用行为工具与药物治疗改善 ADHD 的专注力 | Dr. John Kruse

Andrew Huberman：欢迎收听 Huberman Lab 播客。在这里，我们讨论科学以及以科学为基础、可用于日常生活的工具。我是 Andrew Huberman，是斯坦福大学医学院神经生物学与眼科学教授。今天的嘉宾是 John Kruse 医生。John Kruse 医生拥有医学博士和哲学博士学位，是一名执业精神科医生，专门治疗儿童和成人的 ADHD。正如你将在本期节目中看到的，Kruse 医生是理解 ADHD 各种治疗方式，以及帮助人们克服非临床性专注和注意力问题的世界顶尖专家之一。当然，我们会讨论 ADHD 的药物治疗，包括 Adderall、Ritalin、Vyvanse、Modafinil、Wellbutrin，基本上涵盖用于治疗 ADHD 的所有药物，并比较它们各自的优势和劣势。我们还会谈到用咖啡因来提高专注，以及咖啡因如何与这些药物相互作用。Kruse 医生还会解释一些具体行为如何影响我们的注意力和专注水平，例如睡眠时间，不只是睡多久，还包括什么时候睡；以及饮食、运动和所有这些因素的作用。这些内容当然不仅与正在经历注意力和专注困难的人或患有 ADHD 的人有关，也与所有人有关。Kruse 医生不只是一名精神科医生，他还拥有昼夜节律生物学研究背景，并提出了一个很有启发性的观点：在很多情况下，ADHD 以及其他专注力不足，可能是昼夜节律失调的结果。他会告诉我们如何检验这一想法，以及如何可能对其进行纠正。听完本期节目，你将了解兴奋剂的作用、儿童和成人 ADHD 可能的起源，以及行为治疗、药物治疗和非处方方法如何帮助应对脑雾与专注困难。因此，到节目结束时，你会掌握大量新知识，也会得到许多可以实际应用的工具。在开始之前，我想强调，这档播客与我在斯坦福大学的教学和研究工作相互独立。不过，它确实体现了我向公众提供零成本科学及科学相关工具信息的愿望和努力。为了贯彻这一主题，本期节目包含赞助商内容。现在开始我与 John Kruse 医生的对谈。John Kruse 医生，欢迎你。

Dr. John Kruse：很高兴今天来到这里。

Andrew Huberman：我们来谈谈 ADHD。也许最好先说明它是什么。这里的 H，也就是“多动”这一部分，是不是总会存在？儿童 ADHD 和成人 ADHD 又有什么区别？能否先给我们一个总体轮廓，然后我们再根据不同情境、不同需要，讨论对付 ADHD 的方法之类的问题？

Dr. John Kruse：我先说，和神经科学及精神病学中的大多数问题一样，我们有一些定义，也有许多不同的思路和框架来处理它们。我先从诊断类别，也就是我们如何诊断 ADHD 说起：共有 18 种不同症状，其中 9 种属于多动—冲动，9 种属于注意力不集中。注意力不集中的表现包括忘记把事情做完、丢失物品、容易分心等。冲动和多动的表现包括在交谈中打断别人、脱口而出、到处跑动、坐立不安。但这些定义本身是在儿童人群的背景下设计的，因为直到大约 20 世纪 90 年代中期，人们还把它当作一种儿童期神经发育疾病，并认为每个患儿都会长大后摆脱它。这是严重错误的。有些孩子确实会摆脱，但大多数不会。最新研究表明，大多数成年人的 ADHD 症状严重程度会随时间波动。回到定义上来：我们有这 18 种不同症状。成人至少需要有其中 5 种，而且这里所谓“有这些症状”，指的都是正常人在任何时候也可能表现出的行为。我们任何人都可能打断别人、坐不住，或难以专注于某项任务。但要符合诊断标准，这些行为必须出现得过于频繁，或程度过高，以至于造成某种功能损害或痛苦，而且必须在生活中的多个领域出现。如果你只是在工作中难以完成任务，那可能与老板、椅子不舒服或其他因素有关。因此，这些特征必须在生活的多个领域表现出来；同样，它们必须造成痛苦或功能损害，并且超出正常人的程度。奇怪的是，ADHD 经常受到污名化，人们质疑它是否是真正的诊断，部分原因在于它没有某种——用一个专业词来说——特异性极强的典型症状。比如精神分裂症有幻觉，大多数人不会出现幻觉；如果你出现了，可能是精神分裂症或药物作用，但这很不寻常。相比之下，ADHD 的所有行为都很常见，只是出现到了不寻常的程度。因此，ADHD 的诊断经常受到污名和质疑：这不就是把正常行为推到了荒谬的程度吗？

Andrew Huberman：你提到症状可能高度依赖环境。有一件事是我以及很多人都想知道的：随着越来越多人在家工作，尤其是在封锁期间，孩子也在家上学。一个患有 ADHD 的人处在家中环境时，通常有更多可做的事情，那么症状是否会比在餐馆、学校、参加体育运动或工作时更严重？这些环境里当然也有多种可以做的事，但人在其中可采取的不同角色和可从事的活动会更受约束。这种情况常见吗？

Dr. John Kruse：是的。先退一步说，和其他心理健康或精神疾病一样，ADHD 显然既有生物学成分，也有社会环境成分。所谓先天与后天的问题，不是二选一，而始终是两者共同作用。我们知道 ADHD 有很强的遗传成分，遗传率大约是 0.8，这与身高或精神分裂症的遗传率大致相当。

Andrew Huberman：这是否意味着，如果你是同卵双胞胎，而你的双胞胎兄弟姐妹患有 ADHD，那么你也有大约 0.8 的概率患 ADHD？还是说这其中——

Dr. John Kruse：是的。遗传率在技术层面上更——

Andrew Huberman：明白。

Dr. John Kruse：……复杂一些，它指的是由基因造成的变异——

Andrew Huberman：明白。

Dr. John Kruse：但可能性确实很高。

Andrew Huberman：嗯。

Dr. John Kruse：所以，这种情况往往会在家族中出现。但再次强调，它也有社会层面。你并不是一个脱离世界的大脑，而是一个与世界互动的大脑。对于 ADHD，我们喜欢把它概括为：结构和要求都很重要。ADHD 的一个方面不同于官方的症状分类或诊断方式；在如今的理解中，我们通常认为它与大脑的执行功能有关，包括大脑的工作记忆如何运作、选择性注意如何运作或无法运作、情绪调节是否正常，以及冲动控制如何运作。基本上，ADHD 大脑不太能自行提供所需的结构，因此更依赖外部世界中的理想结构。比较在家和在办公室工作：在传统办公室里，你会在固定时间开始工作，其他人也会在某个时间做自己的工作，什么时候午餐很明确；可能还有人来询问你，或在走廊里看到你，说：“Larry，你这个编码项目做到哪一步了？能按时完成吗？”在家时，这些强化和结构都没有了。所以，结构是一个“金发姑娘”问题，并不是结构越多越好。因为如果给某人施加过多结构，大多数 ADHD 患者都不适合流水线工作。他们不想只是拿起一个螺栓，把它拧到雷克萨斯车身侧面之类的地方，然后看着汽车沿流水线移动。那样太令人窒息、太受限制、结构过多了。因此，你需要的是适量的结构。新冠疫情、居家工作以及孩子待在家里所造成的一件事，是一天的结构减少了；但与此同时，要求一侧的负担增加了。对很多人来说，认知要求提高了：你不仅要完成工作，还要自己管理时间和日程；你可能还要面对另一间房里哭闹的孩子，或者伴侣有时需要使用那间房进行安静的会议。于是，要求提高，结构减少，这就形成了导致更多 ADHD 表现的完美风暴。从心理健康角度看，真正有意思的是，在新冠疫情最初阶段，公共心理健康领域的人说：“我们知道，如果这是一场大规模疫情，必须进行隔离，那么抑郁会增加，焦虑会增加，酒精和物质滥用会增加，创伤后应激障碍和家庭暴力会增加。”他们还声称自杀会增加。这一点并不正确，我们可以之后再讨论；但我认为其中有一个 ADHD 方面的原因。至少我没有听到有人提到 ADHD 会增加。部分原因是，为了维护 ADHD 作为真正精神科诊断的合法性，患者和该领域许多研究者都非常坚持认为它是生物学状况。既然如此，它为什么会改变？我们可以理解为什么其他状况会增加：更多人受到创伤，Joe 叔叔因新冠咳到肺部不堪重负而去世，创伤后应激障碍就容易理解；抑郁也是如此，你失业了，整个行业都没有了，比如你是餐馆员工，而这个行业不会回来。所以，我们很容易讲出其他疾病增加的故事。但当时没有人预测 ADHD 会增加，我认为这主要是因为 ADHD 群体的防御心理，以及他们不愿充分承认除了先天因素之外还存在真实的后天因素。然而，我们已经看到，仅从处方数量来看，不仅 ADHD 诊断大幅增加，处方兴奋剂在过去几年也显著激增。

Andrew Huberman：我想短暂休息一下，感谢本期赞助商 Eight Sleep。Eight Sleep 制造带有制冷、加热和睡眠追踪功能的智能床垫罩。我以前在这档播客中谈过，我们每晚获得充足、高质量睡眠的重要性。确保睡眠环境温度合适，是获得良好睡眠的最佳方法之一，因为为了入睡并保持深度睡眠，体温实际上需要下降约 1 至 3 度；而为了醒来时感到清醒、有活力，体温又需要上升约 1 至 3 度。Eight Sleep 让你很容易控制睡眠环境温度，可以在夜间开始、中段和结束时分别设置床垫罩的温度。我使用 Eight Sleep 床垫罩将近四年了，它彻底改变并改善了我的睡眠质量。Eight Sleep 最近推出了新一代 Pod 床垫罩 Pod 4 Ultra，制冷和加热能力都有所提升。我觉得这很有用，因为我喜欢刚上床时让床很凉，半夜更凉，然后在醒来时变暖；这能让我获得更多慢波睡眠和快速眼动睡眠。它还具有打鼾检测功能，会自动把你的头部抬高几度，以改善气流并停止打鼾。如果你想试用 Eight Sleep 床垫罩，可以访问 eightsleep.com/huberman，购买 Pod 4 Ultra 最高可节省 350 美元。目前 Eight Sleep 运送至美国、加拿大、英国、欧盟部分国家和澳大利亚。再次说明，网址是 eightsleep.com/huberman。本期节目还由 Joovv 赞助。Joovv 制造医疗级红光治疗设备。在这档播客中，我一直强调光线对生物学的巨大影响。除了阳光之外，红光和近红外光源已经显示出对多种细胞和器官健康方面的积极影响，包括更快的肌肉恢复、更好的皮肤健康和伤口愈合、改善痤疮、减轻疼痛和炎症，甚至改善线粒体功能和视力。Joovv 与众不同、也是我偏好的红光治疗设备之处，在于它使用经过临床验证的波长，也就是把特定的红光和近红外光波长结合起来，以触发最佳的细胞适应。我个人每周使用 Joovv 全身面板约三到四次，也会在家中和旅行时使用手持灯。如果你想试用 Joovv，可以访问 Joovv，也就是 J-O-O-V-V，.com/huberman。Joovv 为所有 Huberman Lab 听众提供专属折扣，产品最高可减 400 美元。再次说明，网址是 Joovv，拼写为 J-O-O-V-V，.com/huberman。我对最佳结构与困难之间的关系很着迷，或者说，对工作中拥有最佳结构与保留一些探索空间之间的关系很感兴趣。我知道很难笼统地说哪些工作和职业最适合 ADHD 患者，但根据你的临床观察，能否指出一些 ADHD 患者容易进入的职业群体，因为他们在那里有足够甚至过人的能力？比如创意艺术，只要他们能让自己到达剧院，通常就能在即兴表演中表现良好；我举的例子有些极端甚至可笑，但这些确实是职业。相反，朝九晚五的“银行家工作时间”或许有结构上的优势，也可能很难；会计工作则要求小数点和每一位数字都不能出错。是不是存在这样的职业群体？

Dr. John Kruse：我先退一步回答。我会回答你的问题，但先从两个角度来框定。第一，我没有创造这个说法，但我认为这是关于 ADHD 最有洞察力的妙语之一：没有 ADHD 的大脑由重要性驱动。如果你知道必须挪车，否则会收到停车罚单，你就会出去挪车；如果知道四月要交税，那是一项无聊又吃力不讨好的工作，可能有少数人喜欢，但我们大多数不是注册会计师的人仍然会把它处理掉。相比之下，ADHD 大脑由兴趣驱动。它会想：“是的，是的，我应该报税，但看看勇士队篮球季后赛打得怎么样；看看这个有趣的猫咪视频。哦，我更想做别的事。”所以在职业或工作方面，我认为最重要的是它对你有趣。我们可以讨论工作领域或某些职业道路，但如果它不能吸引你、不能引起兴趣，即便从结构上看它可能更支持你，你也很难做下去。

Andrew Huberman：这会延伸到生活的其他领域吗？例如，你是否发现 ADHD 患者在育儿方面更困难？并不是说孩子不有趣，只是孩子的某些活动对父母来说可能比其他活动无趣；而我想到的“由重要性驱动”，就是那种非常尽责的人——因为应该做，所以就去做。

