Dr. Journal Club
Dr. Journal Club
N-Acetylcysteine for Endometriosis: An Integrative Medicine Review
Ever wondered if a common supplement could help with endometriosis pain? In our latest episode, we dive into a listener-requested discussion on N-acetylcysteine (NAC). We explore NAC's potential to manage endometriosis-related pain, reduce endometrioma size, and improve fertility.
https://pubmed.ncbi.nlm.nih.gov/36981595/
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Welcome to the Dr Journal Club podcast, the show that goes under the hood of evidence-based integrative medicine. We review recent research articles, interview evidence-based medicine thought leaders and discuss the challenges and opportunities of integrating evidence-based and integrative medicine. Continue your learning after the show at www. d rjournalclub. com.
Dr. Joshua Goldenberg:Please bear in mind that this is for educational and entertainment purposes, only. Talk to your doctor before making any medical decisions, changes etc. Everything we're talking about that's to teach you guys stuff and have fun. We are not your doctors. Also, we would love to answer your specific questions on drjournalclub. com. You can post questions and comments for specific videos, but go ahead and email us directly at josh at drjournalclub. com. That's josh at drjournalclub. com. Send us your listener questions and we will discuss it on our pod.
Dr. Joshua Goldenberg:Hello and welcome to another Dr Journal Club podcast with your host, Josh and Adam. We are back from. I think. We did a little bit of a hiatus for July 4th weekend and the amazing Michele, I think, sent us one of our super speedy summary videos. So we are back in the saddle again. I'm going to talk about NAC, n-a-c, known to his friends as NAC, I guess. Anyway, Adam, how you doing man? What's the latest? I haven't spoken to you in a little bit.
Dr. Adam Sadowski:I'm doing great. Uh, I was in uh Portland, Maine, for Fourth of July. Yeah, oh, very nice, yep yep, yep, awesome.
Dr. Joshua Goldenberg:Was there for a little bit, did some fun stuff there and then, on the way back, visited. Portland, maine, for 4th of July.
Dr. Adam Sadowski:Oh very nice. Yep, yep, yep, yep, awesome. Was there for a little bit, did some fun stuff there. Then, on the way back, visited some family in New Hampshire.
Dr. Joshua Goldenberg:Very cool.
Dr. Adam Sadowski:And then, yeah, it was a nice little getaway. How was your 4th?
Dr. Joshua Goldenberg:Next time you're up in that part of Maine you're going to have to hang out with Jacob Shore et al. Do you know him? No, oh, okay, I for some reason I thought you guys were, you were buddies, but I just uh. Mark Davis, friend of the pod, was just up in Maine too and of course had to do uh required kayaking with said doctor. He's a huge kayaker and they moved to Maine recently and tried desperately to get us to move to Maine because my mom lives there and we were thinking about Portland during the pandemic. But it was just like I remember them sending me like houses and it was like $800,000 for like an abode and it was just a pandemic. Even in Maine it was just like pandemic times. Prices were insane and they're like but think of the kayaking. Anyway, okay, so I digress, let's, let's jump in.
Dr. Joshua Goldenberg:So we have a, we have a request from a listener, a dear listener, for this paper. So that's the selection and sometimes we pick stuff out. Oftentimes you'll find stuff that's being talked about in some of the bigger journals or we'll get sort of tips from folks that on papers that have made it out to the main media, etc. This is sometimes we get requests from listeners, and sometimes from doctors and sometimes from non doctors, for just questions about papers that they've come across. And it's good because I feel like folks that don't have the medical background. You look at a paper and you're like, oh, this, this looks interesting, looks legit, and you know, understandably they don't have the training to kind of take it apart. So that's one of the services I feel like we offer is, while we're geared to you know, doctors, I think we're also kind of geared to the educated and informed you know person at this at the same point, and I feel that way about my patients in general. So cool, so let's jump in any starting questions about this.
