Analytical methods for detecting butane, propane, and their metabolites in biological samples: Implications for inhalant abuse detection.

Worldwide, various inhalants are widely abused for recreational purposes, with butane and propane emerging as among the most commonly misused volatile substances, posing a significant risk of sudden death. The rapid elimination and oxidation of these highly volatile compounds upon inhalation necessitate the identification of butane and propane along with their metabolites in biological samples. Hence, the primary objective of this study is twofold: firstly, to establish a method for analyzing butane, propane, and metabolites, and secondly, to demonstrate the detection window and exposure indicators associated with the inhalation of butane and propane. In pursuit of this objective, we developed analytical methods for the determination of isobutane, n-butane, propane, and their nine metabolites in both blood and urine. Headspace-gas chromatography-mass spectrometry (GC-MS) and solid-phase microextraction-GC-MS were employed for the analyses, demonstrating acceptable precision and accuracy. An animal study revealed that isobutane and n-butane were only detectable below the limit of quantification (LOQ) in rat blood 5 min after exposure. Meanwhile, the three major metabolites-2-methyl-2-propanol, 2-butanol, and 2-butanone-were observed 5 min after exposure but persisted in rat urine even 5 h post-exposure. Additionally, human urine samples identified other metabolites, including acetone, acetoin, and 2,3-butanediol isomers. The presence of specific metabolites corresponding to each inhalant confirmed the abuse of butane and propane. This comprehensive approach provides valuable insights into the detection and assessment of inhalation to these volatile substances.

Nitrous Oxide Inhalant Abuse: Preliminary Results from a Cross-Sectional Study on Knowledge, Attitudes, and Practices of Italian Physicians (2023).

Background and Objectives: Nitrous oxide (N2O) has recently emerged as a cheap alternative to other recreational substances. Although legally available, its chronic use is associated with severe neurological and hematological complications due to the irreversible inactivation of vitamin B12. While no reliable data on abuse of N2O in Italy have been provided to date, we assessed the knowledge, attitudes, and practices of Italian medical professionals on the management of N2O abuse cases. Materials and Methods: A cross-sectional study was performed as a web-based survey through a series of Facebook discussion groups (targeted medical professionals: 12,103), and participants were specifically asked about their previous understanding of N2O abuse and whether they had or not any previous experience in this topic. Results: A total 396 medical professionals participated in the survey. Overall, 115 participants had previous knowledge about N2O abuse (29.04%), with higher odds for professionals with a background in emergency medicine (adjusted odds ratio (aOR) 3.075; 95% confidence intervals (95%CI) 1.071 to 8.828) and lower for specialists in psychiatry (aOR 0.328; 95%CI 0.130 to 0.825). Knowledge status on N2O abuse was largely unsatisfying, as knowledge status, reported as a percent value, was estimated to 45.33% ± 24.71. Having previously managed a case of N2O abuse was associated with higher risk perception of the actual severity of this condition (aOR 5.070; 95%CI 1.520 to 16.980). Conclusions: Our study suggests that N2O poisoning cases are occurring in Italian settings but are not reasonably reported to national authorities. As substantial knowledge gaps of Italian medical workforces were identified, we cannot rule out that the actual abuse of N2O in the population may be far larger than currently suspected.

Un caso de neumotórax espontáneo por inhalación de pegante de policloropreno / A case of spontaneous pneumothorax due to inhalation of polychloroprene glue

El uso de inhalantes como drogas de abuso es una práctica de fácil acceso en menores y jóvenes tanto en países de bajos ingresos como en los de altos ingresos. Dentro de las complicaciones que se pueden presentar se encuentra el neumotórax espontáneo, que se ha relacionado tanto con el daño en el parénquima pulmonar producido por la sustancia y con la técnica de inhalación y/o exposición generando barotrauma. Se presenta un reporte de caso de un hombre joven que inhaló pegante y desarrolló un neumotórax espontáneo completo del pulmón izquierdo. Requirió intervención quirúrgica con colocación de sonda a tórax y su evolución fue satisfactoria. Esta complicación se ha reportado en la literatura con mayor frecuencia en hombres y con el uso de cocaína. Sólo se identificó otro caso similar en el contexto de inhalación de pegante con tolueno en sus componentes. Debido a los pocos reportes encontrados respecto al uso de sustancias inhalantes y al tolueno, es importante resaltar el hallazgo a fin de contribuir al inicio de futuras investigaciones a mayor escala. (AU)

