CN108143726B - 大麻二酚与5-ht2a受体拮抗剂及5-ht再摄取抑制剂的药物组合物及其用途 - Google Patents
大麻二酚与5-ht2a受体拮抗剂及5-ht再摄取抑制剂的药物组合物及其用途 Download PDFInfo
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- CN108143726B CN108143726B CN201611094015.4A CN201611094015A CN108143726B CN 108143726 B CN108143726 B CN 108143726B CN 201611094015 A CN201611094015 A CN 201611094015A CN 108143726 B CN108143726 B CN 108143726B
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Abstract
本发明公开了一种组合物,并且提供了使用这些组合物预防和/或治疗抑郁症的方法,以及所述组合物在制备预防和/或治疗抑郁症的药物中的应用。该组合物包含大麻二酚以及5‑HT2A受体拮抗剂及5‑HT再摄取抑制剂或其可药用盐,且可以包括一种或多种可药用载体或赋形剂,其中大麻二酚的用量和5‑HT2A受体拮抗剂及5‑HT再摄取抑制剂或其可药用盐的用量使得该组合物的作用优于每种用量的药物单独使用时的作用。
Description
技术领域
本发明涉及一种组合物及其在预防和/或治疗抑郁症中的应用,特别涉及一种大麻二酚与 5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)的组合物及其在预防和/或治疗抑郁症中的应用。
背景技术
抑郁症是一种严重影响身心健康的情感障碍性精神疾病,主要表现为明显而持久的心境低落,并伴有思维和行为异常。抑郁症已成为现代社会的常见病。目前,药物治疗是对抑郁症治疗的首要选择。临床上有几种典型的抗抑郁药都是通过提高单胺类物质水平如5-HT、NE发挥抗抑郁作用。
目前抗抑郁药主要分为传统抗抑郁药和新型抗抑郁药。传统抗抑郁药是指单胺氧化酶抑制剂(MAOIs)和三环类抗抑郁药(TCAs)及四环类抗抑郁药。新型抗抑郁药是指选择性5-HT再摄取抑制剂(SSRIs)、五羟色胺去甲肾上腺素重摄取抑制剂(SNRIs)以及 5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)等。
其中,5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)的代表药物为奈法唑酮(Nefazodone)及曲唑酮(Trazodone)。SARIs是一种5-HT增强剂,作用机制较独特,主要通过对5-HT2受体拮抗作用和对5-HT再摄取的抑制作用,最终促进5-HT1a受体调控的神经递质传递。
奈法唑酮口服后吸收快而完全,达峰时间约为1h,首过效应明显,消除半衰期为2~ 4h,与血浆蛋白结合率高,分布容积为0.22L~0.87L/kg。该药也适用于抑郁症的维持治疗及老年期抑郁症,其不足之处在于该药需2次/d用药,对CYP3A3/4的抑制作用明显,引起药物相互作用的可能性大。常见的不良反应为恶心、便秘、嗜睡、头晕、口干、视力模糊、体位性低血压、体重增加等。
曲唑酮是一种相对选择性SARIs,对去甲肾上腺素再摄取的抑制作用较弱。该药已应用于临床多年,其抗抑郁及镇静作用明显,同时具有抗焦虑作用,对性功能影响小。曲唑酮口服易吸收,达峰时间为1~2h,消除半衰期为5~9h,血浆蛋白结合率为89%~95%。适用于老年患者及伴有焦虑及失眠的患者,但需注意用药早期可能发生直立性低血压、体重增加等。
