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.
Assuntos
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
Cannabis is one of the most commonly and widely used psychoactive drugs. The rates of cannabis misuse have been increasing. Therefore, understanding the effects of cannabis use on the brain is important. Adolescent and adult rodents exposed to repeated administration of cannabinoids show persistent microstructural changes in the hippocampus both pre- and post-synaptically. Whether similar alterations exist in human cannabis users, has not yet been demonstrated in vivo. Positron emission tomography (PET) and [11C]UCB-J, a radioligand for the synaptic vesicle glycoprotein 2A (SV2A), were used to study hippocampal synaptic integrity in vivo in an equal number (n = 12) of subjects with DSM-5 cannabis use disorder (CUD) and matched healthy controls (HC). Arterial sampling was used to measure plasma input function. [11C]UCB-J binding potential (BPND) was estimated using a one-tissue (1T) compartment model with centrum semiovale as the reference region. Hippocampal function was assessed using a verbal memory task. Relative to HCs, CUDs showed significantly lower [11C]UCB-J BPND in the hippocampus (~10%, p = 0.008, effect size 1.2) and also performed worse on the verbal memory task. These group differences in hippocampal BPND persisted after correction for volume differences (p = 0.013), and correction for both age and volume (p = 0.03). We demonstrate, for the first time, in vivo evidence of lower hippocampal synaptic density in cannabis use disorder. These results are consistent with the microstructural findings from experimental studies with cannabinoids in animals, and studies of hippocampal macrostructure in human with CUD. Whether the lower hippocampal synaptic density resolves with abstinence warrants further study.
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Abuso de Maconha , Animais , Encéfalo/metabolismo , Hipocampo/metabolismo , Abuso de Maconha/diagnóstico por imagem , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons , PiridinasRESUMO
BACKGROUND: The human brain is inherently organized into distinct networks, as reported widely by resting-state functional magnetic resonance imaging (rs-fMRI), which are based on blood-oxygen-level-dependent (BOLD) signal fluctuations. 11C-UCB-J PET maps synaptic density via synaptic vesicle protein 2A, which is a more direct structural measure underlying brain networks than BOLD rs-fMRI. METHODS: The aim of this study was to identify maximally independent brain source networks, i.e., "spatial patterns with common covariance across subjects", in 11C-UCB-J data using independent component analysis (ICA), a data-driven analysis method. Using a population of 80 healthy controls, we applied ICA to two 40-sample subsets and compared source network replication across samples. We examined the identified source networks at multiple model orders, as the ideal number of maximally independent components (IC) is unknown. In addition, we investigated the relationship between the strength of the loading weights for each source network and age and sex. RESULTS: Thirteen source networks replicated across both samples. We determined that a model order of 18 components provided stable, replicable components, whereas estimations above 18 were not stable. Effects of sex were found in two ICs. Nine ICs showed age-related change, with 4 remaining significant after correction for multiple comparison. CONCLUSION: This study provides the first evidence that human brain synaptic density can be characterized into organized covariance patterns. Furthermore, we demonstrated that multiple synaptic density source networks are associated with age, which supports the potential utility of ICA to identify biologically relevant synaptic density source networks.
Assuntos
Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Glicoproteínas de Membrana/metabolismo , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Sinapses/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons/normas , Piridinas/farmacocinética , Pirrolidinonas/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Fatores Sexuais , Processamento de Sinais Assistido por Computador , Adulto JovemRESUMO
Cannabis is the most widely used illicit drug worldwide, and it is estimated that up to 30% of people who use cannabis will develop a cannabis use disorder (CUD). Demand for treatment of CUD is increasing in almost every region of the world and cannabis use is highly comorbid with mental disorders, where sustained use can reduce treatment compliance and increase risk of relapse. In this narrative review, we outline evidence for psychosocial and pharmacological treatment strategies for CUD, both alone and when comorbid with psychosis, anxiety or depression. Psychosocial treatments such as cognitive behavioural therapy, motivational enhancement therapy and contingency management are currently the most effective strategy for treating CUD but are of limited benefit when comorbid with psychosis. Pharmacological treatments targeting the endocannabinoid system have the potential to reduce cannabis withdrawal and cannabis use in CUD. Mental health comorbidities including anxiety, depression and psychosis hinder effective treatment and should be addressed in treatment provision and clinical decision making to reduce the global burden of CUDs. Antipsychotic medication may decrease cannabis use and cannabis craving as well as psychotic symptoms in patients with CUD and psychosis. Targeted treatments for anxiety and depression when comorbid with CUD are feasible.
