Deep Brain Stimulation of Nucleus Basalis of Meynert improves learning in rat model of dementia.

Background: Deep brain stimulation (DBS) of the nucleus basalis of Meynert (NBM) has been preliminarily investigated as a potential treatment for dementia. The degeneration of NBM cholinergic neurons is a pathological feature of many forms of dementia. Although stimulation of the NBM has been demonstrated to improve learning, the ideal parameters for NBM stimulation have not been elucidated. This study assesses the differential effects of varying stimulation patterns and duration on learning in a dementia rat model. Methods: 192-IgG-saporin (or vehicle) was injected into the NBM to produce dementia in rats. Next, all rats underwent unilateral implantation of a DBS electrode in the NBM. The experimental groups consisted of i-normal, ii-untreated demented, and iii-demented rats receiving NBM DBS. The stimulation paradigms included testing different modes (tonic and burst) and durations (1-hr, 5-hrs, and 24-hrs/day) over 10 daily sessions. Memory was assessed pre- and post-stimulation using two established learning paradigms: novel object recognition (NOR) and auditory operant chamber learning. Results: Both normal and stimulated rats demonstrated improved performance in NOR and auditory learning as compared to the unstimulated demented group. The burst stimulation groups performed better than the tonic stimulated group. Increasing the daily stimulation duration to 24-hr did not further improve cognitive performance in an auditory recognition task and degraded the results on a NOR task as compared with 5-hr. Conclusion: The present findings suggest that naturalistic NBM burst DBS may offer a potential effective therapy for treating dementia and suggests potential strategies for the reevaluation of current human NBM stimulation paradigms.

Xylazine: A Drug Adulterant of Clinical Concern.

PURPOSE OF REVIEW: The opioid epidemic has been responsible for significant morbidity and mortality in the USA and worldwide. As a result, it is essential to recognize the threat these potent drugs can cause when illicitly used. Specifically, introducing fentanyl as a drug adulterant has been shown to impact overdose rates drastically. In this regard, the Drug Enforcement Agency recently released a public safety alert announcing the new threat of a new adulterant called xylazine. Xylazine is a powerful animal sedative with a different mechanism of action when compared to illicit opioids such as heroin and fentanyl. Xylazine is typically injected intravenously via a syringe, often in combination with multiple other drugs. One of the most common drugs, xylazine, is taken in combination with fentanyl, with users of this drug combination describing xylazine as prolonging the euphoric sensation produced by fentanyl. RECENT FINDINGS: Xylazine may cause adverse effects such as bradycardia, brief hypertension followed by hypotension, premature ventricular contractions, ataxia, slurred speech, sedation, and respiratory depression. Much of the recent literature on xylazine use in humans comes from case reports and review articles. Related to widespread use in veterinary medicine and increasing circulation in illicit drug markets, there is a critical need for public awareness and additional clinical-based studies to further increase understanding of mediated or modulated pharmacological effects of xylazine in humans. Further research is urgently needed to more clearly understand the implications of unregulated xylazine in the illicit drug market, to formulate public health interventions, and to implement harm reduction strategies.

Impacts of Self-Administered 3,4-Methylenedioxypyrovalerone (MDPV) Alone, and in Combination with Caffeine, on Recognition Memory and Striatal Monoamine Neurochemistry in Male Sprague Dawley Rats: Comparisons with Methamphetamine and Cocaine.

Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague Dawley rats were provided 90 min or 12 h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12 h access to methamphetamine and those that had 90 min or 12 h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal monoamine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake).

Impacts of Self-Administered 3,4-Methylenedioxypyrovalerone (MDPV) Alone, and in Combination with Caffeine, on Recognition Memory and Striatal Monoamine Neurochemistry in Male Sprague-Dawley Rats: Comparisons with Methamphetamine and Cocaine.

