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PEA: Perspectives from a Pharmaconutritionist with Dr. Adrian Lopresti and Dr. Paul Clayton

Adrian_Lopresti's picture

PEA: Perspectives from a Pharmaconutritionist with Dr. Adrian Lopresti and Dr. Paul Clayton

Paul Clayton is joined by fx Medicine ambassador Dr. Adrian Lopresti, who together deep dive into the role of PEA in all conditions (beyond pain), and where PEA can relieve symptoms and support resolution.

Paul is an advocate of lifestyle and nutrition in the prevention and management of disease. As a pharmaconutritionist, Paul understands the vital importance of how nutrition impacts chronic disease, and the role that chronic inflammation plays in driving ageing, as well as the onset and development of neuroinflammatory and neurodegenerative disease.

Together Dr. Lopresti and Dr. Clayton examine the role of PEA in the treatment of inflammatory disease states, dosage and supplementing, and its use in the effective management of both acute and chronic conditions.

Covered in this episode

(01:18) Welcoming Dr. Paul Clayton
(02:28) What is a Pharmaconutritionst?
(09:34) Drivers of ageing
(11:35) Introduction to PEA
(14:05) Endogenous production of PEA
(14:50) Therapeutic benefits of PEA
(19:00) PEA supplementation
(21:24) PEA and the brain
(22:15) Supplemental dosing
(23:02) Bioavailability of PEA
(25:35) PEA and neuroinflammatory stress
(27:26) Drivers of chronic inflammatory stress
(30:57) PEA in the treatment of neurodegenerative diseases
(31:54) PEA as an alternative to CBD
(34:12) Sources and dosage guidelines
(42:49) Thanking Paul and final remarks

Key takeaways

  • The western diet is pro-inflammatory and void of many naturally occurring anti-inflammatory nutrients, hence the rapidly rising number of neurodegenerative disease and other conditions driven by inflammation.
  • PEA is produced endogenously, so is a safe and effective supplement to consider in both acute and chronic cases of pain and inflammation management.
  • Therapeutic effects of PEA: Anti-inflammatory, antipyretic, immunomodulating, anti-convulsant, neuroprotective
  • Complementary herbs and nutritionals: polyphenols, prebiotic fibre, Levagen+ is a highly bio-available form of PEA

Resources discussed and further reading

Dr. Paul Clayton

Dr. Clayton's website
Article: Palmitoylethanolamide: A Natural Compound for Health Management
Article: Palmitoylethanolamide: A Potential Alternative to Cannabidiol

Palmitoylethanolamide in health management

Article: Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold


Adrian: Hi, and welcome to fx Medicine, where we will bring you the latest in evidence-based, integrative, functional, and complementary medicine. fx Medicine acknowledges the traditional custodians of country throughout Australia, where we live and work, and the connections to land, sea, and community. We pay our respects to the elders, past and present, and extend that respect to all Aboriginal and Torres Strait Islander people today.

Dr. Paul Clayton is a Clinical Pharmacologist and Pharmaconutritionist. He's a strong advocate of lifestyle and nutrition to help prevent and treat disease, and he has written several books, including Out of the Fire and Let Your Food Be Your Pharmaconutrition. Paul works with leading doctors and clinical scientists in many countries where he helps them design and supervise preclinical and clinical trials on pharmaconutrition interventions.

Paul's expertise is in a range of natural therapeutic interventions, and he has recently published a couple of articles on palmitoylethanolamide, otherwise known as PEA. It is his expertise in PEA that we wanted to cover today. Welcome to fx Medicine, Paul. Thanks for being with us today.

Paul: It's a pleasure to catch up with you again, Adrian. Really a pleasure.

Adrian: Yeah. I know we've certainly met on a few occasions, and every time I talk to you, I learn a bit more about nutrition and pharmaconutrition. So, today I wanted to talk about PEA, but before we do that, can you tell us what a Pharmaconutritionist is and how you got into the area?

 Paul: First of all, I need to make it pretty clear that a Pharmaconutritionist actually does not have very much to do with classical nutrition at all. Pharmaconutrition is a portmanteau term, and the name itself applies it's a kind of a synthesis of pharmacology and nutrition.

Fundamentally, it's a movement away from classic Pasteurian medicine. And by Pasteurian, I'm talking about the use of basically the concept of specificity. And this goes all the way back to Hans Gram, the Danish microbiologist, the Gram stain, and then you have the coal tar dyes, the sulfa drugs, the penicillins.
And this lays the foundations for the modern model of reactive healthcare.

