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Blast-related mild traumatic brain injury (blast-mTBI) can result in a spectrum of persistent symptoms leading to substantial functional impairment and reduced quality of life. Clinical evaluation and discernment from other conditions common to military service can be challenging and subject to patient recall bias and the limitations of available assessment measures. The need for objective biomarkers to facilitate accurate diagnosis, not just for symptom management and rehabilitation but for prognostication and disability compensation purposes is clear. Toward this end, we compared regional brain [18F]fluorodeoxyglucose-positron emission tomography ([18F]FDG-PET) intensity-scaled uptake measurements and motor, neuropsychological, and behavioral assessments in 79 combat Veterans with retrospectively recalled blast-mTBI with 41 control participants having no lifetime history of TBI. Using an agnostic and unbiased approach, we found significantly increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI versus control participants, p < 0.0001; q = 3.29 × 10-9 [Cohen's d, 1.38, 95% confidence interval (0.96, 1.79)]. The degree of left pallidum [18F]FDG-uptake correlated with the number of self-reported blast-mTBIs, r2 = 0.22; p < 0.0001. Greater [18F]FDG-uptake in the left pallidum provided excellent discrimination between Veterans with blast-mTBI and controls, with a receiver operator characteristic area under the curve of 0.859 (p < 0.0001) and likelihood ratio of 21.19 (threshold:SUVR ≥ 0.895). Deficits in executive function assessed using the Behavior Rating Inventory of Executive Function-Adult Global Executive Composite T-score were identified in Veterans with blast-mTBI compared with controls, p < 0.0001. Regression-based mediation analyses determined that in Veterans with blast-mTBI, increased [18F]FDG-uptake in the left pallidum-mediated executive function impairments, adjusted causal mediation estimate p = 0.021; total effect estimate, p = 0.039. Measures of working and prospective memory (Auditory Consonant Trigrams test and Memory for Intentions Test, respectively) were negatively correlated with left pallidum [18F]FDG-uptake, p < 0.0001, with mTBI as a covariate. Increased left pallidum [18F]FDG-uptake in Veterans with blast-mTBI compared with controls did not covary with dominant handedness or with motor activity assessed using the Unified Parkinson's Disease Rating Scale. Localized increased [18F]FDG-uptake in the left pallidum may reflect a compensatory response to functional deficits following blast-mTBI. Limited imaging resolution does not allow us to distinguish subregions of the pallidum; however, the significant correlation of our data with behavioral but not motor outcomes suggests involvement of the ventral pallidum, which is known to regulate motivation, behavior, and emotions through basal ganglia-thalamo-cortical circuits. Increased [18F]FDG-uptake in the left pallidum in blast-mTBI versus control participants was consistently identified using two different PET scanners, supporting the generalizability of this finding. Although confirmation of our results by single-subject-to-cohort analyses will be required before clinical deployment, this study provides proof of concept that [18F]FDG-PET bears promise as a readily available noninvasive biomarker for blast-mTBI. Further, our findings support a causative relationship between executive dysfunction and increased [18F]FDG-uptake in the left pallidum.