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Cannabis , Abuso de Maconha/epidemiologia , Abuso de Maconha/terapia , Antipsicóticos/uso terapêutico , Transtornos de Ansiedade/epidemiologia , Transtornos de Ansiedade/terapia , Terapia Cognitivo-Comportamental , Comorbidade , Transtorno Depressivo/epidemiologia , Transtorno Depressivo/terapia , Humanos , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/terapia , Resultado do TratamentoRESUMO
OBJECTIVES: Preclinical and clinical studies suggest that males and females may be differentially affected by cannabis use. This study evaluated the interaction of cannabis use and biological sex on cognition, and the association between observed cognitive deficits and features of cannabis use. METHODS: Cognitive measures were assessed in those with regular, ongoing, cannabis use (N = 40; 22 female) and non-using peers (N = 40; 23 female). Intelligence, psychomotor speed, and verbal working memory were measured with the Wechsler Abbreviated Scale of Intelligence, Digit Symbol Test, and Digit Span and Hopkins Verbal Learning Test, respectively. Associations between cognitive measures and cannabis use features (e.g., lifetime cannabis use, age of initiation, time since last use of cannabis, recent high-concentration tetrahydrocannabinoid exposure) were also evaluated. RESULTS: No main effects of group were observed across measures. Significant interactions between group and biological sex were observed on measures of intelligence, psychomotor speed, and verbal learning, with greatest group differences observed between males with and without regular cannabis use. Psychomotor performance was negatively correlated with lifetime cannabis exposure. Female and male cannabis use groups did not differ in features of cannabis use. CONCLUSIONS: Findings suggest that biological sex influences the relationship between cannabis and cognition, with males potentially being more vulnerable to the neurocognitive deficits related to cannabis use.
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Cannabis , Transtornos Cognitivos , Cognição , Humanos , Memória de Curto Prazo , Testes Neuropsicológicos , Aprendizagem VerbalRESUMO
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
BACKGROUND: The literature on psychosis-relevant outcomes in cannabis users does not adequately address the confounding effects of other substance use/misuse and psychiatric disorders. METHODS: We studied a unique population for whom cannabis use is central and necessary to their way of life. They are forbidden from using other substances, including tobacco and alcohol. Their use of cannabis is heavy, chronic, and begins early. The cases were compared with matched controls who did not use cannabis, alcohol, or drugs. The controls were from the same location and shared similar beliefs and lifestyle, except for cannabis use. Attenuated psychosis-relevant phenomena were assessed with the Schizotypal Personality Questionnaire (SPQ) and cognitive functioning with a culture-neutral computerized cognitive battery. RESULTS: Fifteen cases and 12 matched controls were studied. The cases averaged >30 000 lifetime cannabis exposures. Relative to controls, the cases had significantly higher mean (s.d.) SPQ scores 24 (14.32) v. 13 (8.92), p = 0.031; and poorer cognitive performance, reflected by a lower mean (s.d.) composite cognitive score -0.23 (0.32) v. +0.28 (0.52), p = 0.03. Moderate to large effect sizes were noted for differences in tests of attention, psychomotor speed, working memory, cognitive flexibility, visuo-spatial processing, and verbal memory. A subsample of cases had higher SPQ scores and worse cognitive performance than their siblings not using cannabis. CONCLUSION: Heavy, chronic, and early cannabis use that is not confounded by other drug use is associated with psychosis-relevant phenomena and cognitive deficits. The findings are relevant to the evolving attitudes and laws about cannabis.
Assuntos
Cannabis/efeitos adversos , Transtornos Cognitivos/psicologia , Abuso de Maconha/psicologia , Transtornos Psicóticos/psicologia , Irmãos/psicologia , Adulto , Estudos de Casos e Controles , Cognição/efeitos dos fármacos , Cognição/fisiologia , Transtornos Cognitivos/complicações , Feminino , Humanos , Masculino , Abuso de Maconha/complicações , Memória de Curto Prazo , Pessoa de Meia-Idade , Testes Neuropsicológicos , Escalas de Graduação Psiquiátrica , Transtornos Psicóticos/complicações , Inquéritos e Questionários , Adulto JovemRESUMO
Marijuana is becoming legal in an increasing number of states for both medical and recreational use. Considerable controversy exists regarding the public health impact of these changes. The evidence for the legitimate medical use of marijuana or cannabinoids is limited to a few indications, notably HIV/AIDS cachexia, nausea/vomiting related to chemotherapy, neuropathic pain, and spasticity in multiple sclerosis. Although cannabinoids show therapeutic promise in other areas, robust clinical evidence is still lacking. The relationship between legalization and prevalence is still unknown. Although states where marijuana use is legal have higher rates of use than nonlegal states, these higher rates were generally found even prior to legalization. As states continue to proceed with legalization for both medical and recreational use, certain public health issues have become increasingly relevant, including the effects of acute marijuana intoxication on driving abilities, unintentional ingestion of marijuana products by children, the relationship between marijuana and opioid use, and whether there will be an increase in health problems related to marijuana use, such as dependence/addiction, psychosis, and pulmonary disorders. In light of this rapidly shifting legal landscape, more research is urgently needed to better understand the impact of legalization on public health.
Assuntos
Cannabis , Dronabinol/farmacologia , Drogas Ilícitas/legislação & jurisprudência , Abuso de Maconha/epidemiologia , Fumar Maconha/epidemiologia , Condução de Veículo , Cannabis/intoxicação , Transtornos Cognitivos/etiologia , Dronabinol/administração & dosagem , Humanos , Abuso de Maconha/etiologia , Fumar Maconha/efeitos adversos , Maconha Medicinal , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Prevalência , Transtornos Psicóticos/etiologia , Saúde Pública , Estados UnidosRESUMO
Psychedelic compounds, including psilocybin, LSD (lysergic acid diethylamide), DMT (N,N -dimethyltryptamine), and 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine), all of which are serotonin 2A receptor agonists, are being investigated as potential treatments. This review aims to summarize the current clinical research on these 4 compounds and mescaline to guide future research. Their mechanism(s) of action, pharmacokinetics, pharmacodynamics, efficacy, and safety were reviewed. While evidence for therapeutic indications, with the exception of psilocybin for depression, is still relatively scarce, we noted no differences in psychedelic effects beyond effect duration. Therefore, it remains unclear whether different receptor profiles contribute to the therapeutic potential of these compounds. More research is needed to differentiate these compounds in order to inform which compounds might be best for different therapeutic uses.
Assuntos
Alucinógenos , Dietilamida do Ácido Lisérgico , Psilocibina , Alucinógenos/farmacocinética , Alucinógenos/farmacologia , Humanos , Psilocibina/farmacocinética , Psilocibina/farmacologia , Dietilamida do Ácido Lisérgico/farmacologia , Dietilamida do Ácido Lisérgico/farmacocinética , Agonistas do Receptor 5-HT2 de Serotonina/farmacologia , Agonistas do Receptor 5-HT2 de Serotonina/farmacocinéticaRESUMO
Several phase II studies have demonstrated that psilocybin-assisted therapy shows therapeutic potential across a spectrum of neuropsychiatric conditions, including major depressive disorder (MDD). However, the mechanisms underlying its often persisting beneficial effects remain unclear. Observational research suggests that improvements in psychological flexibility may mediate therapeutic effects. However, no psychedelic trials to date have substantiated this finding in a clinical sample. In an exploratory placebo-controlled, within-subject, fixed-order study, individuals with moderate to severe MDD were administered placebo (n = 19) followed by psilocybin (0.3 mg/kg) (n = 15) 4 weeks later. Dosing sessions were embedded within a manualized psychotherapy that incorporated principles of Acceptance and Commitment Therapy. Depression severity, psychological flexibility, mindfulness, and values-congruent living were measured over a 16-weeks study period. Psychological flexibility, several facets of mindfulness, and values-congruent living significantly improved following psilocybin and were maintained through week 16. Additionally, improvements in psychological flexibility and experiential acceptance were strongly associated with reductions in depression severity following psilocybin. These findings support the theoretical premise of integrating psilocybin treatment with psychotherapeutic platforms that target psychological flexibility and add to emerging evidence that increasing psychological flexibility may be an important putative mechanism of change in psilocybin-assisted therapy for MDD and potentially, other mental health conditions.
Assuntos
Terapia de Aceitação e Compromisso , Transtorno Depressivo Maior , Alucinógenos , Humanos , Psilocibina , Transtorno Depressivo Maior/tratamento farmacológico , Depressão/tratamento farmacológicoRESUMO
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.
Assuntos
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
Rates of opioid-related deaths and overdoses in the United States are at record-high levels. Thus, novel neurobiological targets for the treatment of OUD are greatly needed. Given the close interaction between the endogenous opioid system and the endocannabinoid system (ECS), targeting the ECS may have therapeutic potential in OUD. The various components of the ECS, including cannabinoid receptors, their lipid-derived endogenous ligands (endocannabinoids [eCBs]), and the related enzymes, present potential targets for developing new medications in OUD treatment. The purpose of this paper is to review the clinical and preclinical literature on the dysregulation of the ECS after exposure to opioids. We review the evidence of ECS dysregulation across various study types, exposure protocols, and measurement protocols and summarize the evidence for dysregulation of ECS components at specific brain regions. Preclinical research has shown that opioids disrupt various ECS components that are region-specific. However, the results in the literature are highly heterogenous and sometimes contradictory, possibly due to variety of different methods used. Further research is needed before a confident conclusion could be made on how exposure to opioids can affect ECS components in various brain regions.
Assuntos
Canabinoides , Endocanabinoides , Humanos , Analgésicos Opioides/farmacologia , Receptores de Canabinoides , Encéfalo/metabolismo , Canabinoides/farmacologiaRESUMO
N-methyl-d-aspartate glutamate receptor (NMDAR) hypofunction is implicated in the impaired neuroplasticity and cognitive impairments associated with schizophrenia (CIAS). We hypothesized that enhancing NMDAR function by inhibiting the glycine transporter-1 (GLYT1) would improve neuroplasticity and thereby augment benefits of non-pharmacological cognitive training (CT) strategies. This study examined whether co-administration of a GLYT1 inhibitor and computerized CT would have synergistic effects on CIAS. Stable outpatients with schizophrenia participated in this double-blind, placebo-controlled, within-subject, crossover augmentation study. Participants received placebo or GLYT1 inhibitor (PF-03463275) for two 5-week periods separated by 2 weeks of washout. PF-03463275 doses (40 or 60 mg twice daily) were selected to produce high GLYT1 occupancy. To limit pharmacodynamic variability, only cytochrome P450 2D6 extensive metabolizers were included. Medication adherence was confirmed daily. Participants received 4 weeks of CT in each treatment period. Cognitive performance (MATRICS Consensus Cognitive Battery) and psychotic symptoms (Positive and Negative Syndrome Scale) were assessed in each period. 71 participants were randomized. PF-03463275 in combination with CT was feasible, safe, and well-tolerated at the doses prescribed but did not produce greater improvement in CIAS compared to CT alone. PF-03463275 was not associated with improved CT learning parameters. Participation in CT was associated with improvement in MCCB scores.
