Genetics aside, what else influences our individual biochemistry?
Put Dr Mark Donohoe and Andrew in a room together and you can expect thought-provoking discussion, fascinating tangents and humour sprinkled amongst valuable clinical pearls.
In this episode, Andrew and Dr Donohoe deliver just that, as they dive into a number of the nuances influencing the practice of personalised medicine including our microbes, our cytochrome P450 pathways as well as drug, food and environmental exposures.
Covered in this episode:
[01:17] Welcoming back Dr Mark Donohoe
[01:49] Supplements are dangerous, or a placebo?
[03:35] Learnings from the PAN Pharmaceuticals recall in Australia
[07:15] Individual influencers of drug metabolism
[22:56] Whole plants versus standardisation
[27:56] The antifungal activity of free fatty acids
[35:45] The rise of environmental and ingested chemicals
[41:00] A generation disconnected from real food
Andrew: This is FX Medicine, and I'm Andrew Whitfield-Cook. And joining me again in the studio today is Dr Mark Donohoe, an integrative GP of some decades. And today we're going to go through some interesting articles, one of which really heightened my interest on fatty acids, but we're also going to be talking about some myth-busting issues with some media hype that's been recently on the airwaves, particularly in Australia. So welcome back to FX Medicine, Mark.
Mark: It's joyful to be here.
Andrew: Mark, I first need to cover off an interesting, recent, trump-up and I think it was...I vacillated between, you know, hilarity and a little bit of miff. But it was talking about how supplements are dangerous or a placebo, which I think is interesting.
Mark: Yes, yes, there's a big difference between them there. The criticism is either they do nothing or they do so much that they're dangerous. We should dump them in the ocean because of safety issues.
Andrew: But the thing I think is really interesting is they do both at the same time. They’re nothing and they’re dangerous, which is hilarious. But…
Mark: Yeah. But the thing is, doctors know this. Nothing works that doesn't do harm, and nothing harms that doesn't work in some way. I mean, the biological effect is one of our critical things. In fact, this is one of the criticisms of homeopathy. That, well, “there's nothing in there,” so how could it do anything? So no one doubts the safety of homeopathy, everyone just doubts that it can do anything.
We have an equation which is; you don't get a free lunch in medicine. The things that help also have the potential to harm and that's why you have doctors rather than everyone just walking in and choosing stuff off the shelf. So, it comes as no surprise that things that are powerful molecules in biology always have the potential to do something that's wrong, but the beat-up at the moment is not about that. It's about contaminated products, poor manufacturing.
It's about people saying that there's something in there when there isn't.
Australia has probably the best system in the world for ensuring that what is on the label is actually in the bottle. Or is in the supplement. So most of the criticism that went on on the Four Corners was an American piece of work and thank God it wouldn't happen in Australia because that's exactly what the TGA protects against. And exactly what good manufacturing process is all about.
Andrew: And indeed, this was highlighted in 2003 with what we call the Pan Pharmaceuticals debacle.
Mark: I do remember that day.
Andrew: But, you know, in hindsight, that was actually a good day. It wasn't nice to go through. It was great for certain companies, bad for certain others that lied through their teeth. But anyway, the interesting thing was that was based on actually a pharmaceutical medicine not having the required amount. And it was a variation greater than the allowed variation by the Therapeutic Goods Administration, the TGA.
What I think’s interesting though is that, I mean, and this played out in the court, was that it was based on a pharmaceutical medicine. No natural medicine was found to be outside of that variation and yet it led to that. Which is a very interesting thing. Despite Pan Pharmaceuticals making a very rare antidepressant, rarely prescribed. I think there was something like 200 prescriptions in Australia, and yet the TGA advice was to continue taking those medicines.
Andrew: It was very interesting…
Mark: It surprised me at the time. I was involved in it because there was an outrage and an extension of actions that had no basis in science. It was based on the belief that somehow terrible things were going on and so everything was removed from the shelves. It was quite fascinating.
There was another medication at the time, a brand of Nystatin, that in the midst of the Pan Pharmaceutical cycle came out to say, "Oh, our product is unstable and shouldn't be kept, except in refrigerators, and we've made these terrible errors of a medication that's a seriously prescribed medication." That received absolutely no headlines, whatsoever. So, we have a way of thinking that drug manufacturers' ethical, good and will always do the right thing and they have a lot of money and how could they be wrong?
There was this vague feeling that pharmaceuticals, yes, but complimentary medicines, they must be dodgy. And part of the problem is many complementary medicines are natural molecules, many are herbs. You and I have talked about this many times. I aim to become a herbalist later in life.
