Chronic Stress, Cortisol Resistance, and Modern Disease

You’ve heard of insulin resistance, leptin resistance, and possibly even thyroid resistance.  But have you heard of “cortisol resistance”?  Recent research suggests that resistance of cells and tissues to the actions of cortisol – rather than high cortisol levels in the blood – may be the primary factor in the stress-disease connection.

In this episode, we cover:

1:43  Concrete evidence linking chronic stress to inflammation and modern disease
17:21  The new-found health benefits of probiotics
25:02  What really causes irritable bowel syndrome?
31:56  A non-toxic treatment protocol put 4 cancer patients into remission
53:42  Could low cholesterol be associated with a higher risk of cancer and death?

Links We Discuss:

• Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk
• Gut microbiota is not modified by Randomized, Double-blind, Placebo-controlled Trial of VSL#3
• ALA/N Protocol for People With Metastatic and Nonmetastatic Pancreatic Cancer

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Full Text Transcript:

Steve Wright:  Hi everyone, and welcome to the Revolution Health Radio Show.  I’m Steve Wright from SCDlifestyle.com, and with me is Chris Kresser, health detective and creator of ChrisKresser.com.  How are you doing, man?

Chris Kresser:  Oh, I’m pretty good.  How are you, Steve?

Steve Wright:  I’m good.  I’ve got my green tea next to me, and I’m ready to rock and roll.

Chris Kresser:  Nice.  All right, let’s do it.  I’m always reading studies.  People send them to me.  I find them myself.  I’m, as many of you know, kind of a research dork, so I found some interesting ones this week, and they’re on some themes that I’ve been writing about and talking about the show previously and just thinking about a lot myself, so I want to talk a little bit about some of these studies, and then we should have some time to jump into some questions.  Sound good?

Steve Wright:  Yeah, it sounds like a good plan.  And I was just gonna let everybody know that if they’re new to the Paleo diet or if they’re just interested in optimizing their health, they should check out Beyond Paleo.  It’s a free 13-part email series on burning fat, boosting energy, and preventing and reversing disease without drugs.  To sign up, just go to ChrisKresser.com and look for the giant red box.

Concrete evidence linking chronic stress to inflammation and modern disease

Chris Kresser:  All right, so the first study is right in line with the April Best Your Stress Challenge, and if you haven’t heard of this, go check out my blog, ChrisKresser.com.  You now, there are a lot of 30-day diet challenges.  There’s the Whole30, and there’s the Personal Paleo Code, my program where we ask people to give the Paleo diet a try for 30 days and give it that chance to change their lives and make a big difference in their health.  But I’ve talked a lot about the importance of stress management and improving stress tolerance and mitigating the impacts of the stress that we can’t get rid of on our life, so I thought it would be a good idea to spend April doing a 30-day Best Your Stress Challenge.  So, the idea is to apply that same concept of a 30-day diet challenge to stress management, and I wrote a post about this a little while back, I think, on March 30 and offered some ideas for what people can do to manage their stress throughout the month of April and just to make a commitment and preferably a small, fairly manageable one because oftentimes we have a tendency to commit to more than we can do and then we don’t follow through, so just setting a small goal, like meditating for 10 minutes in the morning or doing a deep relaxation exercise every afternoon or taking a walk in the woods or on the beach — whatever it is that helps you manage your stress — and doing that throughout the whole month of April and seeing how that improves your health overall.

So, the other day, I saw a new study with the title Chronic stress, glucocorticoid receptor resistance, inflammation, and disease risk, and since I’ve been thinking a lot about stress and the effects of stress on disease, I thought it would be a good idea to talk a little bit about this study because it’s really interesting, and it takes our traditional concept of how stress contributes to disease and kinda turns it on its head.  It’s some relatively new information.  I’ve seen a few other studies with a similar theme, and if anything, it just reinforces what we’ve been talking about in terms of the connection between stress and disease and the importance of managing stress and either reducing the symptoms of a disease that we already have or helping to cure it entirely or preventing the risk of acquiring a new disease.  So, stress is associated with just about every modern disease that you can name, from depression to cardiovascular disease to type 2 diabetes to autoimmune conditions like rheumatoid arthritis and Crohn’s disease and multiple sclerosis to upper respiratory infections and even the common cold.  And up until pretty recently and still now, I think, most people think that stress causes disease by dysregulating the hypothalamic-pituitary-adrenal axis, but this notion that stress acts simply by elevating cortisol levels is becoming less and less likely, at least in the current scientific literature.  So, what this new paper and other recent papers suggest is that it’s actually the sensitivity of cells or the target tissue to cortisol, not absolute levels of cortisol that’s most important.  So, glucocorticoid resistance, which is a decrease in sensitivity of immune cells to glucocorticoid hormones like cortisol, makes it more difficult to shut off the inflammatory response.  So, let me break that down.  When you’re insulin resistant, you’re producing enough insulin, but your cells are resistant to the effects of insulin, so it’s like insulin’s knocking on the door, but nobody’s inside or whoever’s inside isn’t listening, so the door doesn’t get open, and insulin can’t perform its function.  The same is true with leptin resistance, and there’s even thyroid hormone resistance where thyroid hormone can’t activate the cellular receptors for thyroid hormone, so even though there’s plenty of thyroid hormone circulating around, you experience all the signs and symptoms of hypothyroidism because thyroid hormone isn’t affecting the receptor.

