Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.022
Filtrar
1.
PLoS One ; 15(3): e0230238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32163506

RESUMO

Social withdrawal in the sub-chronic phencyclidine (PCP) rat model, a behavioral correlate of the negative symptoms of schizophrenia, results from deficits in brain endocannabinoid transmission. As cannabis intake has been shown to affect negatively the course and expression of psychosis, we tested whether the beneficial effects of endocannabinoid-mediated CB1 activation on social withdrawal in PCP-treated rats (5 mg/kg, twice daily for 7 days)also occurred after administration of Δ9-tetrahydrocannabinol (THC; 0.1, 0.3, 1.0 mg/kg, i.p.). In addition, we assessed whether THC affected two correlates of positive symptoms: 1) motor activity induced by d-amphetamine (0.5 mg/kg, i.p.), and 2) dopamine neuron population activity in the ventral tegmental area (VTA). After the motor activity test, the brains from d-amphetamine-treated animals were collected and processed for measurements of endocannabinoids and activation of Akt/GSK3ß, two molecular markers involved in the pathophysiology of schizophrenia. In control rats, THC dose-dependently produced social interaction deficits and aberrant VTA dopamine neuron population activity similar to those observed in PCP-treated animals. In PCP-treated rats, only the lowest dose of THC reversed PCP-induced deficits, as well as PCP-induced elevation of the endocannabinoid anandamide (AEA) in the nucleus accumbens. Last, THC activated the Akt/GSK3ß pathway dose-dependently in both control and PCP-treated animals. Taken together, these data suggest that only low doses of THC have beneficial effects on behavioral, neurochemical and electrophysiological correlates of schizophrenia symptoms. This observation may shed some light on the controversial hypothesis of marijuana use as self-medication in schizophrenic patients.


Assuntos
Dronabinol/administração & dosagem , Fenciclidina/farmacologia , Esquizofrenia/induzido quimicamente , Esquizofrenia/tratamento farmacológico , Animais , Ácidos Araquidônicos/farmacologia , Modelos Animais de Doenças , Endocanabinoides/farmacologia , Glicogênio Sintase Quinase 3 beta/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Alcamidas Poli-Insaturadas/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Área Tegmentar Ventral/efeitos dos fármacos , Área Tegmentar Ventral/metabolismo
2.
Pneumologie ; 74(2): 77-87, 2020 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-32016924

RESUMO

Beginning in April of 2019, the US saw > 2,000 cases of hospitalized, often young, patients with severe acute lung injury, of which over 40 died, and the only existing connection between patients was their use of electronic cigarettes (e-cigarettes). The acronym EVALI ("e-cigarette, or vaping, product use associated lung injury") has since been established for the condition. This review article is intended to provide an overview of recent, mainly US literature on EVALI, including the case definition, epidemiology, clinical presentation, typical disease progression, as well as potential triggers. Ancillary to this, the review further provides a general overview of the basic function of e-cigarettes, the ingredients of the liquids used in these (e-liquids), as well as a brief description of the associated potential inhalation risks.


Assuntos
Lesão Pulmonar Aguda/induzido quimicamente , Dronabinol/efeitos adversos , Sistemas Eletrônicos de Liberação de Nicotina , Vaping/efeitos adversos , Lesão Pulmonar Aguda/epidemiologia , Canabidiol/administração & dosagem , Canabidiol/efeitos adversos , Surtos de Doenças , Dronabinol/administração & dosagem , Humanos , Nicotina/administração & dosagem , Nicotina/efeitos adversos , Fatores de Risco
4.
Lancet ; 394(10214): 2073-2083, 2019 12 07.
Artigo em Inglês | MEDLINE | ID: mdl-31711629

RESUMO

BACKGROUND: An ongoing outbreak of lung injury associated with e-cigarettes or vaping (also known as E-VALI or VALI) started in March, 2019, in the USA. The cause, diagnosis, treatment, and course of this disease remains unknown. METHODS: In this multicentre, prospective, observational, cohort study, we collected data on all patients with lung injury associated with e-cigarettes or vaping seen in Intermountain Healthcare, an integrated health system based in Utah, USA, between June 27 and Oct 4, 2019. Telecritical care, based in Salt Lake City, UT, USA, was used as the central repository for case validation, public reporting, and system-wide dissemination of expertise, which included a proposed diagnosis and treatment guideline for lung injury associated with e-cigarettes or vaping. We extracted data on patient presentation, treatment, and short-term follow-up (2 weeks after discharge) from chart review and interviews with patients undertaken by the Utah Department of Health (Salt Lake City, UT, USA). FINDINGS: 60 patients presented with lung injury associated with e-cigarettes or vaping at 13 hospitals or outpatient clinics in the integrated health system. 33 (55%) of 60 were admitted to an intensive care unit (ICU). 53 (88%) of 60 patients presented with constitutional symptoms, 59 (98%) with respiratory symptoms, and 54 (90%) with gastrointestinal symptoms. 54 (90%) of 60 were given antibiotics and 57 (95%) were given steroids. Six (10%) of 60 patients were readmitted to an ICU or hospital within 2 weeks, three (50%) of whom had relapsed with vaping or e-cigarette use. Of 26 patients who were followed up within 2 weeks, despite clinical and radiographic improvement in all, many had residual abnormalities on chest radiographs (ten [67%] of 15) and pulmonary function tests (six [67%] of nine). Two patients died and lung injury associated with e-cigarettes or vaping was thought to be a contributing factor, but not the cause of death, for both. INTERPRETATION: Lung injury associated with e-cigarettes or vaping is an emerging illness associated with severe lung injury and constitutional and gastrointestinal symptoms. Increased awareness has led to identification of a broad spectrum of severity of illness in patients who were treated with antibiotics and steroids. Despite improvement, at short-term follow-up many patients had residual abnormalities. Lung injury associated with e-cigarettes or vaping remains a clinical diagnosis with symptoms that overlap infectious and other lung diseases. Maintaining a high index of suspicion for this disease is important as work continues in understanding the cause or causes, optimal therapy, and long-term outcomes of these patients. FUNDING: Intermountain Healthcare.