Mark: Yes! Because I do, and I do actually now understand that the whole plant has major advantages over the nice small amounts that we draw out as actives. The downside of it is to control all of the molecules in a plant-based product is almost impossible.
Andrew: No, no way.
Mark: You can get signatures of your actives, you can do those kinds of things. But on the other hand, we as humans have high biological variability. The mythology of pharmaceutical medicine is that the one dose suits everybody. The reality is that with our drug metabolizing CYP enzymes, with all of those, different size of people, different weights of people, different alcohol intake, all of those variables, we just cross our fingers and hope that the doses that are in the box are approximately right.
It's amazing that everything ends up with a zero on the end of it, it's 250 milligrams, it's not 272.3 milligrams. There are no fine distinctions there.
Andrew: But I do remember paracetamol, the initial dosage was 375, wasn't it?
Mark: I don't remember those days. Everything was 500...
Andrew: But we rounded it off to 500, because it's safe.
Mark: Yes. And paracetamol is a good example of the kind of poison that we don't mind administering in fairly large amounts, right on the edge of safety of doses. And plenty of times every year it rolls over that edge and we do get deaths from paracetamol.
Andrew: Indeed, and we're going to get into the microbiome here, so hang on for a tic.
Mark: Oh yeah, stewed apple, it's on my lips.
Andrew: Yeah, wait for it.
But this is a brilliant paper and it was just in the May, I think edition of Nature Review's Microbiology, and to me it is the most important paper certainly to do with the microbiome or microbiota that's come out. And that is basically looking at drug detoxification and how our microbiota help or hinder those drugs. And it's directed. We're talking about digoxin toxicity, so dig toxicity. We've known for some time from a beautiful paper by Catherine Lozupone, I hope I’ve pronounced your name right? I want to do a podcast with this lady.
Talking about p-cresol sulfate and how that can affect paracetamol toxicity. Now, there’s something that's clinically relevant. Being the number one medicine overdose for paediatrics. Hugely important paper and it talks about how we interact with our drugs using the microbes that help to detoxify those.
Mark: The microbes are in fact, our phase zero detox. We talk about phase one, phase two, phase three.
Mark: But phase zero for things that go in our mouth and oddly, for things that go on our skin as well. The microbes get the first bite of the cherry. And so when we put on cosmetics, having good microbes in the skin ...
Andrew: When we put on cosmetics?
Mark: Well, when some of us put on cosmetics, I lack that. I see chemically sensitive to people. They pick it in a minute if I've actually put my perfume on or any of these.
But when we ingest something, or put things on our skin, microbes interact with that first, and we've left that as though it doesn't happen. What goes on in the gut is incredibly complex. The first step is the microbes see it and may be injured, may metabolize it, may use it. We know it with sugar. We put that particular drug into our system, there's fermenting microbes that will produce very, very old things including people who occasionally get drunk just on sugar because it ferments so quickly that they become unsafe driving.
So we know that they get the first bite and we know that many of these biological molecules that we want for drugs are not specific to humans. They work across the spectrum of life. So the unknown thing has always been we put a drug in, we watch how it goes in a trial. Often, they're injected to get around this variability, or they’re used intranasally. Or in rat studies, they have different microbiomes completely from ours. And so the apparent toxicity may not be the true toxicity for everybody.
We have the added problem and I see it by patient population. That those who've had antibiotics and have got diarrhoea after… following the antibiotics, have terrible reactions to medications that they could previously take very easily. So it's clinically really important and relevant that people need to be careful about their antidepressants. Their Proton-pump inhibitors, their antifungals. They need to be really, really careful about those after they've had a course of antibiotics. Because the apparent adverse effects and beneficial things change very, very dramatically. We've got to deal with that somehow.
Many years ago, there was a dipping of the toe in from some of the major pharmaceutical manufacturers to say, "Hey, we might do genomic testing on everybody as a precursor to drug therapy. Because the drug dose is only right for around about 60% of the population."
Andrew: Yes. I think it was less than that?
Mark: Well, you may have been right. But it was adequate, the adequate control. But that meant 40% of all prescriptions were outside adequate control.
Andrew: Yeah, that's right.
Mark: I think what they were dabbling in was, we want to do the extra business of testing. So everyone knows their cytochrome P450, the kind of, web of drug-metabolising enzymes. But when the first thing was half of us are not giving the right drug dose in these packets, in the shelf that looks so neat on the supermarkets, they withdrew...
Andrew: Sorry, drugs in the supermarkets?
Andrew: Don't start me.
Mark: Oh, no. Well, we're going to have the pharmacists in the supermarkets to administer those drugs fairly soon, too, I understand it.
