Improved analgesia and safety of CBD over THC or THC+CBD: dose-addition analysis

CBD 比 THC 或 THC CBD 改善镇痛和安全性：剂量添加分析

• 批准号: 8701187
• 负责人: Sara J Ward
• 金额: $ 11.67万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8701187
• 关键词: Absence of pain sensation; Acute; Adult; Adverse effects; Affect; Agonist; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Anxiety; Attention; Attention Concentration; Attenuated; Award; Behavioral; Behavioral Sciences; Biological Assay; Cannabidiol; Cannabinoids; Cannabis; Cannabis sativa plant; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Cognition; Cognitive; Cognitive deficits; Dependence; Development; Discrimination; Dose; Drug Addiction; Drug Formulations; Drug abuse; Goals; Human; Impaired cognition; Investigation; Lead; Learning; Light; Malignant Neoplasms; Marijuana; Measures; Medical; Memory; Mission; Modeling; Multiple Sclerosis; Mus; Neuropathy; Outcome; Paclitaxel; Pain; Performance; Pharmacotherapy; Physical Dependence; Pre-Clinical Model; Relative (related person); Reporting; Research; Safety; Sativex; Stimulus; Testing; Tetrahydrocannabinol; Therapeutic; Therapeutic Index; Time; Withdrawal; base; cannabinoid receptor; chemotherapy; chronic pain; clinical effect; clinically relevant; conditioning; experience; improved; innovation; interest; knowledge base; mechanical allodynia; novel; painful neuropathy; pre-clinical; preference; public health relevance; research study; social; success

DESCRIPTION (provided by applicant): Up to 80% of adults in the US with chronic pain report inadequate treatment. Investigation into the analgesic actions of Cannabis have focused on the primary constituent 9-tetrahydrocannabinol (THC) and its synthetic counterparts, however the psychoactive effects of the cannabinoid receptor agonists hamper their use in the clinic, as have questions regarding their overall efficacy. Recently the second most abundant phytocannabinoid cannabidiol (CBD) was added to THC clinically (the buccal spray Sativex) to decrease THC's psychoactive effects, but clinical evidence challenges the success of this concept as recent reports demonstrate that Sativex produces similar subjective and other effects to THC, including "high" and "marijuana-like", and impairs cognition and attention. At the same time, a handful of preclinical reports have now shown robust analgesic efficacy of CBD administered alone. The long-term goal of this research is to identify highly efficacious and safe cannabinoid-based pharmacotherapies for the treatment of neuropathic pain using innovative preclinical pain, abuse liability, and cognition assays. The objective of the R03 Behavioral Science Track Award application is to quantitatively determine by dose-addition analysis the relative efficacies of two putative analgesic Cannabis constituents, CBD and THC, alone and in combination using stimulus- and non- evoked neuropathic pain assays and adverse effect tests. The central hypothesis is that CBD is a more efficacious anti-neuropathic agent than THC and that CBD+THC combinations will produce additive, but not synergistic, analgesic effects. We hypothesize that CBD will not produce dependence or cognitive impairment as compared with THC, and that CBD+THC combinations will be similar to THC alone on these adverse effect measures. Aim 1 will demonstrate that CBD is more effective than THC in producing a conditioned place preference in mice experiencing chemotherapy-induced neuropathic pain. Results will also demonstrate a lack of synergy between CBD and THC's analgesic actions. Aim 2 will demonstrate CBD's improved safety profile over CBD. Chronic administration of THC alone or THC+CBD will lead to physical dependence while acute treatments will produce cognitive impairments. CBD alone will not produce physical dependence or affect cognitive performance. The proposed research is significant and innovative because it diverges from the current focus on CBD as a putative adjunct to THC for pain relief toward the identification of CBD alone as an anti-neuropathic agent with improved efficacy and safely. Innovation is also achieved with the incorporation of rigorous quantification by use of dose-addition analysis across several behavioral endpoints to provide a comprehensive comparison of the safety and efficacy of THC, CBD and THC+CBD. Innovation is also achieved by the combined use of stimulus-evoked and non-evoked assays for neuropathic pain testing as well as more novel abuse liability and cognitive assays for CB-based pharmacotherapies.

描述（由申请人提供）：在美国，高达80%的慢性疼痛成年人报告治疗不足。对大麻镇痛作用的研究集中在主要成分9-四氢大麻酚（THC）及其合成对应物上，然而大麻素受体激动剂的精神活性影响阻碍了它们在临床上的使用，因为它们的总体疗效存在问题。最近，第二丰富的植物大麻素大麻二酚（CBD）在临床上被添加到THC中（口腔喷雾Sativex）以减少THC的精神活性作用，但临床证据挑战了这一概念的成功，因为最近的报告表明，Sativex产生与THC相似的主观和其他效果，包括“高”和“大麻样”，并损害认知和注意力。与此同时，一些临床前报告现在已经显示出单独使用CBD的强大镇痛效果。这项研究的长期目标是使用创新的临床前疼痛，滥用倾向和认知测定来确定高度有效和安全的基于大麻素的药物疗法用于治疗神经性疼痛。R 03行为科学跟踪奖申请的目的是通过剂量相加分析，使用刺激和非诱发的神经性疼痛测定和不良反应测试，定量确定两种推定的镇痛大麻成分CBD和THC单独和组合的相对功效。中心假设是CBD是比THC更有效的抗神经病剂，并且CBD+THC组合将产生相加的但不是协同的镇痛作用。我们假设，与THC相比，CBD不会产生依赖性或认知障碍，并且CBD+THC组合在这些不良反应措施上与单独的THC相似。目的1将证明CBD比THC更有效地在经历化疗诱导的神经性疼痛的小鼠中产生条件性位置偏好。结果还表明CBD和THC的镇痛作用之间缺乏协同作用。目标2将证明CBD的安全性优于CBD。长期单独使用THC或THC+CBD会导致身体依赖，而急性治疗会产生认知障碍。CBD本身不会产生身体依赖或影响认知能力。这项研究具有重要意义和创新性，因为它偏离了目前对CBD作为THC缓解疼痛的公认辅助药物的关注，而是将CBD单独鉴定为具有改善疗效和安全性的抗神经病药物。创新还通过在几个行为终点中使用剂量添加分析来结合严格的量化来实现，以提供THC，CBD和THC+CBD的安全性和有效性的全面比较。创新还通过组合使用刺激诱发和非诱发测定进行神经性疼痛测试以及用于基于CB的药物疗法的更新颖的滥用倾向和认知测定来实现。