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Antipsicóticos , Esquizofrenia , Humanos , Esquizofrenia/complicações , Esquizofrenia/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Glicina , Treino Cognitivo , Antipsicóticos/uso terapêutico , Plasticidade Neuronal , Método Duplo-CegoRESUMO
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.
Assuntos
Condução de Veículo , Alucinógenos , Humanos , Dronabinol , Etanol , Autorrelato , Desempenho Psicomotor , Alucinógenos/farmacologia , Método Duplo-CegoRESUMO
BACKGROUND AND HYPOTHESIS: Risk for cannabis use and schizophrenia is influenced in part by genetic factors, and there is evidence that genetic risk for schizophrenia is associated with subclinical psychotic-like experiences (PLEs). Few studies to date have examined whether genetic risk for schizophrenia is associated with cannabis-related PLEs. STUDY DESIGN: We tested whether measures of cannabis involvement and polygenic risk scores (PRS) for schizophrenia were associated with self-reported cannabis-related experiences in a sample ascertained for alcohol use disorders (AUDs), the Collaborative Study on the Genetics of Alcoholism (COGA). We analyzed 4832 subjects (3128 of European ancestry and 1704 of African ancestry; 42% female; 74% meeting lifetime criteria for an AUD). STUDY RESULTS: Cannabis use disorder (CUD) was prevalent in this analytic sample (70%), with 40% classified as mild, 25% as moderate, and 35% as severe. Polygenic risk for schizophrenia was positively associated with cannabis-related paranoia, feeling depressed or anhedonia, social withdrawal, and cognitive difficulties, even when controlling for duration of daily cannabis use, CUD, and age at first cannabis use. The schizophrenia PRS was most robustly associated with cannabis-related cognitive difficulties (ß = 0.22, SE = 0.04, P = 5.2e-7). In an independent replication sample (N = 1446), associations between the schizophrenia PRS and cannabis-related experiences were in the expected direction and not statistically different in magnitude from those in the COGA sample. CONCLUSIONS: Among individuals who regularly use cannabis, genetic liability for schizophrenia-even in those without clinical features-may increase the likelihood of reporting unusual experiences related to cannabis use.
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Alcoolismo , Cannabis , Esquizofrenia , Humanos , Feminino , Masculino , Esquizofrenia/epidemiologia , Esquizofrenia/genética , Cannabis/efeitos adversos , Predisposição Genética para Doença , Fatores de Risco , Herança MultifatorialRESUMO
The development of psychedelics as medicines faces several challenges.
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Alucinógenos , Transtornos Mentais , Plasticidade Neuronal , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Transtornos Mentais/tratamento farmacológico , Humanos , Desenvolvimento de Medicamentos , Plasticidade Neuronal/efeitos dos fármacosRESUMO
Cannabis has been implicated as both a potential cause and adverse prognostic factor in psychotic disorders. Investigating the contributory role of cannabis toward the overall burden of psychotic illnesses may represent an important step toward psychosis prevention and treatment. The current study samples consecutive admissions (N = 246) to two community based first-episode psychosis services to characterize timing of cannabis use relative to psychosis and attenuated symptom onset, differences between those with and without cannabis exposure, and the association of age at first cannabis exposure with clinical and demographic variables. Both cannabis exposure (78%) and cannabis use disorders (47%) were highly prevalent at admission. In 94% of participants, cannabis use preceded the onset of both attenuated and full-threshold psychosis symptoms by several years. Earlier age at first exposure to cannabis was associated with younger age at prodrome and psychosis onset, worse premorbid functioning, and greater severity of cannabis use disorder at admission. The timing of first exposure to cannabis may have individual prognostic as well as public health significance. Documenting the prevalence and impact of cannabis use in early psychosis samples, as well as the overall incidence of psychotic disorders, will be of vital public health significance as the United States enacts cannabis legalization and cannabis products become more widely available.