But they withdrew, at full force. Because the one myth that you have to maintain is medicine is safe, we know what we're doing, the dosage is right for everybody. And they leave it to the practitioner, the GP, and the specialist to work out, "Well, that's a complete stuff up."
Andrew: So, I think it's really interesting that two points, hopefully, we'll get a question out of this. One is, you know, drugs are very commonly added to...or sorry, firstly, increased in dose, and then maybe added to. Poster child's here are statins, and antidepressants. A little swipe here is that despite the supposed real risk of St. John's Wort, antidepressants are commonly combined if they’re resistant in patient’s depression.
But what I think is interesting when you're talking about drug dosage is the story of Stilnox, and this is something where I smell a rat. Now, Stilnox was supposedly released onto the market having all of the trials done to show the safe and corrective dose...correct dose. That works. And yet, after a furor of adverse events, the drug was threatened, if you like, to be taken off the market. But what they came back with was, "Oh no, it's okay, we'll just use half the dose."
Well, hang on. There's two issues here. One is if half the dose worked, why didn't you release that as the first dose? And secondly, if you're now releasing that as half the dose, and the first dose was the one that worked, then aren't you releasing a sub-therapeutic dose? So, either way, I smell a rat. That something wrong has gone on with the original research or the original registration of that drug.
Mark: I think you overestimate what drug companies do. They pick a number, they do a trial, if it seems to work, it's released at that trial. This is not as sophisticated as people make out. You make sure you don't kill too many rats along the way. That's always a negative thing at a particular dose. If the rats survive, you get to move on to the, you know, first preliminary...
Mark: Yes, human safety trials. Try not to kill any humans along the way, that's point number two. Killing humans is a negative for the FDA and TGA applications.
After that, it's pretty arbitrary. Dosages are picked on the basis of, will it harm? What's the majority of the population going to be okay with? And how do we drag that back if we find that there's adverse reactions? That's the post-marketing surveillance. And post-marketing surveillance is something I think doctors are terrible at.
We see adverse reactions all the time. To put the 15 minutes in to do the report is unpaid time for doctors and it...my colleagues say all the time, "Oh, yeah, I've seen terrible… did you report? No, I don't report." I do the same thing.
I have an example of one which you will love, Ketoconazole. Ketoconazole is an antifungal. 30 years ago, had around about a 1 per 5,000 people, had abnormal liver function tests after taking it. The papers in 1999 to 2000, said, "Why has this rate changed from 1 in 5,000 to about 1 in 100 or 1 in 80?" And the outcome of that was something's changed in the environment or the gut, or something has changed to induce enzymes in the liver, of the whole population. That were not being induced before and now that's increased the toxicity of that.
The suspicion was that it was food additives. That some of the typical food additives, just stuff that was going into the food, was getting to the gut, inducing enzymes or inducing microbes to metabolize it and the massive increase in toxicity for Ketoconazole, meant, doctors left it alone. We now use maybe other azole groups, always crossing our fingers that the same thing is not going to happen to them and make them useless drugs. So fluconazole and the like are now typically prescribed. Stronger drugs, but so far just hanging on by their teeth and they're not causing the liver damage that we were seeing before.
So it's a moving game. Dosages may change by half in order of magnitude. Originally, we were scared to give a million units of penicillin and then we kind of moved up the scale and we become a bit blasé about it. So prescribing doctors have not got a strong moral position when we say, "Yeah, here's a dose. Double it if it doesn't work. Double it again, if it still doesn't work. Add another, if that doesn't work…" We have a kind of make-do attitude where we mix things. We do pay attention to serotonin syndromes and the like, but we don't anticipate them very well.
And I think the big move will be our interaction, the drug interactions, we've always regarded antibiotics because they're not metabolized by the liver as being relatively safe to use with everything. Antibiotics may be the worst because they change the microbial formation in the gut, they change our first level of detox and drug metabolism, and in doing so, things become extremely unpredictable very quickly.
I think it should be in everyone's interest after every course of antibiotics to get right onto a diet and supplementation with probiotics to try and restore gut integrity. And that's doubly important if you're on any other medications, especially liver metabolised medications.
Andrew: Absolutely, and that's exactly what this paper in Nature Reviews Microbiology was pointing out. It was just poignant to me, it was so important.
Mark: We grew up with those bugs, right?
Mark: Those bugs in us, take new threats. And new drugs are threats. Drugs are poisons. You know, the dosage that is used for therapeutic effect is very, very close to the poisonous effect, and the microbes help buffer that. They take the hit, they may die off, they may change. But what they do is pre-metabolise things, so that we don't have to do the entire job ourselves.
Andrew: So, one thing that's really interesting to me is, and I don't know the answer, it's a question, is do you find, do you see that, let's say Australia is a huge alcohol intake nation. Do you find a greater propensity for generalised drug pharmaceutical interactions in the Australian population as say to, you know, India?