Recent data suggest that 3,4-methylenedioxypyrovalerone (MDPV) has neurotoxic effects; however, the cognitive and neurochemical consequences of MDPV self-administration remain largely unexplored. Furthermore, despite the fact that drug preparations that contain MDPV often also contain caffeine, little is known regarding the toxic effects produced by the co-use of these two stimulants. The current study investigated the degree to which self-administered MDPV, or a mixture of MDPV+caffeine can produce deficits in recognition memory and alter neurochemistry relative to prototypical stimulants. Male Sprague-Dawley rats were provided 90-min or 12-h access to MDPV, MDPV+caffeine, methamphetamine, cocaine, or saline for 6 weeks. Novel object recognition (NOR) memory was evaluated prior to any drug self-administration history and 3 weeks after the final self-administration session. Rats that had 12-h access to methamphetamine and those that had 90-min or 12-h access to MDPV+caffeine exhibited significant deficits in NOR, whereas no significant deficits were observed in rats that self-administered cocaine or MDPV. Striatal mono-amine levels were not systematically affected. These data demonstrate synergism between MDPV and caffeine with regard to producing recognition memory deficits and lethality, highlighting the importance of recapitulating the manner in which drugs are used (e.g., in mixtures containing multiple stimulants, binge-like patterns of intake).

Overview of Methamphetamine-Associated Pulmonary Arterial Hypertension.

TOPIC IMPORTANCE: The global surge in methamphetamine use is a critical public health concern, particularly due to its robust correlation with methamphetamine-associated pulmonary arterial hypertension (MA-PAH). This association raises urgent alarms about the potential escalation of MA-PAH incidence, posing a significant and imminent challenge to global public health. REVIEW FINDINGS: This comprehensive review meticulously explores MA-PAH, offering insights into its epidemiology, pathophysiology, clinical presentation, diagnostic intricacies, and management strategies. The pathogenesis, yet to be fully described, involves complex molecular interactions, including alterations in serotonin signaling, reduced activity of carboxylesterase 1, oxidative stress, and dysregulation of pulmonary vasoconstrictors and vasodilators. These processes culminate in the structural remodeling of the pulmonary vasculature, resulting in pulmonary arterial hypertension. MA-PAH exhibits a more severe clinical profile in functional class and hemodynamics compared with idiopathic pulmonary arterial hypertension. Management involves a multifaceted approach, integrating pulmonary vasodilators, cessation of methamphetamine use, and implementing social and rehabilitation programs. These measures aim to enhance patient outcomes and detect potential relapses for timely intervention. SUMMARY: This review consolidates our understanding of MA-PAH, pinpointing knowledge gaps for future studies. Addressing these gaps is crucial for advancing diagnostic accuracy, unraveling mechanisms, and optimizing treatment for MA-PAH, thereby addressing the evolving landscape of this complex health concern.

Methamphetamine-associated pulmonary arterial hypertension: data from the national biological sample and data repository for pulmonary arterial hypertension (PAH Biobank).

OBJECTIVE: This study compares the clinical and haemodynamic severity of methamphetamine-associated pulmonary arterial hypertension (MA-PAH) with idiopathic pulmonary arterial hypertension (IPAH) and connective tissue-associated pulmonary arterial hypertension (CTD-PAH). It also examines sex differences in clinical and physiological parameters among those with MA-PAH. DESIGN: This is a cross-sectional study using clinically derived data from the National Biological Sample and Data Repository for Pulmonary Arterial Hypertension (PAH biobank), a US-based registry, to compare clinical and physiological characteristics between males and females with MA-PAH. POPULATION: The analysis included 1830 patients enrolled in the PAH biobank, with a diagnosis of MA-PAH (n=42), IPAH (n=1073), or CTD-PAH (n=715). MAIN OUTCOME MEASURES: The study assessed and compared the clinical and haemodynamic parameters of patients with MA-PAH, IPAH and CTD-PAH. RESULTS: Among the patients analysed, 42 had MA-PAH, with 69.1% being female. There were no statistically significant differences in functional class among patients with MA-PAH, IPAH and CTD-PAH. The per cent predicted 6-min walk distance (6MWD) was comparable between the three groups. Patients with MA-PAH had similar mean pulmonary artery pressure and pulmonary vascular resistance to patients with IPAH but higher compared with patients with CTD-PAH. Male patients with MA-PAH exhibited a worse functional class and lower per cent predicted 6MWD, but no significant differences in haemodynamic findings were observed between the sexes. CONCLUSION: There were no differences in haemodynamic between MA-PAH and IPAH but we found that MA-PAH differed from CTD-PAH. The study did not find evidence of sex differences in MA-PAH. Further research is necessary to identify risk factors and underlying mechanisms of MA-PAH, particularly considering the increasing prevalence of methamphetamine use. Such investigations will contribute to the development of effective prevention and treatment strategies for this condition.

