Synthesis of Smokable Synthetic Cannabinoids ('Spice') for Human Study

描述(申请人提供)：作为大麻替代品的合成大麻素(“香料”)的滥用正在迅速增加。尽管它们被广泛使用，但这些产品的风险尚不清楚。根据香料的主要成分JWH-018和JWH-073的药理作用，合成大麻素与大麻相比，造成物质使用障碍的风险更大。拟议的研究对于进行后续的人体实验室研究至关重要，以通过提供适合于人体研究的试剂来解决这些广泛滥用的化合物的生理风险和行为影响。拟议的研究将为未来对这类化合物的研究提供技术、方法和模型，并可推广到可能出现的其他化学类别的大麻类化合物。目的1：JWH合成：尽管JWH化合物在非法市场上随处可见，但没有一种是根据受控人体实验室调查所需的标准生产的。因此，我们将利用cGMP合成用于人类药物的JWH-018和JWH-073。合成化合物的纯度和完整性将由FDA注册的独立实验室进行验证。目标2：卷烟制备：我们将制定标准化合成大麻素卷烟生产的程序。将使用NIDA安慰剂大麻植物物质制备不同浓度的JWH-018和JWH-073香烟。为了验证该方法在生产一致的、特定浓度的JWH-018和JWH-073香烟方面的有效性，将使用高效液相色谱-串联质谱仪(HPLC/MS/MS)对香烟进行分析(Teske等人，2012年)。目的：确定用高效液相色谱/质谱仪测定人血浆中JWH-018和JWH-073及其代谢物的最佳条件。人的血浆会随着母体化合物和代谢物浓度的增加而添加，并在不同的温度(-80℃、-20℃或4℃)和不同的保存时间(24小时)下保存。-4周。)。化合物和代谢物的稳定性将作为时间和温度的函数进行评估。冲击力。拟议的研究将完成所需的第一步，以解决合成大麻素滥用迅速增加这一紧迫的重大公共卫生问题，而且由于我们在合成化合物方面的丰富专业知识，这项研究是可能的。

DESCRIPTION (provided by applicant): Abuse of synthetic cannabinoids ('Spice') as an alternative to cannabis is increasing rapidly. Despite their widespread use, the risks of these products are unknown. Based upon the pharmacology of the primary constituents of Spice, JWH-018 and JWH-073, the synthetic cannabinoids pose a greater risk for substance use disorder than cannabis. The proposed studies are critical in order to conduct subsequent human laboratory studies to address the physiological risks and behavioral effects of these widely-abused compounds by providing agents appropriate for research in humans. The proposed study will provide techniques, methods and models for future research with this class of compounds and can be extended to other chemical classes of cannabinoids that may emerge. Aim 1: JWH Synthesis: Although the JWH compounds are widely available on the illicit market, none are manufactured according to standards required for controlled human laboratory investigation. Therefore, we will synthesize JWH-018 and JWH-073 using cGMP for human pharmaceuticals. The purity and integrity of synthesized compounds will be verified by an independent FDA-registered laboratory. Aim 2: Cigarette Preparation: We will develop procedures for standardizing synthetic cannabinoid cigarette production. Cigarettes of various JWH-018 and JWH-073 concentrations will be prepared using NIDA placebo cannabis plant matter. To verify the effectiveness of the method in producing consistent, concentration-specific JWH-018 and JWH-073 cigarettes, cigarettes will be analyzed using high-performance liquid chromatography tandem mass spectrometry (HPLC/MS/MS) (Teske et al., 2012). Aim 3: Determine the optimal conditions required for reliable in vitro detection of JWH-018 and JWH-073 and respective metabolites in human plasma using HPLC/MS/MS. Human plasma will be spiked with increasing concentrations of the parent compounds and metabolites and stored at varying temperatures (-80, -20, or 4¿ C) and duration (24 hr. - 4 wks.). Stability of the compounds and metabolites will be assessed as a function of time and temperature. Impact. The proposed study will accomplish the first steps needed to address the immediate, significant public health concern of the rapid rise in synthetic cannabinoid abuse, and is possible because of our substantial expertise in synthesizing compounds of particular