Mark: I haven't worked in India long enough to be able to tell you that. I mean, I know we have enzyme inducers, alcohol and caffeine are the big, big ones and they’re the ones that are very, very tricky to do controls for. In fact, we, you know, we see some products out now with caffeine as an enzyme inducer to bring up metabolic function of the liver. We...
Andrew: And, indeed, to help paracetamol.
Mark: That's true. Yeah. So we end up with combinations of what we use in our diet. There's plenty of enzyme inducers in the foods, you know, grapefruit juice. People love their grapefruit juice and their coffees in the morning.
Andrew: Ick. Not when they're on blood a pressure table.
Mark: Yes, and we pay scant attention to it. I don't know of all that many doctors that even ask what the diet is like, for the medications that they've got people on.
Andrew: Thankfully, we've got pharmacists that have a nice little label saying, "Don't take grapefruit juice with this medicine."
Mark: Well, we also...and I'm capable of blaming ourself here. We use antifungals. The antifungals, the azole groups have CYP enzyme inhibition. They prolong the half-life of many, many, many other drugs.
We are effectively overdosing people when we give people a quick course of Diflucan for thrush or a course of Ketoconazole on the skin or as ointments. We always are running the risk of causing a change in the dosage of something else. But no one pays much attention to it. The adverse drug reactions with herbs are very often in that same area. St. John's Wort, it will induce certain things. We don't have that many known pregnancies from inducing enzymes which rapidly metabolise oestrogen in the pill and clear it out. But it has happened.
And the paying attention to that no divisions between complementary medicines and orthodox medicines. I still think we lack terribly in that area. Doctors pay lip service, "Oh, tell me all the pills you're on." The next line is usually, "Well, stop all of those because that will affect the drugs."
I had a patient going for surgery, cosmetic surgery, and on the cosmetic surgeon's list is the medications to be off. And fourth on the list was the Mediterranean diet. And the fifth on the list was anything with fish. Because it was known that these Mediterranean diets and anything to do with fish would cause you to bleed massively at the other end of an operation.
Andrew: This is despite the work by Professor Frank Rosenfeldt and his team, doing the Integrative Cardiac Medicine Group, I think I've got that right? At the Alfred Hospital in Victoria.
And they were doing...this is using a fish oil, high dose Pharmaceutical Grade Fish Oil. Plus magnesium orotate, lipoic acid, selenium and Coenzyme Q10. So Coenzyme Q10 and fish oil would be the “Ahh, they're going to make you bleed supplements, right?” And yet these supplements were taken in good therapeutic doses right up to the night before surgery. That was when they stopped them. And they had, as research by professor, Associate Professor Leslie Braun, they did have a statistically significant increase in blood loss and it was like half a cup. To the cardiac surgeons, it was nothing. Nothing that was clinically significant, so they said, "Pffft, whatever."
Mark: That's the difference between significant statistically and clinically significant, and that's a good example of it. But what gets me is what do you go on for cosmetic surgery? Do you go on a high junk food diet because that will rapidly make everything clot?
Mark: Right? Do you put up with the cardiovascular risk of let’s embolise somebody…
Andrew: Therapeutic golden arches? No!
Mark: There is, in my view, kind of senseless conflation of if something has an effect, then it must have a terrible danger. There is something about biology in life that normalises. We have self-normalising systems. The bugs in the gut are part of it. The liver enzymes are like a web where one goes up and another will go down. The most important things by far is when we choose one molecule from a plant, you know, we choose maybe a Ketoconazole as that's the way the biological systems fight each other. We identify the active ingredient, we give a lot of that, and all of the other modifying agents that would have been in the original plant are left for dead.
The idea being we can control that to the microgram as if biology was controlled at the microgram. We're going to say, we take this brilliantly constructed molecule correct to the microgram and shove it into a messy system, that may have been drinking last night, may been having coffee in the morning, maybe eating grapefruits, maybe 125 kilograms, maybe 44 kilograms. We just throw them in as though these are magic answers and they're not. Every person needs their doctor or their practitioner to be thinking about every herb, every nutrient, and we need to have a concept of what is biological in nature. What are the molecules of life? This is part of the molecules that are patented, the things that the body has never seen before.
Andrew: But we see herbal medicine getting this way. What you're talking about is the thing, the concept of standardizations. And to me, it's a bastardisation of nature in that we go down the road thinking that its the "active." Now that's fine if you have isolated that active and studied that active, good luck to you, you've now got a pharmaceutical drug. But we should not be changing herbal medicine to be little pharmacists or doctors. To me, it robs us.