Inhalants as drugs of abuse is an accessible practice in minors and young people in low-income countries as well as high-income ones. Spontaneous pneumothorax is a possible complication, which has been related both to damage of the lung parenchyma produced by the substance and inhalation and/or exposure technique making barotrauma. A case report of young man who inhaled glue with toluene and developed a complete spontaneous pneumothorax of the left lung is presented. He required surgical intervention with placement of a chest tube and his evolution was satisfactory. This complication has been reported in the literature more frequently in men and with the use of cocaine. Only one other similar case report was identified in the context of inhalation of glue with toluene in its components. Due to the few reports found regarding use of inhalant substances and toluene, it is important to highlight the finding to contribute to the initiation of future research on a larger scale. (AU)

The Clinical Assessment and Treatment of Inhalant Abuse.

Although inhalant abuse is common, it is one of the most neglected and overlooked forms of substance abuse. Inhalants refer to a wide variety of substances including volatile solvents, aerosols, gases, and nitrites. The mechanism of action of inhalants has not been fully defined. Several molecular targets contribute to the pharmacology, including ion-channel proteins that control neuronal excitability. These agents interact with various receptors and can cause changes in cell-membrane fluidity and nerve-membrane ion channels. Three main pharmacologic categories of inhalants, namely, volatile solvents and anesthetic gases, nitrous oxide, and volatile alkyl nitrites, have distinct pharmacologies, mechanisms of action, and toxicities. Inhalants are linked to multisystem damage affecting the pulmonary, cardiac, dermatologic, renal, hematologic, gastrointestinal, hepatic, and neurologic systems. Chronic inhalant abuse can also cause psychiatric, cognitive, behavioral, and anatomical deficits in humans, leading to reduced productivity and quality of life. Inhalant abuse during pregnancy is associated with fetal abnormalities. Clinical assessment for inhalant abuse should be done systematically. After decontamination and stabilization of the patient, further history and physical examination is necessary to establish an appropriate diagnosis based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Laboratory testing for inhalant abuse is very limited, and imaging studies may be helpful in certain situations. The treatment of inhalant use disorder is similar to that of other substance abuse disorders and includes supportive care, pharmacotherapy, and behavioral therapy. Preventive measures are essential.

Skeletal Fluorosis: A Case of Inhalant Abuse Leading to a Diagnosis of Colon Cancer.

Skeletal fluorosis is a long-term bone disease that develops when prolonged fluoride toxicity leads to osteosclerosis and bone deformities that result in crippling pain and debility. The disease is endemic to many countries due to environmental or industrial exposures. However, rare cases in the United States have been reported from various causes including heavy toothpaste ingestion, excessive tea consumption, voriconazole use, and inhalant abuse. Here, we present a case of a 41-year-old man who presented for weight loss and severe joint pains due to bony sclerotic lesions found on X-rays. Social history revealed that he had been recreationally inhaling compressed air dusters used for cleaning electronics. Owing to concern for malignancy, he underwent an extensive work-up which led to a diagnosis of colon cancer, but positron emission tomography/computed tomography (PET/CT) and bone biopsy were unexpectedly negative for metastatic bone disease. Further characterization of his lesions by skeletal survey led to a diagnosis of skeletal fluorosis secondary to inhalant abuse. As in this patient, the disease can be difficult for clinicians to recognize as it can be mistaken for various boney diseases such as metastatic cancer. However, once there is clinical suspicion for skeletal fluorosis, various tests to help confirm the diagnosis can include serum and urine fluoride levels, skeletal survey, and bone ash fluoride concentration. Treatment of skeletal fluorosis primarily involves cessation of fluoride exposure, and recovery can take years. Ultimately, further study is required to develop recommendations and guidelines for diagnosis, management, and prognosis of the disease in the United States.

Chronic thinner inhalation alters olfactory behaviors in adult mice.