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Biomarcadores , Traumatismos por Explosões , Concussão Encefálica , Disfunção Cognitiva , Função Executiva , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Veteranos , Humanos , Masculino , Traumatismos por Explosões/diagnóstico por imagem , Traumatismos por Explosões/complicações , Traumatismos por Explosões/psicologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/metabolismo , Adulto , Tomografia por Emissão de Pósitrons/métodos , Feminino , Concussão Encefálica/diagnóstico por imagem , Concussão Encefálica/complicações , Concussão Encefálica/psicologia , Função Executiva/fisiologia , Biomarcadores/metabolismo , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Estudos RetrospectivosRESUMO
Introduction: Cannabis use disorder (CUD) is prevalent in ~2-5% of adults in the United States and is anticipated to increase as restrictions to cannabis decrease and tetrahydrocannabinol (THC) content in cannabis products increase. No FDA-approved medications for CUD are currently available, despite trials of dozens of re-purposed and novel drugs. Psychedelics have garnered interest as a therapeutic class in other substance use disorders, and self-report surveys suggest they may result in positive outcomes for CUD. Herein, we review the existing literature pertaining to psychedelic use in persons with or at risk for CUD and consider the potential rationale underpinning psychedelics as a treatment for CUD. Methods: A systematic search was performed in several databases. Inclusion criteria were primary research reporting use of psychedelics or related substances and CUD for treatment in human subjects. Exclusion criteria were results including psychedelics or related substances without changes in cannabis use or risks associated with CUD. Results: Three hundred and five unique results were returned. One article was identified using the non-classical psychedelic ketamine in CUD; three articles were identified as topically relevant based on their secondary data or consideration of mechanism. Additional articles were reviewed for purposes of background, review of safety considerations, and formulating rationale. Conclusion: Limited data and reporting are available on the use of psychedelics in persons with CUD, and more research is needed given the anticipated increase in CUD incidence and increasing interest in psychedelic use. While psychedelics, broadly, have a high therapeutic index with infrequent serious adverse effects, particular adverse effects at risk in the CUD population, such as psychosis and cardiovascular events, should be considered. Possible mechanisms by which psychedelics have therapeutic potential in CUD are explored.
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BACKGROUND: Excessive noradrenergic signaling contributes to aversive symptoms of alcohol withdrawal that interfere with abstinence or reductions in harmful use. METHODS: To address this aspect of alcohol use disorder, 102 active-duty soldiers participating in command-mandated Army outpatient alcohol treatment were randomized to also receive the brain-penetrant alpha-1 adrenergic receptor antagonist prazosin or placebo for 13 weeks. Primary outcomes were scores on the Penn Alcohol Craving Scale (PACS), standard drink units (SDUs) per day averaged over each week, % days of any drinking per week, and % days of heavy drinking per week. RESULTS: PACS declines did not differ significantly between the prazosin and placebo groups in the overall sample. In the subgroup with comorbid PTSD (n = 48), PACS declines were significantly greater in the prazosin than in the placebo condition (p < 0.05). Baseline alcohol consumption was markedly reduced by the pre-randomization outpatient alcohol treatment program, but the addition of prazosin treatment produced a greater slope of decline in SDUs per day compared to placebo (p = 0.01). Preplanned subgroup analyses were performed in soldiers with elevated baseline cardiovascular measures consistent with increased noradrenergic signaling. In soldiers with elevated standing heart rate (n = 15), prazosin reduced SDUs per day (p = 0.01), % days drinking (p = 0.03), and % days heavy drinking (p = 0.001) relative to placebo. In soldiers with elevated standing systolic blood pressure (n = 27), prazosin reduced SDUs per day (p = 0.04) and tended to reduce % days drinking (p = 0.056). Prazosin also reduced depressive symptoms and the incidence of emergent depressed mood more than placebo (p = 0.05 and p = 0.01, respectively). During the final 4 weeks of prazosin vs. placebo treatment that followed completion of Army outpatient AUD treatment, alcohol consumption in soldiers with elevated baseline cardiovascular measures increased in those receiving placebo but remained suppressed in those receiving prazosin. CONCLUSIONS: These results extend reports that higher pretreatment cardiovascular measures predict beneficial effects of prazosin, which may be useful for relapse prevention in patients with AUD.
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Alcoolismo , Militares , Síndrome de Abstinência a Substâncias , Humanos , Prazosina/uso terapêutico , Alcoolismo/tratamento farmacológico , Alcoolismo/epidemiologia , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Consumo de Bebidas Alcoólicas/tratamento farmacológico , Etanol/uso terapêutico , Método Duplo-Cego , Resultado do TratamentoRESUMO
We recently reported our experience with implanted vagus nerve stimulators (VNS) in 62 children over a 7-year period. Here, we present a case of a VNS that successfully reduced the number and severity of seizures in a patient with an unusual seizure pattern, and failed to function shortly after a lightning storm. To our knowledge, the failure of VNS or any implantable electrical devices by lightning has not been reported in the literature. This mechanism of electrical interference, while unusual, may require more attention as these devices are expected to be used more frequently.