So, this study and others like it suggest that there’s a similar phenomenon with cortisol resistance.  So, it’s not high levels of cortisol, per se, that are contributing to an increased susceptibility of disease, but it’s instead the insensitivity of cellular receptors to cortisol that’s the problem, because one of cortisol’s jobs is to turn off the inflammatory response once it gets started.  So, let’s say you catch a cold or you get a cut or you have some kind of injury or illness, and inflammation is the natural response to that.  Inflammation is not all bad.  In an acute setting, inflammation is what helps us to heal.  The problem happens when inflammation doesn’t get turned off appropriately, and then it just kinda runs wild and you get chronic inflammation, and it’s that chronic inflammation that is a risk factor for disease, not the acute inflammation that helps us to heal.  So, in a normal functioning person, what would happen is that you’d get a cold or you’d get some kind of injury or acute condition that causes inflammation, and then the glucocorticoids, like cortisol, are produced and they turn off the inflammatory response by activating the glucocorticoid receptors.  So, what these researchers have found is that people who are under chronic stress, that doesn’t work right.  The cortisol gets secreted, but it doesn’t activate the receptors, and then you get a runaway inflammatory response.  And this has been shown in other studies.  They’ve found that cortisol resistance is present in spouses of brain cancer patients, in parents of children with cancer, and in people that are very lonely, and all of those populations are known to be experiencing significant stress.

So, in this study, the researchers used, I think, a pretty ingenious model to demonstrate this effect.  I mean, it’s well established that chronic stress increases the susceptibility to the common cold and upper respiratory infections, as I mentioned earlier.  So, the researchers actually did two studies in one.  The first one was meant to determine whether stress causes cortisol resistance and whether people with cortisol resistance are more likely to develop a common cold in the first place.  And then the second one was meant to determine whether cortisol resistance could predict the amount of local inflammation in the nose, for example, in response to a viral infection.  So what they did is they actually purposely infected people with a virus, a rhinovirus that causes the common cold and respiratory infection, and as expected in the first study, the results did show that exposure to stress increased cortisol resistance, and in the control group they found that exposure to an acute stressor was associated with white blood cell count, but in the group that was under chronic stress there was no association.  So, in other words, what should happen is that when you’re exposed to a stressor, as I mentioned, cortisol should turn off the inflammatory response and reduce the white blood cell count, but that didn’t happen in people that were under chronic stress and had cortisol resistance.

In the second study, they found a correlation between cortisol resistance and the levels of various proinflammatory cytokines locally, like interleukin-6 and TNF-alpha.  And then they also saw a decreased sensitivity of white blood cells to the inhibitory effects of cortisol, like we’ve been talking about.  So, in other words, when you’re stressed out, the immune system cannot turn off the inflammatory response like it’s supposed to, and then you’re more likely not only to get sick in the first place, but you’re more likely to stay sick for longer because that inflammatory process doesn’t get inhibited.  So, the interesting thing also about this study is that there was no correlation between actual cortisol levels, like circulating cortisol levels, and disease risk or inflammation.  So, it seems like it’s the cellular receptivity to cortisol, the sensitivity of the receptors to the actions of cortisol, that’s the most important, rather than the circulating levels of cortisol themselves.  So, I thought that was pretty interesting, and it may not change things from from an end-user perspective too much because the idea is still that you want to take steps to manage your stress, but for me, every study I see like this is just another affirmation of the importance of stress management, and I see it in my work with my patients, I see it in my own life and my own experience, and people might be getting tired of hearing me talk about it, but I’m gonna keep talking about it because I thinks it’s kinda the elephant in the room in a lot of cases.  In my patient population, I think I can pretty safely say that people who are taking active steps to manage their stress have significantly better clinical outcomes than people who don’t, and I just think it’s a much bigger contributor to the whole disease process than most of us really realize.

Steve Wright:  That’s pretty insightful, man.  And I thinks it’s awesome that we’re getting more data on what the problem is because you do hear a lot about, well, you’re not totally stressed out or you can go do another CrossFit workout as long as your cortisol isn’t over 20 or something like that.

Chris Kresser:  Yeah.

Steve Wright:  So, this is cool to have a new model.  Now, do you know if, for instance, because we’re a little bit better at measuring insulin resistance and leptin resistance, are the three correlated?  So, if I’m insulin resistant, I’m likely leptin resistant or I am leptin resistant.  Am I also cortisol resistant then?

Chris Kresser:  I don’t know what the exact relationship between all of those would be, but I certainly think that HPA axis dysregulation can contribute in some way to leptin and insulin resistance and probably vice versa.  I wish there was a way of testing for cortisol resistance in the commercial setting.  I don’t think there is.  I think it’s only available in research settings.  But what’s interesting about this study is that I think, like you said, the idea that we can just run an adrenal stress index or any kind of hormone profile where we measure cortisol, and if the person has normal cortisol we say:  OK, you’re clear to do, you know, five CrossFit workouts a week.  We can’t really make that assumption because that test is not gonna show cortisol resistance in the white blood cells.  I think ultimately just paying attention to symptoms is a pretty good guide because if you have this cortisol resistance pattern, you’re gonna have more difficulty recovering from workouts because that inflammatory response won’t get turned off.  I mean, working out, especially lifting weights, but doing any kind of intense workout is basically like a controlled stimulation of inflammation.  You’re breaking down tissue when you lift weights.  You’re breaking down your muscle tissue, and the idea is that when it builds back, it builds back bigger and more able to deal with the next stressor, in that case, lifting weights.  So, that works well if you give the body long enough to recover, if you give the body long enough to turn off that inflammation and then to start the anabolic process rather than the catabolic process of building the tissue back up.  And if you’re a healthy person with no significant stress levels and you’re not dealing with any chronic inflammatory condition, that should happen fairly quickly and commensurately with the amount of exercise that you did.  But if you’re dealing with chronic stress and you have cortisol resistance, here’s what’s gonna happen:  You’ll do the intense workout, you break your tissue down, which is what happens and is the whole point, but the recovery process will be very, very slow, and the inflammation will persist.  So, instead of taking one day or maybe two days to get back to baseline and then start building new tissue, stronger tissue, you’ll take several days to get back to baseline, or maybe you really never fully do get back to baseline.  And then you do another intense workout, so then you break down more tissue and cause more inflammation, and then it’s a downhill slide from there.  And I see this a lot in the CrossFit community, people who come to me who have been doing CrossFit.  And this is not all people who do CrossFit.  I’m talking about people who are under significant stress and who may be dealing with a chronic health challenge.  But the fact is most of us in this modern world are under stress, and some of us are better at managing it than others, and some of us pay more attention to that than others, but I think this is a very real phenomenon and it’s not just affecting people who have kids with cancer or spouses with cancer or people who are socially isolated.  It’s affecting all of us to some degree or another.