Assuntos
Lesão Pulmonar Aguda/etiologia , Vaping/efeitos adversos , Lesão Pulmonar Aguda/diagnóstico por imagem , Lesão Pulmonar Aguda/epidemiologia , Lesão Pulmonar Aguda/terapia , Adulto , Antibacterianos/uso terapêutico , Broncoscopia , Canabidiol/administração & dosagem , Estudos de Coortes , Surtos de Doenças , Dronabinol/administração & dosagem , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Glucocorticoides/uso terapêutico , Humanos , Tempo de Internação , Masculino , Nicotina/administração & dosagem , Ventilação não Invasiva , Oxigenoterapia , Estudos Prospectivos , Respiração Artificial , Tomografia Computadorizada por Raios X , Utah/epidemiologia , Adulto Jovem
5.
Drugs Aging ; 36(11): 1035-1045, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31552597

RESUMO

BACKGROUND: Synthetic oral cannabinoids (nabilone and dronabinol) may have adverse respiratory effects. Our purpose was to describe the scope, pattern, and patient characteristics associated with incident off-label synthetic oral cannabinoid use among older adults with chronic obstructive pulmonary disease (COPD) compared to older adults without COPD. METHODS: This was a retrospective, population-based, cohort study using Ontario, Canada, heath administrative data. Individuals aged 66 years or older were included, and physician-diagnosed COPD was identified using a previously validated, highly specific algorithm. Incident off-label oral cannabinoid use was examined between April 1, 2005 and March 31, 2015. Descriptive statistics were used to describe drug use patterns. Multiple logistic regression was used to identify patient characteristics associated with incident drug use. RESULTS: There were 172,282 older adults with COPD and 1,068,256 older adults without COPD identified between April 1, 2005 and March 31, 2015. Incident synthetic oral cannabinoid use during this period occurred with significantly greater (p < 0.001) frequency among older adults with COPD (0.6%) versus older adults without COPD (0.3%). Compared to those without COPD, older adults with COPD used synthetic cannabinoids for significantly longer durations and more frequently at higher doses. CONCLUSIONS: Although incident off-label oral cannabinoid use was relatively low among all older Ontarian adults, this drug class was used with greater frequency and more often in potentially concerning ways among older adults with COPD. These findings raise possible safety concerns, but further research on the respiratory safety of oral cannabinoids among individuals with COPD is needed.


Assuntos
Dronabinol/análogos & derivados , Uso de Medicamentos/estatística & dados numéricos , Prescrição Inadequada/estatística & dados numéricos , Uso Off-Label/estatística & dados numéricos , Medicamentos sob Prescrição/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Idoso , Algoritmos , Estudos de Coortes , Dronabinol/administração & dosagem , Dronabinol/efeitos adversos , Dronabinol/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Ontário , Medicamentos sob Prescrição/efeitos adversos , Medicamentos sob Prescrição/uso terapêutico , Estudos Retrospectivos
6.
BMC Neurol ; 19(1): 222, 2019 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-31493784

RESUMO

BACKGROUND: Treatment of spasticity poses a major challenge in amyotrophic lateral sclerosis (ALS) patient management. Delta-9-tetrahydrocannabinol (THC):cannabidiol (CBD) oromucosal spray (THC:CBD), approved for the treatment of spasticity in multiple sclerosis, serves as a complementary off-label treatment option in ALS-related spasticity. However, few structured data are available on THC:CBD in the treatment of spasticity in ALS. METHOD: A retrospective mono-centric cohort study was realised in 32 patients that meet the following criteria: 1) diagnosis of ALS, 2) ALS-related spasticity; 3) treatment with THC:CBD. Spasticity was rated using the Numeric Rating Scale (NRS). Patient's experience with THC:CBD was assessed using the net promoter score (NPS) and treatment satisfaction questionnaire for medication (TSMQ-9) as captured through telephone survey or online assessment. RESULTS: The mean dose THC:CBD were 5.5 daily actuations (range < 1 to 20). Three subgroups of patients were identified: 1) high-dose daily use (≥ 7 daily actuations, 34%, n = 11), 2) low-dose daily use (< 7 daily actuations, 50%, n = 16), 3) infrequent use (< 1 daily actuation, 16%, n = 5). Overall NPS was + 4.9 (values above 0 express a positive recommendation to fellow patients). Remarkably, patients with moderate to severe spasticity (NRS ≥ 4) reported a high recommendation rate (NPS: + 29) in contrast to patients with mild spasticity (NRS < 4; NPS: - 44). For the three main domains of TSQM-9 high mean satisfaction levels were found (maximum value 100): effectiveness 70.5 (±22.3), convenience 76.6 (±23.3) and global satisfaction 75.0 (±24.7). CONCLUSION: THC:CBD is used in a wide dose range suggesting that the drug was applied on the basis of individual patients' needs and preferences. Contributing to this notion, moderate to severe spasticity was associated with an elevated number of daily THC:CBD actuations and stronger recommendation rate (NPS) as compared to patients with mild spasticity. Overall, treatment satisfaction (TSQM-9) was high. The results suggest that THC:CBD may serve as a valuable addition in the spectrum of symptomatic therapy in ALS. However, prospective studies and head-to-head comparisons to other spasticity medications are of interest to further explore the effectiveness of THC:CBD in the management of spasticity, and other ALS-related symptoms.


