the response going on? The body's always trying to maintain homeostasis, which would include not having cholesterol collect in the walls of the arteries.

Kaczor: That's awesome. I appreciate that perspective. I think it's really helpful for us because we want the quickest most linear path to a conclusion, so it's good to remember to step back once in a while.

Chong: For sure.

Kaczor: We don't have time to go into labs, other labs in great detail, but what other laboratory parameters would you consider must haves? I'm going to give you a typical case, a patient comes to your office, they themselves have no history of cardiovascular disease. They have both sides lots of cardiovascular risk, so they believe that maybe there might be something going on there. What's your bare minimum of labs? What would you do?

Chong: Especially in today's world where we're not necessarily billing insurance or whatever personally, for me, if I'm trying to get the most bang for my patient's buck in the realm of cholesterol I'm going to measure an apo A1, or apolipoprotein A1, I'm going to measure an apolipoprotein B, which for those people that aren't fully aware it's essentially like getting more precise HDL and LDL. Apo A1 is like getting a bit more precise HDL count and apo B is like getting a more precise particle count. Again, that's the name of the game, especially looking at the ratio between those two.

I'm also going to measure a lipoprotein a, which has its own independent impact on things and is not necessarily going to be responsive to medications or dietary changes that do impact these other markers. It's a very important marker to assess and you can never really predict whether or not somebody's going to have high levels of that or not, but definitely the potential goes up with a strong family history.

Then, beyond that in the realm of inflammation I'm at least going to want to see an HSCRP, I'm at least going to want to do some fundamental blood sugar metabolism related markers. I personally like to check a fasting insulin, and then potentially a hemoglobin A1c as well, although that sometimes has some questionable value depending on each patient. Beyond that, it starts getting a little bit more spliced out and potentially, depending on each patient, what you might go from there. I do check vitamin Ds pretty often, I check ferritin, and iron binding capacity pretty often at least screening that once to make sure there's no hemochromatosis going on. Those are probably the main ones I'm going to want to see. I will definitely do a CBC as well.

Kaczor: The one I didn't hear you say, and I'm curious if you do, is homocysteine.

Chong: Sorry, thank you Dr. Kaczor. Yes, absolutely homocysteine as well. Again, whenever I have the opportunity especially if there is a strong history and there's good reason to want to delve more deeply than average there are definitely some other markers I would typically run with people, but those would be a great starting point.

I don't know if we're going to talk later about going outside of blood tests, but just long story short I don't consider an assessment truly complete without some type of imaging at least on the high risk population.

Kaczor: By that, you mean?

Chong: Sorry, carotid ultrasound, IMT, or a coronary calcium score.

Kaczor: I can vouch for that. I've had several patients with cholesterols that didn't look too impressive, but their coronary calcium scores came back very, very good, and so they didn't have any [inaudible 00:24:42].

Chong: I will say one pearl type of information about that, the value of coronary calcium scores specifically goes up with age. The value of risk assessment using that test goes up with age. In other words, occasionally if a person is still relatively young, typically under about 55, you may have a situation where that person has a decent amount of soft plaque that has not been calcified yet and it will make their calcium score looks pretty good, but then if you check a carotid ultrasound it doesn't look so good. I have seen some mismatches in that regard with some of the slightly younger people, so my tendency is to measure carotid ultrasound, IMT tests with the understanding, obviously, that you're not checking the coronary arteries, but there's an over 90% correlation between the two. To me, a carotid ultrasound is a little pickier, a little more fine-tuned than the other one, but absolutely the high calcium score is a very powerful risk predictor. It's just whether or not you're going to catch everybody that way.

Kaczor: Great. Dr. Chong, thank you so much for joining me today, I appreciate your expertise, taking the time. I think this is a to be continued type of thing because we didn't talk about what to do.

Chong: I would love to keep talking, yes because I feel like we just started scratching the surface. Happy to delve more into some of these other details because there's a lot of other things to consider.

Kaczor: We'll talk about treatments and we can talk a little bit more about imaging techniques next time. Thanks again.

Chong: Super, yeah. Thank you.

Apr 4, 2018

In this interview, nutrition expert Jolie Root describes the health benefits of the Mediterranean diet and how practitioners can enhance compliance with their patients. Listeners will learn how to effectively utilize this diet in clinical practice.

Approximate listening time: 32 minutes

About the Expert

Jolie Root

Jolie Root, LPN, LNC, is a nutritionist, health educator, nurse, medical journalist and well-known radio personality. She travels North America attending medical conferences and educating the public about the roles of nutrition in integrative medicine. She also spreads the word through informational articles published in magazines and newsletters across the country, including Alternative Medicine, Whole Foods, Taste for Life, and Senior Living. In addition, she hosts a weekly talk show called “Food for Thought,” which can be heard Fridays at 10:00 a.m. Eastern Time on AM 1160 WVNJ.

About the Sponsor

Carlson Laboratories

Since 1965, Carlson has produced pure, quality, award-winning vitamins, minerals, omega-3s, and other nutritional supplements. Carlson began with a single vitamin E product, helped launch the omega-3 market in North America in the early 1980s, and now offers a product line with more than 200 nutritional supplements. Carlson is most renowned for the high quality of their award-winning omega-3s, and now they’re available in a premium olive oil. Olive Your Heart® blends cold-pressed Greek Terra Creta extra virgin olive oil with premium Norwegian marine oil sourced from deep, cold-water fish and is available in basil, lemon, garlic, and natural flavor. Each serving provides 1,480 mg of omega-3s, including EPA and DHA. Olive Your Heart® is mild and smooth, and makes it easy and delicious to add heart healthy nutrients into your diet.


Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today, we are going to explore the efficacy of key components of the Mediterranean Diet. We'll also be talking about enhancing patient compliance to this diet. Before we begin, I'd like to thank the sponsor of this topic, who is Carlson Laboratories. My guest is nutritionist Jolie Root. Jolie, thank you for joining me.

Jolie Root, LPN, LNC: Oh. It's a pleasure to be with you, Karolyn. Thanks for the opportunity.

Gazella: Well, this is a great topic. We've actually written about this topic a lot in our journal, and I am a big fan of the Mediterranean Diet. I think most practitioners know what makes up the Mediterranean Diet, but can you remind us what the key components of the diet are that contribute most to its health promoting aspects?

Root: Yes. It is a diet that is high in plant foods, so that means fruits, and vegetables, and whole grains, and whole grain breads, legumes, and nuts, and seeds. They also use hefty amounts of extra virgin olive oil, and it may or may not include moderate amounts of red wine, and also fish, and poultry, dairy, and eggs are featured, and red meat is minimized. It's only very occasionally that there will be red meat in this diet. It's a plant-based diet with a variety of fruits and vegetables, fresh foods, and whole grains, legumes, nuts, and seeds, and olive oil.

Gazella: Now, let's talk about the olive oil, because it seems like the healthy fats are a big component of this diet. What are some examples of the healthy fats in the diet, and why are these fats better for patients?

Root: Well, I think that you could say that part of the overarching benefit of walking away from unhealthier fats and towards healthy fats in the diet has to do with inflammation. We know in Western culture that we have an imbalance of fats that promote inflammation relative to an inadequate intake of fats that help to balance inflammation, so specifically I'm saying that one of the really I think imminent qualities of the Mediterranean Diet is that it relies on olive oil and then omega-3s from nuts and from fish, and it's low in omega-6s. That's the problem when you contrast that to the Western pattern diet, which is much higher than it should be in omega-6 relative to omega-3, and in the US, in North America, people rarely use olive oil as their main cooking oil.

Here in the West we eat a diet that promotes inflammation, and it's not just inflammation. It also promotes an unhealthy level of clotting in the blood and constricted blood vessels, so the result of that is high blood pressure and arterial stiffness. The Mediterranean approach, using olive oil and omega-3s from nuts and from fish oil, relaxes the blood vessels, helps to govern excess inflammation, and promotes health in areas from heart disease all the way to cognitive function.

Gazella: Now, I'd like to continue to deconstruct the diet a bit more, but let's stick with the conditions that you just mentioned, and I'd like to talk about first prevention and then treatment. Let's talk first about prevention. Purely from a preventative standpoint, which conditions benefit most from the Mediterranean Diet? You mentioned heart conditions, but can you expand on that a little bit more?

Root: Well, cardiovascular disease, so disease of the heart and the blood vessels, so that would mean not just heart disease with its inherent health risks, but cardiovascular death as an endpoint is something that has seen reduction in the double-blind, randomized, controlled studies and even in single-blind, controlled studies with the Mediterranean Diet, so the Lyon Heart Diet Study and the PREDIMED Study are studies that practitioners can look up and read. They saw a reduction in heart disease and a reduction in heart disease deaths as an endpoint, but along with that we also see blood vessel issues, so hypertension and endothelial function as components of heart disease, are improved on the Mediterranean Diet, because some of the elements in the Mediterranean Diet relax the blood vessels, and that allows for supporting blood pressure in a normal range.

The other thing is when you look at the heart, before we have heart disease, we may have diabetes or metabolic syndrome, conditions leading up to sometimes an increased likelihood of an endpoint of heart disease. The Mediterranean Diet helps with blood sugar stability and some of the issues that contribute to the metabolic syndrome, such as derangement of lipids, so cholesterol numbers that are not where we want them, triglycerides that are elevated, and that blood sugar control, and higher than what would be optimal inflammatory markers, and then that's metabolic syndrome, which also sometimes we might call pre-diabetes, but also diabetes itself is something that we have seen benefit in reducing risk of with Mediterranean Diets.

That's kind of in the cardiovascular realm, but if you want to go to the cognitive realm, we have seen improvement in cognition in elderly people who followed a Mediterranean Diet with either additional nuts or additional olive oil, and we have even seen some changes in some of the suspected markers of Alzheimer's risk, things like amyloid deposits and amyloid protein. So, earlier in life we're concerned about heart disease. We're concerned about metabolic syndrome, diabetes. Later in life we start thinking about dementia and ultimately with the worst endpoint there, which would be Alzheimer's.

Gazella: Yeah. I mean, that's a pretty broad range of conditions. I'm curious. When we switch over to treatment intervention, can the diet be used as a treatment intervention for many of these same conditions?

Root: Well, I wouldn't go so far as to say that it would be a treatment for Alzheimer's. We don't generally find that treating Alzheimer's works particularly well once that disease itself has set in, although I would urge practitioners to look up Dale Bredesen and the work that he's doing. However, the cardiovascular disease? Yes. I would recommend the Mediterranean Diet as a treatment if someone were to come to me and ask for a recommendation, because of the ability to change the inflammatory markers, the lipid balances back to a more favorable profile.

There is, for example, one of the elements ... I know we're going to talk about this in more depth as we go forward, but think about resveratrol, which is known to enhance nitric oxide production, and that means relaxing blood vessels and promoting endothelial health. In those cases, people that are in pre-diabetes, metabolic syndrome, or actually know that they have cardiovascular disease are looking to improve these factors, and Mediterranean Diet has shown to do exactly that.

Gazella: Before I leave this subject, are there any studies on obesity? It seems like obesity can increase the risk of so many things, not only heart disease, but also some cancers, and of course diabetes, and metabolic syndrome, and some of the other things that you've mentioned. Are there any studies showing that the Mediterranean Diet will help people lose weight?

