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

描述（由申请人提供）：滥用合成大麻素（“香料”）作为大麻的替代品正在迅速增加。尽管这些产品被广泛使用，但其风险尚不清楚。根据香料JWH-018和JWH-073的主要成分的药理学，合成大麻素比大麻对物质使用障碍的风险更大。为了进行后续的人体实验室研究，以通过提供适用于人体研究的药物来解决这些广泛滥用的化合物的生理风险和行为影响，拟议的研究至关重要。拟议的研究将为这类化合物的未来研究提供技术，方法和模型，并可以扩展到可能出现的其他化学类别的大麻素。目标1：JWH合成：虽然JWH化合物在非法市场上广泛存在，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，我们将使用cGMP合成JWH-018和JWH-073用于人用药物。合成化合物的纯度和完整性将由独立的FDA注册实验室进行验证。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各种JWH-018和JWH-073浓度的香烟。为了验证该方法在生产一致的、浓度特异性的JWH-018和JWH-073香烟中的有效性，将使用高效液相色谱串联质谱法（HPLC/MS/MS）分析香烟（Teske等人，2012年）。目标3：确定采用HPLC/MS/MS法可靠体外检测人血浆中JWH-018和JWH-073及其相应代谢物所需的最佳条件。人血浆将加标浓度递增的母体化合物和代谢物，并在不同温度（-80 ℃、-20 ℃或4 ℃）和持续时间（24小时- 4周）下储存。将根据时间和温度评估化合物和代谢物的稳定性。冲击这项拟议的研究将完成解决合成大麻素滥用迅速增加的直接，重大公共卫生问题所需的第一步，并且由于我们在合成特别是合成大麻素的化合物方面的大量专业知识，

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