正是由于SARIs类药物的低毒性,其能够用于老年患者,且改善睡眠效果值得肯定,但是随之带来的是这类药物单独使用抗抑郁效果并不强,给药剂量高或给药频次多,患者体重由减轻到增加,同时长期使用奈法唑酮易导致肝损伤。
可见,确定挖掘新型的、疗效明确、副作用小的抗抑郁药,或新的组合治疗方案是亟待继续解决的重要问题。为了更有效地进行治疗,实际应用时通常会将不同的药物的作用机理进行互补应用,从而实现药物的组合使用或联合应用。例如CN101939017B公开了植物大麻素与阿立哌唑组合用于预防或治疗精神病或精神障碍,以减少或消除阿立哌唑的不良副作用,其中减少或消除的不良副作用选自僵住症和下垂症。
大麻作为医药的应用早已知晓,并且在19世纪,大麻制品被推荐作为催眠镇静剂,其可用于治疗癔症、精神错乱、癫痫症、神经性失眠症、偏头痛和痛经。
20世纪40年代,研究人员从大麻中分离得到大麻二酚(CBD),体内实验发现CBD 不但能拮抗THC激动大麻素I型受体(CB1R)所引发的精神活性,而且具有抗惊厥、抗焦虑、抗精神病、镇静催眠、抗炎及神经保护作用。临床前及临床研究表明,CBD药动学性质良好,注射后能迅速透过血脑屏障,脑神经保护作用显著。CBD能够通过多途径发挥神经保护作用,并且其毒性弱、副作用少。目前,FDA已经授予含有大麻二酚的药物三种罕见病(儿童发作性癫痫LGS、Dravet癫痫综合症、新生儿缺氧缺血性脑病(NHIE)) 药物资格。
尽管CN101939017B公开了植物大麻素大麻二酚与阿立哌唑组合用于预防或治疗精神病或精神障碍,以减少或消除阿立哌唑的不良副作用。但是由于CBD有镇静催眠的作用,在临床实验中发现,CBD在治疗精神类疾病时,最常见的副作用为腹泻、体重下降、嗜睡、疲劳等。同时,可以获知的是,目前很多药物的联合应用,效果并不好,有时还会出现严重的不良反应。如选择性5-HT再摄取抑制剂(SSRI)类药物与曲唑酮联合应用可引发5-HT 综合征,进而发生的潜在致命综合征。其特征包括精神状态改变、神经肌肉兴奋及自主神经功能紊乱。因此,需要可用于治疗抑郁症的新的组合物,该组合物有效且不会引起与现有技术化合物有关的有害的副作用。
因此,本发明的发明人将一定量的5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)或其可药用的盐与大麻二酚(CBD)制成组合物用于抑郁症的治疗,获得了很好的治疗效果,不但可以治疗抑郁症,且在低剂量下就能起到有效的治疗效果,同时能够降低体重增加的风险,以及避免肝损伤等不良反应。
发明内容
在阅读了优选实施方案和所附权利要求的详细描述后,本发明的这些和其他目的、优点和用途将对本领域技术人员显示出来。本发明旨在提供一种新组合物,并且提供了使用这些组合物预防和/或治疗抑郁症的方法,以及所述组合物制备预防和/或治疗抑郁症的药物中的应用。
申请人出人意料的发现,大麻二酚(CBD)与5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)类药物能够实现良好的联合应用,具有协同作用,二者联合应用后,互相减轻或消除副作用。据此,本发明提供了一种药物组合物,它包括一定量的大麻二酚或其可药用形式以及一定量的5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)或其可药用形式,且可以包括一种或多种可药用载体或赋形剂,其中大麻二酚的使用能够降低5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)的用量,使得该组合物的作用优于每种用量的药物单独使用时的作用。因此,当将大麻二酚与5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs) 用于预防和/或治疗抑郁症及相关病症时,它们确实具有协同作用。结果是大麻二酚与 5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)的联合应用在更多患者中具有优于各药物单独使用产生的作用。这种良好的作用可以使副作用更低或在个体患者或治疗组患者总体结果方面恢复得更快或更完全。在治疗上述各种抑郁症的治疗过程中优选使用该药物组合物。
