RESUMO
BACKGROUND: The group-I metabotropic glutamate receptor subtype 5 (mGlu5) has been implicated in methamphetamine exposure in animals and in human cognition. Because people with methamphetamine use disorder (MUD) exhibit cognitive deficits, we evaluated mGlu5 in people with MUD and controls and tested its association with cognitive performance. METHODS: Positron emission tomography was performed to measure the total VT of [18F]FPEB, a radiotracer for mGlu5, in brains of participants with MUD (abstinent from methamphetamine for at least 2 weeks, N = 14) and a control group (N = 14). Drug use history questionnaires and tests of verbal learning, spatial working memory, and executive function were administered. Associations of VT with methamphetamine use, tobacco use, and cognitive performance were tested. RESULTS: MUD participants did not differ from controls in global or regional VT, and measures of methamphetamine use were not correlated with VT. VT was significantly higher globally in nonsmoking vs smoking participants (main effect, P = .0041). MUD participants showed nonsignificant weakness on the Rey Auditory Verbal Learning Task and the Stroop test vs controls (P = .08 and P = .13, respectively) with moderate to large effect sizes, and significantly underperformed controls on the Spatial Capacity Delayed Response Test (P = .015). Across groups, Rey Auditory Verbal Learning Task performance correlated with VT in the dorsolateral prefrontal cortex and superior frontal gyrus. CONCLUSION: Abstinent MUD patients show no evidence of mGlu5 downregulation in brain, but association of VT in dorsolateral prefrontal cortex with verbal learning suggests that medications that target mGlu5 may improve cognitive performance.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas , Encéfalo , Fumar Cigarros , Metanfetamina , Tomografia por Emissão de Pósitrons , Receptor de Glutamato Metabotrópico 5 , Humanos , Masculino , Receptor de Glutamato Metabotrópico 5/metabolismo , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Metanfetamina/administração & dosagem , Metanfetamina/farmacologia , Feminino , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/diagnóstico por imagem , Fumar Cigarros/metabolismo , Cognição/efeitos dos fármacos , Pessoa de Meia-Idade , Função Executiva/efeitos dos fármacos , Função Executiva/fisiologia , Adulto Jovem , Testes Neuropsicológicos , Estimulantes do Sistema Nervoso Central/farmacologia , Estimulantes do Sistema Nervoso Central/administração & dosagemRESUMO
Cigarette smoking has a major impact on global health and morbidity, and positron emission tomographic research has provided evidence for reduced inflammation in the human brain associated with cigarette smoking. Given the consequences of inflammatory dysfunction for health, the question of whether cigarette smoking affects neuroinflammation warrants further investigation. The goal of this project therefore was to validate and extend evidence of hypoinflammation related to smoking, and to examine the potential contribution of inflammation to clinical features of smoking. Using magnetic resonance spectroscopy, we measured levels of neurometabolites that are putative neuroinflammatory markers. N-acetyl compounds (N-acetylaspartate + N-acetylaspartylglutamate), glutamate, creatine, choline-compounds (phosphocholine + glycerophosphocholine), and myo-inositol, have all been linked to neuroinflammation, but they have not been examined as such with respect to smoking. We tested whether people who smoke cigarettes have brain levels of these metabolites consistent with decreased neuroinflammation, and whether clinical features of smoking are associated with levels of these metabolites. The dorsal anterior cingulate cortex was chosen as the region-of-interest because of previous evidence linking it to smoking and related states. Fifty-four adults who smoked daily maintained overnight smoking abstinence before testing and were compared with 37 nonsmoking participants. Among the smoking participants, we tested for associations of metabolite levels with tobacco dependence, smoking history, craving, and withdrawal. Levels of N-acetyl compounds and glutamate were higher, whereas levels of creatine and choline compounds were lower in the smoking group as compared with the nonsmoking group. In the smoking group, glutamate and creatine levels correlated negatively with tobacco dependence, and creatine correlated negatively with lifetime smoking, but none of the metabolite levels correlated with craving or withdrawal. The findings indicate a link between smoking and a hypoinflammatory state in the brain, specifically in the dorsal anterior cingulate cortex. Smoking may thereby increase vulnerability to infection and brain injury.
Assuntos
Tabagismo , Adulto , Humanos , Giro do Cíngulo/metabolismo , Creatina/metabolismo , Doenças Neuroinflamatórias , Ácido Glutâmico/metabolismo , Colina , FumarRESUMO
Research using rodent models has established a relationship between the steroid hormone estrogen and dopamine function, by revealing changes throughout the estrous cycle and by directly manipulating neuroendocrine signaling through ovariectomy and administration of estrogen. However, a direct link between estrogen levels and dopamine signaling had not been established in humans. The goal of this study, therefore, was to assess the relationship between circulating 17ß-estradiol and dopamine signaling in the human brain by testing for a relationship between two proxies for these variables: peripheral 17ß-estradiol and striatal dopamine D2-type receptor availability, measured with [18F]fallypride and positron emission tomography (PET). Sixteen (23-45 years of age) women were tested on 2 days of the menstrual cycle estimated prospectively to occur during (a) the early follicular phase, when estrogen levels are near their nadir, and (b) the periovulatory phase, when estrogen levels peak. PET scans with [18F]fallypride were performed on these 2 days, and serum 17ß-estradiol was measured using radioimmunoassay. Dopamine D2-type receptor availability did not differ significantly in the whole striatum or the caudate, putamen, or accumbens subregions during the high-estrogen vs. the low-estrogen phases of the menstrual cycle. We conclude that circulating estrogen levels do not affect dopamine D2-type receptor availability in the human striatum although other indices of dopaminergic function may be affected.
Assuntos
Dopamina , Receptores de Dopamina D2 , Corpo Estriado/metabolismo , Estradiol , Feminino , Humanos , Tomografia por Emissão de Pósitrons , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D3/metabolismoRESUMO
Gonadal hormones influence neuronal organization and plasticity. Yet the consequences of altering their concentrations by administering contraceptive agents, which are used by most reproductive-age women in the United States, are unclear. Cross-sectional studies have found both larger and smaller cortical regions alongside a variety of mood alterations in women who use oral contraceptive pills (OCPs) compared to naturally-cycling women. The goal of this study, therefore, was to determine whether there is an effect of OCPs on MRI measures of prefrontal cortical brain structure that may influence regulation of mood. We performed a double-blind, placebo-controlled, randomized crossover study comparing effects of OCPs (0.15 mg levonorgestrel + 0.30 µg ethinyl estradiol) vs placebo (N = 26) on MRI measures of prefrontal cortical thickness and on mood, as indicated by self-report on the Daily Record of Severity of Problems, which also includes one item related to somatic symptoms. MRI measures that reflect cortical thickness were smaller bilaterally in the pars triangularis and in the pars opercularis and frontal pole of the right hemisphere during the OCP arm vs. placebo. Only the effect in the right pars triangularis survived multiple comparisons correction. Right pars triangularis MRI measures of cortical thickness were not related to mood symptoms, but negatively correlated across conditions with severity of somatic symptoms on the DSRP. The somatic symptoms and MRI measures may be independently related to the actions of steroid hormones in OCPs, with OCPs simultaneously inducing both more effects on MRI measures of cortical thickness and somatic symptoms.
Assuntos
Anticoncepcionais Orais Combinados , Etinilestradiol , Estudos Cross-Over , Estudos Transversais , Feminino , Humanos , Imageamento por Ressonância MagnéticaRESUMO
Methamphetamine use is surging globally as a cause of morbidity and mortality. Treatment is typically sought in early abstinence, when craving and depressive symptoms are intense, contributing to relapse and poor outcomes. To advance an understanding of this problem and identify therapeutic targets, we conducted a retrospective analysis of brain structure in 89 adults with Methamphetamine Use Disorder who were in early abstinence and 89 healthy controls. Unlike most prior research, the participants did not significantly differ in age, sex and recent use of alcohol and tobacco (p-values ≥ 0.400). We analysed thickness across the entire cerebral cortex by fitting a general linear model to identify differences between groups. Follow-up regressions were performed to determine whether cortical thickness in regions showing group differences was related to craving, measured on a visual analogue scale, or to the Beck Depression Inventory score. Participants in early methamphetamine abstinence (M ± SD = 22.1 ± 25.6 days) exhibited thinner cortex in clusters within bilateral frontal, parietal, temporal, insular, and right cingulate cortices relative to controls (p-values < 0.001, corrected for multiple comparisons). Unlike craving (ß = 0.007, p = 0.947), depressive symptoms were positively correlated with cortical thickness across clusters (ß = 0.239, p = 0.030) and with thickness in the anterior cingulate cluster (ß = 0.246, p = 0.027) in the methamphetamine-dependent group. Inasmuch as anterior cingulate pathology predicts response to antidepressants for Major Depressive Disorder, cingulate structure may also identify patients with Methamphetamine Use Disorder who can benefit from antidepressant medication.
Assuntos
Transtorno Depressivo Maior , Metanfetamina , Adulto , Antidepressivos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/patologia , Depressão/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Metanfetamina/efeitos adversos , Estudos RetrospectivosRESUMO
Ibudilast, a neuroimmune modulator, shows promise as a pharmacotherapy for alcohol use disorder (AUD). In vivo administration of ibudilast reduces the expression of pro-inflammatory cytokines in animal models, but its effects on markers of inflammation in humans are unknown. This preliminary study examined the effect of ibudilast on peripheral and potential central markers of inflammation in individuals with AUD. This study also explored the predictive relationship of neurometabolite markers with subsequent drinking in the trial. Non-treatment-seeking individuals with an AUD (n = 52) were randomized to receive oral ibudilast (n = 24) or placebo (n = 28) for 2 weeks. Plasma levels of peripheral inflammatory markers were measured at baseline and after 1 and 2 weeks of medication. At study mid-point, proton magnetic resonance spectroscopy was performed to measure potential neurometabolite markers of inflammation: choline-compounds (Cho), myo-inositol (MI) and creatine + phosphocreatine (Cr) in frontal and cingulate cortices from 43 participants (ibudilast: n = 20; placebo: n = 23). The treatment groups were compared on peripheral and central markers. Ibudilast-treated participants had lower Cho in superior frontal white matter and nominally lower MI in pregenual anterior cingulate cortex. Ibudilast-treated participants had nominally lower C-reactive protein levels at visit 2 and nominally lower TNF-α/IL-10 ratios, relative to placebo. C-reactive protein and Cho levels were correlated, controlling for medication. Superior frontal white matter Cho predicted drinking in the following week. Micro-longitudinal ibudilast treatment may induce peripheral and putative central anti-inflammatory responses in patients with AUD. The neurometabolite responses may be associated with reduction in drinking, suggesting an anti-inflammatory component to the therapeutic action of ibudilast.
Assuntos
Alcoolismo , Consumo de Bebidas Alcoólicas/metabolismo , Alcoolismo/tratamento farmacológico , Alcoolismo/metabolismo , Animais , Ácido Aspártico , Proteína C-Reativa , Colina/metabolismo , Creatina/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inositol/metabolismo , PiridinasRESUMO
BACKGROUND: Cigarette craving, which can negatively impact smoking cessation, is reportedly stronger in women than in men when they initiate abstinence from smoking. Identifying approaches to counteract craving in people of different sexes may facilitate the development of personalized treatments for Tobacco Use Disorder, which disproportionately affects women. Because cigarette craving is associated with nicotine dependence and structure of the insula, this study addressed whether a person's sex influences these associations. METHODS: The research participants (n = 99, 48 women) reported daily cigarette smoking and provided self-reports of nicotine dependence. After overnight abstinence from smoking, they underwent structural magnetic resonance imaging scanning to determine cortical thickness of the left and right anterior circular insular sulcus, and self-rated their cigarette craving before and after their first cigarette of the day. RESULTS: Women reported stronger craving than men irrespective of smoking condition (i.e., pre- and post-smoking) (P = .048), and smoking reduced craving irrespective of sex (P < .001). A 3-way interaction of sex, smoking condition, and right anterior circular insular sulcus thickness on craving (P = .033) reflected a negative association of cortical thickness with pre-smoking craving in women only (P = .012). No effects of cortical thickness in the left anterior circular insular sulcus were detected. Nicotine dependence was positively associated with craving (P < .001) across groups and sessions, with no sex differences in this association. CONCLUSIONS: A negative association of right anterior insula thickness with craving in women only suggests that this region may be a relevant therapeutic target for brain-based smoking cessation interventions in women.
Assuntos
Fumar Cigarros/fisiopatologia , Fissura/fisiologia , Córtex Insular/patologia , Tabagismo/fisiopatologia , Adolescente , Adulto , Feminino , Humanos , Córtex Insular/diagnóstico por imagem , Imageamento por Ressonância Magnética , Masculino , Caracteres Sexuais , Adulto JovemRESUMO
Chronic methamphetamine use is linked to abnormalities in brain structure, which may reflect neurotoxicity related to metabolism of the drug. As the cytochrome P450 2D6 (CYP2D6) enzyme is central to the metabolism of methamphetamine, genotypic variation in its activity may moderate effects of methamphetamine on brain structure and function. This study explored the relationship between CYP2D6 genotype and measures of brain structure and cognition in methamphetamine users. Based on the function of genetic variants, a CYP2D6 activity score was determined in 82 methamphetamine-dependent (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition [DSM-IV] criteria) and 79 healthy-control participants who completed tests of cognitive function (i.e., attention, memory, and executive function); most were also evaluated with structural magnetic resonance imaging (MRI) (66 methamphetamine-dependent and 52 controls). The relationship between CYP2D6 activity score and whole brain cortical thickness differed by group (interaction p = 0.024), as increasing CYP2D6 activity was associated with thinner cortical thickness in the methamphetamine users (ß = -0.254; p = 0.035), but not in control subjects (ß = 0.095; p = 0.52). Interactions between CYP2D6 activity and group were nonsignificant for hippocampal volume (ps > 0.05), but both hippocampi showed trends similar to those observed for cortical thickness (negative relationships in methamphetamine users [ps < 0.05], and no relationships in controls [ps > 0.50]). Methamphetamine users had lower cognitive scores than control subjects (p = 0.007), but there was no interaction between CYP2D6 activity score and group on cognition (p > 0.05). Results suggest that CYP2D6 genotypes linked to higher enzymatic activity may confer risk for methamphetamine-induced deficits in brain structure. The behavioral consequences of these effects are unclear and warrant additional investigation.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/genética , Encéfalo/patologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Citocromo P-450 CYP2D6/genética , Metanfetamina/efeitos adversos , Adolescente , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Encéfalo/diagnóstico por imagem , Estudos de Casos e Controles , Estimulantes do Sistema Nervoso Central/metabolismo , Cognição/efeitos dos fármacos , Feminino , Genótipo , Humanos , Imageamento por Ressonância Magnética , Masculino , Memória , Metanfetamina/metabolismo , Pessoa de Meia-Idade , Adulto JovemRESUMO
Brain asymmetry reflects left-right hemispheric differentiation, which is a quantitative brain phenotype that develops with age and can vary with psychiatric diagnoses. Previous studies have shown that substance dependence is associated with altered brain structure and function. However, it is unknown whether structural brain asymmetries are different in individuals with substance dependence compared with nondependent participants. Here, a mega-analysis was performed using a collection of 22 structural brain MRI datasets from the ENIGMA Addiction Working Group. Structural asymmetries of cortical and subcortical regions were compared between individuals who were dependent on alcohol, nicotine, cocaine, methamphetamine, or cannabis (n = 1,796) and nondependent participants (n = 996). Substance-general and substance-specific effects on structural asymmetry were examined using separate models. We found that substance dependence was significantly associated with differences in volume asymmetry of the nucleus accumbens (NAcc; less rightward; Cohen's d = 0.15). This effect was driven by differences from controls in individuals with alcohol dependence (less rightward; Cohen's d = 0.10) and nicotine dependence (less rightward; Cohen's d = 0.11). These findings suggest that disrupted structural asymmetry in the NAcc may be a characteristic of substance dependence.
Assuntos
Córtex Cerebelar/patologia , Transtornos Relacionados ao Uso de Substâncias/diagnóstico por imagem , Adulto , Alcoolismo/diagnóstico por imagem , Comportamento Aditivo/diagnóstico por imagem , Encéfalo/patologia , Espessura Cortical do Cérebro , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Núcleo Accumbens/patologia , Tabagismo/diagnóstico por imagem , Adulto JovemRESUMO
Background: Brain structural findings in chronic methamphetamine users have been inconsistent. Identifying contributing influences (e.g., sex, abstinence duration) can help clarify the clinical course of recovery.Objectives: We studied the effects of long-term methamphetamine abstinence on gray-matter volume. Our hypothesis was that smaller volume early in abstinence would precede long-term recovery.Methods: Individuals who used methamphetamine (≥100 g lifetime use, mandated to residential treatment for methamphetamine-positive urine; 40 men, 21 women), undergoing supervised abstinence (men: 12-400 days; women: 130-594 days), were compared to healthy controls (49 men, 36 women) using T1-weighted MRI. Volumes of orbitofrontal, anterior cingulate and parietal cortex, hippocampus, and striatum were measured using Freesurfer software. Associations of volumes with abstinence duration were tested in males and females separately because their abstinence times differed (121.5 ± 124.5 vs. 348.0 ± 128.6 days, p < 0.001); only males were studied in early abstinence. The General Linear Model was used to test effects of abstinence duration and group (methamphetamine users vs. controls).Results: In males, duration of abstinence was multivariate significant for gray-matter volumes (p = 0.017). Abstinence duration was associated with increases in volumes of the orbitofrontal and parietal cortices (ps = 0.031, 0.016) and hippocampi (ps = 0.044). Irrespective of abstinence, male methamphetamine users had smaller hippocampi than male controls (p = 0.008). Females showed no significant effects of group or abstinence.Conclusions: In males, abstinence from methamphetamine appears to result in volumetric increases in regions important for cognitive function, which may affect recovery during the course of treatment. Data from the period of early abstinence are required to evaluate volumetric changes in females.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Substância Cinzenta/efeitos dos fármacos , Metanfetamina/farmacologia , Adolescente , Adulto , Estudos de Casos e Controles , China , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Adulto JovemRESUMO
BACKGROUND: Negative emotional states contribute to cigarette smoking, and difficulties in regulating these states can hinder smoking cessation. Understanding the neural bases of these difficulties in smokers may facilitate development of novel therapies for Tobacco Use Disorder. METHODS: Thirty-seven participants (18 smokers, 19 nonsmokers; 16-21 years old) completed the Difficulties in Emotion Regulation Scale (DERS), which is comprised of 6 subscales (lack of emotional clarity, lack of emotional awareness, limited access to emotion regulation strategies, nonacceptance of emotional responses, difficulties engaging in goal-directed behaviors, and impulse control difficulties) that combine to provide a total score. Participants also underwent functional magnetic resonance imaging to determine resting-state functional connectivity of the amygdala. Separate ANOVAs were used to determine group differences in self-reports on the DERS. Voxel-wise linear mixed models were performed to determine whether group influenced relationships between whole-brain functional connectivity of the amygdala and scores on the DERS. RESULTS: Compared with nonsmokers, smokers reported greater difficulties in emotion regulation, denoted by higher total scores on the DERS. Group differences were observed on a subscale of lack of emotional clarity, but no other subscale differences on the DERS were observed. Nonsmokers exhibited a greater negative correlation than smokers between lack of emotional clarity scores and connectivity of the amygdala with the left inferior frontal gyrus. Finally, this amygdala-to-left inferior frontal gyrus connectivity was weaker in smokers than in nonsmokers. CONCLUSIONS: These findings suggest that difficulties in emotion regulation in smokers are at least partially due to lack of emotional clarity. Given the role of the inferior frontal gyrus in understanding emotional states, strengthening connectivity between the amygdala and the inferior frontal gyrus may improve emotional clarity to help smokers regulate their negative emotions, thereby improving their ability to quit smoking.
Assuntos
Regulação Emocional , Fumar Tabaco/efeitos adversos , Fumar Tabaco/psicologia , Tabagismo/psicologia , Adolescente , Tonsila do Cerebelo/diagnóstico por imagem , Emoções , Feminino , Lobo Frontal/fisiologia , Lateralidade Funcional/fisiologia , Humanos , Modelos Lineares , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/diagnóstico por imagem , Testes Neuropsicológicos , Descanso , Autorrelato , Inquéritos e Questionários , Tabagismo/diagnóstico por imagem , Adulto JovemRESUMO
While imaging studies have demonstrated volumetric differences in subcortical structures associated with dependence on various abused substances, findings to date have not been wholly consistent. Moreover, most studies have not compared brain morphology across those dependent on different substances of abuse to identify substance-specific and substance-general dependence effects. By pooling large multinational datasets from 33 imaging sites, this study examined subcortical surface morphology in 1628 nondependent controls and 2277 individuals with dependence on alcohol, nicotine, cocaine, methamphetamine, and/or cannabis. Subcortical structures were defined by FreeSurfer segmentation and converted to a mesh surface to extract two vertex-level metrics-the radial distance (RD) of the structure surface from a medial curve and the log of the Jacobian determinant (JD)-that, respectively, describe local thickness and surface area dilation/contraction. Mega-analyses were performed on measures of RD and JD to test for the main effect of substance dependence, controlling for age, sex, intracranial volume, and imaging site. Widespread differences between dependent users and nondependent controls were found across subcortical structures, driven primarily by users dependent on alcohol. Alcohol dependence was associated with localized lower RD and JD across most structures, with the strongest effects in the hippocampus, thalamus, putamen, and amygdala. Meanwhile, nicotine use was associated with greater RD and JD relative to nonsmokers in multiple regions, with the strongest effects in the bilateral hippocampus and right nucleus accumbens. By demonstrating subcortical morphological differences unique to alcohol and nicotine use, rather than dependence across all substances, results suggest substance-specific relationships with subcortical brain structures.
Assuntos
Encéfalo/diagnóstico por imagem , Neuroimagem , Transtornos Relacionados ao Uso de Substâncias/diagnóstico por imagem , Adolescente , Adulto , Cannabis/efeitos adversos , Cocaína/efeitos adversos , Etanol/efeitos adversos , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Metanfetamina/efeitos adversos , Nicotina/efeitos adversos , Adulto JovemRESUMO
Background: Emerging evidence suggests that opioid receptor antagonists, such as naltrexone, are effective pharmacotherapies for alcohol, opioid, and possibly stimulant use disorders. It is posited that naltrexone exerts its effects, in part, by increasing functional connectivity between neural reward circuitry and frontal systems implicated in executive function. Yet no studies had examined whether executive function moderates these effects. Objectives: This study examined whether a composite measure of executive function (EF) moderates the effect of naltrexone on craving for methamphetamine and subjective responses following infusion of the drug. Methods: Individuals with methamphetamine use disorder (N = 30; 27% female) completed baseline neurocognitive assessments of premorbid and executive function, and an executive function factor was computed. Participants then underwent a randomized, double-blind, cross-over study of titration with naltrexone and placebo. Participants then received a 30-mg intravenous methamphetamine infusion and completed subjective response questionnaires at 8 times in the 120 minutes post-infusion. Results: Multilevel mixed models indicated a significant EF × medication interaction, reflecting greater effects of naltrexone to decrease "desire to access the drug", "want more of the drug", "crave the drug", "feel drug effects" and "feel high" in participants with low EF compared to those with high EF (Bs = .36-1.29, SEs = .14-.17, ps<0.01). These effects remained significant after controlling for premorbid cognitive functioning, baseline responses to methamphetamine, severity of methamphetamine use, and methamphetamine-related functional problems. Conclusion: Naltrexone may be especially effective in methamphetamine-dependent individuals with low EF. Neuropsychological assessments may also provide predictive clinical utility not captured by traditional measures of substance use severity.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Fissura/efeitos dos fármacos , Função Executiva , Metanfetamina/farmacologia , Naltrexona/uso terapêutico , Antagonistas de Entorpecentes/uso terapêutico , Adulto , Cognição/efeitos dos fármacos , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Los Angeles , Masculino , Adulto JovemRESUMO
Objectives: Despite the prevalence of methamphetamine-associated psychosis, how characteristics of drug use affect the severity and clinical course, and its optimal treatments have not been established. We addressed these questions, assessing clinical features of methamphetamine-associated psychosis, and compared it with primary psychosis.Methods: Hospitalised patients with methamphetamine-associated (n = 70) or primary schizophrenic psychosis (n = 70) were matched on sex, age and duration of psychosis. Association of drug use variables (age at initiation, duration of methamphetamine use) with the Brief Psychiatric Rating Scale (BPRS) scores and psychosis duration were examined for patients with methamphetamine-associated psychosis, and the groups were compared on the BPRS scores.Results: Methamphetamine use initiation age correlated negatively with the BPRS total score and the Activation subscale score; methamphetamine use duration correlated positively with psychosis duration. Methamphetamine-associated psychosis group scored lower on the Hostility-Suspiciousness and Anergia subscales of the BPRS (adjusted p values < .05).Conclusions: Association of early initiation of methamphetamine with psychosis severity may suggest a lasting effect on brain development. Correlation of drug use and psychosis durations may suggest a cumulative effect of methamphetamine exposure. Less severe paranoia and negative symptoms in the methamphetamine-using group could implicate better social functioning of these patients. Further mechanistic studies are warranted.Key pointsEarly initiation of methamphetamine use is associated with psychosis severity.Methamphetamine use duration associates with psychosis duration.Methamphetamine-associated and primary schizophrenic psychoses were similar in symptoms.Methamphetamine psychosis patients were less severe in paranoia and negative symptoms.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Estimulantes do Sistema Nervoso Central/efeitos adversos , Metanfetamina/efeitos adversos , Transtornos Paranoides/fisiopatologia , Psicoses Induzidas por Substâncias/fisiopatologia , Transtornos Psicóticos/fisiopatologia , Esquizofrenia/fisiopatologia , Adulto , Idade de Início , Transtornos Relacionados ao Uso de Anfetaminas/complicações , Escalas de Graduação Psiquiátrica Breve , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicoses Induzidas por Substâncias/etiologia , Índice de Gravidade de Doença , Fatores de TempoRESUMO
BACKGROUND: Selective serotonin reuptake inhibitors are often used in alcohol use disorders. Clinical trials with selective serotonin reuptake inhibitors for alcohol use disorders, however, have yielded mixed results. The goal of this project was to assess whether a single i.v. dose of a selective serotonin reuptake inhibitor reduces craving for alcohol and/or simultaneously increases striatal dopamine concentration in individuals with alcohol dependence. METHODS: Alcohol-dependent (DSM-IV-TR criteria) volunteers and matched controls (n = 10/group) underwent a double-blind, placebo-controlled, within-subjects study. Participants received i.v. citalopram (40 mg) or saline (counter-balanced) followed by a cue-induced craving assessment and [18F]-fallypride positron emission tomography scanning. RESULTS: In the alcohol-dependent individuals, the citalopram (compared with saline) resulted in decreased cue-induced craving for alcohol. For the whole study group, cue-induced alcohol craving was inversely correlated with thalamic (but not striatal) dopamine D2/3 receptor availability. CONCLUSIONS: Acute serotonin reuptake inhibition reduces cue-induced alcohol craving. Furthermore, thalamic dopamine abnormalities and the striatal hyperdopaminergic hypothesis of alcohol use disorder are supported.
Assuntos
Alcoolismo/tratamento farmacológico , Citalopram/farmacocinética , Corpo Estriado/efeitos dos fármacos , Fissura/efeitos dos fármacos , Receptores de Dopamina D2/efeitos dos fármacos , Receptores de Dopamina D3/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Tálamo/efeitos dos fármacos , Administração Intravenosa , Adulto , Benzamidas , Citalopram/administração & dosagem , Sinais (Psicologia) , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons , Pirrolidinas , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagemRESUMO
Background: Methamphetamine induces neuronal N-acetyl-aspartate synthesis in preclinical studies. In a preliminary human proton magnetic resonance spectroscopic imaging investigation, we also observed that N-acetyl-aspartate+N-acetyl-aspartyl-glutamate in right inferior frontal cortex correlated with years of heavy methamphetamine abuse. In the same brain region, glutamate+glutamine is lower in methamphetamine users than in controls and is negatively correlated with depression. N-acetyl and glutamatergic neurochemistries therefore merit further investigation in methamphetamine abuse and the associated mood symptoms. Methods: Magnetic resonance spectroscopic imaging was used to measure N-acetyl-aspartate+N-acetyl-aspartyl-glutamate and glutamate+glutamine in bilateral inferior frontal cortex and insula, a neighboring perisylvian region affected by methamphetamine, of 45 abstinent methamphetamine-dependent and 45 healthy control participants. Regional neurometabolite levels were tested for group differences and associations with duration of heavy methamphetamine use, depressive symptoms, and state anxiety. Results: In right inferior frontal cortex, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate correlated with years of heavy methamphetamine use (r = +0.45); glutamate+glutamine was lower in methamphetamine users than in controls (9.3%) and correlated negatively with depressive symptoms (r = -0.44). In left insula, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate was 9.1% higher in methamphetamine users than controls. In right insula, glutamate+glutamine was 12.3% lower in methamphetamine users than controls and correlated negatively with depressive symptoms (r = -0.51) and state anxiety (r = -0.47). Conclusions: The inferior frontal cortex and insula show methamphetamine-related abnormalities, consistent with prior observations of increased cortical N-acetyl-aspartate in methamphetamine-exposed animal models and associations between cortical glutamate and mood in human methamphetamine users.
Assuntos
Transtornos Relacionados ao Uso de Anfetaminas/diagnóstico por imagem , Transtornos Relacionados ao Uso de Anfetaminas/metabolismo , Ácido Aspártico/análogos & derivados , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Ácido Glutâmico/metabolismo , Adolescente , Adulto , Transtornos Relacionados ao Uso de Anfetaminas/psicologia , Ansiedade/diagnóstico por imagem , Ansiedade/metabolismo , Ácido Aspártico/metabolismo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Córtex Cerebral/efeitos dos fármacos , Estudos Transversais , Depressão/diagnóstico por imagem , Depressão/metabolismo , Feminino , Glutamina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Metanfetamina/efeitos adversos , Pessoa de Meia-Idade , Adulto JovemRESUMO
Smoking-induced relief of craving and withdrawal promotes continued cigarette use. Understanding how relief is produced and the role of nicotine in this process may facilitate development of new smoking-cessation therapies. As the US Food and Drug Administration considers setting a standard for reduced nicotine content in cigarettes to improve public health, knowledge of how nicotine contributes to relief also can inform policy. We assessed effects of nicotine using resting state functional magnetic resonance imaging (MRI) and behavioral assessments of craving and negative affect. Twenty-one young (18-25 years old) daily smokers underwent overnight abstinence on 4 days. On each of the following mornings, they self-rated their cigarette craving and negative affect and underwent resting-state functional MRI (fMRI) before and after smoking a cigarette that delivered 0.027, 0.110, 0.231, or 0.763 mg of nicotine. Functional connectivity between the anterior insula and anterior cingulate cortex (ACC) and between the nucleus accumbens and orbitofrontal cortex (OFC) was assessed. Smoking reduced craving, negative affect, and nucleus accumbens-OFC connectivity irrespective of nicotine dose, with positive correlations of the effects on behavioral and connectivity measures. Only the highest nicotine dose (0.763 mg) reduced right anterior insula-ACC connectivity; this reduction was positively correlated with the behavioral effects of the 0.763-mg dose only. While nicotine-based therapies may act on right anterior insula-ACC functional circuits to facilitate smoking cessation, non-nicotine (eg, the conditioned and sensorimotor) aspects of smoking may promote cessation by reducing OFC-accumbens connectivity to alleviate withdrawal.
Assuntos
Encéfalo/diagnóstico por imagem , Fumar Cigarros , Fissura/fisiologia , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Síndrome de Abstinência a Substâncias/diagnóstico por imagem , Adolescente , Adulto , Afeto , Encéfalo/fisiopatologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiopatologia , Relação Dose-Resposta a Droga , Feminino , Giro do Cíngulo/diagnóstico por imagem , Giro do Cíngulo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Nicotina/efeitos adversos , Agonistas Nicotínicos/efeitos adversos , Núcleo Accumbens/diagnóstico por imagem , Núcleo Accumbens/fisiopatologia , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/fisiopatologia , Síndrome de Abstinência a Substâncias/etiologia , Síndrome de Abstinência a Substâncias/fisiopatologia , Adulto JovemRESUMO
Background: Cannabis is the most widely used illicit substance worldwide, and legalization for recreational and medical purposes has substantially increased its availability and use in the United States.Objectives: Decades of research have suggested that recreational cannabis use confers risk for cognitive impairment across various domains, and structural and functional differences in the brain have been linked to early and heavy cannabis use.Methods: With substantial evidence for the role of the endocannabinoid system in neural development and understanding that brain development continues into early adulthood, the rising use of cannabis in adolescents and young adults raises major concerns. Yet some formulations of cannabinoid compounds are FDA-approved for medical uses, including applications in children.Results: Potential effects on the trajectory of brain morphology and cognition, therefore, should be considered. The goal of this review is to update and consolidate relevant findings in order to inform attitudes and public policy regarding the recreational and medical use of cannabis and cannabinoid compounds.Conclusions: The findings point to considerations for age limits and guidelines for use.
Assuntos
Encéfalo/efeitos dos fármacos , Canabidiol/farmacologia , Cognição/efeitos dos fármacos , Dronabinol/farmacologia , Maconha Medicinal/uso terapêutico , Fatores Etários , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Espectro Autista/tratamento farmacológico , Encéfalo/patologia , Canabidiol/uso terapêutico , Endocanabinoides/metabolismo , Epilepsias Mioclônicas/tratamento farmacológico , Humanos , Lactente , Síndrome de Lennox-Gastaut/tratamento farmacológico , Tamanho do Órgão , Espasmos Infantis/tratamento farmacológicoRESUMO
Background: Alexithymia is a personality trait associated with emotion regulation difficulties. Up to 67% of alcohol-dependent patients in treatment have alexithymia. Objectives: The objective of this study was to investigate the direct and indirect effects of alexithymia, negative mood (stress, anxiety, and depression) and alcohol craving on alcohol dependence severity. Methods: Three hundred and fifty-five outpatients (mean age = 38.70, SD = 11.00, 244 males, range 18-71 years) undergoing Cognitive-Behavioral Therapy for alcohol dependence completed the Toronto Alexithymia Scale (TAS-20), Depression Anxiety Stress Scales (DASS-21), Obsessive Compulsive Drinking Scale (OCDS), and Alcohol Use Disorders Identification Test (AUDIT) prior to the first treatment session. Results: Alexithymia had an indirect effect on alcohol dependence severity, via both negative mood and alcohol craving (b = 0.03, seb = 0.008, 95% CI: 0.02-0.05). An indirect effect of negative mood on alcohol dependence via alcohol craving was also observed (b = 0.12, seb = 0.03, 95% CI: 0.07-0.16). Conclusions/importance: Alexithymia worked through negative mood and alcohol craving leading to increased alcohol dependence severity, indicating that craving had an indirect effect on the relationship between alexithymia and alcohol dependence severity. Targeting alcohol craving and negative mood for alcohol-dependent patients with alexithymia seems warranted.
Assuntos
Afeto/fisiologia , Sintomas Afetivos/psicologia , Alcoolismo/psicologia , Fissura , Adolescente , Adulto , Idoso , Consumo de Bebidas Alcoólicas/psicologia , Ansiedade/psicologia , Depressão/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estresse Psicológico/psicologia , Adulto JovemRESUMO
Background: Although nicotine alters serotonergic neurochemistry, clinical trials of serotonergic medications for smoking cessation have provided mixed results. Understanding the role of serotonergic dysfunction in tobacco use disorder may advance development of novel pharmacotherapies. Methods: Functional magnetic resonance imaging was used to measure resting-state functional connectivity of the raphe nuclei as an indicator of serotonergic function. Connectivity of the dorsal and median raphe nuclei was compared between 18 young smokers (briefly abstinent, ~40 minutes post-smoking) and 19 young nonsmokers (16-21 years old); connectivity was also examined in a separate sample of overnight-abstinent smokers (18-25 years old), before and after smoking the first cigarette of the day. Relationships between connectivity of the raphe nuclei with psychological withdrawal and craving were tested in smokers. Results: Connectivity of the median raphe nucleus with the right hippocampal complex was weaker in smokers than in nonsmokers and was negatively correlated with psychological withdrawal in smokers. In overnight-abstinent smokers, smoking increased connectivity of the median raphe nucleus with the right hippocampal complex, and the increase was positively correlated with the decrease in psychological withdrawal. Conclusions: Relief of withdrawal due to smoking is potentially linked to the serotonergic pathway that includes the median raphe nucleus and hippocampal complex. These results suggest that serotonergic medications may be especially beneficial for smokers who endorse strong psychological withdrawal during abstinence from smoking.