Assuntos
Esclerose Amiotrófica Lateral/tratamento farmacológico , Canabidiol/administração & dosagem , Dronabinol/administração & dosagem , Espasticidade Muscular/tratamento farmacológico , Adulto , Idoso , Esclerose Amiotrófica Lateral/complicações , Estudos de Coortes , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Satisfação do Paciente , Estudos Retrospectivos
7.
Pharmacol Biochem Behav ; 185: 172764, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31449820

RESUMO

Zebra finches are songbirds that learn vocal patterns during a sensitive period of development that approximates adolescence. Exposure of these animals to a cannabinoid agonist during their period of sensorimotor vocal learning alters song patterns produced in adulthood. Thus, songbirds have unique value in studying developmental effects of drug exposure on a naturally learned behavior. A missing feature of this animal model has been a method to study drug reinforcement of behavior. To address this gap we have adapted place conditioning methods, used previously to determine that singing behavior is rewarding, to study cocaine reinforcement of behavior. We have found that cocaine dose-dependently reinforces both place conditioning and aversion at potencies consistent with those observed in mammalian species. Use of this place conditioning method has allowed us to determine that, when administered during periods of sensorimotor vocal learning, delta-9-THC, but not nicotine persistently increases sensitivity to cocaine through adulthood. Establishment of this method significantly expands the songbird drug exposure model, and holds promise for better appreciation of mechanisms important to sensorimotor learning that is dependent upon successful progress through sensitive periods of CNS development.


Assuntos
Cocaína/farmacologia , Dronabinol/farmacologia , Tentilhões/crescimento & desenvolvimento , Aprendizagem/efeitos dos fármacos , Reforço Psicológico , Vocalização Animal/efeitos dos fármacos , Análise de Variância , Animais , Comportamento Animal/efeitos dos fármacos , Cocaína/administração & dosagem , Condicionamento Clássico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Feminino , Masculino , Nicotina/administração & dosagem , Nicotina/farmacologia , Recompensa , Córtex Sensório-Motor/efeitos dos fármacos , Fatores Sexuais
8.
Expert Rev Med Devices ; 16(9): 835-840, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31393179

RESUMO

Background: Patients with multiple sclerosis spasticity (MSS) and upper limb/hand impairment who are taking 9-delta-tetrahydrocannabinol:cannabidiol (THC:CBD) oromucosal spray (Sativex®) may have difficulty self-administering their medication, possibly limiting adherence and treatment effectiveness. A Class I EU device is available to support the administration of THC:CBD spray. Pre-production testing was undertaken in a patient sample. Methods: Current users of THC:CBD spray were recruited to review the instruction leaflet and test the device. Patients and observing health-care professionals (HCP) completed a purpose-designed questionnaire which captured user experience and HCP opinion. Results: Fifteen patients participated. Mean treatment time with THC:CBD spray was 4 (range: 0.1-6.1) years. 87% of participants 'always', 'often' or 'sometimes' had hand impairment, and 53% reported difficulty administering THC:CBD spray. Participants reported better application using the device (73%), with less strength required (54%). Most participants (93%) considered the instruction leaflet to be clear and many (66%) expressed interest in using the device. Most HCPs (93%) did not foresee any difficulties in use of the device. Conclusion: The proposed adherence device was useful to address self-application difficulties with THC:CBD spray in our sample. Providing the device to MSS patients with upper limb/hand spasticity impairment may restore autonomy and support adherence to THC:CBD spray.


