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1.
ACS Chem Neurosci ; 13(8): 1281-1295, 2022 04 20.
Artículo en Inglés | MEDLINE | ID: mdl-35404067

RESUMEN

Synthetic cannabinoid receptor agonists (SCRAs) are a diverse class of new psychoactive substances (NPS). They commonly comprise N-alkylated indole, indazole, or 7-azaindole scaffolds with amide-linked pendant amino acid groups. To explore the contribution of the amino acid side chain to the cannabinoid pharmacology of SCRA NPS, a systematic library of side chain-modified SCRAs was prepared based on the recent detections of amino acid derivatives 17 (5F-AB-PINACA), 18 (5F-ADB-PINACA), 15 (PX-1), 19 (PX-2), and 20 (NNL-1). In vitro binding affinities and functional activities at cannabinoid type 1 and 2 receptors (CB1 and CB2, respectively) were determined for all the library members using radioligand competition experiments and a fluorescence-based membrane potential assay. Binding affinities and functional activities varied widely across compounds (Ki = 0.32 to >10 000 nM, EC50 = 0.24-1259 nM), with several clear structure-activity relationships (SARs) emerging. Affinity and potency at CB1 changed as a function of the heterocyclic core (indazole > indole > 7-azaindole) and the pendant amino acid side chain (tert-butyl > iso-propyl > iso-butyl > benzyl > ethyl > methyl > hydrogen). Ensemble docking at CB1 revealed a clear steric basis for observed SAR trends. Interestingly, although 15 (PX-1) and 19 (PX-2) have been detected in recreational drug markets, they failed to induce centrally CB1-mediated effects (e.g., hypothermia) in mice using radiobiotelemetry. Together, these data provide insights regarding structural contributions to the cannabimimetic profiles of 17 (5F-AB-PINACA), 18 (5F-ADB-PINACA), 15 (PX-1), 19 (PX-2), 20 (NNL-1), and other SCRA NPS.


Asunto(s)
Agonistas de Receptores de Cannabinoides , Cannabinoides , Animales , Agonistas de Receptores de Cannabinoides/química , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/química , Fármacos del Sistema Nervioso Central , Indazoles/química , Indazoles/farmacología , Ratones , Receptor Cannabinoide CB1 , Receptor Cannabinoide CB2 , Receptores de Cannabinoides , Valina/análogos & derivados
2.
ACS Chem Neurosci ; 13(9): 1395-1409, 2022 05 04.
Artículo en Inglés | MEDLINE | ID: mdl-35442021

RESUMEN

Synthetic cannabinoid receptor agonists (SCRAs) are a large and growing class of new psychoactive substances (NPSs). Two recently identified compounds, MEPIRAPIM and 5F-BEPIRAPIM (NNL-2), have not been confirmed as agonists of either cannabinoid receptor subtype but share structural similarities with both SCRAs and a class of T-type calcium channel (CaV3) inhibitors under development as new treatments for epilepsy and pain. In this study, MEPIRAPIM and 5F-BEPIRAPIM and 10 systematic analogues were synthesized, analytically characterized, and pharmacologically evaluated using in vitro cannabinoid receptor and CaV3 assays. Several compounds showed micromolar affinities for CB1 and/or CB2, with several functioning as low potency agonists of CB1 and CB2 in a membrane potential assay. 5F-BEPIRAPIM and four other derivatives were identified as potential CaV3 inhibitors through a functional calcium flux assay (>70% inhibition), which was further confirmed using whole-cell patch-clamp electrophysiology. Additionally, MEPIRAPIM and 5F-BEPIRAPIM were evaluated in vivo using a cannabimimetic mouse model. Despite detections of MEPIRAPIM and 5F-BEPIRAPIM in the NPS market, only the highest MEPIRAPIM dose (30 mg/kg) elicited a mild hypothermic response in mice, with no hypothermia observed for 5F-BEPIRAPIM, suggesting minimal central CB1 receptor activity.