Immunotherapeutic treatment of inflammation in mice exposed to methamphetamine.

Introduction: Currently, there are no FDA-approved medications to treat methamphetamine addiction, including the inflammatory, neurotoxic, and adverse neuropsychiatric effects. We have shown that partial (p)MHC class II constructs (i.e., Recombinant T-cell receptor Ligand - RTL1000), comprised of the extracellular α1 and ß1 domains of MHC class II molecules linked covalently to myelin oligodendrocyte glycoprotein (MOG)-35-55 peptide, can address the neuroimmune effects of methamphetamine addiction through its ability to bind to and down-regulate CD74 expression, block macrophage migration inhibitory factor (MIF) signaling, and reduce levels of pro-inflammatory chemokine ligand 2 (CCL2). The present study evaluated the effects of our third-generation pMHC II construct, DRmQ, on cognitive function and concentration of inflammatory cytokines in the frontal cortex, a region critical for cognitive functions such as memory, impulse control, and problem solving. Methods: Female and male C57BL/6J mice were exposed to methamphetamine (or saline) via subcutaneous (s.c.) injections administered four times per day every other day for 14 days. Following methamphetamine exposure, mice received immunotherapy (DRmQ or ibudilast) or vehicle s.c. injections daily for five days. Cognitive function was assessed using the novel object recognition test (NORT). To evaluate the effects of immunotherapy on inflammation in the frontal cortex, multiplex immunoassays were conducted. ANOVA was used to compare exploration times on the NORT and immune factor concentrations. Results: Post hoc analysis revealed increased novel object exploration time in MA-DRmQ treated mice, as compared to MA-VEH treated mice (non-significant trend). One-way ANOVA detected a significant difference across the groups in the concentration of macrophage inflammatory protein-2 (MIP-2) (p = 0.03). Post hoc tests indicated that mice treated with methamphetamine and DRmQ or ibudilast had significantly lower levels of MIP-2 in frontal cortex, as compared to mice treated with methamphetamine and vehicle (p > 0.05). Discussion: By specifically targeting CD74, our DRQ constructs can block the signaling of MIF, inhibiting the downstream signaling and pro-inflammatory effects that contribute to and perpetuate methamphetamine addiction.

Social-geographic disparities in suicidal ideations among methamphetamine users in the USA.

IMPORTANCE: Methamphetamine use is a growing public health concern nationwide. Suicide is the second leading cause of death in 2019 for US citizens aged 10-14 years and 25-34 years and is also a significant public health concern. Understanding the intersection of methamphetamine use and suicidal ideation (SI) is necessary to develop public health and policy solutions that mitigate these ongoing severe public health issues. OBJECTIVE: Our objective was to examine SI in methamphetamine users to allow us to determine prevalence and trends by age, sex, race, and geographical region. DESIGN, SETTINGS, AND PARTICIPANTS: Using data collected between 2008 and 2019 from the National Inpatient Sample (NIS) database, we identified hospital admissions (HA) of patients ≥18 years of age with a primary or secondary diagnosis of SI who were also diagnosed as methamphetamine users. Those who used other substances with methamphetamine were excluded from the analysis. MAIN OUTCOME AND MEASURES: To determine the trend and prevalence of hospital admissions due to SI and SI among methamphetamine users, we used trend weights to calculate the national estimates and performed design-based analysis to account for complex survey design and sampling weights on data collected between 2008 and 2019 in the US. RESULTS: The prevalence ratio (PR) of hospitalizations with concurrent SI and methamphetamine use increased 16-fold from 2008 to 2019. The most significant increase occurred between 2015 and 2016; the PR doubled from 6.07 to 12.14. The PR of hospitalizations with concurrent SI and methamphetamine use was highest in patients aged 26-40 (49.08%) and 41-64 (28.49%). Patients aged 41-64 showed the most significant increase from 2008 to 2019 (15.8-fold). While non-Hispanic White patients comprised most of these hospitalizations (77.02%), non-Hispanic Black patients showed the highest proportional increase (39.1-fold). The Southern and Western regions in the US showed the highest PR for these hospitalizations (34.86% and 34.31%, respectively). CONCLUSION AND RELEVANCE: Our findings indicate that SI in methamphetamine users has been increasing for some time and is likely to grow. In addition, our results suggest that these patients are demographically different. Both conditions are associated with a lesser likelihood of seeking and receiving care. Therefore, when addressing increased SI or methamphetamine use, learning more about patients who share both conditions is necessary to ensure proper care.