So first of all, you wait until someone got sick, and then once they do get sick, you try to alter a very specific receptor, or enzyme, or protein, or these days, a gene, in order to modify that disease. Now, that approach worked extremely well back in the 19th century when the main causes of the illness and death were infections. Doesn't work at all well in the 21st century where the vast majority of cases of diseases and death are due to chronic degenerative diseases. Now, these are not caused in the main by single infectious agents. They may play into it, but broadly speaking, they're caused by multiple metabolic errors, which are in turn driven by multiple nutritional imbalances.

And so this is where pharmaconutrition comes in. It's not specific. It's the opposite of Pasteurian medicine. It's actually Bernardian. Now, I'm referring now to Claude Bernard, who is Pasteur's contemporary and compatriot. And Bernard talks about the milieu intérieur, and his work is taken up by Walter Cannon, who talks to us about homeostasis. And what pharmaconutrition does, it relies on using the known pharmacological functions of different foods and food derivatives and cross-references those against the multiple metabolic errors that are driving disease.

So it's not the magic bullet, it's really more of a support system. And what we find when you use those types of interventions, the NCDs, the non-communicable chronic degenerative diseases that we've always thought of as being entropic, the idea that it's a wear-and-tear thing, well, that's nonsense. That's a way of thinking that it's probably applicable to mechanical systems. It's not applicable to living systems, all of which have a capacity for repair and regeneration. It turns out that when you nullify these multiple metabolic errors, which is what the pharmaconutrition is all about, then the body's ability, these processes to do with repair and regeneration, come to the fore. They overcome, in many cases, the catabolic drivers.

And what you actually see is that these conditions, these so-called diseases of civilisation, start to slow down, symptoms become less, requirements for pharmaceuticals become less, and then over time, many of the patients that we're treating go into remission and they become pharmaceutically independent. Not all of them, I must say that right away, but probably between 7 and 9 out of 10 of them. So this is a very extremely productive new way of thinking about healthcare. And it lends itself very, very well to preventive rather than reactive models of healthcare. You can't use pharmaceuticals in a preventative system, they're just too darn toxic.

And frankly, the latest polygenic risk analyses show that you can't even identify who's going to become sick. That was the last best hope, I think, of the Pasteurian model, and it's failed. But when you're talking about Pharmaconutritional regimes, they're so incredibly safe. The therapeutic indices of these approaches are so wide, you can give them to just about everybody. They're cheap as chips because there's no IP really. And it's, I think it’s going to be the next model of healthcare delivery because the current model is ruinously expensive and it's run out of road, quite frankly.

Adrian: So I know you lecture throughout the world. So, is it increased in popularity? Are you noticing that people are more interested in pharmaconutrition?

Paul: Oh, absolutely. And I think that the reason is that there's been an enormous proliferation of studies looking at the relationship between diet and disease, looking at the pharmacology, the cytochemistry, the endocrinology. It's abundantly clear now from our studies of Blue Zones islands, geographically defined, and one or two cases islands in time, which no longer exist. It's very clear that there are other ways of aging which are far more successful than the patterns of aging that we see around us. And what these Blue Zones of various sorts show us is that many of the symptoms that we thought were intrinsically part of the aging process, such as the thinning of bone, or the furring up of arteries, or the progressive loss of brain cells aren't actually essentially part of the aging process at all.

Other cultures that live in a much healthier way than we do don't experience them to anything like the same extent that we do, if at all. And so, if you look at groups like the Hadza, who are hunter-gatherers in Tanzania, or the Tsimane, who are forager horticulturalists in Bolivia, what you find is a population that as they get older, their blood pressure doesn't go up. They don't develop essential hypertension, which we think of as an intrinsic part of aging. Clearly it isn't. In males, they do not develop benign prostatic hyperplasia. So that's another symptom of aging that we think is normal that isn't. As they get older, their kidneys do not lose the ability to form concentrated urine.

And that's something else we thought was an essential part of the aging process because that's what we see around us, but isn't. And that might sound trivial, but if your kidneys are still capable of producing concentrated urine, you are not as likely to become dehydrated. And dehydration as is now becoming blindingly obvious as a key driver of many aspects of the aging process.

