Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity | Huberman Lab Podcast

发布时间 2023-08-07 12:00:31 来源

安德鲁·休伯曼 (Andrew Huberman) 的 Huberman Lab 播客节目重点讨论了氯胺酮，包括它在治疗抑郁症、自杀倾向和 PTSD (创伤后应激障碍) 方面的临床益处，其潜在的滥用风险，以及它在大脑中的作用机制。休伯曼解释说，氯胺酮是一种分离性麻醉剂，类似于 PCP (苯环利定)，它已经从主要被视为一种街头毒品，转变成为一种临床上使用的治疗方法。他首先驳斥了抑郁症的单胺假说，该假说认为血清素、多巴胺或去甲肾上腺素的缺乏会导致抑郁症。虽然增加这些单胺的药物可以为某些人提供缓解，但它们只对大约 40% 的抑郁症患者有效，并且常常伴随副作用。这促使人们寻找替代疗法，例如氯胺酮。休伯曼随后详细介绍了氯胺酮临床使用的历史。抑郁症的动物模型，例如“习得性无助”模型，表明氯胺酮可以让动物为自己的生命抗争更长时间，暗示了抗抑郁作用。这导致了在人类中的临床试验，该试验表明氯胺酮可以迅速缓解抑郁症，即使在难治性病例中也是如此。它还显示出治疗双相情感障碍、PTSD、强迫症、焦虑症和物质成瘾的潜力。然而，氯胺酮的快速作用与它的短暂效应相伴随，需要频繁给药。这引发了人们对潜在滥用和成瘾的担忧。研究已经探索了给药方案，例如每周两次，持续三周，这显示出抗抑郁效果具有一定的持久性。这表明存在多种作用机制：立即缓解、短期缓解以及神经回路的长期变化。休伯曼深入研究了氯胺酮的神经生物学机制，强调了神经可塑性，即大脑根据经验改变的能力。他解释说，氯胺酮阻断了 NMDA 受体，这种受体对于许多形式的神经可塑性至关重要。然而，氯胺酮的抗抑郁作用似乎是矛盾的，因为 NMDA 受体的阻断表面上会*降低*神经可塑性。他通过描述两种主要的神经元类型来解释这个悖论：兴奋性神经元和抑制性神经元。氯胺酮阻断抑制性神经元上的 NMDA 受体，减少它们对特定大脑回路中兴奋性神经元的抑制性输出。这使得兴奋性神经元可以“爆发”出电活动，这是一种完美的模式，可以诱导与情绪、奖励和自我反思相关的神经回路的短期和长期变化。爆发性放电导致 BDNF (脑源性神经营养因子) 的释放，这是一种对于所有形式的学习和记忆至关重要的分子。 BDNF 与其受体结合并触发一系列事件，包括将新的谷氨酸受体插入神经元，使它们对输入更加敏感。在某些情况下，氯胺酮本身也可以模拟 BDNF 的效果。他澄清说，虽然 NMDA 受体很重要，但氯胺酮也会影响阿片类通路，该通路在疼痛和情绪中起着重要作用。氯胺酮代谢成羟基去甲氯胺酮 (HNK)，选择性地激活阿片类系统。研究表明，用纳曲酮阻断阿片类系统会减弱氯胺酮的抗抑郁作用，这表明阿片类系统是氯胺酮临床益处的一个关键贡献者。休伯曼强调了将氯胺酮的即时主观效应与其长期临床益处区分开来的重要性。患者在氯胺酮影响下的体验会引发一系列事件，最终导致神经回路和神经递质系统的变化。休伯曼讨论了氯胺酮改变的特定大脑回路，包括减弱失望回路 (缰核) 和奖励回路之间的连接。氯胺酮可以改善额叶皮层和奖励通路之间的连接，这使得人们对自己的成就以及如何从自己的行为中获得结果更加敏感。然后，他讨论了氯胺酮的主观效应（例如分离感）是如何由皮层和皮层下大脑网络解耦以及独特脑电波模式的出现而产生的。接着他提到氯胺酮的不同给药方式，其中注射型氯胺酮具有最高的生物利用度，其次是舌下给药，最后是口服。他还将 "K-hole" 定义为服用娱乐性氯胺酮剂量，其剂量足以引起完全麻醉。他警告说，氯胺酮的剂量和敏感性因人而异，并且受到给药途径的影响。他还讨论了各种 SR (缓释) 版本的氯胺酮，其中 SR 组合形式在缓解抑郁症症状方面更有效。他最后表示，截至目前，没有已发表的临床证据支持氯胺酮微剂量给药能够有效缓解抑郁症。最后，休伯曼强调，抗抑郁行为，例如寻求社会参与和规律睡眠，对于加强通过氯胺酮治疗获得的积极变化至关重要。

Andrew Huberman's Huberman Lab podcast episode focuses on ketamine, its clinical benefits for depression, suicidality, and PTSD, its potential for abuse, and its mechanisms of action in the brain. Huberman explains that ketamine is a dissociative anesthetic, similar to PCP, that has transitioned from being primarily viewed as a street drug to a clinically utilized treatment. He begins by debunking the monoamine hypothesis of depression, which posits that deficiencies in serotonin, dopamine, or norepinephrine cause depression. While drugs that increase these monoamines can provide relief for some, they only work in about 40% of depressed individuals and often come with side effects. This led to the search for alternative treatments, like ketamine. Huberman then details the history of ketamine's clinical use. Animal models of depression, such as the "learned helplessness" model, revealed that ketamine allowed animals to fight for their lives longer, suggesting antidepressant effects. This led to clinical trials in humans, which demonstrated that ketamine could provide rapid relief from depression, even in treatment-resistant cases. It also showed promise for bipolar depression, PTSD, OCD, anxiety, and substance addiction. However, ketamine's rapid-acting nature is coupled with its short-lived effects, requiring frequent dosing. This raises concerns about potential abuse and addiction. Studies have explored dosing regimens such as twice a week for three weeks, which showed some durability in antidepressant effects. This suggests multiple mechanisms of action: immediate relief, short-term relief, and long-term changes in neural circuitry. Huberman delves into the neurobiological mechanisms of ketamine, emphasizing neuroplasticity, the brain's ability to change in response to experience. He explains that ketamine blocks the NMDA receptor, a crucial receptor for many forms of neuroplasticity. However, ketamine's antidepressant effects appear paradoxical, since NMDA receptor blockage would ostensibly *reduce* neuroplasticity. He explains this paradox by describing the two major types of neurons: excitatory and inhibitory. Ketamine blocks NMDA receptors on inhibitory neurons, reducing their inhibitory output onto excitatory neurons in specific brain circuits. This allows excitatory neurons to "burst" with electrical activity, a perfect pattern to induce both short- and long-term changes in neural circuits associated with mood, reward, and self-reflection. The burst firing leads to the release of BDNF (Brain-Derived Neurotrophic Factor), a molecule critical for all forms of learning and memory. BDNF binds to its receptors and triggers a cascade of events, including the insertion of new glutamate receptors on neurons, making them more sensitive to input. In some cases, ketamine itself can also mimic the effects of BDNF. He clarifies that while the NMDA receptor is important, ketamine also impacts the opioid pathway, which plays a major role in pain and mood. Ketamine metabolizes into hydroxynorketamine (HNK), which selectively activates the opioid system. Studies have shown that blocking the opioid system with naltrexone attenuates the antidepressant effects of ketamine, suggesting the opioid system as a key contributor to ketamine's clinical benefits. Huberman underscores the importance of separating the immediate subjective effects of ketamine from its long-term clinical benefits. The patient's experience while under the influence of ketamine sets off a series of events that ultimately lead to changes in neural circuitry and neurotransmitter systems. Huberman discusses the specific brain circuits altered by ketamine, including the weakening of the connection between the disappointment circuit (habenula) and the reward circuitry. Ketamine can improve connectivity between the frontal cortex and the reward pathways, which makes people more sensitive to their achievements and to how to get results from their behaviors. He then discusses how the subjective effects of ketamine, such as dissociation, arise from an uncoupling of cortical and subcortical brain networks, and the emergence of unique brain wave patterns. He then addresses the different delivery methods of ketamine, with injectable ketamine having higher bioavailability, then sublingual and then oral routes. He then defines a "K-hole" as taking a recreational ketamine dose high enough to cause full anesthesia. He cautions that ketamine dosage and sensitivity vary greatly among individuals and are influenced by the route of administration. He also discusses various SR versions of ketamine, with the SR combined form being more potent at relieving depression symptoms. He ends by stating that as of today, there is zero published clinical evidence to support the effectiveness of microdosing ketamine to relieve depression. Finally, Huberman emphasizes that antidepressant behaviors, such as seeking social engagement, and regular sleep, are essential to reinforcing positive changes achieved through ketamine treatment.