Asunto(s)
Canales de Calcio Tipo T , Cannabinoides , Hipotermia , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/química , Cannabinoides/farmacología , Indazoles/farmacología , Ratones , Receptor Cannabinoide CB1 , Receptor Cannabinoide CB2 , Receptores de Cannabinoides
3.
BMJ Open ; 12(4): e053715, 2022 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-35387810

RESUMEN

BACKGROUND: The Protective Behavioural Strategies for Marijuana (PBSM-17) scale serves to identify and measure strategies employed by young adults before, during or after cannabis use. After the adaptation and translation of the PBSM-17 into French, a methodological study was conducted to evaluate the psychometric properties of this French version (FV) and of the original English version (EV) in a sample of bilingual Canadian university students. METHODS: A total of 211 cannabis users (mean age=22.1 years) completed a sociodemographic questionnaire, a question on frequency of cannabis use (four categories: 1-3 times a month, once a week, more than once a week, everyday) and both versions (FV and EV) of the PBSM-17. RESULTS: Both versions had similar internal reliability (α=0.91; α=0.88). The one-factor solution explained 36.46% of the variance for the FV and 42.26% for the EV. As hypothesised, greater use of protective behavioural strategies was related to lower frequency of cannabis use. One-way ANOVA test results revealed a statistically significant difference in use of strategies by frequency of cannabis use for both the FV (F(3, 207)=27.38, p<0.001) and EV (F(3, 207)=29.32, p<0.001). Post hoc comparisons showed that everyday users employed fewer strategies on average than lower-frequency users. CONCLUSION: The FV and EV of the PBSM-17 demonstrated satisfactory psychometric properties. The proposed FV of the PBSM-17 is a reliable instrument that could be used for research and clinical purposes. Protective behavioural strategies can serve as indicator of lower-risk cannabis use and could be targeted in prevention interventions.


Asunto(s)
Cannabis , Adulto , Canadá , Agonistas de Receptores de Cannabinoides , Humanos , Psicometría , Reproducibilidad de los Resultados , Estudiantes , Encuestas y Cuestionarios , Universidades , Adulto Joven
4.
Cells ; 11(7)2022 03 28.
Artículo en Inglés | MEDLINE | ID: mdl-35406706

RESUMEN

The use of cannabis preparations has steadily increased. Although cannabis was traditionally assumed to only have mild vegetative side effects, it has become evident in recent years that severe cardiovascular complications can occur. Cannabis use has recently even been added to the risk factors for myocardial infarction. This review is dedicated to pathogenetic factors contributing to cannabis-related myocardial infarction. Tachycardia is highly important in this respect, and we provide evidence that activation of CB1 receptors in brain regions important for cardiovascular regulation and of presynaptic CB1 receptors on sympathetic and/or parasympathetic nerve fibers are involved. The prototypical factors for myocardial infarction, i.e., thrombus formation and coronary constriction, have also been considered, but there is little evidence that they play a decisive role. On the other hand, an increase in the formation of carboxyhemoglobin, impaired mitochondrial respiration, cardiotoxic reactions and tachyarrhythmias associated with the increased sympathetic tone are factors possibly intensifying myocardial infarction. A particularly important factor is that cannabis use is frequently accompanied by tobacco smoking. In conclusion, additional research is warranted to decipher the mechanisms involved, since cannabis use is being legalized increasingly and Δ9-tetrahydrocannabinol and its synthetic analogue nabilone are indicated for the treatment of various disease states.


Asunto(s)
Cannabinoides , Cannabis , Infarto del Miocardio , Adolescente , Analgésicos , Agonistas de Receptores de Cannabinoides , Cannabinoides/efectos adversos , Cannabis/efectos adversos , Corazón , Humanos , Infarto del Miocardio/inducido químicamente , Infarto del Miocardio/tratamiento farmacológico
5.
eNeuro ; 9(2)2022.
Artículo en Inglés | MEDLINE | ID: mdl-35361667

RESUMEN

Cannabinoid receptor 1 (CB1R) has strong effects on neurogenesis and axon pathfinding in the prenatal brain. Endocannabinoids that activate CB1R are abundant in the early postnatal brain and in mother's milk, but few studies have investigated their function in newborns. We examined postnatal CB1R expression in the major striatonigral circuit from striosomes of the striatum to the dopamine-containing neurons of the substantia nigra. CB1R enrichment was first detectable between postnatal day (P)5 and P7, and this timing coincided with the formation of "striosome-dendron bouquets," the elaborate anatomic structures by which striosomal neurons control dopaminergic cell activity through inhibitory synapses. In Cnr1-/- knock-out mice lacking CB1R expression, striosome-dendron bouquets were markedly disorganized by P11 and at adulthood, suggesting a postnatal pathfinding connectivity function for CB1R in connecting striosomal axons and dopaminergic neurons analogous to CB1R's prenatal function in other brain regions. Our finding that CB1R plays a major role in postnatal wiring of the striatonigral dopamine-control system, with lasting consequences at least in mice, points to a crucial need to determine whether lactating mothers' use of CB1R agonists (e.g., in marijuana) or antagonists (e.g., type 2 diabetes therapies) can disrupt brain development in nursing offspring.


Asunto(s)
Diabetes Mellitus Tipo 2 , Dopamina , Animales , Antracenos , Agonistas de Receptores de Cannabinoides/farmacología , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Femenino , Lactancia , Ratones , Receptor Cannabinoide CB1/genética , Receptores de Cannabinoides
6.
Cannabis Cannabinoid Res ; 7(2): 152-155, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35451859

RESUMEN

This meeting report describes the University of California's (UC) Cannabis Research Workshop on May 26-27, 2021, which was organized by the UC Office of the President (UCOP) in partnership with the University of California, Davis (UCD). The event was designed to explore ways to strengthen research collaborations within and between campuses, discuss federal and state regulations and scientific priorities, and provide updates on current or recent cannabis and cannabinoid research studies. Topical areas were highlighted in four breakout sessions, including: 1) agronomy and environmental impacts; 2) biomedicine and public health; 3) economics, law, public policy, and social science; and 4) administrative considerations for supporting university research on cannabis and cannabinoids.


Asunto(s)
Cannabinoides , Cannabis , Alucinógenos , Analgésicos , Agonistas de Receptores de Cannabinoides , Cannabinoides/uso terapéutico , Humanos
7.
Biomolecules ; 12(4)2022 03 24.
Artículo en Inglés | MEDLINE | ID: mdl-35454080

RESUMEN

Cancer is a complex family of diseases affecting millions of people worldwide. Gliomas are primary brain tumors that account for ~80% of all malignant brain tumors. Glioblastoma multiforme (GBM) is the most common, invasive, and lethal subtype of glioma. Therapy resistance and intra-GBM tumoral heterogeneity are promoted by subpopulations of glioma stem cells (GSCs). Cannabis sativa produces hundreds of secondary metabolites, such as flavonoids, terpenes, and phytocannabinoids. Around 160 phytocannabinoids have been identified in C. sativa. Cannabis is commonly used to treat various medical conditions, and it is used in the palliative care of cancer patients. The anti-cancer properties of cannabis compounds include cytotoxic, anti-proliferative, and anti-migratory activities on cancer cells and cancer stem cells. The endocannabinoids system is widely distributed in the body, and its dysregulation is associated with different diseases, including various types of cancer. Anti-cancer activities of phytocannabinoids are mediated in glioma cells, at least partially, by the endocannabinoid receptors, triggering various cellular signaling pathways, including the endoplasmic reticulum (ER) stress pathway. Specific combinations of multiple phytocannabinoids act synergistically against cancer cells and may trigger different anti-cancer signaling pathways. Yet, due to scarcity of clinical trials, there remains no solid basis for the anti-cancer therapeutic potential of cannabis compounds.


Asunto(s)
Antineoplásicos , Cannabinoides , Cannabis , Glioblastoma , Glioma , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Agonistas de Receptores de Cannabinoides/uso terapéutico , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Endocannabinoides/farmacología , Glioblastoma/tratamiento farmacológico , Glioma/tratamiento farmacológico , Humanos , Células Madre Neoplásicas
8.
Addict Biol ; 27(3): e13169, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35470553

RESUMEN

BACKGROUND AND AIMS: Social norms and legality surrounding the use of medical and recreational cannabis are changing rapidly. The prevalence of cannabis use in adolescence is increasing. The aim of this study was to assess any sex-based neurobiological effects of chronically inhaled, vaporised cannabis on adolescent female and male mice. METHODS: Female and male mice were exposed daily to vaporised cannabis (10.3% Δ-9-tetrahydrocannabinol [THC] and 0.05% cannabidiol [CBD]) or placebo from postnatal day 23 to day 51. Following cessation of treatment, mice were examined for changes in brain structure and function using noninvasive multimodal magnetic resonance imaging (MRI). Data from voxel-based morphometry, diffusion weighted imaging and rest state functional connectivity were registered to and analysed with a 3D mouse atlas with 139 brain areas. Following imaging, mice were tested for their preference for a novel object. RESULTS: The effects were sexually dimorphic with females showing a unique distribution and inverse correlation between measures of fractional anisotropy and apparent diffusion coefficient localised to the forebrain and hindbrain. In contrast males displayed significant increased functional coupling with the thalamus, hypothalamus and brainstem reticular activating system as compared with controls. Cannabis males also presented with altered hippocampal coupling and deficits in cognitive function. CONCLUSION: Chronic exposure to inhaled vaporised cannabis had significant effects on brain structure and function in early adulthood corroborating much of the literature. Females presented with changes in grey matter microarchitecture, while males showed altered functional connectivity in hippocampal circuitry and deficits in object recognition.


Asunto(s)
Cannabis , Analgésicos , Animales , Encéfalo , Agonistas de Receptores de Cannabinoides/farmacología , Dronabinol/farmacología , Femenino , Imagen por Resonancia Magnética , Masculino , Ratones
9.
Pharmacol Res Perspect ; 10(3): e00950, 2022 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-35466560

RESUMEN

Sexual dimorphisms are observed in cannabinoid pharmacology. It is widely reported that female animals are more sensitive to the cataleptic, hypothermic, antinociceptive, and anti-locomotive effects of cannabinoid receptor agonists such as CP55,940. Despite awareness of these sex differences, there is little consideration for the pharmacodynamic differences within females. The mouse estrus cycle spans 4-5 days and consists of four sex hormone-mediated phases: proestrus, estrus, metestrus, and diestrus. The endocannabinoid system interacts with female sex hormones including ß-estradiol, which may influence receptor expression throughout the estrus cycle. In the current study, sexually mature female C57BL/6 mice in either proestrus or metestrus were administered either 1 mg/kg i.p. of the cannabinoid receptor agonist CP55,940 or vehicle. Mice then underwent the tetrad battery of behavioral assays measuring catalepsy, internal body temperature, thermal nociception, and locomotion. Compared with female mice in metestrus, those in proestrus were more sensitive to the anti-nociceptive effects of CP55,940. A similar trend was observed in CP55,940-induced catalepsy; however, this difference was not significant. As for cannabinoid receptor expression in brain regions underlying antinociception, the spine tissue of proestrus mice that received CP55,940 exhibited increased expression of cannabinoid receptor type 1 relative to treatment-matched mice in metestrus. These results affirm the importance of testing cannabinoid effects in the context of the female estrus cycle.


Asunto(s)
Agonistas de Receptores de Cannabinoides , Cannabinoides , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Catalepsia/inducido químicamente , Catalepsia/tratamiento farmacológico , Estro , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Receptores de Cannabinoides
10.
Eur Rev Med Pharmacol Sci ; 26(4): 1224-1234, 2022 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-35253178

RESUMEN

OBJECTIVE: Chronic pain is one of the most common medical conditions in developed countries. The 2020 Italian National Report on Medicines shows how, in the last years, there was a light but constant increase in the prescription of pain medications. The purpose of our study was to assess the effects of long-term cannabis-based oil consumption on the distribution of patients with analgesics prescriptions for chronic pain in a Pain Medicine Unit in Northern Italy. PATIENTS AND METHODS: This is a retrospective, observational study in which patients treated with long-term medical cannabis-based oils, followed between June 2016 and July 2019, were enrolled. The effects of cannabis-based oil consumption on the distribution of patients with pain medications, before and after its long-term use, were evaluated with a Related Samples McNemar Test. Subgroups analyses were performed based on sex, age, comorbidity, duration of cannabis treatment, and condition driving cannabis prescription. RESULTS: A significant difference in opioid non-users after a long-term cannabis-based oil therapy was identified (from 32.1% to 55.4%, p = 0.0023), while no significant differences were found in the distribution of anticonvulsant, antidepressant, and benzodiazepine users. A high benzodiazepine use prevalence was revealed, while subgroup analyses showed increased antidepressant use in people over 65 years old (from 93.7% to 56.2%; p = 0.0313). CONCLUSIONS: Pain medication patterns of prescribing show how necessary it is to improve prescription practices among chronic pain patients. Opioid-sparing medications represent a crucial aspect of the pain treatment process, along with deprescribing protocols. Clinicians and clinical pharmacologists must cooperate to meet the need of a guide that can represent the most possible appropriate therapy for these patients.


Asunto(s)
Cannabis , Dolor Crónico , Marihuana Medicinal , Anciano , Analgésicos/uso terapéutico , Analgésicos Opioides/uso terapéutico , Benzodiazepinas/uso terapéutico , Agonistas de Receptores de Cannabinoides , Dolor Crónico/tratamiento farmacológico , Humanos , Marihuana Medicinal/uso terapéutico , Aceites/uso terapéutico
11.
J Biol Chem ; 298(4): 101764, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35227761

RESUMEN

Cannabinoid receptor 1 (CB1) is a therapeutically relevant drug target for controlling pain, obesity, and other central nervous system disorders. However, full agonists and antagonists of CB1 have been reported to cause serious side effects in patients. Therefore, partial agonists have emerged as a viable alternative as they can mitigate overstimulation and side effects. One of the key bottlenecks in the design of partial agonists, however, is the lack of understanding of the molecular mechanism of partial agonism itself. In this study, we examine two mechanistic hypotheses for the origin of partial agonism in cannabinoid receptors and predict the mechanistic basis of partial agonism exhibited by Δ9-Tetrahydrocannabinol (THC) against CB1. In particular, we inspect whether partial agonism emerges from the ability of THC to bind in both agonist and antagonist-binding poses or from its ability to only partially activate the receptor. We used extensive molecular dynamics simulations and Markov state modeling to capture the THC binding in both antagonist and agonist-binding poses in the CB1 receptor. Furthermore, we predict that binding of THC in the agonist-binding pose leads to rotation of toggle switch residues and causes partial outward movement of intracellular transmembrane helix 6 (TM6). Our simulations also suggest that the alkyl side chain of THC plays a crucial role in determining partial agonism by stabilizing the ligand in the agonist and antagonist-like poses within the pocket. Taken together, this study provides important insights into the mechanistic origin of the partial agonism of THC.


Asunto(s)
Agonistas de Receptores de Cannabinoides , Dronabinol , Receptor Cannabinoide CB1 , Agonistas de Receptores de Cannabinoides/química , Agonistas de Receptores de Cannabinoides/farmacología , Dronabinol/química , Dronabinol/farmacología , Humanos , Ligandos , Simulación de Dinámica Molecular , Receptor Cannabinoide CB1/química , Receptor Cannabinoide CB1/efectos de los fármacos
12.
Drug Alcohol Depend ; 234: 109413, 2022 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-35339972

RESUMEN

BACKGROUND: Nicotine vaping and cannabis use are common among youth. Among youth who use e-cigarettes, little is known about how and why they use cannabis and patterns of cannabis and nicotine co-use. Given the popularity of both products among youth, the study aim is to utilize qualitative data to better understand cannabis use among youth who use e-cigarettes. METHOD: Six focus groups of high schoolers who reported past-month e-cigarette use (N = 50; 52% male) were conducted to inform e-cigarette cessation programming. We conducted secondary data analysis examining report of cannabis use during focus groups. Transcripts were examined for report of cannabis use, reasons for use, and nicotine and cannabis co-use. RESULTS: In focus groups, cannabis was commonly discussed. Youth reported vaping cannabis, however other forms of cannabis delivery were common (e.g. blunts, joints). Themes related to reasons for simultaneous use of nicotine and cannabis were to experience stronger psychoactive effects than using either product alone and needing to use less nicotine product overall. Reasons for liking cannabis were positive psychoactive effects and stress relief. Reasons for disliking were related to health concerns. Notably, when youth reported disliking cannabis due to health concerns, a common discussion was strategies to acquire and continue cannabis use in ways that they perceived mitigated health concerns. CONCLUSION: Qualitative evidence identified associations between e-cigarette use and cannabis use among youth. Research and interventions targeting youth using e-cigarettes should consider how to address dual use of these products.


Asunto(s)
Cannabis , Sistemas Electrónicos de Liberación de Nicotina , Alucinógenos , Vapeo , Adolescente , Agonistas de Receptores de Cannabinoides , Femenino , Humanos , Masculino , Nicotina , Encuestas y Cuestionarios
13.
Behav Pharmacol ; 33(2&3): 195-205, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35288510

RESUMEN

Cessation of cannabinoid use in humans often leads to a withdrawal state that includes sleep disruption. Despite important health implications, little is known about how cannabinoid abstention affects sleep architecture, in part because spontaneous cannabinoid withdrawal is difficult to model in animals. In concurrent work we report that repeated administration of the high-efficacy cannabinoid 1 (CB1) receptor agonist AM2389 to mice for 5 days led to heightened locomotor activity and paw tremor following treatment discontinuation, potentially indicative of spontaneous cannabinoid withdrawal. Here, we performed parallel studies to examine effects on sleep. Using implantable electroencephalography (EEG) and electromyography (EMG) telemetry we examined sleep and neurophysiological measures before, during, and after 5 days of twice-daily AM2389 injections. We report that AM2389 produces decreases in locomotor activity that wane with repeated treatment, whereas discontinuation produces rebound increases in activity that persist for several days. Likewise, AM2389 initially produces profound increases in slow-wave sleep (SWS) and decreases in rapid eye movement (REM) sleep, as well as consolidation of sleep. By the third AM2389 treatment, this pattern transitions to decreases in SWS and total time sleeping. This pattern persists following AM2389 discontinuation and is accompanied by emergence of sleep fragmentation. Double-labeling immunohistochemistry for hypocretin/orexin (a sleep-regulating peptide) and c-Fos (a neuronal activity marker) in lateral hypothalamus revealed decreases in c-Fos/orexin+ cells following acute AM2389 and increases following discontinuation, aligning with the sleep changes. These findings indicate that AM2389 profoundly alters sleep in mice and suggest that sleep disruption following treatment cessation reflects spontaneous cannabinoid withdrawal.


Asunto(s)
Cannabinoides , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Electroencefalografía , Masculino , Ratones , Orexinas , Sueño , Sueño REM/fisiología
14.
Alcohol Clin Exp Res ; 46(4): 530-541, 2022 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-35229336

RESUMEN

BACKGROUND: Simultaneous or concurrent use (co-use) of alcohol and cannabis is associated with greater use of both substances over time, academic difficulties, more severe substance use consequences, and adverse impacts on cognitive functioning than the use of a single substance or no substance use. This study examined potential neural mechanisms underlying co-use behaviors in comparison to single substance use. Specifically, we compared alcohol cue reactivity and stress-cue reactivity among individuals who reported frequent same-day co-use of alcohol and cannabis and individuals who reported only alcohol use. METHODS: The sample included 88 individuals (41 women) who reported only alcohol use and 24 individuals (8 women) who reported co-use of alcohol and cannabis on at least 50% of drinking occasions. All participants completed fMRI stress and alcohol cue reactivity tasks. Because of known sex effects on stress reactivity and alcohol cue reactivity, we tested sex by co-use interactions. RESULTS: During alcohol cue presentation, co-users had less activation in the thalamus and dorsomedial prefrontal cortex than alcohol-only users, effects that were driven by differences in responses to neutral cues. Examination of stress cue reactivity revealed sex by co-use interactions in the lingual gyrus, with women co-users showing a greater difference between negative and neutral cue reactivity than all other groups. In addition, women co-users had greater connectivity between the nucleus accumbens and both the medial orbitofrontal cortex and the rostral anterior cingulate cortex during negative cue presentation than the other groups. CONCLUSIONS: These results provide preliminary evidence of enhanced stress cue reactivity in individuals reporting co-use of alcohol and cannabis, particularly women co-users.


Asunto(s)
Cannabis , Trastornos Relacionados con Sustancias , Encéfalo/diagnóstico por imagen , Agonistas de Receptores de Cannabinoides , Señales (Psicología) , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino
15.
Drug Alcohol Depend ; 233: 109374, 2022 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-35272186

RESUMEN

BACKGROUND: Cannabis is obtained from a variety retail and illicit sources, with unknown implications for youth cannabis use. This study assessed whether source of obtaining cannabis was associated with future cannabis use among adolescents. METHODS: High-schoolers (N = 835) completed 3 semiannual surveys, reporting use of 7 cannabis sources (i.e., free, bought from someone, from an online dispensary, with a [valid/invalid] medical card, self-grown, or other; separate dichotomous exposure variables) at wave 1 (n = 621; M[SD] age=17.14[.40]) or wave 2 (n = 622; M[SD] age=17.51[.39]). Past-6-month (yes/no) and number of past-30-day (0-30) non-medical use of any cannabis product, combustible, edible, and vaporized cannabis, blunts, and concentrates (i.e., dabs) were reported at waves 2-3. Random-effect time-lagged repeated-measures regression was used to test longitudinal associations of youth's cannabis source (waves 1-2; time-varying exposure) with cannabis use outcomes 6 months later (waves 2-3). RESULTS: Most youth (72.1%) received cannabis for free; 50.9% bought cannabis from someone, 15.9% used a valid medical card at a brick-and-mortar dispensary, and 3.9% grew cannabis. Buying cannabis from someone (OR=1.46, 95% CI: 1.07-1.99, p = .02) or using a valid medical card (OR=1.99, 95% CI: 1.20-3.31, p = .008) conferred greater odds of any cannabis product use 6 months later. Buying from someone predicted subsequent past-30-day use frequency (RR=1.25, 95% CI:1.05-1.48, p = .01). Some associations between particular cannabis sources and products were observed. CONCLUSIONS: Adolescents may access cannabis from several sources. Those who purchase cannabis illicitly from someone or from a brick-and-mortar dispensary using a valid medical card may be at increased risk for more persistent and frequent patterns of non-medical cannabis use.


Asunto(s)
Conducta del Adolescente , Cannabis , Alucinógenos , Adolescente , Analgésicos , Agonistas de Receptores de Cannabinoides , Cannabis/efectos adversos , Humanos , Encuestas y Cuestionarios
16.
Drug Alcohol Depend ; 234: 109388, 2022 05 01.
Artículo en Inglés | MEDLINE | ID: mdl-35316689

RESUMEN

BACKGROUND: Mood, sleep and pain problems are common comorbidities among treatment-seeking cannabis-dependent patients. There is limited evidence suggesting treatment for cannabis dependence is associated with their improvement. This study explored the impact of cannabis dependence treatment on these comorbidities. METHODS: This is a secondary analysis from a 12-week double-blind placebo-controlled trial testing the efficacy of a cannabis agonist (nabiximols) against placebo in reducing illicit cannabis use in 128 cannabis-dependent participants. Outcome measurements including DASS-21 (Depression, Anxiety, and Stress subscales); Insomnia Severity Index (ISI); and Brief Pain Inventory (BPI), were performed at weeks 0, 4, 8, 12 and 24. Each was analysed as continuous outcomes and as binary cases based on validated clinical cut-offs. RESULTS: Among those whose DASS and ISI scores were in the moderate to severe range at baseline, after controlling for cannabis use, there was a gradual decrease in severity of symptoms over the course of the trial. BPI decreased significantly until week 12 and then rose again in the post-treatment period during weeks 12-24. Neither pharmacotherapy type (nabiximols vs placebo) nor number of counselling sessions contributed significant explanatory power to any of the models and were excluded from the final analyses for both continuous and categorical outcomes. CONCLUSIONS: Participants in this trial who qualified as cases at baseline had elevated comorbidity symptoms. There was no evidence that nabiximols treatment is a barrier to achieving reductions in the comorbid symptoms examined. Cannabis dependence treatment reduced illicit cannabis use and improved comorbidity symptoms, even when complete abstinence was not achieved.


Asunto(s)
Cannabis , Alucinógenos , Abuso de Marihuana , Marihuana Medicinal , Analgésicos/uso terapéutico , Cannabidiol , Agonistas de Receptores de Cannabinoides/uso terapéutico , Comorbilidad , Método Doble Ciego , Dronabinol , Combinación de Medicamentos , Alucinógenos/uso terapéutico , Humanos , Abuso de Marihuana/terapia , Marihuana Medicinal/uso terapéutico , Dolor/tratamiento farmacológico , Sueño , Resultado del Tratamiento
17.
Int J Drug Policy ; 103: 103645, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35276401

RESUMEN

BACKGROUND: Cannabis edibles were legalized for recreational use across Canada in October 2019. The Canadian Cannabis Act requires legally produced edibles to be sold in plain single-color packages with limited branded elements and prominent health warning labels, serving size and nutritional information, and product ingredients including amounts of cannabis compounds. Little research, however, assesses what consumers think of standardized packaging, and how product packaging influences perceptions of cannabis edibles. METHODS: Eight focus groups with young adults (ages 18-24; n = 57) were conducted in November 2018. Participants were recruited from a Canadian university, and asked to assess sample images of cannabis packaging approved by Health Canada. They then discussed the information they would like to see on packages. Focus group discussions were transcribed and analyzed using a descriptive, qualitative approach following methods of process evaluation and inductive coding. RESULTS: Discussions generally pertained to four main themes: dosage and consumption recommendations; food and nutritional information; concerns for children; and health warning labels. Participants suggested improvements for cannabis packaging, including standardized THC units, non-numerical consumption instructions, and unit-dose packaging. Instead of recommending packaging that deters consumption, participants requested packaging features that promote safe consumption by adults while also protecting children. Findings reveal how packages function as communicative objects that convey meanings about safety and risk, yet these meanings may not resonate with Canadian young adults' perceptions of cannabis as relatively safe. CONCLUSIONS: While the packaging regulated for use in Canada may be assumed, due to its plain, standardized format, to communicate "little", we highlight tensions in the meanings of such packaging to young adults-especially around competing ideas related to safety and risk.


Asunto(s)
Cannabis , Alucinógenos , Adolescente , Adulto , Analgésicos , Canadá , Agonistas de Receptores de Cannabinoides , Niño , Humanos , Etiquetado de Productos , Embalaje de Productos/métodos , Adulto Joven
18.
Adv Pharmacol ; 93: 275-333, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35341569

RESUMEN

Cannabis legalization continues to progress in many US states and other countries. Δ9-tetrahydrocannabinol (Δ9-THC) is the major psychoactive constituent in cannabis underlying both its abuse potential and the majority of therapeutic applications. However, the neural mechanisms underlying cannabis action are not fully understood. In this chapter, we first review recent progress in cannabinoid receptor research, and then examine the acute CNS effects of Δ9-THC or other cannabinoids (WIN55212-2) with a focus on their receptor mechanisms. In experimental animals, Δ9-THC or WIN55212-2 produces classical pharmacological effects (analgesia, catalepsy, hypothermia, hypolocomotion), biphasic changes in affect (reward vs. aversion, anxiety vs. anxiety relief), and cognitive deficits (spatial learning and memory, short-term memory). Accumulating evidence indicates that activation of CB1Rs underlies the majority of Δ9-THC or WIN55121-2's pharmacological and behavioral effects. Unexpectedly, glutamatergic CB1Rs preferentially underlie cannabis action relative to GABAergic CB1Rs. Functional roles for CB1Rs expressed on astrocytes and mitochondria have also been uncovered. In addition, Δ9-THC or WIN55212-2 is an agonist at CB2R, GPR55 and PPARγ receptors and recent studies implicate these receptors in a number of their CNS effects. Other receptors (such as serotonin, opioid, and adenosine receptors) also modulate Δ9-THC's actions and their contributions are detailed. This chapter describes the neural mechanisms underlying cannabis action, which may lead to new discoveries in cannabis-based medication development for the treatment of cannabis use disorder and other human diseases.


Asunto(s)
Cannabinoides , Cannabis , Alucinógenos , Animales , Agonistas de Receptores de Cannabinoides/farmacología , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Dronabinol/farmacología , Humanos , Receptores de Cannabinoides
19.
Int J Drug Policy ; 103: 103629, 2022 May.
Artículo en Inglés | MEDLINE | ID: mdl-35228057

RESUMEN

INTRODUCTION: Since recreational legalization of cannabis in Canada in 2018, self-reported use in New Brunswick (NB) has increased from 15.1% to 20.3%, the largest increase of any province. Current literature on the impact of recreational cannabis legislation in other jurisdictions is conflicting, though retail availability has often been delayed on enactment. Given the immediate availability of cannabis in NB after legalization, we sought to establish the effect this had on post-mortem cannabinoid detection. Furthermore, we wanted to investigate the impact that age, sex, and manner of death had on cannabis use. We also established if there were any increases in commonly detected drugs over the study period. METHODS: A retrospective chart review was conducted on all adult Coroner's cases with toxicology analysis in NB between January 2014 and May 2020 (n = 3060). Differences in the proportion of cannabinoid-positive samples pre- versus post-legalization in the overall cohort as well as within each demographic parameter were assessed using chi-square tests. The effects of demographic parameters on cannabis presence were further assessed by logistic regression. Lastly, chi-square tests for trend were performed to identify increasing trends in cannabis detection, as well as cocaine, ethanol, opiates/opioids, benzodiazepines, and amphetamines over the study period. RESULTS: After controlling for age, sex, and manner of death, participants that died after recreational legalization had higher odds of having cannabis present post-mortem than those that died pre-legalization. In addition, demographic sub-analysis identified a greater proportion of cannabinoid-positive samples post-legalization in 25- to 44-year-olds and in deaths classified as either suicide or accidental compared to pre-legalization. We also observed a significant increase in the presence of cocaine and amphetamines in post-mortem samples over the study period. CONCLUSION: This study demonstrates that cannabis use has increased post-legalization in NB, particularly within young adults and those dying by suicide or accidental means. It also highlights the need for future research into the impact that legalization has on cannabis use in other jurisdictions.


Asunto(s)
Cannabinoides , Cannabis , Cocaína , Alucinógenos , Analgésicos , Analgésicos Opioides , Agonistas de Receptores de Cannabinoides , Humanos , Legislación de Medicamentos , Nuevo Brunswick , Estudios Retrospectivos , Adulto Joven
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