Steve Wright:  Way to wrap that up.  I think it’s important to keep learning about it.

The newfound health benefits of probiotics

Chris Kresser:  So, here’s another study that I think you’ll be interested in, Steve and Jordan.  It’s about probiotics.  The common assumption is that probiotics work by restoring normal gut flora, and this is partly because several studies have shown that the gut microbiota in people with gut diseases is different than the gut microbiota in people that are healthy, and I’ve talked about this a lot, and I’ve written about it a lot, and there’s certainly a lot of evidence to support that, but over the last maybe, I don’t know, probably just two or three years, there have been some really interesting studies that have come out suggesting another possibility for how probiotics work, and the idea in these studies or what these studies suggest is that probiotics don’t work by altering the gut flora, per se, but through a whole bunch of other immunomodulatory, anti-inflammatory effects.  So, these could include antibacterial and antiviral properties, an increase in mucus production in the intestinal epithelium, reducing the migration of neutrophils, white blood cells, into the intestinal epithelium, and all of these properties can basically reduce the neurochemical and impaired motor function found in conditions like irritable bowel syndrome.

So, this study that I saw was on VSL3, which is a probiotic formulation that’s very potent, and it has several different strains of probiotics at a very high concentration, and it’s one of the most studied probiotics in the medical literature, and it’s been shown to improve inflammatory bowel disease and IBS and some other gut conditions.  So, what was unique about this study, really interesting, is that previous studies have looked at this question of if you take probiotics, does it really change your gut flora?  Does it create a permanent change in your gut flora?  And a couple earlier studies used stool microscopy to answer that question, stool culture, and I think we’ve talked about that on a previous show.  That’s basically where they take stool and they put it under a microscope or they culture it and they look for organisms, whether beneficial organisms or pathological organisms, in the stool.  And it’s not very accurate for a number of reasons, but one reason is the culture can’t identify certain strains of bacteria very well.  So, this study, instead of using a stool culture, they used DNA PCR analysis, which is a much more accurate way of characterizing the commensal gut flora, and so they administered VSL3 at a pretty high dose.  I think that people were taking about 600 to 900 billion CFU a day, which is a very high dose, and they did that for a period of time.  They looked at their gut flora before they started taking the VSL3, and then they looked at the gut flora at the end of the study after they had taken it.  And they found in the study that, sure enough, the people who took the probiotics experienced significant improvements in a number of different ways, but they also found that the gut microbiota in those people was essentially unchanged from the beginning to the end of the study, which is really interesting, right?  It sorta goes against our idea of what probiotics are doing.

So, these researchers hypothesized that the probiotics, like VSL3 or other probiotics, work by some of the mechanisms that I just described, antibacterial, antiviral, increasing mucus production.  They can alter stool and gas formation, which in turn can reduce constipation and diarrhea.  They have anti-inflammatory effects.  For example, people with IBS, it’s now known that they have an abnormal ratio of inflammatory cytokines, like interleukin-12 and interleukin-10, and that taking probiotics like VSL3 can normalize that ratio.  Certain probiotics like E. coli Nissle have been shown to affect intestinal motility.  They have strong immunomodulatory properties.  They can prevent the invasion of pathogens into the mucosa.  They can induce the synthesis of antimicrobial peptides, so not only do they have antimicrobial effects themselves, but they can increase the synthesis of antimicrobial peptides.  And then they also promote the synthesis of tight junction proteins in the gut epithelium, and as we’ve discussed on previous shows, leaky gut or intestinal permeability involves a dysfunction of the tight junctions in the gut, so essentially this suggests that probiotics, one way that they might work is by tightening up those tight junctions and making the gut less permeable.

And there are other possibilities too, like the probiotics, when you introduce a large amount of bacteria and yeast into the gut, that stimulates an immune response, possibly in a similar way that helminth therapy or other pathogens have kind of a tuning effect on the immune system.  I wrote an article recently about the “hygiene hypothesis,” also referred to as the “old friends hypothesis,” where we coevolved with a number of organisms like helminths and other organisms that we might have been exposed to in the soil, and those organisms have a balancing and modulating effect on the immune system, and it’s possible that probiotics are working in a similar way.  So, again from an end-user perspective, this might not change things very much because the studies are still suggesting that probiotics have beneficial effects for people with these kinds of gut conditions and other conditions, but the mechanism by which that effect is happening may be different than we assumed originally.

Steve Wright:  Yeah, it seems like more of a better justification because it’s easy to come across a lot of opinions on the Internet who say:  Well, there’s no need to take probiotics because they’re only transient, and there’s no reason to eat fermented yogurt or kefir because it’s only transient, the bacteria are.  But I’ve read some of the same research you have, and it’s really cool to see this stream continue to get wider, and it’s gonna be really cool in the future when we can start pinpointing certain strains that might come down the line, and if you have a motility problem you’ll take this strain, and if you have an immune modulation problem you’ll take this strain, and I think that’s gonna be a future that we’ll see pretty soon.