Volatile solvents exposure can result in various behavioral impairments that have been partly associated to altered adult hippocampal neurogenesis. Despite recent evidence supporting this association, few studies have been devoted to examine the impact on olfactory functioning and olfactory bulb (OB) neurogenesis, although olfactory system is directly in contact with volatile molecules. Thus, this study was designed to evaluate in adult mice the potential modifications of the olfactory functioning after acute (1 day), subchronic (6 weeks) and chronic (12 weeks) exposure to thinner vapor at both behavioral and cellular levels. Firstly, behavioral evaluations showed that chronic thinner exposure impacts on odor detection ability of treated mice but does not affect mice ability to efficiently discriminate between two different odors. Moreover, chronic thinner exposure produces impairment in the olfactory-mediated associative memory. Secondly, analysis of the effects of thinner exposure in the subventricular zone (SVZ) of the lateral ventricle and in the OB revealed that thinner treatments do not induce apoptosis nor glial activation. Thirdly, immunohistochemical quantification of different markers of adult olfactory neurogenesis showed that inhalant treatments do not change the number of proliferating progenitors in the SVZ and the rostral migratory stream (RMS), as well as the number of newborn cells reaching and integrating in the OB circuitry. Altogether, our data highlight that the impaired olfactory performances in chronically-exposed mice are not associated to an alteration of adult neurogenesis in the SVZ-OB system.

Rare Case of Diffuse Skeletal Fluorosis Due to Inhalant Abuse of Difluoroethane.

CASE: We present a rare case of diffuse skeletal fluorosis in a 56-year-old man with a history of inhalation and topical abuse of aerosolized dust cleaner containing difluoroethane and prior industrial exposure to chlorofluorocarbon-rich organic solvent cleaners. This patient had diffuse osteosclerotic bone disease on radiographs that elicited concern for a potentially aggressive physiologic or pathologic process, until increased fluoremia was identified as the cause. Management was conservative with removal of the causative agent. CONCLUSION: Skeletal fluorosis is an osteosclerotic bone disease caused by excessive ingestion of fluoride. Although this pathology is endemic in some parts of the world where drinking water contains high levels of fluoride, it should be considered as a differential diagnosis for patients with characteristic radiographic findings and a history of inhalant abuse. Chronic exposure to chlorofluorocarbon-rich products should also be considered.

Inhalant Abuse of Ethyl Chloride Spray: A Case Report.

Ethyl chloride spray, which is usually used to relieve pain after injuries, is increasingly being used as a sniffing alternative. The number of people using this is rising due to its easy availability, cost-effectiveness and legality. The high lipid solubility of ethyl chloride leads to a rapid absorption of it in the lungs. However, data on the biotransformation of ethyl chloride in humans are sparse. We present the case of a 53-year-old male who had been inhaling ethyl chloride up to 3 times a week since 25 years, and describe his symptoms and the circumstances of abuse. This should help raise awareness of this issue so that abuse can be recognized early and rapid action taken.

The last two decades on preclinical and clinical research on inhalant effects.

This paper reviews the scientific evidence generated in the last two decades on the effects and mechanisms of action of most commonly misused inhalants. In the first section, we define what inhalants are, how they are used, and their prevalence worldwide. The second section presents specific characteristics that define the main groups of inhalants: (a) organic solvents; (b) aerosols, gases, and volatile anesthetics; and (c) alkyl nitrites. We include a table with the molecular formula, structure, synonyms, uses, physicochemical properties and exposure limits of representative compounds within each group. The third and fourth sections review the direct acute and chronic effects of common inhalants on health and behavior with a summary of mechanisms of action, respectively. In the fifth section, we address inhalant intoxication signs and available treatment. The sixth section examines the health effects, intoxication, and treatment of nitrites. The seventh section reviews current intervention strategies. Finally, we propose a research agenda to promote the study of (a) solvents other than toluene; (b) inhalant mixtures; (c) effects in combination with other drugs of abuse; (d) age and (e) sex differences in inhalant effects; (f) the long-lasting behavioral effects of animals exposed in utero to inhalants; (g) abstinence signs and neurochemical changes after interrupting inhalant exposure; (h) brain networks involved in inhalant effects; and finally (i) strategies to promote recovery of inhalant users.

Toluene-induced leukodystrophy from glue sniffing.