Markers of quality or indeed authenticity ahh, yes. Now, there's a point for "standardisation." But to rely on one chemical of that plant, you can easily spike it. We've even seen, I remember Professor Rudy Bauer, years ago, I think it was 1999, talking about Echinacea being spiked with alkalamides.
Andrew: You know, another one is St. John's Wort. Years ago, in my day it was, “oh”.. and I went down this route. ‘It's got to be standardized.’ And it was hypericin, was the active. And then it was “oh no, it’s hyperacins,” and then we've moved, now moved, to hyperforin. But if you look at the research, the high hyperforin, they’re the extracts that don't work. It's the low hyperforin, high bioflavonoid ones that seem to work. That's the extract that's shown beneficial, and they seem to think that it might be the bioflavonoids, to isolate one thing.
Mark: We're learning something in pharmacology. We always learned the dose-response curve, you know, the S-curve?
Mark: You know, there is a low dose and then the effect goes up. And you could look at that curve a few different ways.
I think what now we're aware of, you know, even from medicines like amitriptyline. That a particular dosage may have an utterly different effect in different areas, in different dosages. And we're now seeing more this U-shaped curve. That there is side effects, high side effects, even at low dose, when you get up to therapeutic doses, it may be better and then it goes off again. You have some that have a different effect of very low dose compared to high dose. And so most people don't know the tricyclic antidepressant started life as antihistamines. They were antiallergy drugs that were found by people as depressed at high-dose. It probably had a bit to do with the fact they did have an antihistamine effect and that antihistamine effect was beneficial.
So, the learning of that, the learning of the biology of humans and the interaction with our natural environment, which was foods and plants and herbs. And evolution, never planned for us to be able to isolate these things. This is a trick that humans have got up to. What we can do is use that to absolutely be certain of safety and no contamination. And the very things that were looked at in the Four Corners program or the American version of the Four Corners program. You want your things to be safe. You don't want them contaminated. You want the active or the ingredient that you believe to be there, to be there at the right dose and that's the value.
But becoming little medicine, I think that's just the wrong path to go. The value of herbal medicine is that these are the plants and the molecules that we grew up with. And that biology determined that we should be able to manage. And used therapeutically and wisely with the wisdom of thousands of years? That's a very, very safe path to go. The big one’s cannabis right now, isn't it?
Andrew: Yeah, yeah.
Mark: Do you extract it and turn it into a very high-cost drug unavailable to almost everybody...
Andrew: With high side effect profile. If you don't have the balancing...
Mark: Cannabidiols versus...
Andrew: Antidote, yeah.
Mark: So you want the effects of the entire plant, but you want to be able to deliver it in a drug-like way that's nice and clean and appeals to doctors and prescription pads. And that's getting messy because we don't know what those right ratios are.
So one view is we already use that. We have thousands of years of using cannabis. Let's pay attention to how it was used and deliver things in a way that's useful that has been discovered. The other one is let's do a billion dollars' worth of research to have highly active ingredients, remove it down to something that we know the microgram dose of and then pretend it works.
And I think that what we're finding now is the battle lines are drawn again in medicine itself. There's a group of medical doctors who say, "This is a herbal tradition and we should respect the whole plant," and it's the whole plant that gives the benefits and the low side effects.
Andrew: That's right.
Mark: It's not the actives that you can pull out to make a doctor happy that this is a 300-milligram dose of something...
Andrew: Well, my concern with that is if they do that, cannabis won't work. See you later, goodbye. And that's my concern is, you know...
Mark: The downside of bad drug trials is you lose...
Andrew: ...it depends on which side of the fence I'm on on that day, you know, is it, what do you call it? Conspiracy theory? You know, my conspiracy theory side would say, "Well, that's a setup." Then the other type would say, "Well, it's just, you know, idiotic, ignorance."
Mark: Hard to determine the difference sometimes. Especially when it comes to regulation. You can be a conspiracist, they have a conspiracy on the other side.
Andrew: But why can't we call a polypill?
But anyway, you spoke just before about these molecules of life. And you sent me a very interesting paper about the antifungal activity of free fatty acids. Let's delve into this because this is really interesting. And to me it belies this thing that I support, that we've got to stop getting into this kill, kill…
Andrew: Forgive me, Medicos, ‘doctor mentality’ of, "there it is, hit it with a hammer quick." And when we're talking about dysbiosis, when we're talking about "parasitic infection." Whatever you define that is, I would hope that somebody actually defines it, rather than just says it. But if somebody’s got a problem with an infestation, the first thing we should be doing is nourishing our own immune system so that it can do what it can to normalise that terrain. And this is where I just wholeheartedly embrace the teachings of Mike Ash. He changed my way of thinking. You've sent me this paper and it's talking about antifungal activity of fatty acids. Can you explain a little bit about this?
