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2024-03-07 18:15:19

通灵, 出体与松果体分泌DMT的关系【转载】 - 知乎

通灵, 出体与松果体分泌DMT的关系【转载】 - 知乎首发于思考与白日梦切换模式写文章登录/注册通灵, 出体与松果体分泌DMT的关系【转载】Josie 木熙Youtube频道 Josie’s Mind & Soul【转自：鹿溪星籽杂记】人体内的DMT，产生於人脑的松果体，有些人认为DMT参与了一些心理和神经状态的运作。其中之一是自然做梦状况下的视觉效果，好比做梦有看到甚麽的。另一个参与的就是人的濒死经验，还有宗教的遥视，预见未来等。现鹿溪星籽杂记以通灵丶出体与松果体分泌DMT的关系，来阐述医学研究人员对DMT的研究分析，让大家更能了解。新历年推荐大家阅读David Wilcock的《源场调查》，中译本的书中第二章第67页，就提到DMT (Dimethyltrptamine)，David Wilcock特别谈到它具有压电发光的现象，让松果体里充满压电微晶体，让这个第三眼吸收更多的光子，使松果体看得见。因此，DMT可说是人与灵界交流的神经化学物(星球内共振的语言分子)，一些亚马逊河原始部落的巫师，透过它，和大自然对话，现在，巴西一些教会也会使用它来让信徒们的精神灵性很快就能回归大自然，融入大自然中。DMT可以说是一种自然界生成的强力迷幻剂，化学结构颇类似於麦角酸二乙醯胺(lysergic acid diethylamide, LSD)。因为他是自然界的产物，性质较LSD温和。DMT分子核心的吲哚环具有阻断脑部血清素(serotonin)的功能。本剂的迷幻作用约於注射後5分钟开始，可持续一小时左右。DMT在精神分裂患者的体液内可见，且可以藉化学法合成。柯合巴(cohoba)是西班牙拓荒早期南美奥利诺科平原(Orinoco Plain)和千里达岛印第安人爱吸的一种迷幻性鼻烟，一般相信里面亦含有DMT。人体内内源性的DMT，产生於人脑松果体，有些人认为DMT参与了一些心理和神经状态的运作。其中之一是自然做梦状况下的视觉效果，好比做梦有看到甚麽的。DMT另一个参与的就是人的濒死经验，还有宗教的遥视(预见未来)。医学研究人员赛马卡拉威提出一系列的DMT生化机制，在1988他提出DMT可能是连接梦境与视觉现象的介质，在他的研究中，做梦时会有DMT 周期性的浓度上升，诱发做梦时的视觉效果和其他可能自然出现状态的意识。他的一个新的假设是，DMT除了参与梦境意识改变，内源性DMT亦参与正常的清醒状态的意识。他认为，正常的意识觉醒状况可以被看作是一个DMT作用下的迷幻状况经过控制後的一个正常状况。也就是说，一般人正常生活状况就有DMT介入，但当DMT控制的不过好，或者控制这些DMT系统变得松散，他们的行为就不再联结到外部世界，此时意识变异状况就发生。 Rick Strassman里克.斯特拉斯曼医学博士在其着作中，认为DMT是在神奇的松果体pineal gland所产在，而要产生DMT的酵素methyltranferase就在pineal gland松果体内。(DMT和serotonin , melatonin化学式很相关，而serotoin 和melatonin又和睡眠有关)。Strassman博士把DMT称做灵性分子Spirit molecule，1990年时在新墨西哥大学进行DMT研究，有60位自愿接受DMT注射的人接受测试。结果显示出DMT在死亡或濒临死亡NDE前，会被松果体大量分泌出来，造成所谓濒临死亡经验现象。此际会看到神丶看到光丶看到佛丶先人等。有趣的是DMT在人还在胚胎时是第49天就开始分泌，因此有人认为这时才是灵魂在体内活动的开始。从他的一些测试对象报告，发现被实验的人都可感觉到濒死体验式的声音或视觉幻相。另外有些打DMT实验的人甚至说有接触到外星人，像reptilian爬虫类外星人，而且被这些外星人所探索，测试，操纵，肢解，教导，做爱，甚至被强奸。看到这里大家可能会想说那些通灵，或接受再联接疗法Reconnective healing後，说有看到光丶神等，或看到XX… 之类的都是DMT造成的幻影吗?对於那些通灵丶那些催眠回朔後所产生的画面都是DMT所造成的虚假幻影? 是这样吗? 最早DMT是某些北美及南美巫师要通灵时，会吃一些DMT成份的药草协助，来快速达到通灵。DMT的影响开始在两分钟内就达到高峰，并在20分钟效果开始减弱。对血压丶心率丶体温丶瞳孔放大皆大幅上升。 Rick. Strassman博士的研究发现，在某些情况下，松果体是不分泌褪黑激素melatonin而转而分泌DMT。70年代初Strassman 也开始研究禅佛教寺院的僧侣。许多僧侣与他分享他们冥想的方式後，所看到的非现实世界景象，修行後pineal gland分泌DMT上升，会造成冥想中遇到的幻象。然而佛教寺要他停止继续研究，因为这样会冒犯佛教的修行者，让人误以为大家冥想都是在幻想。Strassman博士的实验最後停止了, 因为医疗道德的原因.因为DMT毕竟是影响心灵层面的一个物质他研究最後认为 DMT 乃是影响大脑的接收信息能力，而非造成大脑产生任何幻影。他们还认为，DMT可以使我们的大脑接收宇宙暗物质讯息(宇宙有一大半的组成是DARK MATTER)，以David wilcock 的观点，就是源场的光子信息。人体内源的DMT乃是在调控人脑内的接收管道，就好像调控电视天线方向，对比，聚焦，这样就可以连接到不同平行宇宙的东西。DMT 可以让人连结到非物质的世界，Straussman 个人观点是冥想打坐看到的东西可能和DMT有关，让人可以连结更高层次的世界。但灵魂出窍看到的东西又是另一回事，Strassman 博士认为OBE(灵魂出窍)和脑部的颞叶有关。数千年来，亚马逊河流域的诸多部落一直在用这种死藤Ayahuasca治病。根据当地的传统风俗，死藤被看作是神圣的象徵，只有部落的萨满或草医懂得制备“神奇饮料”死藤水的方法。在南美洲印加人盖邱亚族语中，Ayahuasca意思是“死亡或灵魂之藤”，俗称死藤。它是亚马逊河流域热带雨林中的一种药用植物，这种植物和其他几种植物混合起来煮的汤药，具有祛病提神丶强身健体的功效。采集和制备死藤也是很神圣的事，要通过专门的宗教仪式来进行。死藤的水煮物有效成分：二甲基色胺。DMT作用与LSD很像，但作用时间短，副作用比较少。60年代时以饮用死藤水进行宗教仪式的教派，一度从南美传播到北美洲和欧洲。後来因为各国政府的取缔禁药行动，而被列为禁药之列。後来该教派也转入地下活动，继续使用死藤水。不过巴西政府的研究发现饮用死藤水不但不会上瘾，饮用过的人也不会变成毒虫或精神病患；使用者反而更健康丶积极丶开朗丶甚至还可以用来戒酒丶戒海洛因。所以死藤在巴西是完全合法的。到了90年代末，包括美国也开始开放LSD丶MDMA及其他迷幻药物的学术研究，死藤水才在精神治疗上的用途又开始受到注意。这些药物起作用要有背景，背景就是你修行累积的程度。有关此类迷幻性化学物质，大部分的国家与社会皆排斥这类研究，但跳开这种保守与恐惧的想法，来省视大自然为何有这类产物来让人类进入另一层次的意识情境，却值得我们反省不能一直限制研究它；当然，在它还没清清楚楚解开其真正对於身体精神无害的影响机构前，以及安全剂量是多少，大家还是不要轻易随便尝试吧! 以下视讯稍为长一点，但很重要，且已经翻译成简体中文字幕，确实很值得从头到尾浏览一遍。关於死藤水的体验。死藤水（奇楚瓦语：Ayahuasca，Template:IPA-qu）是九节属植物煎熬成的一种饮料。饮用後其中的二甲基色胺等物质会发挥效用，使人陷入所谓「通灵」状态。因此被南美原住民广泛应用於宗教仪式中。1950年哈佛大学植物学家 Richard Evans Schultes 记录，他在哥伦比亚的亚马逊雨林中发现死藤水被当地人用於宗教和医疗中。二甲基色胺，第一类精神药品，色胺类致幻剂。不仅存在於植物中，还以痕量见於人体中，由色胺-N-转甲基酶催化产生，但具体功能不明。结构上与神经递质血清素和其他色胺类致幻剂5-甲氧基二甲基色胺丶蟾毒色胺丶脱磷酸裸盖菇素类似。（之所以转载这篇文章是因为它解释了在我身上一直发生的现象。如果我所看到的“超屏幕视觉”和“超听觉”是因为松果体被激活而分泌的dmt，并且接受到的信息也都不是幻觉的话，那么，这个东西也就有其研究价值。也就可以解释为什么很多人也有同样的经验。但是非常不推荐个人因为好奇而去使用精神类药品，这是非常危险的做法。因为本人即使是在清醒状态下都没有办法控制自己如何与灵界存在沟通，并且人生功课会变得更加的困难。试想，物质世界的磨炼都还没有搞定，用毫不坚定和愚昧无知的状态去接触精神世界是非常危险的！请千万不要去盲目尝试！）发布于 2020-02-07 13:13通灵灵魂出体神秘学（Mysticism）赞同 15726 条评论分享喜欢收藏申请转载文章被以下专栏收录思考与白日梦这是一个关于生命的不负责

对苯二甲酸二甲酯_百度百科

酸二甲酯_百度百科网页新闻贴吧知道网盘图片视频地图文库资讯采购百科百度首页登录注册进入词条全站搜索帮助首页秒懂百科特色百科知识专题加入百科百科团队权威合作下载百科APP个人中心收藏查看我的收藏0有用+10对苯二甲酸二甲酯播报讨论上传视频一种聚酯的单体对苯二甲酸二甲酯（DMT），是一种聚酯的单体。无色斜方晶系结晶体。溶于热乙醇、甲醇、乙醚、氯仿，不溶于水。主要用于合成聚酯纤维、树脂、薄膜、聚酯漆及工程塑料等。中文名对苯二甲酸二甲酯外文名Dimethyl terephthalateD.M.T.; Terephthalic acid dimethyl ester; Benzene-1,4-dicarboxylic acid dimethyl ester~Terephthalic acid dimethyl ester别名1,4-苯二甲酸二甲酯; DMT; 对酞酸二甲酯化学式C10H10O4分子量194.184CAS登录号120-61-6EINECS登录号204-411-8熔点140.6 ℃沸点284.99 ℃密度1.175 g/cm³外观无色斜方晶系结晶体闪点148.04 ℃溶解性不溶于水，溶于热乙醇，溶于乙醚。目录1物化性质2主要类别3安全信息4用途5生产方法6上游7下游8安全术语9危险性概述10急救措施11消防措施12泄漏应急处理物化性质播报编辑InChIInChI=1/C10H10O4/c1-13-9(11)7-3-5-8(6-4-7)10(12)14-2/h3-6H,1-2H3熔点140-143℃密度1.29沸点288℃闪点154℃物化性质性状无色斜方晶系结晶体。熔点 140.6℃沸点 283℃相对密度 1.084折射率 1.4752溶解性不溶于水，溶于乙醚和热乙醇。 [1]相关类别: Color Former & Related Compounds;Functional Materials;Sensitizer;Alpha sort;D;DAlphabetic;DID - DIN;Pesticides&Metabolites;C10 to C11;Carbonyl Compounds;Esters;Aromatics;Isotope Labelled Compounds;Miscellaneous Reagents;ester series;芳烃;Microscopy Reagents;Various Chemicals;Analytical Reagents;Analytical/Chromatography;Building Blocks;C10 to C11;Carbonyl Compounds;Chemical Synthesis;Organic Building Blocks;分析标准品;通用试剂;酯;分析纯;原料Mol文件: 120-61-6.mol [2]主要类别播报编辑易燃液体毒性分级低毒急性毒性口服- 大鼠 LD50: >3200 毫克/ 公斤刺激数据眼- 兔子 500 毫克/ 24小时轻度爆炸物危险特性与空气混合可爆可燃性危险特性遇明火、高温、强氧化剂可燃；燃烧排放刺激烟雾储运特性包装完整、轻装轻放; 库房通风、远离明火、高温、与氧化剂分开存放灭火剂泡沫、二氧化碳、干粉、砂土、雾状水职业标准 STEL 0.1 毫克/ 立方米 [2]安全信息播报编辑危险类别码 36/37/38安全说明 24/25危险品运输编号 3256WGK Germany 1RTECS号 WZ1225000 [2]用途播报编辑主要用于合成聚酯纤维、树脂、薄膜、聚酯漆及工程塑料等 [1]生产方法播报编辑由对二甲苯生产聚酯的单体──对苯二甲酸乙二酯可经DMT，也可由对苯二甲酸与甲醇直接酯化得到。1963年以前，由于难以得到满足聚酯生产要求的高纯度对苯二甲酸，所得粗对苯二甲酸需先制成容易精制的DMT,经减压精馏或在甲醇中进行再结晶提纯后生产聚酯。1963年，精制对苯二甲酸的方法研究成功，开始由对苯二甲酸不经DMT而直接生产聚酯。进入70年代,这一趋势更明显。由于精制对苯二甲酸还有一定困难，成本较高，近年DMT的产量仍大于对苯二甲酸的产量。DMT由对苯二甲酸与甲醇酯化而得：早先采用硫酸催化剂，反应温度较低，但甲醇损失量大。近年采用高温、高压液相酯化,反应温度250～300℃,压力2～2.5MPa，可采用锡、锌、锑化物为催化剂,也可以不用催化剂，以对苯二甲酸计的收率可达96%～98%或更高。另一种生产DMT的方法是通过威顿法或称威顿-赫格里斯 (Witten-Hercules)法制得的。此法在对二甲苯的两个甲基氧化过程中,把先氧化的羧基进行甲酯化,以免在下一步氧化时发生副反应：为了简化流程，可把两步氧化合并在一个氧化反应器中进行，两步酯化也合并在一个酯化反应器中进行：合并氧化过程在塔式反应器中进行,反应温度140～170℃，压力0.4～0.7MPa，用钴盐或钴、锰盐为催化剂(见络合催化剂)。合并酯化过程在 200～280℃、2%～2.5MPa下进行，可不用催化剂。总收率以对二甲苯计为87%，以甲醇计为80%。此法在进行氧化反应时不用溶剂，反应器不需用钛材，产品容易提纯，因此从50年代后，被许多国家采用。缺点是以对二甲苯计总收率较低。 [2]图1图3图2上游播报编辑1,4-苯二甲酸、对苯二甲酸、甲醇、甲醇 [1]下游播报编辑聚酯切片、聚酯树脂漆类、F级聚酯酰亚胺绝缘漆 [1]安全术语播报编辑S24/25Avoid contact with skin and eyes. [3]避免与皮肤和眼睛接触。危险性概述播报编辑本品的刺激作用阈浓度为0．2mg/m3。接触者可引起植物一血管张力障碍，胃肠道方面的损伤，心区痛，皮肤瘙痒。还可引起贫血、中性白细胞减少、淋巴增多等。对皮肤和眼睛有刺激作用。 [4]急救措施播报编辑皮肤接触：脱去污染的衣着，用肥皂水及清水彻底冲洗。眼睛接触：立即翻开上下眼睑，用流动清水冲洗15分钟。就医。吸入：脱离现场至空气新鲜处。就医。食入：误服者给饮足量温水，催吐，就医。 [4]消防措施播报编辑危险特性：遇高热、明火或与氧化剂接触，有引起燃烧的危险。粉体与空气可形成爆炸性混合物，当达到一定的浓度时，遇火星会发生爆炸。有害燃烧产物：一氧化碳、二氧化碳。灭火方法及灭火剂：雾状水、二氧化碳、泡沫、砂土。消防员的个体防护：消防人员须佩戴防毒面具、穿全身消防服，在上风向灭火。 [4]泄漏应急处理播报编辑应急处理：切断火源。戴好口罩和手套。用砂土、干燥石灰或苏打灰混合，然后收集运到空旷处焚烧。如大量泄漏，收集回收或无害处理后废弃。 [4]新手上路成长任务编辑入门编辑规则本人编辑我有疑问内容质疑在线客服官方贴吧意见反馈投诉建议举报不良信息未通过词条申诉投诉侵权信息封禁查询与解封©2024 Baidu 使用百度前必读 | 百科协议 | 隐私政策 | 百度百科合作平台 | 京ICP证030173号京公网安备110000020000

