Chronic pain, allergies, inflammation and gut homeostasis: the game-changing potential of two emerging compounds .
In this episode naturopath Christine Lennon takes us through the latest research and therapeutic considerations for palmitoyl-ethanolamine PEA and its “sister compound” oleoylethanolamide (OEA).
Christine shares how PEA and OEA, though related, exert their therapeutic benefits quite differently but have the unique potential to work synergistically to produce an “entourage effect.” Christine also takes us through how practitioners might consider applying PEA and OEA for conditions beyond neuralgias and nerve pain, such as eosinophilic oesophagitis, allergies, endometriosis, multiple sclerosis and even regulating our appetite.
Covered in this episode
[00:47] Welcoming Christine Lennon
[01:18] What is palmitoyl-ethanolamine (PEA)?
[03:08] PEA’s sister compound: oleoylethanolamide (OEA)
[03:51] How PEA and OEA work in the body
[07:02] The entourage effect
[08:45] The role of PEA in mast cell degranulation and overactivation
[12:28] OEA’s effects on appetite
[18:50] Clinical trials of PEA in humans
[19:40] Using PEA to reduce pain and inflammation
[23:36] PEA and multiple sclerosis
[24:32] The safety and pharmacokinetics of PEA
[27:29] Guidelines for dosing
[29:22] Additional resources
[30:44] Closing remarks
Andrew: This is FX Medicine. I'm Andrew Whitfield-Cook. Joining us on the line today is Christine Lennon, who graduated from Endeavour College of Natural Medicine with a Bachelor of Health Science in Naturopathy. Christine's passion in commercial product development lies in analysing new ingredients and formulations and assessing their therapeutic value for patients.
And today we'll be discussing palmitoyl-ethanolamine (PEA). Welcome to FX Medicine, Christine. How are you?
Christine: I'm great, thank you. How are you?
Christine: So, PEA is an endogenous fatty acid amide, or a fatty acid mediator. So, we have things like endocannabinoids, phytocannabinoids, and then the kind of left-of-field, adjacent cannabinoid family called the N-acetylethanolamines. It's a group of compounds that we endogenously make and PEA is one of them.
So, for a long time, people thought that PEA was one of the endocannabinoids, but it's actually not. It turns out that it doesn't actually have a direct action on any of the cannabinoid receptors but more of an indirect action, and that's why it was mistakenly thought of as an endocannabinoid for such a long time.
Andrew: Got you. So, where did the research on PEA begin? Like, was it in eicosanoids, or how do they twig to this compound?
Christine: So, a long time ago, there was a bunch of research done in animals, and they were actually giving animals egg yolk powder as a treatment, and realised that, for some reason, these animals experienced significantly less pain than the placebo counterpart. That's how they discovered PEA, because egg yolks are actually quite high in PEA.
Christine: Now, that kind of turned into a much bigger area of research, but it all started from giving some animals just egg yolk.
Andrew: And for what conditions?
Christine: So, now, PEA is heavily researched for neuralgias and nerve pain.
Christine: Yes. OEA, so oleoylethanolamide. It's really chemically quite similar to PEA. They're in the same fatty acid family. They seem to have a lot of the same actions in the body, so they use a lot of the same receptor sites. But they have vastly different outcomes in the body, which I think is really interesting. The way that we look at chemicals and compounds a lot now is that it has an action of this receptor and therefore has this outcome. But these two are kind of sisters or cousins within their family, but end up having really different outcomes.
Andrew: So, still working on… We’re going to talk about this a little bit later, about the endocannabinoid system, but are they still working on, or around the endocannabinoid system? Both of those compounds?
Christine: So it's more around. So they don't directly have any impact on CB1 or CB2, but what has been found is that… So PEA in the body can actually be synthesised from anandamide, which is one of our endocannabinoids. And there seems to be the reverse as well. So the giving of exogenous PEA can also increase anandamide's activity and also its affinity for its receptor sites as well. So, in that indirect way, giving exogenous PEA can actually increase the use of anandamide in the body.
Andrew: Okay. What about when you're talking about receptors, can you downregulate receptors i.e. if you give a big whack of PEA or OEA, can that have an effect of downregulating the downstream receptors so that you end up with the same problem, of pain for instance?
Christine: Not that we've seen. So, from all the research that's being done, these are pro-resolving or prohomeostatic compounds. So, the way that they're used in the body and the way that they're endogenously produced, the reason that they are is to be a kind of negative feedback. So it's turning off those things that were turned up.