And I'll tell you just one more thing, one more thing that they don't show that we do. As we get older, you see hippocampal and hypothalamic deterioration, which is really important because you're talking about the hippocampus anyway as one of the sites in the brain where neurogenesis is still going on throughout life. In the West, in developed nations, hippocampal deterioration is very, very common. It's a forerunner of other neurodegenerative conditions. When you look at people amongst the Hadza or the Tsimane or other Blue Zone groups, they don't seem to display that.

So some of the really profound drivers of aging or symptoms of aging that we think of as being a natural part of the process clearly are not. They're, in fact, artifacts and they're caused by the very unhealthy exposome that we live in and on and around. So that's, in a nutshell, in a very large nutshell, that's what pharmaconutrition is.

 Adrian: So we can certainly...it's a fascinating topic. I know that you're extremely passionate about that area. And obviously, nutrition plays a big part. There's obviously also lifestyle factors too that are impacting on general health and longevity and so forth, too.

Paul: Yes. And I don't mean to underestimate the importance of the classical things. I tell people don't smoke, don't drink too much high-octane alcohol, take a little bit of exercise, good sleep, relaxation techniques. All of that plays into it. And I'm not going to be reductionist about this and say that it's all about your diet. But when you parse all the multiple variables that constitute what we call, laughably, civilisation, there's so many thousands of variables, but it isn't really very helpful to consider them individually.

What I and my colleagues have been trying to do for decades now is to peer through that curtain and see whether there might be a smaller number of drivers of disease that one could theoretically develop antidotes for. And I think that's the point where we now are, a number of these drivers have been identified. And it turns out that if you neutralise them, or put antidotes in place, you interfere with some very substantial drivers of the aging process. And these are the techniques that we're now using in over 100 countries now to slow and, as I said, often stop, and in some cases even reverse what we used to think of as deep aspects of the aging process. It turns out that they're amenable.

And the reason why the medical profession has thought of these conditions as being progressive and irreversibly progressive is because they've been using the wrong tools. If you use pharmaceuticals, you are probably not going to be able to slow and modify them. But if you modify the drivers of disease, at that point, medical miracles start to happen. Now, I say medical miracles, they seemed pretty miraculous to us when we first started down this road. And we’re at that ho hum stage now because we see so many of these types of recoveries now, they've just simply become a part of routine practice.

 Adrian: Yeah. One particular compound is PEA. And I know that you've got expertise in a whole range of different areas, but I know that you've written some papers on PEA, and that's what I specifically wanted to talk about. So if we move on to PEA, do you want to tell us what is it and how is it produced in the body?

Paul: Well, I can answer that in various ways. Technically, in terms of its molecular structure, it's a fatty acid amide, and I'm interested in it because you can think of it as an atypical nutrient. In terms of its function, it's an autacoid. So it's a physiologically active substance, and you can think of it as a very, very locally active, very transient hormone. It's produced, as far as I know, in every different type of cell within the membrane bilayer. And there's a whole family of similar compounds. So, we mentioned PEA, which is palmitoylethanolamide, but you have ethanolamides of many of the other fatty acids.

So, some of the other really well knowns, you've got stearoylethanolamide, oleoyl, palmitoyl, and then you have arachidonoyl ethanolamide, which is anandamide, and that's one of the endogenous cannabinoids. And I just want to mention that because it's in contrast to the exogenous cannabinoids, which are better known, such as cannabidiol or CBD. And I think we're going to come to that later. And you take all this whole family of fatty acid amides together, they're termed ALIA Amides, which stands for autacoid local injury antagonist amides. And that I think came out from Rita Levi-Montalcini's lab, she and her group. She won the Nobel Prize for her work on these molecules.

Adrian: So PEA, obviously, can we derive it from food? Is it obtained from foods?

Paul: Yes, you can. Absolutely. That's really why I consider it to be a nutrient. So it's obviously an endogenous molecule, but you can derive it from egg yolk, and in fact, some of the very earliest studies that began from whether this molecule was initially characterized was done with egg yolk. Peanut skins is another, sort of, reasonably well-known source. And soybeans, of course, these all contain PEA at very different levels. I would think if you wanted to obtain pharmacologically active levels of PEA from any food, you'd probably do best to stick to egg yolks.

 Adrian: Okay. And so we produce it endogenously. So, is there anything that kind of impacts on our production of PEA negatively or positively?