“4ACO-DMT”能不能认定为毒品？ - 知乎

“4ACO-DMT”能不能认定为毒品？ - 知乎切换模式写文章登录/注册“4ACO-DMT”能不能认定为毒品？知乎用户brsMOB案例导入17岁的金某某通过微信联系潘某某，向潘某某金出售“4ACO-DMT”粉剂，并事先收取潘3500元。随即，金某某向上家购入0.6克“4ACO-DMT”粉剂，用胶囊进行分装。分装完成后，金某某携带0.17克“4ACO-DMT”粉剂至某酒吧，在与潘某某交易时被抓获。一、“4ACO-DMT”是什么？“4ACO-DMT” ，全称为“4-乙酰氧基-N,N-二甲基色胺”，是一种半合成色胺，又被称为“化学中间体”或“医药中间体”，通常情况下是褐色或灰白色粉末，可与水混合，制成药片、片剂、胶囊和凝胶片等制剂，属于半合成蘑菇素，是一种新精神活性物质。二、“4ACO-DMT”有什么效果？因为“4ACO-DMT”是一种化学合成物质，人类使用的时间很短，目前对其食用后的危害还没有准确的结论。目前显示，“4ACO-DMT”具有镇静的作用，能够达到致幻蘑菇、LSD、MDMA、DMT等迷幻药的效果。服用后会感觉触觉增强，身体形态发生变化，伴随有恶心、抑制体温调节、肌肉收缩松弛、尿频、鼻涕唾液增多、瞳孔扩张等副作用，还会出现幻觉，甚至癫痫。三、“4ACO-DMT”有没有被列管？“DMT”属于被我国管制的精神药品，被列管在《精神药品品种目录》第一类第六条中，又被称为二甲基色胺。但“4ACO-DMT”属于合成的物质，相当于是通过对化学分子式进行改造后，策划出来的新物质。截至目前，“4ACO-DMT”没有被联合国列管，也不属于我国法律所管制的麻醉药品和精神药品。我国的《麻醉药品品种目录》《精神药品品种目录》《非药用类麻醉药品和精神药品品种目录》中均没有对该物质进行列管。四、“4ACO-DMT”能不能认定为毒品？“4ACO-DMT”能够起到毒品的效果，但我国《刑法》规定，毒品是指鸦片、海洛因、冰毒等，以及国家规定管制的其他能够使人形成瘾癖的麻醉药品和精神药品。由于“4ACO-DMT”没有被列管，所以理论上说，纯粹的“4ACO-DMT”不能被认定为毒品。“4ACO-DMT”的确能达到毒品的效果，其分子式与致幻蘑菇中的赛洛西宾（Psilocybine）一样，可以通过人体代谢为赛洛新（Psilocine）。目前多起“4ACO-DMT”案件中，均检测出赛洛新成份。赛洛新被列管在《精神药品品种目录（2013年版）》第一类第21位，属于我国法律意义上的毒品。所以，从“4ACO-DMT”检测出赛洛新成份后，即会被认定为含有赛洛新的毒品。我国法律规定，毒品不以纯度折算，根据《非法药物折算表》，1克赛洛新相当于1克海洛因，即1克含赛洛新的“4ACO-DMT”，相当于1克海洛因。所以，被鉴定出赛洛新的“4ACO-DMT”，可能会被认定为毒品，但“4ACO-DMT”中，为何会含有赛洛新，是一个需要重点关注的问题。汤建彬律师提示您：擦亮眼，识别新型毒品！汤建彬律师北京市京都律师事务所高级合伙人擅长毒品犯罪及死刑复核辩护汤建彬律师，北京市京都律师事务所高级合伙人，北京律协刑事诉讼专业委员会委员，中国药物滥用防治协会会员。承办案件入选2018年度最高人民法院八大毒品犯罪典型案例及2019年度最高人民法院十大毒品犯罪典型案例。发布于 2021-07-30 18:10DMT毒品毒品犯罪赞同 83 条评论分享喜欢收藏申请

二甲基色胺_百度百科

胺_百度百科网页新闻贴吧知道网盘图片视频地图文库资讯采购百科百度首页登录注册进入词条全站搜索帮助首页秒懂百科特色百科知识专题加入百科百科团队权威合作下载百科APP个人中心收藏查看我的收藏0有用+10二甲基色胺播报讨论上传视频精神药品二甲基色胺，是一种有机化合物，化学式为C12H16N2。是第一类精神药品，属于色胺类致幻剂。不仅存在于植物中，还以痕量见于人体中，由色胺-N-转甲基酶催化产生，但具体功能不明。结构上与神经递质、血清素和其他色胺类致幻剂5-甲氧基二甲基色胺、蟾毒色胺、脱磷酸裸盖菇素类似。药品名称二甲基色胺外文名Dimethyltryptamine（DMT）别名N,N-二甲基-1H-吲哚-3-乙胺、N,N-二甲基色胺运动员慎用是是否纳入医保否药品类型化学药品化学式C12H16N2分子量188.269外观黄褐色固体CAS登录号61-50-7EINECS登录号200-508-4密度1.076 g/cm³熔点42 至 44 ℃沸点332.1 ℃闪点154.7 ℃目录1基本信息2理化性质3分子结构数据4计算化学数据基本信息播报编辑化学式：C12H16N2分子量：188.269CAS号：61-50-7EINECS号：200-508-4理化性质播报编辑密度：1.076g/cm3熔点：42-44ºC沸点：332.1ºC闪点：154.7ºC折射率：1.615外观与性状：黄褐色固体分子结构数据播报编辑摩尔折射率：61.06摩尔体积（cm3/mol）：174.9等张比容（90.2K）：452.5表面张力（dyne/cm）：44.7极化率（10-24cm3）：24.20计算化学数据播报编辑疏水参数计算参考值（XlogP）：无氢键供体数量：1氢键受体数量：1可旋转化学键数量：3互变异构体数量：0拓扑分子极性表面积：19重原子数量：14表面电荷：0复杂度：179同位素原子数量：0确定原子立构中心数量：0不确定原子立构中心数：:0确定化学键立构中心数量：0不确定化学键立构中心数量：0共价键单元数量：1新手上路成长任务编辑入门编辑规则本人编辑我有疑问内容质疑在线客服官方贴吧意见反馈投诉建议举报不良信息未通过词条申诉投诉侵权信息封禁查询与解封©2024 Baidu 使用百度前必读 | 百科协议 | 隐私政策 | 百度百科合作平台 | 京ICP证030173号京公网安备110000020000

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1,4-苯二甲酸二甲酯(Dimethyl terephthalate)

CAS: 120-61-6

化学式: C10H10O4

主页产品有机原料分子砌块 DMT

1,4-苯二甲酸二甲酯，也被称为PTMEG（聚四氢呋喃）或PTMG（聚四甲基二氧杂环己烷）是一种有机化合物。以下是关于它的一些性质、用途、制法和安全信息的介绍：

性质:

- PTMEG是无色液体，具有特殊的气味。

- 它具有低粘度和低表面张力，是一种相对稳定的化合物。

- 它在室温下不溶于水，但可溶于许多有机溶剂。

- PTMEG具有良好的热稳定性和化学稳定性，能够耐受多种化学物质的影响。

用途:

- PTMEG广泛用于制备弹性体、合成纤维和涂料等材料。

- 它是聚氨酯弹性体的主要原料，在制造汽车座椅、鞋类、服装等弹性材料时起到关键作用。

- PTMEG也被用于制备防滑塑料、食品包装膜、医疗器械等产品。

制法:

- 1,4-苯二甲酸二甲酯的制备通常是通过对苯二甲酸二甲酯进行酯交换反应得到的。

- 该反应一般在高温下进行，使用醇类作为酯交换反应中的醇基。

- 通常使用甲醇或乙醇作为反应物，反应时加入催化剂，如碱金属或碱金属醇。

安全信息:

- PTMEG在正常使用和储存条件下一般是安全的。

- 然而，它可能会导致皮肤刺激和眼睛刺激，因此在使用时需要注意个人防护措施。

- 如接触到皮肤，应立即用肥皂和水冲洗。如不慎接触到眼睛，应立即用大量清水冲洗并寻求医疗帮助。

- 在操作和储存PTMEG时，应远离火源和高温，以防止其燃烧和爆炸的风险。

请注意，以上简要介绍的性质、用途、制法和安全信息只供参考。在实际应用中，应仔细阅读相关的安全数据表（SDS）和操作说明，并遵循适当的操作和安全规范。最后更新：2023-12-21 00:21:33

中文名 1,4-苯二甲酸二甲酯英文名 Dimethyl terephthalate别名对酞酸二甲酯苯二甲酸二甲酯对苯二酸二甲酯对苯二甲酸二甲酯1,4-苯二甲酸二甲酯对苯二甲酸二甲酯 DMT对苯二甲酸二甲酯(标准品)苯二甲酸二甲酯,1,4-苯二羧酸二甲酯,1,4-苯二甲酸二甲酯,对酞酸二甲酯英文别名 DMTD.M.T.NCI-C50055Dimethyl terephthalateTerephthalate, dimethylterephthalicacidmethylesterTerephthalic acid methyl ester4-(methoxycarbonyl)benzoic acidTEREPHTHALIC ACID DIMETHYL ESTERTerephthalic acid dimethyl estermethylp-(methoxycarbonyl)benzoatedimethyl benzene-1,2-dicarboxylatedimethyl benzene-1,4-dicarboxylate1,3-benzodioxol-5-yl methylcarbamatedimethyl cyclohexane-1,4-dicarboxylate1,4-Benzenedicarboxylicaciddimethylester1,4-Benzenedicarboxylicacid,dimethylesterBenzene-1,4-dicarboxylic acid dimethyl esterCAS 120-61-6EINECS 204-411-8化学式 C10H10O4分子量 194.18InChI InChI=1/C10H10O4/c1-13-9(11)7-5-3-4-6-8(7)10(12)14-2/h3-6H,1-2H3密度 1,29 g/cm3熔点 140 °C沸点 288 °C闪点 154 °C水溶性 It is slightly soluble in water but soluble in hot alcohol and ether.蒸汽压 1.15 mm Hg ( 93 °C)蒸汽密度 1.04 (vs air)溶解度水: 20 °C时微溶0.0493g/L 折射率 1.4752酸度系数 0[at 20 ℃]存储条件 Store below +30°C.稳定性稳定。与强酸、强碱、强氧化剂不相容。外观薄片或颗粒颜色 WhiteMerck 14,9162BRN 1107185爆炸极限值 0.8-11.8%(V)物化性质无色斜方晶系结晶体。不溶于水，溶于乙醚和热乙醇。MDL号 MFCD00008440风险术语 36/37/38 - 刺激眼睛、呼吸系统和皮肤。

安全术语 24/25 - 避免与皮肤和眼睛接触。

危险品运输编号 3256WGK Germany 1RTECS WZ1225000TSCA Yes海关编号 2917 37 00上游原料对苯二甲酸对苯二甲酸甲醇甲醇下游产品聚对苯二甲酸乙二醇酯树脂抗静电整理剂 1,4-环己烷二甲醇双(2-羟基乙基)对苯二甲酸酯对二甲苯-D6 反式-1,4-环已烷二甲醇参考资料展开查看 1. [IF=7.514] Nan Zhang et al."Hydrophilic carboxyl supported immobilization of UiO-66 for novel bar sorptive extraction of non-steroidal anti-inflammatory drugs in food samples."Food Chem. 2021 Sep;355:129623

DMT - 性质可信数据无色斜方晶系结晶体。熔点140.6℃。液体相对密度1. 084。沸点283℃。热至230℃即升华。折射率1. 4752。黏度(150℃)o．965mPa -s。着火点155℃。不溶于水，溶于乙醚和热乙醇。

最后更新：2024-01-02 23:10:35DMT - 制法可信数据其基本工艺路线为对苯二甲酸与甲醇在硫酸或其他催化剂催化下酯化生成。具体有间歇、连续，常压、加压等不同的工艺方法。较先进的工艺是连续合并氧化合并酯化法（威顿法）以对二甲苯和

对甲基苯甲酸甲酯为原料，以钴、锰金属盐为催化剂加压氧化，继而用甲醇连续酯化得对苯二甲酸二甲酯。

最后更新：2022-01-01 10:44:22DMT - 用途可信数据涤纶树脂的中间体。也用于生产绝缘漆、黏合剂。还可用于生产增塑剂对苯二甲酸二辛酯。

最后更新：2022-01-01 10:44:22DMT - 安全性可信数据

本品毒性很低，也无皮肤刺激作用。大鼠经口LD50为lOg/kg。

采用塑料编织袋包装。贮于阴凉通风处。

最后更新：2022-01-01 10:44:23

查看DMT结构式

供应商列表

山东金悦源新材料有限公司主打产品现货供应产品名: 对苯二甲酸二甲酯

询盘CAS: 120-61-6产地: 韩国包装: 900kg/包规格: 99.9库存: 现货电话: 18615187817手机: 18615187817电子邮件: 2793152786@qq.comQQ: 2793152786 微信: 18615187817产品描述: 对苯二甲酸二甲酯(DMT)，是一种聚酯的单体。主要用于合成聚酯纤维、树脂、薄膜、聚酯漆及工程塑料等山东西亚化学有限公司现货供应产品名: 对苯二甲酸二甲酯

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询盘CAS: 120-61-6产地: 山东包装: 100g,2.5kg,25g,500g规格: ≥99.0%|≥99.0%|≥99.0%|≥99.0%价格: 46.00,256.00,36.00,81.00库存: 现货电话: 400-990-3999手机: 13395399280电子邮件: 861669111@qq.comQQ: 1903368307 微信: 13355009207 湖北扬信医药科技有限公司现货供应产品名: 对苯二甲酸二甲酯

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询盘CAS: 120-61-6产地: 中国-STD包装: 支规格: 10mg，25mg，50mg，100mg价格: 电询库存: 现货电话: 0714-3999186手机: 15671228036电子邮件: 2853786052@qq.comQQ: 2853786052 微信: 15671228036产品描述: AN0221 前衍化学科技（武汉）有限公司产品名: 对苯二甲酸二甲酯

询盘CAS: 120-61-6产地: 湖北电话: 13247110337手机: 13247110337电子邮件: 2205437118@qq.comQQ: 2205437118 微信: 13247110337产品描述: 前衍化学是化学品的一站式供采平台，致力于通过数字化+专业服务让化学品交易更高效。前衍核心团队已有10年以上行业服务经验，平台2019年正式成立以来，已为5万+单更多广东翁江化学试剂有限公司产品名: 1,4-苯二甲酸二甲酯

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询盘CAS: 120-61-6产地: 广东包装: 1kg/25kg/200kg, purity99.9%价格: 电联或QQ微信咨询电话: 19849939632手机: 19849939632(微信同号）电子邮件: 2470479589@qq.comQQ: 2470479589 微信: +86 19849939632产品描述: 我司价格有优势,可分装长期现货大量小量均可供应前衍化学科技（武汉）有限公司现货供应产品名: 对苯二甲酸二甲酯

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询盘CAS: 120-61-6产地: 湖北武汉包装: 500g, 1kg, 10kg, 100kg价格: 电联、邮件库存: 现货供应手机: 13247110337电子邮件: 2205437118@qq.comQQ: 2205437118 产品描述: 前衍化学是化学品的一站式供采平台，致力于通过数字化+专业服务让化学品交易更高效。前衍核心团队已有10年以上行业服务经验，平台2019年正式成立以来，已为5万+单更多产品目录: 点此进入湖北隆信化工实业有限公司现货供应产品名: 对苯二甲酸二甲酯

询盘CAS: 120-61-6产地: 国产包装: 100g 500g 1kg 25kg价格: 电联库存: 是电话: 15335994747手机: 15335994747电子邮件: ycwlb056@yeah.netQQ: 3521670276 产品描述: 对苯二甲酸二甲酯是我司主打产品之一，且随货可提供检验分析单，少量样品可以免费提供，公司优势是厂家直发合肥天健化工有限公司产品名: 1,4-苯二甲酸二甲酯

询盘CAS: 120-61-6产地: 安徽电话: 0086-551-65418679手机: 15856988503电子邮件: sales@tnjchem.com　　　　　 info@tnjchem.comQQ: 2881500842 微信: 0086 189 4982 3763产品目录: 点此进入河北贞田食品添加剂有限公司产品名: 1,4-苯二甲酸二甲酯

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山东金悦源新材料有限公司主打产品现货供应产品名: 对苯二甲酸二甲酯

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询盘CAS: 120-61-6产地: 河北电话: 0319-5925599手机: 13373390591电子邮件: 13313091926@163.com微信: 13373390591

DMT的上游原料

对苯二甲酸对苯二甲酸甲醇甲醇

DMT的下游产品

聚酯漆对苯二甲酸单甲酯环三(1,4-对苯二甲酸丁二醇酯) 对苯二甲酸二乙二醇酯双(2-羟基乙基)对苯二甲酸酯

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你需要了解的关于DMT的一切

甘樂

2019-04-06 16:11:15

文章来源于YOUTUBE视频：DMT-Everything You Need to Know-(TheExperience丨Trip Report丨 Science丨Spirtually），本文为方便读者阅读，提取其中解说部分并翻译，原视频来源：https://www.youtube.com/watch?v=ConB1jqknVw翻译/校对：苏南

文章仅代表作者观点，与灵魂列车立场无关文章仅作为科普，绝无教唆他人使用违禁药品意图大家好，我是丹尼尔·爱，今天我们在lucida指南，讨论你需要了解的一个强大且可能改变你生活的物质，二甲基色胺，又称DMT。我们将涵盖，基本法律安全，迷幻的体验，很多感兴趣的人在意识的探索中根本不可否认它的吸引力，提供超凡脱俗的体验，尤其是改变思维的药物，迷幻化合物。可以说所有影响你大脑的物质都是DMT提供那些勇于冒险的人进入其领土的经验，可以超越语言，动摇哲学和存在的基石。DMT是强大的，这是自然中产生的奇迹，也在人体和许多其他生物的体内发现。在视觉上它看起来像白色或黄色结晶物质，虽然糟糕的提取可能导致他变成一个黄色蜡状材料，DMT有独特的和不同的香味，有些人把它比作樟脑丸或麝香，使用DMT后的很多用户报告，他们感觉到它的气味到处都是。最受欢迎的服用DMT的方法是吸入其蒸汽，但也可以使用ayahuasca口服。传统上它也被用作鼻烟，剂量范围为10至60，30至60的毫克是最多的，经过三次长时间的深呼吸，它有些刺鼻味道。DMT是一种非法药物，在美国和几乎所有国家都是非法的，虽然它被认为是无害的，并且在其用户中没有成瘾性，但很少有科学家对身体的长期影响有研究。换句话说，一些广泛流传的，这都是假设或者与任何强力药物一样的猜测。这深刻地改变了其复杂性，我们应该继续思考，保持适当的谨慎安全和尊重。那些有精神疾病或有精神疾病的家族史的人应该特别谨慎，因为他可能会触发一个潜在的风险。最近的研究也表明使用DMT有希望治疗长期抑郁症。在体验时，你几乎处于一个完全丧失能力的状态，因此你应该像睡觉一样，只能用于安全的安全和放松的环境，那些信任的床或舒适的地方是必不可少的，有一个清醒和值得信赖的伙伴是个明智之举，监视着你DMT的体验。大约10分钟，令人难以置信，大多数有经验的人承认根本就没有文字能够描述它，甚至有经验使用过的人，心理健康者与迷幻者普遍震惊于它的强度和特殊性。找到一个舒适的地方在体验期间躺下，然后借助一个伙伴的帮助下继续深入吸入，只要迅速，在这一点上，大多数人都会已经感受到了他的强度，几何画面的快速出现，其中其实包括了一个人的愿景和现实之间的融化，好像在一个高峰期。在LSD旅行时，一般大多数人都觉得他们有过的最高感受。三分之一觉得这是难以置信的。然而，第三次吸入是至关重要的，为在突破全新的体验，你的朋友和你可以躺在床上，闭上眼睛，大约在10到20秒之后，你与任何连接物质世界的感觉都会失去，这可能涉及失去存在的感觉，穿过超空间隧道，或只是完全出现不同的迷幻几何空间。这被称为等待房间。大多数人只有基本的意识蒸发，最重要的是这可能是一个可怕的经历，一个人正在死去是一种常见的恐惧，然而，保持冷静至关重要，简单地放松一下然后松开，但是这说起来容易做起来难，时间似乎也失去了，每次呼吸的时间似乎无限长，这也可以引起一个人根本没有的恐惧。停止呼吸这种自我死亡倾向常常在候诊室里发生，这是一个空间，被描述为像遁入复杂的几何空间，或者像是多维宇宙的门口。现在成为了一种可能会被某些感觉所打动的独立实体的形式，他们似乎是由同样形成的不断变化的万花筒环境形成的，这些生物可以在你面前展现出来各种各样的形式，你的父母，或者其他生物。如果剂量是正确的，那这都是正常的，门口和超空间本身经常由实体引导，所有尝试从这一点开始的描述都是毫无意义的。接下来的10分钟，经历者可以感觉像是永恒，本身感觉好像已经进入了完全替代现实，一个在我们世界的所有规则变得毫无用处的地方，他们仿佛变成一个婴儿，有令人难以置信的混乱和巨大的不同的宇宙，但体验总是被报道为超现实，或感觉人生的报告比生活本身更真实，来自外星人的各种信息实验，与上帝沟通或进入上帝特有的宇宙，遇到俏皮的宇宙小丑，或任何完全不可能预测到的奇怪的经历。统计显示每次旅行的经历完全与个性无关，在Crest的用户经常会报告，看似深刻的实体洞察他们的生活状态，人性或其他精神启示。当然和梦中的经历一样，谨慎服用是很重要的。这些见解完全取决于表面，因为某些东西感受很深并不总是意味着它真的是什么，你对DMT的看法是他们对科学或精神的或某处联系，要记住潜意识心灵和任何潜在的超凡脱俗实体，与任何人一样有能力欺骗或操纵你。保持健康是关键，之后8分钟和10分钟你身体的意识慢慢回归，会感觉好像自己记得一个人的存在，个性和自我开始融合，状态迅速返回，常常有人脱离自我后在感觉这里有不止一个人在房间里，似乎你是清醒的，正常的现实感觉非常舒适，令人欣慰，很像回家后很长一段时间，像是异国情调的旅程。任何旅行报告都像是一个梦，记忆会很快消失，显然大多数人几乎都会在15到30分钟之间回到正常，经历几分钟后，但是你的想法可能会有点动摇，这是不是一个完全不同的世界？DMT是一种引人深思的迷人物质，他能让人认识关于自我和自然本质的问题，在现实中它不仅是有趣的，足够的，不需要探究关于它在大脑中的应用或者死亡，而推测是很好的，我们保持清醒是件好事，理解DMT是一个了不起的，具有悠久历史的化学品。而且我相信这取决于每个人个人评估身体而参与的心理风险，使用 DMT的经历可能会动摇你对各种各样的存在理解的基础，它的哲学和精神问题取决于你自己给自己的结论。我建议那些对此和其他物质感兴趣的，首先尝试开发你清醒的梦，然后使用梦去控制探索这些药物内的安全性，梦幻世界和其他人一样令人着迷，令人信服的体验就是这样。一个清醒的DMT经历是令人惊讶的，是真实的东西。您还将获得额外奖励解锁的钥匙，关于你自己的个人生物虚拟现实，如果你喜欢探索，很喜欢这个视频请点击“喜欢”按钮，如果你是新来的，可以点击“订阅”按钮，我会很高兴听到您对DMT的体验是真实的，在下面的评论中评论你的DMT历经，告诉我们这个奇怪的梦，和我们一起发现神秘的宇宙。这是丹尼尔的清醒指南，直到下一个时间甜蜜的梦。

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金涛教授：新格局下的多发性硬化疾病治疗新选择丨NCN2021_腾讯新闻

金涛教授：新格局下的多发性硬化疾病治疗新选择丨NCN2021

由中华医学会、中华医学会神经病学分会主办、广东省医学会承办，中山大学附属第一医院、广东省珠海市人民医院协办的中华医学会第二十四次全国神经病学学术会议正如火如荼的进行中。9月24日，由渤健公司主办的多发性硬化学术专场受到参会专家的广泛好评。本次学术专场诚邀上海交通大学医学院附属仁济医院的管阳太教授担任主席，特邀吉林大学白求恩第一医院的金涛教授带来了题为“新格局下的多发性硬化疾病治疗新选择”的精彩报告。本文将精彩内容进行简要总结，以飨读者。

专家简介

管阳太教授

•上海交通大学医学院附属仁济医院神经内科主任、主任医师/教授、博士生导师

专家简介

金涛教授

•吉林大学白求恩第一医院神经内科副主任、主任医师、教授、博导

多发性硬化（MS）治疗存在诸多挑战

1. MS是目前全球常见的青壮年致残性神经系统疾病之一

2016年，全球MS患病人数约222万，患病率30.1/10万，自1990年增长了10.4%；中国大陆MS患病人数超10万，自1990年增长了45.6%。

经年龄、性别调整后，我国MS发病率是0.235/10万/年；MS发病的地理分布与南北纬度梯度、东西向海拔梯度有关，高纬度和高海拔地区的居民更容易发生MS；女性发病率约为男性的2.02倍，发病年龄峰值为40-49岁（图1）。

图1 2016-2018年所有年龄段男性/女性的MS粗发病率

2.MS的高致残性导致社会劳动力下降，增加社会负担

有研究显示，随着残疾进展，MS患者 (

3.MS病理和症状均具有异质性，增加了疾病长期管理的难度

MS是一种复杂的、进行性的中枢神经系统脱髓鞘疾病，其病因可能与免疫、易感基因、感染、环境等多种因素相关（图2）。MS病理上表现为中枢神经系统（CNS）多发髓鞘脱失、炎症、轴突变性等多种特征。MS临床表现多样，其常见症状包括视力下降、复视、肢体感觉障碍、肢体运动障碍、共济失调、膀胱或直肠功能障碍等。

在MS各个阶段都提倡以患者为中心的积极管理，最大程度减少疾病影响，最大化生活质量、培养健康理念，处理MS症状是疾病管理的关键组成部分。

图2 MS病理和症状均具有异质性

富马酸二甲酯肠溶胶囊是疾病修正治疗（DMT）的全新选择

MS为终身性疾病，其缓解期治疗以控制疾病进展为主要目标。缓解期是MS治疗的理想时间窗（图3），从CIS进展到RRMS，建立有效治疗的机会逐渐减少。

图3 MS 疾病进展和治疗理想时间窗

国内外指南/共识推荐MS缓解期应尽早启动DMT治疗（图4），据2021年中国多发性硬化患者生存报告数据的分析显示，目前中国DMT治疗率仅为18%，远低于美国和欧盟的治疗率（80%）。

图4 国内外指南/共识推荐MS缓解期应尽早启动DMT治疗

然而，我国DMT药物可及性滞后于欧美地区（共22个），中国仅有3个DMT进入医保目录，富马酸二甲酯2021年新获批、目前准备进入医保中。

1. 富马酸二甲酯是全球处方量最大的MS口服DMT药物，超过50万患者接受治疗

2021年4月，富马酸二甲酯肠溶胶囊在中国获批, 用于治疗成人RMS，包括CIS、RRMS和活动性SPMS。富马酸二甲酯是全球处方量最大的多发性硬化口服DMT药物，全球超50万患者见证富马酸二甲酯的疗效和安全性，为RMS患者提供更多治疗选择。

2. 富马酸二甲酯双重机制：同时作用于外周免疫和中枢神经系统，应对MS的发病特征

我国现有DMT药物均主要作用于外周免疫，需要具有新型作用机制的药物来应对MS异质性。富马酸二甲酯具有中枢神经系统和免疫调节的双重机制（图5）：在中枢神经系统中，富马酸二甲酯可通过多种通路对神经元、少突胶质细胞、小胶质细胞和星形胶质细胞产生直接作用，保护中枢神经系统。同时，富马酸二甲酯通过调节不同类型淋巴细胞的数量和功能，来调节外周免疫系统。众多指南/共识及权威杂志综述均将富马酸二甲酯列为一线DMT药物（图6）。

图5 富马酸二甲酯的双重机制

图6 指南/共识及权威杂志综述推荐

3. 持续10年接受富马酸二甲酯治疗，45%的RMS患者无复发，77%的RMS患者行走不受限

III期研究DEFINE和CONFIRM研究综合分析显示（图7），富马酸二甲酯治疗2年，年复发率降低49%，残疾进展风险降低32%。

图7 DEFINE和CONFIRM研究结果

ENDORSE研究是DEFINE和CONFIRM研究的拓展随访研究（图8），随访长达13年,研究显示持续 10 年接受富马酸二甲酯治疗，45%的患者无复发，77%的患者行走不受限。

图8 ENDORSE研究结果

此外，金涛教授还介绍了丹麦全国性队列研究、瑞士队列研究等。真实世界研究证实，在控制复发方面，富马酸二甲酯疗效显著优于特立氟胺，同时因疾病进展导致的停药率低于特立氟胺。在控制疾病进展方面，富马酸二甲酯与芬戈莫德疗效相当。

4. 富马酸二甲酯安全性可控，无需额外起始监测及延长洗脱期，可灵活安排生育计划

2021 AAN大会最新发表结果显示，富马酸二甲酯与潮红的发生风险较大显著相关。常见不良反应以轻中度为主, 安全性可控。超过10年的安全性数据显示，富马酸二甲酯安全性可控，在任何时间点，感染、严重感染、胃肠不良事件、MS复发、潮红、恶心肿瘤的发生率均未见升高。

富马酸二甲酯起始用药监测负担小，且可通过定期监测尽可能避免不良事件的发生。其活性代谢产物富马酸单甲酯(MMF）半衰期约1小时，大多数人在24小时后体内没有循环的富马酸二甲酯，不需要延长洗脱期，便于育龄期女性灵活制定妊娠计划及调整治疗方案（图9）。

图9 富马酸二甲酯起始用药监测情况

氨吡啶缓释片为步行障碍患者提供突破性治疗

MS治疗不仅需重视长期疾病管理，也需关注当下功能障碍的改善。行走功能障碍在MS患者中十分常见，高达58%的患者在MS确诊后第一年报告了某些方面的活动能力问题；到10年后，患者比例高达93%；70%的行走困难患者表示，这是MS最具挑战性的方面，影响患者身心生活等各方面。

1. 氨吡啶缓释片是首个且目前唯一获批用于改善MS患者步行功能障碍的药物

我国临床一直缺乏适合MS各病程阶段的有效改善行走功能障碍的治疗手段。氨吡啶的上市可以说是实现了零的突破，氨吡啶缓释片是全球首个且目前唯一获批用于改善MS步行功能障碍的药物（EDSS 4-7），可单独使用，或联合DMT药物、物理治疗和其他对症疗法用于所有亚型MS患者。

2. 氨吡啶缓释片有效改善MS患者步行能力、且安全性良好

多项RCT和真实世界研究数据证实，氨吡啶可显著改善MS患者的步行能力，提高患者步行速度。在III期临床试验F203/204中，对氨吡啶缓释片治疗应答的患者T25FW（定时25英尺步行）改善的患者比例为38%，显著优于安慰剂组（图10）。

图10 III期临床试验F203/204 研究结果

同时，F203/204汇总分析显示：无论何种MS类型、无论是否使用DMT药物或使用何种DMT药物，氨吡啶均能显著改善患者T25FW步行应答率（图11）。

图11 III期临床试验F203/204 研究结果

另外，氨吡啶安全性良好，大多数AE的严重程度均为轻至中度，通常不会导致治疗终止，且长期治疗后未观察到新的不良事件或趋势。

小结

最后，管阳太教授总结道，富马酸二甲酯尽管在国内刚上市，但是在全球已经有长达十几年的使用经验。而且研究显示，长期使用其疗效、安全性良好。并强调富马酸二甲酯半衰期很短，有利于洗脱，对于MS患者、尤其是育龄期女性患者来说，增加了用药的方便性。氨吡啶对症治疗、改善MS患者步行功能障碍，尤其是对于EDSS 4-7的患者，获益显著。

富马酸二甲酯肠溶胶囊、氨吡啶缓释片两个创新产品的上市，改变了我国MS治疗的格局，将为MS领域提供长期减少疾病致残进展，短期改善步行能力的综合治疗方案，为中国医生治疗MS提供了强有力的工具，为患者带来了更多的治疗选择。

DMT - 搜狗百科

- 搜狗百科二甲基色胺(DMT，dimethyltryptamine)第一类精神药品，色胺类致幻剂，药性强。不仅存在于植物中，还以痕量见于人体中，由色胺-N-转甲基酶催化产生，但具体功能不明。结构上与神经递质血清素和其他色胺类致幻剂5-甲氧基二甲基色胺、蟾毒色胺、脱磷酸裸盖菇素类似。该品可口服(与单胺氧化酶抑制剂)、吹入、直肠、吸入、肌注、静注。网页微信知乎图片视频医疗汉语问问百科更多»登录帮助首页任务任务中心公益百科积分商城个人中心DMT编辑词条添加义项同义词收藏分享分享到QQ空间新浪微博二甲基色胺（DMT，dimethyltryptamine）第一类精神药品，色胺类致幻剂，药性强。不仅存在于植物中，还以痕量见于人体中，由色胺-N-转甲基酶催化产生，但具体功能不明。结构上与神经递质血清素和其他色胺类致幻剂5-甲氧基二甲基色胺、蟾毒色胺、脱磷酸裸盖菇素类似。该品可口服（与单胺氧化酶抑制剂）、吹入、直肠、吸入、肌注、静注。中文名DMT展开分子量188.269 g/mol展开化学式 C12H16N2展开密度1.099 g/cm³展开词条标签：药剂药理技术通信技术服务器免责声明搜狗百科词条内容由用户共同创建和维护，不代表搜狗百科立场。如果您需要医学、法律、投资理财等专业领域的建议，我们强烈建议您独自对内容的可信性进行评估，并咨询相关专业人士。词条信息词条浏览：44629次最近更新：20.06.05编辑次数：11次创建者：精诚所突出贡献者：新手指引了解百科编辑规范用户体系商城兑换问题解答关于审核关于编辑关于创建常见问题意见反馈及投诉举报与质疑举报非法用户未通过申诉反馈侵权信息对外合作邮件合作任务领取官方微博微信公众号搜索词条编辑词条收藏查看我的收藏分享分享到QQ空间新浪微博投诉登录企业推广免责声明用户协议隐私政策编辑帮助意见反馈及投诉© SOGOU.COM 京ICP备11001839号-1 京公网安备110000020000

Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain | Scientific Reports

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Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain

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Published: 27 June 2019

Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain

Jon G. Dean1,7, Tiecheng Liu1, Sean Huff1, Ben Sheler1, Steven A. Barker2, Rick J. Strassman3, Michael M. Wang1,4,5,6 & …Jimo Borjigin

ORCID: orcid.org/0000-0001-7246-42321,4,5,7 Show authors

Scientific Reports

volume 9, Article number: 9333 (2019)

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ImmunochemistryMolecular neuroscienceNeurochemistryRNATransferases

AbstractN,N-dimethyltryptamine (DMT), a psychedelic compound identified endogenously in mammals, is biosynthesized by aromatic-L-amino acid decarboxylase (AADC) and indolethylamine-N-methyltransferase (INMT). Whether DMT is biosynthesized in the mammalian brain is unknown. We investigated brain expression of INMT transcript in rats and humans, co-expression of INMT and AADC mRNA in rat brain and periphery, and brain concentrations of DMT in rats. INMT transcripts were identified in the cerebral cortex, pineal gland, and choroid plexus of both rats and humans via in situ hybridization. Notably, INMT mRNA was colocalized with AADC transcript in rat brain tissues, in contrast to rat peripheral tissues where there existed little overlapping expression of INMT with AADC transcripts. Additionally, extracellular concentrations of DMT in the cerebral cortex of normal behaving rats, with or without the pineal gland, were similar to those of canonical monoamine neurotransmitters including serotonin. A significant increase of DMT levels in the rat visual cortex was observed following induction of experimental cardiac arrest, a finding independent of an intact pineal gland. These results show for the first time that the rat brain is capable of synthesizing and releasing DMT at concentrations comparable to known monoamine neurotransmitters and raise the possibility that this phenomenon may occur similarly in human brains.

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IntroductionN,N-dimethyltryptamine (DMT) belongs to a class of serotonergic psychedelics that includes lysergic acid diethylamide (LSD) and psilocybin1. DMT, like all serotonergic psychedelics, reliably elicits a wide spectrum of subjective effects on brain functions including perception, affect, and cognition2. These compounds share structural and functional similarities with serotonin (5-hydroxytryptamine, 5-HT), and interact with 5-HT and other receptors to produce their effects3,4,5. Unlike other psychedelics, however, DMT is endogenously produced in animals6,7,8, including humans9,10,11. In addition to the subjective psychedelic effects exogenous administration of DMT has on conscious experience, it has other well-documented anti-hypoxic12, antidepressant13, and plasticity-promoting actions14. Taking these facts together, a further understanding of why DMT is present in mammals is of interest.Biosynthesis of DMT from tryptamine requires double methylation reactions catalyzed by indolethylamine-N-methyltransferase (INMT)15,16. INMT mRNA was identified at high levels in peripheral tissues in rabbits17 and in humans18. However, this peripheral INMT also methylates other ligands such as histamine17,19. In the brain, INMT mRNA was found at very low levels in rabbits17 and was undetectable in humans18. No study to date has yet identified INMT in the cerebral cortex in any species. In addition to INMT, production of DMT requires aromatic-L-amino acid decarboxylase (AADC), which removes the carboxyl group from dietary tryptophan to form tryptamine, the essential DMT precursor that can be rapidly metabolized by monoamine oxidase20. While high levels of INMT mRNA expression in the periphery17,18 have been assumed to indicate the potential for correspondingly high levels of DMT, cellular colocalization of INMT and AADC transcripts has not yet been reported in any tissue. Moreover, studies to date assessing levels of DMT in human peripheral bodily fluids have only reported it in trace amounts11, calling into question any physiological role.In order to address some of these issues, this study examined expression of INMT mRNA in rat and human brain tissues using in situ hybridization. In addition, we conducted double in situ hybridization studies to probe the co-expression of INMT and AADC mRNA in rat brain and periphery. To investigate the presence of DMT in rat brain, we analyzed DMT content in microdialysis samples collected directly from the visual cortices of living pineal-intact and pinealectomized rats. Pinealectomized animals were studied because previous data established the presence of DMT in living rat pineal dialysate8. To investigate whether DMT brain levels are inducible by physiological alterations, we assessed its levels in rat brain following cardiac arrest with or without the pineal gland, as a prior study from our lab demonstrated a surge in the levels of select neurotransmitters in rat visual cortex following cardiac arrest using this technique21.ResultsINMT mRNA is expressed in rat and human brainTo investigate the cortical localization of INMT transcripts, we first conducted in situ hybridization for INMT mRNA on formalin-fixed paraffin-embedded (FFPE) rat brain tissue sections (Fig. 1). INMT mRNA, stained red/pink for the single staining in situ experiments, was consistently detected in rat visual cortex (panel A), human medial frontal cortex (panel B), rat (panel C) and human (panel D) pineal gland, and rat (panel E) and human (panel F) choroid plexus.Figure 1INMT mRNA is expressed in the brain. Images show results of in situ hybridization of INMT mRNA probes on rat (first column) or human (second column) brain FFPE sections. Where applicable, small black and white arrows denote exemplary cells positive and negative for INMT mRNA expression, respectively. Insets are magnifications of these cells. INMT mRNA expression is seen as pink punctate dots in cortical cells within rat visual cortex (A), in cells of the human medial frontal cerebral cortex (B), in pinealocytes within rat (C) and human (D) pineal gland, and in select ependymal cells of rat (E) and human (F) choroid plexus. In this and the additional in situ panels in Figs 2 and 3, nuclear counterstain (blue/gray staining in all images) identifies all cells/nuclei = 50% hematoxylin. All large panel images = 100x oil magnification. Histology sections are all coronal.Full size imageINMT and AADC mRNA colocalize in rat brain tissuesA series of double in situ hybridization experiments was conducted on rat brain tissue sections (Fig. 2), adjacent to those used for single in situ hybridization (Fig. 1), to assess cellular colocalization of INMT with AADC transcripts. INMT (green) and AADC (red) mRNA colocalized extensively within the visual cortex (panel A), the hippocampus (panel B), the pineal gland (panel C), and the choroid plexus (panel D).Figure 2INMT mRNA is colocalized with AADC mRNA in the brain. Images show results of in situ hybridization on rat brain FFPE sections using INMT (green) and AADC (pink) mRNA probes. (A) INMT and AADC mRNA are colocalized in cells of the visual cortex (panel A), in cells of the hippocampus (B), in the pinealocytes (C), and in the ependymal cells of the choroid plexus (D).Full size imageA series of control experiments using positive and negative control probes was conducted to assess the in situ technique, as well as to sample mRNA quality. As shown in Fig. S1, positive control probes (targeting PPIB and POLR2A, see Supplemental Information) produced the expected staining patterns in each of the rat brain sections (Fig. S1A,D,G,J), adjacent to those used in Fig. 2A–D; this demonstrates proper preparation of the rat brain FFPE sections. As expected, the negative control probe (a bacteria-specific gene, dapB) showed no appreciable staining (Fig. S1B,E,H,K) in the rat brain sections adjacent to those in Fig. 2A–D. Quantification of mRNA signal strength (calculated as fraction of total area in pixels) in Figs 2 and S1 images showed that the summated INMT and AADC mRNA signals in each rat brain tissue section were comparable to that of the positive control probes and well above negative control staining levels (Fig. S1C,F,I,L), thereby confirming the quality of the INMT and AADC mRNA signals following the chromogenic double in situ procedures. These data provide validation of the duplex in situ technique used to demonstrate the cellular colocalization of INMT and AADC mRNA (Fig. 2).INMT and AADC mRNA are sparsely colocalized in rat peripheral tissuesThe in situ hybridization duplex assay was repeated on rat peripheral tissues including adrenal, kidney, lung, and heart (Fig. 3). While INMT mRNA was found at varying levels in all tissues tested (Fig. 3), AADC mRNA was only detectable in a subset of these tissues. The adrenal cortex was positive for INMT but not for AADC transcript (panel A), whereas the adrenal medulla stained more abundantly for AADC mRNA, with INMT transcript staining noted in only some cells (panel B). This pattern of adrenal medulla-specific AADC mRNA localization accords with previous literature22,23. Colocalization for INMT and AADC mRNA in rat adrenal gland was sparse, detected within select cells in adrenal medulla only (black arrows in panel B). INMT and AADC transcripts were both expressed in renal tubules in the kidney (panels C and D), but they were compartmentalized to discrete anatomical locales. Consistent with previous literature22,23, AADC mRNA expression was restricted to the renal cortex (panel C) with no appreciable expression observable in the kidney medulla (panel D). In clear contrast to AADC mRNA expression, INMT mRNA was localized to the kidney medulla (panel D) rather than the cortex (panel C). INMT mRNA was abundantly found in the lung, but AADC mRNA expression was scant (panels E and F), in accord with previous studies assessing AADC mRNA in rodent lung tissues23. Very few cells in rat lung tissues were found to express both INMT and AADC transcripts (panels E and F). Likewise, INMT mRNA was highly expressed in rat heart in selected areas (panel G), as noted in previous Northern blot data reported in humans18, but AADC expression was not observed in appreciable levels (panels G and H), consistent with a prior study in rodents23.Figure 3INMT and AADC mRNA expression is largely non-overlapping in rat peripheral tissues. Two representative regions (Area A and Area B) are shown for each tissue type. Insets show magnifications of areas of the main images wherein cells are positive (black arrows) or negative (white arrows) for either INMT (A,D–G), AADC (C), or both INMT and AADC (B) transcripts. INMT mRNA (green punctate dots) was highly expressed in the adrenal cortex (A), the renal tubules of the kidney medulla (D), the lung (E,F), and the heart (G). INMT transcripts were not uniformly distributed in these tissues, as INMT is found at very low levels in the adrenal medulla (B), renal cortex (C), and select areas of the heart (H). AADC mRNA (pink punctate dots) was expressed in adrenal medulla (B), where it is colocalized with INMT mRNA in select cells (black arrows in B), and in renal cortex (C) where it is not found together with INMT in the same cells. In the lung (E,F) and heart (G,H), AADC mRNA was nearly absent.Full size imageDMT is present in the brain at concentrations comparable to known monoamine neurotransmittersTo determine if DMT is present in the brain, we quantified rat brain microdialysates by conventional fluorescence detection coupled to a HPLC system (Fig. 4), a method that has been used in our laboratory to detect physiological neurochemicals like 5-HT and melatonin24. DMT as well as 5-HT were detected in rat brain (Fig. 4) in microdialysates collected from the visual cortex via this technique24. Under baseline conditions, the normal rat brain contained detectable levels of DMT (seen at retention time of 7.2 min; blue tracing in panel Aa), ranging 0.05–1.8 nM with an average of 0.56 nM (blue dots in panel Ab).Figure 4DMT is present in the brain at concentrations comparable to known monoamine neurotransmitters. (A) DMT levels in pineal-intact rats (n = 25) rose following cardiac arrest. DMT, sampled 0.5 hr before cardiac arrest shown (retention time = 7.2 minutes) on a representative raw chromatogram (a, blue tracing), ranged between 0.05–1.8 nM (averaged 0.56 nM; b, blue dots) during baseline. DMT levels increased within one hr of cardiac arrest (a, red tracing), averaging 1.35 nM with maximum 5.01 nM (b, red dots). DMT increase was significant (***p = 0.00027; mean of differences = 0.80; SD = 0.93; 95% CI = 0.41 to 1.18; t(24) = −4.26). (B) DMT levels persisted in brains of pinealectomized rats (n = 11). DMT levels sampled 0.5–1 hr following cardiac arrest shown (retention time = 7.5 minutes) on a representative raw chromatogram (a, blue tracing), ranged between 0.25–2.2 nM (averaged 1.02 nM; b, blue dots) during baseline. DMT levels increased within one hr of cardiac arrest (a, red tracing), averaging 1.83 nM with maximum of 5.11 nM (b, red dots). DMT increase was significant (*p = 0.034; mean of differences = 0.81; SD = 1.10; 95% CI = 0.075 to 1.55; t(10) = 2.45). (C) There was no difference in brain concentrations of DMT at baseline (a) between rats without (−pineal; mean = 1.02 nM; SD, blue bar = 0.63) and with ( + pineal; mean = 0.56 nM; SD, blue bar = 0.49) the pineal gland (p = 0.05, Welch’s unpaired t-test). No difference between brain concentrations of DMT following cardiac arrest (b) without (− pineal; mean = 1.83 nM; SD, red bar = 1.38) and with (+pineal; mean = 1.35 nM; SD, red bar = 1.27) the pineal gland was detected (p = 0.34, unpaired t-test with Welch’s correction). Baseline levels of DMT were about half those of 5-HT levels (c; *p = 0.026; mean of differences = 1.08; SD = 1.37; 95% CI = 0.16 to 2.0; t(10) = −2.62) in the visual cortex of pinealectomized rats (mean DMT = 1.02 nM; SD, blue bar = 0.63; mean 5-HT = 2.10 nM; SD, blue bar = 1.67).Full size imageIn our previous report of DMT in the rat brain8, it was unclear whether the detected DMT was from the cerebral cortex, pineal gland, or both, since the microdialysis probe traversed the rat brain through both the cortex as well as the pineal gland (see probe design in24). To determine the contribution of the cortex to DMT secretion, we compared normal rats (panel A) to pineolectomized animals (panel B). DMT in rats without the pineal gland, still detectable under baseline (seen at retention time of 7.5 min; blue tracing in panel Ba), ranged 0.25–2.2 nM with an average of 1.02 nM (blue dots in panel Bb). Cortical levels of DMT did not show significant difference between rats with and without the pineal gland under baseline conditions (panel Ca; p = 0.05, via unpaired t-tests with Welch’s correction).To determine if DMT levels in the rat brain are regulated by physiological perturbations, we monitored the brain concentration of DMT before and after experimentally-induced cardiac arrest. Several hours of DMT baseline levels were first established in the brains of freely behaving and pineal-intact (panel A) and pinealectomized rats (panel B). DMT concentrations following cardiac arrest (red tracings) increased significantly over baseline (blue tracings) in both brains of the pineal-intact group (panel Ab; p = 0.00027) and the pinealectomized group (panel Bb; p = 0.034). We found that 60% (15/25) of normal pineal-intact rats demonstrated more than two-fold increases in DMT while 32% (8/25) showed less than 1.5-fold change (panel Ab). Of the rats without the pineal gland, 45% (5/11) showed more than two-fold increase in DMT whereas 55% (6/11) of rats exhibited minimum change (<1.5-fold; panel Bb) following the onset of cardiac arrest. Average fold increase following cardiac arrest for DMT in the brain was 2.84 ± 1.65 for the pineal-intact group (with a maximum of 6.18-fold), and 1.84 ± 0.89 for the pinealectomized group (with a maximum of 3.47-fold). DMT concentrations in rats exposed to experimentally-induced cardiac arrest did not differ significantly between pineal-intact and pinealectomized rats (panel Cb; p = 0.34 via unpaired t-tests with Welch’s correction).To probe the relative abundance of extracellular DMT compared to 5-HT in cortical dialysates from the same rats, we quantified brain 5-HT, a monoamine neurotransmitter structurally related to DMT, in rats without the pineal gland. 5-HT was clearly detectable at baseline in the rat cerebral cortex in the absence of the pineal gland (panel Ba). Mean extracellular concentration of 5-HT was 2.10 ± 1.67 nM in these rat brain dialysates (panel Cc). In comparison, basal DMT levels were 1.02 ± 0.63 nM from the same cortical dialysates (panel Cc). Although DMT concentrations are lower than those of 5-HT levels (Fig. 4Cc) under basal conditions, they are comparable to the extracellular levels of all known monoamine neurotransmitters measured by in vivo microdialysis in rat brain25.DiscussionWe report [1] cortical expression of INMT mRNA in rat and human brain, [2] colocalization of INMT and AADC mRNA in the same cells in rat brain, and [3] predominately non-overlapping expression of INMT with AADC mRNA in rat peripheral organs including the adrenal, kidney, lung, and heart. We further show that DMT is present in rat visual cortex in pineal-intact and pinealectomized animals. Moreover, we show DMT levels are significantly elevated by experimentally-induced cardiac arrest. Collectively, these data support the notion that DMT is synthesized in rat brain and at concentrations consistent with that of other known monoamine neurotransmitters. Our demonstration of INMT mRNA expression in human cerebral cortex, choroid plexus, and pineal gland also suggest that DMT biosynthesis may similarly occur in the human brain.This study demonstrates for the first time that INMT mRNA, the transcript for a key DMT synthetic enzyme, is widely expressed in the cerebral cortex in rats. Importantly, INMT and AADC transcripts are co-expressed in the same brain cells, providing a plausible mechanism for cellular synthesis of DMT in the mammalian neocortex. DMT is a monoamine produced from tryptophan. If endogenous DMT functions as a non-classical monoamine neurotransmitter in the brain, DMT would be the only monoamine whose biosynthesis takes place within the cerebral cortex where it may directly influence cognitive functions of the brain.While AADC expression in the brain is well known26, INMT expression in the brain was unclear prior to our study. Earlier studies showed that INMT mRNA was only weakly present in rabbit brain tissues17, and undetectable in human brain tissues18. These prior reports are all based on Northern blot analysis, which provides no information on cellular distribution of INMT mRNA and is less sensitive compared to quantitative polymerase chain reaction or the in situ hybridization method used in our study. We were able to identify INMT mRNA in both rat and human brain tissues using the RNAscope in situ assay system, in part because of the high sensitivity afforded by this technique27, which allowed robust and unambiguous identification of INMT mRNA in both rat and human brain FFPE tissues for the first time (see Fig. 1).AADC is best characterized as one of the enzymes necessary for the synthesis of all canonical monoamine neurotransmitters, including 5-HT [together with tryptophan hydroxylase (TPH)] and dopamine/norepinephrine [together with tyrosine hydroxylase (TH)]. In the pineal gland, AADC (together with TPH) is well known to mediate the synthesis of 5-HT, the precursor for melatonin production28. In the brain, AADC mRNA is present abundantly in the monoamine neurons in the brainstem26. However, AADC mRNA and protein have also been reported in neurons of the cerebral cortex and hippocampus26 that do not contain TH/TPH in mice, rats and humans29,30,31,32,33. To date, the function of these AADC-positive and TH/TPH-negative neurons is unknown.Using the RNAscope in situ hybridization technique, we identified AADC mRNA in several regions of the rat brain (Fig. 2), including the cerebral cortex and hippocampus (Fig. 2), consistent with what has been reported in mouse brain26. Critically, we found in each of these rat structures that AADC mRNA is colocalized with an INMT transcript (Fig. 2), suggesting that these INMT-positive and AADC-positive neurons may function as DMT-producing neurons (or D-neurons) and that DMT, a non-canonical monoamine, may possibly be the principle neurotransmitter in these widely distributed brain D-neurons. A functional role of the D-neurons will need to be explored in future studies. For example, INMT-deficient animals are necessary to demonstrate unequivocally that INMT is responsible for the endogenous production of DMT.INMT protein was also found in monkey pineal gland in a prior study34. Our study expanded this finding and demonstrated an abundant expression of INMT mRNA in the pineal gland in both rats and humans (Fig. 1). Co-expression of INMT and AADC mRNA in rat pinealocytes was confirmed by double in situ hybridization analysis (Fig. 2), suggesting that a potential mechanism for DMT biosynthesis, as in the rat visual cortex, exists in the pineal gland. Transcripts for DMT synthetic enzymes were detected additionally in the choroid plexus, a venous network lining the ventricles of the brain that produce CSF, a fluid in which DMT has been detected11. The choroid plexus contains a high density of 5-HT2C receptors whose stimulation by agonists leads to marked reduction of CSF production35. As DMT is an agonist at the 5-HT2C receptor4,5,36 and LSD binds to the 5-HT2C receptor in cultured choroid plexus epithelial cells to stimulate their activity37, the effect of endogenous DMT on CSF regulation deserves additional investigation.The high levels of INMT mRNA previously found in peripheral tissues18 have led to speculation that DMT is released from peripheral stores and subsequently transported to the brain. Consistent with earlier Northern blot analysis of human tissues18, we found high levels of INMT mRNA expression in rat kidney, lung, heart, and adrenal (Fig. 3). However, INMT mRNA expression in rat peripheral tissues showed very limited overlap with AADC mRNA at the cellular level, suggesting that INMT may have functions independent of DMT synthesis in the periphery. Although our present data suggest that DMT in the brain does not originate from peripheral sources but, rather, is produced locally in specific brain tissues, future studies (using brain-specific INMT knockout animals, for example) could be conducted to conclusively demonstrate that DMT found in brain dialysates originates from the brain. Peripheral INMT may be responsible for established DMT-independent functions such as methylation of sulfur-containing compounds38, histamine17,19, and selenium metabolism39.DMT is an endogenous monoamine whose physiological functions remain unknown. Furthermore, since exogenous DMT can bind with nanomolar affinities to various receptors including 5-HT receptors40,41,42,43 and trace-amine associated receptors (reviewed in ref.44), endogenous DMT may influence brain functions via the same receptors. If DMT were indeed to function as a non-canonical monoamine neurotransmitter, however, it must be present in the brain at a physiologically relevant concentration. Presence of DMT has been reported in various species including rats6,7,8,9,10,11, yet its in vivo concentration in living brain has not been reported. This study represents the first quantification of DMT in the extracellular fluid of the brain in freely moving and normal behaving animals.The baseline concentration of DMT in cortical microdialysates ranged between 0.05 to 1.8 nM (blue dots in Fig. 4Ab) in pineal-intact rats, and between 0.25 to 2.2 nM (blue dots in Fig. 4Bb) in pinealectomized rats. DMT levels showed no significant difference between rats with the pineal and without the pineal gland (Fig. 4Ca). Importantly, this cortical concentration of DMT (average 1.02 nM) is only slightly lower than that of 5-HT detected in the same dialysates, which averaged around 2 nM in rats without the pineal gland (Fig. 4Cc). This value of 5-HT in brain dialysates is consistent with what others have found in rats (average 0.87 nM; 0.12–3.4 nM range) [reviewed in ref.25]. In fact, the basal DMT concentrations (Fig. 4Ab; average 1.02 nM; 0.25–2.2 nM range) in the brain microdialysates are well within the known range of all three canonical monoamine neurotransmitters25: 5-HT (average 0.87 nM; 0.12–3.4 nM range), norepinephrine (average 1.77 nM; 0.19–4.4 nM range), and dopamine (average 1.5 nM; 0.07–4.9 nM range). We wish to emphasize that our microdialysates were collected and analyzed online in real time from rats without any pretreatment to block the activity of monoamine oxidase, an enzyme that rapidly degrades DMT in vivo15,45. The mechanism and function of cortical DMT production remain to be fully investigated.DMT was previously detected in freely moving rats8. However, DMT was not quantified in that study. Furthermore, the microdialysates used for DMT analysis8 were collected from both the pineal gland and the surrounding visual cortex of rats and it was unclear whether the detected DMT was from the pineal alone, the cortex alone, or both. To address this latter issue, we surgically removed the pineal gland and monitored DMT levels in rats both under baseline and following cardiac arrest (Fig. 4B). We found that DMT concentrations in the brain are independent of the pineal gland, as cortical DMT levels show no significant difference with or without the pineal gland (Fig. 4Ca). These data suggest that the cortex may be one of the major sources of released DMT from the brain. At this point, it is uncertain to what extent, if any, the pineal contributes to DMT production8. It is also unclear whether DMT detected in the brain extracellular fluid is secreted from neurons and/or glial cells. Colocalization studies using both an INMT probe and cell-type specific markers should be used in future studies to clarify this.The extensive colocalization of INMT and AADC transcripts in pinealocytes (Fig. 2C), and the apparent lack of the pineal’s contribution to the brain production of DMT (Fig. 4Ca) present a paradox. We reasoned that there may be two competing pathways for tryptophan in the pineal: (1) conversion of tryptophan to 5-HT via sequential actions of TPH and AADC, and (2) the potential conversion of tryptophan to DMT via sequential actions of AADC and INMT. It is plausible that in the pineal, the first pathway is overwhelmingly dominant, resulting in high production of 5-HT at the expense of DMT. The established properties of the enzymes support this: the affinity of tryptophan for TPH (Km = 41.3 uM)46 in the 5-HT/melatonin synthesis pathway is substantially higher compared to the reported affinity of tryptophan for AADC (Km = 3000 uM)47 in the DMT biosynthetic pathway. Thus, if the same cell expresses both TPH and AADC, tryptophan will be more likely to be converted to 5-hydroxytryptophyan (destined to 5-HT) than to tryptamine (destined to DMT). Additionally, 5-hydroxytryptophan binds to AADC with substantially higher affinity than tryptophan (Km = 160 uM48 versus Km = 3000 uM)47. As a result, high levels of 5-hydroxytryptophan found in the pineal are likely to competitively inhibit AADC conversion of tryptophan to tryptamine, further reducing this intermediate in DMT production. The relatively low affinity of AADC for tryptophan thus reduces the production of DMT in pineal cells that contain both TPH and AADC. These data may explain the possibility that the pineal gland contributes little to DMT production, despite the abundant co-expression of AADC and INMT in the pinealocytes. We could not, however, rule out the possibility that there may be compensatory increases in DMT’s biosynthesis in other brain areas following the loss of the pineal gland.In our previous studies, we have observed a marked elevation of some, but not all, critical neurotransmitters in rat brain during asphyxic cardiac arrest21, which we posit may contribute to the elevated conscious information processing observed in dying rats21,49. These data also suggest that global ischemia (by cardiac arrest, as in the current study), similar to global hypoxia (by asphyxia, as in21), leads to a tightly regulated release of a select set of neurotransmitters21. To test whether DMT concentrations are regulated by physiological alterations, we monitored DMT levels in rat brain dialysates following experimentally-induced cardiac arrest, and identified a significant rise in DMT levels in animals with (Fig. 4A) and without the pineal (Fig. 4B).The cardiac arrest-induced increase of endogenous DMT release may be related to near-death experiences (NDEs), as a recent study reports NDE-like mental states in human subjects given exogenous DMT50. Not all rats in our current study exhibited a surge of DMT following cardiac arrest (Fig. 4), an interesting observation in light of the fact that NDEs are reported by less than 20% of patients who survive cardiac arrests51. It is unknown whether the concentrations of DMT reported in our study at cardiac arrest can elicit the effects of an exogenous psychedelic dose of DMT, or whether this surge of endogenous DMT similarly occurs in humans. Moreover, the conscious states reported by NDE survivors may involve contributions from several of the other neurotransmitters found to surge at cardiac arrest in our prior rodent study21. Further investigation is clearly warranted to investigate whether DMT plays a role in generating neural correlates of near-death consciousness.In conclusion, we present evidence for the brain expression of mRNA for INMT, the key DMT synthetic enzyme previously thought to exist only in the periphery, and demonstrate that, unlike in the periphery, transcripts for the DMT synthetic enzymes AADC and INMT are co-expressed in the same cells within the rat brain. The wide co-expression of transcripts for the DMT synthetic enzymes in the rat brain and basal concentrations of DMT comparable to that of other monoamine neurotransmitters indicate that endogenous DMT may influence brain function.Materials and MethodsAnimalsAdult (2–5 months of age) male Wistar rats (Harlan Laboratories, Indianapolis, IN) were divided into two groups for in vivo microdialysis: rats with intact pineal glands (n = 25; average weight = 334 g) and pinealectomized rats (n = 11; average weight = 335 g). All animals were housed in an 12:12 light:dark cycle in a controlled light environment (250 Lux at the cage level). The 12 hours of light began at 6 am and the 12 hours of dark began at 6 pm. The animals were given food and water ad libitum. The study was approved by the Animal Care and Use Committee at the University of Michigan, Ann Arbor, Michigan. All methods were performed in accordance with the relevant guidelines and regulations laid down by the Committee.Rat formalin-fixed paraffin-embedded (FFPE) tissuesFollowing euthanasia, rat brains and peripheral organs were harvested immediately and perfused in 1:10 formalin for one week. Tissues were then placed into 70% ethanol, dissected, and sectioned to a thickness of 5 µm by the University of Michigan Cancer Histology Core.Human FFPE tissuesFFPE human tissues used in Fig. 1 were archived from the University of Michigan. All samples were obtained from human autopsies and de-identified and, as such, were deemed exempt for regulation by the Institutional Review Boards at the University of Michigan.INMT and AADC mRNA in situ hybridizationFor single staining experiments, in situ probes for rat INMT (Catalog No. 418021) and human INMT (Catalog No. 459961) and the chromogenic RNAscope® 2.0 HD Detection Kit (RED) for FFPE tissues (an alkaline phosphatase system, Catalog No. 310036) were purchased from Advanced Cell Diagnostics (Hayward, CA, USA). Protocol was followed according to the RNAscope® Sample Preparation Pretreatment Guide for FFPE (Catalog No. 320511) and RNAscope® 2.0 HD Detection Kit (RED) User Manual Part 2 (Catalog No. 320487). INMT mRNA was stained red and counterstained with 50% hematoxylin. For double staining experiments, in situ positive control probes [ready to use (RTU) mixture of two probes targeting PPIB and POLR2A (Catalog No. 313921) and negative control probes (Catalog No. 310043 – dapB; RTU probe targeting a bacterial gene), as well as probes for rat INMT (Catalog No. 418021) and AADC (Catalog No. 428331-C2), and the RNAscope® 2.5 HD Duplex Detection Kit (Chromogenic) for FFPE (a mixed alkaline phosphatase and horseradish peroxidase system, Catalog No. 322430) were likewise purchased from Advanced Cell Diagnostics. Protocol was followed according to the FFPE Sample Preparation and Pretreatment User Manual for the RNAscope® 2.5 Assay Part 1 (Document No. 322452-USM) as well as the RNAscope® 2.5 HD Duplex Detection Kit (Chromogenic) User Manual Part 2 (Document No. 322500-USM). The only change in the protocol was to increase AMP 5 and AMP 9 incubation from 30 minutes to 1 hour per recommendation of Advanced Cell Diagnostics. INMT mRNA was stained green (horseradish peroxidase) while AADC mRNA was stained red (alkaline phosphatase). Single and double staining experiments were both completed in single day-long sessions. Slides were counterstained with 50% hematoxylin. Positive and negative control probes were run on samples in dual channels to assay for mRNA quality and background signal in samples, as well as to verify kit performance. Positive staining was defined by signal intensity stronger than that of the negative control. In general, small-punctate dots are taken to represent a single transcript whereas larger dark clusters represent multiple transcripts in close proximity, i.e., signal intensity is a qualitative measure of transcript level27. Semi-quantitative analysis of mRNA signal was conducted for duplex staining on rat brain experimental tissues for comparison to control images in all duplex images using ImageJ (Version 1.50i) as defined in the proceeding section. All images were captured on an Olympus BX-51 with a DP70 camera. Magnifications are specified in figure legends. Images were processed with Adobe Photoshop CC 2015.5 (Adobe Systems Inc.).Semi-quantitative analysis of mRNA duplex staining in rat brain tissues using ImageJExperimental rat brain tissue sections subjected to duplex staining for INMT and AADC mRNA and positive and negative control probes on adjacent brain sections (images in Figs 2 and S1) were quantified using ImageJ to estimate the fraction of total area in pixels of mRNA signals by summating both colormetric channel pixels as per a prior publication analyzing this variable in brightfield images of rat FFPE brain tissues following RNAscope in situ52. Results of mRNA quantification are presented in Fig. S1 (summated INMT and AADC signals for comparison of experimental versus control tissue sections). Briefly, blue channel staining was quantified in all Figs 2 and S1 images with the following Color Threshold command adjustments (under the Adjust command). All default settings were used, except hue was set for 0–163, saturation was set for 0 to 90–255, depending on background, and brightness was set for 0–215 to 255, depending on background. Similarly for red channel staining, all default settings were used, except HSB color space was changed to YUV, and Y was set for 0–135 to 200, depending on background, U was set for 0–255, and V was set for 135–185 to 255, depending on background. Particles were then analyzed using the Analyze Particles command and default settings therein along with the Summarize box option checked. Outputs from the Summarize box for %Area for both colormetric channels were entered into GraphPad Prism Version 7.0a for Mac OS X to construct graphs in Fig. S1. All images were processed beforehand with the same microscope settings and Adobe Photoshop CC 2015.5 (Adobe Systems Inc.) filters.Surgical implantation of microdialysis probesMicrodialysis probes were constructed as previously described24 and their surgical implantation was conducted on each rat (n = 36) for pineal and/or cortical dialysate collection using a method modified from a published protocol and under strictly aseptic conditions24. The rats were anesthetized lightly first using a combination of ketamine (10 mg//kg, i.m.) and xylazine (2 mg/kg, i.m.). The animal’s head was shaved and positioned in a stereotaxic instrument with the head flat. For the rest of the surgery, anesthesia was provided by 1.8% (1.5–2%) isoflurane. The skull was exposed by a 2 cm coronal incision between the two ears along the interaural line. Three stabilizing stainless steel screws 1 mm in diameter were placed to allow the positioning of the probes on the skull. Two small burr holes were created on both sides of the skull. The smaller hole on the right side was ~0.5 mm in diameter, which prevented the tip of the 25-gauge dialysis needle from penetrating the skull, whereas the larger hole on the left side was ~1 mm in diameter and allowed the probe to easily exit the skull during implantation. Next, the right probe was carefully pushed into the brain tissue through the pineal from the right side of the skull leaving the epoxy ball outside of the skull. Following the completion of probe insertion, the epoxy on the left side was removed using cautery and the tungsten rod was then carefully pulled out of the probe. The excess dialysis fiber was cut and the hollow fiber tip was then secured to the tip of the second part of the probe using epoxy resin. The probe setup was fixed to the anchor screws on top of the skull with dental cement. Finally, the skin was sutured, leaving two probes: one to introduce the perfusate, and the other end to collect dialysate. The entire procedure took less than two hours per animal. The animals were returned to their cages, housed individually, and allowed to recover from the surgery for 7 days before microdialysis recording proceeded. Target was verified via HPLC assessment of dialysate for melatonin, which emanates specifically from the pineal in the brain.PinealectomyThe pineal gland was first surgically removed from 11 rats. After the pineal gland was removed from the brain, a microdialysis probe was then inserted into the pinealectomized visual cortex using the same coordinates we used when the pineal gland was intact8. Animals were allowed 7 days to recover before baseline microdialysis sampling began. Pineal removal was further confirmed, via HPLC, by the absence of melatonin in the dialysate.

In vivo measurement of DMT secretionAn automated system combining microdialysis with real time HPLC analysis was utilized for measurement of DMT secretion in both normal (n = 25) and pinealectomized animals (n = 11) at baseline and following induction of cardiac arrest. The system is outlined with illustrations elsewhere24. DMT retention times were determined using reference standards, as in our previous publication8. The HPLC system consisted of one Shimadzu SCL-10A VP controller, two Shimadzu LC-20AD isocratic pumps, a CTO-20AC column oven containing 2 Supelco C18 reversed phase columns, two RF-10AXL detectors, two VICI Cheminert® sample injectors (2-position/10-port actuator), and a VICI digital sequence programmer.Each HPLC system was designed to analyze data simultaneously from 4 rats, with 2 rats using each detector. Following one week of recovery, animals were placed within a light-controlled microdialysis chamber that held 2 cages. Rats were housed at 250 lux on an light:dark cycle with a dark period of 18:00–6:00 and were allowed to move freely throughout due to a swivel mounted on a counterbalance arm. The 21-gauge needle base was connected with PEEK tubing and a syringe to link two rats each to an Instech peristaltic pump. Microdialysis was performed at a continuous 2 μL/min flow rate with an artificial cerebrospinal fluid (CSF) solution consisting of NaCl (148 mM), KCl (3 mM), CaCl2·2H2O (1.4 mM), MgCl2·6H2O (0.8 mM), Na2HPO4·7H2O (0.8 mM), and NaH2PO4·H2O (0.2 mM). Pineal/cortical dialysates were collected from two rats in 15 or 30 minute intervals and delivered to a sample loop (Instech, Plymouth Meeting, PA, USA) during which time previously collected samples for two rats were injected by a VICI Cheminert® sample injector (2-position/10-port valve) into a reversed phase C18 column, 250 × 4.6 mmm with 5 μm packing (Sigma, St Louis, MO, USA) maintained at 45 °C. A Shimadzu LC-20AD isocratic pump (Shimadzu, Tokyo, Japan) delivered the mobile phase, which consisted of 34% methanol with 10 mM sodium acetate, at 1.5 mL per minute. Since DMT is naturally fluorescent, as are all other compounds derived from tryptophan, samples were analyzed online by a Shimadzu fluorescence detector (excitation: 280 nm; emission: 345 nm) without any derivatization. The automated control was carried out with an external computer using Shimadzu chromatography software.Dialysates were collected in 15 or 30 minute intervals for several hours or days to establish baseline levels, at which point rats were euthanized by injection of 10% KCl to the heart between approximately 11:00–12:00. Content of DMT, melatonin, and 5-HT in the dialysates were identified using internal controls and quantified as previously described8,24. Data collection and sequence processing were performed on CLASS-VP firmware from Shimadzu. Baseline values for DMT were calculated as the average of 3 stable time points 2 hours prior to induction of cardiac arrest and compared to the maximum peak DMT value following induction of cardiac arrest. The automated analysis of these compounds at baseline and maximum points following induction of cardiac arrest was confirmed manually if necessary.Experimental design and statistical analysisStatistical analysis was conducted using RStudio (Macintosh Version 0.99.903) for paired two-tailed t-tests and unpaired t-tests with Welch’s correction. Exact p-values and means, means of differences, standard deviations, 95% confidence intervals, t values, and degrees of freedom are reported throughout the manuscript and completely in Figure legends. All plots and graphs were created with GraphPad Prism Version 7.0a for Mac OS X (La Jolla, CA) and further edited in Adobe Photoshop CC 2015.5 and Illustrator CC 2015.3 (Adobe Systems Inc.).

Data Availability

Original data that support the findings of this study are available from the corresponding author (J.B.).

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Download referencesAcknowledgementsThis work was supported by the Startup Award (to J.B.) from the Department of Molecular and Integrative Physiology at the University of Michigan. The authors wish to thank Kelly Young and Soo Jung Lee for assistance with in situ technique on FFPE tissues, Bruce Donohoe and Pennelope Blakely at the University of Michigan Microscopy and Imaging Analysis Laboratory for help with imaging, Chris Andrews of the University of Michigan Center for Statistical Consultation and Research unit for help with statistical analysis, Drs. Mark Womble and Gary Hammer, and Aaron Mrvelj for their helpful discussion on the use of human FFPE tissues, Kate Fleming for her comments on the manuscript, and Nick Barbush and Fangyun Tian for helping with Figures.Author informationAuthors and AffiliationsDepartment of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USAJon G. Dean, Tiecheng Liu, Sean Huff, Ben Sheler, Michael M. Wang & Jimo BorjiginDepartment of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USASteven A. BarkerDepartment of Psychiatry, University of New Mexico School of Medicine, Albuquerque, NM, USARick J. StrassmanDepartment of Neurology, University of Michigan, Ann Arbor, MI, USAMichael M. Wang & Jimo BorjiginNeuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USAMichael M. Wang & Jimo BorjiginVA Ann Arbor Healthcare System, Ann Arbor, MI, USAMichael M. WangCenter for Consciousness Science, University of Michigan, Ann Arbor, MI, USAJon G. Dean & Jimo BorjiginAuthorsJon G. DeanView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsJ.B. and M.M.W. conceived the project and planned experiments; J.G.D., T.L., S.H. and B.S. conducted the experiments with the help from S.A.B.; J.G.D. and J.B. wrote the paper with the help from S.A.B., R.J.S. and M.M.W.Corresponding authorCorrespondence to

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N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo | Translational Psychiatry

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N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

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Published: 28 September 2020

N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo

Jose A. Morales-Garcia

ORCID: orcid.org/0000-0001-9008-00561,2,3,4, Javier Calleja-Conde

ORCID: orcid.org/0000-0003-0573-38635, Jose A. Lopez-Moreno

ORCID: orcid.org/0000-0001-6668-65685, Sandra Alonso-Gil1,2, Marina Sanz-SanCristobal1,2, Jordi Riba6 & …Ana Perez-Castillo

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Translational Psychiatry

volume 10, Article number: 331 (2020)

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AbstractN,N-dimethyltryptamine (DMT) is a component of the ayahuasca brew traditionally used for ritual and therapeutic purposes across several South American countries. Here, we have examined, in vitro and vivo, the potential neurogenic effect of DMT. Our results demonstrate that DMT administration activates the main adult neurogenic niche, the subgranular zone of the dentate gyrus of the hippocampus, promoting newly generated neurons in the granular zone. Moreover, these mice performed better, compared to control non-treated animals, in memory tests, which suggest a functional relevance for the DMT-induced new production of neurons in the hippocampus. Interestingly, the neurogenic effect of DMT appears to involve signaling via sigma-1 receptor (S1R) activation since S1R antagonist blocked the neurogenic effect. Taken together, our results demonstrate that DMT treatment activates the subgranular neurogenic niche regulating the proliferation of neural stem cells, the migration of neuroblasts, and promoting the generation of new neurons in the hippocampus, therefore enhancing adult neurogenesis and improving spatial learning and memory tasks.

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IntroductionN,N-dimethyltryptamine (DMT) is a natural compound found in numerous plant species and botanical preparations, such as the hallucinogenic infusion known as ayahuasca1 classified as a hallucinogenic compound that induces intense modifications in perception, emotion, and cognition in humans2,3,4. DMT is present in several animal tissues, such as the lung5 and brain6, being considered as an endogenous trace neurotransmitter with different physiological roles, including neural signaling and brain/peripheral immunological actions7,8,9,10. DMT is also present in human blood, urine, and cerebrospinal fluid11,12,13. Furthermore, some evidence suggests that DMT can be sequestered into and stored in the vesicle system of the brain and that environmental stress increases its levels in mammals’ central nervous system (CNS)14,15,16. DMT binds and exerts an agonist activity on subtypes 1A and 2A of the serotonin receptor (5-HT)17,18. These receptors are G-protein-coupled receptors (GPCRs) belonging to the family of serotonergic receptors and are involved in numerous cascades of intracellular signaling, with high expression in several regions of the CNS. Some studies have demonstrated that DMT also binds with low affinity to non-serotonergic receptors, such as the sigma-1 receptor (S1R). The S1R, traditionally thought to be an opioid receptor, is now classified as a highly conserved transmembrane protein member of an orphan family and located mainly in the membrane of the endoplasmic reticulum. σR‐1 is widespread in the CNS, mainly in the prefrontal cortex, hippocampus, and striatum19. Interestingly, in mammals, one of the natural endogenous ligands of the σR-1 is DMT14. This receptor has been associated with several cellular functions, including the brain, such as lipid transport, metabolism regulation, cellular differentiation, signaling (in response to stress), cellular protection against oxidant agents, myelination and, most recently, neurogenesis20,21,22,23,24.Neurogenesis is the process of generating new functional neurons, mainly in the SVZ and the subgranular zone of the DG of the hippocampus. In mammals, this process occurs mostly during the prenatal period, being significantly reduced in adults25,26,27,28,29,30. In humans, although the presence of adult neurogenesis has been recently reported during aging31,32,33, most of the studies indicate that there are no substantial evidence to support it. A recent review by Duque and Spector suggests that, in adult age, preservation of the existing neurons is more important in contrast to the generation of new ones34. Neurogenesis is a complex process involving multiple cellular activities including the proliferation of neural stem cells (NSC; progenitors), migration and differentiation, survival, acquisition of cell fate and maturation, and integration of these newly born neurons in existing neuronal circuits. All these processes are precisely regulated by multiple factors35. Advancements in the knowledge of these factors and their mechanism of action could help us to investigate possible new instruments that will allow us to expand the limited endogenous neurogenic capacity of the adult brain and, consequently, opening new fields for the development of effective therapies in the treatment of brain damage and neurodegenerative diseases.Neurodegenerative diseases (including Parkinson’s, Alzheimer’s, Hungtinton’s, etc.) and acute neural damage (such as stroke and traumatic brain injury) are characterized by a gradual and selective loss of neurons in the affected regions of the nervous system. One common feature in these disorders is an impairment in the proliferation of progenitor cells in the neurogenic niches36,37. In animal models reproducing the pathological hallmarks of Alzheimer disease, a loss of neurogenic capacity has been described in the SVZ38. This decrease is also observed in the postmortem brains of Parkinson’s patients, suggesting that the loss of neurogenic activity is due to the loss of dopamine, affecting the neural precursors in the adult39. These data support the fact that in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, not only degeneration and death of mature neurons occur but also the process of formation of new neuronal progenitors in the adult brain is negatively affected. According to these data, the stimulation of endogenous populations of stem cells and neuronal progenitors could be a promising approach to improve the functionality of some of the regions affected by neurodegenerative pathologies. In fact, the stimulation of neurogenesis has already been proposed as a new therapeutic strategy for psychiatric and neurological diseases40,41,42,43,44, and several studies have reported that the clinical efficacy of antidepressant drugs is frequently linked to the capacity of these drugs to induce neurogenesis45,46,47,48.Based on the data above mentioned including our results on the potent neurogenic effect of the other components of the Ayahuasca49, the main objective of this work was to analyze the possible role of DMT in adult neurogenesis, as well as to elucidate its mechanism of action.Materials and methodsAnimals and ethicsAdult male C57/BL6 mice (3-months old) were used in this study following the animal experimental procedures and protocols specifically approved by the “Ethics Committee for Animal Experimentation” of the Institute for Biomedical Research (CSIC-UAM) and carried out in accordance with the European Communities Council, directive 2010/63/EEC and National regulations, normative RD1386/2018. Adequate measures were taken to minimize the pain or discomfort experienced by the mice.Adult precursor isolationNSCs were isolated from the subgranular zone (SGZ) of the hippocampus of adult mice and prepared the following previously described methods49. A total number of 24 animals were used divided into four different pools (six animals/pool). Briefly, tissue was carefully dissected, dissociated in DMEM medium with glutamine, gentamicin, and fungizone, and then digested with 0.1% trypsin-EDTA + 0.1% DNAse + 0.01% hyaluronidase for 15 min at 37 °C. The isolated stem cells were seeded into six-well dishes at a density of ~40,000 cells per cm2 in DMEM/F12 (1:1) containing 10 ng/mL epidermal growth factor (EGF), 10 ng/mL fibroblast growth factor (FGF), and N2 medium.Neurosphere culture and treatmentsAfter 1 week in culture under standard conditions, small neural progenitor-enriched growing spheres known as neurospheres (NS) were formed. At this point, with all NS having the same stage and size, cultures were treated daily for 7 days under proliferative conditions (in the presence of exogenous growth factors, EGF and FGF) with vehicle or DMT (1 μM). Some cultures were individually pre-treated for 1 h at 1 μM with antagonists of the different receptors that bind DMT: BD1063 (BD, sigma-1R), methiothepin (Met, 5-HT1A/2A), ritanserin (Rit, 5-HT2A), and WAY100635 (WAY, 5-HT1A). None of the tested drugs affected the viability of cultured cells at this dosage (data not shown).Growth and proliferation measurementsAfter 7 days on culture in the presence or not of compounds, proliferation and growth analysis was assessed, and the number and size of NS in ten wells per condition were quantified using the Nikon Digital Sight, SD-L1 software. At least 50 neurospheres per condition were quantified. Next, some of these proliferating NS were used for immunoblotting analysis, while others were seeded onto coverslips and cultured again in the presence of DMT (1 μM) and/or DMT + antagonist (1 μM) during 24 h under differentiation conditions (medium containing 1% fetal bovine serum and without exogenous growth factors). NS were then fixed in paraformaldehyde 4% during no more than 20 min, and then immunocytochemistry analysis was performed using a specific antibody for proliferation. The remaining NS were cultured for differentiation studies.Differentiation of NS culturesTo determine the ability of DMT to stimulate neurons, astrocytes, or oligodendrocytes formation, NS from 7-day-old cultures were seeded onto poly-l-lysine-precoated six-well plates and/or on coverslips and cultured in the presence of DMT (1 μM) and/or DMT + antagonist (1 μM) under differentiation conditions (medium containing 1% fetal bovine serum and without exogenous growth factors). Once neurospheres were differentiated (72 h), those grown on coated six-well plates were used for immunoblotting and those on coverslips for immunocytochemical analysis.Protein extraction and western blot analysisCultured NS on coated six-well plates were resuspended in ice-cold cell lysis buffer (Cell Signaling Technology) with protease inhibitor cocktail (Roche) and incubated for 15–30 min on ice. A total amount of 30 µg of protein was loaded on a 10% or 12% SDS-PAGE gel and transferred to nitrocellulose membranes (Protran, Whatman). The membranes were blocked in Tris-buffered saline with 0.05% Tween-20 and 5% skimmed milk or 4% BSA (MAP-2 blots), incubated with primary and secondary antibodies, and washed according to standard procedures. The values in figures are the average of the quantification of 12 blots corresponding to four different cellular pools with three independent experiments/pool.ImmunocytochemistryAfter 1 week in culture when NS were formed, some of them were immunostained using a rabbit anti-sigma-1 receptor antibody (Abcam ab53852) combined with a mouse anti-nestin antibody (Abcam ab6142). At the end of the treatment period, NS grown on glass coverslips were fixed 15–20 min at room temperature in 4% paraformaldehyde, permeabilized with 0.1% Triton X-100, and incubated at 37 °C for 1 h with the corresponding primary antibody. Then cells were washed with PBS and incubated with Alexa-488 goat anti-rabbit and Alexa-647 goat anti-mouse antibodies (1:500, Molecular Probes) for 45 min at 37 °C. To study proliferation, a rabbit anti-ki67 (1:200, Abcam ab833) antibody was used. For differentiation of NS into the different neural cell types, next antibodies were used: rabbit β-III-tubulin (1:400, TuJ-1 clone; Abcam ab68193), and mouse anti-MAP-2 (1:200, mouse; Sigma M4403) for neurons; mouse anti-GFAP (1/500, Sigma G3893) for astroglial cells, and rabbit anti-CNPase (1:100, Cell Signaling #2986) as an oligodendrocyte marker. Staining of nuclei was performed using 4′, 6-diamidino-2-phenylindole (DAPI, 1/500). Finally, images were acquired in LSM710 laser-scanning spectral confocal microscope (Zeiss). Confocal microscope settings were adjusted to produce the optimum signal-to-noise ratio. Representative images of at least eight neurospheres/condition from four different cellular pools are shown.Neurogenic studies in vivoMice housed in a 12-h light–dark cycle animal facility were divided, according to the treatment administered. (1) Short-term animals (n = 5 per experimental group), which received daily an intraperitoneal (i.p.) injection during 4 consecutive days with DMT (2 mg per kg of bodyweight) alone or in combination with the antagonists BD1063 (sigma-1R), methiothepin (5-HT1A/2A), ritanserin (5-HT2A) and WAY100635 (5-HT1A). On day 4, mice were intraperitoneally (i.p.) injected with 5-bromo-2-deoxyuridine (BrdU; 50 mg/kg) and sacrificed on day 5. (2) Long-term mice (n = 5 per experimental group), which received every other day an i.p. injection of DMT (2 mg per kg of bodyweight) alone or in combination with the correspondent antagonist during 21 consecutive days. To label proliferating cells for long-term studies on survival and differentiation, mice were intraperitoneally injected with BrdU (50 mg/kg) on day 1. All intraperitoneal treatments were administered 1 h after clorgyline (1 mg/kg, ip) injection. The dose of compounds was chosen based on previous studies14,50,51.Tissue preparation and immunohistochemistryAfter treatment, the animals previously anesthetized were perfused transcardially with 4% paraformaldehyde solution, and brains were processed as previously described52. Sections were then incubated with anti-sigma 1 receptor rabbit (Abcam ab53852) combined with anti-nestin mouse (Abcam ab6142), anti-BrdU mouse monoclonal (DAKO M0744) combined with anti-nestin rabbit (Abcam ab7659), anti-NeuN rabbit (Millipore ABN78), or anti-doublecortin (DCX, Santa Cruz sc-8066) antibodies at 4 °C overnight, washed three times and incubated with AlexaFluor 488 goat anti-mouse and Alexa-647 goat anti-rabbit secondary antibodies for 1 h at room temperature. After rinses, sections were mounted with Vectashield. Images were obtained using a LSM710 laser-scanning spectral confocal microscope (Zeiss). Confocal microscope settings were adjusted to produce the optimum signal-to-noise ratio. Five animals from each experimental group were analyzed.Cell count analysisTo estimate the total numbers of cells stained with a particular marker, a modified stereological approach was used on brain coronal sections containing the SGZ, as previously described53. Images were processed with the image processing package Fiji54. Five mice per group were used. The results were expressed as the total number of labeled cells in the DG of the hippocampus by multiplying the average number of labeled cells/structure section by the total number of 30-μm-thick sections containing the DG. Values represent the means from three different experiments and five animals/experiment/experimental group. **P ≤ 0.01.Behavioral studiesFor behavioral studies, mice were i.p. injected as mentioned above with DMT (2 mg/kg) alone or in combination with ritanserin (0.2 μg/animal) during 21 consecutive days. Then behavioral analysis was performed as previously described45 during 10 days, and finally, animals were sacrificed on day 31. Control animals were injected with vehicle. All intraperitoneal treatments were administered 1 h after clorgyline (1 mg/kg, ip) injection. Twelve animals per experimental group were used.Statistical analysisNo statistical methods were used to determine the sample size for each experiment. The sample size and animal numbers were estimated based on our previous studies. For animal studies, no randomization was used. Statistics analysis data from Figs. 1–5 were analyzed using a one-way ANOVA. In Fig. 5, data from the learning curve and cued learning were analyzed using a two-way mixed ANOVA. After confirming the significance of the primary findings using ANOVA, a significance level of P < 0.05 was applied to all remaining post hoc statistical analyses (Tukey test). The SPSS statistical software package (version 20.0) for Windows (Chicago, IL) was used for all statistical analyses.Fig. 1: N,N-dimethyltryptamine (DMT) activates the hippocampal subgranular neurogenic niche through sigma-1 receptor (S1R).SGZ-derived neurospheres (NS) were treated during 7 days with DMT alone or in combination with the antagonists BD1063 (BD), methiothepin (Met), ritanserin (Rit), and WAY100635 (WAY). a Expression of the S1R (green) on neural stem cells (NSCs) (red-labeled with nestin) determined by immunocytochemistry (n = 8 neurospheres) and western blot analysis (n = 12 blots). b Representative western blots and quantification showing expression levels of the stemness markers musashi-1, nestin, and SOX-2 in NSCs. c Representative phase-contrast micrographs showing NS formation and quantification of the number and diameter of NS (n = 50 neurospheres per condition). Scale bar = 100 μm. d Confocal fluorescent images showing the expression of the cellular marker for proliferation ki67 (green) in NS after treatments (n = 8 per condition). DAPI was used for nuclear staining. Scale bar = 50 μm. e Representative western blots and quantification showing the proliferating cell nuclear antigen (PCNA) levels in NS. Values in bar graphs indicate mean ± SD of the quantification of four different cellular pools with three independent experiments/pool (n = 12 blots). After confirming the significance of the primary findings using ANOVA, a significance level of P < 0.05 was applied to all remaining post hoc (Tukey test) statistical analyses. **P ≤ 0.01 indicates significant results versus non-treated (basal) cultures.Full size imageFig. 2: N,N-dimethyltryptamine (DMT) promotes stem cell differentiation toward all neural phenotypes.SGZ-derived neurospheres were cultured for 7 days in the presence of DMT alone or in combination with the antagonists BD1063 (BD), methiothepin (Met), ritanserin (Rit), and WAY100635 (WAY) and then were adhered on a substrate and allowed to differentiate for 3 days. a Confocal fluorescent images showing the expression of the neuronal markers β-III-Tubulin (TuJ-1 clone, green) and MAP-2 (red) in NS (n = 8 per condition). DAPI was used for nuclear staining. Scale bar = 50 μm. b Representative western blots and quantification of β-tubulin and MAP-2. c Immunofluorescence images showing NS expressing the glial fibrillary acidic protein (GFAP, red) that stains astrocytes, and in green, the oligodendrocyte marker CNPase (n = 8 per condition). DAPI was used for nuclear staining. Scale bar = 50 μm. d Representative western blots of CNPase and GFAP and quantification. Results are the mean ± SD of four different cellular pools with three independent experiments/pool (n = 12). After confirming the significance of the primary findings using ANOVA, a significance level of P < 0.05 was applied to all remaining post hoc (Tukey test) statistical analyses. **P ≤ 0.01; ***P ≤ 0.001 indicate significant results versus non-treated (basal) cultures.Full size imageFig. 3: N,N-dimethyltryptamine (DMT) promotes in vivo activation of the neurogenic niche located in the SGZ of the dentate gyrus in the hippocampus.a Representative images (n = 3 animals) showing the expression of the sigma-1 receptor (S1R, green) on neural stem cells (NSCs) (red-labeled with nestin) in the subgranular zone of the dentate gyrus. S1R expression was also determined by western blot on hippocampal tissue (n = 3 animals). b Schematic representation of experimental design and treatment schedule for in vivo short-term neurogenic study. DMT alone or in combination with the antagonists BD1063 (BD), methiothepin (Met), ritanserin (Rit), or WAY100635 (WAY) was daily intraperitoneally injected during 4 days. To label proliferating cells, on day 4 mice were i.p. injected with 5-bromo-2-deoxyuridine (BrdU) and sacrificed on day 5. c Confocal maximum intensity projection images showing BrdU/Nestin co-staining on the SGZ of adult mice. BrdU is shown in green and nestin in red. Scale bar = 25 μm. d Quantification of the number of double BrdU/Nestin cells in the DG performed on confocal orthogonal images is shown. e Double BrdU+-DCX+ expressing cells in the SGZ. Confocal maximum intensity projection images show BrdU in green and DCX in red. Scale bar = 25 μm. f Quantification of the number of BrdU+- DCX+ cells in the DG is shown. All quantification values represent the mean ± SD (n = 5 animals per group). After confirming the significance of the primary findings using ANOVA, a significance level of P < 0.05 was applied to all remaining post hoc (Tukey test) statistical analyses. **P ≤ 0.01; ***P ≤ 0.001 indicate significant results versus vehicle-treated (basal) animals.Full size imageFig. 4: N,N-dimethyltryptamine (DMT) promotes in vivo neurogenesis on the subgranular zone of the dentate gyrus in the hippocampus.a Schematic representation of the experimental design and treatment schedule for in vivo long-term neurogenic study. DMT alone or in combination with the antagonists BD1063 (BD), methiothepin (Met), ritanserin (Rit), or WAY100635 (WAY) was intraperitoneal injected on alternate days during 21 days. To label proliferating cells, on day 1 mice were i.p. injected with 5-bromo-2-deoxyuridine (BrdU) and sacrificed on day 21. b BrdU-DCX-expressing cells in the DG. Representative confocal images are shown. Scale bar = 25 μm. c Quantification of the number of BrdU+-DCX+-expressing cells in the DG based on confocal orthogonal images. d Confocal maximum intensity projection images showing the colocalization of BrdU (green) and neuN (red) cells in the dentate gyrus of the hippocampus of adult mice. Scale bar = 25 μm. e Quantification of the number of BrdU+/NeuN+ cells performed on confocal orthogonal images in DG. Values represent the mean ± SD (n = 5 animals per group). After confirming the significance of the primary findings using ANOVA, a significance level of P < 0.05 was applied to all remaining post hoc (Tukey test) statistical analyses. **P ≤ 0.01; ***P ≤ 0.001 indicate significant results versus vehicle-treated (basal) animals.Full size imageFig. 5: N,N-dimethyltryptamine (DMT) promotes improved performance in learning tasks linked to hippocampal neurogenesis.a Schematic representation of the experimental design for behavioral tests. DMT alone or in combination with the antagonist ritanserin (Rit) was intraperitoneally injected on alternating days for 21 days. Then, behavioral tests were performed for 10 days, and finally animals were sacrificed on day 31. b Data from Morris water maze test. *P < 0.05; **P < 0.01; ***P < 0.001 versus the control group. #P < 0.05 versus DMT + ritanserin group. c Data from the novel object recognition test. Values represent the mean ± SEM (n = 12 per group). *P < 0.05 versus the control group. #P < 0.05; ##P < 0.01; ###P < 0.001 versus old object. After confirming the significance of the primary findings using ANOVA, a significance level of P < 0.05 was applied to all remaining post hoc (Tukey test) statistical analyses.Full size imageResultsDMT controls the stemness of neural progenitors in vitro through the S1RWe first analyzed whether the sigma-1 receptor (S1R) was expressed on murine NSCs isolated from the subgranular zone of the dentate gyrus of the hippocampus. Figure 1a shows S1R expression on neurospheres in the basal state determined by immunocytochemistry and western blot analysis. To analyze the “stemness” of cultured neurospheres, we determined the expression of potentiality markers of this state. Then, we performed WB analysis after treatment of these cultures during 7 days under proliferative conditions (see “Materials and methods”) with DMT alone or in combination with the different antagonists. Our results (Fig. 1b) show significant reductions in protein levels of musashi-1, nestin, and SOX-2 in the SGZ-derived neurospheres after treatment with DMT, suggesting a loss of stemness in NSCs in the NS cultures. When these cultures were pre-treated with BD1063, a specific antagonist for S1R, this effect was reversed, and stemness marker levels were similar to those observed in basal conditions. On the contrary, the expression of stemness markers in those cultures treated with DMT together with the mixed serotonin 5-HT1A/2A receptor antagonist methiothepin, the selective 5-HT2A receptor antagonist ritanserin, or the selective 5-HT1A receptor antagonist WAY100635, significantly decreased stemness as occurred in DMT-treated cultures. These results suggest that DMT promotes a loss of “stemness” or and undifferentiated state of the neurospheres, through the S1R.DMT promotes the proliferation in vitro of NSCsOther NS cultures were used to study proliferation; thereby, the number and diameter of the neurospheres were evaluated (Fig. 1c). DMT notably increased the number and size of the neurospheres in NS cultures after 7 days of treatment, indicating that DMT promotes the proliferation of adult hippocampal-derived neural progenitors. DMT proliferative effect was blocked when cultures were treated with BD1063 showing a significant decrease in the number and size of neurospheres, similar to basal conditions. Also, significant differences, in number and size of neurospheres, were observed when cultures were treated with DMT combined with methiothepin, ritanserin, or WAY100635.We next analyzed changes in two well-known markers for proliferation, ki67 and proliferating cell nuclear antigen (PCNA) (Fig. 1d, e). Fluorescent immunocytochemical analysis of ki67 expression (Fig. 1d) showed an increase in the number of ki67+ cells in the NS after treatment with DMT, suggesting a direct effect of DMT on the proliferation ability of NSCs. This effect was clearly reverted when cultures were also incubated with the antagonist BD1063 (BD). Similar results were obtained by western blot analysis and subsequent quantification of PCNA (Fig. 1e). No significant differences in the expression of ki67 and PCNA were observed when cultures were preincubated with other DMT antagonists. These results indicate that DMT stimulates in vitro, through the S1R, the proliferation of neural progenitors of the adult neurogenic niche of the hippocampus.DMT promotes the differentiation in vitro of NSCs toward the three main neural cellular typesTreated neurospheres during 7 days in the presence of DMT, alone or in combination with the different antagonists, under differentiation conditions (medium with 1% fetal bovine serum and absence of growth factors) were used. To study the ability to differentiate into a certain neural phenotype, the expression of specific proteins linked to every neural subtype was analyzed (Fig. 2). To detect neurons, β-III-tubulin (clone TuJ-1), found exclusively in neurons and MAP-2 (microtubule-associated protein 2), present in mature neurons, were used (Fig. 2a, b). To study its differentiation toward an astroglial or oligodendroglial phenotype (Fig. 2c, d), we analyzed the expression of GFAP (astrocytes) and CNPase (oligodendrocytes).Figure 2a, b shows a striking increase in the expression of β-III-tubulin and MAP-2 in neurospheres treated with DMT, compared with basal (non-treated) cultures. This neurogenic effect is clearly blocked by BD. No differences in the expression of neuronal markers were observed when cultures were treated with DMT in combination with metiotepine, ritanserin, or WAY. These results suggest that DMT stimulates the in vitro differentiation of neural progenitors toward a neuronal phenotype through S1R.Related to gliogenesis, Fig. 2c, d shows an increase in the expression levels of GFAP and CNPase, after DMT treatment. This promotion of astroglial cells and oligodendrocytes generation was blocked when cultures were pre-treated with the antagonist BD. We did not observe differences in the expression of GFAP and CNPase when neurospheres were pre-treated with the other antagonists. These results may suggest a direct effect of DMT on in vitro differentiation of neural progenitors toward astrocytes and oligodendrocytes via S1R.DMT activates in vivo the subgranular zone neurogenic niche in adult miceTo confirm our in vitro results on the role of the S1R on DMT neurogenic action, we first determined the expression of S1R in the subgranular neurogenic niche. To that end, brain coronal sections, including the hippocampus and protein samples isolated from the SGZ, were analyzed. As can be observed in Fig. 3a, immunofluorescence on the subgranular zone and western blot analysis shows the expression of S1R in this brain area. We next analyzed whether DMT also exerted an effect stimulating the proliferation kinetics of NSCs in the SGZ in vivo. To that end, adult mice were intraperitoneally injected during 4 (short-term) or 21 days (long-term) with DMT alone or in combination with antagonists, followed by BrdU administration for 24 h (Fig. 3) or 21 days (Fig. 4) before sacrifice. In short-term animals (Fig. 3b), immunohistochemical and cell count analysis performed on brain serial coronal sections containing the SGZ (Fig. 3c, d) demonstrated that DMT significantly increased the number of double BrdU/Nestin-stained cells in the SGZ, in comparison with control values (clorgyline-treated group). This neurogenic stimulation seemed to be mediated by the S1R since no neurogenic effect was observed when DMT is administered together with the antagonist BD1063. No differences were found in BrdU and nestin immunostaining in those animals injected with DMT in combination with the antagonist methiothepin and WAY100635.During the neurogenic process, proliferation is crucial but also the migration of the newly generated precursor from the SGZ to the granular layer. To study the migration of neural precursors, serial coronal brain sections were stained for doublecortin (DCX). The results shown in Fig. 3e, f show a higher immunopositive BrdU/DCX cells in the SGZ of DMT-treated animals. Additionally, DCX-stained cells in DMT-treated animals exhibited extensive dendritic arborizations. No difference was observed when animals were treated with DMT combined with antagonists. Contrarily, when DMT was injected with BD1063, Brdu, or DCX expression was not increased. These results confirm that DMT-treated mice exhibit enhanced proliferation and migration of neural precursors in the SGZ after 4 days of treatment, suggesting a modulating effect of this compound on hippocampal neurogenesis in vivo.In order to know whether these new migrating neuroblasts were able to properly reach the granular cell layer, long-term (21 days) treated animals were used (Fig. 4a). Quantification analysis of confocal images demonstrates an increase in DCX+/BrdU+-cell in the SGZ after DMT treatment (Fig. 4b, c). No differences were found in those animals treated with DMT together with methiothepin or WAY100635. Once again, combined treatment of DMT with BD1063 blocked the migration increase observed in animals treated only with DMT. In addition, at this time when neuroblasts have reached the granular cell layer, a noticeable increase in the amount of newly generated neurons (BrdU+/NeuN+ cells) was seen in this layer (Fig. 4d, e) in DMT-treated animals. This increase in the number of newly generated granular cells was blocked when mice treated with DMT together with BD1063. Altogether, these observations clearly indicate that DMT increases in vivo the number of new neurons originated in the hippocampus, action mediated by S1R.Taking into account these results, we finally analyzed the functional consequences of DMT treatment by performing behavioral tasks (Fig. 5a) to analyze if memory and learning are affected. Figure 5b (left panel) shows the results obtained by the Morris water maze test. During the learning curve, there were significant differences between groups only on days 4 and 5, showing that the DMT group tended to reduce the escape latency compared with DMT + ritanserin and control groups, respectively. In the probe trial, DMT and DMT + ritanserin groups showed a significant reduction in escape latency compared with the control group. In this line, we found that the control group performed less platform crosses and spent less time in target annulus around the previous platform location. Data from the probe trial indicate that the DMT and DMT + ritanserin remembered more effectively the zone where the hidden escape platform was. During the 3 days of cued learning, no differences were observed between groups, indicating that the differences observed in the learning curve and probe trial were not due to differences in the motivation of animals to escape from the water nor sensorimotor abilities.Regarding the new object recognition test (Fig. 5c, right panel), the DMT group showed a longer exploration time of the new object and a greater number of approaches to it. In addition, this group tended to explore the new object before the old one. DMT + ritanserin group spent more time exploring the new object and approached it more times. Finally, the control group only spent more time exploring the new object. In addition, we obtained differences in the latency of the first approach and exploration time between DMT and control groups. These results suggest that DMT and DMT + ritanserin groups showed better episodic memory compared to the control group.DiscussionWe have previously described that β-carbolines alkaloids, the three main alkaloids present in Banisteriopsis caapi and harmol, the main metabolite of harmine in humans, play an important role as key regulators on adult neural stem cell activity49. Using an in vitro model of adult neurogenesis, we showed that they promote the proliferation and migration of progenitor cells and induced their differentiation mainly into a neuronal phenotype. The main limitation to that work was that the potential role of DMT, other active compounds contained in ayahuasca brews, was not described. Moreover, previous studies performed on rodents and primates55,56,57,58, and more interestingly in humans4,59, suggest that ayahuasca infusion has antidepressant activity, a therapeutic effect usually linked to hippocampal neurogenesis. This work extends our previous results indicating the role of DMT, one of the main compounds of the hallucinogenic infusion ayahuasca, in adult neurogenesis.Our results in vitro and in vivo show that DMT is a key regulator in the activity of adult NSCs, since this compound plays an important role in regulating the expansion and differentiation of the stem cell population located in the SGZ, one of the main adult neurogenic niches. This is revealed in vitro by an increase in the number and size of primary neurospheres and an increased expression of ki67 and PCNA, which indicates a high rate of proliferation and loss of stemness after treatment with DMT. Increased proliferation does not indicate neuronal commitment60; however, DMT also induced an increase in β-III-tubulin+ and MAP-2 + cells, suggesting promotion of differentiation toward a neuronal phenotype and increasing the total numbers of the neuron that reach neuronal maturity. Interestingly, in contrast to that previously described on the action of carbolines in vitro49, we have also found an increase in the number of other neural cells such as astrocytes and oligodendrocytes after DMT treatment. Similar results were observed in vivo, with an increased proliferation rate of the NSCs and a larger population of doublecortin expressing neuroblasts migrating to the hippocampal granular layer to generate new neurons. Moreover, these have a functional impact since DMT treatment during 21 days clearly improved mouse performance in learning and memory tasks, in which the hippocampus is considered to play an essential role. These observations are in agreement with previous works showing that adult hippocampal neurogenesis plays an important role in these cognitive functions61,62,63,64,65. Considering these effects, we can determine that the DMT has the capacity to regulate the expansion and destination of stem cell populations and therefore contribute to memory and learning processing in the dentate gyrus.Neurogenesis consists of proliferation and loss of stemness of the NSCs, migration of neuroblasts and differentiation into functional neurons. Results here obtained demonstrate that DMT controls all these stages. Interestingly, in addition to the neurogenic potential, DMT also induced the formation of astrocytes and oligodendrocytes. This ability for controlling neurogenesis is of great interest, since in pathological conditions, the renewal of the neurons must be optimized by acting simultaneously on several processes40,66. We have previously indicated that many molecules67,68,69,70,71 and recently β-carbolines contained in ayahuasca49 exerted and effect on cell proliferation and differentiation, therefore the effect of DMT stimulating cell proliferation and differentiation is not exclusive to this compound. One of the goals of this work is that additionally to its neurogenic effect, DMT also stimulated migration and new generation of astroglial cells and oligodendrocytes, what highlights the versatility of this compound as it can promote all the processes involved in full adult neurogenesis. Specifically, astrocytes are known to support the proliferation, survival, and maturation of developing neurons and neuroblasts that have already committed to neuronal lineages72 but also to promote neurogenesis73,74. In fact, previous works demonstrated that astrocytes in vitro could be directly converted into neurons or stem-like cells, pointing to the plasticity of these somatic glial cells75,76,77. No previous studies on the neurogenic effect of DMT have been described, but in comparison with the effect of other ayahuasca components such as β-carbolines49, we can conclude that the effect of DMT on adult neurogenesis is considerably more potent. As an additional value to the generation of neurons, the glial cells formation induced by DMT might be an ideal target for in vivo neuronal conversion after neural injury, since some studies have achieved to generate proliferating, non-tumorigenic neuroblasts from resident astrocytes78. The main therapeutical implication of the results here obtained is derived from the close relationship between neurogenesis and antidepressant activity described in several animal models79.DMT is considered a serotoninergic drug because its mechanism of action consists in agonism at different serotoninergic receptors, especially the 5-HT2A receptors widely described as inducers of neurogenesis80, but also psychedelics (reviewed by Dos Santos and Hallak81). One of the main limitations that arise when designing a possible drug from the results obtained is to achieve the desired neurogenic effect without causing the patient hallucinogenic effects secondary to treatment with DMT, through the activation of 5-HT2A receptors. The results here obtained indicate that the observed effects of DMT are mediated by the activation of the S1R. In this regard, it has been shown that the stimulation of the S1R by different agonists enhances neurogenesis in the hippocampus23,82. Moreover, in vivo evidence suggests that the σ1R deficiency interrupts the adult neurogenesis22. In humans, the use of S1R agonists, such as fluvoxamine, shows its involvement in neuroplasticity83, suggesting an important role in improving learning mechanism. In clinical studies, some S1R agonists, including fluvoxamine, donepezil, and neurosteroids, improve cognitive impairment84,85. Adult hippocampal neurogenesis is widespread in mammals, including humans, and may act as a key regulator in cognition, memory, and emotion-related behavior86. Deficits in adult neurogenesis are associated with the physiopathology of depression and modulation of neurogenesis is behind the action of several antidepressants79.Recently, a previous study has described the role of other psychoactive tryptamine, 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), in neurogenesis87. In contrast to the intracerebral injection of 5-MeO-DMT administered by these authors, we used DMT i.p. that can cross the blood–brain–barrier, which facilitates its future administration in humans. Moreover, the neurogenic effect of DMT through the S1R activation is combined to the antagonism of 5-HT2A receptor, avoiding the hallucinogenic effects of these tryptamine derivatives. This information could be very useful for the future development of new treatments against neurodegeneration.In conclusion, this study shows that DMT present in the ayahuasca infusion promotes neurogenesis by stimulating the expansion of neural progenitors populations, and by inducing the differentiation of these NSCs. Moreover, the neurogenic stimulation observed after DMT treatment correlates with an improvement in spatial learning and memory tasks in vivo. Stimulation of the neurogenic niches of the adult brain can contribute substantially to the antidepressant effects of ayahuasca in recent clinical studies. The versatility and complete neurogenic capacity of the DMT guarantee future research regarding this compound. In addition, its ability to modulate brain plasticity indicates its therapeutic potential for a wide range of psychiatric and neurological disorders, among which are neurodegenerative diseases.

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Download referencesAcknowledgementsThis work was supported by the MINECO (SAF2017-85199-P to A.P.-C.) and was partially financed with FEDER funds. J.R. received funding from the Beckley Foundation. CIBERNED is funded by the Health Institute “Carlos III”.Author informationAuthors and AffiliationsInstitute for Biomedical Research “A. Sols” (CSIC-UAM). Arturo Duperier 4, 28029, Madrid, SpainJose A. Morales-Garcia, Sandra Alonso-Gil, Marina Sanz-SanCristobal & Ana Perez-CastilloSpanish Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), c/ Valderrebollo 5, 28031, Madrid, SpainJose A. Morales-Garcia, Sandra Alonso-Gil, Marina Sanz-SanCristobal & Ana Perez-CastilloDepartment of Cellular Biology, School of Medicine, Complutense University of Madrid, Plaza Ramón y Cajal, 28040, Madrid, SpainJose A. Morales-GarciaCellular Neurobiology Laboratory, Neurobiology Department, UCS-UCM, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid, SpainJose A. Morales-Garcia & Ana Perez-CastilloDepartment of Psychobiology and Behavioural Sciences Methods, Faculty of Psychology, Complutense University of Madrid, Carretera de Humera, 28223, Madrid, SpainJavier Calleja-Conde & Jose A. Lopez-MorenoDepartment of Neuropsychology and Psychopharmacology, Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, 6229 ER, The NetherlandsJordi RibaAuthorsJose A. Morales-GarciaView author publicationsYou can also search for this author in

PubMed Google ScholarJavier Calleja-CondeView author publicationsYou can also search for this author in

PubMed Google ScholarJose A. Lopez-MorenoView author publicationsYou can also search for this author in

PubMed Google ScholarSandra Alonso-GilView author publicationsYou can also search for this author in

PubMed Google ScholarMarina Sanz-SanCristobalView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsJ.A.M.-G., J.R., and A.P.-C. conceived the project, designed and supervised the research, analyzed the data, and wrote the paper. J.C.-C. and J.A.L.-M. performed behavioral test, analyzed the data, and wrote the paper. S.A.-G. and M.S.-S.C. performed experimental work.Corresponding authorsCorrespondence to

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This paper is dedicated to the memory of our dear colleague and co-author Jordi Riba, who passed away while this paper was being peer-reviewed.

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Reprints and permissionsAbout this articleCite this articleMorales-Garcia, J.A., Calleja-Conde, J., Lopez-Moreno, J.A. et al. N,N-dimethyltryptamine compound found in the hallucinogenic tea ayahuasca, regulates adult neurogenesis in vitro and in vivo.

Transl Psychiatry 10, 331 (2020). https://doi.org/10.1038/s41398-020-01011-0Download citationReceived: 21 April 2020Revised: 02 September 2020Accepted: 07 September 2020Published: 28 September 2020DOI: https://doi.org/10.1038/s41398-020-01011-0Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard

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Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain | Scientific Reports

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