Root: Yes. They weren't looking at that as an endpoint, so I'm not aware of studies, Karolyn, where they were specifically looking for weight loss as an endpoint in the study, but they have seen, as an aside, the additional benefit in some of the big studies of Mediterranean Diet of weight loss, although that wasn't really what they were after or what their intent was. People do seem to lose weight when they follow, when they adhere to a Mediterranean Diet. There's the key.

Gazella: Right.

Root: You know, that's the key in everything that we do, either successfully or not, when we talk about integrative health. But the weight loss factor seems to be more pronounced than in people who follow something like a low fat diet. I think that it's a happy additional benefit of following a Mediterranean Diet.

Gazella: Well, that's good. Now, is there anybody who should not be on the Mediterranean Diet? Are there any contraindications or safety issues?

Root: I can't think of any. I thought about that. I expected you to ask me that question, and I thought about that. I can't think of any, because the factors in Mediterranean cooking and following that approach are varied enough that if you had ... Let's say, okay, one caution is always what if you have a really strong food sensitivity or food intolerance, so a gluten issue, or what if you have a real sensitivity to nightshades? You could avoid those foods and still follow a Mediterranean approach, so there's enough variety I think in the foods in a Mediterranean lifestyle, a Mediterranean Diet, that I can't think of anyone that really would be a problem.

If you choose to be a vegetarian, omit the fish and include more olive oil and nuts for healthy fats. If you are avoiding gluten, then don't eat the gluten containing foods that are part of the diet. There's no hard and fast rule that says that you absolutely must include every element of the diet. If you have an issue with alcohol, you do not have to have the red wine. But as far as just a strict avoidance, I can't think of anyone.

Gazella: You know, I would agree. I have not seen anything ... I mean the diet is so fluid and so varied, so I think that that's definitely one of the benefits. I'd like to continue to kind of deconstruct this diet a bit more. You know, you mentioned healthy fats. You mentioned resveratrol. This diet includes a lot of key nutrients. It comes from the spices and the other foods that are featured in the diet. Can you give us some more examples of the specific polyphenols and other compounds that we can find when we break down this diet?

Root: Definitely. Let's say tomatoes, which are certainly something that people in Italy, and people in Spain, and France, and most of the Mediterranean countries enjoy, so with tomatoes we have lycopene, and lycopene is one of the dominant antioxidants in the bloodstream when people do eat a Mediterranean Diet. Lycopene itself has been associated with protecting the prostate health in men, reducing certain aspects of risk factors for health disease. So, lycopene from tomatoes is an example.

If you look at the leafy greens that are in the diet, then we can talk about lutein and zeaxanthin, and we'd also have to talk about the magnesium that is a very strong element benefit of leafy greens, and the carotenoids, the betacarotene, but lutein has been shown to be very beneficial for the retina. You know, dating back to the 90s, more lutein, even a single serving of spinach a day, reduced macular degeneration by more than 40% in men who were eating a healthy diet including spinach on a daily basis. Lutein is there in the leafy greens.

Think about garlic. You've got allicin, and you've got a lot of phenolic compounds in the garlic. Garlic is a benefit for being, first of all, an antioxidant, but also an antifungal. It's just a very healthy food. It also helps to normalize lipids. It helps with blood vessel expansion, so garlic is another element. I mentioned the resveratrol in the red wine. You wouldn't need to do red wine. You could get resveratrol from the purple grapes and from other red foods that are in the diet. If you eat blueberries, you could get pterostilbene, which is another very potent blood vessel health supporting antioxidant.

Let's not even get started on the dark chocolate, which is one of the elements, and we love that part, in moderation, meaning about an ounce a day of a good dark chocolate, full of flavonoids, beneficial for the blood vessels. Turmeric, so in the spice cabinet we have the turmeric, which provides us with the curcumin, which is an antioxidant, protects the lining of the blood vessels, associated with benefits in the brain, associated with a reduction in the amyloid deposits. You know, those are just some that come to mind.

Then the olive oil, which is certainly a big part of this. There's the oleuropein. There's the oleocanthal. These are antiinflammatory. When you get a good olive oil, you get a little sting in your throat if it's a really good one. Antioxidant, antiinflammatory. We're always a little reluctant to talk about cancer, but anti-proliferation. There are some studies that have shown the biological activity of oleuropein too, and that's an olive oil compound, antimicrobial, antiviral. So, you could apply that to heart disease, absolutely, diabetes, but also neurological diseases. There are just so many mechanisms from the specific compounds that would benefit almost the entire lifespan. I can't think of ... Even children would benefit from having these very nutritionally potent foods as the centerpiece of their diet, rather than pop tarts.

Gazella: Yeah. Exactly. It is a long list. I have to say that I've only heard one complaint about the Mediterranean Diet from a clinical perspective, and that is that sometimes practitioners feel like it's not specific enough. You know, the DASH Diet and some of the other diets, they have very specific directions on how to follow the diet, X number of this and X number of this. Now, how do you describe the Mediterranean Diet in very specific terms to ensure proper adherence to the diet?

Root: Well, I try to describe the things to include and the things to avoid in order to hopefully be following it quite well. So, we don't include added sugar, for example. I say get rid of that. I talk about limiting and hearty limits on red meats, and instead fish, and also feel free to have days where you don't have an animal protein or the animal protein might be cheese or eggs, but that we keep eggs even limited somewhat. What we're doing is changing out saturated fats for unsaturated fat. I'm not one of these that thinks that saturated fats are all bad, but this is a diet that emphasizes olive oil, rather than butter.

When we start to make these changes and we begin to develop a taste for these more natural and less processed foods, your taste buds change, and you begin to find it easier to embrace this more ... It's a simpler approach to cooking, so very few things from boxes, for example, in the Mediterranean Diet. People always say, "But what about pasta?" I say, "Well, what about whole grains? What about exploring using bulgur wheat? If you're going to do a pasta, do something like a couscous. You know?" Fewer things from boxes, fewer things from cans, although tomatoes from cans I think are okay. More fresh herbs, less salt, and more fresh herbs and seasoning as spices.

As far as adherence goes, I recommend cookbooks, Karolyn. I think that it's easier to take a kitchen table approach to this. I find a lot of times when diets are specified very strictly, people get very frustrated and overwhelmed with the weights and measures of it all. How do we actually keep ourselves to 200 milligrams of cholesterol in a day, for example? How many milligrams of cholesterol are in an egg? I take a different approach as far as specificity and try to encourage a variety of colors of fruits and vegetables, less canned and boxed and more fresh.

Shop more often, not less often, so that you're going and you're getting some fresh produce, and you're going home and having it in the next couple of days. Several meals a week that don't feature meat. At least two or three meals a week that do feature fish, so that you're getting those omega-3s. If you're going to do the eggs, get the omega-3 eggs, because those are full of a very absorbable form of DHA, and also lutein, and other nutrients, the choline that your brain needs.

I take more of a Food Network approach to it than I do an American Medical Association approach to it, and I recommend cookbooks. I have a favorite cookbook. It's the Complete Mediterranean Cookbook, and it's done by the people that do Cooks Illustrated Magazine, so it's America's Test Kitchen. I got it from Amazon. It's got 500 recipes in it. I haven't found one that I haven't liked.

Gazella: I love that kitchen table approach. You bring up so many good things. When you're describing it to patients, you're talking about ... Just by telling them what to avoid, it's going to automatically be including healthier options in their diets, you know, like swapping out butter for olive oil and shopping more often. That's a great piece of advice as it relates to a Mediterranean Diet. I think those are some great tips. Now, in addition to describing the diet in those specific terms, is there anything else that healthcare professionals can do to improve compliance?

Root: I think there is. I think it brings up a piece of the Mediterranean Diet that we don't talk about enough, and that is imagine yourself in the South of France. Imagine yourself on the Island of Crete. Think about the way that they approach their day, their meals, their habits. These are people that are moving at a slower pace than we do here, so it's not as much about convenience as it is about community. The meals are a point of shared experience for the family, the extended family, your neighbors, people that you ... Even when you're doing business with people, you bring them to your table, and you break bread, and you have a glass of wine. It's a much more relaxed, chill approach to things than in our zooming from point A to point B, and running into the deli, and grabbing something, and running back out kind of approach to life.

You saunter through the market with a basket over your arm and pick up some fresh veggies, and some fresh fruit, and maybe a nice piece of fish, and maybe they've just baked some crusty bread, and you're going to take that home and break the bread, and dip it in some of that olive oil, which you've ground some seasoning and some spices in, maybe a little balsamic vinegar. You take a very slow approach to that meal. Maybe you're all cooking it together and having it a little bit at a time, but there's this sort of attitude, and this piece of mind, and this slow approach that they take. I think that that is as important to adopt that mindset as it is to be aware of the nuts, and the bolts, and the mechanics, and the ingredients of the diet.

Gazella: I am so glad that you brought that up, because you're right. A big part of the Mediterranean eating is social and communal. Honestly, I don't hear a lot of doctors talking about that benefit. I would agree with you. I think that does add to the health promoting aspects of the diet. Yeah. I think that's a great thing to emphasize to patients. Now, for those people who are having difficulty consistently following the Mediterranean Diet, do you recommend dietary supplements. If you do, take us through some of ... I know this might be kind of an unfair question, because it's not a one size fits all, but are there maybe your top three recommendations that would probably be good for 90% of the people?

Root: Well, of course, you know, I have my favorites, but fish oils, so a good, high quality omega-3 supplement. Obviously you want a trusted company, because you want it purified. These days, with the omega-3s we are taking the approach of reaching an optimal intake, and that's measurable now. There's actually a little finger stick blood test that we can do now to see where you stand as your omega-3 score is concerned. For most adults we actually need a little more than what had been the recommendation. High quality fish oil that provides somewhere around 1,500 milligrams of the active components, the EPA and the DHA, is one thing, fish oil and with olive oil as your main cooking oil.

There's even a functional food supplement now that is even a combination of the two that you don't actually heat up to cook with, but you could use it for salad dressing, or you could use it to do that dip the bread in thing that I described, which is the first course of so many Mediterranean meals. So, that's a place to start is a good, high quality omega-3 or a combination omega-3/olive oil supplement.

Then I think something that not enough people are taking that more people probably would benefit from is a good curcumin supplement. It's made from turmeric. The curcumin itself is not really well absorbed, so you want to take it at mealtime. Get one that is CurcuWIN or one of the trademarked turmeric supplements, because the manufacturers have helped with the absorption. Always in a meal with fat is the best way to take either a fish oil supplement or the curcumin supplement. Those are the first two things that come to mind.

Then if I were going to pick a third thing for Mediterranean Diet, it would probably be a resveratrol or a pterostilbene. Those are things that maybe people aren't getting enough of in their diet, and especially teetotalers. If you're not drinking red wine, then you may not be getting much resveratrol, and there really does seem to be some longevity associated with that.

Gazella: Yeah. I was going to ask you about resveratrol, because even if you are drinking maybe a glass or two, I think that enhancing the resveratrol amount in the diet is probably a good idea. It's such a powerful nutrient.