摘要

In this episode, I explain how ketamine causes rewiring of brain circuits and dissociative states to relieve symptoms of depression and post-traumatic stress disorder (PTSD). I explain how ketamine impacts both the brain’s glutamate and its endogenous opioid pathways, which together regulate mood and well-being. I discuss how ketamine therapy is used clinically to treat major depression, bipolar depression, obsessive-compulsive disorder (OCD), suicidality and other psychiatric challenges. I also describe how ketamine causes the subjective effects of dissociation and euphoria and, at higher doses, is an anesthetic. I compare the different routes of ketamine administration, dosages and forms of ketamine, and if micro-dosing ketamine is effective. I also highlight the potential risks of recreational ketamine use (and the colloquial term ‘K-holes’). This episode should interest anyone interested in ketamine, treatments for depression, neuroplasticity mechanisms, psychiatry and mental health. #HubermanLab #Science Thank you to our sponsors AG1: https://drinkag1.com/huberman ROKA: https://roka.com/huberman Eight Sleep: https://eightsleep.com/huberman LMNT: https://drinklmnt.com/huberman Supplements from Momentous https://www.livemomentous.com/huberman Social & Website Instagram: https://www.instagram.com/hubermanlab Threads: https://www.threads.net/@hubermanlab Twitter: https://twitter.com/hubermanlab Facebook: https://www.facebook.com/hubermanlab TikTok: https://www.tiktok.com/@hubermanlab LinkedIn: https://www.linkedin.com/in/andrew-huberman Website: https://hubermanlab.com Newsletter: https://hubermanlab.com/neural-network Articles Antidepressant effects of ketamine in depressed patients: https://bit.ly/44YTGxY Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism: https://go.nature.com/3qesrR8 atai Life Sciences Announces Results from Phase 2a Trial of PCN-101 (R-ketamine) for Treatment-Resistant Depression: https://bit.ly/47j6wsC Comparative effects of (S)-ketamine and racemic (R/S)-ketamine on psychopathology, state of consciousness and neurocognitive performance in healthy volunteers: https://bit.ly/44WMxOR Ketamine Metabolite (2R,6R)-Hydroxynorketamine Interacts with μ and κ Opioid Receptors: https://bit.ly/44e4SWB Other Resources The Science & Treatment of Bipolar Disorder (Huberman Lab episode): https://hubermanlab.com/the-science-and-treatment-of-bipolar-disorder/ Timestamps 00:00:00 Ketamine 00:02:29 Sponsors: ROKA & Eight Sleep 00:05:13 Ketamine & PCP; Clinical & Recreational Use 00:09:00 Depression & Current Treatments 00:15:17 Preclinical Models of Depression & Ketamine; “Learned Helplessness” 00:22:11 Ketamine & Clinical Uses; Depression & Suicidality 00:28:32 Ketamine & Other Psychiatric Challenges; Relief & Durability 00:33:24 Sponsor: AG1 00:34:29 NMDA Receptor & Neuroplasticity 00:41:36 Excitatory & Inhibitory Communication, Seizure, NMDA Receptors & Ketamine 00:48:26 How Ketamine Functions in Brain; Acute & Long-Term Effects 00:55:36 Brain-Derived Neurotrophic Factor (BDNF) & Ketamine Therapy 01:02:28 Sponsor: LMNT 01:03:40 Ketamine & Opioid Pathway 01:10:00 Divergent Mechanisms of Immediate & Long-Term Effects 00:15:45 Habenula, Pro-Depressive Behaviors & Ketamine Therapy 01:20:36 Ketamine & Context-Dependent Strategy; Reward Pathway 01:22:45 Dissociative States 01:26:04 Doses & Routes of Administration; “K-holes”; Risk & Caution 01:32:25 Ketamine Forms; R-, S- vs R/S- Ketamine; Micro-Dosing 01:38:24 Ketamine: Effects & Therapy 01:40:40 Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Momentous, Social Media, Neural Network Newsletter The Huberman Lab podcast is for general informational purposes only and does not constitute the practice of medicine, nursing or other professional health care services, including the giving of medical advice, and no doctor/patient relationship is formed. The use of information on this podcast or materials linked from this podcast is at the user’s own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they may have and should seek the assistance of their health care professionals for any such conditions. Title Card Photo Credit: Mike Blabac - https://www.blabacphoto.com

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Welcome to the Huberman Lab podcast where we discuss science and science-based tools for everyday life. I'm Andrew Huberman and I'm a professor of neurobiology and Ophthalmology at Stanford School of Medicine. Today we are discussing ketamine. Ketamine is a fascinating compound and it's one that nowadays is being used both clinically for the treatment of depression and suicidality and PTSD, and it is also a drug that is commonly abused. That is, ketamine is often used recreationally and it has a high potential for abuse.

欢迎收听 Huberman Lab 播客节目，在这里我们会讨论有关科学以及与日常生活相关的科学工具。我是 Andrew Huberman，是斯坦福医学院的神经生物学和眼科学教授。今天我们要讨论的话题是氯胺酮（俗称K粉）。氯胺酮是一种非常有趣的化合物，目前它被用于临床上治疗抑郁症、自杀倾向和创伤后应激障碍（PTSD）。然而，它也是一种常被滥用的药物。也就是说，氯胺酮经常被用于娱乐目的，并且有很高的滥用潜力。

So today we are going to discuss both the research on the clinical benefits of ketamine as well as the risks of ketamine. We are going to discuss the mechanisms of action by which ketamine produces what are called dissociative states. I will define for you what a so-called K-hole is in scientific terms. I will talk about dosages of ketamine. I will talk about delivery routes of ketamine and throughout I will be emphasizing both the clinical benefits and the risks, that is, the potential harms of using ketamine out of the appropriate clinical context.

今天我们将讨论关于氯胺酮的临床益处及其风险的研究。我们会探讨氯胺酮如何通过其作用机制产生所谓的分离状态。我会用科学术语为大家定义什么是所谓的“K洞”。同时，我们还会谈论氯胺酮的剂量和不同的给药途径。在整个讨论中，我将重点讲解氯胺酮的临床益处及其风险，也就是在不适当的临床环境下使用氯胺酮可能带来的潜在危害。

So by the end of today's episode, you will understand thoroughly what ketamine is, how it works in the brain and body to produce dissociative states and to relieve depression, and you will understand how it can actually change neural circuitry. This is an important thing to understand about ketamine. The acute or immediate effects of ketamine while one is under the influence of ketamine are just part of the story of how ketamine modifies the brain for the treatment of depression, suicidality, and PTSD.

所以，在今天这一集结束时，你将彻底理解什么是氯胺酮，它如何在大脑和身体中产生解离状态以及缓解抑郁症，并且你将理解它如何真正改变神经回路。这是关于氯胺酮的重要知识。氯胺酮的急性或即时效果，即在其影响下的体验，只是其如何修改大脑以治疗抑郁症、自杀倾向和创伤后应激障碍的部分内容。

And by extension, when people use ketamine recreationally, there are those immediate acute effects of ketamine, but there are also long-term changes in the brain that are important to understand. During today's discussion, we will also be talking a lot about neuroplasticity or your nervous system's ability to change in response to experience. And we will be talking about neuroplasticity not just in the context of ketamine, but as a general theme for how your nervous system changes anytime you learn anything.

扩展来说，当人们娱乐性地使用氯胺酮时，除了立刻的急性效果外，大脑还会发生一些长期的变化，而我们需要了解这些变化。在今天的讨论中，我们也会深入探讨神经可塑性，也就是你的神经系统对经历的反应能力。我们不仅会在氯胺酮的背景下讨论神经可塑性，还会将其作为一个普遍主题来探讨神经系统在你学习任何东西时是如何变化的。

In that discussion, you're going to hear a lot about BDNF or brain-derived neurotrophic factor. Brain-derived neurotrophic factor is a critical molecule for all forms of learning and memory and changes to your nervous system. So in addition to learning about ketamine and how it works clinically and its relevance to recreational use and abuse, you will also learn a lot about neuroplasticity and BDNF and what it's doing in your brain right now as you learn.

在那次讨论中，你会听到很多关于BDNF（脑源性神经营养因子）的内容。脑源性神经营养因子是对所有形式的学习、记忆以及神经系统变化至关重要的分子。所以，除了了解氯胺酮的临床作用及其在娱乐和滥用方面的相关性，你还会学到很多关于神经可塑性和BDNF的信息，以及在你学习过程中，它在你大脑中所起的作用。

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford. It is, however, part of my desire and effort to bring zero-cost to consumer information about science and science-related tools to the general public. In keeping with that theme, I'd like to thank the sponsors of today's podcast. Our first sponsor is Roka. Roka makes eyeglasses and sunglasses that are the absolute highest quality. The company was founded by two all-American swimmers from Stanford and everything about Roka eyeglasses and sunglasses were designed with performance in mind.

在我们开始之前，我想强调一下，这个播客与我在斯坦福的教学和研究工作是分开的。然而，这是我希望向公众提供零成本的科学信息和科学相关工具的一部分努力。本着这种精神，我想感谢今天播客的赞助商。我们的第一个赞助商是Roka。Roka是一家生产眼镜和太阳镜的公司，其质量绝对顶尖。该公司由两位来自斯坦福的全美游泳运动员创立，Roka的每一副眼镜和太阳镜都是以性能为设计核心的。

I spent a lifetime working on the biology of the visual system. And I can tell you that your visual system has to contend with an enormous number of different challenges in order for you to be able to see clearly. When, for instance, you go from a shady area to a sunny area when you look at something up close or off in the distance, Roka understands all of that and have designed their eyeglasses and sunglasses so that regardless of conditions, you always see with perfect clarity.

我毕生致力于研究视觉系统的生物学。我可以告诉你，为了让你看得清楚，你的视觉系统需要面对大量不同的挑战。比如，当你从阴凉的地方走到阳光明媚的地方，或者当你看近处或远处的东西时，你的视觉系统都在不断调整。Roka深知这些挑战，并设计了他们的眼镜和太阳镜，不论在什么环境下，都能让你始终看到得清晰。

Their glasses are also extremely lightweight and they won't slip off your face if you get sweaty. In fact, initially, Roka eyeglasses and sunglasses were designed for use in sports, things like running and cycling, etc. And they still can be used for that. But really, their eyeglasses and sunglasses are designed to be worn anytime. I wear readers at night or when I drive at night and I'll sometimes wear sunglasses in the middle of the day.

他们的眼镜也非常轻便，即使出汗也不会从脸上滑落。实际上，Roka 眼镜和太阳镜最初是为运动场合设计的，如跑步和骑自行车等。而现在它们仍然可以用于这些场合。不过，Roka 眼镜和太阳镜实际上是为了随时佩戴而设计的。我在晚上或开车时戴阅读眼镜，有时也会在白天戴太阳镜。

Although, of course, I do not wear sunglasses when I do my morning sunlight exposure, which everyone should be doing to set their circadian rhythm. If you'd like to try Roka eyeglasses or sunglasses, simply go to roca.com and enter the code huberman to save 20% off your first order. Again, that's roca.com and enter the code huberman at checkout. Today's episode is also brought to us by 8Sleep. 8Sleep makes smart mattress covers with cooling, heating and sleep tracking capacity.

当然，当我进行早晨阳光照射时，我不会戴太阳镜，因为每个人都应该这样做来调整他们的昼夜节律。如果你想试试Roka的眼镜或太阳镜，只需访问roca.com并在结账时输入代码huberman，就可以享受首单8折优惠。再重复一遍，访问roca.com并在结账时输入代码huberman。今天的节目还由8Sleep赞助。8Sleep生产具有制冷、加热和睡眠跟踪功能的智能床垫套。

Now, I've spoken many times before in this podcast and elsewhere about the fact that sleep is the foundation of mental health, physical health and performance. When we're sleeping well and enough, all of those things are improved and when we are not sleeping well or enough, all of those things, mental health, physical health and performance all get worse.

在这个播客和其他地方，我已经多次谈到，睡眠是心理健康、身体健康和表现的基础。当我们睡得好而且充足时，这些方面都会得到改善；而当我们睡得不好或不足时，心理健康、身体健康和表现都会变差。

Now, a key component to getting a great night's sleep is that the temperature of your sleeping environment has to be such that your body temperature drops by one to three degrees in order to fall and stay deeply asleep, and that your body temperature increases by about one to three degrees in order to wake up feeling refreshed. With 8Sleep mattress covers, you can customize the temperature of your sleeping environment, such that you always get the best possible night's sleep.

现在，获得良好睡眠的一个关键因素是你的睡眠环境温度需要使你的体温降低一到三度，以便更容易进入深度睡眠；而醒来时，体温需要上升一到三度，这样你才能感到神清气爽。使用8Sleep床垫套，你可以根据需要调整睡眠环境的温度，从而始终获得最佳的睡眠体验。

I've been sleeping on an 8Sleep mattress cover for about two years now, and I must say it is vastly improved my sleep. If you'd like to try 8Sleep, you can go to 8Sleep.com slash Huberman and save $150 off off their pod three cover. They currently ship in the USA, Canada, UK, select countries in the EU and Australia. Again, that's 8Sleep.com slash Huberman.