Paul: Theoretically, there might be because we know, the thing is this molecule is so important, but actually there's a bunch of different synthetic roots in the body. That's how important it is. So there's a certain amount of redundancy. If you block one, there's going to be other mechanisms that'll still produce it, and you're simply working from fatty acids plus ethanolamine. So they're pretty widely present in the body. And I think what that does is it underscores the importance of these molecules. And I'll sort of stay with PEA for a moment, but its properties are shared to more or less an extent by the other fatty acid and amides I mentioned.

 Paul: When you ask, what does it do in the body, well, I think I'd have to ask you, well, what doesn't it do? It's absolutely pleiotropic. So it has anti-inflammatory effects. And these, I think, were some of the very first effects to be noted. And that goes all the way back to the 1950s. But more recently, it's been shown to be effectively an analgesic. It's an anti-convulsant. It has antimicrobial and antipyretic effects. It has anti-atheromatist effects, and it's an immunomodulator and it's neuroprotective.

It's working through so many different receptor types in the body. So probably you could say that maybe the primary target might be your nuclear receptor peroxisome proliferator-activated alpha receptor. So that's PPAR alpha, but it's also acting on the novel cannabinoid receptors. And these are the G protein-coupled receptors 55 and 119. But then you have some indirect activation of the typical or the classical cannabinoid receptors. So you've got CB1 and CB2. But that's a bit of a different effect. That's the entourage effect.

And because what's happening is if PEA is being synthesised, you're actually inhibiting the degradation of anandamide. And because what you're doing is, as the PEA is being synthesised, or if you're taking PEA, it's inhibiting or it's occupying the relatively limited bandwidth, perhaps capacity is a better word, of the enzyme fatty acid amide hydrolase, that's FAAH. It's also inhibiting mast cell degranulation. Yeah, it acts at the vanilloid-1 receptor, so that adds anti-allergy effects. So together with the mast cell degranulation thing and further analgesic effects.

So fundamentally, what this is doing, it's the body's tripwire response, the very first response to tissue stress and injury and damage. It's a dampening or a modulatory system. It's one of the ways in which we protect ourselves. We insulate ourselves from the slings and arrows of outrageous fortune, of heat, of physical trauma, of cold, or any kind of noxious stimuli. As soon as you're exposed to that, the body immediately ramps up PEA synthesis in an attempt to downregulate the intensity of what would otherwise be a distracting or possibly even a disabling input from outside.

Adrian: So what happens when the toxic insults or this inflammation or factors going on that's just chronic, does it continue to remain high or do levels of PEA then eventually kind of reduce and lower?

Paul: So, you have to think of PEA as a kind of pro-homeostatic factor. So, as I said, it's one of the first responders to cellular injuries, not the only thing. And there's other things going on as well in response to damage. So you're getting different patterns of protein expression, and you've got a kind of post-transcriptional triage going on as well.

But yeah, you're right, damage upregulates PEA production. So initially, PEA levels increase during, let's say, inflammation or tissue damage, at least initially. But eventually, the buffering mechanism is exhausted, you run out of PEA. And that's what you need when you think about it because, at a certain point, if whatever's happening to the body is really destructive, at a certain point, you don't want to continue to buffer it. You want the body to understand that there is something bad going on that you need to withdraw. So this is a very short-acting buffering or homeostatic system, and it does get exhausted. And what happens is the synthetic root starts to slow. You might also get an increase in breakdown, which is being broken down by this acid I talked about, FAAH, which is primarily in the endoplasmic reticulum.

So you do run out of PEA eventually, and this is where the rationale for exogenous PEA or PEA in supplemental form comes in.

 Adrian: And so what does the research say with regards to PEA in supplement form? In what conditions is it particularly helpful?

Paul: Well, and to give you kind of a little bit of a historic analysis, the very first study we used egg yolk and some scientists initially showed that this reduced recurrences of rheumatoid arthritis and exerted anti-allergy effects. And those first studies go back, I think into the late '30s, early '40s, and extended into the '50s. And then, of course, a lot of work was done all over the world subsequently, and it became progressively more sophisticated and more precise. And about 20 years later, the anti-inflammatory effects had become pretty well characterised. And then in the late '70s, there were some military studies, three or four of them, I think. And they showed that PEA reduced influenza symptoms in a bunch of soldiers. I think mostly the effects they were looking for were antipyretic effects. And these were all army trials and part of a very old tradition of research into enhancing military resources.

Then there is evidence on the neuroprotective side, and some of that is preclinical, and some of that is clinical.