Root: Me too. There are a lot of people that a glass or two is absolutely as much as they ought to do, women. Really you've got to keep alcohol at a small to moderate level, because extra is so bad. So, we've just seen a look at early onset dementia with chronic, heavy drinking, and it was much worse in men, but that's because men are more likely to be the chronic, heavy drinker, but it was scary when I was reading about it, because these men that it's four to five drinks a day ... So, this is a see something, say something for family members. If you know somebody that's drinking that much, it's intervention time. It takes 20 years off of their life. With the resveratrol a little bit of red wine, great, but I wouldn't do more red wine in order to meet my resveratrol goal. I would take a resveratrol supplement.

Gazella: Yeah. That's such a great point. Well, before we wrap up, Jolie, I'm wondering if there's anything else that you'd like to share to our listeners about the Mediterranean Diet and how they could or should be using it in their clinical practice.

Root: I would encourage physicians to use any kind of teaching tool that they can. There is now the ... I'm drawing a blank on this. The Department of Agriculture makes dietary recommendations, and they actually have one now that talks about Mediterranean Diet, and they help people follow it, a Mediterranean style diet, but there is a wealth of information on the internet from trusted sources that can help with sort of the guidelines for the Mediterranean Diet.

I think Oldways has a Mediterranean Diet pyramid. Maybe even keep some good cookbooks in the office, and hold them up, and say, "Here is a great way to get started," and they can order them, or you can give them a gift or something. People need practical advice, and remind them of the community benefit, the gathering the family around the table, because that's not just about the Mediterranean Diet. That's something that really is missing in our busy culture, and everyone I think would be healthier if they were able to do more sharing over meals.

Gazella: Yeah. I would agree. I think the Mediterranean Diet is such a powerful clinical tool that practitioners can use. Well, once again, I'd like to thank today's sponsor of this topic, Carlson Laboratories, and I'd like to thank you, Jolie, for joining me today and sharing this information with us.

Root: It was a treat, Karolyn. It was so nice to talk to you.

Gazella: Yeah. Well, great. You have a great day.

Root: You too.

Mar 13, 2018

Sponsored by Perque Integrative Health

By Natural Medicine Journal

There is a significant link between lack of sleep and hormonal, inflammatory, and immune system health. In this interview, Russell Jaffe, MD, PhD, describes the connection and then provides information about his comprehensive, integrative approach to sleep issues.

About the Expert

Russell M. Jaffe, MD, PhD, is CEO and Chairman of PERQUE Integrative Health (PIH). He is considered one of the pioneers of integrative and regenerative medicine. Since inventing the world’s first single step amplified (ELISA) procedure in 1984, a process for measuring and monitoring all delayed allergies, Jaffe has continually sought new ways to help speed the transition from our current healthcare system’s symptom reactive model to a more functionally integrated, effective, and compassionate system. PIH is the outcome of years of Dr. Jaffe’s scientific research. It brings to market 3 decades of rethinking safer, more effective, novel, and proprietary dietary supplements, supplement delivery systems, diagnostic testing, and validation studies.

About the Sponsor

Perque Integrative Health

PERQUE Integrative Health (PIH) is dedicated to speeding the transition from sickness care to healthful caring. Delivering novel, personalized health solutions, PIH gives physicians and their patients the tools needed to achieve sustained optimal wellness. Combining the best in functional, evidence-based testing with premium professional supplements and healthful lifestyle guides, PIH solutions deliver successful outcomes in even the toughest cases.


Karolyn Gazella: Hello, I'm Karolyn Gazella, the publisher of The Natural Medicine Journal. Today, I have one of my favorite guests, Dr. Russell Jaffe, with me. Our topic is sleep. But before we begin, I'd like to thank the sponsor of this interview, who is PERQUE Integrative Health.

Dr. Jaffe, thank you so much for joining me.

Russell Jaffe, MD, PhD: A pleasure to be with you, Karolyn.

Gazella: Yes, it's always a pleasure. This is an important great topic. Now, the CDC has said that lack of sleep is a significant national health problem. It's reached epidemic proportions. Now, why do you think so many people today don't get enough quality sleep?

Jaffe: Well, first I commend my colleagues at the Center for Disease Control for waking up. Yes, sleep deprivation in our time, in this 21st century, it is at least epidemic, and it may be endemic. Endemic means beyond epidemic. If it becomes so usual that it's like the normal, we don't notice it.

Fortunately, CDC has noticed that sleep deprivation causes all sorts of "tsuris." That's a Yiddish word for problems. It causes all sorts of amplifications of dispositions to ill health. Not necessarily the sole cause or the single bullet in the problem that a person has, but anything you have will be made better by good restorative sleep. Anything, any health challenge you have, any performance issue, any life quality issue, will be made better by good quality of sleep and worse by a lack of restorative sleep. The emphasis here is on restorative, not just on being unconscious.

Gazella: Right, I would agree with that. I want to dig into some of the technical aspects of sleep. Can you first explain to us the intricacies of the hormonal regulation of sleep? What's going on?

Jaffe: Well, half a step back if you permit me, which is in biology, in life, it's always about proportion, or ratios, or balance or imbalance. We can, and I'm happy to talk about the hormones and the neurochemicals, and the sources of these neurochemicals that are amino acids. The sources of some of these neurohormones that are either a vitamin or a fatty acid, a dietary source again.

As Hippocrates said several millennia ago, "Let your food be your medicine. Let your medicine be your food." If you start with a healthy, all foods diet that you can digest, assimilate and eliminate, you will then take in a healthy balance of the precursors to all of these neurochemicals, neurohormones, et cetera, and the body will figure out how to utilize them in an efficient and effective way.

Now I know that's a kind of high level view. But when we talk about these rhythms, which sleep is a particular example of biological rhythms in action, we do know certain things. There are four phases to sleep. At the end of the fourth phase is the time when a release of growth hormone, a release of neurochemicals, a release of neurohormones occurs, and abnormal cells are identified and eliminated. It's called apoptosis for those of you who speak Greek. But it means that everybody makes abnormal cells, abnormal cells you could hear as cancer. But everyone makes abnormal cells every day. The reason we don't all have cancer is because at night we have a restorative and reparative system that also identifies abnormal cells and eliminates them.

Now I mentioned the importance of rhythm, and you asked me about hormones, which is the right question to ask for sure, one of them. One of the hormones we know in relation to stress resilience, and stress adaptation and stress response is cortisol coming out of the adrenal under the stimulation of the pituitary, which in turn is controlled by the pineal, and we'll get upstream at some point.

When cortisol goes up because we're under stress, if DHEA, the companion molecule on the other side, the source of the androgens and estrogens, if DHEA goes up in proportion to the cortisol going up, we're fine. It's when the stress hormone cortisol goes up and the DHEA is exhausted and cannot go up, that's when we have a first level of problem. That's when people feel invincible, but they're not. They're cruising for a bruising, but they're not aware of it because the cortisol overrides the commonsense of the DHEA and those androgen and estrogen compounds.

There are other hormone ... Go ahead.

Gazella: Yeah, that makes a lot of sense, and I was going to ask you, but are there hormonal connections, so please continue.

Jaffe: Oh. If I may, there are other modulators. One important balance point or ratio is the cortisol to DHEA. But then there are others including the adrenaline to serotonin. Now adrenaline derived from the amino acid tyrosine, derived from our dietary protein, adrenaline says, "Go and you can persevere until the success shall be won." In contrast, serotonin says, "Now hold on there. Maybe we don't have the fuel to go all the way to the end. Maybe we should be a little more sensible here and not get exhausted."

Now serotonin comes from tryptophan just like adrenaline comes from tyrosine. Both of these come from the proteins we eat. If we're a carnivore, we'll have more of those amino acids. If we're a vegan or a vegetarian, we'll have less. If you think your engine is burning too hot because of too much adrenaline, if you think that it would be better for you to be more on the calm than on the assertive side, my suggestion is try a plant based diet.

You might not want to be a vegan or a strict vegetarian cause I think you should have a wide variety of foods that you can digest, assimilate and eliminate without immune burden, and I'm not making any political statements about ... Although my personal preference is a more plant-based diet cause I think that's healthier. I think that's less polluted. I also think that's better for the planet.

But I put my little advertisement in, and now I'll get back to the fact that tryptophan becomes not just serotonin, the soothing counterbalance to adrenaline, but serotonin becomes melatonin in the pineal, this deep control center. We've learned about the pituitary as the master gland, but the mistress or the master of the master gland is the pineal, modulated through the thalamus and the hypothalamus. We can get into all those tracks if you want cause I really am a biochemist and a neuroanatomist.

But the point is that amino acids derived from our diet become the neurochemicals whose balance we express in our personality, in our resilience, or in the way in which we're distressed. The people who have mood issues, the people who have endurance issues, the people who are concerned that sometimes they, maybe either overreact, or they're just not in tune with what's going on and people misunderstand. In any of those situations, you have an imbalance of cortisol to DHEA and/or an imbalance of adrenaline to serotonin.

Gazella: Right, that makes a lot of sense. I love how you brought adrenaline and serotonin to life. That was perfect. I want to stick with the topic of amino acids here. You know, I've heard varying views about tryptophan versus 5-HTP regarding sleep. Can you clear up that confusion for us?

Jaffe: I absolutely can. There was a time when tryptophan was the favorite approach, the more natural approach to sleep, to sleep enhancement, sleep quality. Then it fell under a cloud because of something called Eosinophilia–myalgia Syndrome. At that time ... This was the late 80s, early 90s ... there was voluntary recall of tryptophan. At the same time, interestingly, that serotonin reuptake inhibitors were being advocated on the pharma side.

Tryptophan fell under a cloud until it became clear that due to a change in production techniques, one company called Takeda had inadvertently, not intentionally, but they had changed the way in which they produced tryptophan. It was cheaper for them to produce large bulk of tryptophan. But they also included what turned out to be something called Peak E, which was a dimer. It was two tryptophan molecules bridged by a small carbon bridge. The consequence was induction of pain, myalgia, muscle pain, and an allergic-like response, eosinophilia. The FDA, out of an excess of caution, asked the industry to voluntarily recall tryptophan and they did, which was the right thing to do, in my opinion.

At the same time, my group published a clinical observation, which is we had uncontaminated tryptophan, and we gave it to people with this Eosinophilia–myalgia Syndrome, and it helped them get better, and we published that. If tryptophan was the real culprit, then giving them tryptophan would have made them worse, and it made them better, and we published that.

Now the agency, the FDA did not yet know about the contaminate now known as Peak E, this dimer of tryptophan that somehow jangles things up or messes things up. In fact, we do know how it does that. It bridges across two receptors in a way that makes the cell very unhappy.

Out of an excess of caution, the FDA asked the industry to withdraw tryptophan. In the absence of tryptophan, 5-HTP became popular because it's a tryptophan derivative. That sounds okay. Until you learn that it most often goes to quinolinic acid, and a series of excito-neurotoxin consequences that are not so good. You don't get as much of the serotonin to melatonin conversion when you go through 5-HTP. It's actually better to go directly from tryptophan to melatonin and bypass the 5-HTP.

5-HTP is a supplement. It is available in health food stores and online today. It is not my preferred form because I always believed in tryptophan. I still believe in tryptophan. My recommendation is enhanced uptake tryptophan. Because it turns out when you have a little B6, a little B3, a little zinc, a little of the right fiber, then you double, triple or quadruple the uptake from the intestines into the body so you get smoother uptake and better total absorbability, or what we call bioavailability. That is basically what we recommend.

Gazella: Interesting. With the tryptophan, is there a dosage range for sleep that you typically recommend?

Jaffe: Well yes, in regard to the tryptophan ... And I do recommend the enhanced uptake and the chaperone delivery. But for the tryptophan itself, it's anywhere from 500 milligrams of free amino acid to 1,000, maybe even 2,000. It is absolutely safe for people to start at the lower end, which would be one capsule, say 500 milligrams, and go up anywhere from two to four, depending on their body mass, depending on their situation.

Then often people ask me the question, "Well, what if I get up in the middle of the night?" "Well, why did you get up in the middle of the night? If you got up to go to the bathroom, go to the bathroom and get back to bed. If you want, you can take a second dose of the tryptophan because the peak occurs at 30 minutes. It has really done its job after four hours. If you are in a deep sleep and you stay restorative in your sleep, you don't need more. But if you get up, for whatever reason, my suggestion is take another dose. Take another one, two, three, four capsules, whatever dose works for you, 500 to 2,000 milligrams per dose. You can take that two or three times in a night."

Now occasionally, people do tell us that if they take more than 500 milligrams, they sleep really soundly. But when they get up, they're a little bit groggy before they really get going. That feels, to me, like a little too much. "Metabolism does play into this individuality," as Roger Williams told us. Biochemical and individual natures of our metabolism, how robust is our liver, how effective is our spleen and kidney at any moment in time, these are important variables.

Gazella: Yeah, and I'm glad that you mentioned that about the breakthrough insomnia, because I think that a lot of people are affected by that, where they will wake up at 2:00 in the morning and then they're frustrated, so that's good to know about the tryptophan. Now are there any-

Jaffe: Well, let me add if I can jump in on that, cause it is very, very common. It is also very common in people who are more creative, more sensitive and more aware. Why? Because they're worrying. I think you know this, but the Dalai Lama is my daughter's godfather. One of the things he said to me is, "Don't worry."

Gazella: Good advice.

Jaffe: Good advice, hard to do. You have to practice it and that's the point. Sometimes two, three, four o'clock, maybe even five o'clock in the morning, it may feel early, but that's the preferred time for monks to meditate. They go to bed early, but they get up early.

If you're one of those people ... And I'm in that phase of my life. I tend to go to bed early now, and I tend to get up early. I find those few hours before dawn a delicious time to either relax, or stretch or meditate, or just have a few quiet moments to myself where the phone doesn't ring.

Gazella: Yeah, I would agree. Now are there any other amino acids that can be helpful with regulating sleep and mood?

Jaffe: Well, yes, and there's two parts to this discussion. There are the amino acids related to detoxification. Then there are the amino acids related to mood stability. If I can take those in reverse order, in regard to mood, it turns out that glycine, the simplest amino acid, is also a neurotransmitter. It's a soothing neurochemical. If the nerves are excited, glycine calms them down. If the nerves are exhausted, glycine provides an energy source to wake them back up. Glycine's really very important in the brain, also important in the gut nervous system.

In addition, if you combine glycine with methionine, a methylating detoxifying amino acid, and combine those two with magnesium aspartate, an amino acid that in its own right has been studied as a mood modulator, as an antidepressant. But when combined with the detoxifying methionine and the neuro-balancing glycine, that's a very interesting combo of simple amino acids that in combination with the tryptophan can give even deeper and more restorative sleep.

Gazella: Perfect. Then now you mentioned the detox side of things?

Jaffe: Right. Now the other side is there are three phases to detoxification, phase one, phase two, phase three. Within the detoxification system, you want sulfur containing amino acids like cysteine, C-Y-S-T-E-I-N-E, you want methionine, but you might want a little phenylalanine because in order for sleep to occur, you must have enough adrenaline in the deep brain sleep center so that the adrenaline falls at the same time that the serotonin rises. That's called going to sleep at the cellular, molecular, biochemical level.

Now what happens if the serotonin rises cause you're tired, and your body wants to go to bed, but there isn't enough phenylalanine-derived adrenaline to fall, you'll be exhausted, but you'll still be awake. What about the other side? What if the adrenaline falls, but you didn't take in enough tryptophan so the serotonin doesn't rise? You'll be groggy, but you won't have restorative sleep. We need to have the fall of adrenaline and the rise of serotonin at the time when we're horizontal, not vertical.

Gazella: Right. I want to kind of circle back to what's going on when we're sleeping because you mentioned previously when we're sleeping, the body is really quite active. I've read studies associated with inflammation for example. If you get six hours or less in just one night, you put your body in an inflamed state. We know that there's a strong connection between the immune system and the inflammatory system. What's going on with those two systems in particular, and why is it so damaging if we're not getting enough sleep?

Jaffe: A profound, important question, and a question for our time, our 21st century challenging time. There is so much that occupies people today, so many screens, so many calls, so many distractions, so many attractions, that most people do not appreciate that sleep is essential for quality of life. If you want to add life to years and you want add years to life, you must have a quality of sleep.

Most of us, at some point, we become tired and/or exhausted. We do get into bed. Most of us even take our clothes off before we do that. But most people ... And I'm the exception here and I would advocate being the exception. Most people do not have a roughly half an hour or so during which they prepare for a restive, restorative, rehabilitative sleep time. They might even dream. They might even be able to solve a problem and bring a solution back into waking time. It turns out you can do things called lucid dreaming if you're inclined towards that.

But the bottom line is that sleep, preparation for sleep, and appreciation of the importance of sleep has been massively devalued in our society. Where we're supposed to go as close to 24/7 as we can and sleeping is somehow either depreciated, deprecated, or seen as a sign of sloth.

Now when I was a young doctor in the academic medical world, I can tell you that I slept so little that when Rebecca and I got together ... Cause she's a fine artist who values her sleep, and she's a terrific human being if she gets 10 to 12 hours of sleep a day. At the time, I was sleeping about four hours a day and thought that was just fine, which meant we had to choreograph being together, but we figured it out.

My point is that very often the very people who would benefit from mindfulness and restorative sleep don't "have the time." They can't fit it in. They're too driven to succeed. Or, as the Dalai Lama says, "They sacrifice their health to gain wealth. Then they give back their wealth to regain their health and they are so busy living in the past or ruminating about the future, that when they pass in the moment, they have barely lived."

That's a classic Buddhist perspective. I'm not particularly Buddhist, although I've done of lot of mindfulness myself. I have found that it helps to not just to feel that I've indulged in sleep, but to know that with wisdom and more years, having the ability now to go to bed early and get up early is delicious. I don't miss going out to the Kennedy Center as much.

Occasionally, I still want to go out and socialize. I have friends over. I prefer to cook for them than to go to a restaurant cause when I cook, I know what they're going to eat. I know we're going to sleep better because it's going to be food you can digest, assimilate and eliminate without any burden. I'm even going to take into account what their biochemical individuality might be and sometimes I get it right, sometimes I don't, but I always try.

Sleep is our friend. Sleep is to be appreciated for the positive side, not for the absence of usual consciousness.

Gazella: You know, I want to get back to specific nutrients cause we've already talked a lot about amino acids. But before I talk about other nutrients, I'd like to talk about sleep medications. There are some pretty potent prescription sleep medications. There are over the counter sleep medications. Do you have an overarching view of these sleep medications and if they're helpful or if you think it's better to try to get patients off of these sleep medications? What's your view?

Jaffe: Well, actually it's interesting. My view is more or less the same as the FDA. The FDA's official view is if you can do without them, please do. If you can possibly do without them, do. Because the adverse effects are clearly known. The benefits are also statistically defined. If you absolutely need them, they are beneficial at least within the reductionist frame of our scientific method.

But while I agree with the FDA, I often find that if people will follow through on what we're talking about. Including, having a diet that's appropriate for them, that they can digest, assimilate, and eliminate without a burden.

When they have enough of the essential vitamins, include vitamin D, which is really a neural hormone and other essential nutrients. So that their cells can deal with the challenges and stresses of the day without being so overexcited or overexhausted, those are two extremes which we want to avoid. Being overexcited or overexhausted.

We want to be resilient, we want to be in the middle. Sleep is just really important for all of that. Now with regard to prescriptions, the most common question I get is, can we approach this nature, nurture, and wholeness approach to sleep ... these amino acids and these fatty acids that are the precursors for these complicated molecules.

Can I increase nature's sleep balancing, stress balancing molecules? The answer is yes, although in many cases—especially, in the cases of Ambien and other serotonin reuptake inhibitors—when you bring in nature's team, the full valet or symphony of life, very often you can taper the pharmaceutical hypnogogic sleep medicines.

Taper them, eliminate them slowly. The importance of that is that it's known and it's been proven in many scientific studies. That you do sleep, however you don't dream and you don't have the normal sleep rhythms phase one, two, three, four. You don't have the normal release of growth hormone, which is so important to identify abnormal cells and eliminate them.

So sleep prescriptive medicines are benefits with a cost. I usually find that when we bring in the essential nutrients that people can't make. That they must take in from their diet or supplements, that they can then taper safely and effectively, the pharmaceutical sleep medications.

Gazella: Yeah, that's good to know. Certainly long-term use is definitely not indicated with those pharmaceuticals. Talk a little bit about those specific nutrients that practitioners who are listening can use to help improve sleep quality.

Jaffe: Well, we've talked about amino acids, so I'd like to note turn towards the fats. Those essential fatty acids, the omega-3 and omega-6 fats are the sources for the prostaglandins. They're the sources for the thromboxanes, which are the really active but short lived molecules inside the body.

We can measure the balance of omega-3 to 6 in laboratories. Neil Harris has devoted decades to validating the omega-3 index. My colleague, Artemus Simopolous, has looked at the NHANES National Health and Nutrition survey data.

She says that Americans now, instead of having a balance of omega-3 to -6, because of edible oils, and fats in our diet, and these foods that are crisped, and chipped, and so forth. It's typical for Americans to have 20, 30, 50, 80 times more omega-6 than omega-3, which is pro-inflammatory.

That makes you feel worse faster. That makes you more inflamed, and creaky, and uncomfortable faster. Folks like me no longer use edible oils. We cook with wine, or we cook with broth, or we cook with beer, and whole foods.

When you do that, you can restore a typical four to one ratio and not be so pro-inflammatory. Many people that I meet today look, feel, and function as if their body is under assault, inflammatory assault as if it's not repairing itself.

Inflammatory is really repair deficit. When your body can repair itself, you don't have inflammation. So we don't want to have zero omega-6 intake, but we don't want to have 50 times omega-6 to omega-3.

There is an omega-3 index test. It's one of the eight predictive biomarkers. It can help you take in the sources of fat that are essential and good. By the way, there is good fat. Omega-3 and omega-6 fats are good unless they're damaged by air and oxygen, in which case they're bad.

So you want them distilled under nitrogen. You want them in whole food sources. You want them in the healthier forms so that your body can convert the omega-3 fats into the prostaglandins that repair you while you still have a little bit of omega-6 to activate the system. But not so much that it creates repair deficit commonly known as inflammation.

Gazella: Perfect. Now in addition to the EFAs, before I move on to my next question, are there any other nutrients that you'd like to highlight?

Jaffe: Well, yes and it's in the broad category of, life is connected at every level with every thing. But when we think about, say sleep, and how the systems that convert these amino acids or these fats into the quality of sleep molecules that we're looking for.