我已经在8Sleep床垫套上睡了大约两年了，我必须说它极大地改善了我的睡眠。如果你想试试8Sleep，你可以访问8Sleep.com斜杠Huberman，并可享受150美元的折扣。他们目前在美国、加拿大、英国、欧洲部分国家和澳大利亚发货。再次提醒，网址是8Sleep.com斜杠Huberman。

Okay, let's talk about ketamine. I realize that many people have heard of ketamine, but most people don't realize that ketamine is very similar to another drug called PCP or Fenncyclidine, which goes by the street name's Angel Dust or Shurm. It has some other street names as well. When I was growing up, I heard a lot about PCP. They taught us about it in school. You'd hear about it on cop shows, on television.

好的，我们来谈谈氯胺酮。我意识到很多人都听说过氯胺酮，但大多数人不知道它和另一种叫做PCP或苯环利定的药物非常相似，这种药物在街头的俗称是“天使尘”或“Shurm”。它还有一些其他的街头名字。在我成长过程中，我经常听到关于PCP的事情，学校里也教过我们这方面的知识。在警察题材的电视节目中，你也能听到这类信息。

The lore was that PCP would eliminate people's perception of pain and would make them violent. You'd hear these stories in drug education classes that when people are on PCP, they're punching light poles and breaking their hands. They can fight off eight or 10 police officers who are trying to handcuff them. I don't know whether or not any of that is true or not, but we heard a lot about PCP and it was associated with drugs of abuse, things like cocaine, methamphetamine. It was lumped into that category.

传说中，PCP（天使尘）可以消除人们对疼痛的感知，还会让他们变得暴力。在毒品教育课上，我们经常听到这样的故事：有些人吸食PCP后，会用拳头打灯柱，结果弄断了自己的手。他们甚至能摆脱八到十个警察的控制，难以被铐住。我不确定这些说法是否属实，但我们确实听到了很多关于PCP的事情，它常常与可卡因、冰毒等滥用药物联系在一起，被归为同一类。

Nowadays, when we hear about ketamine, rarely do people mention that ketamine and PCP actually have the same mode of action, more or less. Okay, I'm not talking about the specifics. I'm talking broadly. They have the same mode of action in the brain. The both of them are dissociative anesthetics. And nowadays, usually when we hear about ketamine, we are hearing about its benefits.

在当今，当我们听到氯胺酮（K药）这个词时，很少有人提到氯胺酮和PCP（天使尘）实际上在作用方式上大致相同。好的，我不是在讲具体细节，而是从整体上说。它们在大脑中的作用方式是一样的，都是解离性麻醉剂。而现在，通常当我们听到氯胺酮时，我们听到的都是它的益处。

We are hearing that it can help cure depression. We are hearing that it can help reduce or cure suicidality that it can be used to treat PTSD. And indeed, all of that is true in the appropriate clinical context at the appropriate dosages and given at the appropriate frequency. Ketamine has proven to be a miraculous drug for some people, not all people, for the treatment of depression, suicidality and PTSD.

我们听说它可以帮助治疗抑郁症。听说它还可以减少或治愈自杀倾向，并可用于治疗创伤后应激障碍（PTSD）。实际上，在合适的临床环境中，以适当的剂量和频率使用，这些都是正确的。对一些人来说，氯胺酮被证明是一种神奇的药物，可以治疗抑郁症、自杀倾向和PTSD。不过，它并不是对所有人都有效。

That said, ketamine also has a very high potential for abuse. And so it may come as no surprise that we often hear about ketamine nowadays, also in the context of its use at parties. You hear about people going into so-called K-holes, which is a particular state associated with overdoing the dosage of ketamine, a little or a lot. We'll get back to that a little bit later, what it is, how dangerous it is, etc.

尽管如此，氯胺酮也有很高的滥用潜力。因此，我们现在常听到关于氯胺酮的信息，这一点也不足为奇，包括它在聚会中的使用。你可能听说过人们进入所谓的“K洞”状态，这是与过量使用氯胺酮有关的一种特定状态，无论是数量多还是少。稍后我们会详细讨论这种状态到底是什么，有多危险等等。

In any case, ketamine is an incredible drug, very similar to PCP, fancycidine. And it is a drug that nowadays there is crossover between the clinical uses of ketamine for treatment of depression, etc. and its recreational use. What do I mean by that? What I'm referring to is people accessing ketamine legally for the purpose of treating depression, but taking that ketamine out of the clinic, out of the doctor's office, which is a very different set of conditions than most of the studies that have been done on ketamine and its role in depression.

无论如何，氯胺酮是一种非常神奇的药物，与天使尘（PCP, fancycidine）非常相似。近年来，氯胺酮在用于治疗抑郁症等临床用途和娱乐用途之间有所交叉。我的意思是什么呢？我指的是，某些人通过合法渠道获得氯胺酮用于治疗抑郁症，但他们将这些氯胺酮从诊所或医生办公室带走，而这种情境与大多数关于氯胺酮在抑郁症治疗中的研究条件非常不同。

And not surprisingly, if there is increased access to a drug like ketamine, really any drug that has a potential for abuse, then we also see an increase in the number of people that are using that drug recreationally and some of them do indeed get addicted to ketamine. So I know many of you are probably wondering, can you get addicted to ketamine? Indeed, people can get addicted to ketamine.

如果像氯胺酮这样的药物获得了更广泛的使用权限，也就是说任何有滥用潜力的药物，那么我们也会看到使用这种药物进行娱乐的人数增加，其中确实有些人会对氯胺酮上瘾。所以，我知道很多人可能会问，你会对氯胺酮上瘾吗？的确，人们是会对氯胺酮产生上瘾的。

There are some people who like its effects enough that they find themselves compelled to use ketamine even though the use of ketamine is degrading their overall life performance, so work, school, relationships, finances, etc. That said, ketamine does have these established clinical uses. So nowadays the landscape around ketamine is so different than it was 10 or 20 years ago when it was lumped very closely with PCP, fancycidine, and really just looked at as a drug of abuse.

有些人非常喜欢氯胺酮的效果，以至于即使这种药物正在损害他们的整体生活表现，比如工作、学习、社交和财务等，他们仍然感到不得不使用它。然而，氯胺酮确实有一些已被认可的临床用途。因此，如今对于氯胺酮的看法与10或20年前大不相同，那时它被与PCP（天使尘）及其他滥用药物混为一谈。

There were some early cases in the 1970s of the use of ketamine in order to treat PTSD. This was mainly in soldiers in Vietnam or people coming back from Vietnam, but really the clinical use of ketamine for the treatment of depression, suicidality, and PTSD has really just taken off in the last five to 10 years. And that's what's brought us to this new landscape of interest and understanding and use of ketamine in the clinical and recreational context. So how is it that a drug that at one time was really just viewed as a street drug that was bad, bad, bad, is now being prescribed widely and has all this interest surrounding it.

在20世纪70年代早期，就有使用氯胺酮治疗创伤后应激障碍（PTSD）的案例。这主要是针对在越南的士兵或从越南返回的人。然而，氯胺酮在抑郁症、自杀倾向和PTSD治疗方面的临床应用，实际上是在最近的五到十年才真正兴起。这引发了人们对氯胺酮的临床与娱乐用途的兴趣和理解。那么，曾经被视为危险街头毒品的氯胺酮，现如今是如何广泛地被开处方使用并引起如此多关注的呢？

And really this has to do with our understanding of what depression is and what depression isn't. So I'd like to just take one or two minutes and explain to you a little bit about the history of depression and its treatment. What we observed starting about the middle of the last centuries, around 1950, but really taking off in the early 1980s and 90s is the so-called monoamine hypothesis of depression. Monoamines, as the name suggests, are synthesized from amino acids. That's a good way to remember monoamines. Monoamines include things like serotonin, dopamine, and norepinephrine, although there are other monoamines as well.

这其实涉及到我们对抑郁症是什么以及不是什么的理解。因此，我想花一两分钟向你解释一下关于抑郁症及其治疗的历史。大约从上世纪中叶开始，也就是1950年前后，但真正开始在1980和90年代取得进展的是所谓的抑郁症单胺假说。单胺，顾名思义，是由氨基酸合成的。记住单胺的一个好方法是：它们包括像5-羟色胺（也就是血清素）、多巴胺和去甲肾上腺素，尽管实际上还有其他单胺类物质。

Monoamines are neurotransmitters, or more specifically, they are neuro modulators, meaning they change the activity of neural circuits in the brain and body. They can ramp up levels of activity in lots of different brain areas, or they can reduce the activity of neural circuits in lots of different brain areas, as well as within the body. Your gut has serotonin and needs serotonin, dopamine also plays important roles in the body, etc., etc. The monoamine hypothesis of depression is really centered around the idea that it is deficiencies in these monoamines, either serotonin or dopamine or norepinephrine, or some combination of those that gives rise to depression.

单胺类物质是神经递质，更具体地说，它们是神经调节剂。这意味着它们可以改变大脑和身体中的神经回路活动。单胺类物质可以提升多个大脑区域的活动水平，也可以降低这些区域的神经回路活动，还能影响身体内的活动。比如，肠道中含有血清素，并且需要血清素，另外，多巴胺也在体内起着重要作用，等等。关于抑郁症的单胺假说主要集中在这样的观点上：抑郁症是由于这些单胺物质的不足引起的，这些物质包括血清素、多巴胺、去甲肾上腺素，或者它们的某种组合。

Now, in reality, there is very little, if any, evidence, that there is a deficiency of monoamines in any form of depression. However, it is very clear that drugs that increase certain monoamines, so drugs like prozac or zoloph that increase serotonin, or drugs like bupriorin, which is often called well-butrin, which is its commercial name, which increases dopamine and norepinephrine, can often provide relief for certain symptoms of depression in some people. However, what we've learned over the last 30 or 40 years is that drugs that are designed to increase certain monoamines in order to treat depression only work in about 40% of depressed people that take them, and they have a lot of side effects.

实际上，目前并没有确凿的证据表明任何形式的抑郁症是由单胺类物质缺乏引起的。然而，很明显，一些能够增加特定单胺类物质的药物，比如提高血清素的药物如百忧解（Prozac）或左洛复（Zoloft），或者增加多巴胺和去甲肾上腺素的药物如安非他酮（商业名为Wellbutrin），可以在某些人中缓解抑郁症的某些症状。不过，通过过去30到40年的研究，我们了解到，这些旨在增加特定单胺类物质的药物，仅对大约40%的服药抑郁症患者有效，并且它们有许多副作用。

Now, some people are lucky enough that they can use a low enough dose, or perhaps even a high enough dose that gives them relief from their depressive symptoms, but does not give them side effects that make it so uncomfortable for them to use that drug that they would choose rather to not take that drug. However, a lot of people that do get depression relief from things like zoloft or paxil, or from bupriorin, find that the side effects, which include things like dry mouth, although more commonly reductions, or increases in appetite, or vast reductions in libido, or changes in their sleep patterns, etc., that those side effects really make it impossible, or at least very uncomfortable for them to take those drugs.