Assuntos
Canabidiol/administração & dosagem , Canabidiol/uso terapêutico , Dronabinol/administração & dosagem , Mucosa Bucal/efeitos dos fármacos , Espasticidade Muscular/tratamento farmacológico , Sprays Orais , Adulto , Idoso , Canabidiol/farmacologia , Combinação de Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários
9.
Expert Opin Drug Deliv ; 16(10): 1031-1035, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31393180

RESUMO

Introduction: Sativex® spray is clinically utilized to deliver delta9-tetrahydrocannabinol and cannabidiol to oral mucosa for systemic absorption. We challenge the consensus that the mechanism of absorption following the oro-mucosal application occurs via the buccal tissue. Areas covered: Correctness of the consensus of this absorption pathway arose when reviewing publications regarding the influence fed versus fasting states have on pharmacokinetics of these cannabinoids administered to the oral mucosa. This finding is more suitable for peroral administration, where stomach content affects the absorption profile. We hypothesize that these cannabinoids are ingested and absorbed in the gastrointestinal tract. Expert opinion: Although clinical importance of Sativex® is not disputed, the wide acceptance of its being a successful example of drug delivery through oral mucosa is questionable. Sativex® acts as an example for other drugs delivered to oral mucosa for systemic absorption and unintentionally washed by the saliva flow into the gastrointestinal tract. Delivery of each medicine through oral mucosa should be validated in-vivo to ensure this route to be the predominant one. Revealing the underlying absorption mechanisms would enable predicting the impact of different physiological parameters such as saliva flow and fed/fasting states on the pharmacokinetics of the delivered medication.


Assuntos
Canabidiol/administração & dosagem , Dronabinol/administração & dosagem , Sistemas de Liberação de Medicamentos , Mucosa Bucal/metabolismo , Absorção Fisiológica , Administração Oral , Canabinoides/administração & dosagem , Combinação de Medicamentos , Jejum , Trato Gastrointestinal/metabolismo , Humanos , Saliva/metabolismo
10.
Pharmacol Biochem Behav ; 184: 172739, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31283908

RESUMO

The high prevalence of concomitant cannabis and nicotine use has implications for sensory and cognitive processing. While nicotine tends to enhance function in these domains, cannabis use has been associated with both sensory and cognitive impairments, though the underlying mechanisms are unclear. Additionally, the interaction of the nicotinic (nAChR) and cannabinoid (CB1) receptor systems has received limited study in terms of sensory/cognitive processes. This study involving healthy volunteers assessed the acute separate and combined effects of nabilone (a CB1 agonist) and nicotine on sensory processing as assessed by auditory deviance detection and indexed by the mismatch negativity (MMN) event-related potential. It was hypothesized that nabilone would impair auditory discriminability as shown by diminished MMN amplitudes, but not when administered in combination with nicotine. 20 male non-smokers and non-cannabis-users were assessed using a 5-stimulus 'optimal' multi-feature MMN paradigm within a randomized, placebo controlled design (placebo; nabilone [0.5 mg]; nicotine [6 mg]; and nicotine + nabilone). Treatment effects were region- and deviant-dependent. At the temporal regions (mastoid sites), MMN was reduced by nabilone and nicotine separately, whereas co-administration resulted in no impairment. At the frontal region, MMN was enhanced by co-administration of nicotine and nabilone, with no MMN effects being found with separate treatment. These neural effects have relevance for sensory/cognitive processes influenced by separate and simultaneous use of cannabis and tobacco and may have treatment implications for disorders associated with sensory dysfunction and impairments in endocannabinoid and nicotinic cholinergic neurotransmission.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Dronabinol/análogos & derivados , Potenciais Evocados Auditivos/efeitos dos fármacos , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Estimulação Acústica/métodos , Adulto , Agonistas de Receptores de Canabinoides/administração & dosagem , Método Duplo-Cego , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Quimioterapia Combinada/métodos , Eletroencefalografia/métodos , Eletroculografia/métodos , Lobo Frontal/efeitos dos fármacos , Voluntários Saudáveis , Humanos , Masculino , Nicotina/administração & dosagem , Agonistas Nicotínicos/administração & dosagem , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/metabolismo , Receptores Nicotínicos/metabolismo , Esquizofrenia/tratamento farmacológico , Lobo Temporal/efeitos dos fármacos , Adulto Jovem
11.
Pharmacol Biochem Behav ; 184: 172741, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31336109

RESUMO

RATIONALE: Cannabidiol (CBD), a compound found in many strains of the Cannabis genus, is increasingly available in e-cigarette liquids as well as other products. CBD use has been promoted for numerous purported benefits which have not been rigorously assessed in preclinical studies. OBJECTIVE: To further validate an inhalation model to assess CBD effects in the rat. The primary goal was to determine plasma CBD levels after vapor inhalation and compare that with the levels observed after injection. Secondary goals were to determine if hypothermia is produced in male Sprague-Dawley rats and if CBD affects nociception measured by the warm water tail-withdrawal assay. METHODS: Blood samples were collected from rats exposed for 30 min to vapor generated by an e-cigarette device using CBD (100, 400 mg/mL in the propylene glycol vehicle). Separate experiments assessed the body temperature response to CBD in combination with nicotine (30 mg/mL) and the anti-nociceptive response to CBD. RESULTS: Vapor inhalation of CBD produced concentration-related plasma CBD levels in male and female Wistar rats that were within the range of levels produced by 10 or 30 mg/kg, CBD, i.p. Dose-related hypothermia was produced by CBD in male Sprague-Dawley rats, and nicotine (30 mg/mL) inhalation enhanced this effect. CBD inhalation had no effect on anti-nociception alone or in combination with Δ9-tetrahydrocannabinol inhalation. CONCLUSIONS: The vapor-inhalation approach is a suitable pre-clinical model for the investigation of the effects of inhaled CBD. This route of administration produces hypothermia in rats, while i.p. injection does not, at comparable plasma CBD levels.