What really causes irritable bowel syndrome?

Chris Kresser:  Yeah, that’s right, and what’s gonna be part of that is breaking down the various diseases into more distinct categories.  Like, I think it’s pretty clear at this point that IBS, or irritable bowel syndrome, is not a single disease, that it’s really probably a number of different conditions with different etiologies, different causes.  You know, postinfectious IBS, for example, might be a distinct entity, where the initial problem was an infection of some sort, and that dysregulated the gut flora and caused a number of other issues because of that, and then there may be another form of IBS that is more mediated by the gut-brain axis.  There may be another form of IBS that is more related to small bowel bacterial overgrowth.  So, we’re learning a lot more.  This thing that we call IBS, it’s not really a clinical entity in itself.  It’s a diagnosis of exclusion, which means that if you go in to the doctor and you say:  Oh, I have gas and bloating and abdominal pain.  And they say:  OK, well, let’s do a colonoscopy and an endoscopy.  And they do that, and they don’t find any ulcer.  They don’t find any inflammatory bowel disease, ulcerative colitis, or Crohn’s.  They don’t find diverticulosis or diverticulitis.  They don’t find anything structurally wrong with your gut, and then they ask you a few questions about your symptoms.  You’re gonna walk out of there with the diagnosis of irritable bowel syndrome, which is kind of maybe a letdown because you go in there and you say:  Hey, doctor, my bowel is irritable.  You go through all of these tests, and then they tell you:  Guess what?  You have irritable bowel syndrome!  And you’re like:  Thanks a lot.  Thanks for the diagnosis.  But when you look at the current scientific literature around IBS, we find that actually there’s quite a lot going on there.  It just isn’t stuff that can be found with a colonoscopy and an endoscopy.  We have a lot of evidence for fructose intolerance, strong correlation for fructose intolerance and irritable bowel syndrome, and that’s probably mediated by small bowel bacterial overgrowth, and so something like 40-plus percent of people with IBS have been shown to have small bowel bacterial overgrowth.  We have disruptions in the gut-brain axis that have been very well demonstrated now.  The inflammation in the brain, chronic stress response that can cause decreased output into the vagus nerve, which innervates the whole digestive tract, and then that causes “IBS.”

Then we have dysbiosis, which we’ve been talking about now, changes in the gut microbiota because of an infection that’s either still present — I think a lot of people who are diagnosed with IBS actually have a gut infection.  I see that in my practice a lot.  You know, they come to me and they say:  I have IBS.  And do a Metametrix stool test and find out that they have H. pylori or they have some other kind of opportunistic or pathogenic bacteria, or they have a fungal infection, which is actually less common.  I see a lot more bacterial infections than fungal infections, and that’s one of the reasons I think candida is really overdiagnosed.

So, my point is there are a lot of different diseases that are right now characterized as irritable bowel syndrome, and getting more specific about what the causes are in each case is the very first step in successfully treating it, because the drugs for IBS are a joke.  They’re drugs that increase motility or decrease motility or just kind of they’re pain-relieving drugs, but they don’t do anything to address those underlying causes, whatever they may be.  So, I think a combination of getting a lot more specific about what’s actually going on, which is happening at least in the scientific literature, and then, like you said, Steve, getting more specific about particular strains of bacteria or emerging treatments like fecal microbiota transplants or even helminth therapy is kinda the wave of the future here.  It’s like in the 20th century it was all about antibiotics and things that would just indiscriminately kill bacteria, and now it seems like the 21st century is much more about immunomodulation with probiotic organisms or any kind of organisms that can modulate the immune system.

Steve Wright:  Yeah, I think you hit the nail on the head there that IBS is a joke.  I was told it by several doctors, and like you said, the standard treatment is fiber or a couple drugs that don’t help at all, but I think with all of the digestive conditions, because it seems that if you have diverticulitis or Crohn’s or ulcerative colitis, normally you have all of the IBS symptoms as well, and so I really feel bad for those folks who talk to a conventional gastroenterologist who doesn’t really help them address their IBS symptoms on top of their ulcerations lower in the intestinal tract, because they’re really getting the brunt end of the stick there.

Chris Kresser:  Yeah, definitely.  One of these days when I can carve out the time, I really want to write a series on a kind of 21st century view of IBS.  Like, we know so much more about it than the conventional understanding of it.  It’s such a hot topic in the research literature, and we’re really coming to the point where we have the tools diagnostically to identify underlying causes and address them, and like you said, it’s really a shame that that’s not happening more, and I’m itching to write that series, but I just haven’t been able to find the time for it yet, but soon enough.

Steve Wright:  We’re gonna need to clone you.  Is that OK?

A non-toxic treatment protocol put 4 cancer patients into remission

Chris Kresser:  I don’t know.  I’ll have to think about that!  So, let’s move on.  I could say a lot more about that, but I’ll save some of it for the series.  The next study I want to talk about, really interesting.  I’ve talked about low-dose naltrexone before, and that’s partly what this study is about.  It’s about a natural treatment for cancer that is being used at the Integrative Medical Center of New Mexico.  So, the study basically reports four cases of people with aggressive forms of pancreatic cancer, and most of you probably know that pancreatic cancer is very serious.  The prognosis is not good.  The usual length of survival is something like three to six months, and patients with advanced disease rarely live more than a few weeks.  I’m sure most people who are listening to this are aware that Steve Jobs died of pancreatic cancer.  So, anything that can potentially successfully treat pancreatic cancer is pretty exciting because it’s one of the most aggressive forms of cancer and one of the worst prognoses that you can have.