Updated Perspectives on the Neurobiology of Substance Use Disorders Using Neuroimaging.

Substance use problems impair social functioning, academic achievement, and employability. Psychological, biological, social, and environmental factors can contribute to substance use disorders. In recent years, neuroimaging breakthroughs have helped elucidate the mechanisms of substance misuse and its effects on the brain. Functional magnetic resonance imaging (MRI), positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance spectroscopy (MRS) are all examples. Neuroimaging studies suggest substance misuse affects executive function, reward, memory, and stress systems. Recent neuroimaging research attempts have provided clinicians with improved tools to diagnose patients who misuse substances, comprehend the complicated neuroanatomy and neurobiology involved, and devise individually tailored and monitorable treatment regimens for individuals with substance use disorders. This review describes the most recent developments in drug misuse neuroimaging, including the neurobiology of substance use disorders, neuroimaging, and substance use disorders, established neuroimaging techniques, recent developments with established neuroimaging techniques and substance use disorders, and emerging clinical neuroimaging technology.

Tianeptine, an Antidepressant with Opioid Agonist Effects: Pharmacology and Abuse Potential, a Narrative Review.

Tianeptine is an antidepressant drug approved for the treatment of major depressive disorder in countries other than the US. It is classified as an atypical tricyclic antidepressant and has shown potential benefits in addressing anxiety and irritable bowel disease. However, it is important to note that tianeptine is not approved for any use by the United States Federal Drug Administration (FDA). Despite its lack of approval by the FDA, tianeptine has been distributed online and at small retail locations. The term "gas station drugs" refers to a wide range of substances typically available for purchase from gas stations, corner stores, bodegas, mini marts, smoke shops, and the Internet. These substances may be produced commercially by drug manufacturers or in clandestine laboratories to mimic the effects of more well-known illicit/controlled substances such as marijuana, cocaine, opioids, etc. Tianeptine has made its way to convenience stores and gas station shelves, branded as "Zaza" and "Tianna Red." It can also be obtained online from independent vendors without a prescription. Misuse of tianeptine can lead to euphoric, opioid-like highs with the potential for chronic users to develop dependence and tolerance. Overdose and use in suicide attempts have also been documented. This manuscript is a narrative review, highlighting the dangers of tianeptine and other gas station drugs and underscoring the urgent need to regulate these substances.

The Use of Oxytocin for the Treatment of Opioid Use Disorder.

Nearly 27 million people have an opioid use disorder (OUD) according to the 2016 Global Burden of Disease study, most of which occur in the US where opioids are a common class of medication used to treat acute and chronic pain. In 2016 alone, more than 60 million patients had at least one prescription for opioids filled or refilled. Over the past decade, prescription rates have risen astronomically and have created an epidemic in the US dubbed the "opioid crisis." In this regard, there has been an increase in overdoses and OUD diagnoses. Several studies have found dysregulation of balance between several neurotransmitters involved in the neural circuitry that subserves several behavioral domains, such as reward recognition, motivation, learning, and memory, affect, stress, and executive function, that contribute to the manifestation of craving. On the horizon is a new treatment approach consisting of the neuropeptide oxytocin, which may be involved in the overlapping mechanisms of stable attachment formation and coping with stress. Through this mechanism, it can shift processing from novelty and reward-seeking to an appreciation of familiarity and thus reduce stress and increase resilience in the face of addiction. It has been hypothesized that there is a connection between the glutaminergic and oxytocinergic systems, making oxytocin a possible therapeutic agent in reducing drug-induced actions seen in OUD patients. This manuscript will review the potential and feasible use of oxytocin in treating OUD.