现在，有些人很幸运，他们可以使用足够低或足够高的药物剂量来缓解抑郁症状，而不会出现让他们觉得不舒服的副作用，以至于宁愿不服用这种药。然而，很多使用抗抑郁药物如左洛复或帕罗西汀，以及安非他酮获得抑郁症缓解的人，发现这些药物的副作用，比如口干，或者更常见的是食欲变化、性欲大幅降低、睡眠模式变化等，使得他们无法或至少在服用这些药物时感到非常不舒服。

And of course, there are the 60% of depressed people who do not respond to those drugs at all. Now, I want to be very clear. Things like SSRIs, things like well butroin have helped a tremendous number of people get relief from depressive symptoms, and in many cases have warded off suicidality as well. However, there are also a great number of people who have experienced a lot of side effects and problems from these drugs. Hence the desire to find other compounds that can treat depression without creating similar side effect profiles, and that ideally can provide relief not just for 40%, but for all people suffering from depression.

当然，还有60%的抑郁症患者对这些药物没有任何反应。现在，我想说得非常清楚，像SSRIs（选择性5-羟色胺再摄取抑制剂）和Wellbutrin这样的药物确实帮助了许多人缓解了抑郁症状，在很多情况下也预防了自杀的发生。然而，这些药物也让很多人经历了众多的副作用和问题。因此，人们渴望找到其他能够治疗抑郁症的化合物，这些新药物不仅不会产生类似的副作用，而且理想情况下可以为所有抑郁症患者提供缓解，而不仅仅是其中的40%。

So that's where ketamine enters the picture. Prior to the 1990s, they were mainly studied in neuroscience and pharmacology laboratories for their abuse properties, and for their anesthetic properties. So ketamine is a dissociative anesthetic. It's actually used to induce certain forms of anesthesia for surgery. It's not always used, but it's often used. This is something that if you've ever had a surgery, you might want to ask your anesthesiologist about, you know, what sorts of drugs are you giving me to go under, what sorts of drugs are you keeping me to stay under, and maybe even what sorts of drugs are you giving me to bring me out of anesthesia?

这就是氯胺酮的用武之地。在20世纪90年代之前，氯胺酮主要在神经科学和药理学实验室中被研究，主要关注其滥用特性和麻醉特性。氯胺酮是一种解离性麻醉剂，实际上用于诱导某些外科手术的麻醉状态。虽然不总是使用，但却经常被采用。如果你曾经接受过手术，你可能想询问麻醉师，你将使用哪些药物让我进入麻醉状态，是哪些药物保持这种状态，又有哪些药物帮助醒过来。

Because it turns out that when you go into anesthesia, your anesthesiologist is rarely giving you just one drug. Typically they're giving you one drug to, you know, kill off a little bit of anxiety and maybe eliminate a little bit of pain sometimes, and then they'll give you another drug to drop you into a deeper plane of anesthesia. And then nowadays, there are sophisticated ways to monitor your plane of anesthesia, and there are sophisticated ways to, if necessary, get you out of a deep plane of anesthesia if that plane of anesthesia is too deep.

因为事实证明，当你进行麻醉时，麻醉师很少只给你一种药物。通常，他们会给你一种药物，以减轻一些焦虑，有时也能减轻一些疼痛。然后，他们会再给你另一种药物，让你进入更深层次的麻醉状态。现在，有先进的方法来监测你的麻醉深度，如果麻醉过深，还有先进的方法来让你脱离过深的麻醉状态。

When I talk about a plane of anesthesia, I'm just talking about going from full wakefulness to, you know, a reduction in anxiety, to falling asleep, to a sleep, to the point where even if someone were to pinch your toe or your arm, like a really intense pinch, that you wouldn't wake up from that. Okay. So ketamine has the property of being an anesthetic. It kills the response to pain, and at certain doses, it can bring you into deep planes of anesthesia, at lesser dosages.

当我谈及麻醉的层面时，我指的是从完全清醒到逐渐放松、减少焦虑，再到入睡、深度睡眠的过程，甚至达到即使有人大力捏你的脚趾或手臂，你也不会因此醒来的程度。好的。那么氯胺酮具有麻醉的特性，它可以消除对疼痛的反应，并且在一定剂量下，可以让人进入深度的麻醉状态，而在较低剂量下，则不会如此。

It can take you into transition points between awake and deeply anesthetized. And it's really that transition point between awake and deeply anesthetized, which we are going to call the dissociative state. It's kind of this liminal state, a little bit like dreaming. It can have some dreamlike qualities to it. That's the state that has most often been sought after or employed for the treatment of depression, suicidality, and PTSD, which brings up a really important point, which is that when people use ketamine recreationally, it's not clear exactly what plane of anesthesia or dissociation they are actually seeking.

它可以将你带入清醒和深度麻醉之间的过渡状态。我们将这种从清醒到深度麻醉的过渡状态称为解离状态。这是一种类似梦境的边缘状态，有时具备一些梦幻般的特征。这个状态通常被用于治疗抑郁症、自杀倾向和创伤后应激障碍（PTSD）。这也引出了一个非常重要的问题，那就是当人们娱乐性地使用氯胺酮时，并不明确他们实际上在寻找哪种麻醉或解离的状态。

And this is why we hear about some of the desired effects of ketamine that are driving people to use it recreationally. And why we also hear about people having some unpleasant or even very unpleasant or dangerous experiences when using ketamine recreationally. Because we're talking about a drug that has a lot of different effects depending on the dosages, and as we'll soon talk about, individuals vary tremendously in their response to different dosages of ketamine, and the delivery route for ketamine, whether or not it's delivered early in the form of a pill or put sublingually in what's called a trosh that dissolves under the tongue or it's injected, or then that's injected into the vein or intramuscularly, etc. Each of those can produce very different effects in terms of the speed of onset of the drug and the type of effects that it produces in the brain and body.

这就是为什么我们听说有人因为一些理想的效果而娱乐性使用氯胺酮。同时，我们也听到有人在娱乐性使用氯胺酮时遇到不愉快、甚至非常不愉快或危险的体验。原因在于氯胺酮在不同剂量下会产生许多不同的效果，并且个体对不同剂量的反应差异很大。氯胺酮的给药方式也有很多，比如以药片形式早期摄入、舌下含化的片剂、或者注射，比如静脉注射或肌肉注射等。每种方式都会对药物的起效速度以及它在大脑和身体中产生的效果带来很大的不同。

So what happened in the early 90s is that laboratories that were studying animal models, what we call pre-clinical models of things like depression and learning and memory, and to some extent ketamine, but mainly focusing on learning and memory and depression, made an interesting discovery. There's a certain pre-clinical model of depression that's pretty common in laboratories that involves taking a rat or a mouse and putting it into a small container, like it looks like a beaker or a jar, sometimes it's a tray and it has water in it. And you might be surprised to learn, perhaps not, that if you put a rat or a mouse into water, it will swim.

在90年代初，研究动物模型的实验室，也就是我们所说的用于研究抑郁症和学习记忆的临床前模型的实验室，甚至有些研究氯胺酮，做出了一个有趣的发现。实验室中有一种很常见的抑郁症临床前模型，这个模型的做法是将老鼠放入一个小容器中，这个容器看起来像一个大烧杯或罐子，有时是一只装水的托盘。可能会让你感到惊讶（也可能不会），那就是如果你把老鼠放进水里，它会游泳。

Okay, so it's treading water in order to keep its head above water and not drown. I realize for some of you this might be a bit of an aversive topic to hear about animal research, but this is one of the common pre-clinical models of depression, which is put a rat or a mouse into water, let it swim and see at what point it gives up. Because what happens is if you put a rat or mouse into water, it will attempt to save its own life by swimming, but at some point it will just give up and it will just start sinking.

好的，所以它正在原地划水，以保持自己不被淹没。我知道对于你们中的一些人来说，谈论动物实验可能是个有点让人反感的话题，但这是一种常见的抑郁症前期临床模型，就是把一只老鼠或鼠类放入水中，让它游泳并观察它在什么时刻放弃。因为如果你把一只老鼠放进水里，它会试图通过游泳来自救，但在某个时刻，它会放弃并开始下沉。

And then of course the researcher needs to rescue the rat or mouse, put it back into its home cage, dry it off, give it some food, et cetera. This pre-clinical model is called the model of learned helplessness. And it's become a prominent pre-clinical model of depression because, of course, we can't ask mice or rats if they are depressed or happy. I suppose you can ask them, but they're not going to answer in any kind of meaningful way. So we can only look at their behavior in order to understand whether or not they have a sense of happiness or a sense of depression.

然后，研究人员当然需要救助老鼠或小鼠，把它放回它的笼子里，给它擦干，喂些食物，等等。这种临床前模型被称为习得性无助模型。它成为了一种重要的抑郁症临床前模型，因为我们无法直接询问老鼠或小鼠是否感到抑郁或快乐。当然，你可以问它们，但它们不会用任何有意义的方式回答。所以，我们只能通过观察它们的行为来了解它们是否有快乐感或抑郁感。

And of course that's very hard to gauge in an animal model of any kind. You could make guesses based on other behaviors like are they grooming regularly or they eating regularly, you know, things that more or less parallel what we think of as health or lack of health in a human who's happy or depressed, but in the context of trying to understand depression in these pre-clinical animal models, having a behavior that you can really quantify carefully across a lot of different animals and conditions is really beneficial.

当然，在任何动物模型中要衡量这一点都是非常困难的。你可以根据其他行为来做出猜测，例如它们是否定期梳理毛发或正常进食，这些行为或多或少与我们认为人类健康或不健康、快乐或抑郁的状态相似。但在试图理解这些临床前动物模型中的抑郁症时，拥有一种可以在许多不同动物和条件下仔细量化的行为是非常有益的。

So this thing of putting a rat or mouse into water and seeing how long it takes before they give up to save their own life is called the model of learned helplessness. And what it allowed researchers to do was to take rats and mice, put them into water, see how long it took before they gave up, and then to give them different drugs to see whether or not any of those drugs either hastened, sped up, or prolonged the duration over which the animal would attempt to save its own life. This actually has some meaningful parallels to human depression. You know, one of the hallmarks of depression is that people stop thinking positively about their future. Depression of course can include a lot of other symptoms. You know, one of the most prominent symptoms of depression, for instance, is consistently waking up around 2.30 or 3.30 in the morning and not being able to fall back asleep again.