Dr. Joshua Goldenberg:So this is we'll put the link in the show notes and I'm actually going to write down link in large letters and send it to Michele, because I always say I'm going to send to Michele and then I never send it to Michelle. So this time is on a post it note, so it's going to happen. So this is about NAC for endometriosis-related pain and endometriomas as well as fertility outcomes. I do not do anything with endometriosis, I know very little about it, and I've used NAC and acetylcysteine when I was in primary practice, mostly for like mucolytic effects, like when people had colds and stuff. So that was sort of like the extent of my background knowledge. So clinically I'm kind of a neophyte here. How about you? Have you used NAC a lot? Have you played with it? Do you see a lot of endometriosis?
Dr. Adam Sadowski:Yeah, so I am familiar with endometriosis. It comes up quite a bit in the primary care setting. I'm familiar with it in that, in that regards. With regards to NAC, my experience has mostly been around addiction, medicine with it and mental health related things. Oh yeah, there's some interesting research there.
Dr. Joshua Goldenberg:Interesting, oh okay. Well, there's a chock full of stuff that potentially used for I feel like there might even be oncology outcomes for it.
Dr. Adam Sadowski:I could be wrong about that, but it's also a precursor to a more well-known antioxidant known as glutathione, and so that's kind of like. The mechanism of action behind NAC is that it's a precursor to glutathione, and so NAC is oftentimes used for things with any sort of like inflammatory conditions. It has some you know reported benefits with regards to liver health, and so it's used for that. This is not yeah, not medical advice. By the way. Yeah, none of this is not yeah, not medical advice by the way.
Dr. Joshua Goldenberg:Yeah, none of this is we don't know what we're talking about. Don't listen to us. Talk to your doctors. We're just evidence experts. We'll just, we'll break apart the study, but talk to your own doctors, guys. Um, so that's it. Yeah, I have seen it actually in a lot of protocols for liver stuff and the glutathione connection makes sense. My understanding is glutathione is like apparently magic, but it's very hard to get bioavailable and so like you try to push it in other ways. Is that kind of the rationale behind? Yeah, yeah, yeah, and it's uh, what, what cup is that? Just just keep going, okay all right.
Dr. Joshua Goldenberg:All right, I got distracted, squirrel, okay, anyway. So yeah, so it's basically a cheaper, bioavailable way of pushing. Glutathione and anti-inflammatory actions is one proposed mechanism of action and of course everything's connected to inflammation, so pain and endometriosis makes sense as well. So I want to say, because this was recommended from someone who doesn't have a background in in medical science, I want to kind of give my red flag thoughts as I read through it to kind of help the reader that doesn't have a lot of training in this understand. You know what are some things that we look at, that kind of like our ears jump up and be like what, and I don't know about you.
Dr. Joshua Goldenberg:But the first one that I saw was like three sentences in in the abstract, which was the primary objective of this prospective single cohort study was to confirm the effectiveness of NAC in reducing endometriosis related pain and the size of ovarian endometriomas. So just that statement that the purpose of this study is going to confirm the effectiveness, all my bells and whistles went off. Like that is a very strong statement. My first thought was oh my goodness, they must have in science anyway. It's a very strong statement. They must have conflicts of interest and they must own all the NAC production in the world.
Dr. Joshua Goldenberg:I couldn't find any evidence of that, but that kind of language is a red flag in and of itself. And then to say that based upon a cohort without a control, so we use randomized control trials to understand efficacy and effectiveness right, and this idea of looking at a single cohort where you don't have any control and that's going to confirm the effectiveness and it's like our objective. It doesn't matter what the results are, it's not to see what happens, our objective is to confirm this effectiveness. So that was, at least for me. That was my first kind of red flag, just like three sentences in. How did that get caught in your craw craw at all, or did you, uh, anything else that you wanted to touch in on on that?
Dr. Adam Sadowski:yeah, uh, there was. There was one um, the, the confirmatory component to it, um, but I also recognize that these. This was coming out of italy, so there may have been some translation issues.
Dr. Joshua Goldenberg:Uh, with regards to that, oh, you're always kinder with that. You always bring that with that. You always bring that up. That's a fair point. Maybe it's a translation thing.
Dr. Adam Sadowski:There's that. But then also, you know, if you're going to be publishing in an English written journal like you, better have someone who's very fluent in the English lexicon where you know things like these kind of language nuances are not going to be present. Yeah, so there's. You know, there these kind of language nuances are not going to be present. Yeah, so there's. You know there's kind of like that onus on the authors or pay a lot of money for someone to to provide a very accurate um translation. So that's one thing. Two is in in medical research we're very, you know, I would say, almost never proving something. It's. It's really about disproving something.