Methamphetamine and Designer Stimulants Modulate Tonic Human Cerebrovascular Smooth Muscle Contractility: Relevance to Drug-Induced Neurovascular Stress.

To avoid criminal prosecution, clandestine chemists produce designer stimulants that mimic the pharmacological and psychoactive effects of conventional stimulants, such as methamphetamine. Following persistent or high-dose exposure, both acute vasoconstriction and loss of vascular homeostasis are reported dangers of conventional stimulants, and designer stimulants may pose even greater dangers. To compare the effects of a conventional stimulant and two designer stimulants on vascular contraction, this study examined the direct effects of 1,3-benzodioxolylbutanamine (BDB) and N-butylpentylone in comparison to methamphetamine on the function of human brain vascular smooth muscle cells (HBVSMCs). HBVSMCs suspended in collagen gels were exposed to varying concentrations of each drug, and the degree of constriction was assessed over one week. The MTT assay was used to measure the impact of the three drugs on the cellular metabolic activity as a marker of cellular toxicity. The highest concentration tested of either methamphetamine or N-butylpentylone produced a loss of HBVSMC contractility and impaired cellular metabolism. BDB showed a similar pattern of effects, but, uniquely, it also induced vasoconstrictive effects at substantially lower concentrations. Each drug produced direct effects on HBVSMC contraction that may be a mechanism by which the cardiovascular system is damaged following high-dose or persistent exposure, and this could be exacerbated by any sympathomimetic effects of these compounds in whole organisms. BDB appears to impact HBVSMC function in ways distinct from methamphetamine and N-butylpentylone, which may present unique dangers.

Topical cannabidiol is well tolerated in individuals with a history of elite physical performance and chronic lower extremity pain.

INTRODUCTION: Cannabidiol (CBD) is a potential therapeutic for pain management. Yet, there exists a dearth of studies of its tolerability and efficacy, especially in special populations. Former elite athletes are a special population both susceptible to chronic pain and also highly trained and attuned to assess medication tolerability concerns. The purpose of the present open-label pilot study was to assess the tolerability of CBD in this population. MATERIALS AND METHODS: Retrospective analysis was conducted in deidentified data from 20 individuals who were all previously professional athletes in US/American football, track and field, or basketball, with careers ranging from 4 to 10 years. Participants received topical CBD (10 mg twice daily by controlled dispenser) for chronic pain resulting from acute lower extremity injuries. Assessments of tolerability and secondary analyses of pain, pain-related disability, and activities of daily living were collected by self-report over the 6-week study period. Data were analyzed by descriptive statistics, pairwise t-test, and linear regression. RESULTS: Seventy percent of participants completed the study. Of the individuals who completed the study, 50% reported minor adverse effects, none of which required medical attention, and 50% did not report any adverse effects. The mostly commonly reported effects were skin dryness (43% of study completers) and skin rash (21% of study completers), which rapidly resolved. There was a significant improvement in self-reported pain levels (intake mean 3.5 ± 0.29; exit mean 1.7 ± 0.23; P < 0.001) and pain-related disability, including family and home responsibilities, life support activities, occupational activities, recreational activities, self-care, sexual function, and social activities (all P < 0.001). DISCUSSION: To the best of our knowledge, this is the first study to assess CBD treatment in elite athletes, who are disproportionally susceptible to disabling injuries. Topical administration of CBD was tolerated well by this population and resulted in only minor adverse effects. As elite athletes are trained and attuned to assess their own bodies due to their professional lives, this population is likely to detect tolerability concerns. However, this study was limited to a convenience sample and self-reported data. These pilot findings warrant further study of topical CBD in randomized and controlled studies of elite athletes.

Exploring psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder.