Mark: Like, I can. The reason I found it fascinating, we all have in our mind, caprylic acid and undecanoic acid. We have particular names and we think of these are antifungal. What the South African research showed is, well, actually, pretty well all the fatty acids are antifungal. But different chain lengths and different methylation states and different hydroxylation states have entirely different ways of inhibiting particular fungi.
These are not the answers that I was expecting. I was expecting simply that there were very, you know… the undecanoic, the 11-chain fatty acids would be inhibitory. Interestingly, it's not inhibitory to candida whatsoever. It is inhibitory to other fungi and it is the 8, the octo fatty acids and the 12, and most interestingly to me, highly antifungal is the EPA and DHA. The 22-chain amino acid, I would have imagined that all the benefits were related to, you know, brain development. We've heard all of the good things, but what I never anticipated was less very, very specifically anti-candida albicans and other candida species.
Butyrate, the things that we require for gut nourishment have strong antifungal activities and they’re things that you can nourish just with, you know, with semi-soluble fibers and the dietary aspects of that. That keeps us in an antifungal state where the balance between microbes, the bacteria, and the fungi are kept in check. Fungi are normal, they're in the gut, they're there the whole time. Some people have a terrible time with them and you know, this goes back to Ritchie Shoemaker's stuff on “who are the susceptible people for whom fungi is just bad news all the time.” But for the majority of us, it's only fungal overgrowths that we pay attention to.
What I hadn't really anticipated is; what produces all of those different chain length fatty acids? The microbes that are already down in the gut. The very things that Mike Ash and others were all nourishing. One of the things that we're nourishing is putting the bullets in them for the biological warfare that they have with their own fungi.
Soaps also, although it's very unpopular to eat soap. But soaps which are, you know, fat plus acid together, produces a soap and saponins are also highly toxic to the fungi.
Andrew: But you talk there, I mean, you could...A herbalist would use high saponin containing plants.
Mark: Yes. So, you don't have to use, you know, Palmolive.
Andrew: Always with meals, I might add.
Mark: Yes. But the whole subtlety of our rethinking the microbiome project opens up whole new vistas of, this is not war that's going on down there, this is a communication of your, "Hey, back off. This is my territory." The bacteria do it to the fungi, the fungi do it to the parasites. All of them have got their own little tricks. Nystatin is derived from a fungus, it's a fungal toxin for one fungus to inhibit others.
So nearly all of our tricks come from biological molecules that are altered enough to make them patentable. And oddly, to make them more toxic. And if we really do unravel this microbiome in the way that I think it's going to unravel. What we will see is there's ways of protecting and preserving the diversity there, that has a buffering, which is way, way more important than whether we can use a drug to do a particular job.
You may use a drug for life-threatening conditions or serious conditions to put the hammer in and say, "Hey, back off," and you know, for, I have personal experience, patients on chemotherapy. You do not want a fungus getting out of control. So that conazoles and those type of azoles are life-saving.
But when it comes to reestablishing safety and life and balance in the gut, we're going to be learning the language of the microbes, the fatty acids produced and the way that they encourage the growth or the shrinking away of the fungi, and fungi clearly have their purpose.
One thing that I just adore is Candida Albicans. A growth factor for candida is human estrogen, not just estrogens in general. But the human estrogen is a growth factor for the fungus. Everybody who's been on the pill will probably appreciate that that's the case. But we do need to rethink our relationship with them if they use our hormones for their growth and we rely on them for something, we had best understand it.
I've been part of a vanguard that always, that I've gone after candida and the candida-affected people and done everything I can to clear it out. It's not a good health outcome. It's a lack of fungus outcome that may help certain people.
Andrew: I've seen these patients and they are usually ladies, a handful of patients, thankfully, only. On their long-term anti-candida diet and they are the most emaciated, unwell people. It was never ever supposed to be that. But my issue was that we always thought of this bug as something to kill, that it's alien. Rather than a commensal and it just needs to be kept in balance. The problem was that we were wiping out the things that were keeping it in balance.
Mark: Yeah, and so the enemy of my enemy is my friend is...We hate...Medicine just hates little things, tiny microscopic things. We go after them. We’ve had a century of chasing germs as though they're evil. We're relearning that relationship. I have hopes that the relearning of that relationship will see medicine grow up. Not into a more specific, highly technical profession. But to one where we understand the limits of balance and the limits of what we can do and how we encourage the movement of biology into a particular state. Not how we hammer it into that state.