Assuntos
Canabidiol/administração & dosagem , Canabidiol/farmacologia , Vapor do Cigarro Eletrônico/farmacologia , Extratos Vegetais/administração & dosagem , Extratos Vegetais/farmacologia , Administração por Inalação , Animais , Temperatura Corporal/efeitos dos fármacos , Canabidiol/sangue , Cannabis/química , Estudos de Coortes , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/farmacologia , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Hipotermia/induzido quimicamente , Masculino , Modelos Animais , Nicotina/administração & dosagem , Nicotina/farmacologia , Nociceptividade/efeitos dos fármacos , Extratos Vegetais/sangue , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Receptor 5-HT1A de Serotonina/metabolismo
12.
Psychopharmacology (Berl) ; 236(11): 3209-3219, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31187152

RESUMO

RATIONALE: The catechol-O-methyl transferase (COMT) enzyme has been implicated in determining dopaminergic tone and the effects of delta-9-tetrahydrocannabinol (THC) in the human brain. OBJECTIVE: This study was designed to evaluate the effect of (1) a functional polymorphism and (2) acute pharmacological inhibition of COMT on the acute response to THC in humans. METHODS: Sub-study I: The effect of intravenous (IV) THC (0.05 mg/kg) was investigated in 74 healthy subjects genotyped for the COMT rs4680 (Val/Met) polymorphism in a 2-test-day double-blind, randomized, placebo-controlled study. Sub-study II: COMT rs4680 homozygous subjects (Val/Val and Met/Met) from sub-study I received the COMT enzyme inhibitor tolcapone (200 mg) followed by IV THC or placebo on two additional test days. Subjective, behavioral, and cognitive data were obtained periodically on each test day. RESULTS: Sub-study I: Val/Val individuals were most sensitive to THC-induced attention and working memory deficits. In contrast, the psychotomimetic and subjective effects of THC were not influenced by COMT genotype. Sub-study II: Tolcapone reduced THC-induced working memory deficits, but not THC's psychotomimetic effects. Tolcapone and COMT genotype (met/met) were associated with an increased report of feeling "mellow." CONCLUSIONS: The interaction between COMT rs4680 polymorphisms and tolcapone on the cognitive, but not on the psychotomimetic and overall subjective effects of THC, suggests that modulation of dopaminergic signaling may selectively influence specific cannabinoid effects in healthy individuals. The role of dopaminergic signaling in the cognitive effects of cannabinoids should be considered in drug development efforts targeting these effects. CLINICALTRIALS.GOV REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00678730?term=NCT00678730&rank=1 ClinicalTrials.gov Identifier: NCT00678730.


Assuntos
Encéfalo/metabolismo , Inibidores de Catecol O-Metiltransferase/administração & dosagem , Catecol O-Metiltransferase/genética , Dopamina/metabolismo , Dronabinol/administração & dosagem , Variação Genética/genética , Administração Intravenosa , Adolescente , Adulto , Atenção/efeitos dos fármacos , Atenção/fisiologia , Encéfalo/efeitos dos fármacos , Agonistas de Receptores de Canabinoides/administração & dosagem , Método Duplo-Cego , Feminino , Humanos , Masculino , Memória de Curto Prazo/efeitos dos fármacos , Memória de Curto Prazo/fisiologia , Polimorfismo Genético/genética , Adulto Jovem
13.
Psychopharmacology (Berl) ; 236(9): 2713-2724, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31044290

RESUMO

BACKGROUND: The main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), can impair driving performance. Cannabidiol (CBD), a non-intoxicating cannabis component, is thought to mitigate certain adverse effects of THC. It is possible then that cannabis containing equivalent CBD and THC will differentially affect driving and cognition relative to THC-dominant cannabis. AIMS: The present study investigated and compared the effects of THC-dominant and THC/CBD equivalent cannabis on simulated driving and cognitive performance. METHODS: In a randomized, double-blind, within-subjects crossover design, healthy volunteers (n = 14) with a history of light cannabis use attended three outpatient experimental test sessions in which simulated driving and cognitive performance were assessed at two timepoints (20-60 min and 200-240 min) following vaporization of 125 mg THC-dominant (11% THC; < 1% CBD), THC/CBD equivalent (11% THC, 11% CBD), or placebo (< 1% THC/CBD) cannabis. RESULTS/OUTCOMES: Both active cannabis types increased lane weaving during a car-following task but had little effect on other driving performance measures. Active cannabis types impaired performance on the Digit Symbol Substitution Task (DSST), Divided Attention Task (DAT) and Paced Auditory Serial Addition Task (PASAT) with impairment on the latter two tasks worse with THC/CBD equivalent cannabis. Subjective drug effects (e.g., "stoned") and confidence in driving ability did not vary with CBD content. Peak plasma THC concentrations were higher following THC/CBD equivalent cannabis relative to THC-dominant cannabis, suggesting a possible pharmacokinetic interaction. CONCLUSIONS/INTERPRETATION: Cannabis containing equivalent concentrations of CBD and THC appears no less impairing than THC-dominant cannabis, and in some circumstances, CBD may actually exacerbate THC-induced impairment.