本发明旨在提供一种组合物,并且提供了该组合物的组成及其在治疗抑郁症中的应用。
本发明提供一种低剂量的用于治疗抑郁症的组合物,包括5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)或其可药用的盐和大麻二酚(CBD)。
制备上述组合物的方法,包括如下步骤:将所述5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)或其可药用的盐与CBD按比例混合均匀,得到所述组合物。
本发明所述的5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)可以是曲唑酮或奈法唑酮,其可药用的盐包括以无机酸或有机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸等;所述有机酸例如乙酸、丙酸、己酸、庚酸、丙酮酸、乳酸、丙二酸、丁二酸、苹果酸、马来酸、富马酸、酒石酸、柠檬酸、苯甲酸、邻-(4-羟基苯甲酰基)苯甲酸、肉桂酸、扁桃酸、甲磺酸、乙磺酸、叔戊酸、叔丁基乙酸、十二烷基硫酸、葡萄糖酸、谷氨酸、萘甲酸、水杨酸、硬脂酸等。
本发明所述的组合物可制成具体的剂型,通过任何适当的途径例如口服,直肠、鼻、肺部、局部(包括口腔和舌下)、透皮、脑池内、腹腔内、阴道和胃肠外(包括皮下、肌内、鞘内、静脉内和皮内)途径给药,优选为口服途径。应理解,优选途径取决于待治疗患者的一般情况和年龄、待治疗疾病的性质和具体活性成分或所选择的活性成分。
口服给药的组合物包括固体剂型,例如胶囊剂、片剂、糖衣片、丸剂、锭剂、粉末剂和颗粒剂。
口服给药的组合物还包括液体剂型,例如溶液剂、乳剂、混悬剂、糖浆剂和酏剂。
胃肠外给药的组合物包括无菌的水性和非水性可注射溶液、分散液、混悬液或乳液,以及在使用前重新溶解于无菌可注射溶液或分散液的无菌粉末。
其它的适合给药剂型包括栓剂、喷雾剂、软膏剂、乳膏剂、凝胶剂、吸入剂、皮肤贴片、埋植剂等。
本发明的组合物或根据本发明生产的组合物可通过任何适当的途径给予,例如以片剂、胶囊剂、粉末剂、糖浆剂等形式口服,或以溶液的形式胃肠外注射。为了制备这种组合物,可采用本领域已知的方法,而且可采用本领域内通常使用的任何药物可接受的载体、稀释剂、赋形剂或其它添加剂。
对于胃肠外给药,可以使用一种或多种活性成分的无菌水溶液、含水丙二醇溶液、含水维他命E溶液或芝麻油或花生油溶液。如果有必要,这种含水溶液应恰当缓冲,而且液体稀释剂首先用足够的盐或葡萄糖制成等渗的。含水溶液尤其适合于静脉内、肌内、皮下和腹腔内给药。通过本领域技术人员已知的标准技术容易制得所采用的无菌含水介质。
通过将一种或多种活性成分和可能的添加剂溶解于一部分注射用溶剂(优选无菌水),调整溶液至所需体积,灭菌溶液并将其灌注到适当的安瓿或小瓶中,可制备注射用溶液。可加入本领域内常用的任何恰当添加剂,例如张力剂、防腐剂、抗氧化剂等。
恰当的药物载体包括惰性固体稀释剂或填充剂、无菌水溶液和各种有机溶剂。
固体载体的实例有乳糖、白土、蔗糖、环糊精、滑石粉、琼脂、果胶、阿拉伯胶、硬脂酸、纤维素的低级烷基醚、玉米淀粉、马铃薯淀粉、滑石粉、硬脂酸镁、明胶、乳糖、胶等。
可使用任何其它通常用于着色、矫味、防腐等目的的辅料或添加剂,只要它们和活性成分或已使用的成分相容。
液体载体的实例有糖浆、花生油、橄榄油、磷脂、脂肪酸、脂肪酸胺、聚氧乙烯和水。相似的,载体或稀释剂可以包含本领域内已知的任何缓释材料,例如单独的或与蜡混合的单硬脂酸甘油酯或二硬脂酸甘油酯。
