Oral pre- and early postnatal cannabis exposure disinhibits ventral tegmental area dopamine neuron activity but does not influence cocaine preference in offspring in mice.

Cannabis consumption has increased from 1.5% to 2.5% in Canada between 2012 and 2019. Clinical studies have indicated effects of prenatal cannabis exposure on birth weight, substance use, and neurodevelopmental disorders, but are confounded by several difficult to control variables. Animal models allow for examination of the mechanism of cannabis-induced changes in neurodevelopment and behavior, while controlling dose and timing. Several animal models of prenatal cannabis exposure exist which provide varying levels of construct validity, control of dose, and exposure to maternal stress. Using a voluntary oral consumption model, mouse dams received 5 mg/kg Δ9-tetrahydrocannabinol (THC) whole cannabis oil in peanut butter daily from gestational day 1 (GD1) to postnatal day 10 (PD10). At GD1, GD18, PD1, PD10, and PD15, maternal plasma was collected; pup brains were collected from GD18 onward. Pup brains had higher levels of THC and cannabidiol at each time point, each of which persisted in maternal plasma and pup brains past the end of treatment (PD15). Male and female adolescent offspring were examined for changes to ventral tegmental area (VTA) dopamine neuron activity and cocaine-seeking behavior. Prenatal and early postnatal (GD1-PD10) cannabis-exposed male, but not female mice had decreased gamma-aminobutyric acid (GABAergic) input, depolarized resting membrane potential, and increased spontaneous firing of VTA dopamine neurons. Cannabis-exposed offspring showed faster decay of N-methyl-D-aspartate (NMDA) currents in both sexes. However, no differences in cocaine-seeking behavior were noted. These data characterize a voluntary prenatal cannabis exposure model and demonstrates VTA dopamine neuronal activity is disinhibited in offspring.

Prenatal tetrahydrocannabinol and cannabidiol exposure produce sex-specific pathophysiological phenotypes in the adolescent prefrontal cortex and hippocampus.

Clinical and preclinical evidence has demonstrated an increased risk for neuropsychiatric disorders following prenatal cannabinoid exposure. However, given the phytochemical complexity of cannabis, there is a need to understand how specific components of cannabis may contribute to these neurodevelopmental risks later in life. To investigate this, a rat model of prenatal cannabinoid exposure was utilized to examine the impacts of specific cannabis constituents (Δ9-tetrahydrocannabinol [THC]; cannabidiol [CBD]) alone and in combination on future neuropsychiatric liability in male and female offspring. Prenatal THC and CBD exposure were associated with low birth weight. At adolescence, offspring displayed sex-specific behavioural changes in anxiety, temporal order and social cognition, and sensorimotor gating. These phenotypes were associated with sex and treatment-specific neuronal and gene transcriptional alterations in the prefrontal cortex, and ventral hippocampus, regions where the endocannabinoid system is implicated in affective and cognitive development. Electrophysiology and RT-qPCR analysis in these regions implicated dysregulation of the endocannabinoid system and balance of excitatory and inhibitory signalling in the developmental consequences of prenatal cannabinoids. These findings reveal critical insights into how specific cannabinoids can differentially impact the developing fetal brains of males and females to enhance subsequent neuropsychiatric risk.

Investigation of the intrinsic cannabinoid activity of hemp-derived and semisynthetic cannabinoids with ß-arrestin2 recruitment assays-and how this matters for the harm potential of seized drugs.

Cultivation of industrial low-Δ9-tetrahydrocannabinol (Δ9-THC) hemp has created an oversupply of cannabidiol (CBD)-rich products. The fact that phytocannabinoids, including CBD, can be used as precursors to synthetically produce a range of THC variants-potentially located in a legal loophole-has led to a diversification of cannabis recreational drug markets. 'Hemp-compliant', 'hemp-derived' and 'semisynthetic' cannabinoid products are emerging and being advertised as (legal) alternatives for Δ9-THC. This study included a large panel (n = 30) of THC isomers, homologs, and analogs that might be derived via semisynthetic procedures. As a proxy for the abuse potential of these compounds, we assessed their potential to activate the CB1 cannabinoid receptor with a ß-arrestin2 recruitment bioassay (picomolar-micromolar concentrations). Multiple THC homologs (tetrahydrocannabihexol, THCH; tetrahydrocannabiphorol, THCP; tetrahydrocannabinol-C8, THC-C8) and THC analogs (hexahydrocannabinol, HHC; hexahydrocannabiphorol, HHCP) were identified that showed higher potential for CB1 activation than Δ9-THC, based on either higher efficacy (Emax) or higher potency (EC50). Structure-activity relationships were assessed for Δ9-THC and Δ8-THC homologs encompassing elongated alkyl chains. Additionally, stereoisomer-specific differences in CB1 activity were established for various THC isomers (Δ7-THC, Δ10-THC) and analogs (HHC, HHCP). Evaluation of the relative abundance of 9(S)-HHC and 9(R)-HHC epimers in seized drug material revealed varying epimeric compositions between batches. Increased abundance of the less active 9(S)-HHC epimer empirically resulted in decreased potency, but sustained efficacy for the resulting diastereomeric mixture. In conclusion, monitoring of semisynthetic cannabinoids is encouraged as the dosing and the relative composition of stereoisomers can impact the harm potential of these drugs, relative to Δ9-THC products.