So, these folks at this Integrative Medical Center in New Mexico have been using a protocol that involves a few different components.  The main two components are intravenous administration of alpha lipoic acid at 300 mg to 600 mg two days a week and 4.5 mg of low-dose naltrexone, which is the standard low dose of naltrexone.  They also were giving 600 mg per day, which is a pretty high dose, of oral alpha lipoic acid; 400 mcg per day of selenium — I wish they would’ve said which form they’re using.  I imagine they’re using the methylselenocysteine form, which is the one that’s been shown to have more anticancer effects than other forms, and then they’re using 1200 mg per day of milk thistle extract, which is another potent antioxidant.  So, I’m sure they’ve done this with more than four patients, but they reported on four patients in particular with pancreatic cancer.  The first patient, J.A., had pancreatic cancer with metastases to the liver, so this isn’t just pancreatic cancer; it’s metastatic pancreatic cancer.  The doctor basically told J.A.:  Get your life in order.  There’s nothing we can do.  You probably have a few weeks to live.  And he went to the center in New Mexico, and he did the protocol.  Seventy-eight months later, he is in complete remission with no signs of cancer at all and feels like a totally normal person.

Steve Wright:  Did you say seven or eight?

Chris Kresser:  Seventy-eight!

Steve Wright:  Woo!

Chris Kresser:  Seventy-eight months later.  So I mean, considering that the usual length of survival for pancreatic cancer is three to six months and the usual length of survival for metastatic advanced pancreatic cancer is a few weeks, seventy-eight months is pretty impressive.

Steve Wright:  Yeah.

Chris Kresser:  The next patient, G.B., was diagnosed with pancreatic cancer and refused chemo because of religious reasons, and she did the protocol and is now alive and symptom-free 39 months after diagnosis at the time the paper was published.  So, another really impressive result.  J.K. was diagnosed with pancreatic carcinoma with metastasis to the liver, and she was jaundiced, exhausted, in constant abdominal pain and nausea when she first came to the center.  And after a few weeks of the protocol she improved significantly, and after six months her PET scan showed absolutely no sign of cancer, and she felt normal, without any pain or nausea.  And unfortunately — and this is very sad — she returned to her home state because she had traveled to New Mexico specifically for this treatment.  So, she goes back home, and her doctors refused to continue the protocol even though she had basically no signs of cancer, and then she died within a couple of months after going home.

Steve Wright: That’s sad.

Chris Kresser:  Yeah.  I’m gonna have to resist going off on a tangent here about —

Steve Wright:  You didn’t say.  So, once they started that treatment, the intravenous drip as well as the supplements, they were on that for life basically then?

Chris Kresser:  Yeah, it seems to be that this is not curative.  It doesn’t look like you do this for a period of time and then you stop and you’re fine.  I think you have to continue with the protocol, but when you compare this to, like, chemotherapy, you’re doing a supplement regime plus low-dose naltrexone, which is an extremely well-tolerated, very low dose of a medication that has no documented complications or risks, and then an IV of alpha lipoic acid a couple times a week.  I think that’s a pretty small price to pay to survive pancreatic cancer.

Steve Wright:  Totally.

Chris Kresser:  But the sad thing is that this poor woman goes home and even though she has proof that she’s free of cancer and feeling great, the doctors wouldn’t do it.  It just blows my mind, and nothing makes me more upset than that.  It’s just crazy.  Anyhow, the next patient, R.C., had three malignancies.  Three.  Prostate adenocarcinoma, non-Hodgkin’s lymphoma, and pancreatic adenocarcinoma.  You know, two of those, in particular, are very lethal.  So, he improved significantly on the protocol, and he felt so much better that he decided to have surgery to internalize his percutaneous biliary drain, which is something that people use when they have serious gallbladder issues, and unfortunately he died from complications of the surgery.  So, the protocol worked in his case, but he got septicemia from the surgery and he passed away.

So, in all of these cases, the protocol worked extremely well.  In two cases, the people are still alive with no signs of cancer and are continuing the protocol.  In another case, the protocol worked well, but she wasn’t able to continue it and she passed away.  And then in the fourth case, the protocol worked very well, but the person died of unrelated surgical complications.  So, pretty impressive.  This is certainly something, like, if myself or a family member or a friend or anybody I knew was diagnosed with not only pancreatic cancer, but just about any cancer, because there’s nothing in these results that suggest that they’re unique to pancreatic cancer, I would definitely consider this protocol, either going to New Mexico or trying to convince your doctor to do it, because it’s not that exotic.  I mean, the supplements are readily available.  You could order them from just about any online source.  And then the IV alpha lipoic acid, you’d just have to find someone who’s willing to do a drip.  Alpha lipoic acid is cheap and readily available, and low-dose naltrexone is off patent, very affordable, and fairly easy to obtain if you find a doctor who’s familiar with the oncology literature.

Steve Wright:  Chris, so the milk thistle, the alpha lipoic acid, the selenium — those all make sense to me.  So, what role do you think LDN is playing here?