Methamphetamine use disorder is a chronic relapsing condition associated with substantial mental, physical, and social harms and increasing rates of mortality. Contingency management and psychotherapy interventions are the mainstays of treatment but are modestly effective with high relapse rates, while pharmacological treatments have shown little to no efficacy. Psilocybin-assisted psychotherapy is emerging as a promising treatment for a range of difficult-to-treat conditions, including substance use disorders; however, no studies have yet been published looking at psilocybin-assisted psychotherapy in the treatment of methamphetamine use disorder. Here we review the rationale for psilocybin-assisted psychotherapy as a potential treatment for this indication, and describe practical considerations based on our early experience designing and implementing four separate clinical trials of psilocybin-assisted psychotherapy for methamphetamine use disorder.

Transcranial Stimulation for the Treatment of Stimulant Use Disorder.

The increasing prevalence of stimulant use disorder (StUD) involving methamphetamine and cocaine has been a growing healthcare concern in the United States. Cocaine usage is associated with atherosclerosis, systolic and diastolic dysfunction, and arrhythmias. Furthermore, approximately one of every four MIs is cocaine-induced among patients aged 18 to 45. Methamphetamine use has been associated with nerve terminal damage in the dopaminergic system resulting in impaired motor function, cognitive decline, and co-morbid psychiatric disorders. Current treatment options for StUD are extremely limited, and there are currently no FDA-approved pharmacotherapies. Behavioral interventions are considered first-line treatment; however, in a recent meta-analysis comparing behavioral treatment options for cocaine, contingency management programs provided the only significant reduction in use. Current evidence points to the potential of various neuromodulation techniques as the next best modality in treating StUD. The most promising evidence thus far has been transcranial magnetic stimulation which several studies have shown to reduce risk factors associated with relapse. Another more invasive neuromodulation technique being studied is deep-brain stimulation, which has shown promising results in its ability to modulate reward circuits to treat addiction. Results showing the impact of transcranial magnetic stimulation (TMS) in the treatment of StUD are limited by the lack of studies conducted and the limited understanding of the neurological involvement driving addiction-based diseases such as StUD. Future studies should seek to provide data on consumption-reducing effects rather than craving evaluations.

Ketamine Evolving Clinical Roles and Potential Effects with Cognitive, Motor and Driving Ability.

While driving under the influence of drugs, drivers are more likely to be involved in and cause more accidents than drivers who do not drive under the influence. Ketamine is derived from phencyclidine and acts as a noncompetitive antagonist and allosteric modulator of N-methyl-D-aspartate receptors. Ketamine has been used to treat a variety of psychiatric disorders, with the most notable being treatment-resistant depression. With the rise of at-home ketamine treatment companies, the safety of unsupervised administration remains under evaluation. A study with ketamine and a ketamine-like medication, rapasitnel, showed that those who were given ketamine experienced more sleepiness and had decreased self-reported motivation and confidence in their driving abilities. Moreover, there seem to be significant differences in the acute versus persistent effects of ketamine, as well as the anesthetic versus subanesthetic doses, both in terms of effects and outcomes. These divergent effects complicate the clinical uses of ketamine, specifically involving driving, drowsiness, and cognitive abilities. This review aims to describe not only the various clinical uses of ketamine but also the potentially detrimental effects of driving under the influence, which should be understood to help with counseling the patients who use these substances, both for their well-being and to protect public safety.

New Synthetic Opioids: Clinical Considerations and Dangers.

Since the early 2010s, synthetic opioids have significantly contributed to overall opioid-related overdose mortalities. For point of reference, of the 68,630 opioid-related deaths recorded in 2020, 56,516 involved synthetic opioids. During much of this period, fentanyl has been the most commonly used synthetic opioid. This time when fentanyl was the most popular opioid has been called the "third wave" of the opioid crisis, partly because it led to a sharp rise in deaths from overdoses. Other synthetic opioids, such as carfentanil, protonitazene, and isotonitazene, have also become more widely diverted for nonmedical used. Carfentanil is an even more potent fentanyl derivative that was initially used in the mid-1980s as a general anesthetic for large animals such as elephants. Related to its strong affinity for mu opioid receptors, carfentanil is still utilized in medicine and science today as a radiotracer for positron emission tomography imaging. Protonitazene and isotonitazene belong to a novel class of synthetic opioids called benzimidazoles that were manufactured in the 1950s as novel analgesics. These agents have come under recent scrutiny as designer synthetic opioids becoming more prevalent. However, to date, there is incomplete data regarding the prevalence of synthetic opioids, as traditional toxicology screenings may not be sensitive to detect these compounds at such low doses post-mortem, particularly when blood is drawn from the periphery instead of central tissues such as the brain, lung, or heart. This narrative review aims to highlight the clinical challenges presented by these new synthetic opioids.

