Behavioral Pharmacology of Cannabinoid and Terpenoid Effects and Interactions

广泛的立法改革，允许合法销售和使用医用和非医用大麻 (例如，娱乐)目的极大地扩大了大麻的获取途径，并导致了新的 大麻产品。有选择地培育大麻，使其具有针对大麻素和萜类的特征， 它们在市场上被标榜为具有实质上不同的主观和药用效果。然而，这些说法 是基于轶事或营销，而不是受控的科学发现。THC是主要的 大麻的精神活性成分，并已显示出治疗价值(治疗恶病质和 恶心/呕吐)，但也与许多不良反应有关。相信是有理论基础的 THC的某些作用可能受丰富的天然植物产物--萜类化合物的调节 广泛存在于各种大麻品种中。本项目中感兴趣的萜类化合物柠檬烯， 月桂烯和蒎烯是人类饮食中常见的物质，通常被认为是安全的(GRAS) 食品和药物管理局。然而，人体实验室研究测试了THC和THC的单独和联合影响 萜类化合物很稀少，甚至根本不存在。柠檬烯(抗焦虑)、品烯(认知)的独特作用 增强)、月桂烯(镇静剂)在独立研究中已被阐明，表明这些 物质可减轻或增强THC的特定影响。该项目的目标是系统地 评估四氢呋喃、柠檬烯、月桂烯和蒎烯的单独和联合作用，以评估其有效性。 所谓的大麻“环境”效应(认为整个植物提供了实质上不同的效应 而不仅仅是THC)。三项双盲、安慰剂对照的受试者内交叉研究将完成 单独评估每种萜类化合物，并与中剂量和高剂量的THC联合使用。健康志愿者 报告过去而不是当前(过去一个月)大麻使用情况的人将参加9次门诊实验室会议和 服用以下药物：1)安慰剂，2)THC(15毫克)，3)THC(30 Mg)，4)低剂量萜类化合物，5)高剂量 萜类化合物，6)THC(15 Mg)+低剂量萜类化合物，7)THC(15 Mg)+高剂量萜类化合物，8)THC(30 Mg)+低 9)THC(30 Mg)+高剂量萜类。剂量顺序将是随机和重复的 评估将以行为、生理、认知和主观影响为特征。两个词的用法 THC和每个萜类化合物的剂量允许在不同的比率下评估THC-萜类化合物的相互作用 两者都最大限度地增加了观察到目标THC影响的可能性，并减少了第二类错误的可能性。 这一结果将促进我们对大麻的行为药理学的理解。演示 THC效应的减弱将支持大麻的“环境”效应，并为 开发可减轻THC不良反应的新型大麻素药物。相比之下， 没有这些萜类化合物的调节将表明需要评估其他目标，并将 支持在医药中使用药用大麻素产品，而不是植物性产品。

Widespread legislative reforms allowing for the legal sale and use of cannabis for medical and non-medical (e.g., recreational) purposes has greatly expanded access to cannabis and resulted in the proliferation of novel cannabis products. Cannabis is being selectively bred to have targeted cannabinoid and terpenoid profiles, which are marketed as having substantively different subjective and medicinal effects. However, these claims are based on anecdote or marketing, rather than controlled scientific discovery. THC is the primary psychoactive constituent of cannabis and has demonstrated therapeutic value (treatment of cachexia and nausea/emesis), but is also associated with many adverse effects. There is a theoretical basis for believing that some effects of THC may be modulated by terpenoids, abundant naturally occurring plant products prevalent within a variety of cannabis strains. The terpenoids of interest in the present project, limonene, myrcene, and pinene are common to human diets and designated Generally Recognized as Safe (GRAS) by the FDA. However, human laboratory research testing the separate and combined effects of THC and terpenoids is scarce to non-existent. The unique effects of limonene (anxiolytic), pinene (cognitive enhancement), myrcene (sedative) that have been elucidated in independent studies suggest that these substances may mitigate or enhance specific effects of THC. The aim of this project is to systematically evaluate the effects of THC, limonene, myrcene, and pinene, alone, and in combination, to evaluate the validity of the purported cannabis “entourage” effect (belief that whole plant provides substantively different effects than THC alone). Three double-blind, placebo-controlled within-subjects crossover studies will be completed to evaluate each terpenoid alone and in combination with moderate and high doses of THC. Healthy volunteers who report past, but not current (past month) cannabis use will attend 9 outpatient laboratory sessions and receive the following: 1) Placebo, 2) THC (15mg), 3) THC (30mg), 4) low dose terpenoid, 5) high dose terpenoid, 6) THC (15mg) + low dose terpenoid, 7) THC (15mg) + high dose terpenoid, 8) THC (30mg) + low dose terpenoid, and 9) THC (30mg) + high dose terpenoid. Dose order will be randomized and repeated assessments will characterize behavioral, physiological, cognitive, and subjective effects. The use of two doses of THC and each terpenoid allows for evaluation of THC-terpenoid interactions at different ratios and both maximizes the likelihood of observing targeted THC effects and reduces the likelihood of Type II error. Results will advance our understanding of the behavioral pharmacology of cannabis. Demonstrating an attenuation of THC effects would support the cannabis “entourage” effect and provide data useful for the development of novel cannabinoid medications that can mitigate adverse effects of THC. In contrast, the absence of THC modulation by these terpenoids would indicate the need to evaluate other targets, and would support use of pharmaceutical cannabinoid products versus plant-based products in medicine.