Chris Kresser:  Yeah, well, let me tell you a little bit more about alpha lipoic acid, because some people might not be familiar with it, and I think it’s really interesting in the context of cancer.  Alpha lipoic acid is a cofactor that’s active in a number of different enzyme complexes that control metabolism, including the conversion of pyruvate to energy in the mitochondria.  So, it helps us to transform the food that we eat into usable energy.  But it’s also really effective as a free radical scavenger, which means it reduces oxidative stress.  That’s very important in any inflammatory disease, and it’s definitely important in cancer.  Alpha lipoic acid also induces hyperacetylation of histones, and histones are proteins that are active in the proliferation of a lot of different cancer cell types, and anything that inhibits histones will drive the cancer cells to apoptosis, which is cell death, programmed cell death.  And indeed, human cancer lines have been shown to become apoptotic after exposure to alpha lipoic acid, so alpha lipoic acid helps kill cancer cells.  Another mechanism that it might work by is that ALA, which is the shortened name of alpha lipoic acid, stabilizes nuclear factor kappa beta or NF-KB, for short.  And when NF-KB is activated, it launches the induction of more than 200 genes that suppress apoptosis, and that will, in turn, increase cellular proliferation, invasion, metastasis, chemo resistance, and inflammation, which are all characteristics of cancer.  And so, studies have shown that high doses of ALA have been shown to inhibit the activation of nuclear factor kappa beta.  Another mechanism is that ALA selectively stimulates apoptosis in cancer cells.  So, in other words, it promotes the death of cancer cells without harming normal cells, and that’s, I mean, that’s amazing.  That’s kind of the holy grail in cancer treatment, right?  The ability to shut down cancer cells without harming the normal cells, because that means the side effects of the treatment are not gonna be extremely harmful, as is the case with chemotherapy.

Steve Wright:  Quick follow-up question here on ALA:  So, just for everyone listening, there’s no known upper limit for ALA?  No side effects?

Chris Kresser:  Actually, that’s a good question.  I wouldn’t recommend that anybody do this without supervision.  And I hope that goes without saying when we’re talking about cancer.  I don’t prescribe more than 200 mg or 300 mg a day of alpha lipoic acid unless the circumstances are pretty extreme.  And that’s one of the things.  When you’re dealing with terminal cancer, you’re a little bit less concerned about any potential short-term side effects from a treatment like this because, you know, what’s the alternative?  For example, selenium has been shown to be potentially toxic at doses of 400 mcg a day, but in this case, the antioxidant benefit of selenium over this period of time and because there’s so much oxidative damage, those effects are less likely to be a concern.  So, yeah, thanks for pointing that out.

Steve Wright:  Well, yeah, because I’m sure I’m not the only listener of this podcast who has read The 4-Hour Body by Tim Ferriss, and in that, actually his weight loss, his non-stimulant weight loss stack that he recommends includes about 300 mg of alpha lipoic acid per meal, so I think that’s somewhere between 900 mg to 1200 mg a day.  So, I was just curious if there was, because being familiar with that knowledge and hearing the study, milligram doses, I was like:  Wow, it’s not quite as high as what I would’ve thought it would’ve been.

Chris Kresser:  No, because it doesn’t really need to be much higher.

Steve Wright:  OK.

Chris Kresser:  I think a lot of times supplements, there’s a kind of more-is-better mentality, you know, with supplements, and that’s definitely not always true, because as in the case of selenium, like I was just saying, there’s a sweet spot where too little is not good and too much is not good because selenium in excess can be toxic.  So, I don’t know what the toxic dose of ALA would be, but I would be hesitant to recommend that somebody take almost 2 grams a day of it for any significant length of time.

Steve Wright:  OK.

Chris Kresser:  I’ll have to look into that more, and we can talk about it on another episode.

Steve Wright:  Yeah, well, I think you pointed out the most important thing, which is most supplements operate on a U-curve, which means that there’s a sweet spot in the middle and if you’re underdosing you’re not really gonna get the effect, and if you’re overdosing you’re probably gonna cause something else to happen that you don’t want to.

Chris Kresser:  Right.  And as is the case as we’ll see with low-dose naltrexone, in some cases if you increase the dose, it doesn’t work the way that you want it to.  So, low-dose naltrexone is, as the name implies, a low dose of a drug called naltrexone.  And the full dose of naltrexone at 50 mg used to be used a while back, I think, in the ‘70s and ‘80s for opiate withdrawal, like with people who were addicted to heroin and also, I think, in some cases with alcoholics, because what it does at the full dose is it completely blocks the opiate receptors in the brain, and the opiate receptors are what mediate our experience of pleasure, so if you block those receptors, somebody like a heroin addict who took 50 mg of naltrexone could shoot up and feel pretty much nothing.  Unfortunately, they felt pretty much nothing at all from anything else in their life, so naltrexone turned out to have severe depression, suicidal ideation, things like that as a side effect because people who took it, sure, they didn’t get the stimulation from heroin and it was effective in that sense, but they didn’t experience much of any pleasure in their life at all.

But this pretty brilliant doctor named Dr. Bihari back in the ‘80s and ‘90s, he was treating HIV and AIDS when hardly anybody else was, and he was also starting to treat cancer, and he discovered that if you used a low dose of naltrexone, 4.5 mg, what it does is it blocks the opiate receptors in the brain just like the full dose does, but only for a short time.  So, for example, the typical way of taking LDN is to take it at about 9 o’clock at night and then that creates a 2-to-3-hour blockade of the opiate receptors from, like, 3 to 5 in the morning.  And that has the effect of tricking the body into producing large amounts of opiates in response to the blockade.  So, the blockade happens, the body senses that opiate receptors aren’t being activated, it thinks that that must mean there are not enough opiates in the body, so then it produces a whole bunch.  The reason this is significant is that we now know that white blood cells have receptors for endorphins and opiates, which suggests they play an immunoregulatory role.  Specifically, they balance and regulate the various sides of the immune system.  They stimulate T regulatory cells, the Th3 cells, which turn off the inflammatory response, or they have an overall regulatory effect on the immune system.  So, in the ‘90s, Dr. Bihari gave LDN to about 450 patients with cancer, and these are folks who had failed the standard treatments.  You know, they tried all the other, the chemo and the standard stuff, and they ended up with him.  And of 354 patients that he followed up regularly, 86% showed at least a three-quarters reduction, 75% reduction, in tumor bulk, and 125 of the patients, which is I guess about 33%, were reported to have achieved remission or close to remission.