Adrian: So the majority of the research is around, kind of, pain, is that correct, initially?

Paul: I think that at the moment, most of the work has been done on pain, but there's also a bunch of studies have been done on sports recovery, sleep patterns, various types of epilepsy, and on various types of nerve pain, so neuropathic pain as opposed to nociplastic. Although I think that PEA, I'm pretty certain PEA has an effect on nociplastic pain as well because PEA reduces neuroinflammatory stress. And neuroinflammatory stress in what we call the pain matrix, that is the basis of nociplastic pain. So for me, PEA is very, very interesting analgesically because not only is it tackling two different types of pain, but it's doing so in a very safe way. The body knows how to handle it. It seems to have a very high therapeutic index.

 Adrian: I must admit, when I was preparing for our talk, I read a fair bit about PEA and some of the research being done. It's just fascinating, some of the work. And you mentioned that, what doesn't it do? And I even saw some research looking at, PEA levels and psychosis and bipolar disorder, and there's some differences in PEA levels there. And even in terms of supplementation, there was a couple of studies there whereby it improves some of the negative symptoms associated with those disorders.

Paul: Oh, absolutely. And then when you think about it, some of the clinical anxiety states, certainly some of the depressive states, they appear to have a neuroinflammatory component. And as PEA has the ability to reduce neuroinflammatory stress, I'm not surprised that it's manifesting clinically useful results in these types of conditions.

 Paul: The other thing that I like about this is that this is not always the case when you're working with nutrients. There's been some pretty good dose-ranging work. And if you look at the studies that have been done, the ones you've mentioned, and as you say there are large numbers of them, the dosing is fairly consistently between 10 or 30 milligrams of PEA per kilogram of body weight.

And that gives rise to clinical usage of anywhere between 300 and 1200 milligrams daily. But as I said, from everything that I've seen and my own personal experience, you can wrap that dosage up considerably if you find it useful without worrying that you're going to trigger the types of problems that we routinely see when we use pharmaceutical analgesics.

 Adrian: So with PEA though, you mentioned earlier that its absorption’s bioavailability is an issue. So there's different forms out there that increases absorption, is that correct?

Paul: Yeah, absolutely. This is actually not a very user-friendly molecule in the sense that if you simply look at raw PEA as it were, it's kind of waxy, almost a waxy substance. And bioavailability is very, very poor. And people have tried different ways of getting around this. You get micronised and you got ultra-micronised PEA, and that does give you some improvements.

Consistently, the best bioavailability that I've seen is Australian technology called Lipisperse. I think that was something that was originally developed for pharmaceuticals, but it's been dragged across to the supplemental sector. And there's one version of PEA, that uses this technology to get consistently good plasma levels.

Adrian: And so can you measure PEA levels in the blood? Like, if somebody thought, okay, should I supplement with PEA and can I do a blood test for PEA and see whether my levels are high or low, can you do that?

Paul: Adrian, whatever you do, if you're going to a forensic analytical lab, do not ask for a PEA test because you won't get the right one. As far as the labs go, PEA might stand for I think it's phenethylamine. And it's used as a biomarker for ADHD because phenethylamin is an excitory neurotransmitter, and that's not going to be helpful at all. And then the other thing that PEA stands for is phenylethyl alcohol agar, which is a marker for levels of Gram-positive bacteria in the blood. So, as I said, they're not going to measure what you want.

What we do know is that PEA is physiologically present in human blood, and probably all mammalian blood, frankly, at somewhere around 10 to 15 picomoles per mil. But these are all research-based findings. And frankly, I don't know of any commercial lab that offers a test, you'd have to find a research department that was working on the topic.

Adrian: It'd be interesting, obviously, like you mentioned that you'd have to say the full name and obviously you'd have to learn how to say it because the difficult bit with PEA is learning how to say palmitoylethanolamide. Is that right? Is that how I say it?

Paul: Well, I think once you've got that cracked, the rest of it's easy. Yeah, it's a mouthful.

 Adrian: But then the labs will look at you funny and going, what are you talking about? Because I do know that, certainly research, it was interesting with the bipolar studies that I saw, it was actually initially they were talking about the PEA levels being, and it's just like you mentioned earlier, PEA levels were actually raised in people with bipolar disorder initially, but then over time they had low levels as the disease progressed.