这种将老鼠或大鼠放入水中并观察它们在放弃自救前能坚持多久的实验被称为习得性无助模型。这种实验方法让研究人员能够通过将老鼠放入水中观察它们的坚持时间，然后给予它们不同的药物，来判断药物是否会加速、减慢或延长动物自救的时间。这个实验实际上与人类的抑郁症有一定的相似之处。大家知道，抑郁症的一个显著特征就是人们不再对未来抱有积极的想法。当然，抑郁症还包括许多其他症状，其中之一就是经常在凌晨2点半或3点半醒来，之后再也无法入睡。

Now keep in mind, it is not the case that if you're waking up at 2.30 or 3.30 in the morning and you can't fall back asleep, that you are absolutely depressed. That's simply not the case. But that pattern of lack of sleep plus some other things like lack of anticipation of a positive future, inability to imagine the future in any kind of meaningful or positive way, etc. are part of the key features of what we call a major depressive episode. So this preclinical model of learned helplessness allowed researchers to test a lot of different drugs and establish which drugs at which dosages allowed animals to fight for their life longer when placed into water. It's really that simple as a model, but it revealed some very interesting things.

请记住，如果您凌晨两点半或三点半醒来后无法再次入睡，这并不一定表示您就是抑郁了，事情并不是这样简单。不过，缺乏睡眠的这种模式，再加上一些其他因素，比如对美好未来的缺乏期待，无法以任何有意义或积极的方式想象未来等，都是我们所说的重度抑郁发作的一些关键特征。因此，这种习得性无助的临床前模型让研究人员得以测试许多不同的药物，并确定哪些药物和剂量能让动物在被放入水中时坚持求生更长时间。这个模型其实很简单，但揭示了一些非常有趣的事情。

At least one of which is that when animals were injected with ketamine, this dissociative anesthetic, but they were injected with dosages of ketamine that were below what would induce full anesthesia, these animals would swim for their life for a lot longer. Now to some extent, that ought to be surprising and in fact was surprising to researchers because ketamine is what's called an NMDA receptor blocker. Now when I say blocker, I'm not getting into the details of what specific form of blocker it is, but I do want to mention that a blocker is sometimes referred to as an antagonist, whereas something that promotes the activity of a receptor is called an agonist.

至少其中一个发现是，当动物被注射了氯胺酮这种解离性麻醉药时，尽管注射的剂量低于引起完全麻醉的水平，这些动物在游泳测试中表现得更加顽强，存活时间更长。这种现象让研究人员感到惊讶，因为氯胺酮是一种NMDA受体阻断剂。这里所说的“阻断剂”并没有深入到具体类型，但值得提到的是，阻断剂有时也被称为拮抗剂，而增强受体活动的物质则称为激动剂。

So if you can just remember that ketamine is an NMDA receptor antagonist or blocker, then you should be fine for the rest of today's conversation. Now I haven't told you what NMDA is. NMDA stands for N-methodespartate and you do not need to remember that, but the surprise for researchers was that this drug ketamine is allowing animals to fight for their life for longer. So it has this sort of property of overcoming what we call learned helplessness or a sense of helplessness, aka antidepressant effects. And we also know that it's an NMDA receptor antagonist or blocker and that's perplexing because we also know that the NMDA receptor is critical for changing neural circuitry in the brain.

所以，只要你记住氯胺酮是一种NMDA受体拮抗剂或阻断剂，你就可以顺利理解今天后面的讨论。我还没告诉你什么是NMDA，NMDA代表N-甲基-D-天冬氨酸，你无需记住这个。但研究人员感到惊讶的是，这种药物氯胺酮可以让动物在求生时坚持更长时间。它有一个特性，就是能克服被称为习得性无助或无助感的状态，也就是具有抗抑郁作用。我们也知道它是NMDA受体的拮抗剂或阻断剂，这令人困惑，因为我们也知道NMDA受体对于改变大脑的神经回路很重要。

It's critical for neuroplasticity. So put differently, here's a drug that blocks the receptor that's critical for neuroplasticity for changes in the brain and yet somehow it's allowing these animals to fight for their life longer. It's somehow giving them more of a sense of hope. At least that's the subjective interpretation of what one observes when a mouse or rat is swimming for much longer when it would otherwise just give up and sink to the bottom of the vessel. Now in general, there are two kinds of scientists. There are scientists that take a look at a set of findings like that and say, oh, here's a drug that's supposed to be terrible for us. It's an anesthetic and it blocks NMDA receptors and NMDA receptors are good for neuroplasticity and somehow it's also allowing these animals to swim longer.

这对于神经可塑性至关重要。换句话说，这是一种药物，它阻断了对大脑变化至关重要的受体。然而，这种药物却能让这些动物挣扎求生更长时间，并且似乎赋予它们更多的希望感。至少，当观察到一只老鼠或大鼠坚持游泳更长时间而不是放弃并沉到容器底部时，这是一种主观解读。通常来说，有两类科学家。一类是看到这样的研究结果后，会说：“哦，这是一种对我们可能有害的药物。它是一种麻醉剂，会阻断对神经可塑性有益的NMDA受体，但不知为何，它也让这些动物游得更久。”

And I would say one category of scientists would just look at that and just say, wow, that is a big ball or tangle of confused facts. How does one even reconcile that? Brain change ought to be good and perhaps even lie at the heart of our ability to recover from depression. This is drug that blocks neuroplasticity but somehow is relieving depression. I'm going to walk away from that. I'm going to work on something far simpler. And then there's this other category of scientists which thank goodness exists who looks at that apparent contradiction of, okay, there's a drug which blocks plasticity. Plasticity is thought to be important for getting over depression and yet the drug can provide some relief from depression, at least in these preclinical animal models.

我会说，有一类科学家看到这种情况时会感叹，这真是一团混乱的事实，我们该如何理解呢？大脑的变化应该是有益的，可能甚至是我们从抑郁中恢复的关键。然而，这种药物却阻止了神经可塑性，但却在某种程度上缓解了抑郁。我决定放弃这个问题，去研究一些更简单的东西。但还有另一类科学家，幸好他们存在，他们面对这种表面上的矛盾：一种药物阻止了可塑性，而可塑性被认为对克服抑郁很重要，但这种药物在临床动物模型中却能减轻抑郁症状。

And they say, hmm, I like a good puzzle, right? The more complex the puzzle, the more interesting. And they start digging in with preclinical studies and they start talking to clinicians who are treating patients for depression. And like I said, thank goodness these sorts of scientists exist and thank goodness they did that because it turned out that when clinicians tried ketamine in depressed patients as a means to relieve depression, it had remarkable effects.

他们说，嗯，我喜欢一个好的谜题，对吧？谜题越复杂，就越有趣。他们开始通过临床前研究深入研究，并开始与治疗抑郁症患者的临床医生交流。就像我说的，感谢这些科学家的存在，也感谢他们做了这些研究，因为当临床医生尝试用氯胺酮来缓解抑郁症患者的症状时，结果非常显著。

So it was about the year 2000 when the first sets of papers about the clinical use of ketamine for the treatment of depression started to emerge. Now, we have to remember the context in which all of this was happening. Knowing 2000 drugs like Prozac and some of similar SSRIs, selective serotonin reuptake inhibitors, things like well butrin, were really hitting the market in full force. And as we talked about earlier, some people were getting relief, some people were getting relief with a lot of side effects and therefore deciding not to take those drugs and a lot of people, the majority of people that were taking those drugs were not getting relief.

大约在2000年，关于氯胺酮用于抑郁症治疗的第一批临床研究论文开始出现。我们需要记住当时的背景。早在2000年前后，像百忧解（Prozac）这种选择性5-羟色胺再摄取抑制剂（SSRI），以及一些类似的药物，如Wellbutrin，正大规模进入市场。正如我们之前所讨论的，有些人服用这些药物后感觉症状得到缓解，有些人虽有缓解却伴随严重的副作用，因此选择停止用药。而大多数服用这些药物的人并没有获得症状缓解。

So there was a real urgent need to find other drugs for the treatment of depression. And ketamine, at least based on its apparent profile of being a dissociative anesthetic, would seem like the last drug that you'd want to use to treat depression, right? It dissociates people even here about dissociation as a symptom of depression. And yet, what happened was a small number of very pioneering clinicians started to explore the use of ketamine in the clinic for the treatment of depression and in particular for depression that did not respond to any other treatment.

因此，我们迫切需要找到其他药物来治疗抑郁症。而氯胺酮，至少从它作为一种解离性麻醉药的特性来看，似乎是用于治疗抑郁症的最后一种选择，对吧？它会导致人出现解离，而解离也是抑郁症的一种症状。然而，一些非常有先见之明的临床医生开始在临床上探索使用氯胺酮来治疗抑郁症，特别是对那些对其他治疗没有反应的抑郁症患者。

So there was a real critical need to find other compounds and a bit more motivation to test some of these, let's call them atypical compounds for the treatment of depression. One of the first landmark papers in the use of ketamine for the treatment of depression is entitled Anti-depressant Effects of Ketamine in Depressed Patients. This is a paper that I provided a link to in the show note captions. It's a small study, okay? So it doesn't involve many subjects at all. Really just has seven subjects, all of whom had major depression.

因此，迫切需要寻找其他化合物，并有更多动力去测试一些我们可以称之为非典型的化合物，用于治疗抑郁症。在使用氯胺酮治疗抑郁症方面的首批重要论文之一是《氯胺酮对抑郁患者的抗抑郁效果》。我在节目笔记中提供了这篇论文的链接。这是一项小规模的研究，所以参与的对象并不多。实际上只有七名受试者，且他们皆患有重度抑郁症。

And they did intravenous injections with half a milligram per kilogram of body weight of ketamine. Now that dosage, half a milligram per kilogram of body weight turns out to be very important for today's discussion, because it's going to serve as a reference point for later discussions when we get into other modes of delivery of ketamine, such as oral pill form ketamine or sublingual ketamine. And as it relates to things like the K-hole or the dissociative state or the various effects that ketamine can have depending on the dosage and the delivery route.

他们进行了静脉注射，使用的剂量是每公斤体重半毫克的氯胺酮。这个剂量在今天的讨论中非常重要，因为它将作为一个参考点，帮助我们理解其他服用氯胺酮的方式，如口服药片形式或舌下含服的氯胺酮。同时，这也涉及到剂量和服用方式如何影响氯胺酮的不同效应，如“K洞”或分离状态等。

Meanwhile, going back to this study, what they found is that when they injected patients with severe depression with ketamine, the effects of ketamine took place within minutes within 10 or 15 minutes and that they experienced a sort of peak euphoric state, okay? So they're not inducing deep anesthesia, right? At this dosage, they're getting people into a kind of euphoric, dreamy, semi-dissociative state. That occurred within 15 minutes and really peaked about 45 minutes to an hour after they were injected with the drug. And that the total effects of the drug in terms of euphoria were effectively over by about two hours or so.