Assuntos
Condução de Veículo , Canabidiol/efeitos adversos , Cognição/efeitos dos fármacos , Dronabinol/efeitos adversos , Fumar Maconha/efeitos adversos , Vaping/efeitos adversos , Adulto , Condução de Veículo/psicologia , Canabidiol/administração & dosagem , Cognição/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Dronabinol/administração & dosagem , Feminino , Alucinógenos/administração & dosagem , Alucinógenos/efeitos adversos , Humanos , Masculino , Fumar Maconha/psicologia , Psicotrópicos/efeitos adversos , Vaping/psicologia , Adulto Jovem
14.
Psychopharmacology (Berl) ; 236(9): 2773-2784, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31044291

RESUMO

RATIONALE: Cannabis use is common among adolescents and some research suggests that adolescent cannabis use increases the risk for depression, anxiety, and cognitive impairments in adulthood. In human studies, however, confounds may affect the association between cannabis use and the development of brain disorders. OBJECTIVES: These experiments investigated the effects of adolescent exposure to either cannabis smoke or THC on anxiety- and depressive-like behavior and cognitive performance in adulthood in Long-Evans rats. METHODS: Adolescent rats of both sexes were exposed to either cannabis smoke from postnatal days (P) 29-49 or ascending doses of THC from P35-45. When the rats reached adulthood (P70), anxiety-like behavior was investigated in the large open field and elevated plus maze, depressive-like behavior in the sucrose preference and forced swim tests, and cognitive function in the novel object recognition test. RESULTS: Despite sex differences on some measures in the open field, elevated plus maze, forced swim, and novel object recognition tests, there were no effects of either adolescent cannabis smoke or THC exposure, and only relatively subtle interactions between exposure conditions and sex, such that sex differences on some performance measures were slightly attenuated. CONCLUSION: Neither cannabis smoke nor THC exposure during adolescence produced robust alterations in adult behavior after a period of abstinence, suggesting that adverse effects associated with adolescent cannabis use might be due to non-cannabinoid concomitants of cannabis use.


Assuntos
Cognição/efeitos dos fármacos , Dronabinol/efeitos adversos , Emoções/efeitos dos fármacos , Fumar Maconha/efeitos adversos , Fumar Maconha/psicologia , Fatores Etários , Animais , Cannabis/efeitos adversos , Cognição/fisiologia , Dronabinol/administração & dosagem , Emoções/fisiologia , Feminino , Exposição por Inalação/efeitos adversos , Masculino , Ratos , Ratos Long-Evans , Caracteres Sexuais
15.
Eur J Drug Metab Pharmacokinet ; 44(5): 691-711, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31114948

RESUMO

BACKGROUND AND OBJECTIVES: Lack of information on the pharmacokinetics of the active moiety of Cannabis or the metabolites of delta-9-tetrahydrocannabinol (THC) does not seem to be discouraging medical or recreational use. Cytochrome P450 (CYP) 2C9, the primary enzyme responsible for THC metabolism, has two single nucleotide polymorphisms-Arg144Cys (*2) and Ile359Leu (*3). In the Caucasian population, allelic frequency is between 0.08 and 0.14 for CYP2C9*2 and between 0.04 and 0.16 for CYP2C9*3. In vitro data suggest that metabolic capacity for the variants CYP2C9*2 and CYP2C9*3 is about one-third compared to wild-type CYP2C9. Previous work has suggested exposure to the terminal metabolite is genetically determined. We therefore sought to characterize the pharmacokinetics of THC and its major metabolites 11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) in healthy volunteers with known CYP2C9 status by non-compartmental analysis (NCA), compartmental modeling (CM) and minimal physiologically based pharmacokinetic (mPBPK) modeling. METHODS: Blood samples drawn for THC, THC-OH and THC-COOH after a single intravenous (IV) bolus of 0.1 mg/kg (0.32 µM/kg) THC were analyzed using a validated LC-MS/MS method. NCA generated initial estimates and CM and the mPBPK model were then fit to plasma concentration data using non-linear mixed-effects modeling. Blood samples from orally dosed (10, 25 and 50 mg) THC brownies were added to validate the model. RESULTS: THC can be described as a high hepatic extraction ratio drug with blood flow-dependent metabolism not restricted by protein binding. THC hepatic clearance is dependent on the CYP2C9 genetic variant in the population. High extraction drugs display route-dependent metabolism. When administered via the IV or inhalation routes, induction or inhibition of CYP2C9 should be non-contributory as the elimination of THC is dependent only on liver blood flow. THC-OH is also a high extraction ratio drug, but its hepatic clearance is significantly impacted by the hepatic diffusional barrier that impedes its access to hepatic CYP2C9. THC-COOH is glucuronidated and renally cleared; subjects homozygous for CYP2C9*3 have reduced exposure to this metabolite as a result of the polymorphism reducing THC production, the hepatic diffusional barrier impeding egress from the hepatocyte, and increased renal clearance. CONCLUSION: It has recently been reported that the terminal metabolite THC-COOH is active, implying the exposure difference in individuals homozygous for CYP2C9*3 may become therapeutically relevant. Defining the metabolism of THC in humans is important, as it is increasingly being used as a drug to treat various diseases and its recreational use is also rising. We have used NCA, CM, and mPBPK modeling of THC and its metabolites to partially disentangle the complexity of cannabis disposition in humans.