Paul: Well, I think what's happening is that if the psychological condition is being precipitated by neuroinflammatory stress, then PEA synthesis will initially be upregulated, and that's part of the body's attempt to deal with the initial problem. You'll then, at a certain point, going to run into what I call exhaustion and the levels will undoubtedly fall. Now, does that mean that there is a rationale for treating these conditions with PEA? I think that the clinical data suggests that there may be. I'm not convinced that there's enough clinical data yet to be able to state unequivocally that this is the way to go. But I think we're at that point where PEA is beginning to look like a potentially very useful treatment. I don't think I could honestly state it more strongly than that.

Adrian: I suppose it's like you mentioned earlier, obviously you could use PEA, and the research is really positive and it's showing some really positive findings with a whole range of conditions. But ultimately, it's about looking at the drivers of what's going on, what's the drivers of this inflammation, what's the drivers of the symptoms that people are experiencing and the changes in physiological function that people are experiencing. And that goes down to nutrition and lifestyle factors, and are they smoking and, and other environmental toxins that are going on. You could use it inappropriately, couldn't you, I suppose, just like a pharmaceutical medication.

 Paul: Well, you could, but Adrian, you're opening up a whole can of worms there. Because, clearly chronic inflammatory stress is a hugely important driver of many, many, many medical conditions. And then when you look at the epidemiology of all these conditions, as I said before, they all seem to be increasing and incurring earlier and earlier in life. And then what you have to do is to take a step back and look at what we call the food universe.

But let's sort of at least mention ultra-processed foods. So these are foods which have typically more than six ingredients. They've got ingredients with names like emulsifiers, stabilisers, refrigerants, and things like that, which you wouldn't find in a domestic kitchen. When you look at them, very often they've been extruded or molded, and you can't tell just by looking at them what's in them. It's just a rule of thumb, not a very good definition, but it's a working definition. And if you look at the consumption of these types of products in North America, depending on who you believe, people are consuming between 65% and 75% of all their calories in these types of foods. And Britain and Australia come in at number two and three respectively in the global league tables. They're not very far behind.

Now, the problem with these types of foods is if you look at them in the round, any one of them is not toxic in the acute sense, but if you eat large amounts of these foods for long periods of time, they will make you sick and they will kill you because they create, amongst other things, dysbiosis, and we can get into that if you want, but certainly chronic inflammatory stress, because some of the most important anti-inflammatory nutrients have almost been removed altogether. So I'm talking about the polyunsaturated Omega-3 fatty acids, polyphenols, your prebiotic fibres, your 1,3,/1,6 beta glucans, and most of the polyphenols. For different reasons.

So most of your key anti-inflammatory nutrients have gone, and they've been replaced for different reasons by a number of other compounds, which are highly pro-inflammatory. So lots of sugar, lots of vegetable oils, but also lots of advanced glycation and lipoylation end products. And these are actually produced during the production of these industrial foods during techniques such as spray drying, which use very hot temperatures. And then you get an accumulation of LPS in a lot of what we call pillar packs of fruits and vegetables. These are Gram-negative bugs that grow during refrigeration.

And so you are depriving the body of a lot of anti-inflammatory nutrients that have always been present in traditional diets, and you're replacing them with a bunch of compounds that are highly pro-inflammatory. And then it begins to make sense. Then you can look at the appalling global health statistics, and you think, well, yeah, of course. This is what Barry Popkin calls the nutrition transition, and in every country where we have left traditional diets behind and moved on to this kind of industrial kibble, there's been a huge, a tenfold increase in all of these chronic degenerative diseases and certainly chronic inflammatory stress, including neuroinflammatory stress is a very big part of that.

Now, PEA is one of the tools that I would very often use as an antidote to that. You are right, I wouldn't necessarily use it on its own, but it's a very, very useful tool which can be used in a pharmaceutical manner, i.e. as a standalone. I prefer to use it as part of a more broad-based antiinflammatory program.

 Adrian: That's the thing, obviously we need to really consider it from a holistic perspective, but I'm impressed by the PEA research and as a psychologist, I'm particularly interested in seeing the developments with regards to neurodegenerative diseases like Alzheimer's and dementia as more, I suppose as a preventative, and I see some merit in depression, and obviously that comorbid chronic pain mood conditions, which is often highly comorbid too, I think there's some real benefit there.

Paul: Absolutely. Absolutely. And that's been my personal experience. Although not intriguing my own chronic pain and depression, that's just part of a human condition, but dealing with patients. But in your profession, Adrian, I'm sure you've seen a great deal more of that sort of thing than I have.

