Themed Issue: Cannabinoids in Biology and Medicine, Part I Taming Thc: Potential Cannabis Synergy and Phytocannabinoid-terpenoid Entourage Effects Received Linked Articles the Roots of Cannabis Synergy Phytocannabinoid-terpenoid Entourage Effects Phytocannabinoids, beyond Thc: a Brief Survey
Themed Issue: Cannabinoids in Biology and Medicine, Part I Taming Thc: Potential Cannabis Synergy and Phytocannabinoid-terpenoid Entourage Effects Received Linked Articles the Roots of Cannabis Synergy Phytocannabinoid-terpenoid Entourage Effects Phytocannabinoids, beyond Thc: a Brief Survey
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Ethan B. Russo
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作者：
Ethan B. Russo
自1964年Raphael Mechoulam分离和合成四氢大麻酚(THC)以来，THC一直是大麻研究的主要焦点。最近，大麻二酚对大麻药理和止痛的协同作用已得到科学证明。其他植物大麻素，包括四氢大麻素、大麻酚和大麻黄素，还具有额外的治疗作用。创新的常规植物育种已经产生了大麻化学类型，表达了每种成分的高滴度，用于未来的研究。这篇综述将探索另一类植物治疗药物，大麻萜类化合物：柠檬烯、月桂烯、a-品烯、芳樟醇、b-石竹烯、石竹烯氧化物、橙花醇和植物酚。萜类化合物与植物大麻素具有相同的前体，都是人类饮食中常见的风味和香味成分，已被美国食品和药物管理局和其他监管机构普遍认为是安全的。萜类化合物是非常有效的，当从环境空气中吸入时，其血清水平为个位数ng·mL-1，会影响动物甚至人类的行为。它们表现出独特的治疗效果，这可能对大麻药用提取物的环境效应有重要贡献。将特别注重植物大麻素-萜类化合物的相互作用，这些相互作用可在治疗疼痛、炎症、抑郁、焦虑、成瘾、癫痫、癌症、真菌和细菌感染(包括耐甲氧西林金黄色葡萄球菌)方面产生协同作用。科学证据表明，非大麻类植物成分可能是THC醉酒作用的解毒剂，可能会增加其治疗指数。提出了在今后的实验中研究环境效应的方法。植物大麻素-萜类化合物的协同作用，如果得到证实，增加了从这种古老的植物中开发出广泛的治疗产品的可能性。大麻一直是一种无与伦比的药用植物，反之亦然--在专注于精神活性THC的研究中占据压倒性优势。直到最近，人们才对四氢大麻酚类似物表现出新的兴趣，而大麻及其提取物的其他关键活性成分--大麻萜类化合物--仍未得到充分研究(McPartland和Russo，2001b；Russo和McPartland，2003年)。目前的综述将重新考虑精油(EO)制剂、它们独特的药理作用以及可能与植物大麻素类化合物的治疗相互作用。命名法遵循Alexander等人的惯例。(2009)。植物大麻素和萜类化合物在大麻中合成，在腺毛(图1)内的分泌细胞中合成，腺毛在衰老之前高度集中在未受精的雌花中(Potter，2004；Potter，2009)。香叶基焦磷酸是大麻中通过脱氧果糖途径形成的前体(Fellermeier等人，2001年)，是植物大麻素和萜类化合物的母体化合物(图2)。与橄榄-托利酸或二氢呋喃甲酸偶联后，戊基或丙基大麻碱…
Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, a-pinene, linalool, b-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL-1. They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. Cannabis has been a medicinal plant of unparalleled versa-overwhelming preponderance of research focused on psycho-active THC. Only recently has renewed interest been manifest in THC analogues, while other key components of the activity of cannabis and its extracts, the cannabis terpenoids, remain understudied (McPartland and Russo, 2001b; Russo and McPartland, 2003). The current review will reconsider essential oil (EO) agents, their peculiar pharmacology and possible therapeutic interactions with phytocannab-inoids. Nomenclature follows conventions in Alexander et al. (2009). Phytocannabinoids and terpenoids are synthesized in cannabis, in secretory cells inside glandular trichomes (Figure 1) that are most highly concentrated in unfertilized female flowers prior to senescence (Potter, 2004; Potter, 2009). Geranyl pyrophosphate is formed as a precursor via the deoxyxylulose pathway in cannabis (Fellermeier et al., 2001), and is a parent compound to both phytocannabinoids and terpenoids (Figure 2). After coupling with either olive-tolic acid or divarinic acid, pentyl or propyl cannabinoid …