We must have enough antioxidant ascorbate in the cell to donate electrons and prevent free radical oxidative harm. We must have enough magnesium, choline, and citrate. We advocate advanced uptake in chaperone delivery of magnesium using choline citrate.

So that you can correct the acetylcholine/bile salt deficiency at the same time you've energized and alkalinized the cell, while bringing magnesium into the cell. When very often, there's too much calcium and too little magnesium.

In fact, calcium channel blockers are a major category of pharmaceuticals because there is a relative excess of calcium. But there's an absolute deficiency of magnesium. Magnesium in the diet, Dr. [Rah Aleem 00:06:51] has shown, has dropped half, by 50 percent in the last 50 years.

While the need for magnesium ... because of stress and medicines that waste magnesium. Like, proton pump inhibitors and H2 blockers, and many chemotherapies, and even hypertensive medicines like diuretics are known to waste minerals including magnesium. So, as my grandmother used to say, the rents are going up and the ceilings are coming down.

Gazella: It's true. So, you know the conversation between the patient and the doctor is an important one. I'm wondering for the Healthcare Professionals who are listening, what type of tips do you give patients to help them get a good night's sleep?

I know you believe that it's not just a matter of handing somebody a pill and calling it a day. It's a very comprehensive approach that you have to health. So, what type of advice do you give to people who are struggling with sleep?

Jaffe: Thanks for asking and yes, as important as I believe diet and supplementation are in the 21st century, it's about what you eat, drink, think, and do. So, let's talk about the doing part of preparing for sleep.

Here's what I do, I set aside the half an hour before I'm gonna get into bed. During that half hour, I want to get as much value as I can. So I set a salt and soda bath. I put a half to one cup of Epsom salts and a half to one cup of baking soda.

My skin isn't dry, but if my skin was dry, I might put in a drop of Rosemary or some other Emollient oil, an aromatic. I soak in there for about 20 minutes. While I'm soaking, I do five minutes of deep abdominal breathing.

If you want to know what abdominal breathing is like, get a video of a baby or watch a baby because they all do it correctly. They breathe abdominally. Then, do about 15 minutes of mindfulness practice, or active meditation, or whatever is your preference to let go of the day.

Very often, people fall into bed, reasonably tired and exhausted. But thinking about the stresses of the day and they bring that into the bedroom. In my bedroom, we actually have no screens, we have no clocks, we have no alarm clocks, we have no phones. I know this is hard to believe, but I actually when I go to bed, I don't need to hear the emails coming in on my phone.

I believe, if you can, at the place where you sleep should be a place of serenity. That you should give yourself a half an hour to let go of the day and really let it go. Then, have an active time of restoring yourself through sleep.

If you want the bonus round, it's the green dichromatic light that I learned about from [Banti Darmawarh 00:09:56]. A rather extraordinary monk. Green dichromatic light is known to go directly from the retina to the pineal gland. In the pineal gland, it says everything is okay.

Green is the harmonizing color. This has nothing to do with vision. It has everything to do with the retinal / pineal direct connection, which has been reconfirmed by others. As [Banti 00:10:25] said, well wisdom, new things, millennia ago, and science is catching up and that's a good thing.

Gazella: I have not heard of the green light. That's fascinating to me.

Jaffe: No, it is fascinating. You may have heard about light boxes. There are people with what's called Seasonal Affective Disorder or SAD?

Gazella: Sure.

Jaffe: Norman Rosenthal and NIHMINH, showed that if you stay in front of these fluorescent light boxes for three hours a day, it boosts your pineal, and you get a little more melatonin, and you're less depressed. Banti said, people don't have time for that 20 minutes twice a day in front of the green. That's what we recommend.

Gazella: Wow, that's awesome. What about other hygiene aspects? Like the temperature of the room? Light in the room? Are those valid?

Jaffe: Thanks for asking. The answer to the second question in regard to light. It should be as dark as possible. Now if for some reason, it is not pitch black in the room where you sleep, please get a comfortable eye mask.

You should not have photons of light hitting the retina while your eyes are closed during sleep. If that requires an eye mask, please. They're not expensive, they can be comfortable. Take a flight on the Air Singapore, they'll give them to you. At least in business class. That's the question of dark.

Now, the nature of the room itself, should be comfortable, cool, this is a situation where warm is not your friend. What I have is a latex mattress which is very firm and lets me float. That's a nice thing. I have a duvet, so I have ... Some goose donated some feathers and somebody sewed this together.

In Germany, this is routine. You have this light Duvet on top of you. You have a mattress that will support you. It's cool in the room, you don't want it warm. Does that address your question?

Gazella: Absolutely, absolutely. Those are some great tips that our Practitioners can keep in mind when talking to their patients. I'm just wondering, we're about ready to wrap up, is there anything else that you'd like to talk about sleep for our listeners today?

Jaffe: No. I thank you for the opportunity to come at it in this way. Restorative sleep is one of essentially components of a life well lived. As someone who didn't think that sleep was important for many decades of my life, I can tell you it was a mistake.

I'm correcting that now. But I do also believe there are different phases to a life. I think if you're an adolescent, you have a different sleep rhythm. My understanding today is that young people actually do go to bed later and get up later, although they may or may not be able to do that and still graduate from schools.

But I do think at different seasons of our life, we have different relationships between wake and sleep. I want both my wake time and my sleep time to be as productive as possible because this is the only life that I know I have at this time. Therefore, every moment to me is precious.

Gazella: Yeah, absolutely. Great point, great way to end. So once again, thank you Dr. Jaffe for joining me. I'd also like to thank the sponsor of this interview, Kirk Integrative Health. Thank you and have a great day.

Jaffe: Thank you, Karolyn. A pleasure.

There is a significant link between lack of sleep and hormonal, inflammatory, and immune system health. In this interview, Russell Jaffe, MD, PhD, describes the connection and then provides information about his comprehensive, integrative approach to sleep issues.
Feb 6, 2018

Skin conditions are common in many clinical practices. In this interview, dermatologist and researcher Raja Sivamani, MD, describes how an integrative approach can help improve outcomes, especially with difficult to treat dermatological conditions.

About the Expert

Rava Sivamani

Raja Sivamani, MD, CAT, is a board-certified dermatologist and an associate professor of clinical dermatology at the University of California, Davis, and director of clinical research and the Clinical Trials unit. He is also an adjunct sssistant professor in the Department of Biological Sciences at the California State University, Sacramento. He engages in clinical practice as well as both clinical and translational research that integrates bioengineering, nutrition, cosmetics, and skin biology. With training in both allopathic and Ayurvedic medicine, he takes an integrative approach to his patients and in his research, with a focus on the gut and skin microbiome and lipidome. He has published over 80 peer-reviewed research manuscripts, 10 textbook chapters, and a textbook titled Cosmeceuticals and Active Cosmetics, 3rd Edition. He has a passion for expanding the evidence and boundaries of integrative medicine for skin care.

About the Sponsor

Dermveda Leaders in Dermatology Education

Dermveda is an integrative skin care, beauty, and wellness site dedicated to inspiring and empowering people to develop a healthier, more holistic relationship with their skin. We provide skin education tools and personalized, science-reviewed health content for both consumers and practitioners. Membership is free at

Dermveda's continuing medical education site, LearnSkin, was developed by leading dermatologists and integrative medicine practitioners to support integrative dermatological education throughout the healthcare community. The goal is to share the latest in scientific research and treatment options in dermatology for both Western and Eastern medicine. We aim to meet the growing demand for high-quality, evidence-based education that bridges conventional and alternative medical approaches. The first eczema series will begin in March at

Later this year, Dermveda will be hosting the first annual Integrative Dermatology Symposium in Sacramento, CA, from October 19-21, 2018. Experts from around the world in the practices of Western, Naturopathic, Ayurvedic, and Traditional Chinese Medicine will come together for this special event. The Symposium will feature educational sessions, clinical content, targeted industry trends, practical takeaways, and best practices related to all aspects of skin care. Registration opens in March at


Karolyn Gazella: Hello. My name is Karolyn Gazella and I am the publisher of the Natural Medicine Journal. Today our topic is integrative dermatology and my guest is Dr Raja Sivamani, an integrative skin care expert.

Before we begin, I'd like to thank the sponsor of this topic who is Dermveda.

Dr Sivamani, thank you for joining me today.

Raja Sivamani: Thank you so much for having me. It's a pleasure to be here.

Gazella: Well this is an interesting topic and I have to say that we have not covered this a lot in our journal so I'm super excited to talk to you today.

So, let's start with a very basic question. How do you define or describe integrative medicine specifically as it relates to dermatology?

Sivamani: Karolyn, I agree with you, this is actually a really exciting area when we think about integrative dermatology.

So, to answer the question that you're asking, you know, how does integrative medicine specifically relate. Dermatology really has many facets to it and by in large, many times when you go to see a dermatologist the appointment can be a little rushed and typically you're in there for about 15 minutes or so and many times the conversations will be focused on things like the diagnosis, which is super important and then some basic treatment plans and maybe a surgical treatment plan.

When we start thinking about integrative approaches, really then you start to take into all the other aspects of dermatology that are so vital to providing good care when it comes to anything skin related. So things like psychology, preventative approaches, diet, what you're putting on your skin, daily habits. All these things comes together and so, when I think about integrative approaches to dermatology it really is about a team approach and some of that team can be deployed by the practitioner but many times I also think about this expanded team that's working together in a way that, you know, maybe one practitioner's able to provide certain aspects and then another practitioner is able to provide other aspects of care and then them working together. So, that's how I view integrative.

And integrative, just as an add-on but I do want to talk about is, is not to say its separated from conventional medicine. I think bringing in conventional medicine, making that just as an equal part of the conversation, I think is really important.

Gazella: I would agree and that fits perfectly with the focus of our journal so this is great now.

So, what are some of the more common skin conditions that practitioners are faced with in clinical practice?

Sivamani: It turns out dermatology is so common. A lot of people see people with skin conditions. They did a study at the male clinic where they looked at how often and what kind of skin conditions, sorry, what kind of general conditions come in and skin conditions were really high.

The ones that are common and they tend to be pretty prevalent in the general population are things like acne, of course, these all depend on different age groups as well but, acne is very, very common. When we talk about eczema specifically, atopic dermatitis, that's another one that's common but there's also other conditions that may not be as common as those two but are still pretty common. Things like psoriasis and there's also seborrheic dermatitis, rosacea so, there's quite a few things that come up over and over again.

And, another sub-set of eczema, not atopic dermatitis, which is more dealing with pediatric population, and that does extend into an adult population but then there's also just common irritations that come up on the skin on a day-to-day basis that anyone can get. Things that mean to us as contact dermatitis either from irritation or an allergy.

Gazella: Now out of all of the skin conditions that are out there and, there are a lot of them, what are some of the more difficult to treat skin conditions that practitioners are faced with and, why are they so difficult to treat?

Sivamani: Karolyn, this is such a great question. I really like this question for a couple of reasons. When we talk about difficulty I really break that up into two modes, two facets to what makes a skin condition difficult to treat.

Firstly, a skin condition can be difficult to treat just because it's a rare condition and it will require some treatments that sometimes aren't always well studied because it's rare. And so, you can have conditions that just don't happen that often and when they do often and sometimes you know this condition can be auto-immune or other facets to them that really make it more difficult.