通过将一种或多种本发明的活性成分与药物可接受的载体混合而形成的组合物,然后可以以适合公开给药途径的各种剂型方便地给予。通过药学领域内已知的方法可方便地使制剂以单位剂型存在。
本发明的活性成分可配制为相似或不相似的药物组合物和其单位剂型。
如果口服给药采用固体载体,制剂可以是片剂、置于硬明胶胶囊中的粉末或小丸形式,或可以是含片或锭剂形式。
如果采用液态载体,制剂可以是糖浆剂、乳剂、软明胶胶囊或无菌可注射液体,例如水性或非水性液体混悬剂或溶液。药物制剂可根据药物配方的标准程序方便地制成单位剂型。每单位剂量的活性化合物的量可能会根据活性化合物的性质和预期的剂量方案而改变。
本发明所使用的CBD可以是化学合成产物、生物合成产物、植物提取物或采用其他方式制备得到。优选的,本发明所述的大麻二酚是植物提取物,所述的植物可以为大麻Cannabis sativa L.的秆芯、花、叶、籽和/或籽的外壳。
本发明提供的组合物,将5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)或其可药用的盐和CBD合用,不但可以治疗抑郁症,CBD的使用还可以降低5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)用量,同时减轻或消除单独使用SARIs或其可药用的盐时体重增加的风险,以及避免肝损伤等不良反应。
本发明还提供了一种降低5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)用量的方法,即加入一定比例CBD,使得二者在低剂量下就能够发挥抗抑郁作用。
通过考虑将要组合的每个成分的药物性质、该药物组合的性质和患者症状,决定本发明所用的药物剂量。就本发明组合的应用而言,它应提供活性组分,使得可以获得有效量。当然,产生有效作用所需的5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)(或其药学上可接受的盐或溶剂合物)和大麻二酚的用量可以改变并且最终由医务人员决定。所考虑的因素包括给药途径和制剂的性质、接受者的体重、年龄和一般情况以及所治疗疾病的性质和严重程度。可以将适合于口服给药的制剂制成分散单位,诸如各自含有预定量活性成分的片剂或胶囊。
本申请的发明人出乎意料的发现,当与一定比例CBD联用时,奈法唑酮以及曲唑酮剂量明显降低,且每天给予一次时,均表现出良好的抗抑郁作用。优选地,SARIs或其可药用的盐与CBD的重量比为大约1:0.2-20,更优选地,SARIs或其可药用的盐与CBD的重量比为大约1:1-20,更优选地,SARIs或其可药用的盐与CBD的重量比为大约1:5-20,在本发明实施方式中SARIs或其可药用的盐与CBD的重量比可以为1:0.2、1:0.3、1:0.4、1:0.5、 1:0.6、1:0.7、1:0.8、1:0.9、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:11、1:12、 1:13、1:14、1:15、1:16、1:17、1:18、1:19、1:20。
本发明的另一个目的是提供CBD用于制备药物组合物的用途,该药物组合物和SARIs 或其可药用的盐联用。
另一方面,本发明涉及CBD制备药物组合物的用途,该组合物用于降低5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)的用量。本发明还涉及CBD制备药物组合物的用途,该药物组合物用于减轻或消除单独使用SARIs或其可药用的盐时体重增加的风险,以及避免肝损伤等不良反应。
另一方面,本发明涉及大麻二酚和5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)或其可药用的盐的组合制备药物组合物或药盒的用途,该组合物或药盒用于预防和/或治疗抑郁。优选的,所述的组合物或药盒预防和/或治疗抑郁的同时,减轻或消除体重增加的风险,以及避免肝损伤等不良反应。
另一方面本发明涉及预防和/或治疗抑郁的方法,该方法包括给予有需要的患者治疗有效量的大麻二酚和5-HT2A受体拮抗剂及5-HT再摄取抑制剂(SARIs)或其可药用的盐组合。
进一步地,所述的抑郁包括心因性抑郁、内因性抑郁、疑病型抑郁、焦虑性抑郁、假性痴呆型抑郁、慢性抑郁。更优选的,本发明所述的抑郁为慢性抑郁。优选的,本发明所述的预防和/或治疗抑郁包括预防和/或治疗选自如下的抑郁症状:持续性悲伤、焦虑或空虚情绪、绝望感、悲观、罪恶感、无价值感或无助感、失去曾经享受过的爱好和活动包括性的兴趣或快乐、精力减少、疲劳或迟缓、难于集中精神、记忆困难或难于作决定、失眠、早晨早醒或睡过度、无食欲和/或体重减轻或者吃得过多和体重增加、想到死亡或自杀、自杀企图、多动、易怒、对治疗无反应的持续性身体症状或前述症状的任何组合。
本发明的药物组合物可通过同时给药给予。本文使用的术语“同时给药”指给予大麻二酚和SARIs的时间间隔不超过15分钟,例如最多10分钟,例如最多5分钟,或者例如最多2分钟。大麻二酚和SARIs还可以包含在“同一单位剂型”或“分离的剂型”中。本文使用的术语“同一单位剂型”指既包含大麻二酚,也包含SARIs的剂型。本文使用的术语“分离的剂型”指大麻二酚含在一种剂型中而SARIs含在另一种剂型中。这些组合物以治疗抑郁有效的数量和给药方案向患者给药。
附图说明
图1表示抑郁症大鼠模型给予不同药物组合物一周后大鼠体重变化。(每组柱状图左侧表示给药前体重,右侧表示给药后体重)
图2表示抑郁症大鼠模型给予不同药物组合物一周后丙氨酸氨基转移酶ALT变化。(每组柱状图左侧表示给药前丙氨酸氨基转移酶ALT检测值,右侧表示给药后丙氨酸氨基转移酶 ALT检测值)
具体实施方式
需要说明的是,在不冲突的情况下,本申请中的实施例及实施例中的特征可以相互组合。下面将结合实施例来详细说明本发明。
实施例1 SARIs与CBD的协同抗抑郁作用
强迫游泳实验也叫做“行为绝望”实验,是一个可信的抑郁动物模型,被广泛应用于筛选抗抑郁类药物以及研究抗抑郁药物的作用机理。大量的研究表明,该模型对于绝大多数的抗抑郁药物是敏感的。
取健康昆明种小鼠120只,20-25g。饲养条件:10只/笼,室温22±1℃,湿度50±10%,自然光照,自由摄食饮水。所有动物于饲养环境中适应5天后开始实验,实验前禁食12-16 小时,食水自由。将上述120只小鼠按性别体重随机分为12组,每组10只,雌雄各半:具体分组方法为:
对照组,给予等体积的生理盐水;
CBD组三组,给药量为4、200、400mg/kg体重;
曲唑酮组给药量分别为20mg/kg体重;
曲唑酮+CBD合用组三组,曲唑酮和CBD给药量比例分别为1:0.2、1:10、1:20;
奈法唑酮组给药量分别为20mg/kg体重;
奈法唑酮+CBD合用组三组,奈法唑酮和CBD给药量比例分别为1:0.2、1:10、1:20;
正式测试前24小时,将小鼠置于水深10cm的玻璃圆缸(高25cm,直径10cm)内,水温24±1℃,作强迫游泳训练15分钟。将各组给药后再次将小鼠置于水深10cm的玻璃圆缸内强制游泳6min,观察并记录最后4分钟内小鼠的不动时间。当小鼠停止挣扎,浮在水中保持不动,或仅做一些必要的轻微动作保持头部浮在水面上的时间视为游泳不动时间;其中,CBD组均为在腹腔注射给药CBD后60min再将小鼠置于玻璃圆缸内强制游泳6min,曲唑酮、奈法唑酮组均为在腹腔注射给药后30min再将小鼠置于玻璃圆缸内强制游泳6min,联合用药组(合用组)均为先腹腔注射给药CBD,30min后再腹腔注射给药曲唑酮、奈法唑酮,再过30min后将小鼠置于玻璃圆缸内强制游泳6min。
实验结果见表1。在小鼠的强迫游泳实验中,曲唑酮、奈法唑酮、CBD以及合用组均产生有效抗抑郁作用。其中曲唑酮和CBD的合用组与单独使用曲唑酮比较,合用组游泳不动时间明显缩短,相同CBD剂量下,合用组中与单独使用CBD比较,也呈现出不动时间的明显缩短。CBD和奈法唑酮的合用组呈现类似结果。
