2 Acknowledgment and Dedication I would like to thank Dr. Laurie Coburn for guiding me through the process of writing this thesis and for the invaluable instruction and insight into the world of the radiologist assistant, all while navigating a pandemic. You are truly a blessing and your support will not be forgotten. My gratitude extends to committee members, Dr. Cheryl Walczak and Dr. Joseph Ocel, who expressed sincere interest in methamphetamine cardiopulmonary injury and took the time out of their busy lives to help bring this manuscript to completion. I must include my classmates in the list of those who made this work possible. Thank you for the late-night text messages and encouragement. We did it! Not a single sentence of this work would be possible without my amazing family. My Mom and Dad gave their time, support, and goulash dinners (that probably helped the most). My in-laws have proven to be fabulous dinner hosts and great babysitters! Alex has picked up my slack for the last year, heard the word “thesis” more than his own name, and has taken over laundry and vacuuming tasks completely. Thank you. Last, but certainly not least, my reason for everything -- Noelle. You probably made this work a little harder to finish so I’m not saying “thanks” per se. Never forget: you can do anything you set your mind to. You are my favorite. This is for you. 3 Table of Contents LIST OF FIGURES ................................................................................................................................................ 4 LIST OF TABLES.................................................................................................................................................. 5 ABSTRACT .......................................................................................................................................................... 6 INTRODUCTION ................................................................................................................................................. 7 PURPOSE ............................................................................................................................................................. 9 METHODS ......................................................................................................................................................... 10 REVIEW OF LITERATURE ................................................................................................................................ 12 METHAMPHETAMINE USE CHARACTERISTICS ............................................................................................................... 12 CELLULAR INJURY DUE TO METHAMPHETAMINE........................................................................................................... 16 METHAMPHETAMINE-INDUCED LUNG INJURY ............................................................................................................... 19 METHAMPHETAMINE-INDUCED CARDIOPULMONARY COMPLICATIONS ............................................................................ 24 SCREENING FOR ILLICIT DRUGS .................................................................................................................................. 29 DISCUSSION ...................................................................................................................................................... 31 REFERENCES ..................................................................................................................................................... 34 APPENDIX A ...................................................................................................................................................... 39 FIGURES .................................................................................................................................................................. 39 APPENDIX B ...................................................................................................................................................... 46 TABLES ................................................................................................................................................................... 46 APPENDIX C ...................................................................................................................................................... 48 LIST OF ABBREVIATIONS .......................................................................................................................................... 48 APPENDIX D...................................................................................................................................................... 49 PERMISSIONS ........................................................................................................................................................... 49 4 List of Figures Figure 1. Whole body PET images depicting uptake of radiolabeled methamphetamine. . 39 Figure 2. Methamphetamine-induced eosinophilic pneumonia. ................................................... 40 Figure 3. Chest radiograph following corticosteroid treatment. ................................................... 41 Figure 4. Chest CT image depicting methamphetamine-induced lung injury. ......................... 42 Figure 5. Lung tissue samples from methamphetamine exposed and control rats. .............. 43 Figure 6. Proposed mechanism of injury to pulmonary vessels.................................................... 44 Figure 7. Methamphetamine effects on immune cells in mice. ...................................................... 45 5 List of Tables Table 1. Discharge demographics in the state of California from 2005-2011. ........................ 46 Table 2. NIDA Quick Screen questionnaire. ............................................................................................ 47 6 Abstract The United States is facing a surge in methamphetamine use due to the low cost of the drug and increased purity. Diagnostic medical imaging plays a key role in diagnosing cardiopulmonary injuries. Knowledge of methamphetamine use in patients with these injuries can change the course of treatment dramatically. Oftentimes, the complication may resolve with supportive care and cessation of use without aggressive treatment therapies. Drug screening and testing should be performed routinely when indicators of use are present to avoid unnecessary interventions. 7 Introduction The use of methamphetamine and its derivatives is on the rise in North America. The United Nations 2019 World Drug Report states “North America has the highest prevalence of use of amphetamines (amphetamine and methamphetamine).”1 There are a number of reasons methamphetamine has become popular in the United States: relatively low cost, long-lasting high, and ease of procurement of the drug.2,3 A study by Evren and Bozkurt published in 2018 reported that more than 12 million adults in the United States admitted to using methamphetamine at least once in their lifetime and 440,000 people admitted to using methamphetamine within a year of the study.4 Methamphetamine was first synthesized in 1893 by Japanese chemist, Nagai Nagayoshi, and was widely used during World War II to promote prolonged wakefulness in soldiers.5 Methamphetamine and amphetamine were developed as a synthetic substitute for ephedra.6 In the 1950’s and 1960’s, methamphetamine was manufactured and prescribed in the US to treat depression and obesity. By the 1950’s, the United States and Japan were already experiencing large-scale usage and addiction of methamphetamine.4 Today, methamphetamine is a Schedule II stimulant in the United States. The cost of methamphetamine has remained low, despite its popularity, as the drug can be synthesized in small batches from over-the-counter ingredients, leading to small producers around the country -- particularly in the Midwest.7 According to the United States Drug Enforcement Administration’s 2018 National Drug Threat Assessment, the purity of methamphetamine seized averaged at 90 percent or purer.2 8 Methamphetamine use has been widely documented across geographical areas, socioeconomic backgrounds, age, race, and level of education; however, its abuse is largely stigmatized.8 Methamphetamine can be administered to the user in many different routes: smoking, snorting, intravenous (IV) injection, and oral or anal administration. Street names include meth, crank, glass, ice, crystal, crystal meth, and speed.9 Compared with the half-life of cocaine (one hour), methamphetamine is a highly addictive stimulant with a half-life of 12 hours.10,11 Methamphetamine concentration has shown to be highest in the lungs and kidneys after injection. Due to elevated concentrations in the lungs and the known pulmonary toxicity of methamphetamine, lung injuries in methamphetamine users are common. Racial differences exist in lung uptake, as higher concentrations were found in the the lungs of African Americans than in Caucasians after administration of similar doses. Figure 1 illustrates the uptake of radiolabeled methamphetamine in the organs of African American and Caucasian males by use of Positron Emission Tomography (PET).10 Further study of the differences in uptake between age, race, and gender may broaden the understanding of which demographics of methamphetamine users are at a greater risk for pulmonary injury. Methamphetamine use should be suspected in patients that demonstrate a number of physical and behavioral traits indicating use. Patients may complain of dry mouth, dental symptoms, formication, and frequent sores. Behavioral traits include paranoia, impaired word recall, and difficulty ignoring irrelevant information.8 There are many reported cardiopulmonary health complications of methamphetamine abuse including increased blood pressure, myocardial infarction, aortic dissection, pulmonary toxicity, pneumonia, pulmonary edema, and 9 pulmonary arterial hypertension. Other complications of use include insomnia, increased risk of human immunodeficiency virus (HIV), brain injury, and birth defects in the children of users.8,9,12 Purpose The United States leads the world in methamphetamine abuse1 and is second only to cannabis as identified by the National Forensic Laboratory Information System 2016 Annual Report.2 With widespread use of methamphetamine in the country, healthcare providers can expect to see a variety of methamphetamine-induced complications that include cardiopulmonary injury. The recognition of thoracic imaging findings in the setting of methamphetamine use is important, as the underlying cause of patient’s symptoms may not be known at presentation. Testing for illicit drug use can prevent unnecessary and potentially incorrect treatment when imaging findings may guide diagnosis and management of these patients. Although there are many reports of cardiopulmonary complications attributed to the use of methamphetamines, there are very few studies that include a comprehensive account of those complications and how to treat this specific patient population. The purpose of this report is to elucidate methamphetamine demographics, provide a compilation of methamphetamine use complications with associated imaging findings, report treatment alternatives for methamphetamine induced cardiopulmonary injuries, and provide education and guidance for drug screening in the acute clinical setting with regards to methamphetamine-induced cardiopulmonary injuries. 