Dr. John Kruse：这个领域在 20 世纪 90 年代开始意识到成人也可能患有 ADHD，部分原因是那些为儿童开设 ADHD 门诊的临床医生开始注意到：这个家长接孩子迟到了 20 分钟；另一个家长没有去取处方，结果孩子两周没吃药。他们通过观察这些孩子的父母，逐渐发现成人也有 ADHD，而且这与强遗传联系相符。当然，也有很多患 ADHD 但充满爱、支持和养育能力的父母。但研究试图寻找客观指标，例如在 ADHD 家庭中，事情是否更容易被遗忘、放错、遗失或偏离轨道？答案绝对是肯定的。对 ADHD 儿童而言，除药物之外，最有力的干预之一是基于家庭的训练：帮助全家理解孩子的大脑如何以不同方式运作，或者它可能并没有那么不同，可能正好就是父亲或母亲大脑的运作方式，并帮助父母变得更加一致。另一个偏见是，社会长期珍视这样的人：在 Eastman Kodak 公司工作 50 年，最后拿到金表，仿佛那就是职业生涯应追求的典范。但如果你由兴趣驱动，兴趣会发生变化，那么对很多 ADHD 患者来说，最佳职业可能不是一份持续 50 年的职业，而是十份五年职业，或五份十年职业。随着整个工作世界越来越碎片化、动荡成为常态、硅谷把“快速拆掉并重来”当作口号，我们越来越接受很多职业轨迹不再是一条漂亮的弧线。不过社会仍存在以常态为中心的偏见，认为人应该追求那种轨迹，换职业就是坏事。然而，很多人正是因为经历更多样，才在生活中做出了有价值的事情，并把更多东西带入工作。因此，我们应该重视并接纳这种选择，承认对某些人来说，这可能是最佳职业道路。

Andrew Huberman：我能理解。我花了二十多年训练自己成为一名实验台科学家并管理实验室，现在仍然教学、保留教职，也参与一些研究，但我现在算是进入了第二个职业。

Dr. John Kruse：嗯。

Andrew Huberman：我想还会有第三个。稍后我们可以谈谈你是否认为我有 ADHD。我确实摄入很多咖啡因，之后会回到咖啡因摄入水平与潜在 ADHD 之间的关系。现在先埋下这个讨论点。我们经常听到，社交媒体以及刷 X、Instagram 或 TikTok 会“让人患上 ADHD”。有没有临床或其他数据表明，仅仅在等公交时看一万个不同情境，或者一分钟看 15 个视频，会让人在生活的其他领域更容易分心？

Dr. John Kruse：有很多很好的神经科学或神经心理学数据表明，你沉浸在社交媒体中的时间越长，持续不断的信息轰炸就越多；关键不只是信息量，还在于你不断被打断，而且大多数打断都是有意设计来吸引注意力的。人们越习惯以这种方式思考或存在，就越难长时间维持注意，也会训练自己对任何新干扰过度反应。所以，ADHD 中受损的一些执行功能核心要素，正在让我们所有人变得更像 ADHD。这是我正在写的一本书的主题，书名暂定为《注意力缺陷世界》。令人沮丧的是，关于你问的神经科学问题，也就是大脑是否越来越容易分心，存在很大的脱节。沉浸于媒体、社交媒体或手机世界并非全是坏事。它不只是让集中注意变差：人们可能更擅长检测环境中的视觉项目，也可能更快地多任务处理或在任务之间切换。虽然在没有干扰、只专注于一件事时他们仍然做得更好，但经常沉浸在互联网中的人，确实比不常沉浸的人更擅长多任务处理。关于注意力的研究和通俗书籍很多；我们知道每个人都变得更容易分心。但这些书都说，这只是日常现象，与 ADHD 无关。另一方面，许多优秀的 ADHD 书籍把 ADHD 说成一种离散的疾病，即使承认严重程度存在连续谱，也强调它是非常严重的状况。忘记作业、忘记车钥匙或不记得车停在哪里，人人都会发生，但我们也必须承认 ADHD 是一种严重且可能造成破坏的状况。社会对 ADHD 的刻板印象是看到松鼠就分心、可笑、迷糊、迟到，做出大家拿来开玩笑的事，却忽略了这些现象可能带来更严重的后果。例如，患有 ADHD 的孩子预期寿命大约比没有 ADHD 的同龄人短 10 年，这种寿命损失程度与糖尿病或重度抑郁相当。

Andrew Huberman：这是因为事故、成瘾还是受伤吗？

Dr. John Kruse：几乎全部可以归结为两个因素，而且两者几乎相等。一个是事故，包括机动车事故；如果你开车时分心，就更可能发生事故。但也包括在农场上驾驶拖拉机时更冒险、去挑衅公牛等各种事故，不只是机动车事故。另一个是自杀，其中一部分与抑郁、焦虑和其他因素重叠。但我确信，尽管很少有人从这个角度研究，自杀不只是绝望和痛苦，也有冲动性这一非常重要的因素。很多人会感觉很糟，却不会自杀。我们知道，家中有枪会提高人开枪自杀的可能性；能够快速使用杀人工具的可及性也很重要。这说明，如果让思考过程慢下来、给人更多时间、降低冲动性，他们自杀的可能性就会下降，虽然痛苦可能仍然存在。这也是我解释新冠封锁期间现象的方式：当时抑郁增加，创伤后应激障碍增加，家庭虐待和殴打增加，但自杀率却下降了。

Andrew Huberman：嗯。

Dr. John Kruse：这怎么解释？下降幅度不大，但在此前自杀率逐年上升的背景下，数据非常清楚、明显而且非同寻常。我的解释是，更多人待在家里，孩子不会在旁边玩枪或找到枪；你能知道周围发生了什么，也更容易注意到毒物、从门上悬挂自己之类的其他风险。

Andrew Huberman：非常有意思。我之前不知道 ADHD 会带来这种寿命负担，而 10 年确实是很大的差异。

Dr. John Kruse：ADHD 还有处在两端之间的中间地带。轻的一端是人们把它 caricature 成在餐馆迟到、忘记车钥匙这类可笑而琐碎的事，极端的一端则是死亡。但在两者之间，我们知道 ADHD 能够以可测量的方式扰乱教育、破坏社会关系，并影响一个人的收入潜力。它不只是学业和认知问题，也不只是能否完成学校要求、按时交报告或完成工作；它同样会造成社会层面的影响，而且在所有这些领域都对生活造成可测量、显著且有害的影响。

Andrew Huberman：我的理解是，ADHD 患者能够非常专注于真正引起兴趣的事。我不知道自己是否有 ADHD；即使有，我想也比较轻，或者只是庆幸自己在没有智能手机的时代完成了教育。

Dr. John Kruse：嗯。

Andrew Huberman：我很感谢当时没有智能手机。我读博士时，甚至会拔掉实验室的电话，这样下午 5 点之后就能做实验，因为那是别人唯一能联系我的方式。我很熟悉投入一项活动时近乎药物般的感觉，有时人们称之为心流。今天早晨我写作时，专注了 20 或 30 分钟后，从头到脚都充满愉悦，这种感觉非常强烈。然而，像大多数人一样，我有时很难清除所有干扰，除非有截止日期，这也是我喜欢截止日期的原因。问题是：ADHD 患者是否确实能够专注，只是让他们进入专注状态的神经或神经化学阈值更高？是否需要更强的截止日期恐惧、后果恐惧或对活动的兴奋感才行？

Dr. John Kruse：是的。先退一步说，ADHD 这个名称本身就不完美，因为它强调注意力缺陷和多动；正如你所说，它不是注意力缺陷，即使说有缺陷，也更像是对注意力控制的缺陷。控制注意力至少有三个方面：第一，把注意力指向某处，并在重要事情发生时转移过去；第二，在适合持续的情境中维持注意；第三，在继续停留不合适时离开。ADHD 患者在这三个方面都较少能够凭意志控制注意力。很多患者把过度专注描述成自己的超能力：他们埋头编码，办公室里其他人都离开了，直到晚上 11 点清洁工来倒垃圾，他们才发现自己还在，因为一直专注于项目。有人反对把这种状态称为心流，我先不去完整念 Csik……

Andrew Huberman：Csikszentmihalyi。

Dr. John Kruse：Csikszentmihalyi。

Andrew Huberman：是的，没人会念他的名字。

Dr. John Kruse：这就是他的名字。

Andrew Huberman：能拼对的人更少。

Dr. John Kruse：是。

Andrew Huberman：所以没关系。

Dr. John Kruse：根据我深入研究后的理解，过度专注正是心流状态，因为人们描述了同样的时间感消失，也同样需要一项有些挑战、能让人投入并且有趣的任务。如果只是享受或幸福，你看一朵漂亮的花也可以过度专注，但人们并不是这样描述的。

Andrew Huberman：嗯。

Dr. John Kruse：它需要适量的挑战，不能太容易，也不能太难，必须对你重要且有趣。它不只让人忘记时间，也让人忘记周围的大量空间。因此我认为心流和过度专注非常接近，甚至可能是同一种现象。有些 ADHD 患者学会了哪些情境或内部因素能帮助自己进入这种状态，但很多人仍会遇到问题：在不想专注于某件事时却进入过度专注，或者在需要时又难以调动它。

Andrew Huberman：我有时会用“心不在焉的教授”来解释自己，虽然只是一半开玩笑。我很喜欢一张神经科医生、后来成为作家的 Oliver Sacks 的照片。他写过《错把妻子当帽子》和《觉醒》等作品。照片里他在火车站，周围有许多移动的人影，有些是模糊的；他嘴里似乎叼着烟斗，站在车站外写作。他的包掉在地上，物品正在掉出来。

Dr. John Kruse：嗯。

Andrew Huberman：他曾在相当长的医学和写作生涯中公开承认自己是甲基苯丙胺成瘾者，也暗示过自己有这类倾向。我提到这个例子，是因为我看到那张照片时，看到的是一个人在非常繁忙的环境中处于过度专注。

Dr. John Kruse：嗯。

Andrew Huberman：我研究过他的作品和自传，也和认识他的人交谈过。他似乎不断寻找刺激很多的新环境，而这让他能够进入专注的隧道。独处很久时，他也会有专注时段，但安静本身反而变成了干扰。可以想象，这或许与外部锚点和内部锚点有关，找到两者的最佳位置，需要了解自己以及在特定时间最适合工作的地方。对任何人而言，可能不存在唯一有效的环境：早晨、下午，或度假归来后，最佳环境可能不同。你怎么看待 ADHD 患者或其他人找出最适合自己的条件？昼夜节律时间在这里有多重要？你有昼夜节律生物学背景，这也为理解 ADHD 增加了独特维度。

Dr. John Kruse：很多来找我治疗 ADHD 的人主要关注药物。我们仍然知道，就总体症状减轻程度和受益人数比例而言，兴奋剂是最强的工具。但药物不会改变一切，你也需要关注自己的生活。我总是从日程安排开始。很多 ADHD 患者讨厌安排日程，好像桨船上的奴隶被命令必须一下一下划桨。我告诉他们，帮助你制定有效日程的并不是邪恶的监工，而是你最明智、聪明、友善的那一部分，它看清了更大的目标，并思考如何让当下的行动与目标一致。这个比喻并不完美，但我能想到的最好比喻是：制定日程的部分像一只母鸡，数着小鸡、让事情排列好、把你护在身边照料和养育。在安排工作、作业、学校任务或其他外部任务之前，必须先安排四项基本内容。睡眠远远是最重要的，虽然对所有人都必不可少，对 ADHD 尤其关键，也有特别原因使它更具挑战性。我认识的成功 ADHD 患者都找到了某种办法，让睡眠比原本可能的状态更规律。四项基本内容是睡眠、饮食、运动或某种活动，以及一个杂项类别：属于自己的时间、放松和冥想。它们都需要到位。关于饮食，我在临床上有两个现实观察。我的办公室在一栋维多利亚式老房子里，入口在一条短而陡的车道尽头。我会给每位新患者完全相同的路线说明；唯一会走到房屋正门的人是 ADHD 患者。另一个观察是，如果有人说“昨天下午 4 点我才发现自己一整天没吃东西”，这就会引起我的注意。节食、间歇性禁食的人并不是忘记吃饭，而 ADHD 患者可能确实没有获得身体的内感受提示，或没有注意到这些提示。

Andrew Huberman：嗯。

Dr. John Kruse：不是所有 ADHD 患者都会这样，但他们可能无法得到正确的内感受线索，或没有注意这些线索；这在 ADHD 患者中是可测量的现象。

Andrew Huberman：所以要保持规律的进餐时间。

Dr. John Kruse：是。新冠期间，很多科技行业的人抱怨必须在家工作，因为办公室每天会提供健康、优质的午餐。他们甚至难以安排家庭送餐系统，因为组织和设置本身就让人不堪重负，尽管这些人很聪明，也在生活的大多数方面都很成功。

Andrew Huberman：这些人是否有时会开始吃饭，只吃几口就回去工作，结果这顿饭一直没有真正结束，只是碎片化到一天的其他时间里？

Dr. John Kruse：是的，这可能是一种情况。

Andrew Huberman：嗯。

Dr. John Kruse：但更多时候是完全忘记，或对吃饭毫无察觉。ADHD 还可能表现为时间管理困难和执行功能问题：本来打算出门前吃早餐，但到了出门时间才发现忘了，随后又要给孩子系鞋带，还想起需要买新牙刷，于是上楼查看。时间管理并不在官方 18 项症状清单中。清单只是试图粗略描绘 ADHD 的临床工具，遗漏了很多内容。例如情绪调节问题：大约 60% 的 ADHD 患者承认自己的情绪会爆发、变得更强烈，也更难调节，但官方诊断症状中完全没有这一项。

中文译文：Andrew Huberman: I'd like to take a quick break and thank our sponsor, AG1. AG1 is an all-in-one vitamin, mineral, probiotic drink with adaptogens. I've been taking AG1 daily since 2012, so I'm delighted that they're sponsoring this podcast. The reason I started taking AG1, and the reason I still take AG1, is because it is the highest quality and most complete foundational nutritional supplement. What that means is that AG1 ensures that you're getting all the necessary vitamins, minerals, and other micronutrients to form a strong foundation for your daily health. AG1 also has probiotics and prebiotics that support a healthy gut microbiome. Your gut microbiome consists of trillions of microorganisms that line your digestive tract and impact things such as your immune system status, your metabolic health, your hormone health, and much more. So I've consistently found that when I take AG1 daily, my digestion is improved, my immune system is more robust, and my mood and mental focus are at their best. In fact, if I could take just one supplement, that supplement would be AG1. If you'd like to try AG1, you can go to drinkag1.com/huberman to claim a special offer. They'll give you five free travel packs plus a year's supply of vitamin D3 K2 with your order of AG1. Again, go to drinkag1.com/huberman to claim this special offer. So we've got sleep, eating, exercise or movement, and relaxation. Maybe Before we start talking about some medications and some other factors that modulate ADHD, if we could maybe step through each of those and you could share with us some of your favorite tools that you give your patients and that you teach online. Realizing, of course, that each one of those is a vast topic that we have done entire podcasts on. But I'm curious about your favorite go-to tools. We were talking about a few of these before we started. So sleep, regular to bed and wake-up times?