It's kind of a different viewpoint, so when we look at a chemical and we say, "Okay, well, this much of it has this action," but for PEA and OEA, they really are a pro-resolvent, so they're resolving what's been happening in the body and turning it off, as opposed to necessarily ending up taking too much of it and ramping something up.
Andrew: When we're talking about these pro-resolving compounds, there's these SPMs, these specialised pro-resolving mediators. And just looking briefly at the research and I'm not an expert in it, it seems to me that there was this ratio that appeared to be more beneficial than others. Do we have this sort of issue with PEA and OEA, that we need a balance, if you like?
Christine: PEA and OEA, they work in different areas of the body. So, OEA, we see a lot of it in the intestinal mucosa and, PEA, more so systemically and also in the central nervous system. So, when we talk about, say, an important ratio for these two, it can be kind of hard to determine what's important. It really comes down to that individual person's needs and where their body is struggling.
So, some people might lean more towards the systemic inflammation, so we're looking at the nerve pain but also arthritic pains, things like that. Other people might actually have more gastrointestinal inflammation, and that's where their original issue lies and that's where you would, as a practitioner, you would amend that ratio and work through that treatment as per the patient.
Andrew: Got you. I understand also there might be, similar to what's seen in cannabis, there might be an entourage effect with PEA and OEA. And I think it involves the TRPV1 receptor.
Christine: Yeah. So that's one of the receptors that they both work on.
Christine: It is a little bit of an interesting receptor, the TRPV1.
Christine: So it's often called the “capsaicin receptor” because that's the receptor that's involved in your sensation of having chilli, or capsaicin, so it's the role of heat and pain, which is kind of how we describe inflammation in general. And it's either you're sensitive to it, or you're desensitised from it. So, agonism is desensitising TRPV1 which means that you're less sensitive to the sensation of heat and pain.
Now, both PEA and OEA work on this receptor. So, PEA, it's kind of obvious where you’ve got nerve pain and you can feel heat. It's where that PEA will be really, really effective with this receptor.
Andrew: Like post-hepatic neuralgia.
Christine: Yes, kind of like that. Yeah. And then OEA, where that entourage effect comes in, is that it's interacting with this receptor in the gut, but then that has an impact on that receptor systemically as well, because it's all connected and all of these receptors all kind of join and talk to each other. So that's when we're talking about an entourage effect where OEA is interacting with it in one area, but then it has an impact in another.
Andrew: Is there a link between PEA, OEA, the TRPV1 receptors, and a recalcitrant pigheaded disorder called eosinophilic oesophagitis. It is so finicky, where seemingly innocuous foods trigger them and seemingly bad foods don't have any effect at all, but it causes horrible symptoms in children. Is there any sort of link or potential use here of PEA?
Christine: So, I think PEA could have a use here, and not so much for maybe its role in TRPV1, although that might be really heavily relevant for PEA, but more so for its role in mast cell degranulation.
So, one of its main roles is that PEA inhibits mast cell migration, degranulation, and overactivation, and this includes astrocytes and glial cells as well when we're talking about the central nervous system. So, what happens normally in the body is that a glial cell or a mast cell will actually release histamine in order to tell the body, "I want inflammation here and I want it now." But, at the same time, it also releases PEA for the negative feedback in order to turn down the inflammatory response once it started as well. Because we need those systems in place so that we're not just in inflammation all the time or we're not just being triggered all the time to have a histamine release.
Christine: So my thoughts on eosinophils...obviously mast cells and eosinophils are very closely linked, and we're talking about histamine release and that allergic kind of response.
Andrew: So there, I'm wondering about mast cell activation syndrome.
Christine: Yeah, exactly. When we've got overactivation and that's what PEA is there to inhibit. It's there to stop the overactivation. And when we look at highly inflammatory conditions or nerve pain conditions, they almost consistently have an overactivation and overproliferation of glial cells and mast cells.
Andrew: That's really interesting.
Christine: Yeah, it's really interesting. And that's where PEA can help because it is that pro-resolver and it's correcting things when the body's gone a little bit off the road that it's meant to be on. It hasn't been able to correct itself. So therefore, we can introduce something like PEA to help the body get back to a place of homeostasis.
Andrew: I know that there's a milieu of effects that happen with things like allergies. There are so many chemicals being released there. But, could PEA have…or, how about this? Is there any research on PEA or OEA being used to dampen allergic responses, whether that be food like in the gut with OEA or whether that be, say, inhaled with seasonal rhinitis or perennial rhinitis, or something like that?