Steve Wright:  Wow.

Chris Kresser:  So, that’s pretty impressive.  There’s other research that has shown that LDN has slowed the growth of neuroblastoma cells in culture, so that’s just an in vitro study, but promising.  And then another study showed that LDN plus radiotherapy was more effective than radiotherapy alone for malignant astrocytomas, and malignant astrocytomas are thought to be incurable, also a pretty nasty form of cancer.  And in this study, the survival rates at one year were higher for people who did the LDN plus radiotherapy than people who just did the radiotherapy alone.  So, I think it’s a really promising area of research.  Like I said, if I had a friend or a relative or a patient that was diagnosed with a cancer like this, it’s definitely something that I would advise them to look into.

Steve Wright:  One last question on this, because this treatment is so heavy on the antioxidant side:  There are a lot of papers coming out lately that are saying — I mean, I think they’re mostly epidemiological, but they’re saying that supplementing with antioxidants could actually be a bad thing.  And obviously we talking about very specific compounds in this study versus what you could classify as antioxidant is, I don’t know, thousands of different things, and I was just curious if you had any thoughts on that.

Chris Kresser:  It’s another good question, and I’m glad you brought it up because it allows me to remind everybody again that there is no one-size-fits-all approach, and something that works for people who are sick may actually cause harm in people who are well.  That’s fairly easy to forget, but it should also be fairly obvious.  Chemotherapy can help people to survive cancer, but you would never give chemotherapy to somebody who doesn’t have cancer, right?  And I think that’s a more extreme example than this, but if someone’s just under extreme amounts of oxidative stress, as you find with cancer, something like high doses of all of these antioxidants might be beneficial, but in someone who’s otherwise healthy, it may have undesirable effects.  In the same way, you know, we get questions about diet.  If somebody has no gallbladder and a lot of difficulty digesting fat, they may have trouble with a really high-fat diet, but that doesn’t mean someone who has an intact gallbladder and good digestion is gonna have trouble with a high-fat diet.  So, we always have to consider who we’re talking about, what the goal is, and even what the length of time is that we’re talking about, you know, short-term versus long-term supplementation, or supplementation for therapeutic uses versus supplementation for longer-term, just kind of indiscriminate, indefinite use.  I use supplements a lot in my practice, but I tend to use them more for a specific goal for a specific period of time than I do just, you know, hey, take this forever.  I mean, there are certain exceptions like vitamin D and magnesium, which I’ve talked about on my blog, I think that are good, just smart to take indefinitely because they’re hard to get from the diet, but otherwise it’s always tailored for who the person is, what condition they’re dealing with, and what length of time we need to use them to achieve the effect that we want to achieve.

Steve Wright:  OK.

Chris Kresser:  Here again, I’ve just talked the whole entire episode, and we don’t have any time for questions!  But we’ll do a Q&A episode soon here.

Steve Wright:  I won’t let him talk about any studies next time!  I’m sorry guys.  It’s my fault.

Could low cholesterol be associated with a higher risk of cancer and death?

Chris Kresser:  We’ve got a lot of good questions.  So, this last one is quick, and it’s a follow-up on cholesterol, one of our favorite topics.  I just saw a post by Dr. Briffa, who was reporting on a meeting that happened at the American College of Cardiology.  And they got together specifically, I guess, to discuss the results of a study that was recently published that looked at cholesterol levels 19 years prior to people receiving a diagnosis of cancer, and what they found is that there was a significant association between low cholesterol and cancer.  In other words, people who had low cholesterol were much more likely 19 years later, or at some period of time later, to develop cancer.  Now, as we have discussed with the red meat study, we have to remember that this kind of prospective study does not prove causality.  It’s just an association.  It doesn’t prove that the low cholesterol was the cause of developing cancer, and in fact, some scientists have argued that causality is the other way around in this situation, that those patients had cancer and that’s what caused the low cholesterol, but there are a few things that argue against that:  Number one, the length of the study and the fact that low cholesterol appeared many years before cancer did suggests that reverse causality is not what’s happening, that low cholesterol actually preceded the cancer.  And then there’s another study that found that individuals with a low serum cholesterol maintained over a 20-year period had the worst outlook in terms of overall mortality risk.  The authors of that study actually wrote an editorial, where in their conclusion they said:  “Our present analysis suggests that this [reverse causality] hypothesis is implausible and is unlikely to account for the adverse effects of low cholesterol levels over 20 years.”  So, in other words, according to them, it’s more likely that low cholesterol causes chronic disease than the other way around.