Persisting neurobehavioral consequences of daily or intermittent paternal cannabis administration in F1 and F2 Rats.

Repeated paternal preconception exposure to Δ9-tetrahydrocannabinol (Δ9-THC) alone or together with the other constituents in a cannabis extract has been shown in our earlier studies in rats to cause significant neurobehavioral impairment in their offspring. In the current study, we compared the effects of daily cannabis extract (CE) exposure to cannabis on two consecutive days per week, modeling weekend cannabis use in human. The CE contained Δ9-THC as well as cannabidiol and cannabinol. We also extended the investigation of the study to cross-generational effects of grand-paternal cannabis exposure on the F2 generation and included testing the effects of paternal cannabis exposure on responding for opiate self-administration in F1 and F2 generation offspring. We replicated the findings of neurobehavioral impairment in F1 offspring of male rats exposed to cannabis extract containing 4 mg/kg/day of Δ9-THC daily for four weeks prior to mating with drug naïve females. The 4-week cannabis extract exposure caused a significant decrease in weight gain in the male rats exposed daily. In contrast, their offspring showed significantly greater body weights and anogenital distances (AGD) in the third to fourth weeks after birth. The behavioral effects seen in the F1 generation were increased habituation of locomotor activity in the figure-8 maze in female offspring and increased lever pressing for the opiate drug remifentanil in male offspring. The F2 generation showed significantly impaired negative geotaxis and an elimination of the typical sex-difference in locomotor activity, with effects not seen in the F1 generation. This study shows that daily paternal cannabis exposure for four weeks prior to mating causes significant neurobehavioral impairment in the F1 and F2 offspring. Intermittent exposure on two consecutive days per week for four weeks caused comparable neurobehavioral impairment. In sum, there should be concern about paternal as well as maternal exposure to cannabis concerning neurobehavioral development of their offspring.

Clinical examination findings and electrolyte abnormalities of dogs with marijuana/tetrahydrocannabinol toxicity: 223 cases (January 2017-July 2021).

OBJECTIVE: The goal of this study was to describe the historical, physical, neurologic, and clinicopathologic findings in dogs with a definitive diagnosis of marijuana/tetrahydrocannabinol toxicity. ANIMALS: A total of 223 dogs with known ingestion of marijuana or a positive tetrahydrocannabinol result on human urine multidrug test. METHODS: Retrospective study from January 2017 to July 2021. RESULTS: Median age was 1 year (1 month to 12 years). A common history was becoming acutely neurologic after going outside or to a public place (62/223 [27.8%]). Most owners denied possibility of exposure (152/223 [68%]). Median vitals were normal, but hyperthermia (38/212 [22.6%]), tachycardia (82/222 [37%]), and systemic hypertension (37/61 [60.7%]) were common abnormalities. The most common clinical signs included ataxia (197/223 [88.3%]), hyperesthesia (168/223 [75.3%]), urinary incontinence (102/223 [45.7%]), lethargy (140/223 [62.5%]), and vomiting (58/223 [26%]). The most common combinations of neurologic signs included ataxia and hyperesthesia (157/223 [70.4%]) and ataxia, hyperesthesia, and urinary incontinence (81/223 [36.3%]). Mild hyperkalemia (39/76 [51.3%]) and mild hypercalcemia (53/67 [79.1%]) were common. Twenty-two dogs were hospitalized. Survival was 100%. CLINICAL RELEVANCE: A common presentation for marijuana toxicosis included young dogs with acute ataxia and hyperesthesia, with and without urinary incontinence, after going outside or to a public place. Vitals were often normal, but hyperthermia, tachycardia, and hypertension were common. Bloodwork was mostly normal, but mild hyperkalemia and mild ionized hypercalcemia were common. Marijuana should be high on the differential list with these history, physical examination, neurologic, and electrolyte abnormalities, regardless of owner denial or negative human urine multidrug test.

Cytogenotoxicity and inflammatory response in liver of rats exposed to different doses of cannabis nano emulsions.

Cannabis is the most used illicit substance for recreational purposes around the world. However, it has become increasingly common to witness the use of approved cannabis preparations for symptoms management in various diseases. The aim of this study was to investigate the effects of cannabis nano emulsion in the liver of Wistar rats, with different proportions of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD). For this, a total of 40 male Wistar rats were distributed into 5 groups, as follows (n = 8 per group): Control: G1, Experimental group (G2): treated with cannabis nano emulsion (THC and CBD) at a dose of 2.5 mg/kg, Experimental group (G3): treated with cannabis nano emulsion (THC and CBD) at a dose of 5 mg/kg, Experimental group (G4): treated with cannabis nano emulsion (CBD) at a dose of 2.5 mg/kg; Experimental group (G5): treated with cannabis nano emulsion (CBD) at a dose of 5 mg/kg. Exposure to the nano emulsion was carried out for 21 days, once a day, orally (gavage). Our results showed that cannabis nano emulsions at higher doses (5 mg/kg), regardless of the composition, induced histopathologic changes in the liver (G3 and G5) in comparison with the control group. In line with that, placental glutathione S-transferase (GST-P) positive foci increased in both G3 and G5 (p < 0.05), as well as the immune expression of Ki-67, vascular endothelial growth factor (VEGF) and p53 (p < 0.05). Also, the nano emulsion intake induced an increase in the number of micronucleated hepatocytes in G5 (p < 0.05) whereas G3 showed an increase in binucleated cells (p < 0.05). As for metanuclear alterations, karyolysis and pyknosis had an increased frequency in G3 (p < 0.05). Taken together, the results show that intake of cannabis nano emulsion may induce degenerative changes and genotoxicity in the liver in higher doses, demonstrating a clear dose-response relationship.

Revisão: funcionamento executivo e uso de maconha / Review: executive functioning and cannabis use

OBJETIVO: A maconha é a droga ilícita mais consumida no mundo, porém ainda existem poucos estudos examinando eventuais prejuízos cognitivos relacionados ao seu uso. As manifestações clínicas associadas a esses déficits incluem síndrome amotivacional, prejuízo na flexibilidade cognitiva, desatenção, dificuldade de raciocínio abstrato e formação de conceitos, aspectos intimamente ligados às funções executivas, as quais potencialmente exercem um papel central na dependência de substâncias. O objetivo do estudo foi fazer uma revisão a respeito das implicações do uso da maconha no funcionamento executivo. MÉTODO: Esta revisão foi conduzida utilizando-se bases de dados eletrônicas (MedLine, Pubmed, SciELO and Lilacs). DISCUSSÃO: Em estudos de efeito agudo, doses maiores de tetrahidrocanabinol encontram-se associadas a maior prejuízo no desempenho de usuários leves em tarefas de controle inibitório e planejamento; porém, este efeito dose-resposta não ocorre em usuários crônicos. Embora haja controvérsias no que se refere a efeitos residuais da maconha, déficits persistentes parecem estar presentes após 28 dias de abstinência, ao menos em um subgrupo de usuários crônicos. CONCLUSÕES: Os estudos encontrados não tiveram como objetivo principal a avaliação das funções executivas. A seleção de testes padronizados, desenhos de estudos mais apropriados e o uso concomitante com técnicas de neuroimagem estrutural e funcional podem auxiliar na melhor compreensão das conseqüências deletérias do uso crônico da maconha no funcionamento executivo.

OBJECTIVE: Cannabis is the most used illicit drug worldwide, however only a few studies have examined cognitive deficits related to its use. Clinical manifestations associated with those deficits include amotivational syndrome, impairment in cognitive flexibility, inattention, deficits in abstract reasoning and concept formation, aspects intimately related to the executive functions, which potentially exert a central role in substance dependence. The objective was to make a review about consequences of cannabis use in executive functioning. METHOD: This review was carried out on reports drawn from MedLine, SciELO, and Lilacs. DISCUSSION: In studies investigating acute use effects, higher doses of tetrahydrocannabinol are associated to impairments in performance of nonsevere users in planning and control impulse tasks. However, chronic cannabis users do not show those impairments. Although demonstration of residual effects of cannabis in the executive functioning is controversial, persistent deficits seem to be present at least in a subgroup of chronic users after 28 days of abstinence. CONCLUSIONS: The neuropsychological studies found did not have as a main aim the evaluation of executive functioning. A criterial selection of standardized neuropsychological tests, more appropriate study designs as well as concomitant investigations with structural and functional neuroimaging techniques may improve the understanding of eventual neurotoxicity associated with cannabis use.

Caracteristicas botanicas, quimicas e produtos obtidos da Cannabis / Botanical and chemical characteristics and products obtained from cannabis

A Cannabis (maconha) tem sido utilizada como droga de abuso por varias decadas, ocupando o primeiro lugar entre as drogas ilicitas usadas atualmente em todo o mundo. Sendo seu uso proibido entre nos, e de importancia forense a identificacao do usuario atraves da analise toxicologica do componente principal responsavel pela psicoatividade da droga (THC) bem como de seu principal produto de biotransformacao (THC-COOH) em amostras biologicas. Com a finalidade de fornecer informacoes a respeito dos aspectos botanicos, quimicos, farmacologicos, toxicologicos bem como da legislacao vigente de aspecto legal preparou-se esta monografia