同时，回到这项研究，他们发现当对重度抑郁症患者注射氯胺酮时，药效在几分钟内显现，大约10到15分钟内，患者会体验到一种高峰的欣快状态。要注意的是，他们并没有让患者进入深度麻醉状态。在这种剂量下，患者会进入一种欣快、做梦般的半解离状态。这种状态发生在注射后的15分钟内，并在45分钟到一小时左右达到顶峰。而欣快的总体效果大约在两小时左右基本消退。

And that time course of effects makes perfect sense. If you look at, say, the half life of ketamine, which is how long it takes for half of the drug to be active in the system, etc. But what was really interesting about this study and others like it is that the patient's experience, relief from their depression almost immediately after taking the drug. So within minutes to hours and that it persisted for several days after taking the ketamine, okay? So the dissociative euphoric, dreamlike effects of ketamine take place very quickly. They're very, very salient, right? The person basically is just lying there experiencing this euphoric, dreamlike dissociative state.

这种效果的时间进程非常合乎情理。比如说，如果你看一下氯胺酮的半衰期，也就是这种药物在体内活跃的一半时间。这项研究及类似研究中真正有趣的是，病人在服用药物后几乎立即就体验到了抑郁症状的缓解，可能是在几分钟到几个小时内，而且这种效果在服用氯胺酮后可以持续几天。氯胺酮的解离性欣快和梦境般的效果出现得非常快，非常显著。基本上，使用者会躺在那里，经历这种欣快、梦幻般的解离状态。

And they get some relief from their depression immediately. And yet there's persistent relief from that depression, which lasted at least three days out from the treatment. Now, a key theme of today's discussion is going to be that the antidepressant effects of ketamine appear to be fairly short-lived, at least when one is exploring one or two treatments with ketamine. In other words, the typical contour is that people will take ketamine, get this euphoric dreamlike dissociative effect, come out of that feeling some immediate relief from their depression.

他们立即从抑郁中得到了一些缓解。然而，这种缓解仍然持续，至少在治疗结束后的三天内有效。今天讨论的一个关键主题是，氯胺酮的抗抑郁效果似乎相对短暂，尤其是在仅进行一两次治疗时。换句话说，通常的情况是，人们服用氯胺酮后，会体验到一种欣快的梦幻般的解离效果，从中恢复过来后，他们的抑郁状态得到了一些即刻的缓解。

This is one of the things that makes ketamine an incredibly attractive drug for the treatment of depression, especially depression that hasn't responded to other forms of treatment, which is that people get relief very, very quickly. Indeed, the same day that they initiate the treatment. Now, this is especially important when you think about the fact that the monoamine hypothesis of depression, which drove the discovery and development of all these drugs like SSRIs, wellbutrin, etc. Those drugs often can provide support for people with depression. Again, only 40% of people get true relief from their depression. And again, there are some side effect issues or major side effect issues in some cases that have to be dealt with. But even the positive effects, even under the best conditions, oftentimes those effects don't kick in for weeks or months after somebody initiates taking the drug.

这就是为什么氯胺酮被认为是治疗抑郁症的一个非常有吸引力的药物，尤其是对那些对其他治疗方法没有反应的患者。因为患者在开始治疗的当天就能迅速得到缓解。这一点尤为重要，尤其当你想到抑郁症的单胺假说时。这一假说推动了像SSRIs（选择性5-羟色胺再摄取抑制剂）、Wellbutrin等药物的发现和开发。这些药物常常能帮助抑郁症患者，但只有40%的患者真正感受到抑郁症的缓解。此外，这些药物在某些情况下可能会产生一些严重的副作用，必须加以处理。然而，即便是这些药物在最理想的情况下发挥正面作用，通常情况下效果也是在开始服用药物的几周或几个月后才显现出来。

Now, that might not seem like a long time to wait for some of you. But if you are somebody suffering from depression, even another day, even another hour with depression, seems almost unmanageable. And sadly, many people who have these forms of depression will go on to commit suicide. So it is ever so important that there be rapid treatments for depression, even same day treatments for depression. And based on the study, it appeared that ketamine was, and indeed still remains, that drug. Now, I certainly don't want to position ketamine in your mind as a miracle drug for depression. In fact, I don't actually believe in miracle drugs. I don't think that there is any compound that alone can produce all the desired effects that one wants without any negative effects in a way that could warrant calling it a miracle drug. That's just not how biology works.

现在，对于某些人来说，这可能感觉并不是很长的等待时间。但是，如果你正遭受抑郁症的困扰，那么即使再度过一天，甚至再度过一小时，似乎都几乎无法忍受。更令人痛心的是，许多有这种抑郁症状的人最终会选择自杀。因此，为抑郁症提供快速治疗，甚至是当天治疗，是极其重要的。根据研究，氯胺酮显示出在这方面的效果，实际上它仍然是这种药物。当然，我并不想把氯胺酮描述为你心目中治疗抑郁症的神奇药物。事实上，我并不相信神奇药物。我认为没有任何一种化合物能够仅凭一己之力产生所有理想效果而没有任何负面作用，以至于可以被称为神奇药物。这并不是生物学的运作方式。

There's always an interplay between pharmacology, between our behaviors and what we choose to do or not do. This is a topic we'll get into a little bit later when we talk about antidepressive behaviors and the role of ketamine in bringing about antidepressive behaviors for the relief of depression. Now, with that said, the study that I just mentioned, as well as many, many other studies that followed, emphasize that ketamine could provide significant decreases in not just depression and suicidality, but also the feelings of helplessness and worthlessness that are associated with major depression. And again, it could do that in people that also were not responding to other forms of depression treatment, such as SSRIs, etc.

药理学、我们的行为以及我们选择做或不做的事情之间总是存在相互影响。当我们稍后讨论抗抑郁行为以及氯胺酮在减轻抑郁症中的作用时，会深入探讨这个话题。就像我刚提到的研究以及许多后续研究都表明，氯胺酮不仅可以显著减少抑郁和自杀倾向，还能减轻与重度抑郁相关的无助感和无价值感。此外，它对那些对其他抗抑郁治疗方式（如SSRIs等）无反应的人也同样有效。

So while we don't want to call it a miracle drug, ketamine turned out to be and remains an incredible drug for the treatment of depression in certain cases. Now, in addition to that, ketamine has been shown in clinical studies to provide relief not just for treatment resistant depression of the major depression type. There's many different forms of depression, but major depression is the one that we're normally thinking about or referring to when we talk about depression. But ketamine has also been shown to be effective in treating bipolar depression, sometimes called bipolar disorder, although more commonly nowadays called bipolar depression. I did an entire episode, by the way, on bipolar depression, if you want to know what it is and what it isn't, how it differs from borderline personality disorder, etc.

因此，虽然我们不想称其为“奇迹药物”，但氯胺酮确实被证明是治疗某些抑郁症病例的极佳药物。此外，临床研究表明，氯胺酮不仅对重度抑郁症的耐药性抑郁有效。抑郁症有很多不同类型，但“重度抑郁症”是我们通常谈论或提到抑郁症时所指的。然而，氯胺酮也被证明对治疗躁郁症（有时称为双相情感障碍，但现今更常称为双相抑郁症）有效。顺便提一下，我做过一期关于双相抑郁症的完整节目，如果你想了解它是什么以及不是什么，以及它如何与边缘性人格障碍不同等内容。

You can go to HubertmanLab.com, just put into the search function, bipolar, and it will take you to that episode. Ketamine has also been shown to be useful for the treatment of PTSD and for OCD, obsessive compulsive disorder and for anxiety and for various forms of substance addiction. So ketamine is not a miracle drug, but it does seem to have broad application and to be very successful for the treatment of a lot of major psychiatric challenges. Now, just because ketamine has shown these incredible applications, it also has some serious problems that are directly related to how it works in the brain or at least from what we understand of how it works in the brain.

你可以访问HubermanLab.com，只需在搜索功能中输入“bipolar”（双相情感障碍），它会带你到相关的节目。研究显示，氯胺酮对治疗创伤后应激障碍（PTSD）、强迫症（OCD）以及焦虑和各种形式的物质成瘾也有帮助。所以，虽然氯胺酮并不是神奇药物，但在治疗许多重大精神问题上，它展现出广泛的应用和不错的疗效。然而，尽管氯胺酮有如此显著的应用效果，它也存在一些严重的问题，这些问题直接与其在大脑中的作用机制有关，或至少是基于我们对其在大脑中作用方式的理解。

And what I'm referring to here is yes, ketamine is very rapid acting. It can often provide relief from depression almost immediately, meaning same day. However, it is very short-lived after about three days or a week or so, the antidepressant effects of ketamine often wear off. So that creates a situation where people perhaps need to take ketamine every week. And yet, it creates enough of a dissociative state, meaning it takes people enough out of their normal daily routine that the prospect of people taking ketamine every week is actually not that feasible.

我这里所说的是，没错，氯胺酮的作用非常迅速。它常常能几乎立刻缓解抑郁症状，也就是说，当天就能见效。然而，它的抗抑郁效果维持时间很短，通常在三天或一周左右效果就会消失。这就造成了一种情况：人们可能需要每周都服用氯胺酮。但是，氯胺酮会让人产生一种解离状态，使他们无法正常进行日常活动。因此，每周都服用氯胺酮其实并不太现实。

And also because of some of the propensity for ketamine to become a drug of abuse, that is for it to be habit forming and or addicting. One also worries that if people are doing ketamine every week to treat their depression, that they can become so-called hooked on ketamine. Now, fortunately, there have been studies of ketamine and how it works, not just in the short term, but in the longer term, that have led to some very important clinical studies that have explored, for instance, people taking ketamine twice per week for a duration of three weeks total. And what they find is that yes, after the first time they take it, they get some relief from depression. They take it a second time that week, they get some relief from depression. And they do the same thing the next week and the next week. And when they do that, they get relief from depression the whole way through that entire three weeks.

由于氯胺酮具有一定的滥用潜力，即可能导致成瘾，人们担心如果每周都使用氯胺酮来治疗抑郁症，可能会对其产生所谓的依赖。但值得庆幸的是，已经有关于氯胺酮如何发挥作用的研究，不仅仅是短期的，还有长期的。这些研究推动了一些重要的临床试验，比如让人们每周使用两次氯胺酮，共持续三周。研究发现，第一次使用后，他们就能感受到抑郁症状有所缓解。在同一周的第二次使用后，还有缓解效果。接下来的两周，继续以同样的方式，他们在整个三周期间都能持续感受到抑郁症状的缓解。

But it turns out that there's also some so-called durability to the effect such that if people do this twice a week dosing regimen, so ketamine twice a week for three weeks total, they find that when they end that three weeks, they get some ongoing relief from their depressive symptoms, which can extend months or more before they have to repeat that twice a week for three weeks regimen. Now, certainly not all studies of using ketamine for the treatment of depression have used that exact doses regimen twice a week for three weeks and take some time off repeat. Twice a week for three weeks take some time off repeat. Some have explored giving ketamine once per week or even three times per week or doing it once a week for five weeks and then taking an extended period of time off before repeating the treatment schedule.

结果表明，这种效果有一定的持续性。如果人们采用每周两次的给药方案，即连续三周每周给药两次，他们会发现结束这三周后，抑郁症状会持续得到缓解，这种效果可能持续数月甚至更长时间，然后才需要再次进行每周两次、连续三周的治疗。当然，并不是所有关于使用氯胺酮治疗抑郁症的研究都采用了这种固定的每周两次、连续三周的治疗方案。有些研究探索了每周给药一次或每周三次，或是每周给药一次持续五周，然后才进行长时间的休息后重复治疗计划。

There are a bunch of different studies out there. But when one looks at all of those studies and mass together, it's very clear that ketamine is providing relief from depressive symptoms immediately and in the days after the treatment. But that when those treatments are stacked fairly closely together, that there is some durability, some ongoing relief from depression. And what this tells us is very important. In fact, I hope everybody really highlight this in their minds as they're hearing it. It's very likely that ketamine is acting by at least two and probably three different mechanisms in order to provide relief from depression.

有很多不同的研究存在。当我们把这些研究放在一起看时，很明显，氯胺酮能立即缓解抑郁症状，并且在治疗后的几天内效果持续。但如果这些治疗相对紧密地进行，就能有一定的持久性，提供持续的抑郁缓解。这告诉我们一个非常重要的信息。事实上，我希望大家在听到这点时能重点记住这一点。很可能氯胺酮通过至少两种，甚至三种不同的机制来缓解抑郁症。

One of those mechanisms induces relief from depression very quickly and seems to be associated with that euphoric dissociative dream-like state that one experiences when they are under the influence of ketamine. The second mechanism seems to provide relief from depression in the days and weeks that follow the ketamine treatment. And there also appears to be a third mechanism by which ketamine can induce long lasting changes in the nervous system. And it is those three mechanisms, short, medium and long-term mechanisms that produce the kinds of changes in neurochemistry and more importantly changes in actual neural circuit wiring that allows ketamine to provide this incredible relief from depression.

其中一种机制可以非常快速地缓解抑郁症，并且似乎与人们在使用氯胺酮时所体验到的欣快、梦幻般的分离状态有关。第二种机制似乎是在氯胺酮治疗后的几天或几周中提供抑郁症的缓解。此外，还存在第三种机制，使氯胺酮能够在神经系统中产生持久性的变化。正是这三种机制——即短期、中期和长期机制——带来了神经化学的改变，更重要的是带来了实际神经回路连接的变化，这使氯胺酮能够提供显著的抑郁症缓解效果。

So next we're going to turn to what those mechanisms are because in understanding those mechanisms, you will understand how ketamine provides this relief from depression. But you'll also come to understand the more important broader theme of what depression is really all about at a neural circuit level and how relief from depression is all about neuroplasticity. As many of you know, I've been taking AG1 daily since 2012. So I'm delighted that they're sponsoring the podcast. AG1 is a vitamin mineral probiotic drink that's designed to meet all of your foundational nutrition needs.

接下来，我们将探讨这些机制是什么，因为通过了解这些机制，你会明白氯胺酮如何缓解抑郁。同时，你也会明白更重要的、更广泛的主题，即从神经回路的层面来看抑郁症究竟是什么，以及缓解抑郁症实际上是如何与神经可塑性有关。正如许多人所知道的，自2012年以来，我每天都在服用AG1。所以，我很高兴他们为本次播客提供赞助。AG1是一种含维生素、矿物质和益生菌的饮品，旨在满足你所有基础营养的需求。

Now of course I try to get enough servings of vitamins and minerals through whole food sources that include vegetables and fruits every day, but oftentimes I simply can't get enough servings. But with AG1, I'm sure to get enough vitamins and minerals and the probiotics that I need and it also contains adaptogens to help buffer stress. Simply put, I always feel better when I take AG1. I have more focus and energy and I sleep better and it also happens to taste great. For all these reasons, whenever I'm asked if you could take just one supplement, what would it be? I answer AG1. If you'd like to try AG1, go to drinkag1.com slash huberman to claim a special offer.

现在，我当然尽量每天通过蔬菜和水果等全食物来源摄取足够的维生素和矿物质，但很多时候我并没有摄取足够的份量。不过，有了AG1，我就能确保摄取到足够的维生素、矿物质以及我所需的益生菌，而且它还含有适应原，可以帮助缓解压力。简单来说，每当我服用AG1时，我总是感觉更好，我集中注意力的能力提高，精力充沛，睡眠质量也得到改善，而且它的味道也很棒。因此，每次有人问我如果只能选择一种补充剂，会选什么时，我的答案就是AG1。如果你想尝试AG1，可以访问drinkag1.com/huberman来获得一个特别优惠。

From now until August 12, 2023, AG1 is giving away 10 free travel packs plus a year supply of vitamin D3K2. Again, if you go to drinkag1.com slash you can claim the special offer of 10 free travel packs plus a year supply of vitamin D3K2. So how is ketamine really working? We already established that ketamine blocks the NMDA receptor and that the NMDA receptor is critical for many forms, not all, but many forms of neuroplasticity. Now I realize some of you might be familiar with so-called ligands and receptors, but most of you probably are not. A ligand is a chemical that binds to a receptor and a receptor is like a little parking spot on the outside of a cell. There can also be receptors inside of cells, but most of the time when we're talking about nerve cells, neurons, and you hear the word receptors, you're hearing about receptors on the outside of the cell.

从现在起到2023年8月12日，AG1将赠送10包免费旅行装及一年的维生素D3K2供应。再说一遍，如果你访问drinkag1.com，你可以领取这个特别优惠，获得10包免费旅行装及一年的维生素D3K2供应。那么，氯胺酮究竟是如何起作用的呢？我们已经知道氯胺酮能够阻断NMDA受体，而NMDA受体对于许多形式的神经可塑性（并非所有，但很多形式）都很关键。我知道有些人可能熟悉所谓的配体和受体，但大多数人可能不太了解。配体是一种能够与受体结合的化学物质，而受体就像细胞外的小停车位。细胞内也可能有受体，但大多数情况下，当我们谈论神经细胞和听到“受体”这个词时，我们指的是细胞外的受体。

So the NMDA receptor does not exist in our neurons in order to bind ketamine. It's there actually to bind all sorts of other things that are endogenous, that are naturally made by us, but ketamine has a very high what's called affinity. It has a very high probability of binding to the NMDA receptor if it's introduced to our bloodstream. So when ketamine is taken in pill form, sublingual form, meaning under the tongue, when it's injected into the muscle or the vein, it gets into the bloodstream and then it's able to cross easily across the blood brain barrier, a so-called BBB blood brain barrier. The blood brain barrier keeps a lot of things out of the brain, but ketamine can very readily pass across the blood brain barrier.

NMDA受体在我们的神经元中并不是为了与氯胺酮结合而存在的。它实际上是为了与我们体内自然产生的其他物质结合。然而，氯胺酮对NMDA受体有很高的亲和力，也就是说，如果氯胺酮进入我们的血液中，它与NMDA受体结合的可能性非常高。所以，当氯胺酮以药丸形式、舌下含服形式（即舌下）、肌肉注射或静脉注射的方式进入体内时，它会进入血液，并能够很容易地穿过血脑屏障（即所谓的BBB血脑屏障）。血脑屏障能阻挡许多物质进入大脑，但氯胺酮能非常容易地通过血脑屏障。

Once it's in the brain, it has a very high affinity for, meaning it knows how to seek out and bind to those NMDA receptors. Now, the simplest way to explain how NMDA receptors ordinarily contribute to neuroplasticity is that they represent what's called an AND gate. And an AND gate, as the name suggests, is a function in a cell or in a system where two things have to be present. In fact, for those of you that have a bit of an engineering or computer programming background, you'll be familiar with AND gates. For those of you that don't, don't worry about it. I'm going to explain what an AND gate is right now. An AND gate in the context of nervous system function is when two things are present, like chemical A and chemical B both have to be present in order for some process, say neuroplasticity to occur.

一旦进入大脑，它就具有很高的亲和力，也就是说，它知道如何寻找并结合到那些NMDA受体上。现在，最简单的方式来解释NMDA受体在神经可塑性中的作用是，它们起到了所谓的AND门的作用。AND门，顾名思义，是在一个细胞或系统中，需要两个条件同时满足的一个功能。对于那些有工程或计算机编程背景的人，你们可能会熟悉AND门。对于那些没有相关背景的人，也不用担心，我现在就来解释什么是AND门。在神经系统功能的背景下，AND门意味着需要两个条件同时存在，比如化学物质A和化学物质B都必须存在，某个过程（例如神经可塑性）才能发生。

The NMDA receptor, as I mentioned earlier, is a receptor on the surface of neurons and it binds glutamate, which is a molecule that we all make in our brain and it activates other neurons. It's what's called an excitatory neurotransmitter. Now, there are lots of different receptors for glutamate and those receptors are binding glutamate all the time. However, in order to activate the NMDA receptor, there has to be a lot of glutamate present and it has to happen over a very brief period of time. So the NMDA receptor is an AND gate in the sense that glutamate has to be present and to bind it and it has to get a lot of electrical activity, a lot of input in order for that to happen. So it's a receptor that responds primarily to unusually high or frequent levels of electrical activity.

NMDA受体，如我之前提到的，是位于神经元表面的一种受体，它能够结合谷氨酸，而谷氨酸是一种我们大脑中都会产生的分子，它可以激活其他神经元。这种化学物质被称为兴奋性神经递质。现在，谷氨酸有许多不同的受体，这些受体一直在结合谷氨酸。然而，为了激活NMDA受体，必须在很短的时间内存在大量的谷氨酸。因此，NMDA受体就像一个“与”门（AND门），需要谷氨酸存在并与其结合，而且还需要大量的电活动和大量输入才能实现。这意味着它主要对异常高或频繁的电活动水平做出反应。

Let's place this in real world context so that it makes a bit more sense. I like most all of you in moving my arms around a lot throughout the day. Now, as an adult, my motor cortex, the area of my brain that controls motor coordination of my limbs, has connections from my brain to my spinal cord, from my spinal cord to my muscles and that's what allows me to move my limbs. Under conditions of just moving my limbs and doing things throughout the day, drinking a cup of coffee or your bamaate, you know, walking outside to view some sunlight in the morning, doing the things that I do every single day and that I already know how to do. Glutamate is definitely involved in that process.