I just want to emphasize again that this study doesn’t prove that.  That’s the opinion of the authors, and we can’t know that just from this data, but as I said with the red meat study, one of the ways that you can use this kind of prospective data and epidemiological data is to generate hypotheses and then try to test them.  Now, that’s a little bit difficult in the world of cancer research, and I got an email from a graduate student in epidemiology after we talked about the red meat study, and she brought up some good points that I didn’t mention when we talked about the red meat study, but it is possible to use epidemiological research or to design it in such a way where you can draw conclusions about causality that are a lot more likely to be true.  She pointed out even randomized clinical trials don’t necessarily prove anything, and there’s a Greek researcher, Ioannidis — I’m probably butchering his name.  I really love his work, but he’s written some very interesting editorials.  Like, I think the name of one of them was something to the effect of “All published research is false,” and he’s talking about how bias and all kinds of other methodological problems make it very difficult to rely on even the results of randomized clinical trials.  There are ways of designing epidemiological studies that are more likely to yield conclusions that we can rely on, and in fact, there’s a set of criteria, the Hill criteria, Bradford-Hill criteria, which outline a number of factors that can make the conclusions from epidemiological research more sound.  One of them is whether there’s a plausible mechanism to explain the finding, and that was one of my criticisms of the red meat study, that there was no real plausible mechanism for how red meat was increasing mortality risk, nor was there a plausible mechanism for how red meat was increasing cancer, which has been claimed many times.  In the case of low cholesterol and cancer, of course, then we might ask what is a potential mechanism that can be contributing here?  The truth is I don’t know, but there are a few ideas that come to mind:  One is that cholesterol is the building block of vitamin D.  You can’t produce adequate levels of vitamin D without adequate levels of cholesterol.  When you’re exposed to sunlight, you convert cholesterol into vitamin D, and vitamin D has chemoprotective properties.  Cholesterol is a precursor to all hormone production.  We know that hormones and dysregulation of hormones can be involved in cancer, and cholesterol has antimicrobial and antioxidant properties, and you know, cancer involves oxidative damage, and in some cases infections, viral infections and things like that, can be a trigger for a cancer process.  So, I think there are some plausible mechanisms, and there’s quite a bit of data.

It’s very difficult with cancer to do a randomized clinical trial because cancer takes so long to develop, and the other problem with randomized clinical trials as a means of proving causality is that in certain cases, you’ll never, ever see a randomized clinical trial because ethically it’s not possible.  So, for example, if you want to study whether an herb or a medication causes birth defects, the only way you can really do that is epidemiological data, like, look at a population of people who were taking that substance and see what happens to them in retrospect or prospectively.  It’s not ethical, for obvious reasons, to take two groups of pregnant women and give one of them a drug or an herb and the other one not and see what happens.  That’s obviously never gonna happen.  I think I was perhaps overly dismissive of epidemiological research when we talked about the red meat study and didn’t convey that there are ways of using epidemiological research, designing it better so that we can rely more on the outcomes.  And the kind of classic example of that is that for many years there was never any proof that smoking was causally linked to lung cancer, and that was the defense that the cigarette companies used is, you know, there’s no proof; there’s just this association that people who smoke more are more likely to get lung cancer.  But if you apply the Hill criteria to those studies and you demonstrate that there is a plausible mechanism and you go down the list, you can see that actually we can be pretty certain that that data is reliable and that is points to a causal link.

Steve Wright:  Yeah, I think that it’s really important for — I’m glad you explained it to me again and everybody that’s listening because research of all types is sort of on a sliding scale on how much you should value it, and the unfortunate thing is you can’t label a randomized control trial versus epidemiological because you have to apply that scale individually for every situation.

Chris Kresser:  That’s right.

Steve Wright:  And that’s the problem.  And that’s where it gets really confusing for doctors and just people like me who go to PubMed.  I think one of the best pieces of advice that I heard — and you can go ahead and destroy it if it’s not very good advice — is if you’re gonna dissect a study and really take the results of that study to be concrete in your life, you better make sure that the people in that study, that everything that they’re doing is exactly who you are.  So, for instance, if they studied a bunch of young, college-age women who were taking a supplement and it did some really great stuff, that would not be something that I would take because I’m not a young, college-age woman.  And for instance, if they did this study on ALA and cancer, again, it’s not something that I should be doing because it wasn’t done exactly on my type of who I am and where I am.

Chris Kresser:  Yeah.  That’s one of many variables we need to use when we evaluate a study, and of course, we’ve talked about that a few times in this episode, but another classic example is statin drugs.  They have never been shown to reduce total mortality in women and in certain populations of men, particularly men over the age of 65.  So, the mistake that a lot of primary care doctors and just the general public make is assuming that because statins have been shown to reduce very slightly the risk of total mortality in men with preexisting heart disease and reduce the risk of cardiovascular mortality in other populations, that we just assume that we can extend those results to women and to men and women who are over 65, which we can’t because that’s never been shown.  So, it is a good point, and it’s true.  It makes it really difficult for the average lay person to kind of piece through all of this stuff, but I don’t think that the appropriate response is what I have seen with some people in the blogosphere of just going to the other extreme and saying:  Oh, well, published research is just unreliable then.  We might as well not even pay any attention to studies.  I mean, there are some kind of prominent bloggers out there who that’s their kind of shtick is that studies are worthless.  That’s an oversimplification in the other direction.  Just because a lay person is not qualified to evaluate the quality of a study, that doesn’t mean there aren’t people that are.  I mean, there are a lot of people who work in research settings and even people outside of research settings who are perfectly qualified to evaluate the validity of a study.  So, we just need to apply those standards and be judicious about the conclusions that we draw from studies based on the quality of the study.  We don’t need to get rid of all research or throw out all research results.  We just need to be better and more conscious of what conclusions we draw and more conscious of what studies we’re drawing conclusions from.

Steve Wright:  Yeah, I agree.  There’s no reason to just rule out something just because you can’t make sense of it.

Chris Kresser:  Yeah.  So, OK, we’re a little over an hour here, and we’ll get to your questions.  We will.

Steve Wright:  We swear!  Well, hopefully you listen you next time, because we will do some questions next time.  And we want to thank you for listening this time.  And please keep sending us your questions, they will get to the show, and you can do that at ChrisKresser.com using the podcast submission link.  If you’ve enjoyed listening to the show today, please head over to iTunes and leave us a review.  Thanks.

Chris Kresser:  Bye everybody.