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Terapia por Estimulação Elétrica/instrumentação , Epilepsia/terapia , Falha de Equipamento , Raio , Nervo Vago , Epilepsia/diagnóstico , Feminino , Humanos , Índice de Gravidade de Doença , Adulto JovemRESUMO
Purpose: Recent research has suggested that chronic alcohol exposure induces changes in the endocannabinoid system within the central nervous system and therefore could be an attractive target for better understanding and treating alcohol use disorder (AUD). Much of this research has centered around the CB1 receptor and its endogenous partial agonist, the endocannabinoid anandamide, as the CB1 receptor is densely expressed in brain regions involved in development and maintenance of addictive behaviors. In addition, recent evidence has suggested that chronic alcohol exposure induces changes in the modulation of endocannabinoid concentration and suggests that these changes may contribute to the motivation to abuse alcohol. Therefore, we performed a systematic literature review to evaluate how fatty acid amide hydrolase (FAAH), an enzyme that degrades anandamide, relates to the characteristics and biology of AUD, as well as how modulating FAAH through pharmacologic inhibition or genetic manipulation affects outcomes related to alcohol use and consumption. Method: A search strategy was developed using the terms "endocannabinoids" or "drug delivery systems" and "alcohol dependence" or "alcohol use disorder" or "alcoholism" and "Fatty Acid Amide Hydrolase" and "FAAH" as text words and Medical Subject Headings (i.e., MeSH and EMTREE). We then used this search strategy on the electronic databases PubMed, Embase, and Web of Science. Results: We found 224 records; after removing repeated records (37%), articles that did not fit the topic question (47%), or were not primary research (4%), we included 26 for qualitative synthesis (12%). Discussion: The literature clearly suggests that FAAH has a role in the biology and characteristics of AUD. FAAH inhibition seems especially promising as a target for alcohol withdrawal as it may lead to a reduction in symptoms, including anxiety and a reduction of alcohol intake reinstatement. However, decreased FAAH may also lead to reduced sensitivity to alcohol along with increased preference and intake. Conclusions: Modulation of FAAH is promising for therapeutic intervention of AUD, but requires more research. Pre-clinical studies have indicated that FAAH inhibition may reduce withdrawal characteristics, but may also exacerbate other characteristics of AUD outside of that period.
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Alcoolismo , Síndrome de Abstinência a Substâncias , Consumo de Bebidas Alcoólicas , Alcoolismo/tratamento farmacológico , Amidoidrolases/genética , HumanosRESUMO
Repetitive mild traumatic brain injury (mTBI) has been called the "signature injury" of military service members in the Iraq and Afghanistan wars and is highly comorbid with post-traumatic stress disorder (PTSD). Correct attribution of adverse blast-induced mTBI and/or PTSD remains challenging. Pre-clinical research using animal models can provide important insight into the mechanisms by which blast produces injury and dysfunction-but only to the degree by which such models reflect the human experience. Avoidance of trauma reminders is a hallmark of PTSD. Here, we sought to understand whether a mouse model of blast reproduces this phenomenon, in addition to blast-induced physical injuries. Drawing on well-established work from the chronic stress and Pavlovian conditioning literature, we hypothesized that even while one is anesthetized during blast exposure, environmental cues encountered in the peri-blast environment could be conditioned to evoke aversion/dysphoria and re-experiencing of traumatic stress. Using a pneumatic shock tube that recapitulates battlefield-relevant open-field blast forces, we provide direct evidence that stress is inherent to repetitive blast exposure, resulting in chronic aversive/dysphoric-like responses to previous blast-paired cues. The results in this report demonstrate that, although both single and repetitive blast exposures produce acute stress responses (weight loss, corticosterone increase), only repetitive blast exposure also results in co-occurring aversive/dysphoric-like stress responses. These results extend appreciation of the highly complex nature of repetitive blast exposure; and lend further support for the potential translational relevance of animal modeling approaches currently used by multiple laboratories aimed at elucidating the mechanisms (both molecular and behavioral) of repetitive blast exposure.