 Adrian: Yeah. Now, you touched on earlier about...I'm curious about one of the papers you wrote talked about PEA with CBD and the, kind of, pros and cons of the two. So can you tell us a bit, is it potentially an alternative to CBD?

Paul: I think that's a reasonable way to look at it. CBD's a fairly hot topic and people are using it to treat all kinds of things. My response would be, yes, I think that the evidence is not as extensive as I would like, but I concede that the evidence that does exist indicates that CBD can be quite effective in treating a number of inflammatory conditions and a number of pain conditions. But the problem with this is CBD is not just the fact that there are gaps in the data, but its regulatory status. I think that's the main problem. And that's pretty uneven. It's regarded as being in very different legal frameworks in different countries, and that means that its future, I think at this point anyway, is rather uncertain. The FDA has come down quite strongly against CBD here in the North America in the last 18 months or so. And part of that probably is to do with the fact that we know where it comes from. There are problems to do with that.

Although medical marijuana has now become, again, a political hot topic in the United States and has been rolled out in many of the states. But PEA wasn't derived from cannabis, it's originally a food derivate, and therefore there's no question about its legality. It's been incorporated in medical foods in part of Europe. It's very widely available in a supplement. And there's no question, I don't think, of its current regulatory status being rescinded. So it'll do more or less anything that CBD can do. It seems to do it more consistently. There's more data, I would say, to support it on the efficacy side and really importantly on the safety side too. So, if I was formulating in this area, and I do a lot of formulating work,

I would probably go for PEA every time, simply because, from a regulatory perspective, it's not going to cause the same kinds of problems.

 Adrian: Yeah. I do like it. I think we're certainly going to start incorporating it in practice with clients and potentially see what impact it has. So, most of our listeners are practitioners, so from a dosage point of view, and should people just take in a supplement form? Should they just eat more egg yolks? How do people incorporate it?

Paul: Well, if you want to do it through food, no, I think that would be intense. How many eggs would you have to eat? I think probably between four and six eggs a day if I had to get a pharmacologically effective dose. Or at least the egg yolk, you don't have to eat the whites. I think some people would be concerned about the cholesterol. I wouldn't be, frankly, I don't think cholesterol is really an issue at all. But it's still a significant number of calories and some people are allergic to eggs, and some people just don't like them.

So I think there's a case, it's easier to supplement. If you supplement you know how much you're eating, how much you're actually taking in. With egg yolks, there's probably a certain amount of biological variability. It's non-standardised. Supplements are just easier. You can add them to whatever else you're going to eat. And you don't have that possibility of an allergic reaction, which allergy is one of the other problems. It has become so very common. And again, we can go back to the industrial diet, which absolutely encourages food allergy. So yeah, I prefer to supplement rather than go via food.

Adrian: Yeah, I agree. I think it's a far easier way. And so its dosage, what's the dosage people should be using?

Paul: Well, depending on the condition that you want to treat and it's severity, I think start off with, say, somewhere between 300 or 500 milligrams a day.

Adrian: Do you have that in divided doses?

Paul: Well, maybe. I have to say, Adrian, and I'm not completely convinced, it may be a single dose might work. Is it doing it BID going to give you a better effect? Maybe. But then again, it partly depends on which form you're using. If you are going to use Levagen, and we talked about that before, that's got this really good bioavailability, you are going to achieve pretty good plasma levels, probably functional plasma levels with a smaller dose. And at that point, you could divide it in two, go for BID, and get a better temporal coverage. You can titrate yourself. If 300 to 500 milligrams isn't going to do it, you could very happily and safely go up to 1200, 1500 milligrams. I personally would be comfortable taking 2000, 2,500 milligrams if I was going to use it for personal use, let's say to treat muscle sprain or strain because I do a certain amount of sports still.

As I said, the therapeutic index is very wide. And normally when we're recommending or taking analgesics, if we're using NSAIDs, we worry about peptic ulceration. Paracetamol, there's always a hepatotoxicity issue. Here in North America, we're drowning in opioids, which I don't recommend at all.

Adrian: So can you use it acutely, like if you've got a migraine or a sprain, or an injury and just have higher doses initially? Does it work that way?

Paul: Yeah, absolutely. Gencor did a really good study, in fact, looking at the headaches, and they found that you have a really bad headache, you can knock up a couple of Levagen capsules back and the headache will go away and rather more rapidly than it would do if you had been using one of the pharmaceutical analgesics. I really like the PEA, I find it very useful personally in dealing with customers and patients. And once again, it's the safety aspect. It gives you that security of knowing that whatever else is going on, you're not going to damage your patient in any way.

