RESUMO
PURPOSE: Aging is a major societal concern due to age-related functional losses. Synapses are crucial components of neural circuits, and synaptic density could be a sensitive biomarker to evaluate brain function. [11C]UCB-J is a positron emission tomography (PET) ligand targeting synaptic vesicle glycoprotein 2A (SV2A), which can be used to evaluate brain synaptic density in vivo. METHODS: We evaluated age-related changes in gray matter synaptic density, volume, and blood flow using [11C]UCB-J PET and magnetic resonance imaging (MRI) in a wide age range of 80 cognitive normal subjects (21-83 years old). Partial volume correction was applied to the PET data. RESULTS: Significant age-related decreases were found in 13, two, and nine brain regions for volume, synaptic density, and blood flow, respectively. The prefrontal cortex showed the largest volume decline (4.9% reduction per decade: RPD), while the synaptic density loss was largest in the caudate (3.6% RPD) and medial occipital cortex (3.4% RPD). The reductions in caudate are consistent with previous SV2A PET studies and likely reflect that caudate is the site of nerve terminals for multiple major tracts that undergo substantial age-related neurodegeneration. There was a non-significant negative relationship between volume and synaptic density reductions in 16 gray matter regions. CONCLUSION: MRI and [11]C-UCB-J PET showed age-related decreases of gray matter volume, synaptic density, and blood flow; however, the regional patterns of the reductions in volume and SV2A binding were different. Those patterns suggest that MR-based measures of GM volume may not be directly representative of synaptic density.
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Substância Cinzenta , Glicoproteínas de Membrana , Humanos , Idoso de 80 Anos ou mais , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/metabolismo , Glicoproteínas de Membrana/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Sinapses/metabolismoRESUMO
Brain cannabinoid 1 receptors (CB1Rs) contribute importantly to the regulation of autonomic tone, appetite, mood and cognition. Inconsistent results have been reported from positron emission tomography (PET) studies using different radioligands to examine relationships between age, gender and body mass index (BMI) and CB1R availability in healthy individuals. In this study, we examined these variables in 58 healthy individuals (age range: 18-55 years; 44 male; BMI=27.01±5.56), the largest cohort of subjects studied to date using the CB1R PET ligand [11C]OMAR. There was a significant decline in CB1R availability (VT) with age in the pallidum, cerebellum and posterior cingulate. Adjusting for BMI, age-related decline in VT remained significant in the posterior cingulate among males, and in the cerebellum among women. CB1R availability was higher in women compared to men in the thalamus, pallidum and posterior cingulate. Adjusting for age, CB1R availability negatively correlated with BMI in women but not men. These findings differ from those reported using [11C]OMAR and other radioligands such as [18F]FMPEP-d2 and [18F]MK-9470. Although reasons for these seemingly divergent findings are unclear, the choice of PET radioligand and range of BMI in the current dataset may contribute to the observed differences. This study highlights the need for cross-validation studies using both [11C]OMAR and [18F]FMPEP-d2 within the same cohort of subjects.
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Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Masculino , Humanos , Feminino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Índice de Massa Corporal , Tomografia por Emissão de Pósitrons/métodos , Encéfalo/diagnóstico por imagem , Receptor CB1 de CanabinoideRESUMO
Decreased synaptic spine density has been the most consistently reported postmortem finding in schizophrenia (SCZ). A recently developed in vivo measure of synaptic vesicle density estimated using the novel positron emission tomography (PET) ligand [11C]UCB-J is a proxy measure of synaptic density. In this study we determined whether [11C]UCB-J binding, an in vivo measure of synaptic vesicle density, is altered in SCZ. SCZ patients (n = 13, 3 F) and age-, gender-matched healthy controls (HCs) (n = 15, 3 F) underwent PET imaging using [11C]UCB-J and high-resolution research tomography (HRRT). [11C]UCB-J distribution volume (VT) and binding potential (BPND) were estimated using a 1T model with centrum-semiovale as the reference region. Relative to HCs, SCZ patients, showed significantly lower [11C]UCB-J BPND with significant differences in the frontal cortex (-10%, Cohen's d = 1.01), anterior cingulate (-11%, Cohen's d = 1.24), hippocampus (-15%, Cohen's d = 1.29), occipital cortex (-14%, Cohen's d = 1.34), parietal cortex (-10%, p = 0.03, Cohen's d = 0.85) and temporal cortex (-11%, Cohen's d = 1.23). These differences remained significant after partial volume correction. [11C]UCB-J BPND did not correlate with cumulative antipsychotic exposure or gray-matter volume. Consistent with the postmortem and in vivo findings, synaptic vesicle density is lower across several brain regions in SCZ. Frontal synaptic vesicle density correlated with psychosis symptom severity and cognitive performance on social cognition and processing speed. These findings indicate that [11C]UCB-J PET is a sensitive tool to detect lower synaptic density in SCZ and holds promise for future studies of early detection and disease progression.