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Aprendizagem da Esquiva/fisiologia , Traumatismos por Explosões/sangue , Traumatismos por Explosões/psicologia , Concussão Encefálica/sangue , Concussão Encefálica/psicologia , Sinais (Psicologia) , Animais , Traumatismos por Explosões/complicações , Concussão Encefálica/complicações , Corticosterona/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Odorantes , Estimulação Luminosa/efeitos adversosRESUMO
PURPOSE: Cannabinoid subtype 1 (CB(1)) receptors are found in nearly every organ in the body, may be involved in several neuropsychiatric and metabolic disorders, and are therefore an active target for pharmacotherapy and biomarker development. We recently reported brain imaging of CB(1) receptors with two PET radioligands: (11)C-MePPEP and (18)F-FMPEP-d (2). Here we describe the biodistribution and dosimetry estimates for these two radioligands. METHODS: Seven healthy subjects (four men and three women) underwent whole-body PET scans for 120 min after injection with (11)C-MePPEP. Another seven healthy subjects (two men and five women) underwent whole-body PET scans for 300 min after injection with (18)F-FMPEP-d (2). Residence times were acquired from regions of interest drawn on tomographic images of visually identifiable organs for both radioligands and from radioactivity excreted in urine for (18)F-FMPEP-d (2). RESULTS: The effective doses of (11)C-MePPEP and (18)F-FMPEP-d (2) are 4.6 and 19.7 microSv/MBq, respectively. Both radioligands demonstrated high uptake of radioactivity in liver, lung, and brain shortly after injection and accumulated radioactivity in bone marrow towards the end of the scan. After injection of (11)C-MePPEP, radioactivity apparently underwent hepatobiliary excretion only, while radioactivity from (18)F-FMPEP-d (2) showed both hepatobiliary and urinary excretion. CONCLUSION: (11)C-MePPEP and (18)F-FMPEP-d (2) yield an effective dose similar to other PET radioligands labeled with either (11)C or (18)F. The high uptake in brain confirms the utility of these two radioligands to image CB(1) receptors in brain, and both may also be useful to image CB(1) receptors in the periphery.
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Agonismo Inverso de Drogas , Tomografia por Emissão de Pósitrons/métodos , Pirrolidinonas/farmacologia , Pirrolidinonas/farmacocinética , Receptor CB1 de Canabinoide/metabolismo , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Feminino , Humanos , Masculino , RadiometriaRESUMO
Mounting evidence points to the significance of neurovascular-related dysfunction in veterans with blast-related mTBI, which is also associated with reduced [18F]-fluorodeoxyglucose (FDG) uptake. The goal of this study was to determine whether plasma VEGF-A is altered in veterans with blast-related mTBI and address whether VEGF-A levels correlate with FDG uptake in the cerebellum, a brain region that is vulnerable to blast-related injury 72 veterans with blast-related mTBI (mTBI) and 24 deployed control (DC) veterans with no lifetime history of TBI were studied. Plasma VEGF-A was significantly elevated in mTBIs compared to DCs. Plasma VEGF-A levels in mTBIs were significantly negatively correlated with FDG uptake in cerebellum. In addition, performance on a Stroop color/word interference task was inversely correlated with plasma VEGF-A levels in blast mTBI veterans. Finally, we observed aberrant perivascular VEGF-A immunoreactivity in postmortem cerebellar tissue and not cortical or hippocampal tissues from blast mTBI veterans. These findings add to the limited number of plasma proteins that are chronically elevated in veterans with a history of blast exposure associated with mTBI. It is likely the elevated VEGF-A levels are from peripheral sources. Nonetheless, increasing plasma VEGF-A concentrations correlated with chronically decreased cerebellar glucose metabolism and poorer performance on tasks involving cognitive inhibition and set shifting. These results strengthen an emerging view that cognitive complaints and functional brain deficits caused by blast exposure are associated with chronic blood-brain barrier injury and prolonged recovery in affected regions.