10 Methods Initially, the research began with an interest in the known adverse effects of methamphetamine on the lungs and the associated imaging findings. “Methamphetamine” and “lung injury” were the primary search terms used. Although the search yielded several case studies indicating methamphetamine use as the cause of lung injury, the search was expanded to include cardiopulmonary injury due to the close relationship of the cardiac and pulmonary systems and associated pathologies. In order to further understand how to treat this specific patient population, the search was again extended to include demographics and medical treatments used in the event of cardiopulmonary complications due to methamphetamine use (and its derivatives). Additional research revealed the lack of systematic review and gaps in information on the topic. Therefore, a scoping review was performed in order to identify the current body of knowledge on the topic. A scoping review can be described as a review of a broad topic to evaluate the literature for areas that require further inquiry prior to performing a systematic review or meta-analysis. Scoping reviews pursue all avenues of available research on a topic, thereby lessening reporting bias.13,14 Scholarly databases were searched (i.e. PubMed, Google Scholar, Science Direct, NCBI, MEDLINE, PLOSONE) from November 2019 through the Fall of 2020. Many of the articles’ references were also reviewed and incorporated. The search was limited to published peer-reviewed articles and abstracts, government publications, and a report published by the United Nations. Only publications written in English (or translated to English) were included in the search and subsequent review. 11 The population of the study was defined as adults (aged 18 years and older) who have suffered cardiopulmonary injury due to use of methamphetamine or one of its derivatives. Since methamphetamine is an illicit drug, this study includes results of case studies from patients with known methamphetamine use, including derivatives, as well as demographic information published by the United Nations and other government agencies. Several studies utilizing a murine model were included that contained data on the possible mechanisms of injury to vascular intima and lung parenchyma. Finally, appropriateness criteria for drug screening and testing in the clinical setting was included based on current recommendations from national medical specialty societies. Ultimately, the review of literature was driven by several related questions: • What is methamphetamine and its derivatives? • How is methamphetamine introduced into the body? • What are the population demographics of those that use methamphetamine? • What types of cardiopulmonary complications can be expected in the setting of methamphetamine use? • What are the diagnostic imaging findings of cardiopulmonary injury in the setting of methamphetamine use? • How does or should treatment differ for those with methamphetamine-induced cardiopulmonary injury? • What is the mechanism of injury to the cardiopulmonary vasculature and lung tissue? • What is appropriate use of screening and testing for illicit drug use in the acute clinical setting? 12 Review of Literature Methamphetamine Use Characteristics In a brief report by the United States’ Drug Enforcement Administration (DEA) in 2017, a number of statistics relevant to the study of methamphetamine-induced cardiopulmonary injuries were published. In 2016, 7,663 people died in the US from complications from the use of psychostimulants. While psychostimulants are a broad category including MDMA (3,4- methylenedioxy-methamphetamine) and amphetamines, the Centers for Disease Control stated that most of those deaths were due to methamphetamine abuse.2 The cost of methamphetamine has remained very low as the purity of the drug has improved. It is assumed that the cost of methamphetamine remains low due to the increase in trafficking of the drug into the United States, mostly from the Southern border.1,2 Methamphetamine is classified as a Schedule II stimulant under the authority of the Controlled Substances Act of 1970. Despite being a controlled substance, methamphetamine is a widespread problem, as the prevalence of use reportedly doubled in the US between 2008 and 2017.1 Since methamphetamine can be “cooked” in small batches using over the counter ingredients, not only is the drug quite readily available and widespread, but there is a variation in the chemical makeup of cooked methamphetamine. In 2017, the United States reported discovery and elimination of 3,036 methamphetamine-producing laboratories. The fact that 3,661 methamphetamine labs were reported worldwide that same year sheds light on the methamphetamine epidemic in the United States. Given this staggering number, it’s not surprising that the number of cross-border drug trafficking operations are increasing as well. The use of drones can make smuggling of illicit drugs across the Mexico-United States border 13 simpler, as physical barriers are less problematic, and the drone operators are able to transport illicit substances without risk of apprehension by authorities.1 Methamphetamine (N-methyl-alpha-methylphenethyl-amine), is also known as metamfetamine, N-methylamphetamine, methylamphetamine, and desoxyephedrine. Known effects include euphoria, alertness, wakefulness, hyperactivity, loss of appetite, and increased confidence.4,15 The methamphetamine molecule is a cationic molecule with a phenylethylamine core and differs from amphetamine as it is a synthetic molecule with an additional methyl group.15 There are two stereoisomers of methamphetamine, D-methamphetamine (the dextrorotatory enantiomer) and L-methamphetamine or levmetamfetamine (the levorotatory enantiomer). D-methamphetamine has 3 to 5 times more powerful effect on the central nervous system and longer lasting effects than its enantiomer.15-17 Most samples of methamphetamine seized in Europe are a nearly equal mixture of both the D- and L-enantiomers or a racemic mixture.15,18 Two forms of methamphetamine exist: a base and a salt. The powder and crystal forms of methamphetamine are water soluble, often used for smoking, and usually contain contaminants including caffeine, lactose, and dextrose. Methamphetamine hydrochloride is the most commonly found salt form of the drug. The base form of methamphetamine is a clear, indissoluble oil that may be transformed into the salt form.18 Ephedrine and pseudoephedrine are over-the-counter precursors to methamphetamine used in a “one-step” method for small batch manufacture. Some countries, including the United States, have seen a decrease in this method by means of restricting access to pseudoephedrine and ephedrine.4 In 2005, Congress passed the Combat Methamphetamine Epidemic Act that required all pharmacies and retailers of over-the-counter medications containing 14 pseudoephedrine to keep a log of sales. This act also required limits on the amount of these medications being sold over the counter to individuals.11 However, new methods for production have emerged using phenylacetylcarbinol as a precursor.4 Over the counter nasal decongestants such as the Vicks® VapoInhaler® continue to use L-methamphetamine as the active ingredient. The Proctor & Gamble Company applied for an exclusion of the Vicks® VapoInhaler® with the DEA in 2012 stating that the company had lowered the dose from 113 mg to 50 mg and changed the wording on the packaging from l- desoxyephedrine to levmetamfetamine. As the active ingredient was determined not to be a narcotic but a Schedule II drug, it was allowed to remain on the shelves of pharmacies and general stores for use as a nasal decongestant. The use of the VapoInhaler® and its ingredients for purposes other than as directed is considered illegal according to the United States Drug Enforcement Agency.19 Desoxyn® ((S)-N,α- dimethylbenzeneethanamine hydrochloride or D-methamphetamine) is a prescription medication that is used to treat Attention Deficit Disorder with Hyperactivity (ADHD) in persons 6 years and older. The active ingredient in the medication is the salt form of methamphetamine, methamphetamine hydrochloride. The inactive ingredients include talc, corn starch, lactose and other innocuous binding substances.20 It is worth noting that the D- methamphetamine enantiomer has a higher potential for abuse because it provides a more intense stimulant effect due to more rapid uptake in the primate brain than the levo enantiomer.17 Due to the chemical nature of methamphetamine, the molecule is lipophilic and easily crosses the blood-brain barrier.6,15 Chronic use of the drug induces mitochondrial dysfunction, endoplasmic reticulum stress (ERS), enhanced reactive oxygen species (ROS) production, and neuronal cell death.15,21 Protein synthesis is adversely affected through injury to the 15 endoplasmic reticulum (ER) by methamphetamine. A cascade of reactions can ultimately cause ERS that is severe enough to invoke cell apoptosis.21 While the effects of methamphetamine on neuronal cells have been studied at length, the mechanism of injury to lung parenchyma and the cardiovascular system is yet unclear and requires further research. In 2017, Environmental Toxicology and Pharmacology published a study by Gu et al21 that detailed pulmonary injury in rats due to methamphetamine. Alveolar damage, loss of epithelium of the alveolar wall, and infiltrative inflammatory cells were noted in the groups of rats injected intraperitoneally with methamphetamine. The findings were highly suggestive that elevated ROS contributed to ERS and eventually led to chronic pulmonary injury.21 A 2010 study proposed methamphetamine’s pulmonary toxicity was due to increased concentration within the lung parenchyma. In this one-of-a-kind study, PET was used to assess the whole-body distribution, uptake, and clearance of radiolabeled methamphetamine in 19 men.10 The results concluded the highest uptake within the lungs, liver, and brain after IV injection. The high pulmonary concentration seen with methamphetamine is likely the cause for injury to the lungs. This injury makes the lungs more susceptible to infections and other pathological conditions, confirming the findings of a prior study that involved non-human primates.10,17 As there are several chemical variations of methamphetamine found in the illicit form, further investigation may be warranted in order to understand how each molecular subset behaves within the organ systems. Another interesting finding that necessitates further research was the increased uptake in the 10 African American men when compared to the 9 Caucasian men (Figure 1).10 This suggests that some populations may be more vulnerable to methamphetamine-induced cardiopulmonary injury than others. 16 Cellular Injury Due to Methamphetamine While the exact mechanism of injury to the lungs and pulmonary vasculature has not been fully detailed, several studies in recent years have provided insight on the possible mechanism. A study from 2008 investigated the acute lung injury from inhalation of methamphetamine in mice. This research laid the foundation for further investigation into methamphetamine associated lung injury. Methamphetamine is easily vaporized upon heating, with 81-91% of the drug remaining intact within the vapor.22 Upon inhalation, the drug is readily absorbed. As Volkow et al10 demonstrated in their 2010 study, the lungs accumulate high concentrations of methamphetamine, even when injected intravenously. The lungs of mice exposed to inhalation of methamphetamine vapor, at levels lower than those seen in human methamphetamine users, were noted to have damage to the airway epithelial cells as well as a decrease in the number of small arterioles in peripheral tissues.22 The results of the study on acute inhalation of methamphetamine in mice have been further investigated in rats. Wang et al23 recently published a study in Cell Proliferation that further details the mechanism of lung injury in rats. The research focused on the alveolar epithelium and its function in maintaining pulmonary homeostasis. Chronic methamphetamine exposure was shown to have a negative effect on the tight junctions and adherent junctions of the alveolar epithelial cells (AECs). ZO-1 and E-cadherin are proteins found in epithelial cells and are responsible for maintaining a tight seal between the cells which protects the integrity of the barrier of the epithelial cells.22 The AECs act as a barrier to the submucosa by physically preventing foreign materials and pathogens from infiltrating deeper into the tissue and by activating an immune response. When the AEC barrier is disrupted or injured and unable to be 17 repaired, the alveoli become flooded with extracellular matrix. Eventually, fibrotic scarring can replace normal tissue.24 In the presence of chronic methamphetamine use, ZO-1 and E-cadherin expression were reduced, allowing for disruption and injury to the AECs in rats. Furthermore, the lung tissue, observed in rats exposed to chronic methamphetamine, contained more dense parenchyma. The alveolar walls were thickened with a reduced number of alveolar sacs (Figure 5).23 In addition to the AECs, the pulmonary microvascular endothelial cells (PMVECs) are susceptible to injury from methamphetamine by way of internalization and metabolization. Destruction and subsequent loss of microvessels within the pulmonary vasculature results in the gradual inability of the right heart to pump deoxygenated blood into the lungs in the setting of PAH.25 A 2017 study on human lung samples obtained from patients with healthy lungs, idiopathic PAH, and methamphetamine-induced PAH (METH-PAH) was the first of its kind to identify genes that may be attributed to development of METH-PAH. The study also noted that the PMVECs were capable of metabolizing methamphetamine as they contained carboxylesterase 1 (CES1) and the cytochrome P450 2D6 (CYP2D6), liver enzymes that are largely responsible for metabolizing amphetamine and its derivatives. Orcholski et al25 found that a decrease in CES1 expression within the PMVECs resulted in a higher rate of methamphetamine-induced apoptosis due to increased ROS,21 leading to small vessel loss.25 While further research is required to understand the exact pathway of CES1 and neutralization of methamphetamine toxicity, there is evidence that individuals that have a decreased CES1 and CYP2D6 expression may be at an increased risk for developing PAH in the setting of methamphetamine use.25 18 A study utilizing lung tissue from four recipients of lung transplants -- three of which had a diagnosis of amphetamine-induced PAH and one with idiopathic PAH as well as four control lung donors -- showed that amphetamine or methamphetamine abuse caused DNA damage to pulmonary artery endothelial cells (PAECs). DNA damage was intensified when the PAECs were in a hypoxic state, ultimately causing an increase in mitochondrial ROS and activation of caspase- 3. The use of methamphetamine/amphetamine was found to undermine the cellular function in response to stress and ultimately lead to DNA damage within the PAECs. The study also found that in cases where the patient had stopped using amphetamines for a significant amount of time prior to transplant, DNA damage was still evident. The authors hypothesized that DNA repair mechanisms within the cells remain damaged, even after cessation of use.26 Methamphetamine users are at increased risk for community acquired pneumonia, injection site infections, and viral infections including.1,4,7,11 Using a murine model, a 2012 study examined the effects of methamphetamine on the immune system.27 Methamphetamine was administered via intraperitoneal injection for 14 days while the control group received intraperitoneal saline injections. The spleen and mesenteric lymph nodes were harvested and examined. Findings were consistent with altered immune function (Figure 7) by decreasing the number of natural killer (NK) cells and altering the phenotype of the remaining NK cells, decreasing their responsiveness. GR-1high monocytes/macrophages were depressed as GR- 1low cells increased expression of CD80. Dendritic cells also decreased in number. This study indicates that methamphetamine is disruptive to the homeostasis within the immune system, increasing the risk of more severe infections in users.27 19 Methamphetamine-induced Lung Injury A multitude of cardiopulmonary complications have been reported with the use of methamphetamine use, including non-cardiogenic pulmonary edema,5 respiratory failure, hypotension, pulmonary arterial hypertension,6,8 cardiac arrhythmias,15 pneumothorax,3,12 pneumomediastinum,28 eosinophilic pneumonia,29 aortic dissection,30 emphysema, pneumoconiosis,12 and pulmonary fibrosis.31 Many of these conditions can be life-threatening without intervention; however, prognosis and treatment plans may differ depending on the pathogenesis. As several case studies have reported, supportive therapy and cessation of methamphetamine use is often sufficient for recovery. Although in some cases, such as aortic dissection, more aggressive interventions are necessary. Eosinophilic pneumonia (EP) is a serious condition where eosinophils collect in the lungs. EP may become life-threatening. As EP progresses, the interstitial space is infiltrated by eosinophils as well as a fibrous exudate that will eventually invade the alveoli. Patients suffering from EP may present with a dry cough, chest pain, and dyspnea. The diagnosis of EP is reliant on histopathology evaluation. A 2014 case study published in the Chinese Journal of Physiology documents a 31-year-old man admitted with a high fever, cough, and dyspnea that required mechanical ventilation. At the time of admission, it was unknown that he frequently inhaled crystal amphetamine. Upon presentation to the emergency department, a chest x-ray (CXR) was obtained that demonstrated bilateral, peripheral opacities. Initially, broad-spectrum antibiotic therapy produced improvement in the patient’s condition, but his condition declined on the second day of admission, requiring intubation and mechanical ventilation. Follow up CXR and chest computed tomography (CT) showed worsening progression and consolidation with air 20 bronchograms (Figure 2). At that time, crystal amphetamine use was discovered. Lung biopsy and subsequent histopathology results confirmed EP. Intravenous methylprednisolone was administered and the patient improved, was extubated on day 10, and discharged 19 days later. A CXR taken after corticosteroid treatment shows near complete resolution of the infiltrates (Figure 3).29 Pneumomediastinum and pneumothorax have been documented in the literature as rare complications of inhaled illicit substances.12,28 The proposed mechanism of action for these complications is due to barotrauma – vigorous inhalation followed by Valsalva maneuver when smoking methamphetamine. Rupture of alveoli and dissection of air into the pulmonary interstitium can result in pneumomediastinum, pneumothorax, and rarely pneumopericardium.3,12 Pneumothorax may occur with the intravenous injection of any type of drug when attempting to inject the supraclavicular fossa. This is termed the “pocket-shot” amongst substance users. While attempting to access the subclavian vein for injection, the superior lung is punctured. Associated pyopneumothorax may occur.12 Pneumomediastinum, pneumothorax, and subcutaneous air were reported in a 22-year-old male that presented to the emergency department complaining of chest pain and dyspnea. The patient stated he had run a marathon two days prior; however, his lab work results were unremarkable and inconsistent with recent extreme exercise. This young man had been treated for syphilis and was recently diagnosed with HIV. Urine toxicology confirmed methamphetamine use. After further questioning, the patient stated he had been using methamphetamine for the two months leading up to his admission and that his chest pain developed after 21 methamphetamine inhalation. Chest imaging one month later demonstrated resolution of the prior CXR abnormalities.32 Knowledge of recent use of methamphetamine, especially if inhaled, when pneumomediastinum has been diagnosed may alter the treatment and management of the patient. Respiratory Medicine Case Reports published a case report in 2017 detailing the spontaneous pneumomediastinum with subcutaneous emphysema in a 28-year-old male after smoking methamphetamine without history of trauma. Pneumomediastinum and subcutaneous emphysema were demonstrated on chest radiograph. The patient’s symptoms did not worsen, and he was discharged after receiving supportive oxygen therapy, pain management, and rest.28 This case highlights the importance of knowledge of history of methamphetamine use in the setting of pneumomediastinum. Oftentimes, in the event of a patient presenting with spontaneous pneumomediastinum, a chest CT is performed along with other radiological exams such as a neck CT, esophagram, and bronchoscopy to evaluate for the underlying cause of the pneumomediastinum.33 These types of interventions increase the radiation exposure and dose to the patient, increase the cost to the patient, and carry undue risk to the patient. As Albanese et al28 report, follow up imaging was not necessary after their patient recovered. The patient was discharged without further expense or undue exposure to ionizing radiation as inhalation of methamphetamine was determined to be the cause of the spontaneous pneumomediastinum.28 Non-specific radiological imaging findings on CXR and/or chest CT in the setting of respiratory distress without obvious cause can be an indicator of methamphetamine-induced lung injury. In these cases, the treatment is supportive and the patient’s symptoms resolve after cessation of use of the offending drug. In the European Journal of Case Reports in Internal 22 Medicine, McCarthy and McClain5 discuss the importance of physician knowledge of differential diagnosis including respiratory distress due to methamphetamine abuse. In this case, a 44-year-old male presented to the emergency department with frothy sputum, palpitations, shortness of breath, and a pink-colored productive cough. Initial screening of the patient included questioning about his history of drug use. The patient denied usage of illicit drugs but admitted to smoking 10 cigarettes per day. Patchy bilateral infiltrates were visible on his chest radiograph, suggesting infection. He required oxygen via nasal cannula to maintain saturation above 94%. A chest CT demonstrated additional non-specific findings of minor bibasilar tree-in-bud changes and ground glass opacities in the right upper lobe (Figure 4). IV antibiotics were given for suspected infection. The patient eventually admitted to smoking methamphetamine regularly for the 2 months prior to his emergency department visit. At that time, the antibiotics were discontinued and the patient fully recovered with supportive oxygen therapy.5 Symptoms of methamphetamine lung injury often resolve in a relatively short amount of time after cessation of use and with minor supportive therapy. Acute respiratory distress syndrome (ARDS) and acute respiratory failure can result from methamphetamine inhalation. Nasrullah et al34 describe a 45-year-old female patient presenting with increase shortness of breath. When the patient presented to the facility, she was tachypneic, afebrile, and hemodynamically stable. The patient had been treated for pneumonia at a different facility two days prior to seeking further treatment. At that time, she had been prescribed antibiotics for pneumonia. Upon physical exam, bilateral rhonchi and decreased breath sounds were discovered in both lung bases. Her laboratory results revealed elevated white blood cell (WBC) count of 26,000 ul with 91% neutrophils and procalcitonin of 0.34, 23 indicating a bacterial infection. The patient’s breathing became more labored and she became hypoxic and was subsequently intubated. At that time, the patient was given a more rigorous antibiotic therapy including vancomycin, cefepime, and azithromycin. Her CXR was concerning for ARDS and the CT scan demonstrated diffuse ground-glass opacities with interlobular septal thickening. Negative results returned from the infectious workup for viral or bacterial infection. Drug testing was positive for methamphetamine. On the second day, the patient’s procalcitonin declined to 0.22 and her antibiotics were changed to ceftriaxone. The patient improved and was extubated on the second day. After the patient improved, she admitted to using methamphetamine via inhalation two days prior to admission. She was discharged home with methamphetamine cessation support. Early diagnosis of methamphetamine lung injury is important for proper treatment and reduction of antibiotic overuse.34 Acute pulmonary toxicity due to methamphetamine inhalation has also been reported. One case documented a 41-year-old female that presented with acute dyspnea, fever, right pleuritic chest pain, and hemoptysis. Her oxygen saturation was 75% on room air and WBC count was 23,600 ul, primarily neutrophils. Chest imaging revealed ground glass opacifications bilaterally and a partially loculated pleural effusion. Broad-spectrum antibiotics were used to treat the apparent pneumonia. Infectious workup of blood and sputum showed no growth, and pleural fluid was confirmed to be exudative effusion from laboratory analysis. A chest tube was placed to drain the effusion, and the patient’s condition rapidly improved. The patient admitted to inhaling methamphetamine powder two days prior to admission; unfortunately, the patient left against medical advice. Due to the rapid improvement of symptoms and chest imaging 24 improvement, it was thought that abstinence from use and supportive treatment led to the patient’s swift improvement.35 Chronic lung issues such as emphysema and pulmonary fibrosis have been documented after prolonged use of methamphetamine. In an abstract originally published in the Journal of Hospital Medicine, pulmonary toxicity and fibrosis were reported as a result of inhaled methamphetamine. An axial CT image demonstrated a case of diffuse bullous and fibrotic changes due to methamphetamine use in a 52-year-old female. Even though pulmonary fibrosis is a rare complication of methamphetamine use, as the use of methamphetamines grows, there will likely be more cases of associated pulmonary fibrosis.31 An article published in Respiratory Care in 2013 documented a similar case of pulmonary fibrosis secondary to methamphetamine inhalation. A 49-year-old male with no history of occupational exposure to talc or family history of fibrotic lung disease complained of shortness of breath. CXR discovered bilateral hilar lymphadenopathy and diffuse reticulonodular changes – worse in the upper lobes. The chest CT demonstrated ill-defined reticular nodules in the posterior upper lobes. A subsequent biopsy returned negative. The sample was further analyzed with scanning electron microscopy and energy dispersive x-ray spectrometry. Results were conclusive for talc. The patient had a 20- year-long history of methamphetamine inhalation. As talc is a known filler for illicit methamphetamine, it was concluded that the cause of interstitial pulmonary fibrosis was due to methamphetamine inhalation.36 Methamphetamine-induced Cardiopulmonary Complications Acute cardiac complications are associated with the use of methamphetamine and its derivatives. A detailed case study published in the British Journal of Medical Practitioners 25 documents a methamphetamine overdose in a 38-year-old male. This man presented to the emergency department with shortness of breath, chest tightness, and sweating that began after intravenous injection of crystal methamphetamine. Electrocardiogram revealed sinus tachycardia with evidence of acute left heart failure. Although the gentleman had a history of polysubstance abuse, his symptoms began shortly after injection of crystal methamphetamine; it was decidedly likely that the IV administration of the psychostimulant was responsible for his symptoms. The patient became hypoxic and was determined to be in cardiogenic shock. He was subsequently intubated and given IV Lasix and dopamine. Evidence of pulmonary congestion was visualized on chest radiograph. After treatment with diuretics and dopamine, the patient improved, was extubated, and a cardiac catheterization showed that his left ventricular function had returned to normal. A repeat echocardiogram performed a week later was normal. “Methamphetamine is known to cause acute and chronic cardiomyopathy and the reversal of cardiac failure has been documented after discontinuing the drug.”37 Several studies have documented cases of Methamphetamine-Associated Cardiomyopathy (MAC). In one case, a 38-year-old male presented to the emergency department complaining of dyspnea, palpitations, and a single episode of hemoptysis with the onset shortly after smoking crystal methamphetamine. Examination showed the patient to have a sinus tachycardia rhythm, bilateral lower lobe rales, and was febrile. A point of care ultrasound demonstrated inferior vena cava, biatrial, and biventricular dilation with severely reduced left ventricular ejection fraction (LVEF) of 16% and a pericardial effusion. After cessation of use and medical treatment, the patient improved and his LVEF was 45% four months later.38 This singular case study correlates with the findings published in larger, retrospective studies. 26 The Queen’s Medical Center in Honolulu, Hawaii, retrospectively reviewed medical records from January 2002 to June 2004 for patients under 45 years of age that were treated at the facility with a diagnosis of cardiomyopathy and/or heart failure. Of the 59 patients that met the study criteria, 28 smoked methamphetamine and 31 did not. Among those that abused methamphetamine, the echocardiogram findings demonstrated more severe cardiomyopathy with lower LVEF and higher left ventricular end-diastolic volume.39 While this study does not demonstrate the recovery of MAC patients after cessation of use, a recently published study by Zhao et al40 gives insight into the reversibility of MAC. Between January 2004 and August 2018, all cases of MAC were retrospectively reviewed for a single, large medical center in San Jose, California. The authors defined MAC as a LVEF of ≤ 40% and confirmed methamphetamine use. Those with preexisting conditions or only a single echocardiogram were not included. A total of 357 patients were used in the retrospective study. Of those, 107 patients (30%) were able to reverse their MAC through cessation of use and medical treatment. Those that demonstrated persistent MAC were noted to have increased right ventricular chamber size. The median time for recovery was 16 months, longer than usually suggested before intervention for non-methamphetamine related cardiomyopathy.40 These studies represent a group of patients with symptomatic cardiomyopathy that can improve medically without surgical intervention. It also highlights the importance of cessation of use and thorough screening of young patients with cardiomyopathy to ensure proper treatment and allowance for recovery prior to intervention. A large, retrospective study performed in 2018 compared patients testing positive for methamphetamine with patients testing negative or those not tested that had increased B-type natriuretic peptide (BNP). BNP is a hormone made within the heart that increases due to 27 increased pressure within the chambers. A high level of serum BNP is indicative of heart failure. Out of the 4407 patients that tested positive for methamphetamine, 714 had BNP testing. Increased BNP (>100 pg/mL) was discovered in 10.2 % of the methamphetamine positive group versus 6.7 % in the control group. White male, former smokers were found to have a high rate of heart failure in the setting of methamphetamine use. Furthermore, methamphetamine-positive patients with abnormal BNP values had poorer LVEF percentages than those with normal BNP.41 The findings of this study suggest that abnormally high BNP values in the setting of MAC may place the patient at a higher risk for worse outcomes and a need for more intense intervention. A southern California hospital performed a retrospective study on the number of patients that were admitted with International Classification of Diseases, Ninth Revision (ICD-9) codes related to chronic heart failure (CHF) and methamphetamine use. From January 2009 to December 2014, a 684-licensed-bed hospital in San Diego saw 3705 patients admitted with CHF, with 141 of those having the diagnosis of methamphetamine use. Of those 141 patients presenting with heart failure due to methamphetamine use, 55.6% saw improved New York Heart Association (NYHA) functional class and 38.9 % remained stable with cessation of use. Those that continued to use methamphetamine saw stable (46.2%) or worsening (46.2%) NYHA functional class.42 A similar study analyzed the California state inpatient databases from 2005 to 2011 for ICD-9 codes relating to methamphetamine, chronic obstructive pulmonary disease (COPD) exacerbation, asthma, pneumonia, acute respiratory failure, and tobacco use. The study limited the results to patients 18 years or older with income and sex demographics available. The 28 search yielded a total of 182,766 adults in the state of California between 2005 and 2011 that were discharged with methamphetamine use and a pulmonary comorbidity as previously described. Table 1 illustrates the findings of the study. Those that use methamphetamine were found to have in increased incidence of COPD exacerbation, community-acquired pneumonia, and acute respiratory failure.43 Hypertensive crisis can be a dangerous complication in methamphetamine users. Not only does methamphetamine cause hypertension, prolonged hypertension without treatment may progress into aortic complications. In a retrospective analysis published in the Journal of Cardiac Surgery, the authors give a retrospective analysis of methamphetamine associated aortic dissections seen in the Cardiothoracic Surgery division of the University of Washington from 2002 to 2006. In that time frame, there were 5 patients that tested positive from methamphetamine use that required surgical intervention for aortic dissection repair. The ages of the patients ranged from 35 to 44 years of age. None of the patients had a family history of abdominal aortic aneurysm, aortic dissection, or other risk factors outside of hypertension due to methamphetamine use. The authors recommended routine methamphetamine screening for all patients to more precisely categorize and treat this type of emergency.30 Just as methamphetamine can cause hypertensive crisis, it can adversely affect the pressures within the pulmonary arteries. An article published in 2018 in Advances in Pulmonary Hypertension, details pulmonary arterial hypertension (PAH) in the setting of methamphetamine use and how a single clinic in San Francisco chose to screen patients for drug use. The Pulmonary Hypertension Center at the University of California, San Francisco implemented a policy stating that every patient must be drug tested at intake, unless the patient admits to using 29 illicit drugs. The goal of the policy was to remove the uncomfortable conversation and questionnaire for the provider as well as decreasing feelings of being “singled-out” by the patient. Methamphetamine has been associated with PAH and those with methamphetamine-induced PAH have a higher mortality rate than patients with idiopathic PAH.8 Screening for Illicit Drugs Clinicians face an ethical dilemma when drug testing patients in the emergency department. Not only can these conversations be uncomfortable, but a variety of site-specific practices at different facilities for drug screening exist. Most patients want to participate in their medical care and would feel deceived if not informed of a drug test, especially if the results were positive. Patient autonomy is paramount in the treatment process as well as trusting, honest clinician-patient relationship for positive patient outcomes. In the event of trauma intervention, informed consent is not required; however, in these cases, rarely would the results change the outcome. In other scenarios, the knowledge of drug use may affect the patient’s care or change the treatment dramatically.44 Those with substance use disorders (SUD) are often accessing emergency care. Due to stigma, this population is often apprehensive about disclosure of illicit drug use or misuse of prescription pharmaceuticals.45 People with SUDs routinely use emergency care in the US; it is estimated that 50% of ED visits relate to SUDs. Each time a patient with a SUD enters the emergency department, the provider has an opportunity to connect with their patient. Providers have a chance to explain to the patient that substance abuse is the cause of the medical ailment and provide motivation for cessation. The US Preventative Services Task Force (USPSTF)46 and the American College of Emergency Physicians45 agree that ED physicians are qualified and in a unique position for intervention and 30 recommendation of treatment of alcohol abuse. No formal policy for other abuse drugs existed at the time of this report. Warner et al47 addressed legal and ethical issues involved with obtaining laboratory tests for drug use. At the time of the article, explicit informed consent for a drug testing was not required. In fact, there are many cases that may warrant drug testing such as young people presenting with chest pain, placental abruption, intrauterine growth restriction, and diabetic ketoacidosis. These cases may arouse suspicion and drug testing may be performed in order to provide proper treatment of the symptoms as well as provide a brief intervention.47 In 2006, the American College of Surgeons mandated that all Level I and Level II trauma centers screen for alcohol abuse, illicit drug use, and Post Traumatic Stress Disorder for all injured patients. It also sought to identify other comorbidities such as depression and suicidal thoughts. A survey of Level I and Level II trauma centers in the US was performed in 2014, indicating that over 80% of those centers were routinely screening for alcohol and drugs. Ninety percent of the trauma centers screened for alcohol use with a lab test or questionnaire. Furthermore, most centers were found to offer a consult with a social worker at that time. Forty-nine percent of centers routinely screened for suicidal thoughts. As shown, screening of injured patients in trauma centers has changed the course for screen positive patients.48 The National Institute on Drug Abuse (NIDA) gives providers suggestions on how to approach this uncomfortable subject with patients without judgment. The NIDA Quick Screen is an excellent tool for clinicians for screening each patient. It gives the patients and providers an opportunity for an open and honest conversation about illicit drug use. The NIDA Quick Screen (Table 2) and the NIDA Modified Screen are simple screening techniques that can be memorized 31 easily and utilized with minimal training. If the patient answers “no” to all the questions, then the screening is complete. If the patient indicates “yes” for any of the questions, then a more in-depth screen can be performed such as the NIDA Modified Screen.49 The USPSTF recommends screening by questionnaire for all adult patients 18 years and older in order to better treat patients with health problems related to illicit drug use.46,50 Many organizations have adopted the USPSTF recommendations such as the American Academy of Pediatrics, American College of Obstetricians and Gynecologists, and the Substance Abuse and Mental Health Services Administration (SAMHSA). As previously discussed, the American College of Surgeons and the American College of Emergency Physicians also have implemented their own guidelines regarding routine screening of patients. The Substance Abuse and Mental Health Services Administration recognizes that providers order many types of laboratory tests in order to aid in diagnosis and treatment. SAMHSA states that biological drug testing can be performed for the same reasons. It is recommended that providers speak with the patient prior to testing and after. The administration recommends drug testing or screening survey to evaluate the patient when unexpected symptoms or treatment response occurs. Knowledge of the type of substance used may be useful for further intervention or prior to administration of medications.51 Discussion Healthcare facilities and practitioners can expect to see methamphetamine-associated cardiopulmonary injuries well into the future given the popularity and easy availability of the drug. United States’ emergency departments saw 102,961 methamphetamine-related visits of known users in 2011 alone. The same year, 70,831 visits occurred for issues related to 32 amphetamine use.51 Knowledge of injuries and complications related to methamphetamine may alter the course of treatment for the patient and give the provider an opportunity to intervene and assist in providing treatment options for recovery. As the research has shown, many of the cardiopulmonary complications and lung injuries are self-limiting and require less intervention when the cause is known to be due to methamphetamine use. Radiological exams, invasive procedures, and antibiotics are often unnecessary in these types of complications and increase the cost of care. In many cases, intervention beginning with screening and support for cessation of use will lead to improved health of the individual. Providers and healthcare professionals working in acute clinical settings should be aware of subtle indicators of methamphetamine use as well as related acute complications due to methamphetamine use. If use is suspected, screening by questionnaire or laboratory testing should be performed in a respectful manner conducive to furthering trust in communication between the patient and clinician. This report documents many of the known cardiopulmonary complications due to methamphetamine use. Research defining the action of methamphetamine on a cellular level in the lungs and vasculature is still in early stages. With recent studies utilizing rat and mice models, proposed mechanisms of injury have been described. Further study is needed in order to fully understand the damage produced by methamphetamine on lung and vascular tissues. Finally, education for clinicians is paramount in order to identify possible complications of methamphetamine use on the cardiopulmonary systems. As of 2016, 1,600,000 adults in the US reported using methamphetamine within the past year.11 Those engaged in methamphetamine 33 binging will self-administer doses one to six times per day, on average.52 For perspective, 774,000 of people in the US admitted to using methamphetamine within the last month.11 With numbers increasing, healthcare providers need to understand the methamphetamine epidemic and its associated cardiopulmonary complications to provide proper treatment with lasting outcomes. 34 References 1. United Nations. World Drug Report 2019. https://wdr.unodc.org/wdr2019/. Accessed March 18, 2020. 2. Drug Enforcement Administration. 2018 National Drug Threat Assessment. https://www.dea.gov/sites/default/files/2018-11/DIR-032- 18%202018%20NDTA%20final%20low%20resolution.pdf. Accessed December 3, 2019. 3. Tseng W, Sutter ME, Albertson TE. Stimulants and the Lung. Clinical Reviews in Allergy & Immunology. 2013;46(1):82-100. doi:10.1007/s12016-013-8376-9 4. Evren C, Bozkurt M. Update on methamphetamine: an old problem that we have recently encountered. Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2018;31:1- 10. doi.org/10.5350/DAJPN20183101001 5. McCarthy E, McClain E. Methamphetamine-induced lung injury. EJCRIM 2019;6: doi:10.12890/2019_001067 6. Vearrier D, Greenberg MI, Miller SN, Okaneku JT, Haggerty DA. Methamphetamine: History, Pathophysiology, Adverse Health Effects, Current Trends, and Hazards Associated with the Clandestine Manufacture of Methamphetamine. Disease-a-Month. 2012;58(2):38-89. doi:10.1016/j.disamonth.2011.09.004 7. Galbraith N. The methamphetamine problem: Commentary on … Psychiatric morbidity and socio-occupational dysfunction in residents of a drug rehabilitation centre. BJPsych Bull. 2015;39(5):218–220. doi:10.1192/pb.bp.115.050930 8. Tarango N, Baird AG. Managing the Patient with Pulmonary Arterial Hypertension and Methamphetamine Use: A Practical Perspective for the Clinician. Advances in Pulmonary Hypertension. 2018;17(2):55-62. doi:10.21693/1933-088x-17.2.55 9. Committee Opinion No. 479: Methamphetamine Abuse in Women of Reproductive Age. Obstetrics & Gynecology. 2011;117(3):751-755. doi:10.1097/aog.0b013e318214784e 10. Volkow ND, Fowler JS, Wang G-J, et al. Distribution and Pharmacokinetics of Methamphetamine in the Human Body: Clinical Implications. PLoS ONE. 2010;5(12). doi:10.1371/journal.pone.0015269 11. National Institute on Drug Abuse. Overview. NIDA. https://www.drugabuse.gov/publications/research-reports/methamphetamine/overview. Accessed April 17, 2020. 35 12. Gotway MB, Marder SR, Hanks DK, et al. Thoracic Complications of Illicit Drug Use: An Organ System Approach. RadioGraphics. 2002;22(suppl_1). doi:10.1148/radiographics.22.suppl_1.g02oc01s119 13. Munn Z, Peters MDJ, Stern C, Tufanaru C, Mcarthur A, Aromataris E. Systematic review or scoping review? Guidance for authors when choosing between a systematic or scoping review approach. BMC Medical Research Methodology. 2018;18(1). doi:10.1186/s12874- 018-0611-x 14. Peters MD, Godfrey CM, Khalil H, Mcinerney P, Parker D, Soares CB. Guidance for conducting systematic scoping reviews. International Journal of Evidence-Based Healthcare. 2015;13(3):141-146. doi:10.1097/xeb.0000000000000050 15. Kevil CG, Goeders NE, Woolard MD, et al. Methamphetamine Use and Cardiovascular Disease. Arteriosclerosis, Thrombosis, and Vascular Biology. 2019;39(9):1739-1746. doi:10.1161/atvbaha.119.312461 16. Ciccarone D. Stimulant abuse: pharmacology, cocaine, methamphetamine, treatment, attempts at pharmacotherapy. Prim Care 2011; 38:41-58. doi:10.1016/j.pop.2010.11.004. 17. Fowler JS, Kroll C, Ferrieri R, et al. PET Studies of d-Methamphetamine Pharmacokinetics in Primates: Comparison with l-Methamphetamine and (--)-Cocaine. Journal of Nuclear Medicine. 2007;48(10):1724-1732. doi:10.2967/jnumed.107.040279 18. Exploring Methamphetamine Trends in Europe. https://www.emcdda.europa.eu/publications/emcdda-papers/exploring-methamphetamine-trends- in-Europe_en. Published January 1, 2014. Accessed April 16, 2020. 19. Schedules of Controlled Substances: Table of Excluded Nonnarcotic Products: Vicks® VapoInhaler®. Vol 81.; 2016. 20. Desoxyn. accessdata.fda.gov. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process. Published March 2019. Accessed July 22, 2020. 21. Gu Y-H, Wang Y, Bai Y, Liu M, Wang H-L. Endoplasmic reticulum stress and apoptosis via PERK-eIF2α-CHOP signaling in the methamphetamine-induced chronic pulmonary injury. Environmental Toxicology and Pharmacology. 2017;49:194-201. doi:10.1016/j.etap.2017.01.003 22. Wells SM, Buford MC, Braseth SN, Hutchison JD, Holian A. Acute Inhalation Exposure to Vaporized Methamphetamine Causes Lung Injury in Mice. Inhalation Toxicology. 2008;20(9):829-838. doi:10.1080/08958370801895121 36 23. Wang X, Liu M, Zhu MJ, et al. Resveratrol protects the integrity of alveolar epithelial barrier via SIRT1/PTEN/p‐Akt pathway in methamphetamine‐induced chronic lung injury. Cell Proliferation. 2020;53(3). doi:10.1111/cpr.12773 24. Yanagi S, Tsubouchi H, Miura A, Matsumoto N, Nakazato M. Breakdown of Epithelial Barrier Integrity and Overdrive Activation of Alveolar Epithelial Cells in the Pathogenesis of Acute Respiratory Distress Syndrome and Lung Fibrosis. BioMed Research International. 2015;2015:1-12. doi:10.1155/2015/573210 25. Orcholski ME, Khurshudyan A, Shamskhou EA, et al. Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension. American Journal of Physiology-Lung Cellular and Molecular Physiology. 2017;313(2):252-256. doi:10.1152/ajplung.00453.2016 26. Chen P-I, Cao A, Miyagawa K, et al. Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension. JCI Insight. 2017;2(2). doi:10.1172/jci.insight.90427 27. Harms R, Morsey B, Boyer CW, Fox HS, Sarvetnick N. Methamphetamine Administration Targets Multiple Immune Subsets and Induces Phenotypic Alterations Suggestive of Immunosuppression. PLoS ONE. 2012;7(12). doi:10.1371/journal.pone.0049897 28. Albanese J, Gross C, Azab M, Mahalean S, Makar R. Spontaneous pneumomediastinum: A rare complication of methamphetamine use. Respir Med Case Rep. 2017;21:25–26. Published 2017 Mar 10. doi:10.1016/j.rmcr.2017.03.007 29. Lin S-S. Crystal Amphetamine Smoking-Induced Acute Eosinophilic Pneumonia and Diffuse Alveolar Damage: A Case Report and Literature Review. The Chinese Journal of Physiology. 