Dr. Joshua Goldenberg:So right, or suggesting it's like the strongest word we'll use yeah, and so it's like it's not so much.
Dr. Adam Sadowski:You know, when you're testing a hypothesis, it's really about like, do we kind of, do we reject this hypothesis or not? It's not so much a confirmation. Very few things in in science are like factual. Um, I guess, if you will, now, there's certain things that that are factual. However, when it comes to research, especially early research and stuff where there's really not a lot of evidence to say you're confirming something, you better have the perfect study. Yeah.
Dr. Joshua Goldenberg:Well, and studies like meta-analysis of 20 studies over 20,000 people over 20 years, Right.
Dr. Adam Sadowski:But yeah, I like your idea and also they mentioned it was a cohort, but an intervention was administered, which was really weird.
Dr. Joshua Goldenberg:Yeah.
Dr. Adam Sadowski:Because with cohort studies you're really just looking at an exposure You're not necessarily administering something and you're just trying to see is there an association to some sort of exposure?
Dr. Joshua Goldenberg:Yeah, Okay, so my between the lines here. So this is really good, because you can see how there's a lot of nuance here and we're reading between the lines a lot, and this is this is, uh, knowledge that you know would not be, you know, if you don't, if you're not like read this stuff all day long, um, so one is, everything you said is correct, and my suspicion is they might have gotten pushback from the reviewers saying that it was an intervention study, when you know there was no actual control group and so they had, they were forced to call it a cohort, and so it does sound weird. The other thing is, I think it's all from one clinic and it might have been their clinic, and so maybe what they had planned to do, which is that they have like a protocol, which is that everyone that comes to our clinic, the first thing they do is get NAC at this dose, and then we're just going to kind of measure that. But yeah, I would be curious. I think they did mention that they went through IRB, I believe I'm sure they had to to get published, and that would have been, you know, that would have been interesting, right, it's like you would need permission to give an intervention versus just like observational in nature. So, yeah, that's a really good point too. It sounded very much like an intervention.
Dr. Joshua Goldenberg:The results sounded the way they presented. The results sounded like an intervention. But it's a cohort study and they don't have any control. So, yeah, lots of so a few red flags there, but I like your idea, and one of the things we like to do on our podcast although we do rag on stuff is to steel man as much as possible. So to steel man. These authors maybe it was just a language issue that this sort of nuance got lost or they were kind of overly enthusiastic about NAC for non-financial reasons. I didn't see any financial connection there. So, okay, well, let's jump in. I'm ready to go into methods and materials. How about you?
Dr. Adam Sadowski:Yeah well, they also did use some background data saying that research from their lab has shown that in animal and human tissues that NAC has been able to reduce the size of endometrial tissue. So that kind of set the stage for then this study. And they said the objective of this prospective observational single cohort study was to confirm the effectiveness of NAC in reducing endometriosis-related pain, in the size of endometriomas.
Dr. Joshua Goldenberg:Yeah, so that's fair, so you know. So basically it sounds like they've done some benchtop and animal research and they've seen these effects and so in that context they wanted to confirm those effects in humans and to do a cohort study would be a reasonable first step compared to a trial. So if they're using confirm in that way, I think that would probably be the best way to steel man that. But yeah, I mean, most editors, I feel like in most respectable journals, would be like all over this with red lines like you can't say this sort of stuff, but anyway, okay. So, yeah, so they did do this background and, yep, like we said, they recruited everybody from one hospital. So anyone that was referred to endometriosis outpatient service of this hospital were enrolled. So it seems like my suspicion is that these are folks from that section and from that department and they were looking to see, you know, objective and subjective response to this NAC approach. I guess the dosing was interesting.
Dr. Adam Sadowski:Well, before we get into that, yeah before we get into that, they did go through an ethics committee. So from an IRB standpoint, like you were saying earlier, they did do that.
Dr. Joshua Goldenberg:Good.
Dr. Adam Sadowski:It was individuals between 18 to 45 years old with clinical surgical histological diagnosis of endometriosis. They were excluded if they were not having any sort of menses or if they were menopausal.