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Traumatismos por Explosões , Concussão Encefálica , Transtornos de Estresse Pós-Traumáticos , Veteranos , Traumatismos por Explosões/complicações , Traumatismos por Explosões/diagnóstico por imagem , Humanos , Fator A de Crescimento do Endotélio VascularRESUMO
[11C]MePPEP is a high affinity, CB1 receptor-selective, inverse agonist that has been studied in rodents and monkeys. We examined the ability of [11C]MePPEP to quantify CB1 receptors in human brain as distribution volume calculated with the "gold standard" method of compartmental modeling and compared results with the simple measure of brain uptake. A total of 17 healthy subjects participated in 26 positron emission tomography (PET) scans, with 8 having two PET scans to assess retest variability. After injection of [11C]MePPEP, brain uptake of radioactivity was high (e.g., 3.6 SUV in putamen at approximately 60 min) and washed out very slowly. A two-tissue compartment model yielded values of distribution volume (which is proportional to receptor density) that were both well identified (SE 5%) and stable between 60 and 210 min. The simple measure of brain uptake (average concentration of radioactivity between 40 and 80 min) had good retest variability ( approximately 8%) and moderate intersubject variability (16%, coefficient of variation). In contrast, distribution volume had two-fold greater retest variability ( approximately 15%) and, thus, less precision. In addition, distribution volume had three-fold greater intersubject variability ( approximately 52%). The decreased precision of distribution volume compared to brain uptake was likely due to the slow washout of radioactivity from brain and to noise in measurements of the low concentrations of [11C]MePPEP in plasma. These results suggest that brain uptake can be used for within subject studies (e.g., to measure receptor occupancy by medications) but that distribution volume remains the gold standard for accurate measurements between groups.
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Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Pirrolidinonas , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Adulto , Simulação por Computador , Feminino , Humanos , Cinética , Imageamento por Ressonância Magnética , Masculino , Modelos Neurológicos , Tomografia por Emissão de Pósitrons , Pirrolidinonas/sangue , Pirrolidinonas/farmacocinética , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Despite the high prevalence of blunt smoking among cannabis users, very few studies examine the clinical profile of blunt smokers relative to those using more common methods of cannabis use, such as joints. METHODS: The current study uses baseline data from the ACCENT (Achieving Cannabis Cessation-Evaluating N-acetylcysteine Treatment) study, a multi-site randomized pharmacotherapy clinical trial within the National Drug Abuse Treatment Clinical Trials Network, to predict the association between blunt and joint use frequency and cannabis use characteristics (e.g., grams of cannabis used) and consequences (e.g., withdrawal) among past-month cannabis users (N = 377) who were screened for study participation. RESULTS: After controlling for race, age, gender, other forms of cannabis use (including joint use) and nicotine dependence, multivariable linear regression models indicated that the number of days of blunt use in the past month was a significant predictor of the average amount of cannabis per using day (t = 3.04, p < .01), the estimated average cost of cannabis (t = 2.28, p < .05) and Cannabis Withdrawal Scale scores (t = 1.94, p < .05). Frequency of joint use did not significantly predict any of the cannabis use characteristics or consequences. CONCLUSIONS: Blunt smokers may present to treatment with greater amounts of cannabis smoked and more intense withdrawal symptoms, which may adversely impact their likelihood of successful abstinence. Cannabis-dependent blunt smokers may be more likely to benefit from treatment that targets physiological and mood-related withdrawal symptoms.