I think there's a second facet, though, that really is a challenge as well. And that's conditions that are chronic and that require constant management. We really have to integrate in lifestyle and other approaches and symptom management isn't enough. So, you have conditions like acne that, you know, they just won't cure on their own, you need to have some sort of active management to that in a very, what I believe, holistic conversation and things like eczema require so much activity from, you know, if you're a patient and you're taking care of eczema that's one thing but, if you're a baby, then you're really dependent on caregivers and so then it becomes a conversation with the caregivers and managing how they are approaching the treatment.

And so, I think that that second group where you have chronic conditions that don't necessarily have a cure but, if you can get really good management then it can make a huge difference. I think that is also a pretty big difficulty because it requires constant conversation and a lot of education. I think education is key in those kinds of situations.

Gazella: Yeah, that would make a lot of sense.

Now, I find it interesting that you have training in both allopathic and Ayurvedic medicine. I'd like to focus a bit on Ayurvedic medicine. So, for our listeners, what is Ayurvedic medicine?

Sivamani: Yeah, so, Ayurvedic medicine is, it was born from a tradition that's very rich in India. It's over 5,000 years old and their approach is really looking at homeostasis, meaning when you're in balance. Just to simplify it, is when are we in balance and when are we in a state of imbalance? And so Ayurvedic medicine has some tendance in how it measures what it means to be imbalanced, what is your imbalance state and I'll just use a couple of cavular terms. One is, prakriti which is your state of balance or what they say your original constitution but then you also have this notion of what's known as Vikrity which is your imbalance state and they use the three doshas which are known as vata, pitta, and kapha in a very broad manner to identify what those imbalances are and, a lot of approaches including lifestyle approaches, dietary approaches, what you put on your skin, believe it or not, you can even describe western medicine from an Ayurvedic perspective and the idea is, can you take this imbalance and move it back towards balance?

What I really like about Ayurvedic medicine is that it can really go well in an integrative approach. So, you clearly have conventional approaches that tend to be focused much more on symptom management and then Ayurvedic medicine gives you tools, and I think that's really important, just having this ability to have this conversation to what it means to be in balance so you have these tools to talk about what are different lifestyle changes you can make or what would be an appropriate dietary change that you could make.

If I may add, one of the fun things I think about Ayurvedic medicine is that it gives you the opportunity to personalize and in conventional medicine they're really good about research studies that will study a large group of people and then in many ways you get kind of an average outcome and then you can apply that to each patient.

So, if you bring the two together you have this really powerful system where Ayurvedic medicine allows you to personalize a little bit more on top of what you're going to do and then conventional medicine gives you the ability to have broad-stroke approaches that might give you a good starting point, especially for symptom management.

But, Ayurvedic medicine is really rich on the personalization aspect.

Gazella: I think that's important. That really has become a big emphasis, it's no longer one size fits all. I would assume, especially in the area of dermatology and these difficult to treat skin conditions.

Can you give us a few examples of how you apply Ayurvedic medicine to dermatology in clinical practice?

Sivamani: Sure, you know, that is one of the funnest parts and really interesting parts of my practice. I feel like I get to know my patients better. If I may say, from one of the really key aspects of Ayurvedic medicine is, I have to get to know the patients habits much more and understand what kind of things are they doing in their daily life. That in and of itself gives me a greater connection.

So, for example, if I have a patient coming in with eczema and Atopic dermatitis, we're talking about different management approaches. One of the things that can sometimes come up is if we're just taking a pharmacological approach and we're talking about steroids, a lot of people want to know, am I going to be doing these steroids for the rest of my life, is there any sort of way that I could do management that doesn't require the steroids to be used?

So then you have this rich knowledge in Ayurvedic medicine about all these different oils and how oils are used on the skin and, there's a rich, rich literature, rich history on different oil therapies and what they call oliation and what's known as abhyanga, so self massage or massage with oils. And it really opens up a conversation because you can start talking about moisturization but bringing in the science of natural oils and, this is an area that's started to really grow in dermatology, what's the role of coconut oil, what's the role of olive oil, what's the role of sunflower, safflower oil, this has now started to hit the medical literature.

What Ayurvedic medicine does is it goes one step further and you can do herbal infused oils and I have these conversations with my patients. I tell them, you know, why don't we talk about maybe some simple ways to make a herbally infused oil where you can have a moisturizer that is really based on an oil therapy.

And what starts happening is, people start to become very engaged with themselves. Their skin becomes a part of them that they're not afraid of anymore and they're used to touching themselves in a way that's actually very therapeutic and then, you know, funny thing is, when I have these conversations then they realize that there's a holistic approach and then they're okay with using the steroids and they understand why we're using steroids and then it's part of a bigger picture approach to managing their symptoms.

So that's one example that comes up very frequently in my practice.

Gazella: And now give us an example of a herbal infused oil. Like which herb would you put with the oil for which condition? Is it that simple?

Sivamani: It's a little bit more nuanced.

Gazella: Okay.

Sivamani: What you have is you have different dosha imbalances and different oils, there can be, some oils that are warming in tendency or they can be cooling, I mean, you have to balance that with the doshas but, I'll give you one example, which I think is a pretty good one.

Coconut oil is widely used now as a moisturizer and sometimes what we can do is we can infuse, there's a herb called neem. Neem has both anti-bacterial and anti-fungal properties and we've been studying it. Actually, I have a basic science laboratory as well and we've been looking at neem specifically. But, one thing you can do is you can create an infused oil that has coconut oil as the base with a neem infusion and what that does is it gives you this oil that's not only going to be helpful for bolstering the skin barrier and nourishing the skin and, from that aspect but you also get that extra little antibacterial effect.

Now, I don't want to claim that it's an antibacterial like something that's been studied through the FDA but that being said, in eczema, sometimes, its smaller shifts in the microbiome and one of the things that we try to do is think about, from a practical perspective, can be infusing oil that might be able to touch upon those kind of aspects and then eventually it would be nice if we could start studying them in controlled studies and really looking at how, what is it doing to, for example, the microbiome?

But that's one of the examples of an infused oil that we might use.

Gazella: Yeah, that's a great example.

Now what advice do you have to healthcare professionals who may be struggling to treat some of these difficult to treat skin conditions in their clinical practice?

Sivamani: This is such a fantastic topic to talk about.

When it comes to treating conditions that are a little bit more difficult, I think it's important to realize that there's a team available and there's also the patient perspective. But I think the team approach is really important.

You're not alone and, what I mean is that, if you have someone that has a really bad itch, for example, we can do our best as a, myself, as a dermatologist, I can talk to them about what are some of the things they can do to help their skin not be as dry or are there some treatment options to help reduce the itch even from a pharmacological perspective. But then, I think it's really helpful to start thinking about the psychology of itch. What are the other approaches that we can take so then, if we can get them to one of my colleagues in, for example, traditional Chinese medicine and they can take an approach where maybe they look at acupuncture, and that can channel in on a different aspect to itch and, you know, focusing a little bit more on some of the other approaches, I think that's where it really becomes important.

When you're struggling to treat a more difficult condition that may even be chronic, it's to start thinking about a team approach and I feel like that's the essence of integrative approaches anyway and so if we can start developing teams and developing good partnerships with other healthcare professionals then as a healthcare professional we won't feel alone and as a patient, the patient won't feel alone either and they see that there's a team working for them.

Gazella: Yeah, absolutely, and that definitely is in line with the integrative approach that you described in the very beginning.

Now, you are an advisor to the company Dermveda. Why did you want to work with Dermveda and how is it different from other skincare companies?

Sivamani: What I really like about Dermveda is it's focused on education and, if you look at the founding team, the founding team consisted of people that are really dedicated to dermatology, they're very good teachers and lecturers and, also they have a good education background and, I like education first approaches because I think if you can teach people to start thinking more deeply about their condition, and when I say deeply, not just about maybe the molecular mechanisms or some sort of cellular pathway but really understanding that that's important but, it's also important to think about things that may be affecting you emotionally or psychologically and allowing people the space to see that these are also important and by opening them up to have better conversations with themselves and their practitioners.

That's why I'm so passionate about this company. I'd personally really dedicated to education, I like education in all of its aspects and I think its really important to empower patients and practitioners and so, because of that approach, I really am drawn to the Dermveda's approach and also, the holistic and the integrative approach allowing us to learn about, not just conventional medicine but also thinking about Ayurvedic medicine, traditional Chinese medicine. Our naturopathic colleagues have such great insight into the botanicals and into plant based approaches but I think that, giving a platform for this open discourse that's honest and credible is super important so that's why I'm so interested in this whole approach.

Gazella: Yes, I was thrilled to see that Michael, Dr Michael Traub is on your team. He is a friend of the Natural Medicine Journal and on our editorial board. A very top-notch doctor so, that was exciting for us to see that as well. And now, Dermveda is also hosting an integrative dermatology symposium this October in Sacramento, California. Can you tell us a little bit more about that symposium and why you feel it may be important for practitioners to attend.

Sivamani: We are so excited about the symposium, the integrative dermatology symposium is going to be the first time where we're going to get all the different perspectives into the same room and have a good open discourse and really start talking to each other ina way that we can start building relationships.

This symposium is going to really feature a wide variety of things. You mentioned Dr Traub, he's going to be one of the speakers there.

I still remember one of the first lectures that I saw with him and I was really impressed by, not only was he able to talk about the pharmacological approaches but it was so nice that he put in things about, and this was with eczema, we were talking about treating eczema, he had a lecture on that and, he put in things about a humor and what does that do for a child at the end of the night when they're about to go to bed, if you can have some way of getting them to laugh, does that make a difference?

I think its important to talk about these aspects and what we'd like to do in the symposium is really put that into a situation with all come together in a focused way where we have this combined goal of just making it better for each other to treat our patients and leaning what's new and what's coming out that's in the new literature and realize that any one perspective isn't the full approach.

And, if you can start taking a different perspectives it really makes a difference and, I'll give you an example. So one of the things that we're going to be talking about is like one of the lectures is going to talk about emerging approaches to eczema and there'll be conversations about all these new medications that are now coming out but then there's also going to be conversations about what is the latest science on the oils that are being used for eczema. Which oils seem to be the best, which one's may not be the best.

And then from there, they'll also swing into a conversation about diet and so, I think one of the things that sometimes we miss out on in just the medical education that we might go through is that you might get pieces and bits but when we start thinking about continuing education, you want to start really have good, honest discourse about all the aspects because that's really what the patient really wants. They want to have a good, holistic conversation about everything. They want to know what can I do with diet or, what can I do with my lifestyle approaches.

So, this is going to give practitioners, that attend, the chance to be empowered to understand what is the latest in that but not only that, I think the most exciting part about it is, we're going to get everybody in the same room and you just never know what's going to develop in those kind of situations. What kind of partnership and friendships are going to come out of that and I think that's the way to really push the boundaries of medicine so that when we talk about integrative medicine it really just becomes medicine and it's just the approach that we all would want to take with any patient that comes in.

Gazella: Yeah, that's a very good point and it sounds very comprehensive and we have a link to the conference. So, for our listeners who want to learn about more information about the integrative dermatology symposium, you can just click on that link and then you'll be able to find out more information.