Dr. Joshua Goldenberg:Right.
Dr. Adam Sadowski:They had any sort of known adverse reactions to NAC, which makes sense if they were currently receiving any sort of hormonal treatment, because that is used in the treatment of endometriosis, if they had any cancer or ongoing pregnancy. And then if they were using any sort of NSAIDs. And there's a couple of reasons there. One is because they were looking at endometriosis-related pain and so if they're on NSAIDs like ibuprofen, that would interfere with pain results as well as if we're thinking about anti-inflammatory responses, then that would interfere if they were looking at any sort of inflammatory mediators.
Dr. Joshua Goldenberg:That's a tough one.
Dr. Joshua Goldenberg:I'm going to study now looking at how we measure pain when, like, if you have an intervention for pain and you normally allow people quote-unquote rescue medication like NSAIDs, you know if they're, if they have breakthrough pain.
Dr. Joshua Goldenberg:And it's a major issue methodologically in how you measure outcomes, because of course, if you take an aspirin, you you're going to feel better, and if your drug isn't working, if the drug you're testing is not working, you're going to take more aspirin and then maybe you're going to feel better. So now the people that are taking the drug are reporting better outcomes, but maybe it's just it works less and you're taking the NSAIDs. So it's quite complicated and so it makes sense that they would exclude them or at least have some limitations on the use of rescue medications. But then I think later and maybe I hallucinated this because I did kind of read this in context of severe lack of sleep that they mentioned that there was a decrease in NSAID use in people over time, but I thought it was an exclusion criteria. So I'm not sure, maybe I just misread that. We'll have to look again when we got there.
Dr. Adam Sadowski:Well, let's get there when we get there.
Dr. Joshua Goldenberg:Yeah.
Dr. Adam Sadowski:From a treatment standpoint. It was very oddly worded because this was a three-month study and they said quarterly. Therapy with 600 milligrams of NAC as three tablets a day for three consecutive days of the week was then administered for three months, and so that doesn't make sense, because a quarter of a year is three months.
Dr. Joshua Goldenberg:Right.
Dr. Adam Sadowski:But they're getting quarterly therapy for three months and so that doesn't make sense. And then so the way I read it was they received three tablets a day for three days straight, and then that was the intervention. Yeah, like, and it wasn't repeated. So it would be like monday, tuesday, wednesday, between, let's say, between january and march, you were being studied. Yeah, then I read that as like january 1st, january 2nd and january 3rd, you got three tablets of 600 milligrams nac every single day for three days, so a total dose of like 1800 milligrams on a Monday, 1800 milligrams the next day, 1800 milligrams the next day, and then that was the intervention.
Dr. Joshua Goldenberg:Look, the thing is we don't do this for money. This is pro bono and, quite honestly, the mothership kind of ekes it out every month or so, right, so we do this because we care about this, we think it's important, we think that integrating evidence-based medicine and integrative medicine is essential and there just aren't other resources out there the moment. We find something that does it better, we'll probably drop it. We're busy folks, but right now this is what's out there. Unfortunately, that's it, and so we're going to keep on fighting that good fight. And if you believe in that, if you believe in intellectual honesty in the profession and integrative medicine and being an integrative provider and bringing that into the integrative space, please help us, and you can help us by becoming a member on Dr Journal Club. If you're in need of continuing education credits, take our NANSEAC approved courses. We have ethics courses, pharmacy courses, general courses. Interact with us on social media, listen to the podcast, rate our podcast, tell your friends. These are all ways that you can sort of help support the cause.
Dr. Joshua Goldenberg:Okay, so I read it totally different. So this speaks to like why this is so important to get the language right. So, first of all, are we sure that's three tablets of 1600 of 600 or three tablets equals 600. So they say 600 milligrams and then in parentheses three tablets. So I don't know if that's three tablets of 600 or three tablets made up 600. So it's either two, it's either 600 or 1800 milligrams. That's like the first problem. But NAC is usually dose pretty high, so I mean 1800 would be, I think, pretty high, from at least how I used to use it.
Dr. Adam Sadowski:No, that's, that's pretty standard and in research I've seen like around 1600.