A 33-year-old man with a history of chronic toluene abuse through glue sniffing, developed tremors, cerebellar signs and cognitive decline. MR scan of the brain showed global cerebral and cerebellar atrophy with symmetrical T2-weighted hypointensities in the basal ganglia, thalami and midbrain. After stopping glue sniffing, his tremors, ataxia of gait, speech and cognition partially improved. Early recognition and intervention of toluene-induced leukodystrophy could prevent ongoing morbidity and premature mortality.

Assessment of Annual Cost of Substance Use Disorder in US Hospitals.

Importance: A persistently high US drug overdose death toll and increasing health care use associated with substance use disorder (SUD) create urgency for comprehensive estimates of attributable direct costs, which can assist in identifying cost-effective ways to prevent SUD and help people to receive effective treatment. Objective: To estimate the annual attributable medical cost of SUD in US hospitals from the health care payer perspective. Design, Setting, and Participants: This economic evaluation of observational data used multivariable regression analysis and mathematical modeling of hospital encounter costs, controlling for patient demographic, clinical, and insurance characteristics, and compared encounters with and without secondary SUD diagnosis to statistically identify the total attributable cost of SUD. Nationally representative hospital emergency department (ED) and inpatient encounters from the 2017 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample and National Inpatient Sample were studied. Statistical analysis was performed from March to June 2020. Exposures: International Statistical Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) principal or secondary SUD diagnosis on the hospital discharge record according to the Clinical Classifications Software categories (disorders related to alcohol, cannabis, hallucinogens, inhalants, opioids, sedatives, stimulants, and other substances). Main Outcomes and Measures: Annual attributable SUD medical cost in hospitals overall and by substance type (eg, alcohol). The number of encounters (ED and inpatient) with SUD diagnosis (principal or secondary) and the mean cost attributable to SUD per encounter by substance type are also reported. Results: This study examined a total of 124 573 175 hospital ED encounters and 33 648 910 hospital inpatient encounters from the 2017 Healthcare Cost and Utilization Project Nationwide Emergency Department Sample and National Inpatient Sample. Total annual estimated attributable SUD medical cost in hospitals was $13.2 billion. By substance type, the cost ranged from $4 million for inhalant-related disorders to $7.6 billion for alcohol-related disorders. Conclusions and Relevance: This study's results suggest that the cost of effective prevention and treatment may be substantially offset by a reduction in the high direct medical cost of SUD hospital care. The findings of this study may inform the treatment of patients with SUD during hospitalization, which presents a critical opportunity to engage patients who are at high risk for overdose. Aligning incentives such that prevention cost savings accrue to payers and practitioners that are otherwise responsible for SUD-related medical costs in hospitals and other health care settings may encourage prevention investment.

Adolescent chronic intermittent toluene inhalation dynamically regulates the transcriptome and neuronal methylome within the rat medial prefrontal cortex.

Inhalants containing the volatile solvent toluene are misused to induce euphoria or intoxication. Inhalant abuse is most common during adolescence and can result in cognitive impairments during an important maturational period. Despite evidence suggesting that epigenetic modifications may underpin the cognitive effects of inhalants, no studies to date have thoroughly investigated toluene-induced regulation of the transcriptome or discrete epigenetic modifications within the brain. To address this, we investigated effects of adolescent chronic intermittent toluene (CIT) inhalation on gene expression and DNA methylation profiles within the rat medial prefrontal cortex (mPFC), which undergoes maturation throughout adolescence and has been implicated in toluene-induced cognitive deficits. Employing both RNA-seq and genome-wide Methyl CpG Binding Domain (MBD) Ultra-seq analysis, we demonstrate that adolescent CIT inhalation (10 000 ppm for 1 h/day, 3 days/week for 4 weeks) induces both transient and persistent changes to the transcriptome and DNA methylome within the rat mPFC for at least 2 weeks following toluene exposure. We demonstrate for the first time that adolescent CIT exposure results in dynamic regulation of the mPFC transcriptome likely relating to acute inflammatory responses and persistent deficits in synaptic plasticity. These adaptations may contribute to the cognitive deficits associated with chronic toluene exposure and provide novel molecular targets for preventing long-term neurophysiological abnormalities following chronic toluene inhalation.

Analysis of some commonly found inhalants using gas chromatography-mass spectrometry (GC MS) - Effect of substrates on the identification of inhalants.