Well, once again, Dr Sivamani, thank you so much for joining me and I would also like to once again thank our sponsor, Dermveda.

Sivamani: Thank you so much and it's been a pleasure to be here with you.

Gazella: Great. Have a great day.

Jan 25, 2018

In this video interview, Christopher Shade, PhD, describes the diverse clinical applications of cannabidiol (CBD) oil. Also included is information about safety, dosage, and other issues associated with this somewhat controversial natural substance.

About the Expert

Christopher Shade, PhD

Christopher W. Shade, PhD, founder and CEO of Quicksilver Scientific, specializes in the biological, environmental, and analytical chemistry of mercury in all its forms and their interactions with sulfur compounds, particularly glutathione and its enzyme system. He has patented analytical systems for mercury speciation (separation of different forms of mercury), founded the only clinical lab in the world offering mercury speciation in human samples, and has designed cutting edge systems of nutraceuticals for detoxification and antioxidant protection, including advanced phospholipid delivery systems for both water- and fat-soluble compounds. Quicksilver Scientific is recognized globally for innovating on behalf of the pharmaceutical and nutraceutical industries. Dr. Shade is regularly sought out to speak as an educator on the topics of mercury, environmental toxicities, neuroinflammation, immune dysregulation, and the human detoxification system for practitioners and patients in the United States and internationally.

About the Sponsor

Quicksilver Scientific

Quicksilver Scientific is a leading manufacturer of advanced nutritional systems with a focus on detoxification. We specialize in superior liposomal delivery systems and heavy metal testing to support optimal health. Our advanced liposomal supplements are highly absorbable, and support the body in the elimination of ubiquitous toxins, enabling you to achieve your genetic potential. At Quicksilver Scientific, we are passionate about health and well-being, and are committed to improving the lives of everyone we touch.

To purchase Quicksilver Colorado Hemp Oil as a Practitioner, please access Consumers, please access


Karolyn Gazella: Hello. I'm Karolyn Gazella, the publisher of the Natural Medicine Journal. Today we have a fascinating and somewhat controversial topic to talk about. We're going to be talking about the therapeutic effects of CBD oil from cannabis. Before we begin, I'd like to thank the sponsor of this podcast, who is Quicksilver Scientific. My guest today is Dr. Christopher Shade. Dr. Shade, it's always a pleasure.

Christopher Shade, PhD: Always a pleasure.

Gazella: And I have to ask you first of all, is there a reason that CBD oil would be controversial? Am I right in that?

Shade: Much ado about nothing.

Gazella: Maybe.

Shade: You know, is there a reason for controversy? Controversy's built out of us evolving as a society in which we had instituted cannabis prohibition, and we all had this reefer madness fear around the THC side of cannabis, the psychoactive high-inducing side. But CBD is coming from industrial hemp, which is the THC is bred out of it, and you're left with another component that is big in the resins of cannabis, and it's called cannabidiol. It's chemically different than THC, and its physiological effects are vastly different, and they seem almost magical when you look at so many ... At the variety of things that they do for you, but they don't get you high. They have an effect of balancing and calming the mind, but they have so many different therapeutic benefits, and it's really just getting people out of the fear of the evil weed, into this wonderful, medicinal plant and all the uses it has.

Gazella: I want to get into the mechanisms of action and all the science associated, but first, and I know that you're not a legal expert, but is it available freely? Is CBD oil available for purchase, or are there limitations because cannabis is not legal in many states?

Shade: Yeah. The entrance of CBD into use in the US was made possible by the 2014 Farm Bill, which was allowing the use of industrial hemp for various uses in trade in the US. In those uses came the use of the extracts. Now, by some interpretations, well, that's still cannabis, and that's still scheduled as a drug. Certain parts of the government are saying, "Hey." Like the DEA. "Hey, that should still be scheduled. We didn't say that's okay." Whereas other parts of the government are saying, "Hey, that's all right. That comes underneath the Farm Bill." Most of the states have rolled with this being under the Farm Bill, and being an allowed substance. It's gained so much widespread use, and a lot of that use is from very impaired people that rely on it heavily for their health.

Most places are reluctant to step in and go against the Farm Bill. Certain states, however, Indiana notably, recently the Attorney General said, "No. We're not doing this, except for under certain exemptions. If you have a certain type of a ..." It was probably a seizure disorder, "Then you can get a permit to use this." Missouri, I don't know the extent of their laws, but they're kind of difficult. Most people don't sell it in Missouri. Then other states are taking a tack of trying to adopt it into a state cannabis law. Making it like THC, where it's regulated by the state, just like Colorado regulates THC. It does not regulate CBD independently, but for instance, the State of Florida is trying to bring CBD into their medical marijuana world. We'll see how it rolls in Florida, but right now the places to stay out of are Indiana and Missouri. This is such a moving target that this might change in a month.

Gazella: Right. Now, just to clarify, though, CBD oil or hemp oil does not have THC in it.

Dr. Shade: No. In most of the extracts of industrial hemp ... Industrial hemp is defined in the Farm Bill as a plant that, on a whole plant basis, has less than 0.3% THC. When the Colorado Department of Agriculture goes and certifies a crop here for being harvested and processed, it will take representative plants and analyze them for this threshold of THC. Now, these plants usually have, oh, 7% to 9% to 10%, upwards to peak around 15% CBD as well. There's some residual THC along with the CBD. One of the concerns originally was, "Well, when we concentrate that up, will there be enough THC for people to get high?"

Now, processors who are trying to stay very clean with the law will use extraction technologies and post-extraction purification technologies that minimize the THC. For instance, in our CBD oil, there's virtually indetectable THC. Whereas some oils will have a 20-to-1 CBD to THC ratio, ours is around 500-to-1. It's super clean, and that's nice because a lot of people that want to use the oil have THC testing programs that they're in, if they're firefighters, or policemen, or airline pilots. A lot of the commercial extracts have enough THC that if you're using large amounts to be really therapeutic against something like pain, you will probably have enough THC to tip the scales on some of the analytical techniques looking for THC.

Gazella: Got it. Thanks for that clarification. Now, let's get into the science, which is your area of expertise. What's going on from a mechanism of action standpoint? How does CBD oil work inside the human body?

Dr. Shade: Well, it works on a number of different levels, and when we were describing this, we used to chase after one thing or another. We'd say, "Oh, it's antiinflammatory." Or, "Oh, it helps GABA-glutamate balance." As we go forward, we look at it more and more in this symphony, and this symphony, I call neuro-endo-immune poise, or balance. Neuro means neurotransmitters. Endo is endocrine or hormone, and immune is obvious. It's the immune system. Neurologically is how we used it the most, for damping neuro-inflammation. When I lecture to doctors, I say, "This is the most exciting supplement for us in the last 30 years in functional and integrative medicine."

Because we're treating a lot of people with [mole 00:07:45] toxicity, Lyme disease, mercury toxicity, and all these have as part of their symptomology neuro-inflammation, where you become ... Your autonomic nervous system becomes sympathetically dominant, you've got overactivity of glutamate receptors, there's activation of the immune system in the brain called the microglia, and they're sort of at war with the glutamate receptors. That's causing anxiety first, then brain fog, then a disruption with the autonomic nervous system. You're moving resources and blood in wrong ways throughout the body, and this acts to just stabilize all of that. It will block the excitation of the microglia. It will stabilize the glutamate receptor. That will result in a neuro-stabilization. Your neurotransmitter balance between glutamate and GABA gets balanced. Your autonomic nervous system balance between parasympathetic and sympathetic gets balanced.

But that starts cascading down even farther into the body, and we start to look at really what homeostasis or balance of the biology is, and it's a set of reactions that all have these yin-yang poles, which you want to sit in the middle of and take forays in the yin or yang as needed to handle different perturbations, but you always want to come back to the poise of the center, and CBD is always bringing that back to the middle. In hormones, in women, the organ with the greatest amount of cannabinoid receptors? The uterus. I always pair CBD with bitters, and guess what's in the ovaries, but bitter receptors. We find such a stabilization of the female cycle by taking those things together. Then the immune system. You want inflammation when you need to kill things, but then when it gets stuck on, and it won't turn off, you get things like development of chronic inflammatory states. These can be cardiovascular complications. These can lead to cancer. These are problems, so where's the switch to bring it back? The CB-2 receptor, the cannabinoid number two receptor, and where's that located through the body but on the peripheral immune cells of the body.

CBD lubricates your endo-cannabinoid system. Why would you have cannabinoid receptors if you didn't make cannabinoids. The two main cannabinoids you make are 2-Arachidonoylglycerol and anandamide, and the reason you make them is to zip together the neural system, the endocrine system, and the immune system have that neuro-endo-immune poise, and CBD helps you build more of those endo-cannabinoids and helps potentiate those CB-2 receptors. At the same time, it's up-regulating chemo-protective and antiinflammatory genes and down-regulating pro-inflammatory genes. There's really no one thing that helps you create that poise, that essential homeostasis. Nothing does it like CBD oil does, and that's why it seems like a panacea, because it helps so many things.

Gazella: That was actually my next question, because when I was researching for this interview, I found such a diverse amount of conditions that it was being effective for, so because it works on these multiple pathways, that's why you're saying it works for such a variety of conditions. Do you give practitioners who say, "Wait a minute. That's a little bit too good to be true. How can it be that good for that many things?"

Dr. Shade: Well, then I give them the neuro-endo-immune poise story.

Gazella: Exactly.

Dr. Shade: And as soon as you said neuro-endo-immune poise, they go, "Wow."

Gazella: That's right.

Shade: Because what are the disorders? There's some part of you in that yin-yang balance that's stuck over here, or stuck over there. Anything that helps you zip together so many fundamental processes, everything just starts to come back together again. I mean, it runs through all of our different protocols, because it's that X-factor for zipping it all up again.

Gazella: Right. Now, there's got to be some conditions that bubble to the top, and that was the other thing that I was so impressed with, with the research, is the amount of research associated with CBD oil has grown dramatically. But what conditions? As you're looking through the research and you're kind of identifying the strength of the research, what conditions are bubbling to the top, to say, "Yup, that's really what it's going to work for"?

Shade: Right. In our world, we deal with detoxification, and so we're dealing with people who have various problems that are associated with toxins. Autism is a really big one. That's always ... Unless they're just totally exhausted, autistics, always bringing CBD into that, because of that neurological stabilization. Then we're dealing with various mole toxicity, Lyme disease, and the neuro-inflammation that comes from that, the different metal toxins. All of our detoxification protocols, especially when they're neuro-detoxification protocols, involve the use of CBD. Then in distinct disease states, the big ones, MS, Parkinson's, any kind of tremor. Of course, everybody knows seizure disorders. Those are all crying out for some application of CBD.

But then since I understood the endocrine side of it, women who are having endocrine destabilization or hormone imbalance, we're always recommending CBD along with the bitter herbs to them, and we get great ... You might not think, "Premenstrual syndrome: CBD." But it's fantastic for that. Those are the main ones that we use. Oh, any chronic inflammatory pain. That's a really big one. Cardiovascular complications. That's really big, too. We've seen some great data emerging on the use of CBD, including some doctors who have used ours to get preliminary data, on the health of the inside of the vascular system, and you'll see those cells on the inside of the vascular system all getting less stress, increased poise, and so we recommend it in those cases as well.