Dr. Joshua Goldenberg:Yeah, Is that pretty standard? Okay, all right. So maybe that's that's three of those 600s. But then I read it as three, three days on, four days off, repeated every week for three months. That's how I read that one.
Dr. Adam Sadowski:Oh, I did not read it as that.
Dr. Joshua Goldenberg:Yeah, and I think, if you go through that in the discussion they talk about the rationale for dosing, which I actually really appreciated and was one of the benefits of this paper. I think that makes that begins to make more sense as sort of this pulsed approach, because apparently there's some sort of absorption issue, like you stop absorbing if you continuously take it, and so they were trying to maximize absorption apparently by pulsing it in this way, which I thought was an interesting take. But yeah, so anyway. So we, so I think one of the take homes are is well, so far has been the importance of language, and you and I have completely different reads on how this was dosed, based on the opacity of this writing, unfortunately. But okay, so I think it was pulsed for three months, you think it was done for three days, and so maybe we'll see if we can gather some more information about that. And then they looked at outcomes at the beginning and then after three months of treatment.
Dr. Adam Sadowski:Yep, and the outcomes they looked at were abnormal periods, pain with periods, the size of the endometrioma, specifically within the ovaries. For those who don't know, endometriosis is endometrial-like tissue that is not present within the uterus, and so you have basically uterine tissue not where it's supposed to be, and so in this case they're looking at uterine tissue within the ovaries. And then they also looked at CA-125 levels, which I won't get into. I don't think that, for the sake of this study, that they're clinically relevant, but maybe someone else would argue otherwise. So I kind of looked over that. I looked more so at the size of the endometriomas, dysmenorrhea and dyspareunia, and they estimated the size with the use of transvaginal ultrasound, which is totally kosher in my opinion, and they used the same sonographer every single time. Yeah, yeah.
Dr. Adam Sadowski:Pain was assessed through a visual analog scale. So if you had you know like a ruler from zero to 10, they would say, okay, mark on this ruler, you know where your pain is. They would say, okay, mark on this ruler, you know where where your pain is. And they had a 10 point scale Mild was considered one to four, moderate five to seven and severe eight to 10. And then that was kind of it. They didn't really get into this physical analysis at all and we have no idea if it was like intention to treat or anything like that. They just kind of said, hey, we did a pair T test and this and that and our significant level was less than zero. A paired t-test and this and that in our significant level was less than 0.05, but very anemic statistical analysis methodology.
Dr. Joshua Goldenberg:Yeah, I like that phrase, so I agree with all that I do want to mention brief. I did want to touch on the CA-125. So I'm familiar with that as an ovarian cancer marker and it was interesting to me that it's used also in endometriosis and that it's elevated endometriosis. So I liked in theory, the idea of using it as a tracking marker, an objective tracking marker, I think. My understanding is it's pretty much garbage for diagnostic purposes because it can be elevated in ovarian cancer and endometriosis but not all the time and so it isn't great to diagnose it. But I was curious about using it as an objective marker of improvement, with the theory that it's related to the amount of tissue. So that was interesting to me as and to have an additional objective marker, because otherwise you know you're talking about subjectively reported outcomes and there's no blinding. Everybody knows they're taking the NAC and you're talking about, you know, pain with menses and pain with intercourse and these are all subjectively reported. However, we also have the ultrasound which you point out, which is an objective marker.
Dr. Joshua Goldenberg:But I'll tell you, my wife is a sonographer and the stories that I hear, I mean it is a very subjective quote, unquote science, right, like very subjective If, if the images are, if the images are imperfect or the patient wasn't prepped, or the patient's in a bad position, or the the um, the mass is in the wrong position, little like millimeter differences happen all the time in measurements and I personally I mean I, I don't I'd like to see the studies on this but I personally believe there's a huge amount of variation in in how, the size of the way things are read, and there's no blinding here, of course. And so even though it's the same operator, which is good because that limits some of that variability, and assuming it's the same machine, which also introduces variability, it's just there's knowing that you're in an intervention, you're trying to see if it works, and you're giving sort of like radio, the classic studies on radiologists and how subjective that that reporting is. I think it's the same with sonographers. So I am a little suspicious about that.