Inhalant abuse is a serious and ever-evolving problem for our society. Inhalants are abused more commonly by teenagers and adolescents. Inhalants such as glue, paint thinners, correction fluid, and nail paint remover are easily available in the market which makes them readily abused. Out of various methods of abuse, huffing (placing a piece of cloth soaked with inhalant is placed in the mouth), bagging (placing head in a polythene bag containing inhalant), and ballooning (balloons filled with inhalant are used for inhaling vapors through the mouth) are most common. Inhalant abuse results in multiple target organ dysfunction with neuritis and brain damage due to the dissolution of the myelin sheath. In acute poisoning cases, it might cause death due to asphyxia and sudden sniffing syndrome. In such cases, various articles containing traces of inhalants could be retrieved from the scene of incidence and to detect these traces become an important facet of the investigation. However, it might be difficult due to the rapid evaporation of inhalants and the formation of reaction product species. In the present study, an attempt has been made to study the effect of three substrates (balloon, cloth, polythene) on component profiles of four paint thinners and four nail paint removers. The study suggests that although some components are retained, there is the formation of a large number of reaction product species and these must be taken into consideration before furnishing the opinion. These reaction product species might also be inhalant specific which must be further explored.

Suicídio por autointoxicação entre adolescentes e adultos jovens brasileiros: estudo de séries temporais / Suicidio por autointoxicación entre adolescentes y adultos jóvenes brasileños: estudio de las series temporales / Suicide by self-poisoning among brazilian adolescents and young adults: time-series study

RESUMO Objetivo: analisar a tendência temporal da mortalidade por autointoxicação entre adolescentes e adultos jovens brasileiros no período de 2000 a 2017. Método: estudo de séries temporais da mortalidade por suicídio por autointoxicações (X60 a X69) entre adolescentes e jovens adultos, entre os anos de 2000 a 2017. Calcularam-se os coeficientes de mortalidade por 100.000 habitantes e mortalidade proporcional. Optou-se pela regressão linear de Prais-Winster para análise de tendência. Resultados: percebeu-se uma linearidade na tendência da mortalidade geral por suicídio nessa população. Evidenciou-se uma tendência decrescente entre os indivíduos do sexo feminino, das faixas etárias de 15 a 19 anos e 20 a 24 anos, das regiões Nordeste e Centro-Oeste e que adotaram métodos de suicídio por pesticidas e produtos químicos ou substâncias nocivas não especificadas. Destacou-se também uma tendência crescente da mortalidade pelo uso de todas as classes medicamentosas analisadas, solventes orgânicos e outros inalantes. Conclusão: este estudo identificou um aumento considerável na utilização de medicamentos e inalantes como método para o suicídio entre adolescentes e adultos jovens.

RESUMEN Objetivo: analizar la tendencia temporal de la mortalidad por autointoxicación entre adolescentes y adultos jóvenes brasileños en el período de 2000 a 2017. Método: estudio de las series temporales de la mortalidad por suicidio por autointoxicaciones (X60 a X69) entre adolescentes y jóvenes adultos, entre los años de 2000 a 2017. Se calcularon las tasas de mortalidad por 100.000 habitantes y mortalidad proporcional. Se optó por la regresión lineal de Prais-Winster para análisis de tendencia. Resultados: se percibió una linealidad en la tendencia de la mortalidad general por suicidio enesta población. Se evidenció una tendencia decreciente entre los individuos del sexo femenino, de las franjas de edad de 15 a 19 años y 20 a 24 años, de las regiones Nordeste y Centro-Oeste y que adoptaron métodos de suicidio por plaguicidas y productos químicos o sustancias nocivas no especificadas. Se destacó también una tendencia creciente de la mortalidad por el uso de todas las clases de medicamentos analizadas, solventes orgánicos y otros inhalantes. Conclusión: este estudio identificó un aumento considerable en la utilización de medicamentos einhalantes como método para el suicidio entre adolescentes y adultos jóvenes.