Gazella: Now, what about mental health? You've now just listed some conditions that are related to our physical health, but what about some conditions associated with mental health?

Shade: Anxiety's just hands down the biggest one, because anxiety results from over-excitation of the glutamate receptors, and boom. CBD stabilizes that immediately. It's very, very fast around that. Now, it's interesting, for much more complicated problems, like schizophrenia, here you've got one plant, two chemicals, THC, CBD. THC is like putting the fast forward button on schizophrenia. It's really bad for a schizophrenic, where CBD has fantastic data around stabilizing schizophrenics, so there it's useful as well.

Even in depression. Depression, you think, "Okay, well anxiety, you're really stimulated, and that calms you down." But depression is also often cycling with anxiety, and so depressive disorders, there's been a lot of data around use of CBD too, and most of my favorite integrative psychiatrists like Kelly Brogan, they've showed very clearly that depression is a neuro-inflammatory disorder, and so you've got different reactions to antigens in your food, in your environment. You're having these constant allergic states and cytokines, these pro-inflammatory states that are contributing to depression, and CBD is working against all that, creating that balance again so it can be used in anxiety and depression.

Gazella: Yeah. It's fascinating.

Shade: Yeah.

Gazella: I'd like to talk about safety, because I have to tell you that I've read some conflicting statements associated with safety. Based on your interpretation of the scientific literature, is it safe? Are there any interactions, contraindications that we need to be worried about?

Shade: On its own, without you having to stick something else into your body like a heart pressure medication, CBD is inherently incredibly safe. We've found a couple of people here and there that seem to have an allergy to the plant, and they just feel unhappy on it, but the issue around CBD and safety is that it interacts with some of the cytochrome P450 system, which are metabolizing drugs. If you're taking a drug for blood pressure, CBD may either lower its breakdown, so increase its circulating levels, or increase its breakdown, and thereby decrease their circulating levels. If you're on a lot of pharmaceuticals, you usually have to do a little bit of research and see if there's some interaction between the CBD and the pharmaceutical that you're on. There's starting to be good lists online of the potential interactions. They've got to get a little bit better at where these are really relevant interactions, and where they're not relevant interactions. But this will be one of the things that we come up with in the future, is nice, clear guidelines on whether something's going to positively reinforce a drug, or work against the activity of the drug.

Gazella: I mean, the case that I read was specific to antidepressants, and that's where it was very conflicting. Some reports were, "Yes, it will react," as you describe, and some were, "It will not."

Shade: Because it's not antidepressants. It's, "This list of chemicals."

Gazella: Exactly. Yeah.

Shade: They just happen to be antidepressants to your body that get metabolized down different pathways according to their chemical nature. Your breakdown doesn't care whether it's an antidepressant or whether it's testosterone. It's got a chemical nature, and it's got to fit into the cytochrone that breaks it down. You get a list of antidepressants, they have different chemical natures, and they go into different cytochrome P450 enzymes to break down, and CBD interacts with two or three of those enzymes. If the antidepressant interacts with the same enzyme CBD does, then there could be an interaction, and if it doesn't, then there's no interaction. It's not about antidepressants.

Gazella: Yes, and nothing is ever clearly black and white when we're talking about this type of chemistry.

Shade: No.

Gazella: I'd like to talk a little bit about the product that you specifically formulated, Colorado Hemp Oil. What makes your product unique or special compared to other CBD oil products that are on the market?

Shade: Quicksilver Scientific specializes in delivery systems, ways to get the compounds into little, lipid-based carrier spheres that are so small that they passively diffuse through mucosal membranes, like your oral mucosa, the sublingual space, as you're swallowing, through the stomach, the upper GI. It's the rapid and complete absorption of these little nano-spheres which is what we do, and when we stick CBD in there, there's a very fast uptake, there's a high total uptake, and it's a very rapid uptake. One of the things that's a problem with CBD is there's only net about 10% uptake of all the CBD you swallow. That's a very expensive molecule, as you know, and so you're throwing away a lot of that and not getting a lot. The stuff you do absorb is absorbed over the whole transit time of the GI, so if we look at uptake versus time, you have a very gradual, slow movement into the blood. The blood levels, the peak blood levels never get very, very high.

Now, a lot of what CBD does, it does through interacting with receptors, and gene triggers, like nuclear transcription factors, like NRF-2, which turns up all your glutathione genes. Now, the receptors and those transcription factors react to peak doses. Level versus time, here's a regular CBD oil. Here's ours. You get a very high transient peak dose. You saturate the system. You're able to work very well on the brain. You're able to hit all of those transcription factors. You're able to interact with all of those membranes, and everything happens very quickly, and you get a very strong effect.

The total absorption is anywhere from four to sixfold higher than a regular pill, but even if you took four to six times as much, you don't get as much of an action, because you don't have that peak dose to really induce everything, ring the bell of those receptors. What happens when you hit receptors, you trigger a whole cascade of different proteins to be made, which is affecting the metabolism of the body. That transient peak dose really creates the effect that you're looking for.

Gazella: Now, your label says that the patient needs to hold it in their mouth for 30 seconds. How important is that, and is that all a part of the enhanced absorption of the product?

Shade: It is, because this is a nice space in the oral cavity. Interacting with the oral musoca is a space where your spheres that you've made have not had to interact with stomach acids or bile, so there's nothing modulating them or modifying them, changing their shape, their size. It's a nice, pure space where all the capillaries are very close to the surface, and you can get a whole bunch in. Now, that being said, for some of our products that are water-core, that are liposomes, those are a little bit more sensitive to the GI conditions, and a little bit more important that you do that oral holding. The nano-emulsion that we make, like the CBD, you have an oil core with a membrane around it. These are more resistant against change in the GI tract, and they will make it through, and you'll get the absorption anyways, but it'll be a little bit slower, and a little bit less efficient.

The more you can do the oral hold, the better, but it is not a game-breaker. That's important for a lot of the people that are very taste-sensitive, or if you're working with autistic children, and they won't do that, or you're giving it to your dog or something, goes right down.

Gazella: I don't know. My dog is pretty smart.

Shade: Yeah. You just say, "30 seconds."

Gazella: That's right.

Shade: "No. Five seconds more."

Gazella: It's interesting. I would like to stay on dosing. Is it complicated to dose from a practitioner's standpoint? Because you do have such a diverse offering of conditions that it can help. Is the dosing-

Shade: Yeah. It's really titration dosing. You start at a low amount. One of the doctors in town here, Joe Cohen, goes with two pumps three times a day as a sort of basis dosing for an adult, and then they'll add more as they need it. If you're not getting the effects, how about three pumps three times a day? Then four pumps three times a day? Titrate up until you get the required effect. You can even start down at one a day, like if you're dealing with kids and you want to start low and slow, but just keep titrating up until you get the effect you want, and often once you induce the effect and start training the body into the healthier state, you can bring the doses back down. Just start low and work up until you get what you need.

Gazella: Great. Now, before I talk about the future, because you know I like to talk about the future, I'd like to have you predict the future, is there anything else that practitioners need to know about CBD oil when it comes to using it in their clinical practice?

Shade: No. Don't be afraid to use it for a wide variety of conditions. Work your dosages up until you get the effects that you want. Let people know, especially if they've never had anything like this, the feeling that they have in the first couple of days may be more intense than it will be later, but it's not ... Most of the other supplements, there's more tricks around it and things to watch out for. Not so much with this.

One thing, though, you will, if you're using it alone, you will start to generate detoxification reactions through two mechanisms. One is NRF-2 up-regulation, that nuclear transcription factor that's turning up the glutathione system, and the other is the autonomic balance, bringing yourself over to a parasympathetic state, and detoxification doesn't happen in sympathetic states, because it's a luxury, and you're trying to survive when you're in sympathetic autonomic dominance. This will bring you over to parasympathetic. It'll help turn up these genes, so some people will start to have detoxification reactions. If they start getting headachey, or a little lower back stress, or rashes, give them good quality bitters, like the BitterX that we make, and maybe a little bit of GI binder, like our ultra-binder, or charcoal clay capsules, and that will help them detoxify.

Gazella: Oh, good. That's good to know. Now, the future.

Shade: The future.

Gazella: What excites you the most when it comes to CBD oil research?

Shade: Yeah. It's CBD not being just a standalone, but being an integrated ingredient in formulas, where it's doing this part of it, maybe the autonomic balancing, or the brain balancing, where the other things are doing other parts, and finding which things are synergistic together, which things are antithetical together. We'll find out how to blend it with other things, and really make it work better. Even if we're just working within the cannabis plant itself, there's the essential oils of the plant called the terpenes, very strongly affect the modulation of how CBD and THC work within the body. The science on the terpenes will be worked out, then the science on other nutriceuticals playing in with those will be worked out, and we'll start to see some really beautiful formulas come.

Gazella: What about when we began, we talked about the availability. Do you see things loosening up a little bit?

Shade: That part of the future. It's funny. There seems to be two forces at work within the United States around CBD. There's a liberalization movement that is not necessarily ... It's not coming out of Boulder County in California. It's coming from within the government, where they want to focus on real issues, like narcotics use, prescription pain med addiction, real drugs, heroin, cocaine, and they want to get away from talking about this. On the other side, there's other people who are just ... Some part of them are just working out what's already been started, where they're just really going to want to try to enforce this. We're starting to hear much more sophisticated language from the state departments of health about CBD, and that's towards a contractive thing. And who knows where that's really coming from? I mean, you have pharmaceutical companies getting into this now, and that may be the long, dark arm of the pharmaceutical companies.

There's two things now, contraction and expansion, happening at the same time. Hopefully the light wins and we expand out, and we're able to use this in a broad scale, and do all the research that's really necessary to put this to the best use.

Gazella: I would agree. I think that the therapeutic efficacy of CBD oil is really ... We're shining a light on it in the scientific literature. Even though it seems that it's preliminary, uncertain cases, it just seems like it's growing more [inaudible 00:28:22], it really should be something that we look harder at.

Shade: Oh, it absolutely is, and I can always gauge it by when I'm on a plane, when little old ladies start talking to me about it, or my aunt came over from Florida, and she had a bottle of it, and it's made its way out to the masses. They need it. They want it. We hope it's here to stay.

Gazella: I do too, and you know, we haven't even touched on the pain aspects, because right now we are in the midst of an opioid crisis in this country.

Shade: Oh, yeah.

Gazella: Is there an application for [crosstalk 00:28:57]?

Shade: Oh, absolutely. Maybe little smidges of opioids along with CBD. CBD, and what we'll find is what we can blend with it nutriceutically to increase its effect at stopping pain, but it's got all the right aspects for that, and for some pains, it's magic. For other ones, it doesn't work as well. Well, maybe we'll find certain blends, but it will always, if you're taking it with opioids, it will always lower how much you need of the opioids, and that's one of the most beautiful things to come out of the legalization of medical marijuana in various states. They've seen a lowering of opioid use.

Gazella: Right. It sure seems like CBD oil, hemp oil, is a valuable tool that clinicians can use in their clinical practice.

Shade: Absolutely.

Gazella: Great. Well, Dr. Shade, as per usual, this has been very interesting. Thank you so much for joining me today, and I would also like to thank the sponsor of this interview, who is Quicksilver Scientific. Thank you everybody for joining us. Have a great day.