Assuntos
Dronabinol/administração & dosagem , Dronabinol/farmacocinética , Administração Intravenosa , Administração Oral , Adulto , Citocromo P-450 CYP2C9 , Dronabinol/análogos & derivados , Feminino , Frequência do Gene/genética , Voluntários Saudáveis , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Masculino , Adulto Jovem
16.
Exp Clin Psychopharmacol ; 27(4): 326-337, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30932503

RESUMO

Cannabis is the most popular, illegal drug used by adolescents in the United States. Exposure to cannabis and its main psychoactive ingredient, Δ9-tetrahydrocannabinol (THC), during adolescence may have long-lasting effects on the development of behavioral and neurobiological processes. This study investigated the effects of chronic adolescent exposure to THC on sensitization to the psychomotor-stimulating effects of cocaine and on the reinforcing effects of cocaine in adult male Sprague-Dawley rats. During adolescence (P28-P45), rats were given once-daily intraperitoneal injections of either vehicle or 1 mg/kg THC. On P90, the acute locomotor-stimulating effects of cocaine and sensitization to cocaine were evaluated. Also, cocaine-maintained behavior was evaluated by determining within-session cocaine dose-effect curves, acquisition of behavior maintained by a small cocaine dose (0.1 mg/kg/infusion), and breakpoints on a progressive ratio schedule of reinforcement. In general, there was no effect of adolescent THC exposure on the locomotor-stimulating effects of cocaine following acute or repeated administration. However, the reinforcing effects of cocaine were potentiated in rats treated with THC during adolescence, but this effect was only observed with small doses of cocaine. Rats exposed to THC during adolescence also more rapidly acquired self-administration behavior when a small cocaine dose was available. Together, these results demonstrate that exposure to THC during adolescence may enhance sensitivity to cocaine and/or enhance the reinforcing effects of cocaine even into adulthood under certain conditions. In conclusion, frequent exposure to THC during adolescence may produce long-lasting changes in behavior, possibly increasing susceptibility to addiction. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


Assuntos
Comportamento Animal/efeitos dos fármacos , Cocaína/farmacologia , Dronabinol/farmacologia , Animais , Cocaína/administração & dosagem , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Masculino , Ratos , Ratos Sprague-Dawley , Reforço Psicológico , Autoadministração
17.
Drug Alcohol Depend ; 199: 106-115, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029878

RESUMO

BACKGROUND: With increasing access to legal cannabis across the globe, it is imperative to more closely study its behavioral and physiological effects. Furthermore, with the proliferation of cannabis use, modes of consumption are changing, with edible formulations becoming increasingly popular. Nevertheless, there are relatively few animal models of self-administration of the primary psychoactive component of cannabis, Δ9-tetrahydrocannabinol (THC), and almost all incorporate routes of administration other than those used by humans. The aim of the current study was to develop a model of edible THC self-administration and assess its impact on CB1 receptor-mediated behaviors in female and male mice. METHODS: Mice were given limited access to a palatable dough which occasionally contained THC in doses ranging from 1 to 10 mg/kg. Following dough consumption, mice were assessed for home cage locomotor activity, body temperature, or analgesia. Locomotor activity was also assessed in conjunction with the CB1 receptor antagonist SR141716A. RESULTS: Dough was well-consumed, but consumption decreased at the highest THC concentrations. Edible THC produced dose-dependent decreases in locomotor activity and body temperature in both sexes, and these effects were more pronounced in male mice. Hypolocomotion induced by edible THC was attenuated by SR141716A, indicating mediation by CB1 receptor activation. CONCLUSIONS: In contrast to other cannabinoid self-administration models, edible THC is relatively low in stress and uses a route of administration analogous to one used by humans. Potential applications include chronic THC self-administration, determining THC reward/reinforcement, and investigating consequences of oral THC use.


Assuntos
Temperatura Corporal/efeitos dos fármacos , Dronabinol/administração & dosagem , Atividade Motora/efeitos dos fármacos , Psicotrópicos/administração & dosagem , Recompensa , Animais , Temperatura Corporal/fisiologia , Canabinoides/administração & dosagem , Relação Dose-Resposta a Droga , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/fisiologia , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/fisiologia , Autoadministração
18.
Am J Clin Nutr ; 109(4): 1051-1063, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30949710