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Cannabis/efeitos adversos , Fumar Maconha/epidemiologia , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Fumar/epidemiologia , Síndrome de Abstinência a Substâncias/epidemiologia , Tabagismo/epidemiologia , Adolescente , Adulto , Feminino , Humanos , Modelos Lineares , Masculino , Fumar Maconha/psicologia , Fumar Maconha/terapia , Pessoa de Meia-Idade , Prevalência , Fumar/psicologia , Fumar/terapia , Síndrome de Abstinência a Substâncias/psicologia , Síndrome de Abstinência a Substâncias/terapia , Tabagismo/psicologia , Tabagismo/terapiaRESUMO
BACKGROUND: It is common for cannabis users to also use tobacco. While data suggest that tobacco users have more difficulty achieving cannabis cessation, secondary analyses of clinical trial data sets may provide insight into the moderating variables contributing to this relationship, as well as changes in tobacco use during cannabis treatment. Those were the aims of this secondary analysis. METHODS: The parent study was a multi-site trial of N-acetylcysteine for cannabis dependence conducted within the National Drug Abuse Treatment Clinical Trials Network. Participants were treatment-seeking adults (ages 18-50) who met criteria for cannabis dependence (N = 302). For cigarette smokers (n = 117), tobacco use was assessed via timeline follow-back and nicotine dependence was assessed via the Fagerström Test for Nicotine Dependence (FTND). Outcome measures included: 1) changes in tobacco use based on treatment assignment, nicotine dependence, and concurrent cannabis reduction/abstinence, and 2) independent associations between nicotine dependence and cannabis abstinence. RESULTS: Cigarette smokers accounted for 39% of the sample (117/302), with a median FTND score of 3.0 (10-point scale). Among those with lower baseline nicotine dependence scores, cigarette smoking was reduced in the active treatment group compared to placebo. Those with moderate/high levels of nicotine dependence showed slight increases in smoking following active treatment. Nicotine dependence did not affect cannabis cessation. CONCLUSIONS: Cigarette smoking during cannabis treatment was affected, but depended on baseline nicotine dependence severity, though dependence levels did not impact cannabis abstinence. Interventions that address both tobacco and cannabis are needed, especially due to an increasing prevalence of cannabis use.
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Fumar Cigarros/epidemiologia , Abuso de Maconha/tratamento farmacológico , Abuso de Maconha/epidemiologia , Abandono do Hábito de Fumar/métodos , Tabagismo/epidemiologia , Acetilcisteína/uso terapêutico , Adolescente , Adulto , Fumar Cigarros/psicologia , Feminino , Humanos , Masculino , Abuso de Maconha/psicologia , Maconha Medicinal/uso terapêutico , Pessoa de Meia-Idade , Abandono do Hábito de Fumar/psicologia , Uso de Tabaco/epidemiologia , Uso de Tabaco/psicologia , Tabagismo/diagnóstico , Tabagismo/psicologia , Adulto JovemRESUMO
BACKGROUND: Increases in the quantity or impact of noradrenergic signaling have been implicated in the pathophysiology of posttraumatic stress disorder (PTSD). This increased signaling may result from increased norepinephrine (NE) release, from altered brain responses to NE, or from a combination of both factors. Here, we tested the hypothesis that Veterans reporting a history of trauma exposure would show an increased association between brain NE and mental health symptoms commonly observed after trauma, as compared to Veterans who did not report a history of trauma exposure, consistent with the possibility of increased brain reactivity to NE after traumatic stress. METHODS: Using a convenience sample of 69 male Veterans with a history of combat-theater deployment, we examined the relationship between trauma-related mental health symptoms and the concentration of NE in cerebrospinal fluid (CSF). CSF NE levels were measured by HPLC in CSF from morning lumbar puncture. Behavioral symptoms associated with diagnoses of PTSD, depression, insomnia, or post-concussive syndrome (PCS), which together cover a wide variety of symptoms associated with alterations in arousal systems, such as sleep, mood, concentration, and anxiety, were assessed via self-report (PTSD Checklist [PCL] for PTSD, Patient Health Questionnaire 9 [PHQ9] for depression, Pittsburgh Sleep Quality Index [PSQI] for sleep problems including insomnia, and Neurobehavioral Symptom Inventory [NSI] for PCS) and structured clinical interview (Clinician-Administered PSTD Scale [CAPS]). Individuals meeting criterion A of the DSM-IV diagnostic criteria for PTSD were considered trauma-exposed. Linear regression models were used to quantify the association between CSF NE and symptom intensity in participants with and without a history of trauma exposure, as well as in participants with a history of trauma exposure who were currently taking the noradrenergic receptor antagonist prazosin. RESULTS: Fifty-two Veterans met criteria for a history of trauma exposure; of these, 36 met criteria for PTSD. CSF NE levels were not significantly different in Veterans with a history of trauma compared to those without, nor in Veterans with PTSD as compared to those without. Veterans with a history of trauma and who were not using the medication prazosin demonstrated a significantly more positive correlation between CSF NE and behavioral symptom expression than Veterans who had not experienced traumatic stress. No relationship between CSF NE and behavioral symptom expression was found in Veterans who had experienced traumatic stress and were taking prazosin at the time of the assessments. CONCLUSIONS: These results are consistent with increased central nervous system responsiveness to noradrenergic signaling in individuals with a history of traumatic exposure, raising the possibility that there may be long-lasting physiologic effects of trauma-exposure that exist independently of whether an individual meets criteria for PTSD at any given point in time. Exploration of the mechanism by which brain responsiveness to NE is modulated following trauma holds the possibility of finding new strategies for both preventing and treating PTSD.
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OBJECTIVES: This 2-stage open-label pilot study evaluated the safety and potential efficacy of naltrexone + bupropion as a pharmacotherapy for methamphetamine (MA) use disorder. METHODS: The study was conducted in 2 stages of recruitment across 3 sites; 20 participants were enrolled in stage 1 and 29 participants were enrolled in stage 2. Eight weeks of open-label pharmacotherapy with a combination of extended-release injectable naltrexone (XR-NTX; Vivitrol) plus extended-release oral bupropion (BRP; Wellbutrin XL) were provided with a smartphone-assisted medication adherence platform. Participants met Diagnostic and Statistical Manual of Mental Disorders, 5th Edition criteria for severe MA use disorder, self-reported ≥20 days of MA use in the 30 days prior to consent, and submitted 3 MA-positive urine drug screens (UDS) out of 4 collected during screening. Participants attended clinic twice weekly for observed BRP dosing, UDS testing, assessments, and medical management; XR-NTX was administered at weeks 1 and 5. A BRP taper and follow-up visit occurred in week 9. RESULTS: Analyses evaluated effects of XR-NTXâ+âBRP to determine the number of "responders" according to a statistically predefined response criterion (6 of 8 MA-negative UDS during the last 4 weeks of medication). The 2-stage design required that stage 1 yield ≥3 responders to continue to stage 2; 11 of the 49 participants met responder criteria across both stages (5 in stage 1, 6 in stage 2). CONCLUSIONS: Under the statistical analysis plan, study "success" required ≥9 responders. With 11 responders, the study demonstrated sufficient potential of naltrexone plus bupropion as a combination pharmacotherapy for MA use disorder to warrant further study.