表1 SARIs和CBD对小鼠游泳不动时间的影响
注:与对照组相比*P<0.05;**P<0.01
实施例2本发明组合物对抗抑郁药的不良反应影响实验-小鼠体重变化
建立抑郁症大鼠模型:大鼠60只,180~210g,饲养于标准环境内(室温(22±2)℃,12h黑, 12h白,8:00开灯),自由饮食,饮水。
确立慢性刺激:每天随机给予大鼠电击足底、禁食、冰水游泳、禁水、热刺激、颠倒黑白、无刺激和夹尾刺激,建立慢性不可预计温和应激(chronic unpredictable mildstress,CUMS) 抑郁症大鼠模型,进行下一步实验。
对建模后的大鼠在第21d进行强迫游泳试验,结果表明,经过21d的慢性刺激后,大鼠的不动时间明显延长,与刺激前相比具有显著性差异(P<0.01);大鼠的上窜时间明显缩短 (P<0.01),表现出明显的抑郁样行为,证明模型建立成功。
将抑郁症大鼠随机分为6组:对照组(给予等体积的生理盐水);CBD组(4mg/kg);曲唑酮组(20mg/kg);曲唑酮+CBD合用组(20:4mg/kg);奈法唑酮组(20mg/kg);奈法唑酮+CBD合用组(20:4mg/kg)。
测定抑郁症大鼠模型给予不同药物组合物一周前后大鼠体重变化,结果如图1所示,其中,与相同剂量合用组比较,单独给予曲唑酮或奈法唑酮时,大鼠体重增加较多,不良反应较大。而给予大麻二酚和曲唑酮或大麻二酚和奈法唑酮的组合物大鼠,体重增加不明显,不良反应较小。
实施例3本发明组合物对抗抑郁药的不良反应影响实验-肝损伤
按照实施例2中方法建立抑郁症大鼠模型。
将抑郁症大鼠随机分为6组:阳性对照模型组(以50%CCl4-食用油皮下注射诱导大鼠肝损伤);CBD组(200mg/kg,给药一周);曲唑酮组(10mg/kg,给药一周);曲唑酮+CBD 合用组(10:200mg/kg,给药一周);奈法唑酮组(10mg/kg,给药一周);奈法唑酮+CBD 合用组(10:200mg/kg,给药一周)。
取建模前大鼠眼眶静脉血,给药一周后,再取各组大鼠眼眶静脉血,血浆离心后进行生化检测(丙氨酸氨基转移酶ALT)测定。结果如图2所示,其中曲唑酮、奈法唑酮组以及四氯化碳肝损伤阳性对照模型组在给药后均表现出ALT升高,表示肝细胞受到损伤,而曲唑酮+CBD、奈法唑酮+CBD合用组未表现出明显肝损伤,结果表明予大麻二酚能够降低曲唑酮、奈法唑酮肝损伤风险。
Claims (5)
1.大麻二酚和5-HT2A受体拮抗剂及5-HT再摄取抑制剂SARIs或其可药用的盐制备用于预防和/或治疗抑郁症并且减轻或消除体重增加的风险以及避免肝损伤不良反应的药物组合物的用途,所述的5-HT2A受体拮抗剂及5-HT再摄取抑制剂SARIs或其可药用的盐与大麻二酚CBD的重量比为1:0.2-20,所述的5-HT2A受体拮抗剂及5-HT再摄取抑制剂SARIs选自奈法唑酮或曲唑酮。
2.根据权利要求1所述的用途,其特征在于,所述组合物中5-HT2A受体拮抗剂及5-HT再摄取抑制剂SARIs或其可药用的盐与大麻二酚CBD的重量比为1:1-20。
3.根据权利要求2所述的用途,其特征在于,所述组合物中5-HT2A受体拮抗剂及5-HT再摄取抑制剂SARIs或其可药用的盐与大麻二酚的重量比为1:5-20。
4.根据权利要求1-3任意一项所述的用途,其特征在于,所述组合物选自胶囊剂、片剂、丸剂、锭剂、颗粒剂、乳剂、混悬剂、糖浆剂、注射剂、栓剂、喷雾剂、软膏剂、凝胶剂、吸入剂、皮肤贴片和埋植剂。
5.根据权利要求1所述的用途,其特征在于,所述的抑郁症包括心因性抑郁、内因性抑郁、疑病型抑郁、焦虑性抑郁、假性痴呆型抑郁、慢性抑郁。
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