RESUMO

BACKGROUND: The endocannabinoid system (ECS) is considered a key player in the neurophysiology of food reward. Animal studies suggest that the ECS stimulates the sensory perception of food, thereby increasing its incentive-motivational and/or hedonic properties and driving consumption, possibly via interactions with metabolic hormones. However, it remains unclear to what extent this can be extrapolated to humans. OBJECTIVE: We aimed to investigate the effect of oral Δ9-tetrahydrocannabinol (THC) on subjective and metabolic hormone responses to visual food stimuli and food intake. METHODS: Seventeen healthy subjects participated in a single-blinded, placebo-controlled, 2 × 2 crossover trial. In each of the 4 visits, subjective "liking" and "wanting" ratings of high- and low-calorie food images were acquired after oral THC or placebo administration. The effect on food intake was quantified in 2 ways: via ad libitum oral intake (half of the visits) and intragastric infusion (other half) of chocolate milkshake. Appetite-related sensations and metabolic hormones were measured at set time points throughout each visit. RESULTS: THC increased "liking" (P = 0.031) and "wanting" ratings (P = 0.0096) of the high-calorie, but not the low-calorie images, compared with placebo. Participants consumed significantly more milkshake after THC than after placebo during oral intake (P = 0.0005), but not intragastric infusion, of milkshake. Prospective food consumption ratings during the food image paradigm were higher after THC than after placebo (P = 0.0039). THC also increased plasma motilin (P = 0.0021) and decreased octanoylated ghrelin (P = 0.023) concentrations before milkshake consumption (i.e., in both oral intake and intragastric infusion test sessions), whereas glucagon-like peptide 1 responses to milkshake intake were attenuated by THC during both oral (P = 0.0002) and intragastric (P = 0.0055) administration. CONCLUSIONS: These findings suggest that the ECS drives food intake by interfering with anticipatory, cephalic phase, and metabolic hormone responses. This trial was registered at clinicaltrials.gov as NCT02310347.


Assuntos
Dronabinol/administração & dosagem , Ingestão de Alimentos/efeitos dos fármacos , Hormônios Gastrointestinais/sangue , Grelina/sangue , Adulto , Apetite/efeitos dos fármacos , Feminino , Peptídeo 1 Semelhante ao Glucagon/sangue , Voluntários Saudáveis , Humanos , Masculino , Motilina/sangue , Adulto Jovem
19.
Neuropsychopharmacology ; 44(8): 1406-1414, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30965351

RESUMO

Few preclinical approaches are available to study the health impact of voluntary consumption of edibles containing the psychoactive drug Δ9-tetrahydrocannabinol (THC). We developed and validated such approach by measuring voluntary oral consumption of THC-containing gelatin by rats and used it to study if and how THC consumption during adolescence impacts adult behavior. We found that adolescent rats of both sexes consumed enough THC to trigger acute hypothermia, analgesic, and locomotor responses, and that 15 days of access to THC-gelatin in adolescence resulted in the down-regulation of cannabinoid 1 receptors (CB1Rs) in adulthood in a sex and brain area specific manner. Remarkably, THC consumption by adolescent male rats and not female rats led to impaired Pavlovian reward-predictive cue behaviors in adulthood consistent with a male-specific loss of CB1R-expressing vGlut-1 synaptic terminals in the ventral tegmental area (VTA). Thus, voluntary oral consumption of THC during adolescence is associated with sex-dependent behavioral impairment in adulthood.


Assuntos
Dronabinol/farmacologia , Receptor CB1 de Canabinoide/biossíntese , Recompensa , Administração Oral , Adolescente , Fatores Etários , Animais , Condicionamento Clássico/efeitos dos fármacos , Sinais (Psicologia) , Regulação para Baixo/efeitos dos fármacos , Dronabinol/administração & dosagem , Feminino , Humanos , Masculino , Ratos , Fatores Sexuais , Tegmento Mesencefálico/metabolismo
20.
Psychopharmacology (Berl) ; 236(9): 2635-2640, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30919005

RESUMO

RATIONALE: Δ-9-Tetrahydrocannabinol (Δ-9-THC) produces psychotomimetic effects in humans. However, the role of dopamine signaling in producing such effects is unclear. We hypothesized that dopaminergic antagonism would reduce the psychotomimetic effect of Δ-9-THC. OBJECTIVE: The objective of this study was to evaluate whether pre-treatment with haloperidol would alter the psychotomimetic and perceptual-altering effects of Δ-9-THC, measured by the Positive and Negative Syndrome Scale for Schizophrenia (PANSS) and the Clinician-Administered Dissociative Symptom Scale (CADSS) in humans. METHODS: In a two-test-day double-blind study, 28 healthy individuals were administered with active (0.057 mg/kg) or placebo oral haloperidol, followed 90 and 215 min later by intravenous administration of active (0.0286 mg/kg) Δ-9-THC and placebo, respectively. This secondary analysis was conducted because of the observation in other studies and in our data that a significant proportion of individuals may not have an adequate response to THC (floor effect), thus limiting the ability to test an interaction. Therefore, this analysis was performed including only responders to THC (n = 10), defined as individuals who had an increase of at least one point on the PANSS positive scale, consistent with prior human laboratory studies. RESULTS: In the 10 responders, Δ-9-THC-induced increases in PANSS positive scores were significantly lower in the haloperidol condition (1.1 + 0.35) compared with the placebo condition (2.9 + 0.92). CONCLUSION: This responder analysis showed that haloperidol did reduce the psychotomimetic effect of Δ-9-THC, supporting the hypothesis that dopaminergic signaling may participate in the psychosis-like effects of cannabinoids.


Assuntos
Antipsicóticos/administração & dosagem , Antagonistas de Dopamina/administração & dosagem , Dronabinol/administração & dosagem , Haloperidol/administração & dosagem , Psicotrópicos/administração & dosagem , Administração Intravenosa , Administração Oral , Adolescente , Adulto , Método Duplo-Cego , Feminino , Humanos , Masculino , Percepção/efeitos dos fármacos , Percepção/fisiologia , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/psicologia , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA