大麻的潜在医疗价值及使用风险

目前大麻是全球年销量最大、使用范围最广的一类成瘾性物质。然而由于大麻具有止痛、抗惊厥、抗炎等药理作用,一些国家将大麻列为合法的医用产品。近年来,由于部分国家通过大麻合法化政策,大麻的医用价值与使用风险引发了广泛关注。从大麻植物中可以提取出百余种大麻素,其中最主要的化学成分是δ-9-四氢大麻酚(δ-9-Tetrahydrocannabinol,THC)和大麻二酚(Cannabidiol, CBD)。大麻的医疗作用主要与THC、CBD和其他大麻素化合物的作用有关。但是THC具有较强的精神活性,在使用时会带来滥用、成瘾等诸多风险,因此应严格依法依规进行临床应用。目前研究显示,CBD无成瘾性,且耐受性良好,具有一定医用价值。本文主要从大麻在疾病治疗中的应用及使用风险两方面进行综述,以期为后续评估大麻使用的利弊以及修订、制订大麻相关政策提供理论依据。     

大麻中活性成分的气相色谱分析法及国内主要产区大麻活性成分含量的普查

采用有机溶剂提取大麻活性成分后，再用气相色谱内标法检测大麻中大麻二酚（CBD）、△^9－四氢大麻酚（△^9－THC）和大麻酚（CBN）三种活性成分的方法，方法简便，结果准确。用于全国十个省市大麻样品的检测，对其中大麻主要产区－－新疆和云南大部分地区大麻活性成分含量进行了普查，从而取得了我国大麻中活性成分含量情况的第一手资料。在检测方法建立过程中，作者成功地从大麻植物中提取分离出CBD、△^9－THC和CBN对照品。解决了检测中面临的难题。     

大麻二酚新剂型的研究进展

大麻二酚(cannabidiol,CBD)是从植物大麻中提取的非成瘾性成分,近几年来许多研究表明CBD具有多种药理作用和高安全性,主要包括抗癫痫、抗惊厥、治疗疼痛、抗炎及神经保护特性等。由于CBD的内在性质具有亲脂性高、水溶性差及易经过首过代谢的特点,使其口服生物利用度低,导致CBD的临床用药效率低,不利于其作为常规的制剂使用。本文主要对近几年来提高CBD的溶解性及生物利用度的新型制剂研究进行综述,对透皮传递系统、透黏膜传递系统、自乳化传递系统、新型固体制剂等新技术提高CBD的溶解性及生物利用度试验研究进行阐述并作出展望。     

内源性大麻素系统在精神疾病治疗和麻醉觉醒的调控作用

内源性大麻素系统因其在多种行为和脑功能中的重要作用,以及作为包括焦虑、抑郁等神经精神疾病中的治疗靶点而得到广泛关注。内源性大麻素信号失调会导致负性情绪状态和应激反应增多。对于其潜在的神经细胞特异性和神经环路调节的深入研究,有助于神经精神疾病治疗药物的开发,并有助于更好地了解内源性大麻素系统对包括麻醉觉醒在内的神经功能的环路调节。本文聚焦内源性大麻素系统在神经精神疾病治疗以及麻醉觉醒调节中作用的最新研究进展。     

英国GW制药公司携手诺华等多家公司开发并上市全球首个大麻提取物处方药Sativex

Sativex是由英国GW制药公司研制的全球首个大麻提取物处方药,为一种口腔黏膜喷雾剂,其主要活性成分为 δ—9-四氢大麻酚（THC）和大麻二醇（CBD）等两种大麻素,现已由GW公司及其合作伙伴Almirall公司在英国、西班牙、德国、丹麦、     

大麻素受体在肝纤维化及肝硬化中的作用及研究进展

肝纤维化的发生与发展是一个复杂的病理和细胞生化过程,受到多种细胞因子及细胞内多种信号转导通路网络的调控。在这个复杂的调控网络中涉及到很多作用靶标,但很多靶点在肝纤维化中的作用尚没有完全定论。发生肝纤维化后,如无有效的治疗措施,最终将恶化为肝硬化。肝硬化患者的肝脏结构发生改变,导致肝脏解毒功能下降,从而使循环血液中内毒素增加,导致肝硬化失代偿期出现门脉高压、内毒血症、高动力循环综合征、肝性脑病等并发症。近年来研究发现大麻素受体参与急、慢性肝病及其并发症的改善与恢复过程,被认为是抗肝纤维化的潜在治疗靶点。该文从大麻素系统概述、大麻素受体与肝纤维化、大麻素受体防治肝纤维化的信号通路、大麻素及其受体在肝硬化并发症中的作用等方面综述了大麻素受体在肝纤维化及肝硬化中的作用及研究进展。     

043 GW公司的Safivex有效抑制严重癌性疼痛

GW制药公司公布了大麻提取物Sativex的另一个潜在作用。初步Ⅲ期临床数据显示，该提取物有效抑制严重癌性疼痛。Sativex为大麻全提取物，主要成分有四氢大麻酚(THC)和大麻二酚(CBD)。在英国正在评估其减轻多发性硬化症(MS)症状的效果，在加拿大正在评估其用于MS神经性疼痛的治疗。     

抗肝纤维化药物作用靶点的研究进展

肝纤维化是各种慢性肝病发展到肝硬化阶段的共同病理特点。目前认为,肝纤维化是一个可以逆转的过程。近几年的研究发现,大麻素类物质及其受体在肝纤维化的发生、发展过程中起着重要的作用。简介相关的研究进展,并介绍以大麻素受体为靶点进行抗肝纤维化药物研发的思路。     

大麻的成瘾性和潜在的药用价值

大麻是全世界被滥用最多的精神活性物质,滥用人数快速增长。本文系统回顾了大麻的种植历史;重点介绍了大麻以及主要活性成分四氢大麻酚的成瘾潜力以及大麻成瘾、中毒和戒断的临床诊断标准;总结了内源性大麻和大麻受体的生理功能和药理作用如镇痛、抗惊厥和抗恶心作用,并系统介绍了大麻在多发性硬化症、青光眼和恶性神经胶质瘤等疾病中的治疗作用。总之,对于大麻的成瘾性和危害性值得高度关注,以利于减少大麻危害;同时有必要深入探索和发掘大麻的潜在药物价值,为人类健康服务。     

大麻酚类化合物：治疗恶性神经胶质瘤的新途径

屈大麻酚(dronabinol)是大麻中的主要活性成分,包括其他大麻酚类化合物,能对中枢和周围神经系统产生广泛生理作用,如改变人的认知能力与记忆、产生痛觉缺失、抗惊厥、抗炎、减轻眼内压和镇吐等。屈大麻酚以刺激 AIDS 患者食欲和缓解癌症病人因化疗     

Preliminary data on the potential for unintentional antidoping rule violations by permitted cannabidiol (CBD) use

According to the World Anti-Doping Agency (WADA) regulations, cannabinoids use is prohibited in competition except for cannabidiol (CBD) use. For an adverse analytical finding (AAF) in doping control, cannabinoid misuse is based on identification of the pharmacologically inactive metabolite 11-nor-delta-9-carboxy-tetrahydrocannabinol-9-carboxylic acid (carboxy-THC) in urine at a concentration greater than 180 ng/ml. All other (minor) cannabinoids are reported as AAF when identified, except for CBD that has been explicitly excluded from the class of cannabinoids on WADA's Prohibited List since 2018. However, due to the fact that CBD isolated from cannabis plants may contain additional minor cannabinoids, the permissible use of CBD can lead to unintentional violations of antidoping regulations. An assay for the detection of 16 cannabinoids in human urine was established. The sample preparation consisted of enzymatic hydrolysis of glucuronide conjugates, liquid–liquid extraction, trimethylsilylation, and analysis by gas chromatography/tandem mass spectrometry (GC–MS/MS). Spot urine samples from CBD users, as well as specimens obtained from CBD administration studies conducted with 15 commercially available CBD products, were analyzed, and assay characteristics such as selectivity, reproducibility of detection at the minimum required performance level, limit of detection, and limit of identification were determined. An ethical committee approved controlled single dose commercially available CBD products administration study was conducted to identify 16 cannabinoids in urine samples collected after ingestion or application of the CBD products as well as their presence in spot urine samples of habitual CBD users. Variable patterns of cannabinoids or their metabolites were observed in the urine samples, especially when full spectrum CBD products were consumed. The presence of minor cannabinoids or their metabolites in an athlete's in-competition urine sample represents a substantial risk of an antidoping rule violation.     

Cannabidiol as potential anticancer drug

Over the past years, several lines of evidence support an antitumourigenic effect of cannabinoids including Δ⁹-tetrahydrocannabinol (Δ⁹-THC), synthetic agonists, endocannabinoids and endocannabinoid transport or degradation inhibitors. Indeed, cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization. However, the clinical use of Δ⁹-THC and additional cannabinoid agonists is often limited by their unwanted psychoactive side effects, and for this reason interest in non-psychoactive cannabinoid compounds with structural affinity for Δ⁹-THC, such as cannabidiol (CBD), has substantially increased in recent years. The present review will focus on the efficacy of CBD in the modulation of different steps of tumourigenesis in several types of cancer and highlights the importance of exploring CBD/CBD analogues as alternative therapeutic agents.     