Adrian: Wow, okay. So you could use it acutely, you could also use it more chronically, and then obviously the dosages can vary from 150 milligrams to as high as 2000 milligrams. But ultimately, the studies have primarily been about that, for headaches and migraines and exercise. I think it's between that one 150 and 600 milligrams, is that pretty much what the clinical trials have been using?

Paul: Yeah, a bunch of the studies have. But as I'm saying, if you go back through all the trials that have been done, larger doses have been used at various times without any problems.

Adrian: And any contraindications when people are on medications, can they still take PEA with that?

Paul: Well, there's no evidence that I'm aware of which show up any of contraindications or interactions. There's no limits either on duration of use. Now, it may be that as PEA is more frequently used, as the volumes of PEA being consumed out there increase, we may eventually become aware of problems associated with some rare and unexpected type of interaction or some type of contraindication, but I'm not convinced. If you look at contraindications, as I said, it's an autocoid, this is something the body itself produces when it's been injured or stressed or strained. We are very good at breaking it down when its usefulness has been exceeded. This is not a xeno molecule that you're presenting to the body. It's a molecule that the body is extremely familiar with and very comfortable with.

So as I said, I'm not aware of any contraindications. And as far as interactions go, not with other analgesics, the mode of action is fairly robustly different. Nor am I aware of any contraindications with any other class of pharmaceuticals. Now, that's not to say that something at some point will not emerge, that may well happen and we'll be keeping an eye out for it.

Adrian: Yep. It's certainly got a high safety tolerance, so that's great. What about other...if somebody's experiencing a pain condition, whether it's a chronic back pain or migraines, are there other nutrients that you think would, kind of, complement PEA?

Paul: Oh, golly. Yeah. Where to start? If you're focusing on managing inflammation, and inflammation, of course, is a component of many different types of pain, I think you should consider the general class of polyphenols. I know the popular choices at the moment, a lot of people use the curcuminoids. Personally, I prefer the amphiphilic polyphenols that you get from olives and from marine algae, the phlorotannins. The reason why I like them is, first of all, the bioavailability of these is pretty good. But also they're stored in the body. They're stored in lipid components in the body. So not just adipose tissue but, for example, in cell membranes. The hydrophilic polyphenols are regarded by the body as foreign molecules. And so you tend to break them down fairly quickly and extract them from the body.

And it's a little bit complex because some of the breakdown products are probably active as well. And it's recently become pretty obvious that some of the polyphenols act on the body via the microbiota, the colonic microbiota. So they're not acting directly on physiological systems. So it's all a bit complicated. But the amphiphilic polyphenols are ones I particularly like.

But I think you should also consider the dysbiosis endotoxemia connection. So if you're dysbiotic, you're going to be endotoximic as well, which means a lot of inflammation in different parts of the body, particularly in the liver, the CV system, and the brain. And so I would certainly recommend the use of blended prebiotic fibres as well. Get your patient back to being eubiotic. And at that point, you are removing another very significant driver of pain.

 Adrian: Thank you very much. I think that certainly there's lots of great information that you've presented today, and I think the interest in PEA is going to increase even further. And the research is accumulating. And I must admit, I'm impressed. I'd certainly personally love to do some research in the area, particularly from a brain, kind of, point of view, and I was also impressed on one of the studies with regards to sleep. So it's a great area and great nutrients to really consider with patients, particularly from an inflammatory perspective.

So Paul, thank you very much today for our discussion. I could go forever talking to you. You're a wealth of knowledge, and every time I talk to you, I walk away thinking, wow, you know. So thank you very much for talking with us today. It's been an absolute pleasure talking to you.

Paul: Oh, likewise. Likewise, Adrian. And listen, if you get to the point where you're starting to think of doing a little study with this perhaps generally in the mental health area, I'd love to work with you together on that.

Adrian: Oh, that'd be brilliant. That sounds great. So hopefully we'll be in touch soon to discuss it.

Paul: Ah, terrific. Terrific.

Adrian: Thank you everyone for listening today. Don't forget that you can find all the show notes, transcripts, and other resources from today's episode on the fx Medicine website. I'm Dr. Adrian Lopresti, and thanks for joining us. We'll see you next time.


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