2014;57(5):295-298. doi:10.4077/cjp.2014.bac201 30. Wako E, Ledoux D, Mitsumori L, Aldea GS. The Emerging Epidemic of Methamphetamine- Induced Aortic Dissections. Journal of Cardiac Surgery. 2007;22(5):390-393. doi:10.1111/j.1540-8191.2007.00432.x 31. VanHook, CJ; Laursen, A; Warner, B; Tangel, D. METHAMPHETAMINE PULMONARY TOXICITY: A RARE COMPLICATION OF A COMMON DRUG OF ABUSE. Abstract published at Hospital Medicine 2017, May 1-4, 2017; Las Vegas, Nev. Abstract 771. Journal of Hospital Medicine. 2017; 12 (suppl 2). https://www.shmabstracts.com/abstract/methamphetamine-pulmonary- toxicity-a-rare-complication-of-a-common-drug-of-abuse/. Accessed November 11, 2019. 32. Chen, G.-A & Yang, C.-C. Late diagnosis of methamphetamine inhalation related pneumothorax, pneumomediastinum and diffuse subcutaneous emphysema: A case report. Journal of Acute Medicine. 2018;8(1):30-33. doi:10.6705/j.jacme.201803_8(1).0005. 37 33. Kim KS, Jeon HW, Moon Y, et al. Clinical experience of spontaneous pneumomediastinum: diagnosis and treatment. J Thorac Dis. 2015;7(10):1817–1824. doi:10.3978/j.issn.2072- 1439.2015.10.58 34. Nasrullah A, Javed A, Hayes B, Kapetanos A. Amidst Vaping, Do Not Forget Methamphetamine Induced Lung Injury! D49 Critical Care Case Reports: Causes and Complications of Acute Respiratory Failure. 2020. doi:10.1164/ajrccm-conference. 2020.201.1_meetingabstracts.a7009 35. Labus AM, Sangani R, Hodder C, Hoffmann S. Acute pulmonary toxicity caused by methamphetamine inhalation. Am J Respir Crit Care Med. 2017;195:A5560 36. Baylor P, Sobenes J, Vallyathan V. Interstitial Pulmonary Fibrosis and Progressive Massive Fibrosis Related to Smoking Methamphetamine with Talc as Filler. Respiratory Care. 2013;58(5). doi:10.4187/respcare.01595 37. Ashok Raj Devkota, Alix Dufrense, Premraj Parajuli. Acute reversible cardiomyopathy due to methamphetamine overdose. British Journal of Medical Practitioners. December 2015;8(4):a830 38. Kinas D, Dalley M, Guidry K, Newberry MA, Farcy DA. Point-of-Care Ultrasound Identifies Decompensated Heart Failure in a Young Male with Methamphetamine-Associated Cardiomyopathy Presenting in Severe Sepsis to the Emergency Department. Case Reports in Emergency Medicine. 2018;2018:1-6. doi:10.1155/2018/2859676 39. Ito H, Yeo K-K, Wijetunga M, Seto TB, Tay K, Schatz IJ. A Comparison of Echocardiographic Findings in Young Adults With Cardiomyopathy: With and Without a History of Methamphetamine Abuse. Clinical Cardiology. 2009;32(6). doi:10.1002/clc.20367 40. Zhao SX, Seng S, Deluna A, Yu EC, Crawford MH. Comparison of Clinical Characteristics and Outcomes of Patients With Reversible Versus Persistent Methamphetamine-Associated Cardiomyopathy. The American Journal of Cardiology. 2020;125(1):127-134. doi:10.1016/j.amjcard.2019.09.030 41. Richards JR, Harms BN, Kelly A, Turnipseed SD. Methamphetamine use and heart failure: Prevalence, risk factors, and predictors. The American Journal of Emergency Medicine. 2018;36(8):1423-1428. doi:10.1016/j.ajem.2018.01.001 42. Sliman S, Waalen J, Shaw D. Methamphetamine-Associated Congestive Heart Failure: Increasing Prevalence and Relationship of Clinical Outcomes to Continued Use or Abstinence. Cardiovascular Toxicology. 2015;16(4):381-389. doi:10.1007/s12012-015-9350-y 38 43. Tsai H, Lee J, Hedlin H, Zamanian RT, Perez VADJ. Methamphetamine use association with pulmonary diseases: a retrospective investigation of hospital discharges in California from 2005 to 2011. ERJ Open Research. 2019;5(4):00017-02019. doi:10.1183/23120541.00017- 2019 44. Jalaly JB, Dineen KK, Gronowski AM. A 30-Year-Old Patient Who Refuses to Be Drug Tested. Clinical Chemistry. 2016;62(6):807-809. doi:10.1373/clinchem.2015.246033 45. Hawk K, D’Onofrio G. Emergency department screening and interventions for substance use disorders. Addiction Science & Clinical Practice. 2018;13(1). doi:10.1186/s13722-018-0117-1 46. Draft Recommendation: United States Preventive Services Taskforce. Draft Recommendation | United States Preventive Services Taskforce. https://www.uspreventiveservicestaskforce.org/uspstf/draft-recommendation/drug-use-in-adolescents- and-adults-including-pregnant-women-screening. Accessed April 18, 2020. 47. Warner EA, Walker RM, Friedmann PD. Should informed consent be required for laboratory testing for drugs of abuse in medical settings? The American Journal of Medicine. 2003;115(1):54-58. doi:10.1016/s0002-9343(03)00236-5 48. Love J, Zatzick D. Screening and Intervention for Comorbid Substance Disorders, PTSD, Depression, and Suicide: A Trauma Center Survey. Psychiatric Services. 2014;65(7):918-923. doi:10.1176/appi.ps.201300399 49. National Institute on Drug Abuse. The NIDA Quick Screen. NIDA. https://www.drugabuse.gov/publications/resource-guide-screening-drug-use-in-general-medical- settings/nida-quick-screen. Accessed December 3, 2019. 50. Krist AH, Davidson KW, Mangione CM, et al. Screening for Unhealthy Drug Use. Jama. 2020;323(22):2301. doi:10.1001/jama.2020.8020 51. Substance Abuse and Mental Health Services Administration, Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits. HHS Publication No. (SMA) 13-4760, DAWN Series D-39. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2013. 52. Homer BD, Solomon TM, Moeller RW, Mascia A, Deraleau L, Halkitis PN. Methamphetamine abuse and impairment of social functioning: A review of the underlying neurophysiological causes and behavioral implications. Psychological Bulletin. 2008;134(2):301-310. doi:10.1037/0033-2909.134.2.301 39 Appendix A Figures Figure 1. Whole body PET images depicting uptake of radiolabeled methamphetamine. Increased uptake was noted in African American males in comparison with Caucasian males.10 Reproduced under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. and producesimmunosuppression [23,24], which could contribute to the higher rate of infections in methamphetamine abusers (i.e., TB, HIV). However, this interpretation requires demonstration of a causal relationship between local concentrations of metham-phetamine and immunosuppression, which to our knowledge is currently not available. The heart had lower methamphetamine uptake than other organs (2.6% injected dose at one min after injection) and its retention in heart was very short lasting. This was unexpected since cardiovascular events are among the most frequent medical complications reported in methamphetamine abusers (review [6]). Thus our findings are consistent with the belief that methamphet-amine’s central and peripheral sympathomimetic effects rather than direct effects to myocytes, are responsible for its cardiotoxic effects (review [25]). Nonetheless, the good temporal correspon-dence between methamphetamine’s fast accumulation in heart (peaks 60 seconds) and the fast increasesin blood pressure induced by this drug (peaks at 60 seconds after iv administration), [26] suggests that methamphetamine may also directly affect cardiac tissue. Brain uptake of methamphetamine was lower than in many of the organs (per cc of tissue), which could contribute to its clinical toxicity since significant organ accumulation will occur when the drug isused for recreational purposes. Thisisdistinct from cocaine for which the brain uptake is higher than that observed in other organs [13]. On the other hand methamphetamine’s clearance from brain was very slow, which is likely to result in long lasting exposure of the brain to the sympathomimetic effects of this drug and contribute to its neurotoxicity. The neurotoxic effects of methamphetamine have been extensively documented and are believed to reflect both its vasoactive effects, which can result in ischemia and necrosis as well as its cathecholaminergic effects, which can result in damage to dopamine neurons, psychosis and seizures [27,28]. The pharmacokinetics of [11C]d-methamphetamine in the stomach and liver were similar and were the slowest from all the organs. The hepatic accumulation of [11C]d-methamphetamine was very high (22–24% injected dose; weight 1677 grams) and presumably represents methamphetamine and its metabolites. Some of the liver accumulation could reflect its uptake and excretion through the gallbladder [29]. The unexpected high accumulation in stomach is likely to reflect the acid environment that favors the uptake of a basic drug such asmethamphetamine. We note that the accumulation in stomach was quite variable among subjects, which could reflect in part differences in stomach acidification [30]. [11C]d-Methamphetamine’s uptake and accumulation in lung washigher in AA than C. This isnoteworthy since the prevalence rates of methamphetamine use in AA are much lower than in C [9,10]. Cultural factors aswell asmarket factors in drug accessare likely to contribute to these differences. However, differencescould also reflect genetic factors that make AA more vulnerable to the Figure 2. Whole body images of [11C]d-methamphetamine in an African American (AA) and in a Caucasian (C) who received 7.18 and 6.99 mCi respect ively and location of areas where ROI were obt ained. Imaging was started 4 min post injection moving from head to pelvis in 12 minute segments. The images have been decay corrected. Note the higher accumulation of [11C]d-methamphetamine in the lung of the AA than of the C. The hot spot on the abdominal cavity of the Caucasian corresponds to the stomach where [11C]d-methamphetamine accumulation was high but quite variable across subjects (may reflect its acidic environment that favors trapping of methamphetamine, which is a weak base). doi:10.1371/journal.pone.0015269.g002 Methamphetamine in Human Body 40 Figure 2. Methamphetamine-induced eosinophilic pneumonia. Bilateral lung opacities (black arrow) and bilateral consolidation with air-bronchograms (black arrows) in a patient with methamphetamine-induced eosinophilic pneumonia observed in a chest radiograph (A) and chest CT (B).29 Reproduced with permission from The Chinese Journal of Physiology. 41 Figure 3. Chest radiograph following corticosteroid treatment. Near resolution of infiltrates after corticosteroid treatment in the setting of methamphetamine-induced eosinophilic pneumonia.29 Reproduced with permission from The Chinese Journal of Physiology. 