Dr. Joshua Goldenberg:And so I really liked the CA 125. Because I feel like that is a true objective marker and in a situation where you're not blinded, I was very interested to see, because I don't believe that objective markers are influenced by blinding, and so I was very interested to see that. I think that's all I have to add about that Any comments or criticisms or repudiations of any of that.
Dr. Adam Sadowski:Nope, nope, I think that that that's fine.
Dr. Joshua Goldenberg:Yeah, okay, so we have our outcomes here. Okay, so let's jump into results. You like to talk about what the patients actually look like, which is important. I always skip over table one.
Dr. Adam Sadowski:Yeah, they had 120 people within the study, on average about 33 plus or minus seven years. Mean BMI was 22 plus or minus 4. 28% had prior surgery for endometriosis. 87% used some sort of hormonal treatment prior to the recruitment process. But they didn't mention like If they were excluded or included beyond a certain period of time. So like was part of the exclusion criteria. They just couldn't use any sort of hormonal treatment within three months of recruitment or anything like that. So that was a bit confusing.
Dr. Joshua Goldenberg:Yeah.
Dr. Adam Sadowski:And then they also looked at or excuse me about a third had one pregnancy prior to recruitment.
Dr. Joshua Goldenberg:Gotcha, yeah, and infertility was one of the claimed things that they were interested in. And there and it was a, it was a population in a decent amount of pain. I mean the. The average VAS score was almost seven out of, you know, 0 to 10. So these are people that were in a lot of pain, which makes sense because these are all people referred to an endometriosis center of a hospital, right, so sort of tertiary referral. So we would expect that these would be more severe patients. Okay, so should we talk now about the actual results? I like table two. I thought that presented stuff pretty clearly. Should we go through that one?
Dr. Adam Sadowski:Yeah, sure. So at the start, like you were saying, the mean pain score for painful periods was 7 plus or minus 2. And then at the end of the intervention, so at the three-month mark, it was a 5 plus or minus 2. So basically pain went down by two points, which was considered statistically significant. Pain with intercourse also improved. So at baseline it was six and a half plus or minus two and then after three months it was five plus or minus two, and then chronic pelvic pain at the start was a seven plus or minus two and then went down to a six plus or minus two.
Dr. Adam Sadowski:Use of NSAIDs at the start was about 63% of the participant population, which then went down to 53%, so a 10% reduction there. My assumption is that probably during the study they were not supposed to be like at recruitment, probably not supposed to be daily users. However, during the study they were not supposed to be like at recruitment, probably not supposed to be daily users. However, during the study probably were allowed to use it as sort of like a quote unquote emergency pain relief. So you'll see that a lot in like osteoarthritis studies where you know they'll do like curcumin versus placebo, but both groups. Like curcumin versus placebo. But both groups, ideally prior to the start, are not using NSAIDs. However, during the study, if they need, like you know, acute symptom, you know improvement are, they're not prohibited from using NSAIDs.
Dr. Joshua Goldenberg:Well, I mean, I would agree that that would be the right way to do it. But then, but the T0, the baseline measure, says that 63% of them were on NSAIDs. And I've just reread that exclusion criteria and it pretty much says that was an exclusion criteria. That's another red flag. So they claim that this is an exclusion criteria. But 63% of the people at baseline, as they were recruited in, so normally, as you know, because you've run trials, like the way this works is like you know, you have your recruitment, you pick them, you talk to them on the phone or they come in in person. You say, Are you on NSAIDs? And they say no and then say, Okay, come in for your first visit. You know, a few days later, a week later, and you're gonna do your baseline, 63% of them are taking NSAIDs.
Dr. Joshua Goldenberg:I just feel like that is interesting and suspicious. That should, at the very least, be discussed, but was not. So that's interesting to me. Anyway, I'm gonna shut up now. I think we still did. You talk about the ovarian size, yet the endometrioma size size, yet the endometrioma size no.
Dr. Adam Sadowski:from baseline to the end of the study, the size of the endometrium was reduced by about three and a half millimeters, which was considered statistically significant, and then also the levels of CA-125, also reduced by about 10, which was considered statistically significant.
Dr. Joshua Goldenberg:Yeah, interesting. So the results are like on its face they look statistically and clinically significant Pain levels are. You know, it depends on the condition, but usually we think about a minimal important difference for pain outcomes to be anywhere between like 1.2 or 2 points on the VAS scale. So that's kind of where this stuff landed on average. So, clinically significant results you're seeing reduction in objective markers like size of the endometrioma and serum levels of CA-125. And so you might say, okay, well, the objective markers, you don't have to worry about the blinding issues and maybe you do have to be more worried about the pain levels, but there's no control, so you're not controlling.
Dr. Joshua Goldenberg:You know, yeah, blinding issue, but also like regression to the mean and like everything else, the way disease works is has. That has nothing to do with blinding. It's just like when you get recruited into a study you're at the height of your symptom presentation. Usually that's regression to the mean, and then you know you measure it later they're going to be lower. And because we don't have any control group, we have no way of saying is this what would have happened to people who were not given NAC? In other words, was this did this actually do anything? So I mean one of the obviously the major issues with not having a control group, but just wanted to say that out loud because I know it was screaming in both of our heads.
Dr. Adam Sadowski:Yeah, no, I think you brought up some some valid points there and then that was kind of it for the study. I didn't. I didn't read the discussion at all. It was a terrible study. I'm sorry, that's just the facts. It was not a good study. After I read the methods, honestly, I kind of you got bored. I glanced at the results but I was like this, this is so terrible a study. None of this is really.
Dr. Adam Sadowski:This is just dumpster yeah, it is kind of dumpster at least it wasn't funded well as far as I could tell I guess that that you know there was no funding here. There was no. Did you do a google search? They didn't report anything they didn't report anything.
Dr. Joshua Goldenberg:I didn't do a google search maybe I should have. I also didn't see that they had they registered the study anywhere this is.
Dr. Adam Sadowski:It was just a great example of like a terrible study bad research.
Dr. Joshua Goldenberg:Yeah, it was a great example of bad research and also it's a good example of like, the importance of language and reading between the lines, um, and how, on its face you would look at that abstract, you'd be like, oh my gosh, like this is gonna save everything and maybe it saves everything. But the point is we have no idea scientifically because of the way this was designed and then lots of questions that are raised in its execution. That makes things questionable. Let me, okay and then look at this. So this is more. I want to go through the discussion because I think one of the themes is like the importance of language and how that can give us red flags when we read this. So let me just see here. So here we go. So in patients seeking pregnancy, the use of NAC can be proposed. In fact, NAC proved to be effective and safe. And you know, I just the language is not what I'm used to seeing in science and it seems overly blown conclusions from a non-controlled, apparently not optimally executed study, and so again, those are just really.
Dr. Adam Sadowski:Not. Apparently it was not an excellently. It was a terribly executed study. They didn't report any safety outcomes, so I don't know how they can even claim safety. So don't give them credit if it's due. It was a terrible study.
Dr. Joshua Goldenberg:I thought we were steel manning. Are we not steel manning anymore? You're just done. You're like dumpster, no more steel manning.
Dr. Adam Sadowski:So you can steel man, but let's also not, let's not be overly nice. It was not a good study at all.
Dr. Joshua Goldenberg:It was not I, I would. I would give this critical flaw level.
Dr. Adam Sadowski:The fact that even got published I'm surprised.
Dr. Joshua Goldenberg:Yeah, so I actually. So that was one of the first. I had the same thing. I was like, how did this get published? So I was curious about the journal and you know is is this a reputable journal or not? Because there's just so many red flags, that editorial red flags that should have been caught that I didn't see.
Dr. Joshua Goldenberg:Um, oh, and you know what they do delineate the dose better. In when they're talking about dosing, they say the fraction, fraction, nation into three doses of 600 milligrams. Okay, so that supports your 1800 milligram total daily dose argument. Not three doses of 200 to get to 600, but three doses of 600 to get to 600, but three doses of 600 to get to 1800 a day. And yeah, basically they're giving the rationale for pulsing it based on plasma levels from their previous work, which also seems to be a bit of a stretch of their previous work is in animals, but maybe, maybe there were some humans in the study. I didn't track those down and what else did I want to say? Oh, they say everything's due to inflammation. You know, I know it makes sense, it is a good rationale and probably everything is related to inflammation, but I sometimes just roll my eyes, like when you read these studies, you're like what's the proposed mechanism of action? You're like inflammation. It's like yeah exactly, exactly.
Dr. Joshua Goldenberg:It solves all things, and yeah, so I was curious about that.
Dr. Adam Sadowski:I've also noticed that, like publications that have longer sections dedicated to mechanism of action, when it becomes like a clinical study, the higher, like that, the outcome is going to be just like not important.
Dr. Joshua Goldenberg:It's funny you say that I totally have that same bias. Yeah, I totally have the same bias and, like you're spending so much time on mechanism, you're clearly a benchtop expert, which is fine. But now I'm curious about, like, the actual methods of the clinical trial. You might be too enamored.
Dr. Adam Sadowski:Yeah, and it's like okay, are these results, is like the magnitude even worthwhile, or are the clinical outcomes like relevant, or is it going to be a terrible study?
Dr. Joshua Goldenberg:Yeah, I think that's not a terrible proxy at all. I have the same like intuitive sense about things. What else, anything else? I wanted to say no, we talked about the CA-125, yeah, and then just the conclusion
Dr. Adam Sadowski:Didn't even read it.
Dr. Joshua Goldenberg:Yeah, it was just too rosy.
Dr. Adam Sadowski:Don't even bother reading it.
Dr. Joshua Goldenberg:Yeah, I would say um, I mean, based on what they're saying. These are important effects and they are large effects and clinically meaningful, or at least they're clinically meaningful. What I would say is I don't trust a word of it. That doesn't mean it doesn't do that, it just means I have no idea if that is just poorly executed trial design or this is what would happen with regression to the mean anyway. And I can't answer those questions based on the reporting in this study and the design of this study.
Dr. Joshua Goldenberg:So I've got lots of feels about this one and, yeah, I guess probably one thing you could do is Google. Is Google, all these authors? You know they might just be researchers in the NAC space and just be like intellectually conflicted, which is which is like that happens all the time. Obviously you need experts. You know doing, doing studies. It's an issue in science. But you could just read between the lines Like these folks are obviously super enamored with NAC, the design. Read between the lines like these folks are obviously super enamored with nac, the design is set up to win. I don't know. I've just got all the feels and all the questions. All right, that's that. All right, we'll leave it at that.
Dr. Adam Sadowski:Cool
Dr. Joshua Goldenberg:So thank you, dear listener, and thank you for sending papers. Please continue to send them our way. We like discussing good papers and bad papers and how we can differentiate, which is kind of the whole point of what the heck we're trying to do here with this podcast and with Dr Jerome Club in general. So thanks for listening and we will see you next time.
Dr. Joshua Goldenberg:If you enjoy this podcast, chances are that one of your colleagues and friends probably would as well. Please do us a favor and let them know about the podcast and, if you have a little bit of extra time, even just a few seconds, if you could rate us and review us on Apple Podcast or any other distributor, it would be greatly appreciated. It would mean a lot to us and help get the word out to other people that would really enjoy you. content. Thank you
Dr. Joshua Goldenberg:Hey ya'll, this is Josh. You know we talked about some really interesting stuff today. I think one of the things we're going to do that's relevant. There is a course we have on Dr Journal Club called the EBM Boot Camp. That's really meant for clinicians to sort of help them understand how to critically evaluate the literature, etc. Etc. Some of the things that we've been talking about today. Go ahead and check out the show notes link. We're going to link to it directly. I think it might be of interest. Don't forget to follow us on social and interact with us on social media at DrJournalClub. Drjournalclub on Twitter. We're on Facebook, we're on LinkedIn, etc. Etc. So please reach out to us. We always love to talk to our fans and our listeners. If you have any specific questions you'd like to ask us about research evidence, being a clinician, etc. Don't hesitate to ask.
Introducer:Thank you for listening to the Doctor Journal Club podcast, the show that goes under the hood of evidence-based integrative medicine. We review recent research articles, interview evidence-based medicine thought leaders and discuss the challenges and opportunities of integrating evidence-based and integrative medicine. Be sure to visit www. drjournalclub. com to learn more.