Cannabinoids in bipolar affective disorder: a review and discussion of their therapeutic potential

Bipolar affective disorder is often poorly controlled by prescribed drugs. Cannabis use is common in patients with this disorder and anecdotal reports suggest that some patients take it to alleviate symptoms of both mania and depression. We undertook a literature review of cannabis use by patients with bipolar disorder and of the neuropharmacological properties of cannabinoids suggesting possible therapeutic effects in this condition. No systematic studies of cannabinoids in bipolar disorder were found to exist, although some patients claim that cannabis relieves symptoms of mania and/or depression. The cannabinoids Delta(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) may exert sedative, hypnotic, anxiolytic, antidepressant, antipsychotic and anticonvulsant effects. Pure synthetic cannabinoids, such as dronabinol and nabilone and specific plant extracts containing THC, CBD, or a mixture of the two in known concentrations, are available and can be delivered sublingually. Controlled trials of these cannabinoids as adjunctive medication in bipolar disorder are now indicated.     

Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Delta(9)-tetrahydrocannabinol

Cannabis sativa (marijuana plant) contains myriad cannabinoid compounds; yet, investigative attention has focused almost exclusively on Delta(9)-tetrahydrocannabinol (THC), its primary psychoactive substituent. Interest in modulation of THC's effects by these other cannabinoids (e.g., cannabidiol (CBD)) has been stimulated anew by recent approval by Canada of Sativex (a 1:1 dose ratio combination of CBD:THC) for the treatment of multiple sclerosis. The goal of this study was to determine the degree to which THC's abuse-related effects were altered by co-administration of CBD. To this end, CBD and THC were assessed alone and in combination in a two-lever THC discrimination procedure in Long-Evans rats and in a conditioned place preference/aversion (CPP/A) model in ICR mice. CBD did not alter the discriminative stimulus effects of THC at any CBD:THC dose ratio tested. In contrast, CBD, at CBD:THC dose ratios of 1:1 and 1:10, reversed CPA produced by acute injection with 10mg/kg THC. When administered alone, CBD did not produce effects in either procedure. These results suggest that CBD, when administered with THC at therapeutically relevant ratios, may ameliorate aversive effects (e.g., dysphoria) often associated with initial use of THC alone. While this effect may be beneficial for therapeutic usage of a CBD:THC combination medication, our discrimination results showing that CBD did not alter THC's discriminative stimulus effects suggest that CBD:THC combination medications may also produce THC-like subjective effects at these dose ratios.     

Production of identical retention times and mass spectra for {delta}9-tetrahydrocannabinol and cannabidiol following derivatization with trifluoracetic anhydride with 1,1,1,3,3,3-hexafluoroisopropanol*

The use of perfluorinated anhydrides coupled with perfluoroalcohols for the derivatization of cannabinoids has been well documented. Derivatization is used in the detection of cannabinoids using gas chromatography-mass spectrometry (GC-MS) with both electron impact ionization (EI) and negative chemical ionization (NCI). During method development for the analysis of cannabinoids in biological samples using GC-MS in EI and NCI mode, it was observed that when Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) were derivatized with trifluoroacetic anhydride (TFAA), the resultant derivatives produced the same retention times and mass spectra. This was not observed with the trimethylsilyl (TMS) derivatives of THC and CBD. This complication is due to the conversion of CBD to THC under acidic conditions. The work here highlights the unsuitability of the derivatizing reagent TFAA for the detection of THC and CBD. For the analysis of case samples, even if only THC is of interest, the presence of CBD cannot be excluded, and other derivatization techniques should be used.     

Effects of acute oral Delta9-tetrahydrocannabinol and standardized cannabis extract on the auditory P300 event-related potential in healthy volunteers.