Christine: So I haven't seen that kind of research pop up yet for PEA. A lot of the research has really been cornered into neuropathies and those really quite intense neuralgias. So that's where I've seen most of the research.
There has started to be additional research in more areas where it is more immune, inflammatory-related. So you've got things like endometriosis and primary dysmenorrhea, which you wouldn't really consider a neuropathy but PEA is still really effective in those areas.
And then, when you look at, say, OEA… So OEA has predominantly been studied in obesity, but the main action that it has is about dietary intake and about dietary eating behaviours as well. It's all to do with how our brain regulates our appetite.
And I think that OEA is really, really interesting because some of the neural research that's come out is that it's regulating the abundance of certain bacteria in your gastrointestinal system, which is in line with what research considers to be a “lean phenotype” or even a healthy phenotype for bacteria.
So, when we look at things like allergy in its holistic context, all of those things come into play. So you've got what kind of bacteria you have, what your intestinal mucus is like, and also what your immune system is doing. And OEA and PEA are two pro-resolving compounds in both of these areas that can contribute to a homeostasis.
Andrew: You know, I wonder if these sorts of compounds might have some stabilising effect, anti-inflammatory effect on the blocking of leptin receptors.
Christine: It's really interesting. I think the link to appetite for OEA is particularly interesting. I think this has come up a lot more in research around leptin and ghrelin is usually where we talk about appetite.
Christine: It’s always leptin and ghrelin. So, the link for OEA and appetite I think is a really, really interesting area. When we talk about appetite, we usually always talk about leptin and ghrelin which are really important for appetite. But OEA works a little bit differently.
So, OEA is the least in the intestinal mucosa, and what it does is it's called “prolonging the intermeal interval,” which means it delays meal initiation. So things like leptin and ghrelin are more to do with a response to eating, so it's knowing when you're full and knowing when you're hungry. But then OEA actually prolongs the period in between, so it's making sure that your body knows that it has enough energy and is satiated in that entire period in between eating. And it actually extends that period as well.
So it's kind of a different way to look at appetite, and I think it's really, really interesting as well.
Andrew: Is this work touching on things like PYY, alpha-melanocyte-stimulating hormone, those sort of chemicals, or are we just talking about the end effect of, for instance, aiding intermittent fasting or something like that?
Christine: So, the way that OEA works with appetite I think is really interesting and it's not really the way that we’ve looked at it before. OEA works with PPAR-alpha so it's peroxisome proliferator-activated receptor-alpha. So the way that this works, OEA has a really, really high affinity as an agonist for this receptor. And the effect of OEA, so the outcome of it, is that it reduces food intake overall and decreases body weight. But this doesn't happen in mice that don't have PPAR-alpha, so it can't happen for some reason.
PPAR-alpha null mice are actually hyperphagic, so they end up eating a lot. Even though they still have their ghrelin, their leptin, their CCK, PYY, all of that's still functioning but PPAR-alpha is not functioning. For some reason, they can't control their appetite.
Christine: And that's what OEA does. It's regulating your appetite in conjunction with PPAR-alpha.
Andrew: In these knockout mice?
Christine: Yeah. So, it's an interesting thing because I would not have thought that would have worked at all, because you've got things like leptin and ghrelin in place. But really it seems as though appetite is probably a lot more complicated than we first realised. Also, there's so many compounds involved in making sure that you are eating the right amount of energy that you need and also that you get hungry and not hungry at the right times.
Christine: One of the other things that OEA does is actually it activates vagal afferent nerve fibre as well. So, that is even a bigger picture of what OEA does. It's looking at that holistic gastrointestinal homeostasis.
Andrew: Okay, so that's OEA and PPAR-alpha. That's gut-based, if you like, there’s a whole systemic network that goes into not just appetite control. So, does PEA have any neuronal effects with PPAR-alpha?
Christine: Yes. So, PEA is a PPAR-alpha receptor agonist as well. The theory is that PEA binds to PPAR-alpha and then they translocate into the nucleus. And then it engages in what's called “transcriptional regression" of genes coding for key pro-inflammatory proteins, so that's the TNF-alphas, COX-2, iNOS or inducible nitric oxide synthase, and NF-kappa B.
Andrew: So those are your inflammatory drivers of appetite dysregulation.
Christine: Yes, exactly. And so I think what's really interesting is that PEA and OEA are kind of doing the same thing but the outcome is different. So PEA in the research, it all indicates things like reducing that pain, reducing inflammation really systemically, and then OEA doing the same thing but the outcome is more to do with your energy, homeostasis, your appetite regulation, and reducing inflammation but specifically in the gastrointestinal system.
Christine: So there's been a bunch of clinical trials for PEA. So that's things like sciatica, post-hepatic neuralgia, diabetic neuropathies, multiple sclerosis, chemotherapy-induced neuralgia, trigeminal neuralgia which...trigeminal neuralgia is one of those conditions that's really, really debilitating and really difficult to treat as well. So that's where PEA has been shown to be really quite effective at treating all different types of neuralgias, but I think trigeminal neuralgia is one of those areas that could really be managed a lot better than it is being now.
Andrew: Can we just go back to pathology a little bit? When we're talking about sharp, burning pain, am I correct or incorrect thinking that that's your A fibres, and then you've got your C fibres, the more chronic, dull lower back pain type thing. What's the interplay there? Where does PEA work? On both, or...?
Christine: Well, theoretically it's on both because we're turning down that mast cell activation, and we're turning down those main inflammatory mediators, and we're turning down the sensation of pain overall. So it really can be both. And that's where we say things like, say, endometriosis. Endometriosis isn't really that sharp, nervy pain, but PEA is still a really effective treatment for endometriosis pain.
Andrew: Right, right.
Christine: So it's looking at pain overall.
Andrew: So, because we're dampening down, we're sort of turning down the volume control on pain, I'm wondering about its utilisation in, I mean this is another pigheaded disease: complex regional pain syndrome.
Andrew: Has there been any research in this area especially in humans?
Christine: I haven't seen it specifically there, but looking at all the trials that are being done on PEA, it really is quite a vast range of different types of pain. And if we break down pain and inflammation into its main components, the issue that we see consistently in all diseases of pain is that the body doesn't have the ability to turn it off.
Christine: The body doesn’t have the ability to reduce the inflammation and to stop that process. And that's where PEA comes in and it is a mediator to say, "Okay, we've had enough. The job is over."
Christine: And that's where medications don't always have the same impact that way. They're not necessarily pro-resolving compounds but they have an action in a really specific area.
Andrew: I can see the facility in combining PEA with...let's say if somebody had chronic back pain, CRPS, then the use of your antidepressants, the use of your opioids, that sort of thing, even anti-inflammatories, COX-2 inhibitors, all of these drugs, if they can have the short-term effect of relieving your pain now, and then if you can have something that can manage the resolving of that signal, then that would be a good thing for reducing the long-term requirement for these other medications.
Christine: Absolutely. And we've seen that in the research as well. So, some of these clinical trials have been done in combination with things like oxycodone and tramadol and pregabalin as well, because that's really standard medications that these patients are on.
So, what we've seen in the literature is that they'll be given PEA alongside their standard medication and over time they actually will reduce their opioid use because they don't need it anymore.
Christine: Yeah, well with the doctor as well. Because they don't need the level that it's at, so the dose reduces slowly until eventually they don't actually need the opioid anymore.
Andrew: They're seeing voluntarily reduction of opioid use.
Christine: Yes, because if the pain medication just wasn't needed. The pain was being managed using the PEA. And so, in the trials, they would slowly...and in the case studies, they would slowly reduce their opioid use.
Christine: So there are trials of using PEA in multiple sclerosis.
Christine: Now, PEA isn't going to cure multiple sclerosis by any means but it's an effective way to manage the pain and the nerve pain and the nerve damage. Because if you think about the way that glial cells and astrocytes work in the central nervous system is that, when there are a lot of them and they're highly proliferative and they're degranulating all the time, they cause damage.
So you need that stimulus there to be able to tell it to stop as well. And the more pain you're in, the more prolonged that nerve pain goes on as well, the more glial cells there are, the more that they are proliferating. It's an out-of-control system, which is where PEA can come in and resolve all of that.
Andrew: These trials I would imagine that being a newer compound, I mean I know that you said that early research was back in 1950s, but being a newer compound certainly for Australian practitioners, do we have any long-term benefits, toxicities, concerns, adverse effects, anything?
Christine: Not that we've seen yet. It's not considered an addictive substance. It hasn't had any side effects that we've seen, even with medications. And one of the main reasons it doesn't interact with medications is because it doesn't have to pass through the liver. So it doesn't have any CYP interaction. It's considered to be quite safe with medications as well. As of yet, there hasn't really been any side effects that have come out of the clinical trials.
Andrew: Right, okay. So let’s talk about oral administration then of PEA and OEA. OEA is fine. They're going to get it to the gut because that's where it works. PEA, how is it absorbed?
Christine: This is an interesting one. Obviously, we endogenously make PEA and it's there at the site when you need it. But for PEA to get from an exogenous source into our main bloodstream, we need it to be in an effective form.
So the way PEA is made is that they take palmitic acid and then they synthesise it into PEA, which is the same way that happens in the body as well. We start with palmitic acid and we turn it into PEA.
Now, in the form that it is outside the body, it's highly crystalline, which means it's kind of in these big crystally chunks. And what that means is that it has really, really low dissolution, so you're not really able to absorb it. You can take a lot of it but it won't actually get absorbed into the bloodstream.
In order to mitigate that, PEA needs to be micronised ,which means that it needs to be kind of chopped up into much smaller particle size in order for it to be absorbed.
Andrew: Do we have a mesh size that's optimal at all?
Christine: Native PEA is about 100 to 700 micrometres and so you need it to be kind of around less than 25 micrometres.
Andrew: Right. And what about first-pass metabolism? You say that it doesn't interact with the CYP enzymes, but certainly it's going to go into the enteral circulation. What happens there with digestion and assimilation?
Christine: The type of compound that PEA is, is that it just goes into the bloodstream. It doesn't actually need to have any interaction or activation by any of our enzymes. So don't actually come into contact with any of our enzymes. That's the beauty of it as well, is that it's a fatty acid that can be absorbed but also doesn't actually need to have any interaction with any liver enzymes in order for it to be in its active form.
Andrew: Now we've covered a vast array of conditions from seemingly remedial to extremely recalcitrant. How do you monitor dosing? Is there any guidelines that we can stick to here, or a dosing range that we can use?
Christine: Overall for the PEA studies, what has kind of come out of them is that you need a loading dose.
Christine: So you need to be dosing at around 1,200 milligrams a day up to 1,800 milligrams a day for the first week to three weeks in order for it to have a high enough amount in the system in order for it to really start reducing that inflammation. And then, after that, we drop it down to 600 milligrams a day.
So the way that it's been dosed in clinical trials is in lots of 300 milligrams, so it's either 300, 600, 900, or 1,200 a day. From all of the evidence, always start with the loading dose at 1,200 milligrams a day and drop that down to 600. And then depending on their condition and the patient, you can slowly ease them off the PEA as well, if their inflammation has been resolved.
Andrew: Now, at the moment in Australia, we have PEA available to practitioners. OEA is a different kettle of fish.
Christine: Yes. It's not currently available but there are clinical trials that give OEA. So it does exist but there needs to be quite a bit more research. It doesn't have the same level of clinical trials that PEA has. PEA has quite a big breadth of research.
So, as more research comes out, we'll have more defined dosing instructions and more defined uses for OEA. But it is a really interesting one to look out for though, because it does have some really interesting actions for overall homeostasis.
Christine: So, OEA I think there's been a couple of literature reviews which really got me into quite a lot of depth around their mechanism of action that we can share. There's also one other that I thought is a really good read. So there was a clinical trial using OEA exogenously where it increased the abundance of Akkermansia in people with obesity.
Andrew: Oh really?
Christine: I think I might share that one. I think it's a really good read.
Andrew: Yeah, absolutely. We'll put this up on the FX Medicine website for everybody to learn from and to find out how they can best use these for their patients. I mean this is quite remarkable stuff.
I do, however, sort of put the caveat in there that I don't think this is a direct swap from cannabis. I think cannabis is cannabis and this is PEA. I don't think we're going to have the same actions, do you?
Christine: No, I agree. I think that PEA and cannabis would more likely be a really good synergistic pair than they are to one or the other, because CBD has a really direct action on the CD1, CD2 receptors and then PEA is more of the indirect action. It's more like a really good pair to go together in order to achieve a really good therapeutic outcome.
Andrew: Christine, thank you so much for taking us through. This is really exciting stuff. I can just see, in my mind, I'm going through so many conditions where there's a potential of this stuff to work.
Now, whether it does work or not remains to be seen and we need to follow the science, follow the literature on this, but we'll put as much literature as we can up on the FX Medicine website for everybody to learn from.
Christine: Great. Thank you so much.
Andrew: Thank you so much for taking us through today. This is FX Medicine. I'm Andrew Whitfield-Cook.