Highly socially vulnerable communities exhibit disproportionately increased viral loads as measured in community wastewater.

Wastewater surveillance has proven to be a useful tool for evidence-based epidemiology in the fight against the SARS-CoV-2 virus. It is particularly useful at the population level where acquisition of individual test samples may be time or cost-prohibitive. Wastewater surveillance for SARS-CoV-2 has typically been performed at wastewater treatment plants; however, this study was designed to sample on a local level to monitor the spread of the virus among three communities with distinct social vulnerability indices in Shreveport, Louisiana, located in a socially vulnerable region of the United States. Twice-monthly grab samples were collected from September 30, 2020, to March 23, 2021, during the Beta wave of the pandemic. The goals of the study were to examine whether: 1) concentrations of SARS-CoV-2 RNA in wastewater varied with social vulnerability indices and, 2) the time lag of spikes differed during wastewater monitoring in the distinct communities. The size of the population contributing to each sample was assessed via the quantification of the pepper mild mottle virus (PMMoV), which was significantly higher in the less socially vulnerable community. We found that the communities with higher social vulnerability exhibited greater viral loads as assessed by wastewater when normalized with PMMoV (Kruskal-Wallis, p < 0.05). The timing of the spread of the virus through the three communities appeared to be similar. These results suggest that interconnected communities within a municipality experienced the spread of the SARS-CoV-2 virus at similar times, but areas of high social vulnerability experienced more intense wastewater viral loads.

Using the social vulnerability index to assess COVID-19 vaccine uptake in Louisiana.

Using data from the Louisiana Department of Public Health, we explored the spatial relationships between the Social Vulnerability Index (SVI) and COVID-19-related vaccination and mortality rates. Publicly available COVID-19 vaccination and mortality data accrued from December 2020 to October 2021 was downloaded from the Louisiana Department of Health website and merged with the SVI data; geospatial analysis was then performed to identify the spatial association between the SVI and vaccine uptake and mortality rate. Bivariate Moran's I analysis revealed significant clustering of high SVI ranking with low COVID-19 vaccination rates (1.00, p < 0.001) and high smoothed mortality rates (0.61, p < 0.001). Regression revealed that for each 10% increase in SVI ranking, COVID-19 vaccination rates decreased by 3.02-fold (95% CI = 3.73-2.30), and mortality rates increased by a factor of 1.19 (95% CI = 0.99-1.43). SVI values are spatially linked and significantly associated with Louisiana's COVID-19-related vaccination and mortality rates. We also found that vaccination uptake was higher in whites than in blacks. These findings can help identify regions with low vaccination rates and high mortality, enabling the necessary steps to increase vaccination rates in disadvantaged neighborhoods.

Elucidating the Role of Trauma and Significant Life Stress in the Disease of Addiction may Provide New Targets for Medication Development.

The role of previous life stress and trauma in addiction has been understudied and underappreciated. To date, much previous research has emphasized other aspects of the disease of addiction, including the reward-based neural circuitry. While previous research has offered tremendous value and shaped human understanding of addiction, an increased emphasis on the role of stress and trauma in addiction may provide new targets for therapeutic development. Here, we review both clinical and preclinical literature in support of the hypothesis that addiction is largely initiated and driven by significant previous life stressors and traumas. We describe some of the available quantitative molecular in vitro studies, systematic literature reviews, case-control studies, and cross-sectional studies to summarize the neurobiology of the reward pathway, the influence of stress-related hormones on the brain, and the role of childhood trauma in the development of substance abuse. The current perspective highlights the importance of early intervention during stressful life events for the prevention of future addiction behavior and suggests that elucidating the neurobiology of these systems may provide new targets for medication development for addiction.