42 Figure 4. Chest CT image depicting methamphetamine-induced lung injury. Right upper lobe ground glass opacities seen in the setting of methamphetamine-induced lung injury.5 Reproduced under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. 43 Figure 5. Lung tissue samples from methamphetamine exposed and control rats. Lung tissue from rat's lungs in control group versus methamphetamine (MA) exposed. Control group has fewer inflammatory cells (red arrows) when compared to MA group. Thickened alveolar walls and reduced alveolar sacs were seen in the MA group.23 Reproduced under the Creative Commons Attribution 4.0 International License. 44 Figure 6. Proposed mechanism of injury to pulmonary vessels. A proposed model for reduced expression of carboxylesterase 1 (CES1) increasing reactive oxygen species (ROS) production and ultimately, apoptosis. Pulmonary microvascular endothelial cells (PMVEC), cytochrome P450 2D6 (CYP2DC).25 Reproduced with permission from American Journal of Physiology- Lung Cellular and Molecular Physiology. 45 Figure 7. Methamphetamine effects on immune cells in mice. Effects of methamphetamine on immune cells in mice, demonstrating reduced natural killer cells (NKs).27 Reproduced under the Creative Commons Attribution 4.0 International License. 46 Appendix B Tables Table 1. Discharge demographics in the state of California from 2005-2011. California state inpatient database characteristics 2005-2011 comparing demographics of discharged patients who used methamphetamine to those that did not.43 Reproduced under the Creative Commons Attribution 4.0 International License. 47 Table 2. NIDA Quick Screen questionnaire. Reproduced from the National Institute on Drug Abuse.49 48 Appendix C List of Abbreviations AECs: alveolar epithelial cells ARDS: acute respiratory distress syndrome ARF: acute respiratory failure BNP: B-type natriuretic peptide CES1: carboxylesterase 1 CHF: congestive heart failure COPD: chronic obstructive pulmonary disease CT: computed tomography CXR: chest x-ray CYP2D6: cytochrome P450 2D6 DEA: drug enforcement agency DNA: deoxyribonucleic acid EP: eosinophilic pneumonia ER: endoplasmic reticulum ERS: endoplasmic reticulum stress HIV: human immunodeficiency virus ICD-9: International Classification of Diseases, Ninth Revision IV: intravenous LVEDV: left ventricular end-diastolic volume LVEF: left ventricular ejection fraction MAC: methamphetamine associated cardiomyopathy METH-PAH: methamphetamine-induced pulmonary arterial hypertension NIDA: National Institute on Drug Abuse NK: natural killer cells NYHA: New York Heart Association PAECs: pulmonary artery endothelial cells PAH: pulmonary arterial hypertension PET: positron emission tomography PMVECs: pulmonary microvascular endothelial cells ROS: reactive oxygen species SAMHSA: Substance Abuse and Mental Health Services Administration STD: sexually transmitted disease SUD: substance use disorders USPSTF: U.S. Preventative Service Task Force WBC: white blood cells 49 Appendix D Permissions THE AMERICAN PHYSIOLOGICAL SOCIETY LICENSE TERMS AND CONDITIONS Oct 24, 2020 This Agreement between Heather Berge ("You") and The American Physiological Society ("The American Physiological Society") consists of your license details and the terms and conditions provided by The American Physiological Society and Copyright Clearance Center. License Number 4935480610624 License date Oct 24, 2020 Licensed Content Publisher The American Physiological Society Licensed Content Publication Am J Physiol-Lung, Cellular, and Molecular Physiology Licensed Content Title Reduced carboxylesterase 1 is associated with endothelial injury in methamphetamine-induced pulmonary arterial hypertension Licensed Content Author Mark E. Orcholski, Artyom Khurshudyan, Elya A. Shamskhou, et al Licensed Content Date Aug 1, 2017 Licensed Content 313 50 Volume Licensed Content Issue 2 Type of Use Thesis/Dissertation Requestor type author Readers being charged a fee for this work No Format print and electronic Portion figures/tables/images Number of figures/tables/images 1 Will you be translating? no World Rights no Order reference number Title Methamphetamine-Induced Cardiopulmonary Injuries Institution name Weber State University 51 Expected presentation date Dec 2020 Portions Figure 7 Requestor Location Heather Berge 1804 W 5th Ave N CLEAR LAKE, IA 50428 United States Attn: Heather Berge Billing Type Invoice Billing Address Heather Berge 1804 W 5th Ave N CLEAR LAKE, IA 50428 United States Attn: Heather Berge Total 0.00 USD Terms and Conditions Terms and Conditions: ©The American Physiological Society (APS). All rights reserved. The publisher for this requested copyrighted material is APS. By clicking “accept” in connection with completing this license transaction, you agree to the following terms and conditions that apply to this transaction. At the time you opened your Rightslink account you had agreed to the billing and payment terms and conditions established by Copyright Clearance Center (CCC) available at http://myaccount.copyright.com 52 The APS hereby grants to you a nonexclusive limited license to reuse published material as requested by you, provided you have disclosed complete and accurate details of your proposed reuse of articles, figures, tables, images, and /or data in new or derivative works. Licenses are for a one-time English language use with a maximum distribution equal to the number of copies identified by you in the licensing process, unless additional options for translations or World Rights were included in your request. Any form of print or electronic republication must be completed within three years from the date hereof. Copies prepared before then may be distributed thereafter The following conditions are required for a License of Reuse: Attribution: You must publish in your new or derivative work a citation to the original source of the material(s) being licensed herein, including publication name, author(s), volume, year, and page number prominently displayed in the article or within the figure/image legend. Abstracts: APS Journal article abstracts may be reproduced or translated for noncommercial purposes without requesting permission, provided the citation to the original source of the materials is included as noted above (“Attribution”). Abstracts or portions of abstracts may not be used in advertisements or commercial promotions. Non-profit/noncommercial reuse: APS grants permission for the free reuse of APS published material in new works published for educational purposes, provided there is no charge or fee for the new work and/or the work is not directly or indirectly commercially supported or sponsored. Neither original authors nor non-authors may reuse published material in new works that are commercially supported or sponsored including reuse in a work produced by a commercial publisher without seeking permission. Video and photographs: Some material published in APS publications may belong to other copyright holders and cannot be republished without their permission. The copyright holder of photographs must be ascertained from the original source by the permission requestor. Videos and podcasts may not be rebroadcast without proper attribution and permission as requested here. For further inquiries on reuse of these types of materials, please contact cvillemez@the-aps.org Figures/Tables/Images are available to the requestor from the APS journals website at http://www.the-aps.org/publications/journals/. The obtaining of content is a separate transaction and does not involve Rightslink or CCC, and is the responsibility of the permission seeker. Higher resolution images are available at additional charge from APS; please contact cvillemez@the-aps.org Original Authors of Published Works: To see a full list of original authors rights concerning their own published work http://www.the-aps.org/publications/authorinfo/copyright.htm Content reuse rights awarded by the APS may be exercised immediately upon issuance of 53 this license, provided full disclosure and complete and accurate details of the proposed reuse have been made; no license is finally granted unless and until full payment is received either by the publisher or by CCC as provided in CCC’s Billing and Payment Terms and Conditions. If full payment is not received on a timely basis, then any license preliminarily granted shall be deemed automatically revoked and shall be void as if never granted. Further, in the event that you breach any of these Terms and Conditions or any of CCC’s Billing and Payment Terms and Conditions, the license is automatically revoked and shall be void as if never granted. Use of materials as described in a revoked license, as well as any use of the materials beyond the scope of the license, may constitute copyright infringement and the Publisher reserves the right to take action to protect its copyright of its materials. The APS makes no representations or warranties with respect to the licensed material. You hereby indemnify and agree to hold harmless the publisher and CCC, and their respective officers, directors, employees and agents, from and against any and all claims arising out of your use of the licensed material other than as specifically authorized pursuant to this license. This license is personal to you /your organization and may not be sublicensed, assigned, or transferred by you /your organization to another person /organization without the publisher’s permission.This license may not be amended except in writing signed by both parties, or in the case of the publisher, by CCC on the publisher’s behalf. The APS reserves all rights not specifically granted in the combination of (i) the license details provided by you and accepted in the course of this licensing transaction, (ii) these Terms and Conditions and (iii) CCC’s Billing and Payment Terms and Conditions. v1.0 Questions? customercare@copyright.com or +1-855-239-3415 (toll free in the US) or +1-978-646-2777. 54 55 56 57 58 59 60 61 62