中文译文：Dr. John Kruse: Matthew Walker and his great book on sleep. One of my favorite things about it is he really emphasizes this point, that quality sleep isn't just about eight hours. It isn't just duration. It's getting quality sleep, and the timing of your sleep is every bit as important as the duration. So if you're used to sleeping midnight to 8:00 a.m. and you're staying up dancing or partying until 4:00 a.m. and you say, "Oh, it's a weekend, I can sleep until noon," you may still get those eight hours, but they're not restorative to the same extent as if you had slept at your regular time. My PhD research was on circadian rhythms. We had realms of data back then. So this was 40, 30 plus years ago. We had every bit as much data then that the timing of sleep was as important as the duration, and yet every public service announcement just says, "Get your eight hours of sleep." Why are we leaving out this other piece? We've known for decades that people with ADHD have a strong propensity to being night owls, to have a different chronotype where they're maybe more effective or functional later in the day, a tendency to stay up. For many years now, we've actually known that this is strongly genetically controlled. So there are genetic markers affecting sleep timing that are over-represented strongly in the ADHD community. So some of it is you're pushed that way, but some of it is the nature of ADHD, that if you-- Procrastinating is part of ADHD. If you procrastinate, you're going to push things off till the end of the day. Some people, the end of the day is a better time to work because there's fewer distractions. If everyone else is asleep finally, no one's going to come in and interrupt your work or ask what your thoughts on this project are. But again, getting regular sleep, and regular and sufficient, doesn't mean it has to be what I'd say normal. If it works for you, if you can build your career and your social life around sleeping from 2:00 a.m. till 10:00 a.m. every day, I'd say go for it if you can be consistent with it. So what are the things that help with getting regular sleep? One thing, paradoxically for many people, is actually being on stimulant medications.

中文译文：Andrew Huberman: Mm-hmm.

中文译文：Dr. John Kruse: So stimulants do have, as a side effect, some people have insomnia, some people stay up later, but more people with ADHD tend to, either because the drug is wearing off at the end of the day and there's some crash in alertness or energy, or because they're being more productively expending energy and are more tired at the end of the day, or it's just helping synchronize circadian clocks by getting a consistent start early in the day. We don't know the mechanism by which it works. There's lots of plausible and overlapping ones. But again, daytime alertness medications can help.

中文译文：Andrew Huberman: Can I run something by you in that context-

中文译文：Dr. John Kruse: Sure

中文译文：Andrew Huberman: ... before we jump back? I don't consistently take stimulants except caffeine, and I limit my caffeine intake to prior to 2:00 p.m., and I stack it pretty heavy in the early part of the day. But on occasion, I'll take 25 to 50 milligrams of Wellbutrin, which, as you know better than I, is slightly dopaminergic, but certainly triggers noradrenergic release. So epinephrine, norepinephrine. It's a stimulant. On the days when I take that, which again is very rare, and I track my sleep every night, I notice a significant improvement in my sleep and significant increase in my rapid eye movement sleep. It's extremely consistent. So from that, I sort of reverse engineered the major effect being norepinephrine. Epinephrine, I decided, well, I would do something else that I know raises epinephrine, which is I'll do a cold plunge first thing in the morning of one to three minutes long. And the effect isn't quite as strong, but on those same days when I do that, clearly adrenaline-raising activity, I also see, for me, a significant increase in my rapid eye movement sleep and the quality of sleep later that night. So I think there really is something to this epinephrine obviously going hand-in-hand with stimulants. Epinephrine spike early and throughout the day with better rapid eye movement sleep at night. Does that logically hold for you? It's just a story.

中文译文：Dr. John Kruse: Yeah. I was going to say, as both of us have some science background, so I'd say I'm glad it works, and what's hard to sort out as why it's working is one is potential placebo effect. You're doing it because you're thinking or hoping it works. Good. And two, I'd say maybe even more importantly than the placebo effect is the days that you're deciding to do this, there's something different about those days to begin with, because you're not doing it every day. So those potential issues aside, I'll jump into insomnia, and Matthew Walker talks about some of this. To me, maybe the biggest finding in insomnia sleep medicine in the last 20 years is that almost everyone who has a problem with insomnia doesn't have a problem with sleep. Huh? What? That does sound like I'm contradicting myself. What I mean is The sleep system's intact. It's there. It's waiting to arrive and put you to sleep each night. What the problem, and this is from the sleep researchers, with at least 90% of, probably more, of people who have insomnia problems, is the failure of the daytime arousal system to shut off properly. So normally, we have these two mutually inhibitory systems, a wakefulness arousal system and a sleep sedation system. And usually, when one turns on, the other turns off. And with most people's problem with insomnia, it isn't that sleep is weak or insufficient or not there. It's sitting, it's waiting there. It just can't land on the landing pad because you're too aroused or too awake. Maybe that helps the arousal system to turn off better at the end of the day if it's gotten more fully engaged during the day. I don't know. But it feeds back more into some of the non-medication approaches to helping with sleep, and that is doing everything you can, again, not just to force sleep or push it, because that doesn't work very well. It's getting rid of arousal. It's dampening arousal. So for people with ADHD, one is deciding on what's a reasonable bedtime, thinking about this ahead of time. And two, eliminating any stimulation or arousal. So exercise, I'm a big fan of. I'm a marathon runner. I know you're heavily into exercise as well. Exercising too late in the evening can elevate body temperature, disrupt falling asleep. So physical arousal, we don't want to be doing a lot of late in the day, and emotional, intellectually, cognitive arousal too. So the biggest single tool in modern life is do not have your phone in your bedroom. And that's hard for lots of people to do, but if it's there, you're going to be checking it. Studies have even shown, even if you're not checking it, if it's there, you're thinking about it or looking at it. Just having it away out of sight is better than having it visible and turned off. Two is using, if you have someone you're sharing a bed with or family members, using them to help reinforce. Yes, and it's really helpful to talk about this ahead of time because the exact same words can either be sounding like a nag or someone trying to exert their power over you, rather than with people with ADHD, we know need reminders. They know they need some of that external structure. And if you are on the same page and can have a partner or a kid or someone else present, "Hey, Dad, shouldn't you be turning off the computer and heading to bed right now?" that can be helpful. Again, it can be destructive if it's not done in a framework where both people are on board, and it's not fair to make the other person responsible for your own behavior. But lots of people are usually happy to help the person with ADHD be more organized in their life. So we were also talking a little bit before, one of my favorite tools for falling asleep is actually cyclic sighing. There are other box breathing and other techniques that help someone relax. So we know cyclic sighing engages the parasympathetic nervous system, our rest and digest system. One of the things that happens normally in the transition every night when you fall asleep is you're going from primarily sympathetic tone to primarily parasympathetic tone. So anything that is strengthening or putting you there already makes it easier. I know you have videos about cyclic sighing, and I do too. My own experience, which I was sharing with you before we started talking, was not only does cyclic sighing help me fall asleep better, it actually helped me stay asleep throughout the night better.

中文译文：Andrew Huberman: That's a remarkable thing because many people, including myself, have very little trouble falling asleep, especially given how I stack caffeine in the early part of the day and then stop in the afternoon. It allows me to fall asleep within seconds, somewhere for me, typically around 10:00 p.m. Somewhere between 10:00 and 11:00 p.m. is my typical bedtime. But then I consistently wake up at 3:00 in the morning. Usually get up, use the restroom, and then go back to sleep, most of the time without too much trouble, provided there isn't a lot of stress in my external life and provided the phone is not in the bedroom. But as we were also talking about before we turned on the microphones, this idea that our bladders get smaller as we age is complete nonsense, right? So that can't be the explanation why people wake up more in the middle of the night as they get older.

中文译文：Dr. John Kruse: Yeah. Some might. Some, it may be a prostate issue. Clearly, that isn't accounting for half the population, but I think it's much more the neurologic innervation of our bladder. All our nerves start functioning not quite as well, and they're just getting the signal that I really need to urinate right now, when pretty clearly, most of those people don't. They could wait, but the signal is arriving that says you have to, and it's believable, and you don't want to not listen to it if it is right.

中文译文：Andrew Huberman: How much cyclic sighing are you doing before sleep, and how long before sleep is the cyclic sighing done?

中文译文：Dr. John Kruse: So when I read your paper with Spiegel and others, January, for years, I've said I don't have a meditation practice. Most people think I'm sort of so chill or relaxed that I do.

中文译文：Andrew Huberman: You seem like a pretty mellow dude.

中文译文：Dr. John Kruse: I haven't ever taken the time to do it, which I'm embarrassed by. So I said, read the paper. I can do five minutes a day of cyclic sighing, and I tried, and some days I was getting it in, and many days, I wasn't getting it in till bedtime. I slept really well till I was around 40 and not so well in the next 20 years, both the- Mostly with the trouble falling asleep, even though I knew of relaxation techniques and others. So I wound up just consistently doing it to do it more for the general health, and I do have slightly elevated blood pressure, and relaxation, and to see what effect it would have, and it was clear. So I do about five minutes, and much more than five minutes, I tell people, and I might be doing it a little slower than most, count out about 20 or 25 reps of it. And if you lose track, doesn't matter. Just go back to the lowest number. Because, again, everything we're trying to do is decrease arousal. If you have a timer on it and you do it for five minutes and then you're woken up, you're reversing or mitigating some of the benefit of doing it. So my recommendation is do it for five minutes about, but do it by counting reps and don't focus or if it's six minutes, if it's four. There's so many aspects of this, and we know the exhalation has to be longer. I was trying to find, is anyone systematically, is a four-second exhalation better than 10 versus six? And those studies would be so simplistic and easy to do, but there's lots of variables that we can play with to see what's optimal. I don't think we know at all what's optimal, but we know what's good enough to work.

中文译文：Andrew Huberman: Delighted to hear that it's worked so well for you. As people know, I'm a huge fan of the physiological sigh-

中文译文：Dr. John Kruse: Yes

中文译文：Andrew Huberman: ... and I take no credit for having discovered it. It was discovered by physiologists in the 1930s. Right

中文译文：Dr. John Kruse: So throughout the data point that I shared with you is that prior to trying cyclic sighing at nighttime, I was waking up virtually every single night, once a night to urinate, and in the 18 months, 20 months since I've been doing it, I think it's been a total of four times that I've woken up during the night to urinate.

中文译文：Andrew Huberman: Fantastic. So we're talking about sleep. You mentioned earlier, encouraging people with ADHD or who think they might have ADHD to keep a somewhat regular eating schedule, or at least to make sure that they're eating

中文译文：Dr. John Kruse: Yeah

中文译文：Andrew Huberman: And to not let their meals get fragmented into starting a meal then finishing it later. For some people, it's breakfast, lunch, and dinner. For some people, like myself, it's lunch, snack, dinner. Whatever it is, keeping a regular schedule. Exercise. Aside from encouraging people to not exercise too late in the day, certainly not caffeine and exercise late in the day, are there any data about specific types of exercise being better for ADHD independent of effects on sleep? I realize they're hard to tease apart.

中文译文：Dr. John Kruse: Yeah. There's a few studies looking at acute aerobic exercise. Part of it is that it's hard to study people when they're exercising during many exercise. You're not going to wire someone up when they're swimming, for example. So there's not a lot of studies in any one approach, and there's so much diversity that often it just gets lumped together. So there do seem to be some acute effects of measurably improving some of the executive functions associated with better attention from acute exercise, and there seem to be some more general or longer-term benefits from people who are consistently actively exercising, being able to concentrate longer, being able to switch attention more appropriately or effectively. And there's a huge body of clinical literature of patients reporting, "I know I feel much more alert the day I get my workout in the gym in," or, "I feel better," or, "The week I took off from that was a big mistake." But I would say identifying at what's the most valuable or what's the best duration, I ran through the data about a year or two ago, and I would say that we can't make any conclusions. And I would say at some level, try it and see what works for you, and that's what's important. It isn't what works for everyone.

中文译文：Andrew Huberman: Is there a relationship between ADHD and addiction because of the impulsivity component?

中文译文：Dr. John Kruse: Yes, and so the answer is, and these are really rough statistics. One of my pet peeves is people who quote, "Oh, the rate of this is 27.43%." Well, it might have been in that study, but that's looking at one population, at one set of... So I use ballpark figures. The ballpark figure is Americans in the last 20 years, more than that, about 20% of Americans run into some substance addiction problem, either alcohol or drugs. People with ADHD have a rate that's almost double that, and it's higher in men than in women.

中文译文：Andrew Huberman: Double?

中文译文：Dr. John Kruse: Almost double. Almost 40% risk.

中文译文：Andrew Huberman: And that's for substance abuse and not-

中文译文：Dr. John Kruse: That's substance

中文译文：Andrew Huberman: ... behavioral addictions.

中文译文：Dr. John Kruse: Yeah. That's substance abuse, and that's looking at abuse, and we can get into the related topic of what's misuse versus abuse, and I have pet peeves there. However, kids who are put on stimulant medications when they're young, and I should say the stimulants themselves do have a small potential for addiction, but putting kids on stimulants pretty much normalizes their rate of addiction problems.

中文译文：Andrew Huberman: So it protects them.

中文译文：Dr. John Kruse: It cuts it in half. It protects them.

中文译文：Andrew Huberman: This is a really important point that I think maybe we just hover on for a second, because I think many people, including myself, assume that, well, if you were putting these kids on amphetamines, of which, many of the medications for ADHD are, that we're creating kids that are addicted-

中文译文：Dr. John Kruse: Addicted

中文译文：Andrew Huberman: ... to amphetamines-

中文译文：Dr. John Kruse: Yeah

中文译文：Andrew Huberman: ... or to a hyperstimulation period. But you're telling me it's actually protective to put kids with-

中文译文：Dr. John Kruse: Yeah

中文译文：Andrew Huberman: ... real ADHD on medication for ADHD.

中文译文：Dr. John Kruse: Yeah. I can say not absolutely every study has found this, but several large meta-analyses have gone back, and most of them have found this fairly dramatic benefit to being on stimulants as a kid in terms of specifically reducing substance abuse risk. And some of them that have looked at this, when I said it was a yes and, it seems to be that it's not just the impulsivity traits, but some of the inattentive ones, too. If your teacher's lecturing about the risks of alcohol or this and this, and you're zoning out at the window and looking at the plane flying by, you have less pertinent information on the topics. You may be less attentive to the negative effects that other kids are seeing among the classmates who are stoners at this age or X, Y, or Z. So it seems that both inattentive sets of ADHD symptoms and the impulsive, thrill-seeking, not weighing the consequences as heavily, are all contributing to this heightened risk.

中文译文：Andrew Huberman: I have this model in my head that is perhaps completely wrong, maybe partially wrong. And it goes something like this. That we know that the neural circuits involved in executive control and directing attention and maintaining attention and avoiding distraction, this kind of thing, use dopamine and epinephrine and norepinephrine, at least to some extent. And we know that people with ADHD are capable of focus. As you said, it's a failure to direct that focus, maintain, et cetera. So I've heard from you before this discussion that people that tend to drink lots and lots of caffeine or who can drop into an activity but have a lot of distractibility, that they might have ADHD. So what I'm imagining here is that the threshold to get dopamine, epinephrine, and norepinephrine released is either much higher or more complicated for people with ADHD. And so what they're seeking is these catecholamines, these three chemicals, dopamine, epinephrine, norepinephrine, and that if they're given a medication that puts them in that range where they're getting it, then they're good. They can stop seeking it, so to speak. And I'm raising this now because we're talking about addiction. Addiction is a pursuit of things, essentially. And I guess what I'm saying is it seems to me that the model of ADHD that we hear about is that people can't focus, their dopamine circuits are all out of whack, and then you put them on this dopaminergic drug, and basically you get them addicted to that tunnel vision or something. But I have this model in mind now that what we are all seeking is to have portions of our day where we are directing our focus towards a meaningful build, the things that are generative in our life, work, school, relationships, et cetera. And that whether or not it's pharmacology or exercise or what have you, that it's just about getting into this plane of consciousness. And I say that in no woo or abstract terms. Is that right? Are what we're really talking about here is a failure to access enough of these neuromodulators, and these medications which we're about to talk about are really about putting us in the realm where those neuromodulators are just more accessible?

中文译文：Dr. John Kruse: I'll just say I can go with that.

中文译文：Andrew Huberman: Okay. Well, you're the expert. I'm putting this together based on what we're talking about. Getting enough sleep, to me, is a way of being able to have enough arousal during the day. Exercise or these medications, just different ways of being able to access arousal. If you don't sleep, you can't access arousal during the day. So, okay. Well, I'm going to hold that model in mind, and I'm going to keep testing it to try and destroy it as we go forward. Let's talk about the medications, since you raised those. And the first one I ever heard about was Ritalin.

中文译文：Dr. John Kruse: Mm-hmm.

中文译文：Andrew Huberman: Let's start with Ritalin. How often is Ritalin used nowadays, and what is Ritalin doing neurochemically, and what are your thoughts on Ritalin as a useful drug for childhood and adult ADHD? And I'm happy to repeat those questions.

中文译文：Dr. John Kruse: So Ritalin is, or generic methylphenidate, and there are dozens now of slow-release versions, and there's even a skin patch instead of an oral version. Our definition of what a stimulant is is really squishy and vague. In its broadest sense, it's any drug that has an effect on the body, like the sympathetic nervous system, which is a norepinephrine-driven fight or flight arousal system. So by the loosest criteria, caffeine's a stimulant. Wellbutrin's a stimulant, even though we classify it as an antidepressant. Some of the decongestants are stimulants. But more often when we're talking ADHD medicines, we're using stimulant more specifically for amphetamine-based products like Adderall and Vyvanse, and again, there's a host now of newer branded extended-release forms and methylphenidate. And we lump the two together. Probably most ADHD experts agree with, and this is where I'm going to be disagreeing with most of them. I don't consider Ritalin a full stimulant. So the neuropharmacologists differ a little bit, but amphetamine is a strong dopamine and norepinephrine reuptake blocker. So it prevents what's already been released from being taken back up, so more is available longer. But in addition to that, amphetamine is a pretty potent, let's just say, vesicle manipulator. So it's actually forcing a bigger release from the vesicles when they're synaptically released. So it's not just that the signal lasts longer and is stronger because of that, it's a bigger signal. Depending on what study you look at, most of the studies suggest that methylphenidate is actually a pretty weak vesicular manipulator, and some studies don't find any impact there at all. Which means if methylphenidate is basically a norepinephrine and dopamine reuptake inhibitor, that's what Wellbutrin is. That's one of the components. And so why I would further say, if you look at the efficacy data, how well do these work in resolving ADHD symptoms? All the meta-analyses lump Adderall products, amphetamine, and methylphenidate products here, and say, "They're here because they work better." This is success in reducing ADHD symptoms. And all of our Strattera, atomoxetine, Wellbutrin, I use Cymbalta a lot, modafinil, guanfacine, all these other things are down here as less effective. But if you actually look at any of the plots that I've looked at and separate out, methylphenidate is actually closer to the pack below. It's the amphetamine products are head and shoulders above everything else. Methylphenidate's usually at the top of the rest of the crowd. But if you're just looking at the data objectively, there's a clear decision point. So in terms of efficacy, amphetamine products are stronger. But in terms of some of the side effect that I worry most about, it's not at all common, but it's one of the horrible ones, is amphetamine-induced psychosis. Now that we're finally looking at that a little more closely, because for years, ADHD experts have said, "Yeah, it's really rare. Let's not look at it at all. Let's not pay attention. Move along. Don't look." With amphetamine Adderall products, and that's probably dose-dependent, but it's close to one out of 500 people. I'm going off on a tangent here, but I'll keep following it because it's an important tangent. It's only one out of 500 people. That's uncommon, but this is a really bad condition. So amphetamine-induced psychosis is a schizophrenic-like picture. Usually, someone is really paranoid, really worried that their friends are manipulating them or the police are spying on them. If you drink too much alcohol, you can be batshit crazy, that's a highly technical term there. You can be out of touch with reality. You can be hallucinating. You can be saying all sorts of nasty things. But if it's alcohol-induced, you fall asleep at the end of that night, you wake up the next morning, you may feel horrible with a hangover. You're not hallucinating. You're not psychotic anymore. Hopefully, you're regretting what you did. Probably not remembering much of what you did.

中文译文：Andrew Huberman: People will let you know.

中文译文：Dr. John Kruse: With amphetamine-induced psychosis, on the other hand, classically and characteristically in what I've seen clinically, it continues for days, weeks, or months after stopping the medication, which means we've changed someone's brain, and we don't have lots and lots of data, and it's actually only come to us because people are concerned about marijuana causing a similar picture, so now we're studying this a little more. But with amphetamine-induced psychosis, and these are again, rounding from different studies, if you look 20 years out, about 20% of those people are in a permanent psychotic state still. So again, it's uncommon, but it's such a bad outcome that we really should be alerting people to it. I saw much higher risk of this for, I can get into it if we need the reasons in my population in San Francisco. But I've had people coming from all the most prominent ADHD clinics over the years who just moved to the area. And when I'd say this, give this as my introduction to, I'm happy to continue on this, but are you aware, to a person they said, "No one ever told me that." Now, maybe they have ADHD and weren't listening, but it's so uniformly consistent that they didn't hear or know that that was a side effect.

中文译文：Andrew Huberman: And one in 500 isn't a trivially small number.

中文译文：Dr. John Kruse: No, it's not trivial. And why I got alerted to it is my rate in San Francisco is actually higher than one out of 100. And so I'll go into, I think, a couple different reasons. One is I worked with a lot of HIV positive men, and we know HIV, particularly in the days before we had effective antivirals, is a virus that goes to the brain and affect-- there's a HIV-induced dementia. So probably some of these people had brains that were compromised because of that, and were vulnerable. Two, a high incidence of methamphetamine. So methamphetamine, street speed, is a chemically different molecule than amphetamine, has an extra methyl group, and an extra methyl group can mean a lot. So it's a cousin, but methamphetamine, we know, has higher rates of psychosis, higher rates of addiction, tends to be more rewarding. But again, in that population, and many of them would hide that history from me, but I think that the very first person I had with methamphetamine-induced psychosis, a guy in his 40s, HIV positive for years, this was back in early mid-'90s, was able to finish school in his mid-40s, get a good paying job in two years on stimulants, and then had a full-blown psychotic episode where his dad had died of a heart attack 10 years earlier. He was threatening his mom because he believed his mom had poisoned her. He flew over to Rhode Island where she was living. He was making threats from a payphone, and because Rhode Island's so small, he was actually calling from out of state, so it was a federal crime. He got thrown in federal prison for this. And he stayed psychotic for months after he wasn't using anything. But it later turned out he had had a psychotic episode 10 years earlier on street meth, which he lied about when I did the evaluation. So the other high-risk group I had was I was known in San Francisco as someone who worked with adults with ADHD at the early stages of recognizing ADHD. So, and I was comfortable with a broader range of stimulant dosages, and many providers are. So I had people, and they were all young white males, straight males, and I don't know how many of those demographics are relevant, but who had histories of taking stimulants, having a psychotic episode, again, being really paranoid. And again, the numbers aren't huge, but at least five people with this general profile. But even though they were paranoid, even though they were severely impaired enough that each of them wound up in a psychiatric inpatient hospital, which is pretty hard to get into in this day and age or even 20 years ago, they all liked something about the experience enough that they all wanted to get back on. And all of them knew enough to lie about this past. So they didn't tell me. All of them also had ADHD. They presented with ADHD. They'd say, "I'd been on stimulants before, and I'm not working with that doctor because my insurance changed," or they had moved to the area. So they gave plausible histories, and most of those, within a month or two of restarting it, wound up back in the psychiatric hospital. I had one guy, bright computer programmer, late 20s, calling me from inside the psychiatric hospital to try to get me to prescribe more Adderall to him. And not only that, he had convinced his inpatient psychiatrist that this was a good idea, that this was important to treating his ADHD and helping him retain his job.

中文译文：Andrew Huberman: Wow. So these are, as you said, straight white males who have psychotic episodes on their ADHD meds and continue to seek those meds because they, quote-unquote, "like the experience." It feels like a manic high, the high dopaminergic state.

中文译文：Dr. John Kruse: Yeah, and you put the word mania in there, manic, and lots of people define this as amphetamine-induced mania rather than psychosis. I don't, because one is uniformly, and maybe other people are seeing more, that these people were paranoid, they were worried, they were anxious, they were delusional, but they weren't overtly enjoying it. They weren't having a great time. They weren't saying, "I'm going to party with all you friends, and I'm only worried about the people there." And yes, they were talking more loudly. They were sleeping less, which could be characteristic of mania, but there was no positive affect that I or police reports or often families give you extensive history of everything that was going on, that there was nothing euphoric they were describing about it. I think the second piece is it's unclear how much they actually remember or recall, or either through psychological suppression of it or physiologic, they're in a different enough state, it didn't register properly. It's not clear, but they tend not to recall the paranoia. And by paranoia, it's persecutory delusions. I have people who assaulted family members thinking that they were being spied on, manipulated, when they were the parents trying to take care of their kids.

中文译文：Andrew Huberman: I'd like to take a quick break and thank one of our sponsors, LMNT. LMNT is an electrolyte drink that has everything you need and nothing you don't. That means the electrolytes, sodium, magnesium, and potassium in the correct ratios, but no sugar. We should all know that proper hydration is critical for optimal brain and body function. In fact, even a slight degree of dehydration can diminish your cognitive and physical performance to a considerable degree. It's also important that you're not just hydrated, but that you get adequate amounts of electrolytes in the right ratios. Drinking a packet of LMNT dissolved in water makes it very easy to ensure that you're getting adequate amounts of hydration and electrolytes. To make sure that I'm getting proper amounts of both, I dissolve one packet of LMNT in about 16 to 32 ounces of water when I wake up in the morning, and I drink that basically first thing in the morning. I'll also drink a packet of LMNT dissolved in water during any kind of physical exercise that I'm doing, especially on hot days when I'm sweating a lot and losing water and electrolytes. There are a bunch of different great-tasting flavors of LMNT. I like the watermelon, I like the raspberry, I like the citrus. Basically, I like all of them. If you'd like to try LMNT, you can go to drinklmnt.com/huberman to claim an LMNT sample pack with the purchase of any LMNT drink mix. Again, that's Drink LMNT, spelled L-M-N-T, so it's drinklmnt.com/huberman to claim a free sample pack. What are the options for people that think that they may have ADHD? Let me phrase it differently. Someone comes in, and let's say an adult, they have five of the 18 criteria. They meet the criteria for ADHD. After telling them about sleep, food, exercise, and relaxation, after that's squared away, if the decision is to medicate, and assuming they're not on any other medications, which cluster in this two sets of clusters that you described before, the amphetamine type, the Adderall, Vyvanse, et cetera, versus the, I realize you put Ritalin at the top of the bottom cloud.

中文译文：Dr. John Kruse: Mm-hmm.

中文译文：Andrew Huberman: Wellbutrin, Ritalin, Modafinil, you mentioned Cymbalta. Which cluster do you go to first?

中文译文：Dr. John Kruse: I mean, some of this is just individual style rather than intellectually thinking one is better or not, and my style is usually to listen as closely as I can to what the patient wants. That doesn't mean agree with them, but to explain in as much detail as I can what I perceive the risks and the likelihood of those are and what I perceive the benefits to be. For years, just statistically, I had many more people who were on non-stimulants than stimulants compared to the general ADHD population, and that's even accounting for by many variables I had. I've always worked with a lot of people who are on disability from Medicare. I also work with people who are on Medicaid in the cities, insurance before Obamacare happened. So I worked with, not entirely, but a skewed, more dysfunctional, more severely afflicted population, which again, you would think would be a better match for the more powerful drugs. I'll jump back, but this actually is a situation where we have more powerful drugs. So often when I treat people with depression, they'll try one or two or three antidepressants and say, "Well, give me something that's more powerful." And with depression, maybe we can put ketamine out of the picture, and I know this is a side issue, but all of our antidepressants seem to work equally well. We don't have potent antidepressants and non-- If it got FDA-approved, it works in a certain range of likelihood. But with the stimulants, amphetamine-based products really are more powerful, and more so than with depression or many of our other conditions where it's more a categorical, this will help or not, as long as you're above a threshold, there's a more linear relationship. If a little bit of Wellbutrin helps a lot, it's likely to help more. I mean, you might start getting more side effect issues, and there may be good reasons to not keep going up, but there's a more linear dosage results relationship.

中文译文：Andrew Huberman: Do you worry about strain on the heart with amphetamine products? Just even if it's relatively low dose over time, just the strain on the calcium channels and on the heart. Is it true that stimulant-based medications for ADHD can "weaken the heart?"

中文译文：Dr. John Kruse: When you used that term, I was talking with Rob beforehand about running marathons, and when I ran the 100th anniversary of the Boston Marathon, they had some of the medical literature from the previous decades, and one of the medical warnings was, maybe you could do one or two marathons in your life, but don't do more than that because your heart will wear out. And I've run 100, and my heart, I think, is still beating, so we know things we thought we know at one point. Common cardiovascular effects of not just the stimulants but the non-stimulants that are affecting norepinephrine, so Wellbutrin, Cymbalta, Modafinil, it's less clear, and we can get into that when we talk about Modafinil, but clearly methylphenidate, amphetamine, on average, increase at therapeutic doses, increase heart rate a few points, increase blood pressure a few points. But part of that obscures that probably 80% of people don't have any change, and maybe 20% have maybe a more slightly significant change. So we know that there's some impact there. We know there's some people with extremely rare genetic underlying conditions, usually related to the neurologic wiring of the heart, who are particularly vulnerable to dropping dead from a stimulant. And almost every year, there's a well-trained athlete, either professional player or more often a high school or college player, college, who will take cocaine, take Ritalin, take prescription stimulant, and drop dead of a heart attack. The risk of that's so uncommon. This is 15 years ago, when Adderall XR came out, the Canadian government was worried enough about this risk that they banned Adderall XR for almost a year, and because they have a comprehensive medical system, they could look more extensively at the numbers, and this is looking at kids. The percentage of kids who drop dead with Adderall was tiny, and not just tiny, it was lower than the kids who aren't on Adderall who dropped out of a heart attack. So part of it is, if you're in this rare genetic condition, almost always there's family members, or you've had some other near-death or syncopal episode where you passed out. So history taking of the individual and family history. And if you're at all worried or concerned, you can do EKGs, which detect most of those electrical abnormalities. But the cardiology and lots of my colleagues practice may be a more conservative cover-your-ass medicine approach, where everyone has to have an EKG before they're on a stimulant. But even the cardiology associations have said that seems to be a waste of resources. Absolutely do a thorough history, absolutely do a thorough family history. If there's anything of concern or if the patient's anxious about it, get an EKG. But other than that, these should be generally safe for most people's hearts. So there was a meta-analysis that came out earlier this year on-- So most of the studies looking at more serious, other than just mild hypertension or mild elevation of heart rate, haven't found much, but most of them only look a year out or a year of treatment. Do we see rates of heart attacks? Do we see rates of strokes? Do we see rates of dangerous arrhythmias? And in general, they're looking at a young population where these events are really uncommon anyway, and most of them didn't find any evidence of problems in a year or two out. The more recent study looked as long as 14 years out, and there they found measurable, statistically significant increase in risk that increased during the first three years of being on a stimulant and increased at a much lower rate for the next 10 years. Sort of plateaued out, but still measurably higher than people with ADHD who weren't on a stimulant. But the absolute rate is still really, really low. So for most people, it's not a risk. On the other hand, if you start these medicines when you're 10 or 20 and may be on them for 60 years, we don't know whether potentially more people are getting into more trouble.

中文译文：Andrew Huberman: So if somebody presents as having ADHD as an adult and they've never touched stimulants, would you start them on Ritalin, Wellbutrin or Adderall, or something in the Adderall Vyvanse class?

中文译文：Dr. John Kruse: So thanks for bringing me back to your question.

中文译文：Andrew Huberman: Sure.

中文译文：Dr. John Kruse: And I'm going to jump it. You threw in that sort of qualifying phrase, never been on any stimulant in their life or tried it or something. Or at least-

中文译文：Andrew Huberman: At least not consistently

中文译文：Dr. John Kruse: ... what I would say-

中文译文：Andrew Huberman: Yeah

中文译文：Dr. John Kruse: ... what I would say is these drugs are fairly common in our society, both illicitly and licitly. We know lots of kids, lots of adults with ADHD share their medication. Lots of people have tried these things, even if it's just once or twice, and that itself is valuable clinical data, if they felt too revved up from it. So if they have, I try to find out what dose was it, what did it do for you, what good things did it do for you, what bad things did it do for you? So my presentation is usually, Adderall is likely to be the most strongly effective, or I more often are using Vyvanse. These are the other options. But Adderall also has, again, greater rare, but risk for these bad problems. Does that scare you? Some people are petrified they're not going to go anywhere near that. Some people say, "Nah, I'm not that concerned about it." And most people do come in with some friends at work, family members, X, Y, or Z. They think they know what the drug is likely to have as an effect on them. And I tend to, at least as a starting point, listen to that. And now, there are certain reasons I absolutely would not. My worry, again, I saw more of it than I think most people in a higher rate with amphetamine induced psychosis, but a friend from college was just trying to refer a friend's son who's 27 and had a psychotic episode on marijuana and does have ADHD and is in bed depressed and not going to work and is being evaluated by two New York City doctors, but the psychiatrist kept him on Adderall. Again, the likelihood of recurrence seems so high that if you have a family history of schizophrenia or psychosis or you've had any experience of it, I would not prescribe a stimulant, an amphetamine based stimulant.

中文译文：Andrew Huberman: Okay. Could we go so far as to say, and I suspect the answer is no, but because nowadays we're hearing more about the possibility, I want to highlight possibility, of high THC cannabis causing psychotic episodes. This is something I've stressed on this podcast, on social media. I took a lot of heat for this from the traditional press. And then ironically, they're now putting out information that essentially speaks to the same. I'm not saying this happens in everybody, but there's certainly a possibility there. Would you say that if somebody is a regular high THC cannabis user, that they are at greater risk to developing psychosis if they're taking these stimulant form ADHD meds?

中文译文：Dr. John Kruse: Yeah. You could actually play that both ways. You could claim that if they've already been on an agent without developing psychosis, then maybe they're more impervious to that as a potential side effect. Or where you were coming more from is if we're already on one agent that's pushing them in that direction, why the heck would you ever add another that could also... My approach clinically would be more, what do you think the marijuana's doing for you? And might it be more helpful to just clear that out of the picture before we add anything new onto it? But depending on what they say or don't say. So my reading of the data is very clear that there is some, even at low THC, there is some risk. Is it reefer madness that everyone who puffs a joint is freaking out? Clearly not. But again, it's much more potent than it was 10 year, or that was 70 years ago, I guess.

中文译文：Andrew Huberman: Yeah. Especially as I understand, we had an expert from the cannabis research community on, in edible form in particular, it's harder for people to control the dosage, whereas when people use inhalation as the means to deliver, it seems like they kind of find the right plane without going overboard more often than with edibles. In any case.

中文译文：Dr. John Kruse: Well, one other big factor is that CBD actually seems in some studies to have an antipsychotic effect. So, maybe strains of marijuana 50 years ago that had a, whatever nature thought was a more balanced view, had less of a risk. But now that you can get pure THC products, and I'm sure you've highlighted that a big problem with this whole industry is even in Colorado, which three years ago was the state with the most close regulation and inspection and Almost a majority of what the labels say don't correlate with what you're really getting. So, this is not a well-regulated industry, even though states are trying to regulate their industry. So you may not know what you're getting. CBD, again, may have some protective effects, so getting pure and higher potency THC may be particularly undesirable. So in my own YouTube podcast series, I've researched lots of subjects, and most of them I wind up saying, "We don't have a lot of data on it," and there's not a lot of data on marijuana. It's the one subject I've actually changed my mind from reading what was out there. And for years, I would tell people, because being in San Francisco, even before the wave of legalization, lots of people were using it, lots of people felt it helped them. And what I would tell them is the data we have, and these are from everyday users, is that there are measurable, the characteristic of the classic stoner has a grain of truth to it. So measurably lower motivation, poorer organization of thought, lower energy, are strongly correlated with daily marijuana use. Why would anyone with ADHD want any of that going on? That seems like a perfect misfit for accentuating what's not working right. Over the years, though, I had a handful of people who would swear it worked better for them than stimulants. It worked better for them than the non-stimulant alternatives. Clearly not everybody. And when I looked at the data, there is actually some tiny studies. There are some that are funded by marijuana organizations, so that doesn't mean they're wrong, but it's harder to evaluate how objective they were. But there is some research that suggests there is some subsegment, and I don't think it's people with ADHD in general, but some subset of that population who may actually do better. And most of the time, they were looking at marijuana rather than pure THC. And what I was going to say is there's probably at least 70 or 80 other psychoactive components to marijuana. Not most of them is in higher concentration as the THC or CBD, but they're out there. Maybe they are more important, even at lower concentrations.

中文译文：Andrew Huberman: I've heard this, that for some people, cannabis can help them focus, and I'm certainly not one of those. But it certainly is interesting. As long as we're on cannabis, excuse me, as long as we're discussing cannabis, neither of us are on cannabis to my knowledge. Maybe I could just ping you for the relationship between various compounds that people use that are available over the counter, or with online access to these compounds, and ADHD symptoms specifically. And then at some point, I'd like to return to the amphetamine-based drugs. So let's just start with nicotine. So these days, there's increased use of nicotine pouches, gums, not just smoking, vaping, dipping, and snuffing. And it's certainly a stimulant, and certainly a lot of people, in particular young males, are using it more often. The traditional media is now trying to create this picture of nicotine being part of the wellness and fitness community. But in my observation, many, many more people outside of that category are using it. So what, in your experience, happens when somebody with ADHD, let's assume they're not medicating in any other way, starts dabbling in nicotine use? And let's assume they're going to do this in ways that do not cause cancer, because the smoking, dipping, vaping, snuffing part is what causes the cancer. Let's just talk about the compound nicotine.

中文译文：Dr. John Kruse: Yeah. So there's some well-done research showing nicotine is helpful for improving some of the executive functions, sustained attention, and I'm not sure which of the executive functions, but they help people focus, be sharper, do better. There was actually a major pharmaceutical company who was developing a nicotine receptor product specifically for ADHD, and they abandoned that several years ago, and I haven't been able to find word as to why that was abandoned, whether it was some other side effect. It's worth throwing out there that although nicotine in many ways acts like a stimulant, it actually is moderately unique, and I hate people who say unique means one of a kind, so I can't modify it in any way. Unusual, maybe not the only one. Unusual in that it both arouses people and reduces anxiety simultaneously. Most of our stimulants are, again, banging away at the sympathetic nervous system, and that's banging away on good arousal and bad arousal, so anxiety. So nicotine, again, seems to be both calming and helping alert or focus people. And as long as they're taking it in a way that's not clearly detrimental to their health, which smoking and vaping and probably chewing are, well, not probably, definitely are. And if it's affordable, because some of these products are pretty pricey, at least the chewing gums or the Nicorette that was used for helping people with smoking cessation. I have some people who feel that it's been an important and useful part of their regimen. I have some people, small numbers, who prefer it to any other medications. And almost no, again, other than sort of the basic neurophysiology showing that it can have beneficial effects on executive functions, there's no Research, at least as of a year or two ago, whenever I dipped my toe, not my anything else, into the snuff. Looked into it. There's no clinical research showing does this help or not help.

中文译文：Andrew Huberman: What about caffeine and, in particular, energy drinks? These days, there just seems to be an explosion of drinks that include caffeine, but also fairly high dosages of things like taurine, alpha-GPC, theanine.

中文译文：Dr. John Kruse: And tyrosine.

中文译文：Andrew Huberman: Yeah, tyrosine. So, things that are thought to generally amplify the production or release of neuromodulators, like dopamine, acetylcholine, and so forth.

中文译文：Dr. John Kruse: And so the epidemiologists say that the most widely used psychoactive substance on this planet, and I thought it was alcohol for years, but it's actually caffeine, because lots of groups outlaw alcohol and won't outlaw caffeine. So lots and lots of people use it. And this is a gross oversimplification, but this is what I tell people. Even though it's the most widely used, if you used it as an equivalent dose to our stimulants, essentially we're using it at a lower dose level. It's a pretty lousy stimulant. Separate from that, it's working primarily on adenosine and indirectly working on dopamine. But associated with higher levels of anxiety, higher levels of jitteriness, higher levels of cardiac toxicity, if you were to use it at an equivalent dose. But most people are using at a substantially lower dose. And the ADHD experts sort of historically have fallen into two different camps. Some of them have said, "It's going to interact with your stimulant or other medications. It's complicated. We don't want it messing up the picture. Stay off of it." And the other half say, "It's a stimulant. Lots of people are using it with these other stimulants, both full-blown stimulants and non-stimulant ADHD medications. And as long as you know it's part of the picture and you're trying to be constant with your dosage or aware of it, then fine, and maybe it helps you get away with a lower dose of the prescription." The one little piece I'd add in there is that often you don't know what dose you're getting. So people have the common experience, as I was saying earlier, I've only had three cups of coffee in my whole life, so this is all anecdotal or researched, not personal experience data. But lots of people have the experience, go to their local Starbucks or something and say, "Whoa, that feels way stronger than usual." And then invariably they say, "Oh, that must just be me. I'm more anxious already. I'm jacked up." Or because they think Starbucks, 7 billion stores around the country, everything's automated and precise. Starbucks, they control for the aromaticity, how many minutes each bean is cooked, which side it gets flipped over on. They're not controlling for caffeine intake, which is wild to you and me. So a University of Florida study, and this is several years ago now, went into a Florida Starbucks, bought the same drink every day for three weeks, and compared the caffeine content. The highest day compared to the lowest days was a threefold difference.

中文译文：Andrew Huberman: Wow.

中文译文：Dr. John Kruse: And that's Starbucks. Who knows what smaller... So one is, you may think you know what you're give, and maybe the bane of coffee drinkers, and maybe it sank in a teaspoon that you're dissolving may be the most consistent there. But one of the risks with caffeine, and with pretty much any over-the-counter drug, is you may not know what dose you're getting.

中文译文：Andrew Huberman: Very interesting. As I've said several times in this podcast, I think caffeine is a wonderful drug, mostly because I love the things it comes in, yerba mate being my preferred source of caffeine, but also coffee. And it certainly increases my focus. It's of a narrow plane, though. Two sips too many, and I can start feeling myself veer toward more lack of focus. It doesn't seem to have a very pervasive effect. And dosing it on an empty stomach versus after eating, I'm not that precise about it, but I don't see it as a very reliable stimulant. It's more to get to a plane of just normalcy for me, given how much I've been drinking it since I was a teen, really. I think most people are similar. They drink it to feel normal.

中文译文：Dr. John Kruse: Yeah. Well, and there's also lots of cultural and habitual, if it gives you your warm fuzzies or puts you in the right mode, or you think you're more alert, or you're listening to your favorite newscast in the morning as you're drinking it, that all is adding to its effect. In terms of combining with other over-the-counter things, there is some study looking at caffeine and L-theanine together and having some, at least in a tiny handful of studies, some measurable beneficial effect on, I think it's mostly kids that have been looked at, and nothing dangerous found across a pretty broad range of L-theanine dosages. But I'm not aware of any good research done with adding all the other things that are currently being added to it. And some logically may be doing something, some may be irrelevant, some may be more detrimental.

中文译文：Andrew Huberman: L-theanine certainly is being added to a lot of caffeine-containing drinks because it seems to take the jitters-

中文译文：Dr. John Kruse: Jitters off

中文译文：Andrew Huberman: ... off and the assumption being that people can consume more of that drink as a consequence.

中文译文：Dr. John Kruse: Yeah, there's a tiny bit of evidence that suggests that it may both help with anxiety, but it may directly have some beneficial cognitive executive function Benefits itself.

中文译文：Andrew Huberman: Yeah, this is in keeping with the green tea hypothesis, which I believe green tea is enriched for theanine. You are somebody who, quite refreshingly to me, has talked not just about prescription drugs and behavioral tools for ADHD, but also, actually, I think years ago you were the first person to first share with me the data about fish oil and the EPA omega-3s for depression. Those studies were starting to come out. We were talking about those studies. And nowadays, I think while there's still a little bit of controversy out there about fish oils, I think most everybody believes that getting high quality omega-3s from good clean sources, including fish oil, is mostly beneficial or beneficial. What about fish oil for ADHD in particular, and what threshold dosages are relevant here?

中文译文：Dr. John Kruse: So just as with the fish oil for cardiac benefits, there was a time period where the first few large, and they were pretty large, well-done studies showed benefits for cardiovascular health. The more recent studies with fish oil haven't shown an effect or benefit. And strangely to me, and not very scientifically, the cardiology community sort of looks at the more recent ones and say, "Okay, that's what it is." Well, you have to reconcile all the data in the pool. The ADHD fish oil story is a little the opposite, and it's almost everything with ADHD. It's been kids that have been most strongly looked at. The first few studies with fish oil and kids didn't show any benefits at all, and then subsequently there have been several studies that looked at benefits. And again, and the field jumps to the second set without reconciling, well, how do we do a good meta-analysis with everything in there? And I haven't looked closely enough to know were there methodological differences, dosage differences, population differences that matter. I'd say unless you're taking so big a dose that you're probably at risk for heavy metal poisoning, which is a possible issue with big doses of fish oil. Most of the recommendations are in the range that it seemed, and I'd say that depression has been the most consistent field, and that doesn't mean every study there has been positive either, but the most consistent field for a mental health benefit or a health benefit. And there, the recommendation is usually target about 1,000 milligrams of EPA of eicosapentaenoic acid a day. If you're seeing some benefit, but it feels like that there's more room for improvement, so this is my motto I tell people, then you could probably double it reasonably. There were dramatic studies looking at fish oil for mania, people hospitalized with it, and they used dosages as high as 7,000 milligrams a day.

中文译文：Andrew Huberman: To treat mania?

中文译文：Dr. John Kruse: Yeah. And that study, I think it was a Harvard area clinic that was doing it, the results were so dramatic that they ethically had to stop the study before its intended completion because the benefits seemed to be so robust in the fish oil group compared to the un-- that it was unethical to not put everyone on fish oil.

中文译文：Andrew Huberman: That's a lot of fish oil.

中文译文：Dr. John Kruse: That's a lot of, yeah.

中文译文：Andrew Huberman: You probably need to get it in liquid form so it wasn't so expensive. But I find this recency effect incredible, which you mentioned a few moments ago, that, and I think this is helpful for people to hear, certainly it is for me. We hear studies over the years have explored fish oil for cardiac benefits, and then more recently, as I understand, these have not been demonstrated. And there seems to be a focus on the recent studies as if the old ones don't exist. That's essentially what you described for both cardiac and ADHD. I think it's really important. We hear this with alcohol, too. I've been involved in this debate. I don't care if people drink one way or the other, provided they take care of themselves and others. And if you're an alcoholic adult, don't drink. And if you're a kid, don't drink. But if people want to drink a few drinks a week, I don't have a problem with it. But it's remarkable that every time a study comes out showing a mild benefit of moderate alcohol use, that seems to be the highlight, and then everything else is forgotten. And the inverse is also true. One would think that the meta-analysis would include as many good studies as possible, but I think it's important that people hear that that's not always the case. Just because there's a meta-analysis doesn't mean that it included all the relevant studies. So I'm just restating. Thank you. I make it a point to try and get one to two grams of EPA per day, just as a general mood. I'm not clinically depressed, but just to support my mood, to support focus, to support wellbeing, including cardiac function.

中文译文：Dr. John Kruse: So the other thing that I think is understudied with the fish oil issue is that, and it's a Harvard guy who has a proprietary brand of purified EPA that pushes it. So in nature, whether you're a whale or a human or a butterfly or a, maybe not insects, I'm not sure of that. Across the mammal, bird, reptile kingdom, the omega-3s are found in about a two-to-one ratio of EPA to DHA, eicosapentaenoic acid to docosahexaenoic acid. And what I tell people is, I think Mother Nature's probably smarter than any Harvard professor. And the brain particularly is high in brain membranes of DHA. So some people seek out EPA purified or only EPA brands That to me doesn't make a lot of sense. So I would say we can still count or do the numbering based on about 1,000 milligrams of EPA, but don't worry that you're getting about 300, 400 milligrams of DHA, and probably that's better for you.

中文译文：Andrew Huberman: I'd like to take a quick break and acknowledge one of our sponsors, Matina. Matina makes loose leaf and ready-to-drink yerba mate. Now, I've often discussed yerba mate's benefits, such as regulating blood sugar, its high antioxidant content, the ways it can improve digestion, and its possible neuroprotective effects. It's for all those reasons that yerba mate is my preferred source of caffeine. I also drink yerba mate because I simply love the taste. And while there are a lot of different choices out there of yerba mate drinks, my personal favorite far and away is Matina. It's made of the highest quality ingredients, which gives it a really rich but also a really clean taste, so none of that tannic aftertaste. In fact, given how absolutely amazing Matina tastes and their commitment to quality, I decided to become a part owner in the company last year. In particular, I love the taste of Matina's canned zero sugar cold brew yerba mate, which I personally helped develop. I drink at least three cans of those a day now. I also love their loose leaf Matina, which I drink every morning from the gourd. So I add hot water and sip on that thing, and I'll have some cold brews throughout the morning and early afternoon. I find it gives me terrific energy all day long, and I'm able to fall asleep perfectly well at night, no problems. If you'd like to try Matina, you can go to drinkmatina.com/huberman. Right now, Matina is offering a free one-pound bag of loose leaf yerba mate tea and free shipping with the purchase of two cases of their cold brew yerba mate. Again, that's drinkmatina.com/huberman to get a free bag of yerba mate loose leaf tea and free shipping. You're one of the first people that I ever heard discuss the gut microbiome and ADHD. This is me giving you credit for being way ahead of your time. I don't know how you are at receiving praise, especially on camera and with microphones, but I just want to say that it was over a decade ago that I heard from you about EPA and fish oil for depression and other things, about circadian rhythms, an area that I'm familiar with, and just the critical importance of circadian health for everything that we're talking about today and more, and on and on. And so, again, thank you for raising these points, even if they turn out to be minor effects.

中文译文：Dr. John Kruse: Mm-hmm.

中文译文：Andrew Huberman: I think nowadays we hear about the gut microbiome. I may have actually heard the words gut microbiome first from you. Gosh, yeah, that would be well over almost 20 years ago. Remarkable. So gut microbiome, what do we know about the gut microbiome and supporting it in ADHD?

中文译文：Dr. John Kruse: I'm going to kind of pass on that by just saying it's complicated and probably important and so many variables that it's hard to know what's really valuable in a day-to-day real human living perspective.

中文译文：Andrew Huberman: Do you do anything to support your gut microbiome? Just with your knowledge of the relationship between gut and mental health, does it impact your behavior at all in terms of choices?

中文译文：Dr. John Kruse: Yeah, only to the extent of trying to have a varied diet and eating at somewhat regular intervals, but not more specifically.

中文译文：Andrew Huberman: Great. If that's where we're at, well, that's where we're at. Before we go back to some drugs, I wanted to ask about behavioral tools for ADHD. I've seen some of the literature claiming that certain video games might actually be useful for training focus. I've managed to find a few papers that talk about focus and meditation tasks that kids in particular-

中文译文：Dr. John Kruse: Mm-hmm

中文译文：Andrew Huberman: ... but adults may be able to get better at. Are any of these brain-training games to get people better at focusing, are any of them known to be worthwhile according to real data or clinical observation?

中文译文：Dr. John Kruse: So I'll start first by stepping back a little bit and broadening it. I'll get to the video game things. But one of the effective approaches that helps with symptomatic reduction with ADHD is cognitive behavioral therapy. So that's a form of talking therapy, and my quick overview of it is that it focuses on actions, thoughts, and feelings, and that humans can have direct control of their actions and thoughts, not too much over their feelings, but all three are affecting each other. And the traditional CBT was developed by Aaron Beck to treat depression probably 50 years ago. Maybe longer, '60s, I think, late '60s. Anyway, on the surface, it's a horrible match for ADHD because we know it requires lots of repetitive, boring homework, doing the same thing over. It involves introspection of being aware of what you're doing already, looking at those patterns, looking at what the triggers, to see if you can see triggers for them, and then doing lots and lots of repetitive homework. And when it's successful for depression or PTSD or other venues, we know it actually changes brain wiring and brain chemistry. So lots of people still think talking therapies are sort of up here doing something, and chemicals and medications are really changing the brain. If your thoughts are changing, if your behavior's changing, your brain has changed. That's the only place that thoughts and behaviors come from. But there have been at least two groups, Mary Solanto's in New York and a Harvard group by, I'm blanking on his first, Safran, and some other, Ramsey at Pennsylvania, developed approaches using CBT techniques specifically designed for people with ADHD to help overcome some of those hurdles and barriers. And both of them encourage actually the use of medications in combination with it, because many people with ADHD are too unfocused, too unable to sit down and do it. But these are approaches, and both approaches are amazingly similar, although devised completely independently. At the core of both of those approaches is having a system of scheduling each day. That doesn't mean micromanaging each minute, but it's having the essentials in place, having blocks of time that you know what you're going to do, and having a task list in combination with that, and ways of learning to prioritize and move things up or down. And again, with ADHD being interest-driven rather than importance-driven, you may have a task-- You probably have 17 task lists. One's to do your coffee, one's at the grocery store. One, it's having one consolidated list, because if it's everywhere, then it's nowhere. And two is the simplest triaging or organizing approach is having the things that are both urgent and important. So, if they have to happen today, those get in the A category. The things that are important but aren't as urgent are the B category, and all the other things are the C. And one of the temptations that people with ADHD have is, "It's fun to go buy shoelaces, and that's on my list, so I'll go to buy shoelaces because then I can cross something off my list." But I didn't move the car, I didn't do my taxes, I haven't done my homework, and all the important things remain undone. So it's a system for getting done what's really needed to be done. And eventually, if your shoes don't work, the shoelaces will move up to that A category. But for most people, they're not really there, and it's not a good use of your time to do them first. And there's much more to it so that CBT approach can work with decreasing procrastination. It can help with structuring your own workspace, given that you probably have much more trouble doing that and not doing it spontaneously. It's how to eliminate distractions and modules on even extending your concentration time. So the answer with the video games, there is one product that's actually been FDA-approved for use in ADHD, and the really important thing to remember there is the FDA's system for addressing medications is much more rigorous, much more thorough. You have to demonstrate it really works and does something. When the FDA approves devices, basically, they're saying it's not going to kill anyone, it might help. I mean, it might help tremendously, but having the FDA imprimatur for that doesn't guarantee that or mean that at all.

中文译文：Andrew Huberman: Do you recall if the study of that device, or the study of that video game has a conflict of interest? Was it run by the company?

中文译文：Dr. John Kruse: Yeah.

中文译文：Andrew Huberman: Yeah. Okay.

中文译文：Dr. John Kruse: Yeah. So almost all of them have been run by the company. It's good people at UCSF who are at least partly involved in it.

中文译文：Andrew Huberman: Oh, is this Adam Gazzaley's group?

中文译文：Dr. John Kruse: I think so.

中文译文：Andrew Huberman: Yeah. I should just say that I've followed his work for some years. He's a neuroscientist. I know people who have been in his lab. He's known for doing very high quality and stringent work.

中文译文：Dr. John Kruse: Their product and some of the others can clearly show you get better at their product, and you get better at tests that look exactly like their product. But in terms of real world, how much is this really helping ADHD symptoms on a day-to-day basis? Not a lot of data at all. So again, that doesn't mean it doesn't work. And I'm going to go sideways in talking about neurofeedback, because there's lots and lots of neurofeedback companies across the country that are making lots and lots of money. And there was an article in the "American Journal of Psychiatry" in the last year. I'm not remembering which group did it. And it was another failure to find a significant impact from neurofeedback. And again, I'm not saying it doesn't have an effect, but I've had lots of people writing me, "Should I keep spending hundreds of dollars each week because my insurance isn't covering this?" And the doctor is saying, "Oh, maybe 20 more episodes will retrain your brain." So this gets back to a topic you brought up earlier, how much are we retraining our brains with immersion in social media? And the evidence is we are rewiring our brains. So maybe anything pushing in an opposite direction, or maybe this is reinforcing some of the bad things we don't want. We're in a messy world without clear answers yet.

中文译文：Andrew Huberman: I've made it a point to put social media on an old phone. So those apps are only on that phone. I don't even know the number to that phone. If I need to post something, I AirDrop it onto that phone, and this has helped tremendously in segregating that activity and limiting it. It also means that if people send me something, which would otherwise direct me to social media, it's much more difficult for me to go look it up. It's helped tremendously. I just pass that on because it's one of the things that's really allowed me to restrict my social media time, and yet still be in keeping with the fact that I think social media has its uses, I post there, et cetera.

中文译文：Dr. John Kruse: Yes. So getting back to the scheduling, what I recommend to people, and one of my weak-- I don't know the specific apps, but there are apps that will help shut you out of Facebook or Discord or TikTok or whatever it is. If you can't exert your own willpower, which again, is harder to do if you have ADHD, and if the app approach doesn't work, the next level up is there are All sorts of companies making lockboxes and physical devices where you can lock yourself out of your device for certain hours of the day, and I think that's a good idea for lots of people.

中文译文：Andrew Huberman: I do too, and I think it also helps, at least in my experience, to do things that are very different than social media as well, but still consuming content. So I make it a point to read from an actual physical book a bit each day or night. Also because I was raised doing that and writing by hand is just sort of in keeping with the way that my brain was wired. So maybe that's more specific to me and my generation. But I find that when I'm doing those other activities, when I go onto social media, it feels more like a departure from the rest of life-

中文译文：Dr. John Kruse: Mm-hmm

中文译文：Andrew Huberman: ... as opposed to the other way around. But in any event-

中文译文：Dr. John Kruse: That's a good sign for preserving

中文译文：Andrew Huberman: Yeah. I'd like to talk about some compounds that are not so typical. Meaning, some people may have heard of these, but most people probably haven't, and they are somewhat novel to me. The first one is guanfacine. What is guanfacine, and why is it sometimes used for ADHD?

中文译文：Dr. John Kruse: So guanfacine and a related drug called clonidine, which can be confused with Klonopin and others. So clonidine and guanfacine are both alpha-2 agonists, so they work on a subset of the norepinephrine system. They're both originally antihypertensive for lowering blood pressure. And it was actually studies first in clonidine that suggested this could be helpful with people with ADHD, and I think it was just a serendipitous initial discovery. It wasn't seeking out its mode of action to see if that really worked. One difference between the two of them is clonidine jumps off the norepinephrine alpha-2 receptor really quickly, and for people who skip a dose for their blood pressure medication or stop abruptly, it's not uncommon to have rebound hypertension, and not just mild, but way higher than what you're being originally treated for, to dangerous levels. Guanfacine leaves the receptors more slowly, and there have been formal studies trying to see if this is a problem or issue there. And particularly given that people with ADHD forget their medication or run out and don't fill it in time or just don't remember to take it, the rebound hypertension does not seem to be nearly as common with guanfacine, and that's part of why the research has moved more towards the guanfacine. So there's extensive work by, I'm going to blank on her last-- Amy Arden? She's at Yale.

中文译文：Andrew Huberman: Oh, Arnsten.

中文译文：Dr. John Kruse: Arnsten. Thank you.

中文译文：Andrew Huberman: Yeah.

中文译文：Dr. John Kruse: Yeah. And her lab and related labs have shown that guanfacine's effects seem to deal with strengthening synaptic connections in prefrontal circuitry. So unlike most of our drugs which are just boosting norepinephrine and/or dopamine and work quickly, and I'll throw in this because we didn't really touch this, most of the ADHD experts still say stimulants, amphetamine, and Ritalin work quickly, immediately because they boost dopamine right away. And are drugs like Strattera, which is atomoxetine, or Cymbalta or Wellbutrin work slowly for ADHD because they're antidepressants, and antidepressants work slowly. There's still people saying this, and for 25 years, I've been saying, "This is just wrong from, one, a basic neuroscience point of view, and wrong from don't you ever talk or listen to patients." So neuroscience view, how quickly does dopamine reuptake get blocked by Wellbutrin or by atomoxetine, Strattera, or by Cymbalta within minutes to hours of taking it? So you would expect if you're boosting norepinephrine or dopamine availability right away, you should see effects right away. And if you ask patients who these drugs work for, and they don't work for anybody, all the ones I've worked with say, "It worked just like a stimulant. I could tell. I took it, and I walked out of your office." And one guy I have who loves Cymbalta said, "I took it in your office, and I wasn't sure it was working, and I got downtown to work 15, 20, maybe a half hour later, and there was this guy coming at me on a skateboard on the sidewalk. And I know in my normal ADD state, I would have just been flooded and not be able to process, and I could just step out of the way." So it worked that quickly and dramatically. So that's the aside. So jumping back, guanfacine seems to work slowly, so the synaptic strengthening building, and it seems to be the alpha-2 receptors that are on neurons that receive glutamate as their primary input. The alpha-2 receptor is modulating how glutamate is actually working, and it's actually the NMDA glutamate receptors, not the more common in the brain AMPA glutamate receptors.

中文译文：Andrew Huberman: No, that's an important point. I'll just quickly throw in, if I may, that the NMDA, the N-methyl-D-aspartate glutamate receptors, are the ones that typically are associated with synaptic plasticity. Although, the AMPA receptors can do that, too. But what Dr. Kruse is referring to is the fact that guanfacine indirectly modulates those pathways, so the longer duration to get the effect, it sounds like could be at least partially explained by a real change in neural wiring as opposed to with, you used Cymbalta and Wellbutrin as examples of fast changes in neurotransmitters and neuromodulators that led to this very quick effect in this patient that left your office, got downtown, and was already experiencing effect. Put differently, sounds like guanfacine and clonidine Not to be confused with Klonopin. Clonidine could help ADHD, but might take longer for the effects to manifest than the other drugs that-

中文译文：Dr. John Kruse: Yeah

中文译文：Andrew Huberman: ... we typically hear about.

中文译文：Dr. John Kruse: Yeah. So most often it takes two, three, four weeks. With the stimulants, you see effects right away. It's reinforcing and stimulants often, in addition to having effects on concentration, attention, do boost energy for most people, do boost mood for most people.

中文译文：Andrew Huberman: And can improve sleep if they're not taken too close to sleep, yeah.

中文译文：Dr. John Kruse: Guanfacine's most common side effect tends to be sedating, so most people take it at nighttime, which is, why are you taking a sedating nighttime medication for your ADHD? It's because it helps, it works slowly, indirectly. So Intuniv, the brand name extended-release guanfacine, was approved in kids, because again, most of the research on ADHD is still on kids, for treating ADHD as a solo agent. It clearly works in adults as well, and even before Intuniv was approved, there were a handful of studies with either immediate-release guanfacine or extended-release guanfacine. In the studies so far, the results aren't distinguishable. They both seem to work. So clinically, because it's much cheaper, I actually use immediately release form and all at bedtime. And again, because it's my impression, and I probably don't have an N that's big enough to do a rigorous study, is the sedating effects are relegated to the nighttime and people are feeling okay during the daytime. Some of the rationale with the extended release is you're sort of smearing it over a longer time, so it should be less sedating. But depending on the time curve and how it works, you could actually wind up with being more uniformly sedated day and night with the extended release. So I've seen good results in some people. I've had many who either didn't work or they didn't perceive result, because again, some part for some people, the stimulant benefit is, "I can feel it. I know it's working." So the majority, at least in terms of prescription searches and what clinics tend to be, it looks like most people who are on guanfacine are on it in combination with either a stimulant or a norepinephrine or dopamine-promoting agent.

中文译文：Andrew Huberman: Let's talk about modafinil and armodafinil by extension. We hear about modafinil a lot in communities like the tech community and communities where people are trying to, quote-unquote, "cognitively enhance." What is modafinil? What does it do? What doesn't it do? How might it be useful for ADHD?

中文译文：Dr. John Kruse: So we're going to jump back to your issue with the recency in science and how to incorporate things. So modafinil was a drug developed by a French company and approved there and used for decades, for maybe a decade before it came to the US 25, maybe 35 years ago. And at the time, all the research showed that it was an orexin receptor antagonist. Right, antagonist/agonist works on the orexins.

中文译文：Andrew Huberman: The hypocretin/orexin system, right. Yeah.

中文译文：Dr. John Kruse: So boosting activity, but not working like all of our stimulant alerting drugs, which are working on primarily norepinephrine systems. So it was called the non-stimulant stimulant. Now most of the pharmacology literature refers to it as a dopamine acting drug, and some people are debating whether it's orexin that it's working via or dopamine.

中文译文：Andrew Huberman: Hmm.

中文译文：Dr. John Kruse: I haven't seen anything that to me gives a clear consensus. So I stick with the orexin because that's where I was taught. So orexin, getting back to the sleep-wake in the brain and arousal, as I describe it, there's two ways to wake up in the morning. One way is the normal way that you just wake up, and the other is being alarmed by an alarm clock, your neighbor starting their lawnmower, someone snoring, an earthquake if you're in LA or Hawaii, being startled out of sleep. That wakefulness system is the sympathetic nervous system. The orexin system is the more natural, normal waking system, and it isn't arousing you. It's waking you, but it's not agitating you. Again, the claims originally was that this is how modafinil worked. It was waking you up, but not over-stimulating, over-revving you. So other than being developed by this French company, the entity that spent most research funds looking into what this does or doesn't do was the US military because they have a big investment in wanting people to be alert and ready to kill 24/7, but not being hyperactive, trigger-happy, jittery like stimulants can do. And particularly in the early days, this is really dating me, of the Afghan War, we dropped bombs on Canadian troops by accident in our friendly fire scenario things, and the investigation, the pilot and the crew there blamed their trigger happiness on being revved up by methylphenidate. So for years, the military has relied on traditional stimulants to keep people able to fight around the clock, and they wanted an agent that would keep you alert, awake, but not revved up, not agitated. And I'd say there's some good evidence that that's really sort of how modafinil works or performs. So modafinil was called Provigil for pro-vigilance, and then when they were losing their US patent- Like many drugs, the Provigil is a racemic mixture of left-handed and right-handed versions of the same modafinil molecule. They found that the armodafinil, the right-handed version, was the one that's doing most of the good stuff and has a longer half-life than the combined version. So they got a new patent for armodafinil, which is Nuvigil. So that's the only difference between the two. They're the same active ingredients as far as we can tell. And when it got approval in the US, it was approved for narcolepsy, where people are falling abruptly asleep during the day, so it keeps them alert and awake there. It also got approval for circadian sleep shift work disorder, where because you're on a shift schedule, you're sleeping weirdly. And it got approval for daytime sleepiness from sleep apnea. But even at that time when it was approved, there were dozens of studies that showed, regardless of why you're sleepy, whether it was sedating medication, whether you had lupus or MS, whether you had some other condition, it works pretty well for keeping people alert and awake. So more than keeping alert and awake, there does seem to be evidence that it helps with some of the executive functions of attention, concentration. My clinical experience with it, it tends to be, again, with the amphetamine on top, many fewer people describe it as being helpful or as helpful. On the other hand, there's one study, and I'm forgetting the principal investigators, it was at Brown University, where they used some very clever, sophisticated approach to try to sort out motivation versus pure cognitive functioning. And their claim, and it was a very well-done study, they were comparing it directly to an amphetamine product. Their claim was that modafinil was the one that was actually boosting cognitive functions and not just boosting motivation, whereas that most of amphetamine's benefit for ADHD, when we say, "It helps me concentrate, it helps me sustain focus, it makes me less distracted," their feeling, their analysis was that the stimulant was mostly working on motivation. It's a controlled substance, but not the same schedule as amphetamine and Ritalin, so it's easier for some prescribers to prescribe. Even though it's the non-stimulant stimulant, and I'd say most people do experience, "I feel more alert or awake or better, but I don't feel revved up," about 10% to 15% of people that I've worked with, and others have written about it, so I don't think it's unique, will feel revved up when they take it the first few times. And invariably, the people I've worked with have said, "This feels like bad speed," including people who never even took speed. So I don't know why they came up. It's just weird that people come up with the same terms. But my interpretation is that for some people, this novel substance primarily may be tapping into the orexin system, is serving as a signal, kind of like a panic attack does, that there's something weird, something different, we're being revved up, and that it's, I think, secondarily triggering the sympathetic system. Because for most of those people within a few trials, within a few days, they no longer had that over-revved effect. And again, the important piece for alerting people to that is if they're expecting taking this, I'm not going to feel over-aroused and over-agitated, and they do, then they're even less prepared and more freaked out.

中文译文：Andrew Huberman: Even though I've never tried modafinil, Provigil, that people that I know who have, and I know one who has for treatment of real narcolepsy, so he's narcoleptic, but others who take it for ADHD and for work focus and cognitive enhancement, people who take modafinil and armodafinil really like it. I don't know if it has any reinforcing property, but today is the first that I've heard that it has this dopaminergic aspect. But they seem to really like it and rely on it. Have you seen a kind of a dependence form?

中文译文：Dr. John Kruse: It is a controlled substance because some people are worried about the potential, and there was a woman, an Olympic athlete, 20, 15 years ago, who had Modaf and said she had narcolepsy. I don't know the ver- but was disqualified from the Olympics because of it. Whether it has any real performance-enhancing effects is not clear. It was available in France for a decade, at least, before it came to the US, and they didn't see any rates of substance abuse or problems. It clearly does not have, on any tests or animal studies, the propensity that the amphetamines do, and I'd say it's, to me, not a concluded subject whether there's any potential for addiction with it.

中文译文：Andrew Huberman: What about within the category of Adderall, Vyvanse, and the stimulant-type treatments for ADHD, I don't want to say what are your go-to favorites because that makes it sound very non-clinical, but what are the general trends that you've observed and that others have observed clinically or in any studies about preference for long-acting drugs versus shorter-acting drugs? And maybe this is also a good opportunity for you to be able to chime in about drug holidays, taking weekends off, and things of that sort.

中文译文：Dr. John Kruse: Maybe I'll start with that. So for decades, particularly starting with kids, the dogma has been taking breaks from stimulants is a good idea because it will decrease the likelihood of developing addictions. It will decrease tolerance. And not a lot of rigorous research, but one of the known side effects of stimulants for kids is growth suppression. So height winds up being about two centimeters, not big, but measurably and consistently found there for kids who are routinely on the stimulants for their growth years. And taking breaks that last for several months, like taking it off during the summer, result in overcoming that decrement in height. I looked and I still haven't-- Whether there's any lower rate of addiction, whether there's any lower rate of developing tolerance, there's nothing that shows clinically. It may be true. The other recommendation when I started out was, and this is before the internet, before constant plugged into everything, and before kids had soccer practice and violin lessons and 400 activities, is that kids should take it during the workdays and not take it during the weekends and not take it during the summers. And now, and for many years, we've lived in a world where little Johnny has soccer practice and ballet and piano and has 42 things to get to where he's supposed to be performing and focused and behaving. So the sort of excuse you could have downtime has diminished in many communities. And again, whether there's actual benefits to that or not, other than for the height decrement, which again, there is evidence that taking long breaks, but probably not short breaks, mitigates that. I haven't seen any evidence clearly showing a benefit. That doesn't mean it's not there. Nobody has really studied it rigorously. Sort of related to that, you asked the question about short-acting versus long-acting, and there's differences in the realm of what's clinically helpful or useful, and then there's the issue of risks or side effects. So again, one of the claims is that part of what makes a drug more addictive is not just the level it reaches, but how quickly it's going in and out, and that the short-acting drugs may predispose someone to higher rates of addiction. There are, at least occasionally, some people arguing on the other side that saturating the receptors for longer periods of time, but high doses with a long extended release version, that may actually be more of a risk. But I'd say there's more concern, I think, in the basic science community from the immediate release. And there's a tiny bit of data, but part of it overall is that, we talked earlier about global rates of addiction to any substance. That we have fairly good data on because the CDC tracks it. But in terms of very specifically who gets addicted to Adderall, who gets addicted to Ritalin, there's so little data, and most people just sort the same numbers that, oh, maybe 2% to 3% of kids run into trouble, and it's not common, and that's it. Or they study a much broader question, and that's the issue of misuse combined with abuse. And misuse, by the research definitions, means anyone who didn't use their drug exactly as prescribed, which means if you're taking a short-acting Ritalin and it says take it one every six hours apart during the day, and you acknowledge taking it on one day eight hours difference, you're classified as a misuser by those studies. I'm being maybe a little ridiculous because most of the exceptions aren't that narrow. But there's a big blurring in the research, particularly coming from the people who are worried about addiction. We should be worried about addiction, but we shouldn't be overreacting or creating, pretending it's a problem among those where that, I would say, is not addiction. That's not abuse. That's not using it as directed. But people with ADHD, by their very nature, are not going to use things as directed, either because they forgot or weren't organized enough to get it on time or forgot what you said in the office, even though you wrote it down because they lost the sheet of paper it's written down on. So getting back to patients' experience of it. So the advantages of the immediate release is they tend to work quickly. You can feel it going in. Most people, there's a lot of individual variability, but let's say in the six to eight-hour range will get benefit. Some shorter, some immediate release lasts all day. But you know when it's on, you know when it's off. If you forget to take your medicines in the morning, but you know you have a presentation at 3:00 that afternoon, you could take it at 2:00 and still be able to sleep that night. So it allows more flexibility. It allows more pinpointing of optimizing it for points of the day you want to be using it. Some people philosophically say that in itself is wrong or bad, that you should be absolutely steady and constant because what we're trying to do is be consistent and reproducible. And others would say we're trying to treat individuals who have different demands on them and have different patterns during their day. So there are different philosophies about what's better or worse. One of the big downsides of the immediate release, though, is not only does it go in quickly, it tends to go off quickly. And most people, not all, but most experience some withdrawal as it's going off. And although when we're using this for ADHD, we focus on the cognitive executive function benefits, the focus, the attention, the concentration, and people can experience that. Many people who weren't even aware Of it increasing their energy, feel my energy's crashing as I go off of it, or many people who aren't aware that it was actually elevating mood to any extent feel, "Oh, my God, I'm crashing, and I'm crying and cranky and miserable now." And with the extended release versions, most of them go in more gradually, so it can be harder to detect. They last a longer period of the day, and most of them go out much more gradually at the end of the day. The one I like the most for a long-acting amphetamine product is Vyvanse. And Vyvanse was designed as a slow-release product. It was designed specifically to be unattractive to drug abusers. So Vyvanse chemically links a dextroamphetamine molecule to lysine, one of the amino acids. It's a basic component of proteins and 20 essential amino acids. And if you snort it or inject it, you have an inactive prodrug. You have this dexamphetamine. Your red blood cells actually have an enzyme that cleaves the lysine and leaves you with the free active dextroamphetamine, and that's the slow-release mechanism, is how quickly your red blood cells can do it, and they have limited capacity to do that. So although they designed it to be an anti-drug abuse drug, it actually turns out to be one of the most consistently, evenly entering the body. For some people, it goes in so slowly that they say, "I don't feel it." And also, towards the end of the day, one of the best in terms of not falling off abruptly. The potential downside is, again, that the capacity of the red blood cells is limited, so at some point, for most people, because that's a rate-limiting step, when you're adding more and more, you're actually extending the duration of time more than you're getting a bigger peak because your red blood cells just aren't cleaving it fast enough to make more dextroamphetamine available. Almost invariably, when I'll ask, "How did this compare to your Adderall XR or to a Hanseathr?" They'll say, "Smooth."

中文译文：Andrew Huberman: Smooth.

中文译文：Dr. John Kruse: They're getting it. They're not feeling-

中文译文：Andrew Huberman: Mm-hmm

中文译文：Dr. John Kruse: ... too jarred, too revved up.

中文译文：Andrew Huberman: Yeah, we don't really have a language for these things, right? Hence the bad speed language before. Cracked out, bad speed-

中文译文：Dr. John Kruse: Yeah

中文译文：Andrew Huberman: ... smooth. Because what we're talking about here is the gestalt of the subjective experience of all these neural and chemical mechanisms. Very interesting. Thank you for sharing that. I know that there are a lot of listeners and viewers who have tried these things or are considering or at one point used them, and a lot has evolved in this realm of chemistry for ADHD, but that's very helpful. Before we wrap up, I want to make sure that I ask you about something that's been on my mind a lot in general, but in particular as it relates to ADHD, which is time perception. And I'm basically obsessed with time perception. I've long been fascinated by the fact that we can fine slice time when our arousal is high. That's what-

中文译文：Dr. John Kruse: Mm-hmm

中文译文：Andrew Huberman: ... presumably gives people the kind of slow motion effect in very stressful environments, versus when we're relaxed, our frame rate on life goes down, and it's all very dynamic. It's important our brains are able to do that. But someone recently told me the following. Her partner has ADHD, and she said that the big rescue to their relationship came when they together read a book about ADHD, and something in there read something like this, that people without ADHD keep track of time, whereas people with ADHD don't, but they do know the difference between now and not now. But they're not tracking time. They know that what they're doing in the moment is not what they're-

中文译文：Dr. John Kruse: Mm-hmm

中文译文：Andrew Huberman: ... going to be doing later or what they did in the past, but they're not tracking time the same way. And I think this ties back to this interest-based attention system. What do we know about time perception in ADHD? And by extension, do you think that these drugs are working in part to change time perception?

中文译文：Dr. John Kruse: Good question. So I'd say there's two different angles, and I think, the one that's easier to objectively measure is putting people in a lab, and there's a simple test, a time perception test, and you interrupt them after a certain period-- Say you're going to be estimating how long you're left without interruption. And people with ADHD, they're inconsistently inconsistent. Or consistently-

中文译文：Andrew Huberman: Consistently inconsistent

中文译文：Dr. John Kruse: ... inconsistent. So it's not that they perpetually underestimate or overestimate, but they are estimating incorrectly much more often than people without ADHD. So there's something at a basic time processing level that's aberrant there. But there's also getting the real-world aspect of not paying attention to cues or not noticing other people have left the room, or being distracted, which compounds the situation. And it's also interesting to the extent to which many people aren't aw-- So I often ask, even though it's not one of the 18 symptoms, "Are you chronically late to--" And particularly people who show up late to my office time after time. So one of my favorite quotes is this person who, the session before, we had been talking that her boss was giving her threatening notices because she had come in two hours late one day, and she had all sorts of good excuses of why she couldn't get out the door. And we were talking, "Are you regularly late?" "No." And I said, "Well, why was the boss so upset?" I'd say And then I ask, "Well, when is the expectation?" This is pre-COVID, pre-working from home. "When is the expectation you're there? When do you usually show up?" "Oh, well, office starts at 9:00, and I'm usually there by 9:15, 9:20. That's not late." In her mind, it wasn't late. So when you ask a question, "Are you routinely late?" You're going to get meaningless information on your little checklist, unless you know what that means to the individual. So the second part of the question, I'm sure it's been done, and I don't have the answer, whether stimulants or other drugs measurably improve time perception in that laboratory situation of just, can you estimate how much time has elapsed? I should know that, but I don't have that on top of my-- And the more global question of how central that's sort of the time aspect of organization of thoughts and attention is to the content of disorganization. There are some research groups, I think it's mainly a Danish group, who's feeling that ADHD is primarily a circadian rhythm disruption, that that's the central neurologic issue at play. And there's interesting-- I got to do work in the early '80s on bright light therapy for winter depression, which has a measurable impact as strong as medication. But there is one or two studies done on individuals with ADHD, without any seasonal depression, without any depression at all, and just those same bright lights, showing them a dose of bright lights early in the morning, measurably improved a broad range of ADHD symptoms. And the claim was that that was working because it was helping resynchronize internal rhythms, which are out of sync in ADHD, whether that's exactly the same thing you are getting at. But certainly, even though we have a sort of master clock in the suprachiasmatic nucleus, we also have clocks throughout our body, and they're talking and interacting and ostensibly synchronized and working with each other. But it could well be that for many people they're not, and that getting that to work is essential.

中文译文：Andrew Huberman: Thank you for those reflections. And really, I want to say thank you on behalf of myself and everyone listening and watching, for doing the work you do. You were invited here today because you have an absolutely encyclopedic understanding and knowledge of ADHD and the clinical treatments, and I've watched your YouTube channel, and we'll provide links to all your various resources. I'm looking forward to your upcoming book, "However Long It Takes." I'm sure it'll be spectacular. When you talk about ADHD, you're able to do it from so many different angles, behavioral, supplement-based, nutrition, life and organizational aspects, and of course, the medication, the pharmacology, the neuroscience, and the ways that those different nodes interact with one another, because of course they do. So I just want to be absolutely clear how grateful we are for you for sharing all this knowledge. A lot of people struggle with attention issues, regardless of whether or not they have full-blown ADHD or not. A lot of people have been treated for it. Some people are still wondering if they should be or not. And so today's discussion was nothing short of spectacular. So on behalf of everybody, I want to just thank you for doing what you do and for coming here to educate us. Thank you so much.

中文译文：Dr. John Kruse: Thanks. I'm gobsmacked, so...

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