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Esquizofrenia , Vesículas Sinápticas , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Humanos , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Esquizofrenia/diagnóstico por imagem , Esquizofrenia/metabolismo , Vesículas Sinápticas/metabolismoRESUMO
Preclinical studies have revealed robust and long-lasting alterations in dendritic spines in the brain following cocaine exposure. Such alterations are hypothesized to underlie enduring maladaptive behaviours observed in cocaine use disorder (CUD). The current study explored whether synaptic density is altered in CUD. Fifteen individuals with DSM-5 CUD and 15 demographically matched healthy control (HC) subjects participated in a single 11 C-UCB-J positron emission tomography scan to assess density of synaptic vesicle glycoprotein 2A (SV2A). The volume of distribution (VT ) and the plasma-free fraction-corrected form of the total volume of distribution (VT /fP ) were analysed in the anterior cingulate cortex (ACC), dorsomedial and ventromedial prefrontal cortex (PFC), lateral and medial orbitofrontal cortex (OFC) and ventral striatum. A significant diagnostic-group-by-region interaction was observed for VT and VT /fP . Post hoc analyses revealed no differences on VT , while for VT /fP showed lower values in CUD as compared with HC subjects in the ACC (-10.9%, p = 0.02), ventromedial PFC (-9.9%, p = 0.02) and medial OFC (-9.9%, p = 0.04). Regional VT /fP values in CUD, though unrelated to measures of lifetime cocaine use, were positively correlated with the frequency of recent cocaine use (p = 0.02-0.03) and negatively correlated with cocaine abstinence (p = 0.008-0.03). These findings provide initial preliminary in vivo evidence of altered (lower) synaptic density in the PFC of humans with CUD. Cross-sectional variation in SV2A availability as a function of recent cocaine use and abstinence suggests that synaptic density may be dynamically and plastically regulated by acute cocaine, an observation that merits direct testing by studies using more definitive longitudinal designs.
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Cocaína , Vesículas Sinápticas , Encéfalo/metabolismo , Cocaína/metabolismo , Humanos , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/metabolismo , Piridinas/metabolismo , Vesículas Sinápticas/metabolismoRESUMO
INTRODUCTION: There is increasing interest in the relationship between cannabinoids and psychosis. While individual human laboratory studies have been critical in demonstrating that cannabinoids (e.g., delta-9-tetrahydrocannabinol [THC]) can induce acute transient psychosis-like effects in healthy human volunteers, combining data from multiple studies offers a fine-grained view of these effects. METHODS: THC-induced psychosis-relevant effects were examined using a data repository of 10 double-blind, randomized, placebo-controlled, crossover studies with 400 i.v. THC infusions in healthy human volunteers. The Positive and Negative Syndrome scale was used to measure psychotomimetic effects. The profile of symptoms, frequency of a response, its relationship to THC dose and substance use, latent structure in Positive and Negative Syndrome scale response, and the relationships between psychotomimetic and perceptual alteration symptoms were evaluated. RESULTS: Clinically meaningful increases in positive symptoms were noted in 44.75% infusions; conceptual disorganization, hallucinations, blunted affect, somatic concern, motor retardation, and poor attention were the items most frequently altered by THC. The increase in Positive and Negative Syndrome scale positive symptoms was positively associated with THC dose (beta = 11.13, SE = 4.94, Wald χâ2 = 19.88, P < .001) and negatively associated with frequent cannabis use (beta = -0.575, SE = 0.14, Wald χâ2 = 18.13, P < .001). Furthermore, positive symptoms were strongly correlated with Clinician Administered Dissociative States Scale perceptual alterations score (rs = 0.514, P < .001). CONCLUSION: Intravenous administration of THC consistently induces psychotomimetic effects that include symptoms across Positive and Negative Syndrome scale domains. Moreover, healthy individuals who frequently use cannabis have a blunted psychotomimetic response.