ABSTRACT Objective: to analyze the temporal trend of mortality from self-intoxication among adolescents and young adults in Brazil from 2000 to 2017. Method: time-series study of mortality from suicide from self-intoxication (X60 to X69) among adolescents and young adults, between 2000 to 2017. The coefficients of mortality per 100,000 population and proportional mortality were calculated. The Prais-Winster linear regression was chosen for trend analysis. Results: there was linearity in the trend of overall suicide mortality in this population. A decreasing trend was evidenced among female individuals, aged 15 to 19 years old and 20 to 24 years old, from the Northeast and Midwest regions and who adopted suicide methods by pesticides and chemical products or unspecified harmful substances. A growing trend of mortality due to the use of all drug classes analyzed, organic solvents, and other inhalants were also highlighted. Conclusion: This study identified a considerable increase in the use of medications and inhalants as a method of suicide among adolescents and young adults.

Harms associated with inhalant misuse in adolescent females - a review of the pre-clinical and clinical evidence.

BACKGROUND: Inhalant misuse, or the misuse of products containing toluene is common in adolescents, and is associated with diverse physiological and psychological harms. Females comprise over half those who misuse inhalants in adolescence, however, the majority of the evidence has been derived from male-only or mixed-sex studies without exploration of sex differences. Female adolescence is a critical maturational period with potential for growth, reproductive, cognitive and psychological harms that may lead to long-term health consequences. We therefore summarise evidence of female-specific harms arising from inhalant misuse. METHODS: We synthesised pre-clinical and clinical studies of inhalant misuse which were conducted in females, or where sex-differences were reported, into a narrative literature review. RESULTS: Females experience growth impairments and metabolic dysfunction arising from inhalant misuse, but data on sex-differences are inconclusive. Inhalant misuse in early adolescence may impact menarche and subsequent reproductive capacity, but studies have predominantly focused on the effects of inhalants on offspring rather than on the exposed female. There is limited evidence of sex-differences in relation to cognitive outcomes following exposure to inhalants in pre-clinical models. Females are at an increased risk of psychological harms associated with inhalant misuse, particularly depression and suicidal behaviour. CONCLUSIONS: The type and magnitude of harms associated with inhalant misuse are sex-specific, but data are limited. We recommend that both pre-clinical and clinical studies of inhalant misuse include both males and females, and should specifically test for and report sex-differences. This can be used to build an evidence base for screening and interventions tailored to females.

Nitrous oxide inhalant abuse and massive pulmonary embolism in COVID-19.

A patient presented to the emergency department with altered mental status and lower extremity weakness in the setting of nitrous oxide inhalant abuse and Coronavirus Disease-2019 (COVID-19) infection. He subsequently developed hypotension and severe hypoxia, found to have a saddle pulmonary embolus (PE) with right heart strain requiring alteplase (tPA).

Minocycline prevents neuronal hyperexcitability and neuroinflammation in medial prefrontal cortex, as well as memory impairment caused by repeated toluene inhalation in adolescent rats.

Toluene can be intentionally misused by adolescents to experience psychoactive effects. Toluene has a complex mechanism of action and broad behavioral effects, among which memory impairment is reported consistently. We have previously reported that repeated toluene inhalation (8000 ppm) increases layer 5 prelimbic pyramidal cells' excitability in the medial prefrontal cortex (mPFC) of adolescent rats. Toluene also produces reactive oxygen species (ROS), which activate glial cells. Here, we tested the hypothesis that the anti-inflammatory agent minocycline would decrease toluene's effects because it inhibits NF-κB (nuclear factor enhancer of the kappa light chains of activated B cells) and reduces pro-inflammatory cytokine and ROS production. Our results show that minocycline (50 mg/kg, ip, for 10 days) prevents the hyperexcitability of mPFC neurons observed after repeated 8000 ppm toluene exposure (30 min/day, 2×/day for 10 days). Minocycline prevents toluene-induced hyperexcitability by a mechanism that averts the loss of the slow calcium-dependent potassium current, and normalizes mPFC neurons' firing frequency. These effects are accompanied by significant decreased expression of astrocytes and activated microglia in the mPFC, reduced NLRP3 inflammasome activation and mRNA expression levels of the pro-inflammatory cytokine interleukin 1ß (IL-1ß), as well as increased mRNA expression of the anti-inflammatory cytokine transforming growth factor ß (TGF-ß). Minocycline also prevents toluene-induced memory impairment in adolescent rats in the passive avoidance task and the temporal order memory test in which the mPFC plays a central role. These results show that neuroinflammation produces several effects of repeated toluene administration at high concentrations, and minocycline can significantly prevent them.