Reduced amplitudes of auditory evoked P300 are a robust finding in schizophrenic patients, indicating deficient attentional resource allocation and active working memory. Delta9-Tetrahydrocannabinol (Delta9-THC), the main active constituent of Cannabis sativa, has been known to acutely impair cognitive abilities in several domains, particularly in memory and attention. Given the psychotic-like effects of Delta9-THC, a cannabinoid hypothesis of schizophrenia has been proposed. This prospective, double-blind, placebo-controlled cross-over study investigated the acute effects of cannabinoids on P300 amplitude in 20 healthy volunteers (age 28.2+/-3.1 years, 10 male) by comparing Delta9-THC and standardized cannabis extract containing Delta9-THC and cannabidiol (CBD). P300 waves were recorded during a choice reaction task. As expected, Delta9-THC revealed a significant reduction of P300 amplitude at midline frontal, central, and parietal electrodes. CBD has been known to abolish many of the psychotropic effects of Delta9-THC, but, unexpectedly, failed to demonstrate a reversal of Delta9-THC-induced P300 reduction. Moreover, there were no correlations between cannabinoid plasma concentrations and P300 parameters. These data suggest that Delta(9)-THC may lead to acute impairment of attentional functioning and working memory. It can be speculated whether the lack of effect of CBD may be due to an insufficient dose used or to an involvement of neurotransmitter systems in P300 generation which are not influenced by CBD.     

Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer's disease

Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone [WIN 55,212-2 (WIN)], a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Δ(9)-tetrahydrocannabinol [JWH-133 (JWH)], a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium ([Ca(2+)](i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-[4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl]-6,6-dimethyl-bicyclo[3.1.1]hept-2-ene-2-methanol [HU-308 (HU)], another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.     

Cannabinoid-induced enhancement and depression of cat monosynaptic reflexes

A study of the effects of Δ-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD) on the spinal monosynaptic pathway in unanesthetized spinal cats was undertaken in order to elucidate potential mechanisms of the convulsant and anticonvulsant actions of these cannabinoids. To this end, the effects of the drugs on pre- and posttetanic monosynaptic responses were compared with those of phenytoin (PHT). The data indicated that small doses of Δ⁹-THC enhanced both pre- and posttetanic potentials, a result which suggests that excitatory effects on synaptic transmission may contribute to the convulsant action of the drug. Relatively large doses of Δ⁹-THC, on the other hand, and all doses of CBD depressed the reflex, as did PHT; such depression may account, at least partially, for the anticonvulsant effects of the cannabinoids. The present study provides direct evidence that the cannabinoids produce both excitatory and depressant effects on central synaptic transmission; such results are consistent with the well-documented effects of the cannabinoids on CNS excitability.     

Effects of delta 9-tetrahydrocannabinol, cannabinol and cannabidiol on the immune system in mice. II. In vitro investigation using cultured mouse splenocytes

The effects of the cannabinoids, delta 9-tetrahydrocannabinol (THC), cannabinol (CBN) and cannabidiol (CBD), on the primary-like immune response were investigated in primary cultures of mouse splenocytes. Splenocyte cultures were stimulated with sheep erythrocytes in vitro and incubated with cannabinoids for the first 24 h after antigenic stimulation (prior to initiation of DNA synthesis), from 24 h to 6 days after antigenic stimulation, and for the entire 5-day period. THC (1 and 5 microM) and CBD (5 microM) depressed the primary-like immune response of stimulated mouse splenocytes when incubated for the first 24 h after antigenic stimulation and the entire 6-day culture period. CBN did not show any measurable suppression of the primary-like immune response. Treatment of splenocyte cultures with cannabinoids after the first 24 h after antigenic stimulation showed no impairment of the in vitro primary-like immune response.     

Human skin permeation of Delta8-tetrahydrocannabinol, cannabidiol and cannabinol

The purpose of this study was to quantify the in-vitro human skin transdermal flux of Delta8-tetrahydrocannabinol (Delta8-THC), cannabidiol (CBD) and cannabinol (CBN). These cannabinoids are of interest because they are likely candidates for transdermal combination therapy. Differential thermal analysis and in-vitro diffusion studies with human tissue were completed for the compounds. Heats of fusion, melting points and relative thermodynamic activities were determined for the crystalline compounds, CBD and CBN. Flux, permeability, tissue concentration and lag times were measured in the diffusion experiments. CBN had a lower heat of fusion and corresponding higher calculated relative thermodynamic activity than CBD. Ethanol concentrations of 30 to 33% significantly increased the transdermal flux of Delta8-THC and CBD. Tissue concentrations of Delta8-THC were significantly higher than for CBN. Lag times for CBD were significantly smaller than for CBN. The permeabilities of CBD and CBN were 10-fold higher than for Delta8-THC. Combinations of these cannabinoids with ethanol will be further studied in transdermal patch formulations in vitro and in vivo, as significant flux levels of all the drugs were obtained. CBD, the most polar of the three drugs, and other more polar cannabinoids will also be the focus of future drug design studies for improved transdermal delivery rates.