Assuntos
Cannabis , Abuso de Maconha , Transtornos Psicóticos , Idade de Início , Cannabis/efeitos adversos , Humanos , Abuso de Maconha/complicações , Abuso de Maconha/epidemiologia , Prognóstico , Transtornos Psicóticos/etiologiaRESUMO
Despite years of research, the mechanisms governing the onset, relapse, symptomatology, and treatment of schizophrenia (SZ) remain elusive. The lack of appropriate analytic tools to deal with the heterogeneity and complexity of SZ may be one of the reasons behind this situation. Deep learning, a subfield of artificial intelligence (AI) inspired by the nervous system, has recently provided an accessible way of modeling and analyzing complex, high-dimensional, nonlinear systems. The unprecedented accuracy of deep learning algorithms in classification and prediction tasks has revolutionized a wide range of scientific fields and is rapidly permeating SZ research. Deep learning has the potential of becoming a valuable aid for clinicians in the prediction, diagnosis, and treatment of SZ, especially in combination with principles from Bayesian statistics. Furthermore, deep learning could become a powerful tool for uncovering the mechanisms underlying SZ thanks to a growing number of techniques designed for improving model interpretability and causal reasoning. The purpose of this article is to introduce SZ researchers to the field of deep learning and review its latest applications in SZ research. In general, existing studies have yielded impressive results in classification and outcome prediction tasks. However, methodological concerns related to the assessment of model performance in several studies, the widespread use of small training datasets, and the little clinical value of some models suggest that some of these results should be taken with caution.
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Inteligência Artificial , Esquizofrenia , Algoritmos , Teorema de Bayes , Humanos , Aprendizado de Máquina , Esquizofrenia/terapiaRESUMO
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.
Assuntos
Cannabis , Alucinógenos , Agonistas de Receptores de Canabinoides , Método Duplo-Cego , Dronabinol/farmacologia , Feminino , Alucinógenos/farmacologia , Humanos , Masculino , Caracteres SexuaisRESUMO
There is considerable interest in the therapeutic potential of psychedelic drugs. Dimethyltryptamine (DMT) is a potent, rapid-onset, and short-acting psychedelic drug that has not yet been independently tested for the treatment of depression. The safety, tolerability, and efficacy of intravenous DMT were investigated in treatment-resistant individuals with major depressive disorder (MDD) and healthy controls (HC) in an open-label, fixed-order, dose-escalation (0.1 mg/kg followed by 0.3 mg/kg) exploratory phase 1 study that was conducted in a typical hospital setting with strategic psychoeducation/support, but minimal psychotherapy. Tolerability, safety, cardiovascular function, abuse liability, psychedelic, and psychotomimetic effects, mood, and anxiety were assessed at each dosing session. In addition, depression was measured using the HAMD-17 in MDD participants 1 day after each dosing session. DMT was tolerated by both HC (n = 3) and MDD participants (n = 7) studied; there were no dropouts. HAMD-17 scores decreased significantly (p = 0.017) compared to baseline in MDD participants the day after receiving 0.3 mg/kg DMT (mean difference -4.5 points, 95% CI: -7.80 to -1.20, Hedge's g = 0.75). Adverse events were mostly mild with one self-limited serious event. DMT increased blood pressure, heart rate, anxiety, psychedelic effects, and psychotomimetic effects, which resolved within 20-30 min of injection. There were no dose-related differences in measures of drug reinforcement and abuse liability. In this small exploratory pilot study, intravenous DMT at doses of 0.1 and 0.3 mg/kg was mostly safe and tolerated and may have next-day (rapid) antidepressant effects in patients with treatment-resistant MDD. Further rigorous trials are warranted to replicate these findings and to determine the durability of antidepressant effects.