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Agonistas de Receptores de Canabinoides/efeitos adversos , Dronabinol/efeitos adversos , Psicoses Induzidas por Substâncias/etiologia , Psicoses Induzidas por Substâncias/fisiopatologia , Adulto , Agonistas de Receptores de Canabinoides/administração & dosagem , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Feminino , Humanos , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto/estatística & dados numéricosRESUMO
Preclinical and clinical data suggest that the cannabinoid and glutamatergic systems are implicated in the pathophysiology of schizophrenia (SZ), the prototypical psychotic disorder. This has led to distinct "cannabis" and "ketamine" models of SZ, respectively. However, these two models need not be mutually exclusive. Indeed, in several brain regions implicated in the putative neural circuitry of SZ (e.g., hippocampus, frontal cortex, cerebellum), cannabinoid receptor type 1 (CB1Rs) and glutamate N-methyl-D-aspartate receptors (NMDARs) have direct and indirect interactions. CB1R agonists and NMDAR antagonists act upon gamma-aminobutyric acid (GABA) interneurons to reduce GABAergic neurotransmission. This would be predicted to result in the unsynchronized activity of pyramidal neurons, disrupting neural network oscillations involved in information processing, thus leading to psychotomimetic effects. Hence, the overarching aim of the current review is to synthesize the known literature on cannabinoids and glutamate in the context of neural oscillations in SZ. First, discussion of SZ and the basic mechanisms of neural oscillations are discussed, including a summary of the role of theta (4-7 Hz) and gamma (30-80 Hz) oscillations in neurocognition. Next, a brief review of the role of the cannabinoid and glutamatergic systems in SZ is outlined, followed by discussion of the known synaptic interactions between these two systems. Finally, the potential role of CB1Rs and NMDARs, both independently and in combination, on neural oscillations in relation to psychotic symptoms is considered. It is hoped that this review will yield a series of testable hypotheses that may be used to further elucidate the pathophysiology of SZ.
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Ondas Encefálicas/fisiologia , Canabinoides/metabolismo , Ácido Glutâmico/metabolismo , Neurônios/metabolismo , Transtornos Psicóticos/metabolismo , Animais , Humanos , Transtornos Psicóticos/fisiopatologia , Receptor CB1 de Canabinoide/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismoRESUMO
Disruptions in neural oscillations are believed to be one critical mechanism by which cannabinoids, such as delta-9-tetrahyrdrocannabinol (THC; the primary psychoactive constituent of cannabis), perturbs brain function. Here we briefly review the role of synchronized neural activity, particularly in the gamma (30-80â Hz) and theta (4-7â Hz) frequency range, in sensation, perception, and cognition. This is followed by a review of clinical studies utilizing electroencephalography (EEG) which have demonstrated that both chronic and acute cannabinoid exposure disrupts neural oscillations in humans. We also offer a hypothetical framework through which endocannabinoids modulate neural synchrony at the network level. This also includes speculation on how both chronic and acute cannabinoids disrupt functionally relevant neural oscillations by altering the fine tuning of oscillations and the inhibitory/excitatory balance of neural circuits. Finally, we highlight important clinical implications of such oscillatory disruptions, such as the potential relationship between cannabis use, altered neural synchrony, and disruptions in sensation, perception, and cognition, which are perturbed in disorders such as schizophrenia.
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Canabinoides , Cannabis , Humanos , Canabinoides/farmacologia , Eletroencefalografia , Cognição , Sensação , PercepçãoRESUMO
Background: THC and CBD are the principal phyto-cannabinoids in the cannabis plant. The differential and possibly antagonistic effects of these compounds on specific brain and behavioral responses, and the mechanisms underlying their effects have generated extensive interest in pre-clinical and clinical neuroscience investigations. Methods: In this double-blind randomized placebo-controlled counterbalanced Human Laboratory Study, we examined the effects of three different dose ratios of CBD:THC (1:1, 2:1, and 3:1) on "neural noise," an electrophysiological biomarker of psychosis known to be sensitive to cannabinoids as well as subjective and psychotomimetic effects. Healthy volunteers (n=28, 12 women) with at least one prior exposure to cannabis participated in the study. Outcomes: The lowest CBD (2.5 mg):THC (0.035 mg/kg) ratio (1:1) resulted in maximal attenuation of both THC-induced psychotomimetic effects (Positive and Negative Syndrome Scale [PANSS] positive: Anova Type Statistic [ATS]=7.83, pcorrected=0.015) and neural noise (ATS=8.83, pcorrected=0.009). Further addition of CBD did not reduce the subjective experience of THC-induced "high" (p>0.05 for all CBD doses). Interpretation: These novel results demonstrate that CBD attenuates specific THC-induced subjective and objective effects relevant to psychosis in a dose/ratio-dependent manner. Given the increasing global trend of cannabis liberalization and application for medical indications, these results assume considerable significance given the potential dose-related interactions of these key phyto-cannabinoids. Trial registration: The trial was registered in clinicaltrials.gov ID: NCT01180374.
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Canabidiol , Canabinoides , Cannabis , Alucinógenos , Humanos , Feminino , Canabinoides/farmacologia , Canabidiol/farmacologia , Dronabinol/farmacologia , Alucinógenos/farmacologia , EncéfaloRESUMO
BACKGROUND: Several early phase studies have demonstrated that psilocybin-assisted therapy has rapid-acting and persisting antidepressant effects from just one or two doses. However, methodological limitations (e.g., placebo-control, blinding) limit interpretability of the existing literature. METHODS: In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe major depressive disorder were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within an manualized course of psychotherapy. Enhanced blinding procedures were used. Depression, anxiety, and quality of life were measured over a 16-week study period. RESULTS: Depression and anxiety significantly improved following both placebo and psilocybin with no significant difference in the degree of change between the two conditions. However, antidepressant effect sizes were larger after psilocybin (d' = 1.02-2.27) than after placebo (d' = 0.65-0.99) and there were high rates of response (66.7%) and remission (46.7%) following psilocybin administration. Antidepressant effects following psilocybin persisted, on average, for 2 months and there were persisting improvements in mood-related quality of life domains. The strength of mystical-type experience during psilocybin dosing was not correlated with subsequent antidepressant effects. CONCLUSIONS: The results of this exploratory study highlight the complex interplay between expectancy, therapy effects, and drug/placebo effects in psychedelic-assisted psychotherapy studies. Nonetheless, the acute and persisting clinical improvements observed following psilocybin support further study of its potential in the treatment of major depression. Future studies should more explicitly mitigate and measure expectancy effects and assess the impact of repeated dosing and different forms of psychotherapeutic support.
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Transtorno Depressivo Maior , Alucinógenos , Humanos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Qualidade de VidaRESUMO
BACKGROUND: Evidence suggests that serotonergic psychedelics (e.g. psilocybin), have rapid-acting and long-lasting antidepressant effects after a single dose. However, the mechanism underlying these effects remain unclear. One proposed mechanism is that these drugs promote neuroplasticity. However, this has not been conclusively demonstrated in humans. AIMS: We hypothesized that relative to placebo, psilocybin would: (1) increase electroencephalographic (EEG) correlates of neuroplasticity, (2) reduce depression symptoms, and (3) changes in EEG would correlate with improvements in depression. METHODS: In this double-blind, placebo-controlled, within-subject study, individuals with major depressive disorder (MDD; n = 19) were administered placebo followed by psilocybin (0.3 mg/kg) in a fixed order (placebo, followed by psilocybin 4 weeks later). EEG indices of neuroplasticity (tetanus-induced long-term potentiation) as assessed via auditory evoked theta (4-8 Hz) power and measures of depression (GRID Hamilton Rating Scale for Depression-17 (GRID-HAM-D-17)) were measured at several time-points after placebo and psilocybin (24 h and 2 weeks after each session). RESULTS: EEG theta power doubled in amplitude 2 weeks after a single psychedelic dose of psilocybin but not after placebo. Further, improvements in depression symptoms 2 weeks after psilocybin were correlated with increases in theta power. CONCLUSIONS: The increased theta power observed represents evidence of sustained changes in the brain following psilocybin. Given the correlation with enhancement in depressive symptoms, changes in theta may represent an EEG biomarker of the sustained effects of psilocybin, and may shed light on potential mechanisms of psilocybin's antidepressant effect. Taken together, these results complement the emerging notion that psilocybin, and perhaps other psychedelics, can produce long-term alterations in neuroplasticity.
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Transtorno Depressivo Maior , Alucinógenos , Humanos , Psilocibina/farmacologia , Psilocibina/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Depressão , Eletroencefalografia , Antidepressivos/uso terapêutico , Plasticidade NeuronalRESUMO
RATIONALE: Drug- and alcohol-related motor vehicle accidents are a leading cause of morbidity and mortality worldwide. Compared to alcohol, less is known about the effects of cannabis on driving and even less about their combined effects. OBJECTIVE: To characterize the combined and separate effects of ethanol and tetrahydrocannabinol (THC) on perceived ability to drive, subjective effects, and simulated driving. METHODS: In a within-subject (crossover), randomized, placebo-controlled, double-blind, 2 × 2 design, the effects of oral THC (10 mg [dronabinol] or placebo) and low-dose intravenous ethanol (clamped at BAC 0.04% or placebo) on perceived ability to drive, simulated driving (standard deviation of lateral position [SDLP]), subjective effects (e.g., "high"), and physiological effects (e.g., heart rate) were studied in healthy humans (n = 18). RESULTS: Subjects reported reductions in perceived ability to drive (THC < ethanol < combination) which persisted for ~ 6 h (placebo = ethanol, THC < combination). Ethanol and THC produced synergistic effects on heart rate, significant differences compared to either drug alone on perceived ability to drive and feeling states of intoxication (e.g., high), as well increases in SDLP compared to placebo. CONCLUSIONS: Perceived ability to drive is reduced under the influence of THC against the backdrop of blood alcohol levels that are below the legal limit. People should be aware that the effects of oral THC on driving may persist for up to six hours from administration. Findings are relevant to the increasingly common practice of combining alcohol and cannabinoids and the effects on driving.
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Condução de Veículo , Alucinógenos , Humanos , Dronabinol , Etanol , Autorrelato , Desempenho Psicomotor , Alucinógenos/farmacologia , Método Duplo-CegoRESUMO
OBJECTIVES: Extracellular vesicles, including exosomes, cross the blood brain barrier with their contents intact and can be assayed peripherally. Circulating exosomes have been studied in other neurodegenerative disorders, but there is scarce data in schizophrenia. This study aimed to examine neuropathology-relevant protein biomarkers in circulating plasma-derived exosomes from patients with schizophrenia and age- and sex-matched healthy controls. METHODS: Nanoparticle tracking analysis was used to determine the size and concentration of exosomes. Exosomal membrane marker (CD9) and specific target cargo protein (glial fibrillary acid protein[GFAP], synaptophysin, and α-II-Spectrin) immunopositivity was examined using Western blot analyses with band intensity quantified. Methods were consistent with the 'Minimal information for studies of extracellular vesicles 2018' (MISEV2018) guidelines. RESULTS: Exosomal GFAP concentration was significantly higher and α-II-Spectrin expression significantly lower in plasma obtained from schizophrenia patients. No group differences were observed between in plasma exosomal concentration and size or in CD9, calnexin, or synaptophysin levels. CONCLUSIONS: Our results demonstrate a differential pattern of exosomal protein expression in schizophrenia compared to matched healthy controls, consistent with the hypothesised astroglial pathology in this disorder. These results warrant further examination of circulating exosomes as vehicles of novel peripheral biomarkers of disease in schizophrenia and other neuropsychiatric disorders.
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Exossomos , Esquizofrenia , Astrócitos , Biomarcadores , Humanos , ProteômicaRESUMO
BACKGROUND: Cannabis is the most common illicit drug used in the USA and its use has been rising over the past decade, while the historical gap in rates of use between men and women has been decreasing. Sex differences in the effects of cannabinoids have been reported in animal models, but human studies are sparse and inconsistent. We investigated the sex differences in the acute subjective, psychotomimetic, cognitive, and physiological effects of intravenous (IV) delta-9 tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis. METHODS: Healthy male and female individuals, with limited exposure to cannabis, participated in a double blind, placebo-controlled study of intravenous (IV) placebo or THC at two doses (0.015 mg/kg and 0.03 mg/kg). Visual analog scale (VAS) was used to measure subjective effects, Psychotomimetic States Inventory (PSI) and the Clinician-Administered Dissociative Symptoms Scale (CADSS) were used to assess the psychotomimetic effects and perceptual alterations, respectively, and Rey Auditory Verbal Learning Task (RAVLT) was used to evaluate cognitive effects. Outcome variables were represented as the peak change from baseline for each variable, except RAVLT which was used only once per the test day after the subjective effects. RESULTS: A total of 42 individuals participated in this study. There were no significant differences between male and female participants in background characteristics. There was a significant main effect of sex on the VAS scores for THC-induced "High" (F1,38 = 4.27, p < 0.05) and a significant dose × sex interaction (F2,77 = 3.38, p < 0.05) with female participants having greater "High" scores than male participants at the lower THC dose (0.015 mg/kg). No other sex differences were observed in acute subjective, psychotomimetic, cognitive, or physiological effects of THC. CONCLUSION: There were significant sex differences in subjective effects of feeling "High" at a lower dose of THC. However, there were no other sex-related differences in the subjective, physiological, or cognitive effects of THC.
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Cannabis , Alucinógenos , Agonistas de Receptores de Canabinoides , Método Duplo-Cego , Dronabinol/farmacologia , Feminino , Alucinógenos/farmacologia , Humanos , Masculino , Caracteres SexuaisRESUMO
Accumulating evidence indicates that cannabis use may be a risk factor for schizophrenia (SZ), and chronic cannabis users score higher than non-users on measures of schizotypal personality traits. The purpose of the present study was to investigate the relations between normal personality, schizotypy, and cannabis use. Sixty-two chronic cannabis users and 45 cannabis-naïve controls completed a measure of normal personality, the NEO-Five Factor Inventory (NEO-FFI), and two measures of schizotypy, the schizotypal personality questionnaire (SPQ) and perceptual aberration scale (PAS). Substance use was assessed using the SCID I alcohol/drug module and a locally developed drug use questionnaire. On the NEO-FFI, users scored higher than controls on openness, but lower on agreeableness and conscientiousness, and endorsed greater schizotypy on the SPQ and PAS. Higher neuroticism predicted greater schizotypy in both groups, and, higher Extraversion predicted lower negative-syndrome schizotypy among users. Finally, duration of cannabis use was positively correlated with scores on the SPQ and PAS among users, suggesting a relation between overall cannabis use chronicity and schizotypy. These data show that cannabis users differ from non-users on dimensions of normal personality and schizotypy, and provide further evidence that cannabis use is associated with increased levels of psychosis-related personality traits.
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Abuso de Maconha/psicologia , Personalidade , Transtorno da Personalidade Esquizotípica/psicologia , Adolescente , Adulto , Análise de Variância , Feminino , Humanos , Masculino , Abuso de Maconha/complicações , Transtornos da Percepção/diagnóstico , Transtornos da Percepção/etiologia , Inventário de Personalidade , Escalas de Graduação Psiquiátrica , Psicometria , Transtorno da Personalidade Esquizotípica/complicações , Estatística como Assunto , Inquéritos e Questionários , Adulto JovemRESUMO
Delay eye-blink conditioning is an associative learning task that can be utilized to probe the functional integrity of the cerebellum and related neural circuits. Typically, a single interstimulus interval (ISI) is utilized, and the amplitude of the conditioned response (CR) is the primary dependent variable. To study the timing of the CR, an ISI shift can be introduced (e.g., shifting the ISI from 350 to 850 ms). In each phase, a conditioned stimulus (e.g., a 400- or 900-ms tone) coterminates with a 50-ms corneal air puff unconditioned stimulus. The ability of a subject to adjust the CR to the changing ISI constitutes a critical timing shift. The feasibility of this procedure was examined in healthy human participants (N = 58) using a bidirectional ISI shift procedure while cortical event-related brain potentials were measured. CR acquisition was faster and the responses better timed when a short ISI was used. After the ISI shift, additional training was necessary to allow asymptotic responding at the new ISI. Interestingly, auditory event-related potentials to the CR were not associated with conditioning measures at either ISI.
Assuntos
Estimulação Acústica/métodos , Aprendizagem por Associação , Condicionamento Palpebral/fisiologia , Adulto , Aprendizagem por Associação/fisiologia , Córtex Cerebral/fisiologia , Potenciais Evocados Auditivos/fisiologia , Feminino , Humanos , Masculino , Fatores de TempoRESUMO
Electroencephalography (EEG) measures the brain's electrical activity with high temporal resolution. In comparison to neuroimaging modalities such as MRI or PET, EEG is relatively cheap, non-invasive, portable, and simple to administer, making it an attractive tool for clinical deployment. Despite this, studies utilizing EEG to investigate obsessive-compulsive disorder (OCD) are relatively sparse. This contrasts with a robust literature using other brain imaging methodologies. The present review examines studies that have used EEG to examine predictors and correlates of response in OCD and draws tentative conclusions that may guide much needed future work. Key findings include a limited literature base; few studies have attempted to predict clinical change from EEG signals, and they are confounded by the effects of both pharmacotherapy and psychotherapy. The most robust literature, consisting of several studies, has examined event-related potentials, including the P300, which several studies have reported to be abnormal at baseline in OCD and to normalize with treatment; but even here the literature is quite heterogeneous, and more work is needed. With more robust research, we suggest that the relatively low cost and convenience of EEG, especially in comparison to fMRI and PET, make it well-suited to the development of feasible personalized treatment algorithms.
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Aims: Chronic cannabis users show impairments on laboratory measures of decision making which reflect risk factors for initiation and continued use of cannabis. However, the differential sensitivity of these tasks to cannabis use has not been established. Moreover, studies to date have often lacked assessment of psychiatric histories and use of other illicit substances, both of which may influence decision making outcomes. The current study aimed to address these limitations by (1) including multiple types of decision making tasks, (2) implementing the Probabilistic Reversal Learning Task, a measure of decision making under uncertainty, for the first time in cannabis users, (3) including young adult cannabis users with no other psychiatric disorders, and (4) conducting urinalysis to exclude users of other illicit drugs. Methods: Thirty-three current cannabis users without comorbid psychiatric disorders and 35 cannabis non-users completed behavioral measures of decision-making (Iowa Gambling Task), reward discounting (Delay Discounting Task), choice-outcome learning (the Probabilistic Reversal Learning Task) and a questionnaire assessment of impulsivity (Barratt Impulsiveness Scale). Results: Relative to non-users, cannabis users demonstrated greater preference for immediate vs. delayed rewards on the Delay Discounting Task, made fewer advantageous decisions on the Iowa Gambling Task, and endorsed greater impulsivity on the Barratt Impulsiveness Scale scales. Cannabis users and non-users showed comparable performance on the Probabilistic Reversal Learning Task. Frequency of past-month cannabis use and total years of use did not predict decision making or impulsivity. Conclusions: Young adult cannabis users demonstrated higher discounting rates and impairments in learning cost-benefit contingencies, while reversal learning was unaffected. Self-reported impulsivity was elevated as well. None of these measures correlated with current or lifetime estimates of cannabis use, arguing against a dose-relationship. Interventions that target improvement in affected components of decision making may be helpful in reducing cannabis use and relapse.
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BACKGROUND: Dopaminergic mechanisms that may underlie cannabis' reinforcing effects are not well elucidated in humans. This positron emission tomography (PET) imaging study used the dopamine D2/3 receptor antagonist [11C]raclopride and kinetic modelling testing for transient changes in radiotracer uptake to assess the striatal dopamine response to smoked cannabis in a preliminary sample. METHODS: PET emission data were acquired from regular cannabis users (n = 14; 7 M/7 F; 19-32 years old) over 90 min immediately after [11C]raclopride administration (584 ± 95 MBq) as bolus followed by constant infusion (Kbol = 105 min). Participants smoked a cannabis cigarette, using a paced puff protocol, 35 min after scan start. Plasma concentrations of Δ9-THC and metabolites and ratings of subjective "high" were collected during imaging. Striatal dopamine responses were assessed voxelwise with a kinetic model testing for transient reductions in [11C]raclopride binding, linear-parametric neurotransmitter PET (lp-ntPET) (cerebellum as a reference region). RESULTS: Cannabis smoking increased plasma Δ9-THC levels (peak: 0-10 min) and subjective high (peak: 0-30 min). Significant clusters (>16 voxels) modeled by transient reductions in [11C]raclopride binding were identified for all 12 analyzed scans. In total, 26 clusters of significant responses to cannabis were detected, of which 16 were located in the ventral striatum, including at least one ventral striatum cluster in 11 of the 12 analyzed scans. CONCLUSIONS: These preliminary data support the sensitivity of [11C]raclopride PET with analysis of transient changes in radiotracer uptake to detect cannabis smoking-induced dopamine responses. This approach shows future promise to further elucidate roles of mesolimbic dopaminergic signaling in chronic cannabis use. ClinicalTrials.gov Identifier: NCT02817698.
Assuntos
Cannabis , Fumar Maconha , Estriado Ventral , Adulto , Corpo Estriado/diagnóstico por imagem , Dopamina , Humanos , Tomografia por Emissão de Pósitrons , Racloprida , Adulto JovemRESUMO
Recent advances in knowledge about cannabinoid receptor function have renewed interest in the association between cannabis and psychosis. Converging lines of evidence suggest that cannabinoids can produce a full range of transient schizophrenia-like positive, negative and cognitive symptoms. Cannabinoids also produce some psychophysiological deficits also known to be present in schizophrenia. Also clear is that in individuals with an established psychotic disorder, cannabinoids can exacerbate symptoms, trigger relapse, and have negative consequences on the course of the illness. Increasing evidence suggests that early and heavy cannabis exposure may increase the risk of developing a psychotic disorder such as schizophrenia. The relationship between cannabis exposure and schizophrenia fulfills some, but not all, of the usual criteria for causality. However, most people who use cannabis do not develop schizophrenia, and many people diagnosed with schizophrenia have never used cannabis. Therefore, it is likely that cannabis exposure is a "component cause" that interacts with other factors to "cause" schizophrenia or other psychotic disorder, but is neither necessary nor sufficient to do so alone. In the absence of known causes of schizophrenia, however, and the implications for public health policy should such a link be established the role of component causes such as cannabinoid exposure should remain a focus of further study. Finally, further work is necessary to identify the factors that underlie individual vulnerability to cannabinoid-related psychosis and to elucidate the biological mechanisms underlying this risk.
Assuntos
Canabinoides/efeitos adversos , Abuso de Maconha/complicações , Transtornos Psicóticos/etiologia , Esquizofrenia/etiologia , Canabinoides/metabolismo , Transtornos Cognitivos/etiologia , Progressão da Doença , Humanos , Fatores de RiscoRESUMO
BACKGROUND: Cannabis is one of the most widely used drugs worldwide. Cannabis use disorder is characterised by recurrent use of cannabis that causes significant clinical and functional impairment. There are no approved pharmacological treatments for cannabis use disorder. One approach is to potentiate endocannabinoid signalling by inhibiting fatty acid amide hydrolase (FAAH), the enzyme that degrades the endocannabinoid anandamide. We aimed to test the efficacy and safety of the FAAH-inhibitor PF-04457845 in reduction of cannabis withdrawal and cannabis use in men who were daily cannabis users. METHODS: We did a double-blind, placebo-controlled, parallel group phase 2a trial at one site in men aged 18-55 years with cannabis dependence according to DSM-IV criteria (equivalent to cannabis use disorder in DSM-5). After baseline assessments, participants were randomly assigned (2:1) to receive PF-04457845 (4 mg per day) or placebo using a fixed block size of six participants, stratified by severity of cannabis use and desire to quit. Participants were admitted to hospital for 5 days (maximum 8 days) to achieve abstinence and precipitate cannabis withdrawal, after which they were discharged to continue the remaining 3 weeks of treatment as outpatients. The primary endpoints were treatment-related differences in cannabis withdrawal symptoms during hospital admission, and week 4 (end of treatment) self-reported cannabis use and urine THC-COOH concentrations in the intention-to-treat population. The study is registered at ClinicalTrials.gov, number NCT01618656. FINDINGS: Between Sept 12, 2012, and Jan 18, 2016, 46 men were randomly assigned to PF-04457845 and 24 to placebo. Adherence to study medication was 88%, as confirmed by video-calling and pill count, and corroborated by corresponding drug and anandamide concentrations in blood. Relative to placebo, treatment with PF-04457845 was associated with reduced symptoms of cannabis withdrawal (first day of treatment mean symptom score 11·00 [95% CI 7·78-15·57] vs 6·04 [4·43-8·24]; difference 4·96 [0·71-9·21]; padj=0·048; second day of treatment 11·74 [8·28-16·66] vs 6·02 [4·28-8·47]; difference 5·73 [1·13-10·32]; padj=0·035) and related mood symptoms during the inpatient phase. Additionally, treatment with PF-04457845 was associated with lower self-reported cannabis use at 4 weeks (mean 1·27 joints per day [95% CI 0·82-1·97] vs 0·40 [0·25-0·62]; difference 0·88 [0·29-1·46]; p=0·0003) and lower urinary THC-COOH concentrations (mean 657·92 ng/mL [95% CI 381·60-1134·30] vs 265·55 [175·60-401·57]; difference 392·37 [17·55-767·18)]; p=0·009). Eight (17%) patients in the PF-04457845 group and four (17%) in the placebo group discontinued during the treatment period. During the 4-week treatment phase, 20 (43%) of 46 participants in the PF-04457845 group and 11 (46%) of 24 participants in the placebo group had an adverse event. There were no serious adverse events. INTERPRETATION: PF-04457845, a novel FAAH inhibitor, reduced cannabis withdrawal symptoms and cannabis use in men, and might represent an effective and safe approach for the treatment of cannabis use disorder. FUNDING: United States National Institute of Drug Abuse (NIDA).