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Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Bupropiona/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Metanfetamina/efeitos adversos , Naltrexona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Adulto , Idoso , Bupropiona/administração & dosagem , Bupropiona/efeitos adversos , Preparações de Ação Retardada , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/efeitos adversos , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Naltrexona/administração & dosagem , Naltrexona/efeitos adversos , Antagonistas de Entorpecentes/administração & dosagem , Antagonistas de Entorpecentes/efeitos adversos , Projetos Piloto , Adulto JovemRESUMO
UNLABELLED: We recently demonstrated that (11)C-MePPEP, a PET ligand for CB(1) receptors, has such high uptake in the human brain that it can be imaged for 210 min and that receptor density can be quantified as distribution volume (V(T)) using the gold standard of compartmental modeling. However, (11)C-MePPEP had relatively poor retest and intersubject variabilities, which were likely caused by errors in the measurements of radioligand in plasma at low concentrations by 120 min. We sought to find an analog of (11)C-MePPEP that would provide more accurate plasma measurements. We evaluated several promising analogs in the monkey brain and chose the (18)F-di-deutero fluoromethoxy analog ((18)F-FMPEP-d(2)) to evaluate further in the human brain. METHODS: (11)C-FMePPEP, (18)F-FEPEP, (18)F-FMPEP, and (18)F-FMPEP-d(2) were studied in 5 monkeys with 10 PET scans. We calculated V(T) using compartmental modeling with serial measurements of unchanged parent radioligand in arterial plasma and radioactivity in the brain. Nonspecific binding was determined by administering a receptor-saturating dose of rimonabant, an inverse agonist at the CB(1) receptor. Nine healthy human subjects participated in 17 PET scans using (18)F-FMPEP-d(2), with 8 subjects having 2 PET scans to assess retest variability. To identify sources of error, we compared intersubject and retest variability of brain uptake, arterial plasma measurements, and V(T). RESULTS: (18)F-FMPEP-d(2) had high uptake in the monkey brain, with greater than 80% specific binding, and yielded less radioactivity uptake in bone than did (18)F-FMPEP. High brain uptake with (18)F-FMPEP-d(2) was also observed in humans, in whom V(T) was well identified within approximately 60 min. Retest variability of plasma measurements was good (16%); consequently, V(T) had a good retest variability (14%), intersubject variability (26%), and intraclass correlation coefficient (0.89). V(T) increased after 120 min, suggesting an accumulation of radiometabolites in the brain. Radioactivity accumulated in the skull throughout the entire scan but was thought to be an insignificant source of data contamination. CONCLUSION: Studies in monkeys facilitated our development and selection of (18)F-FMPEP-d(2), compared with (18)F-FMPEP, as a radioligand demonstrating high brain uptake, high percentage of specific binding, and reduced uptake in bone. Retest analysis in human subjects showed that (18)F-FMPEP-d(2) has greater precision and accuracy than (11)C-MePPEP, allowing smaller sample sizes to detect a significant difference between groups.
Assuntos
Encéfalo/diagnóstico por imagem , Fluordesoxiglucose F18 , Pirrolidinonas , Compostos Radiofarmacêuticos , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Adulto , Animais , Área Sob a Curva , Química Encefálica , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Marcação por Isótopo , Macaca mulatta , Masculino , Plasma/diagnóstico por imagem , Cintilografia , Compostos Radiofarmacêuticos/síntese química , Crânio/diagnóstico por imagem , Adulto JovemRESUMO
[11C]MePPEP is an inverse agonist and a radioligand developed to image cannabinoid CB1 receptors with positron emission tomography (PET). It provides reversible, high specific signal in monkey brain. We assessed [11C]MePPEP in rodent brain with regard to receptor selectivity, susceptibility to transport by P-glycoprotein (P-gp), sensitivity to displacement by agonists, and accumulation of radiometabolites. We used CB1 receptor knockout mice and P-gp knockout mice to assess receptor selectivity and sensitivity to efflux transport, respectively. Using serial measurements of PET brain activity and plasma concentrations of [11C]MePPEP, we estimated CB1 receptor density in rat brain as distribution volume. CB1 knockout mice showed only nonspecific brain uptake, and [11C]MePPEP was not a substrate for P-gp. Direct acting agonists anandamide (10 mg/kg), methanandamide (10 mg/kg), CP 55,940 (1 mg/kg), and indirect agonist URB597 (0.3 and 0.6 mg/kg) failed to displace [11C]MePPEP, while the inverse agonist rimonabant (3 and 10 mg/kg) displaced >65% of [11C]MePPEP. Radiometabolites represented ~13% of total radioactivity in brain between 30 and 120 min. [11C]MePPEP was selective for the CB1 receptor, was not a substrate for P-gp, and was more potently displaced by inverse agonists than agonists. The low potency of agonists suggests either a large receptor reserve or non-overlapping binding sites for agonists and inverse agonists. Radiometabolites of [11C]MePPEP in brain caused distribution volume to be overestimated by approximately 13%.