And I think that's why I want to become a herbalist. I really want to learn the art of the molecules of life and how they interact with us. And I think that's the missing part of medical education. We can learn pharmacology, but all that tells you is inside the body, inside the bloodstream, what is that drugs fate and what does it do? And the entire story about what happens with the food, the microbes, the liver, the detoxification processes, our particulars of the fatty acids that we consume, that part's lost in the whole story and we're the poorer for it.
Andrew: So for our listeners, that paper that Mark was talking about is the Antifungal Free Fatty Acids: A Review. The author is Pohl, P-O-H-L, first name, Carolina, initial H, et al, and it's in Science Against Microbial Pathogens: Communicating Current Research and Technological Advances, and it's a really interesting read. I think it was 2011, so we'll put that up. Is it Formatex, is the publisher?
Mark: Yes. Don't you love the names of the journals now? I mean, you can tell when you've lost it. Where your title of your journal runs to two lines or three lines.
Andrew: Let's talk about another paper that you’ve brought up and this is going back a little while. This is quite an old paper, I think it was 1993? But; Neurogenic Inflammation and Sensitivity to Environmental Chemicals. Now, this was your catch cry, this was your expertise that those many decades ago, Mark. For which I first got to know you. You wouldn’t have known me from a bar of soap back then. But I think it was very interesting that...
Mark: You've been famous forever…
Andrew: Can you take us through the early days, from what you thought as a medical practitioner and indeed, an integrative practitioner back then. And how that thought and practice has evolved over the decades?
Mark: Gee, that's a tough one. The going back...
Andrew: Five seconds.
Mark: ...all we saw was people adversely affected by a range of environmental and ingested chemicals. And there was no mechanism for the immune system to recognise or even be affected by this. And so, one of our problems was in 1980s, immunology was on the rise and we knew that it was water soluble molecules and we knew that the type of antigens that the immune system responded to.
When you look back to the '80s, what we didn't know, we didn't know we didn't know. If that makes sense. When you don't know that you're missing important data, when you think that everything is working through immune system and antigen recognition, you tend to see the world in a particular light.
We were seeing people where inflammation was triggered by pesticides, herbicides, solvents, things that they were using in everyday life in their homes and getting very, very sickened by. And, yes, it eventually affected immunology, but the neurological and the central nervous system consequences, in particular, were dramatic.
What was going on though was people were suffering what we regarded as psychiatric disorders. People were hit by chemicals and becoming brain dead. They would describe fatigue, depression, they would describe a lot of symptoms. And when doctors looked at what they were exposed to, they said, "Well, you can't react adversely to those because they're not water-soluble, they're not big enough proteins, they couldn't possibly be doing that, so it must be psychiatric."
And I think what we've seen in emerging times is a), there are immune cells that identify and link to lipid-soluble molecules. They have receptors on their surfaces and they clone in response to that. So one is, there is direct immune recognition of molecules that we seem to think of as too small and too insignificant to affect the immune system.
The second one was it's the nervous system that was being triggered and the nervous system and the immune system together are very tightly correlated. That when the immunology is affected, the nervous system is affected. When the nervous system is affected, immunology is changed. We now kind of recognise that in the microglial cells and we talk about the brain's immune system.
Andrew: But the endocannabinoid system as well.
Mark: Yes. And you know, we have a lot of receptors around there for molecules that we would step back and say, "Really? You react to poppy juice and you react to cannabis? Why are those receptors around in the body?" And biology is relatively thrifty when it comes to its use of receptors. Lots of molecules will bind in different ways to different receptors and we immerse ourselves in the biology around us. And so cannabinoid receptors shouldn't be a surprise. Morphine-like receptors should not be a surprise, but they always are. We're even now seeing that there's insulin receptors and the brain is affected directly by insulin as a neurotransmitter. Who would have thought insulin, a huge molecule compared to the neurotransmitters, would have any effect on the brain?
So, I think all we're seeing is, whenever we introduce poisons, the mechanism of action of those poisons is sometimes unknown. Our targets are the pests, the insects, the plants. We use our glyphosate for what we call ‘weeds’, which is anything that's kind of leafy. And we assume that we are invulnerable. And whether it is via the microbiome, the glyphosate story that Dave Perlmutter gave us. That is now really solidifying well. That the shikimate pathways are in the bacteria in our guts. We don't have them. But we are affected by them because the poisons for the plants affect our own bacteria.
Who would have thought that the molecules, the acetylcholine affecting molecules of the organophosphates, would have direct effect on brain chemistry and then immunology secondary to that? We see it in our practices and removing people from poisonous is, I think, one of the best things doctors can do these days.
You’ll be surprised whether those poisons are gluten in grains or pesticides in grains, my patients focus on organic food. I am impressed by the fact that I don't even need to say it. By the time people have seen me, they work out that even though they pay double or triple for their food, getting those trace amounts of pesticides out has an immense effect. Arguably bigger than many of the pills and potions that we give them.
And so it is extraordinary that people will go broke, but they have to hold onto their organic food. Their children's behavior, their own health is critically dependent on no more poisons getting in. Brain function restores itself to somewhat normal just by getting rid of the poisons that would otherwise be hurting us.
Andrew: Often these very sick people are the ones who, you know, have given up work because they just can't cope. So they're not on a high income, they're not earning anyway, and yet they find it so important to eat organic food.
How important do you find it, or indeed, how easy do you find it actually instigating that when, indeed, organic type foods are that expensive and, b) How easy or hard do you find it to get these patients to take some sort of responsibility to providing their own subsistence around food?
Mark: It's a tough one. I've got to say, most people are referred to me by someone who's already got them onto organic food. And so I see the ones where there was partial improvement. What I'm impressed by is that even though they're out of work and out of money, they will save up to buy organic food and eat organic food rather than just go for the junk.
You can get a McDonald's dinner for less than the cost of a cauliflower, an organic cauliflower, which is tragic. But it does mean that the kids will keep on flouting that they'll keep on going to McDonald's but the parents who know what their kids' behavior is like and what they need to do to get them right will focus on the food. And I think that innate thing, a mother tends to understand that the food and the types of the quality of that food are critically important to their child's health. The chemically sensitive people figure out very swiftly that their health is nonspecifically degraded by the tiny amounts of pesticides that we regard as acceptable.
It amazes me that to not have added chemicals can triple the cost or quadruple the cost of food. You would think that growing things and adding chemicals will be costly, but, of course, that's the modern agriculture. It's high turnover. But getting people to have a taste of what organic food is, to have real food. That, I think, is going to be critical to learning how to be cooperative with nature in the future. We cannot just keep on using the pesticides, robbing the soil of its nutrients, and then expecting the lower and lower nutrient plants that we eat along with the poisons that are still residual, are going to encourage health.
Andrew: If somebody out there has a magic way of introducing organic foods to their patients, please let us know on fxmedicine.com. I'd love to know about it, particularly on a population basis.
Mark: Well, people do grow their own. The other thing that I'll say is when people are really sick with chemicals, they tend to get out of cities. They tend to move to places where they can take control of their own growing and the number of people who then eat from their own gardens and find their health improve that way is I think, very impressive as well.
But it's really hard to be a subsistence farmer in a terrace house in Paddington. You just, you need to have other food and the cost of it can be prohibitive. But my view of it is that's the initial first investment. If you get your kind of, the Mediterranean style diet, low grain, up your avocado, up your olive oil, keep your fish….
Andrew: For your fatty acids…
Andrew: Isn't this interesting?
Mark: It is. And so, putting that pattern together is now a much better dietary choice than the old pyramid. The old pyramid of just eat as much grains as it takes to fill you up and that'll do. Basically, you could fulfill dietary requirements by just having four loaves of bread a day and a couple of vegetables whacked in there. And oddly, the only dietary advice that has sustained itself over 50 years is "Eat more vegetables." The fruits come and go, the meats come and go, the grains come and go. But all we can really say is you eat more vegetables, you have a more alkaline diet. It's a healthier diet and as long as you don't have the poisons on the vegetables, then you have a really good nutritional base to work from.
Andrew: I think the standard Australian diet that was weighted largely to grains might have worked in the post-war era. Where convenience was low, exercise was high and money was short. But when we're talking about our modern lifestyle, it simply does not work. Professor Jennie Brand-Miller has just stated this categorically. She's the hero of the low-glycemic index diet, and she just said these modern guidelines simply have not worked for us. We have an epidemic, a pandemic on our hands. And we need to be trying something different rather than saying, "No, we need to hang on."
Mark: We have a kid, a kind of generation of kids who are growing up without ever having tasted real food and that...
Andrew: Or knowing where it's from.
Mark: And that is the tragedy. That's something that we're really going to struggle with in the future.
Andrew: This is FX Medicine, and I'm Andrew Whitfield-Cook.
Spanogiannopoulos P, Bess EN, Carmody RN, et al. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016 Apr;14(5):273-87.
Lozupone CA, Stombaugh JI, Gordon JI, et al. Diversity, stability and resilience of the human gut microbiota. Nature. 2012 Sep 13;489(7415):220-30.
Pohl, C., Kock, J., and Thibane, V. Antifungal free fatty acids: a Review. Science against Microbial Pathogens: Communicating Current Research and Technological Advances, ed. A. Mendez-Vilas. 2011:61–71.
Other podcasts with Mark Include: