Good morning, everyone. I'd like to thank you all for coming. My name is John Kingray, and I'm joined today by a distinguished panel of methamphetamine experts. I'll let you take that comment whatever way you want. There will be more jokes coming, I'm sure. But we have a really exciting session on something that if you do pulmonary hypertension and this hasn't impacted you, just wait, because it's coming. And I'm joined today by Vijay Balasubramanian from Fresno, and Lana Melendrez-Groves from the University of New Mexico, Namina Sood from UC Davis, and Ihail from Oklahoma City. And we're going to hopefully enlighten you a little bit on the methamphetamine epidemic and how it's coming to a patient near you, okay? Vijay. Aloha, everyone. Okay, so thank you. Welcome to the med session on a bright Tuesday morning, and I want to especially thank our dear friend here, Dr. Kingray, for inviting me to open this chapter. And we are here to talk about something very, very sad but true. My favorite band, Metallica, says that. And we are here to talk about real-world impact of methamphetamine in associated pulmonary hypertension. These are my disclosures. The talk can be kind of what you can gather from this talk, because basically I'm going to be talking about some global and regional burden of methamphetamine and the systemic and vascular effects, as well as what are the special characteristics associated with methamphetamine, associated PAH. Meth is a global threat, okay? The new wave of drugs that's sweeping the world. And if you look at the stats from the World Drug Report, clearly this has skyrocketed. You can see all the skyscrapers over the last two decades, the amount of methamphetamine seizures. Again, these are, again, from the World Drug Report 2022, global estimates of prevalence of drug use. And you can see that methamphetamine is up there. And basically 34 million users is the estimate. Obviously, this is an under-reported value, not everywhere in the world. The reporting system is very effective. Therefore, amphetamines are the second most abused drug in the world, excluding cannabis, and it represents the greatest global threat. Obviously, we contribute a lot to this population because 2.3 percent of the North American population are subject to amphetamine use, and this is substantially more than the rest of the world. And if you look at the annual use of amphetamines globally, it's about .5 percent of the global population. Then this particular report with regards to the regional all-cause mortality or deaths associated for comparison with cocaine and methamphetamine, then you can see the two outstanding sidewards skyscrapers, and that's Australasia and that's North America. So what about magnitude of meth in the USA? Obviously, my dear friend Lana is going to talk more about this, but we are just going to have a little sneak peek. About 1.2 million people, or roughly about .4 percent of the population, have reported meth use in the past one year, and 1.1 percent of all twelfth-graders, scaredy stat. And this map is very simple. The western part of the United States is dominated by meth, and then the eastern part is the fentanyl kingdom. So fairly simple to understand. So just out of kicks, I wanted to kind of see, what is the relationship between all of this? Why is this happening? As you know, music and movies play a very crucial role in influencing the society. It could be a chicken and an egg. They could either set the trend, or they could be reflecting the trend. So I just did a random search on Google about meth-based rock songs. And I found this list, and basically there's one song from 1968. And all of the rest are from after the year 2000, most of them. So you can see that it's a huge influence. So if you look at our counterpart, the methamphetamine-associated heart failure, and that is, again, concentrated in the western half of the United States. And it's substantially lower in the eastern part. Again, the disease burden is highest in the western Pacific region, and constitutes about 75% of the methamphetamine-associated heart failure. And inflation-adjusted charges rose from $42 million to a staggering $400 million. That is within a very short period of time. So this is an amazing type of inflation-adjusted. So if you look at the burden of methamphetamine use in California, so again, there's a 13-fold increase just over the last decade in hospitalizations. And obviously a 17% exponential rise every year. What about local? And where I'm from, Central Valley of California, often referred to as the Met Capital of California, we did our own kind of methamphetamine data out of a database that we had created. And we found over the last five-year period, there was a steady rise in methamphetamine-positive urine drug screens. And this is not pH, I'm just talking about methamphetamine. What about local? Where we are right now? So I call it high in Hawaii. Sorry about the extra cheese. So if you look at the local report for the corona-investigated deaths, then you can see that there's a substantial rise just over the last few years. And the rate of Matthews in Hawaii is far higher than the national average. So if you look at the prevalence of Matthews amongst the Hawaiian workforce, that's increased by about 410%. Anyway, so what is methamphetamine? So it is a highly addictive stimulant drug. It can be snorted, it can be smoked, it can be injected intravenously, eaten, and even rubbed against the gums. It's not toothpaste. It's called, I think, meth toothpaste or something like that. But anyway, it's got many street names, crank, ice, crystal. These are just a few. There's like a long list of it. The terminology is complex. So they are synthetic drugs that do not need extraction from a plant-based plant. So they have to be actually made in a lab, and therefore can be made anywhere in the world, and anyone can cook. Anyway, so what is methamphetamine? So it's basically based around a phenylethylamine core. I know very much about it, and it is distinguishable from the amphetamine analogs by an additional methyl group, and that makes it highly lipophilic, so it crosses the blood-brain barrier effectively. And then the mechanism through which it acts, it basically is a catecholamine release phenomena, and it can do it in multiple ways. I'm not going to go through the whole thing. It's a very busy slide, as you can see. But every little mechanism that is stated there is indicated for catecholamine release. And therefore, it results in neuronal cell death, endoplasmic reticulum stress, mitochondrial dysfunction, and reactive oxygen species production. Therefore, acute increases result in methamphetamine-associated euphoria, and then chronic use can cause neurotoxicity. And pretty much the similar type of pathophysiology for cardiotoxicity as well, including the direct cardiac toxicity from methamphetamine. What about stimulant use in pulmonary arterial hypertension? PH associated with inhalation of crank was first described in 1993. And then Kelly Chin and her colleagues published the first data here from, I think, UCSD, when they found that about roughly just under shy of 30% of idiopathic PH patients had reported meth use. So let's look at the growth of meth and the more increasing recognition of meth from the PH world. In 2009, we thought that it was possibly related as a risk factor. And in 2013, it was kind of reclassified into the likely subcategory. And then by 2018, it was a definitive association. And now it has its special place, which is the drugs and toxins associated with PH. So if you look at the PHAR registry and the data from that, this is specific to methamphetamine-associated PH. You can see that a vast majority of them, about 83% of meth-associated PH participants receive care at PHAR centers in Western U.S. And whereas the distribution of the IPAH counterpart was very similar all over the U.S. Stanford reported its real-world experience, and they did a great job with this. And 541 participants, 22% had meth-associated PH. And what is important is they tend to be younger, they are less likely to be insured, less likely to be college graduates, married, or employed, and reported a lower taxable income per year. And the female predominance continues, although the relative proportion of males are much higher in the Justin and Matthews cohort. They tend to have less favorable hemodynamics than the participants in the IPAH population. So again, when you look at meth-associated PH, it is really still a female-predominant disease, but not relatively as female-predominant as other subtypes. But then if you look at meth-associated cardiomyopathy, then you have the associated other risk factors like alcoholism, hypertension, and they tend to be more male-predominant. So what are some of the characteristics? They tend to have a higher heart rate, lower systolic blood pressure, higher diastolic blood pressure, and hemodynamics, they have a higher right atrial pressure, lower cardiac output index, and a lower stroke volume index. And their survival is obviously much poorer than the idiopathic cohort. And we in Central Valley also had a very similar experience. We reported this in CHEST in 2017 in Toronto. So we are actually presenting this particular poster actually this morning. So this is looking at ADI. ADI is a socioeconomic index, also referred to as the SING index, and basically it's a complex computer calculation, gives you a score, and people use it in taking about seven or eight variables of social determinants of health, and the social gurus, they kind of, when they look at all the economic gurus, they look at this particular index. And we thought, okay, let's use this index and see how that influences meth-associated PAH, and what we found was obviously the meth PAH group were found to have a much higher ADI at the time of diagnosis compared to the counterparts like the national levels or in the non-toxin PAH groups, indicating the severe disparities in social determinants of health. Human lungs have the most rapid uptake and the highest accumulation, about 24 to 31 percent of the injected dose, and therefore makes you think about whether there's organ-specific vulnerability. And there are some unique pathological characteristics, which are very well-described by the Stanford experience, and that's the angiomatoid lesions that can be seen, and collections of micro-crystalline cellulose, and obviously the slit-like vascular channels within the arteries. Okay, so these are all some of the unique aspects of the pathology of these patients. What about methamphetamine-induced vasoconstriction? It is thought to derive from endothelin-1 overactivation, and obviously the arterial TAR-1 signaling, and promotes smooth muscle dysfunction and reduced nitric oxide sensitivity. So the other enzyme that has been described is the carboxyl esterase, which is very exciting data, and this is basically an enzyme that metabolizes the meth. And if you have a little polymorphism that inhibits the carboxyl esterase, then that can actually predispose to meth-associated vasoconstriction and pulmonary hypertension, which is what was noted. And what was interesting is nearly all of the meth PAH patients examined were heterozygous for this polymorphism. Therefore, if you look at phenotype, it's a combination of genes and environment that constitutes phenotype, and obviously we call it like the multiple-hit or the two-hit hypothesis now raises the question, is meth-associated PAH a distinct phenotype? So what about a general overview of the non-pharmacologic treatment approach? So it's education, social support, support groups, peer networking, and obviously de-addiction. And Dr. Kingree will be talking more about this later. And therefore, we need to actually come together. I was very tempted to actually play that song, but I thought it might be a little too cheesy for the morning. And anyway, conclusions. Okay, so stay off the drugs. And these are, meth use is a growing international global threat, increasing burden on global health care, and it has several and severe systemic consequences, and obviously distinct characteristics in PAH. Is it a unique phenotype? With that, I'll just say, wear your Hawaiian shirt, okay? Mahalo. Thank you. I would also like to say good morning to everybody and to say how appreciative I am to Dr. Kingree for having me. I think, you know, the four of us that are going to be speaking this morning, we definitely have, you know, some experience in this, and I was talking with my colleague just yesterday, and so from the East Coast, it tends to be a situation where they don't in the real world experience this problematic patient of methamphetamines and PAH. So I think for all of us, we can learn. Those that do it sort of day in and day out hopefully will gain experiences to be able to bring to those who maybe haven't yet. So as mentioned, I'm Lana Melendrez, and I am at the University of New Mexico, and I am the medical director for our PH program. And interestingly enough, for the purposes of this discussion, I don't have any disclosures except to say that I'm a native New Mexican and born, raised, still live and work in Albuquerque, which just so happens to be the site of sort of this very influential and popular series called Breaking Bad. And one of the other pieces, and Vijay was talking quite a bit about the Stanford experience and Dr. Zemanian, who's my mentor. And when I went out there for my postdoctorate, what I found was that I was intriguing to them because everybody assumed that every person in New Mexico uses methamphetamines. So that was interesting, and I had actually never heard of the show at that point. So as my graduation gift, they gave me the box set of Breaking Bad. So that sort of started my journey, and I thought that it would be nice to sort of pull my journey into this because Breaking Bad really created sort of this mainstream of meth. People who would have never thought about it, never understood it, were all of a sudden weekly hanging on these episodes of what was happening. And I think that they actually cleverly did it because they pulled in people who maybe wouldn't have watched it, but because it was talking about chemistry and this higher level, they pulled in people and then we got sucked into some other very bad things that happened throughout the show. So I'm going to be talking about methamphetamines and that they are a dirty drug destroying the heart of America. So for the objectives, it really is going to focus a bit more on kind of how this has happened in the United States. And so we're going to talk about the origins of this epidemic and then the biases toward the Western United States. And I know that Vijay did talk a bit about it. I think that anything that he spoke about, I'll try to hurry through or skip. And then really wondering, are there certain ethnicities, races, genders, does that predispose you to use of methamphetamines, which may help us moving forward in terms of meth and pH. And then I think it's always important to compare kind of substance use to what we're seeing in meth and that relationship. And then my own sort of provider journey through understanding and managing the meth pH patient. So I did actually put some audience response questions and I'm going to say, I'm tremendously sorry if you haven't seen Breaking Bad because I just hope you're good test takers. So with that, in Breaking Bad, what distracts Walter White from absorbing the news of his cancer diagnosis? Was it the fact that the doctor had mustard on his coat? Was Walt stressing about money? Did the doctor have a lazy eye or was Walt's second cell phone buzzing in his pocket? So I'm going to go ahead and let everyone vote who would like to vote. If you know it, you know it. But also, all right. So not bad. I see I've got about at least 40% of you who've maybe seen the show or maybe it's just been a while. But I also took a journey to the sites of where Breaking Bad, I mean, I really got into this session. I am telling you. So this is the Dog House. It is actually a mainstay in Albuquerque. My father, who is a native New Mexican, went there in high school with his buddies. And it is literally a box. And you drive up and they come out and they serve you. And I went and ate there and it has the best chili cheese fries and everything else. Come to New Mexico, have some. Leave with maybe some heart issues of a different sort. So really getting into the origins. What we saw was that in the 1980s, the United States started to tighten the regulation and sale of ephedrine. And what this really then caused to happen was that the making of crystal meth needed to be utilized in terms of using pseudoephedrine. You may remember when they started pulling everything behind the counters. You couldn't get the cold medicines. And this was so that people could start making crystal meth. And what we saw was that over about the decade from 1994 to 2004, there was this dramatic rise from about under 2% of the U.S. population to 5% of the adult U.S. population in terms of exposure to methamphetamines. And part of that was, as Vijay mentioned, it was much easier to make. You didn't have to have growing plants, you didn't have, right? And so what we saw was that there were these burgeoning markets, and it tended to come from these lower income countries that didn't have strong regulations for the precursor chemicals, specifically in Mexico. And so finally, we recognized that in 2006, this was a real problem. So the United Nations World Drug Report said this is the most abused hard drug on Earth. And in comparison, as Vijay mentioned, we see 34 million people between the ages of 15 and 64 using amphetamines. And that the global seizure rate continued to increase. But not only that, we saw that patients that we were routinely just getting urine on and testing was increasing to a staggering degree. It increased 500% from 2013 to 2019. So we were now seeing things that, as Vijay mentioned, people don't necessarily want to tell you that they're using methamphetamines when they come into your clinic or elsewhere. And I'm not sure how many of you saw the pro-con debate yesterday, but my colleague Hap and Frank showed lots of maps of the US being tremendously good at really terrible things. And once again, we uphold that with our use of methamphetamines here. So Vijay already talked about sort of the staggering numbers that we're seeing. All right, so we're gonna go back into our journey through Breaking Bad and talk about the effects of meth per Breaking Bad now. This may include all of the following except. Digging a hole in the front yard for no real reason. Falling asleep at the wheel. Saying booyah or going to rehab. So I'll give you guys a few moments to be able to log in your response. And I think that this is actually important. One, because, all right. And I think that for those of you who knew this, I mean, falling asleep at the wheel, that's where it really came about, right? It's a stimulant. And so people were using it to stay awake. We were seeing it more in shift workers. I actually went to visit what, and I'm not joking, it is called the Candy Lady in Old Town in Albuquerque. She actually does sell candy, but she has made a huge amount of financial gain off of creating blue crystal meth, sugar. I thought I should bring some of the little packets. Like, they literally have them in the dime-sized packets, and I thought I might get kicked out of chess. So I probably shouldn't, or I might not make it through the airport. But this bias toward the Western United States, I mean, what we were seeing was, and I have no idea. So it was these motorcycle gangs, I guess, in the 1980s that were starting to sort of resurface and make meth and distribute it through Southern California, up through Oregon. But we were really seeing it at that time in Caucasian men. They were truck drivers, they were shift workers, blue collar workers. It was really used to just stay awake. It wasn't necessarily being abused how we're seeing it today. It was also very prevalent in the gay communities. And so what happened was that everybody realized they could do it. So we have these mom and pop homes where, I mean, truly, just inside their house, just like in Breaking Bad, in New Mexico and in Albuquerque, we used to see this all the time on the news. But there were also super labs, and those were more in California and in Northern Mexico. And then the distribution of that was that coming up through Mexico, we started to see really the spread of the methamphetamines throughout New Mexico, Arizona, up into Utah, and then kind of continuing to move everywhere. And you'd say, well, okay, it makes sense, it's in Mexico. But really, it was because of the rurality of these areas. So not that any of you would necessarily know, but when you cook meth, it smells terrible. You can smell it from blocks and blocks away. So it's kind of an easy tell, right? You're driving down the street, well, there it is. And so because New Mexico, Arizona, all these areas are just massive land masses with, I mean, they're beautiful, but nothing there. So people were able to start really just individually being able to manufacture meth without ever being found. So who does it affect? And this, I think, was something that was really interesting to me because I would love to know if certain genders or ethnicities or races were gonna be, as we talked about, this two-hit hypothesis. Was someone going to develop it compared to somebody else? And what I wanna say is that what we found, actually, and what was very concerning to me was I'm gonna highlight the fact that the American, Indian, and Alaska Native had this huge, huge predilection to having the use of methamphetamines. And that, to me, was really concerning. And I'll talk a little bit about that here in a minute. The other thing I wanted to take a look at, knowing that in pH, we really have women being so much more affected, was what was happening in terms of the use of meth and overdoses. And what we could see was, again, as Vijay mentioned, that men use more meth. But we are seeing, when it comes to meth and pH, that women tend to be the ones presenting with it. Now, whether that's because of already a genetic predisposition or something else, we don't know. But I'd like you to kind of keep in mind what these figures are showing, because this is in the United States. And so when you say the men overall over 2011 to 2018 were increasing the sort of the frequency of these overdoses to about 10%. And women, much less so, about 5%. Because I'm gonna bring it back to what we're seeing in New Mexico in a little bit. And that also brings me to just highlighting what we're seeing for this population of non-Hispanic American Indians and Alaska Natives. So in 2011, only 5.6 out of 100,000 people were presenting with overdose deaths. And then when we looked in 2018, it was 26. And that was for men and our women the same. And so what it would tell me is it maybe is more a bit of a social determinants of health that we're recognizing. All right, and that brings us to that. And Vijay very much highlighted this, but I thought, yeah, it's our population that are underserved, that don't have access to medical care, that have incomes of less than 20,000 a year. I mean, these are the individuals that then are not only abusing methamphetamines, they are overdosing on this. And they're now presenting to our clinics with pH, and we're trying to manage them knowing what we're up against. All right, so we're gonna take us a little more into our journey of Breaking Bad. And this is Walter White's transformation from the nerdy high school chemistry teacher to criminal kingpin, all started with what specific medical diagnosis? Really, really tried to pull it back to medicine, guys. I don't know if you can notice that, but. All right, so, all right, I mean, we are at CHESS, so lung cancer, yes. And also, I went to the Crossroads Motel, which is very sketchy, and I will tell you, this is the picture because I stuck my head out of the window of my car, took the picture, and left. But it is actually literally across the street from one of our major hospitals. I mean, like, one of the biggest ones next to the University of New Mexico. And so, just so you, when you do watch Breaking Bad, this is the site of one of the filmings of where they interact with a methamphetamines user. And so, I think that it is my daily life, knowing that this is going on just down the street. So, how does it compare to other illicit drugs? Well, I mean, when you actually compare it, you would say, well, first time users, okay, 100,000 people. But, I mean, that's not good, especially when we start talking about now who's presenting with overdoses and other types of heart failure and things like that. And what we're also seeing is that there is this overlap. So, although Vijay said East Coast fentanyl, West Coast methamphetamines, we're actually seeing that now those things are being seen time and time again together. All right, so now I'm gonna bring it back. Sorry, Breaking Bad is sort of done for the day. But which of the following US cities has the highest percent use of methamphetamines for its population? I mean, I was really trying, right? I mean, I didn't give you an easy out on this with putting an East Coast place in here, but I think I maybe drew you in thinking it would be Albuquerque. We didn't fit the bill, actually. So, what was interesting was it was Phoenix. And I would say that at Stanford, they were like, we're meth capital of the world. And I say, I'm meth capital of the world. And no, actually, Phoenix. 15% of their population use methamphetamines. Albuquerque was a lowly only 11%. But what does it look like in New Mexico? So, I starred our major cities, Las Cruces, Albuquerque, Santa Fe. I mean, that's where the majority of our population are, 2.1 million people in the state. Most of that is about 1.1 million in Albuquerque and surrounding areas. And the red are where we see methamphetamines at its highest use. These are rural. The average income is less than $24,000 a year. We have very few hospital systems of any kind, much less clinics and other providers in those areas. And when we look at in New Mexico, what we're seeing is we, as I mentioned earlier to hopefully keep in mind that graph, over the last seven years or so, we have increased up to almost 16% of our overdose deaths have been from methamphetamines. So we far exceed what we're seeing sort of from the national perspective. And I think that the East Coast pulls down that, obviously. I also wanted to look at age, sex, and ethnicity in this. And I can tell you that in New Mexico, yes, Hispanics present more and die more with methamphetamines because we have more Hispanics there. We are a minority-majority state where 40 plus percent of our population is Hispanic. And so it doesn't spare anybody. In terms of, I mean, I pulled this mainly because I wanted to look at the American Indian population. And what I can tell you is that although we see it, it doesn't seem to be quite as heavily sort of situated the same in New Mexico as it is elsewhere in the United States. And then bringing it back to my population, this is the breakdown of just all my patients when it comes to race and ethnicity in terms of white versus Hispanic. It's very reflective of what we have in New Mexico in terms of our population. And then what does it look like when it comes to drugs and toxins? So our Hispanic make up about 30%, our non-Hispanic whites 53%. And for me, what I wanna bring up is we have 91 living patients with methamphetamine use, most of them continue to use. And so for me, trying to manage this complex patient becomes more and more difficult in that it's a population that has very little resources, they don't necessarily come to appointments. And then the last is, in terms of that multidisciplinary approach, I'm gonna let my colleague go into it in much more detail. But all I can say is, we have to set boundaries, and we have to be consistent with those boundaries. So I think we sort of summarized everything here, but from my perspective, I don't want to leave anybody thinking New Mexico is a terrible place, so please come visit. We have really good food and beautiful views. Thank you. All right, so I'm gonna talk about management, how do you treat these people? And we'll work through this together. I don't think I have all the answers, but we'll try. So I have one question, I think it should come up with the same code, right? Okay, so let me introduce you to Linda. She's a 55-year-old lady who was referred to a clinic. She noticed breathing problems about two years ago. Four months prior, she was admitted to a local hospital with leg swelling and dizziness, was treated with diuretics. An echocardiogram was performed. And as you can see here, it showed slightly reduced LV function. LV size was normal, RV function was reduced, TAPSI was reduced, RV was severely enlarged, dilated, and the RVSP was increased. So she was sent over to a clinic. She said since she got started on diuretics, she was feeling better, was able to walk on flat ground, but unable to go up and incline. She denied any syncopal episodes. She was a farmer, she actually has fruit orchards and works full time, highly functional, very intelligent, very impressive lady. She had a long standing history of meth use, states that she quit about two months ago. Had a history of tobacco use, quit several years ago, and drank alcohol, as everybody does in California. I think wine is our drink. So, on examination, essentially, unremarkable activity was slightly distended and no lower extremity edema. This was her echo. You can see the LV is recovered and RV is still very enlarged and dilated. And there is, TAPSI is reduced. Her PFTs are essentially normal. Walk distance is quite reduced. And rest of the workup is essentially normal other than the BNP being super high and her talk screen at this time was negative. VQ scan was unremarkable and this was her right heart catheterization. She came in and noticed that blood pressure, 150 by 90. RA pressure is 18, her RVDP is 21, mean PA pressure is 65, VEG is 8. Cardiac index is 1.38, giving me a PBR of 12 with ZUNET. They called me from the cat lab and I said, do a talk screen, and it's positive. Here's the profile. It's a little bit different than what you would see in IPH. You would not see that systemic blood pressure with somebody with an RA pressure of 18, and the index is way low, all right? So, if we were to re-stratify this patient based on our current guidelines. Where did all my arrows go? There we go. So this patient then falls into an intermediate high risk category. And for the sake of time, I'm not gonna walk you through this. And if we do the reveal calculation, then she gets a score of ten, which puts her at a high risk category. So if we were to follow our ERS guidelines right now, she would be in a high risk category and you would be putting her somewhere here for treatment. So I'm gonna ask my one question and we'll leave the answer to the end. Would you start on prostacyclin infusion, oral prostacyclin? There's an error here. Ignore number three and just use Rio Ciguat, ARN, PDE5, or none of the above. All right, shall we? Okay, we got a mix of everything. 9% did not want to treat the patient. So we'll go through this and maybe we'll change our minds towards the end. So things that we don't know the answers to. Does the risk stratification apply when the patient has ongoing meth use? Is there benefit of selective vasodilators with ongoing meth use? And there's concern for compliance and how do we monitor these patients? My nurses are saints, there's just no other way to say it. And then there's financial and social constraints in terms of providing therapy for that. And so we can either be a purist and say, well, the meth has to go before I start the treatment. Or just play doctor and give the patient treatment and then they can figure it out on their own. I apologize for the typo. But this is the problem here. The symptoms of pulmonary hypertension are dyspnea, fatigue, feeling tired all the time. And how can they compensate for that? By taking meth. Because if they withdraw from meth, they can sleep for three days. So to pick them up when they have pulmonary hypertension, they use meth more and more. I almost feel like it sometimes even preserves their RV. So what do we know about meth pH? You've already heard a little bit about it. The Stanford data have been discussed before. More advanced heart failure, higher right atrial pressure, lower stroke volume index, exactly what I showed you. And similarly, the FAR registry comparing patients with meth, PH, and IPH tended to have lower cardiac outputs. And this is our sort of numbers in our clinic at UC Davis. You can see that when we look at our PH etiology in UC Davis, the maximum numbers is meth. And I just moved here three years ago. So I came from the Midwest, where IPH was our sort of disease mostly. But when we look at our echocardiogram, and we look at the RVSP in terms of predicting elevated pH pressures, compared to our IPH patients, the meth pH patients, the echo doesn't perform as well. So that was our first observation. The other one was that, yes, our data reflects what Stanford has already published, echo in meth users do poorer than predicting hemodynamics on the right heart cath, and hemodynamic profile can be affected with current use. So that's sort of a confounding thing here. And meth and non-meth patients in our clinic were equally likely to receive prostacyclines. However, when there was worsening functional class, only 20% of the patients who were meth users had an uptake in their prostacycline therapy. And what were the reasons for this? Either it was ongoing meth use or lack of the social structure there, right? So, and then we also realized that we were really not doing a good job tracking the current meth use, and then, because not many patients had repeated screens. Right, so the questions that need to be answered is, what is the long-term benefit of the vasodilators? Does meth pH predict misclinics, visits, and hospitalization? And can we improve outcomes if we address both these things together? So before I go on, I want to acknowledge my fellow, Rebecca Garbet, who did a lot of work on this. And I stole some of her slides too, shamelessly, but here we are. So our goal was to figure out a way to improve outcomes of meth pH patients, improving their cessation from meth. And the hope was that we decrease hospitalization, ER visits, and improve their walk distances and quality of life. So we said we should improve our documentation and screening for meth use disorder. And also treat meth use disorder and pulmonary hypertension at the same time. So we started by improving our questionnaire, making it a little bit more granular, trying to figure out how they're using meth route and frequency and so forth. And then we, this is sort of what it looks like. I'll go through it quickly. And then we also sort of, with the follow-ups, we have a follow-up where we ask for pH symptoms. And here we included this as well. And then we also look for mood disorders. A lot of these patients have previous diagnosis of mental health issues, especially bipolar disorder is not uncommon. So we kind of assess for that as well. And then we said, okay, let us have an intervention where we are aggressively counseling for meth use, and then treating the pulmonary hypertension. And I think John's gonna go into this in more detail, but the three things is this combination, long-acting shot, or counseling, and contingency management. Counseling, though we wanted, it's a buzzword, and now you can do it online, but hasn't shown to show any consistent durable benefit when it comes to cessation. This was a positive drug, but again, getting it, and because we can't administer it in our clinic, and then getting it for the patients with insurance approval and all that, it's like by the time the train's left the station, literally. And then metazapine is something that we are using quite frequently. It has shown that it does reduce meth use a little bit and also helps with the depression gives them better sleep and so forth. So we've been starting to use that a little bit more in that clinic. But contingency management is actually shown to be the most effective where patients for every time they have a negative talk screen are given some monetary result. This is widely used in the VA system but our Medicare Medicaid doesn't approve it. So that's a challenge. And John will go into this some more detail. So I'll just move on. So so that's sort of our sort of current plan in our clinic. We start with metazapine started a low dose increase it referral to substance abuse counselor and then we have Starbucks and Wal-Mart gift cards to give when patients have a negative negative screen. I don't know if it's legal or no but it is. And then we basically use the current guidelines to assess the patient. But of course we hesitate to give these patients infusion therapy because we don't know how they're going to do and what the compliance is going to be. And also these drugs are hugely expensive. And if they're not going to get the results we want then it's the burden of the treatment is much greater than the benefit of the treatment of it. So what how do we do it. We talk screen all our new patients and it doesn't matter. You could be a professor at UC Davis. You come to my clinic for concerns for pH. You get a talk screen because we cannot discriminate. We cannot pick and choose which patients to talk screen. So that's why it is that way. And patients if they have a positive talk screen are told that this is something they're going to they have to accept that if they're going to establish care with us every now and then they're going to have a talk screen. Some get very upset but it is what it is. We're kind of still figuring out kind of gentler ways of doing this extensive counseling on association of meth with pH. The moment you tell them that the meth is causing the pH some uncle and had some cardiopulmonary problem that was never diagnosed by the doctors and that's the reason they have it. So that story goes on and we go back and forth and it just goes on. So pH and then extensive counseling on the pH disease state and therapies including showing them the pumps even though we are not going to give it to them. Mandatory referral to the substance abuse team and pharmaceutical interventions. Those who will agree and then we initiate them on a PD 5 inhibitor and ER in a stepwise manner. So we start them on a PD 5 get them a little bit better bring them back to clinic real quick within the month another talk screen and then maybe we add the ER in it sort of just to kind of get those touch points get the buy in get the sort of this notion that we do care and we want them to get better and and then they get talk screens and follow up visits sometimes they get shouted at for that and then back to my patient and then I should complete this. So if they stay clean and they have abstained from using meth and their hemodynamics are still bad then we would progress on and we give them prostacyclin therapy which could be subcutaneous infusion or oral or even IV in some cases depending on what they need. But once they've established that then we they we escalate up therapy as appropriate for guidelines. But I have to tell you a lot of patients improve dramatically if they quit using so back to my patient we treated her with diuretics as she was informed and threatened with infusion therapy and she was referred to the substance abuse team. I mean there's no you know from the cat lab she was admitted and diaries based on those numbers. And back to my question how would you treat this patient. Anybody change their mind. All right. We think we'll go for it and PD 5 and that's what we did. We put her in a year era and a PD 5 and this is the other thing that I think is unique about meth related pH. Again I'm comparing my experience with IPH and now that you take a patient whose cardiac index is one point three eight. I know have sitting right here and he's saying what were you thinking. I'm at the with an RV DP of 21 and RV that looks near dead and you put them on an era and a PD 5 take away the meth and this is what they look like. The echo starts to look quite a bit better though still not normal. Her walk is still limited. She needs further therapy but now she's been clean for 18 months so we can give her whatever she's willing to take and get better. So but a lot of patients when we hit that point when they start getting better that's actually the highest risk of going back to their old ways and friends and slipping again. So it never ends and they're never home free. So with that I thank you for your attention and that's my new puppy. Well I'd like to thank our methamphetamine experts and for what it's worth. My approach to treating meth is very similar to what Nomina just presented and I would go be as bold to say that this is definitively a different phenotype of pH that's probably more distinguishable than any other phenotype within the pH family. So I have a little bit of a challenge to talk to you about addiction and I'm doing this with the help of Dr. Purdue who's one of our addiction psychiatrists who helped point me in the right direction. I don't have any disclosures that are relevant to this but I want to make sure that you understand that I don't have any affiliation with the pharmaceuticals that I'm going to be discussing today. OK. And there is an industry and I probably could get industry sponsors but I decided not to do it. So we're going to appreciate the power of methamphetamine use and the addiction that comes with it and maybe develop a little bit of a behavioral construct. And then also I'm hoping that through the threads of this you remember your why why we're doing this. So addiction is a chronic relapsing disease of the brain. It's a physiologic disease triggered by repeated exposure to drugs and those who are vulnerable as has been discussed earlier because of environmental and social exposures. It involves being having a compulsion to take a drug then losing control over intake and then having a negative emotional state feeling sad when you take a drug. And then having a negative emotional state feeling sad when you can't get it. OK. And it's related to both impulsivity and compulsivity. We think a lot about the impulsivity of it but poorly planned risky behavior. And but that's coupled with compulsivity of behavior that persists inappropriate to a situation you're doing it just because that's what you do. OK. It almost becomes an identity and then you get relief for from stress when you do it and then you start thinking about it again and you can't get your mind off of it. OK. And over time interestingly drug use shifts from impulsivity to compulsivity and it goes from positive to negative enforcement. And when you get persistent repeated exposure to drug like what happens with a lot of prescription drug. OK. A lot of dopamine release at least two changes in gene expression and synaptic activity. OK. And there's neuromodulatory effects that happen and you start to get reduced amount of dopamine release in the limbic and sensorimotor regions of the brain. You get increased release with exposure to drug cues not so much the drug itself. So if you're if you see the meth pipe that's what kind of starts the high more than the than the meth itself over time. And then really importantly you get diminished activity in the dorsolateral prefrontal cortex especially. And why does that matter. Because this is what the prefrontal cortex does. OK. So there is a physiologic change in the prefrontal cortex. It is where all of your executive functioning takes place. So when we see the poor behavior of addicts and we think that it's just a decision that they're making it's more than that. It's like blaming somebody's tumor. Don't blame the tumor. This is what's happening as part of the disease. OK. So if you can see in the normal in the upper left of that graphic there those blue dots are dopamine and when you expose someone to methamphetamine you get a massive release of dopamine and dopamine is the pleasure hormone. Right. So this has been alluded to already but you get an increase in dopamine you get an increase in norepinephrine and serotonin it's like the world's best SSRI. OK. Like beyond good up to a point. There's also a enzyme that is called VMAT2 that's supposed to reuptake some of those dopamine particles in the presynaptic neuron and that actually gets reversed. So it's just flooding the neuron. OK. So the net effect is is that you get this massive release of norepinephrine and dopamine and serotonin and methamphetamine is really powerful. It's five times more powerful than your Adderall or Ritalin. OK. You get twice as much calcium. And if you look at the effects of dopamine release in the nucleus accumbens. OK. It dwarfs cocaine. It dwarfs sex. It is a massively addictive drug. OK. And as Dr. Perdue pointed out to me the nucleus accumbens is the it's a surrogate right. The level of activity here is a surrogate for the degree of addiction. So not only are you getting a lot of dopamine but you're getting it at the part part in the brain that really controls addiction. So what is methamphetamine. A Japanese pharmacologist in the late 1800s found that you put ephedra with iodine and you can get crystal methamphetamine. So the question my one question for you is what is the half life of methamphetamines. I'm going to give you 15 seconds you guys got to go back to school because it's 10 to 12 hours. OK. So a little bit of metabolism for you. You have multiple ways of getting methamphetamines. It's you can get an IV inhaled snorting oral or you can also get it by what some of my patients call a booty bump and I'll let you figure that out. But it's mucosal. OK. And it happens. The peak concentration is at two and a half hours and the half life is around a half a day. OK. It's primarily excreted in the urine and your urine drug screen can be positive for up to about five days after use. OK. So just a little bit. Lana did a good job of of talking about some of the nuts and bolts of actual drug use but methamphetamine. These are photos taken from a friend of mine who is a assistant U.S. attorney works in Oklahoma City and he's kind of like half attorney half FBI agent. OK. And his job sounds really fun actually. But in the upper right hand corner you see bags kilograms of methamphetamines that are axle greased and that's so that that drug dogs can't smell them. OK. And the lower right is what he called a typical meth bust in Oklahoma City is about 120 pounds of meth sitting on the front of that car. The front of that car and in the lower left hand corner is liquid meth that comes up in diesel tankers from Mexico in huge quantities and they just they distill it out with acetone and heat. And per his estimation based off him and his buddies we have about 500 kilograms of methamphetamines coming into Oklahoma City every week. OK. So I'll breeze through this because in the late 90s and early 2000s methamphetamines was made with Sudafed and you got me. OK. They called this bathtub meth. It was about a half to half a five hundred to a thousand grams per yield. All right. And it was 30 to 60 percent pure. Now what we have is super labs with the help of cartel distribution. We get thousands of kilograms produced in batches that are 98 percent pure. So this is again for my friend Jason who they run methamphetamine purity on all of their bus and it's this it's 98 percent pure. He said everything that they see now in the last five to seven years is 98 percent pure. So now we're getting in an exponentially higher quantities and we've gone from about 50 percent purity to absolutely pure methamphetamines. The price of methamphetamine is subject to market forces like anything else. OK. But in Oklahoma City around 2017 it was about eight thousand dollars for a kilogram. During the pandemic it went up significantly and now it is flowing across the border with a tremendous amount of ease and you can get three and a half out for three and a half grand. You can get a kilogram of meth and one hit is about somewhere between a quarter to one gram. That's a lot of doses of methamphetamines for a very cheap price. OK. So this graph was seen in a different form earlier. The bottom line here is is that death associated with methamphetamine is now on the rise in the late 2000 teens. You see that wave for in that red line that's coming with fentanyl and stimulants. But a DEA agent shared this in an email with me that in 2020 there were six hundred and twenty nine meth related deaths but four hundred ninety two were only meth not fentanyl involved. So it kills you both fast and very slow. OK. This is if you want to see where your state is at in your progression of meth use over the last five years. OK. There's a lot of dark lines in the northeast because it was really really uncommon there. And now it's coming. So it doesn't matter where you live. It is coming. I wish I had more time to share with you some of my my buddy's stories but it's it's coming and methamphetamine is everywhere. This is from the SAMHSA National Survey from 2021 two and a half million users in the United States and that's on the on the on a big rise. Substance use disorder is 12 potential variables. The more you hit the more severe your substance use disorder is and methamphetamine compared to all other illicit drugs has the most severe substance use disorder. These people are really impaired. OK. They have codependence and high morbidity. They use other stuff. And this says that the degree of mental illness is somewhere in the 50 to 60 percent range. I would submit to you that that number is probably somewhere in the 80 to 100 percent range. OK. These are self-reported numbers. Lana has presented on this nicely. These patients are incredibly disadvantaged. So lastly I want to take a step back. OK. And I want you to put yourself in the in your in their shoes for just a minute. OK. Just take a step back and put yourself in the shoes of one of our patients. So imagine that you're 45. You've got kids aged 5 to 15. You used to work in the oil fields in western Oklahoma but you lost your job. You used to have really good insurance and now you're struggling to get sooner care which is our Medicaid and you've done mess since the age of 16. Many start earlier than that. OK. You smoke it every day and now you can't pick up your kids because you get lightheaded. You can't chase them around. OK. In the exam room it's almost all it's ubiquitous. They don't make very good eye contact with you. They're looking down at the floor a lot and their spouse or their significant other is also doing the same. OK. You're embarrassed beyond your ability to express and then you have this. OK. This is what they look like. OK. Nomina gave you the hemodynamics behind this but that's what it looks like. OK. So many of these patients. Stop what you're doing. If you're taking care of these patients put the computer aside put your paperwork aside because if you don't do this and you don't engage them you will lose them. Stop what you're doing. Take a few minutes. You have to take a little bit of time with them. Look them in the eye. Take your doctor hat off and find out about them. Find out about what they do. Find out about what their struggles are why they're doing it because they will be incredibly horrifyingly honest with you because they don't have people in their life they can trust. That's not the life that they live. So they're looking at you as someone that probably they're coming in very skeptical because they don't trust people. You've got to be different. And in order to be different you have to be different with them. It's not business as usual. This isn't a meth addict. It's not a meth patient. It's a dad a brother a son who's dealing with might with a life threatening problem. And that was before they knew that they even had pulmonary hypertension. You have to solve the problem that the patient needs solved. Not the one that you're comfortable solving. Motivational interviewing is a technique to do that. It's something that's used in the psychiatric world a lot. OK. You have to be non judgmental. That's the overriding theme here. Listen to them. Be non judgmental. Ask them questions. Get interested in their life. OK. Don't give them advice that unsolicited advice. Don't tell them what you're what they have to do. Listen to them. OK. And if you don't take anything else away. Nomina alluded to this in what she does in her practice. You've got to get them engaged. If you don't engage them and you don't show them that you love them and that you care about them you are going to lose them. OK. You have to put 100 percent of your focus on how you're going to get the patient to trust you and your team. If you don't do that then go ahead and auto populate your note because they're not coming back. And I will take this moment to say that at least in the Western United States if we took over the 12 the next 12 months incidence of pulmonary arterial hypertension I will bet you that more than 50 percent are methamphetamine related over the next year. This is a major problem and it's not going away. So my request to you OK is that we eliminate this narrative. This is a narrative that is damaging. It's judgmental and it's disrespectful for the disease. We have no idea. You have no idea. I have no idea what these people live and how they live. And yet we kind of throw them into this dirty basket right of patients who just did it to themselves. We can do better than that because the last time I looked in the mirror I was living in a glass house and if you want to throw a stone out you'll find out real quickly that you have a lot of faults of your own right. That's humanity. And this is just a different element of humanity that we're seeing. So we need to remember that there's art to medicine as well as science and that warmth sympathy and understanding will always outweigh the surgeon's knife or the chemist's drug. Thank you so much for coming.

methamphetamine epidemic

pulmonary hypertension

cardiovascular toxicity

methamphetamine-associated PH

regional burden

treating methamphetamine-associated PH

counseling effectiveness

treatment algorithm

multidisciplinary approach

patient trust

PH