让我们把这个放到现实生活中来理解，这样会更容易明白。我和大多数人一样，一整天都会频繁地挥动手臂。现在，作为成年人，我的大脑中负责肢体运动协调的运动皮层已经形成了从大脑到脊髓、再从脊髓到肌肉的连接，这就是让我能够活动四肢的原因。在日常生活中进行肢体动作，比如喝咖啡或茶、早晨外出晒太阳等这些我每天都会做且已经熟悉的事情时，谷氨酸在这个过程中肯定起到了作用。

Glutamate binding to its other receptor types, which are called AMPA receptors for those of you that want to know, that's involved in that process. It's typical levels of activity. If, however, I were to sit down at this desk and be commanded to or decide to do some specific motor limb movement. Let's say, move my hand in a three dot sequence for those of you watching. You can see this for those of you that are listening. Don't worry about it. It's not very interesting to watch. The point is just that I'm going to put my finger down in one, two, three points on the desk and front of me and then three, two, one point coming back to me. Now, that's obviously a motor sequence that I can perform. I just did it.

谷氨酸与另一种受体结合，这种受体叫做AMPA受体，这是参与该过程的一部分。这是一种典型的活动水平。然而，如果我现在坐在这个桌子旁，并被要求或决定做一些特定的运动，比如，我把手以三个点的顺序移动。对那些在观看的人来说，你们可以看到，但对于在听的人来说，不用担心，这其实没有什么特别好看的。重点是，我会在我面前的桌子上按下一个、两个、三个点，然后再从三个、二个、一个点回来。这显然是一个我可以完成的肢体运动序列，而我刚刚也完成了这个动作。

So clearly, I can perform it. But if I were to do that for, let's say, an hour, what would happen is the neurons that are involved in generating that motor sequence of one, two, three, three, two, one, one, two, three, three, two, one would be active over and over and over again. And what would likely happen because of that unusual, frankly, motor behavior is that the neurons responsible for generating that motor behavior would be able to detect it as unusually frequent, unusually high levels of activity in the circuits that generate that behavior.

所以显然，我可以做到这一点。但如果让我连续做一个小时，比如说，一二三三二一，一二三三二一的动作，那负责产生这个动作序列的神经元就会一遍又一遍地活跃起来。由于这种不寻常的、坦白说是怪异的运动行为，这些负责产生这种运动行为的神经元可能会检测到它的活动频率异常高，并在该动作生成的神经回路中表现出极高的活跃程度。

And the increase in glutamate that's impinging on the neurons in that circuit would bind the NMDA receptor, making it change several important things. The first of which is that your nervous system is capable of changing, but that's an energetically demanding process. So the incredible thing about neuroplasticity is that when you generate an unusually high or just an unusual pattern of activity, motor activity, or you're hearing a new language, you're trying to learn that or you're navigating a new city, the neurons are firing in ways that are atypical for them and they are firing a lot more.

在这个回路中的神经元上，谷氨酸浓度的增加会与NMDA受体结合，从而引发一些重要的变化。首先，你的神经系统是能够改变的，但这个改变过程需要消耗大量能量。神经可塑性令人惊叹的地方在于，当你产生一种异常高或只是不同寻常的活动模式时，比如运动活动，或者你正在学习一门新语言，或者在一个陌生的城市中导航时，神经元的发射方式会与以往不同，并且发射的频率更高。

And so the neurons are going to bind glutamate, the NMDA receptor is going to be activated. And then downstream of NMDA receptor activation are a bunch of what we call intracellular processes. A bunch of things that happen in the cells to try and make that behavior occur again and again if needed, but without the huge energetic demand. You've experienced this before when you're trying to learn something and it feels sluggish, it feels hard, it's frustrating, and then eventually you learn it and it's very facile, it's very easy.

因此，神经元会结合谷氨酸，使NMDA受体被激活。NMDA受体激活后，会引发一系列我们称之为细胞内过程的反应。这些反应发生在细胞内部，旨在让这种行为在需要时能一次又一次地发生，而不需要消耗大量能量。你可能已经体验过这种情况：当你试图学习某个东西时，最开始感觉缓慢、困难而且让人沮丧，但最终你学会了它，这时你会发现它变得非常简单。

One of the reasons for that is that when the NMDA receptor is activated by these infrequent or unusual patterns of activity, it can then recruit other glutamate receptors, the more typical kind, the ampah type receptors to the cell surface. And then those receptors can simply bind the glutamate and allow that behavior to occur without this whole process that's involved in neuroplasticity having to engage and do things like build new proteins in the cell, build new machinery, etc.

其中一个原因是，当NMDA受体被这些不常见或异常的活动模式激活时，它能够招募其他类型的谷氨酸受体，即更常见的AMPA型受体到细胞表面。然后，这些受体可以直接结合谷氨酸，使这种行为可以发生，而无需神经可塑性过程的全面参与，也不需要进行诸如在细胞内生成新蛋白质或构建新结构等复杂操作。

So to just step back from this, the way to think about the NMDA receptor is that activation of the NMDA receptor only occurs under conditions of unusually high or simply unusual patterns of activity that the NMDA receptor yes controls neural activity in the immediate sense like when it's activated, it's changing the patterns of activity in the neuron, sure. But it also can engage gene expression and introduce new receptors to the cell, basically giving the cell the ability to then recreate the same patterns of activity without having to do it in such a metabolically demanding way.

为了更好地理解这个问题，我们可以这样来看NMDA受体：NMDA受体的激活仅在异常高或不寻常的活动模式下发生。当NMDA受体被激活时，它确实会直接影响神经元的活动模式。但是，它还可以影响基因表达，并在细胞中引入新的受体，这样一来，细胞就能够在不需要消耗大量能量的情况下，重新创造出相同的活动模式。

In fact, a good analogy for all of this is the way that muscles can hypertrophy, right? If you overload muscles properly through resistance training of any kind and then give them a period of rest, there's recruitment of specific things to the muscle fibers as well as recruitment of changes in the nerves that innovate that control the contraction of those muscles and then those muscles grow, they get stronger, etc. and they're able to function and use that new strength and new growth.

其实，这一切的一个很好类比是肌肉的肥大。通过任何形式的阻力训练，如果适当地对肌肉进行超负荷训练，然后给予它们休息期，就会有特定的元素被吸收到肌肉纤维中，同时也会对控制肌肉收缩的神经产生变化。随后，这些肌肉就会生长、变得更强壮等，从而能够更好地发挥功能并利用这种新的力量和增长。

And you don't have to damage those muscle fibers or trigger those adaptations over and over again to maintain them because you have this new capability. Now I realize that's a lot of details about NMDA receptors and neuroplasticity. But really if we needed to pick one biological mechanism that resides at the center of many, many important forms of neuroplasticity, it would be the NMDA receptor and its functions that I just told you about.

你不需要一遍又一遍地破坏那些肌肉纤维或触发那些适应性反应来维持它们，因为你已经具备了这种新的能力。我意识到涉及NMDA受体和神经可塑性的细节很多。但如果我们需要选择一种位于许多重要神经可塑性形式核心的生物机制，那就是我刚才提到的NMDA受体及其功能。

So now that you have that in mind that these NMDA receptors are critical at detecting unusual activity, making changes to cells so those cells can then respond to that activity in the future, you have in mind the conceptual basis for understanding how ketamine works. Because as I've mentioned several times already, ketamine is an NMDA receptor blocker antagonist.

所以，现在你明白了，NMDA受体在检测异常活动方面起着关键作用，并通过改变细胞让其能够在未来对这些活动做出反应。你已经掌握了理解氯胺酮工作原理的基本概念。正如我之前已经多次提到的，氯胺酮是一种NMDA受体阻断剂。

And yet we know that a lot of the changes in the brain that underlie the transition from a depressed state to a non-depressed state involve neuroplasticity. So what's going on there? Well, what's going on there turns out to be extremely interesting and you can understand it very easily if you understand that there are essentially two major types of neurons in the brain.

尽管如此，我们知道，许多促进从抑郁状态到非抑郁状态转变的大脑变化涉及到神经可塑性。那么，这是怎么回事呢？其实，这个过程非常有趣，而且如果你了解大脑中主要存在两种类型的神经元，你就可以很轻松地理解这个过程。

You have those excitatory neurons, meaning neurons that when they are activated electrically, they activate or excite other neurons. At least they try to. They release neurotransmitter into the synapse, which is the little gap between neurons. The neurons on the other side have receptors. They bind those neurotransmitters. In this case, glutamate, which is the major excitatory neurotransmitter in the brain.

你有那些刺激性神经元，也就是说，当它们被电激活时，会激活或刺激其他神经元。至少它们会尝试这么做。这些神经元会在突触（即神经元之间的小间隙）中释放神经递质。另一侧的神经元有受体，可以结合这些神经递质。在这种情况下，这些神经递质是谷氨酸盐，它是大脑中的主要刺激性神经递质。

And then there's a high probability that those other neurons will be excited that they will be electrically active. That's one major type of so-called neurotransmission in the brain. The other major type of neurotransmission in the brain is called inhibitory neurotransmission. Inhibitory neurotransmission involves neurons that release the neurotransmitter GABA, or sometimes also another molecule called glycine, but mostly GABA. When GABA is released, it has the property of reducing the probability that the next neuron will be electrically active. In fact, GABA's job is to bind the receptors on the next cell and to make it less electrically active. So we've got excitatory neurotransmission and we have inhibitory neurotransmission.

然后，很有可能这些其他的神经元会被激活，表现出电活动。这是大脑中所谓神经传递的一种主要类型。大脑中的另一种主要的神经传递类型称为抑制性神经传递。抑制性神经传递涉及释放神经递质GABA的神经元，有时也涉及另一种叫做甘氨酸的分子，但主要是GABA。当GABA被释放时，它会降低下一个神经元产生电活动的概率。实际上，GABA的作用是结合到下一个细胞的受体上，使其电活动性降低。因此，我们有兴奋性神经传递和抑制性神经传递两种机制。

And just to place inhibitory and excitatory neurotransmission into context, if you think about a condition like epilepsy, which involves seizures of either the smaller type called petite mal seizures or grand mal seizures, which are the type in which people have body-wide convulsions. They are often disengaged from whatever is going on around them in those moments. They're shaking quite a lot, etc. There are many causes of seizures, but to get to the heart of what a seizure is, it is essentially runaway excitation in the brain. A small region of the brain becomes especially electrically active. And then it spreads out from that foci, that focus of the excitation, and it recruits a lot of neurons in a fairly non-specific way, creating these seizure-like motor patterns in the body and patterns of activity in the brain that can involve disengagement from immediate experience and lack of perception.

为了将抑制性和兴奋性神经传递放入背景中来理解，我们可以考虑像癫痫这样的情况。癫痫包括两种类型的发作：较小的称为小发作，或者较大的称为大发作，后者表现为全身抽搐。在这些时刻，患者往往对周围环境失去感知，身体剧烈颤抖等。癫痫发作的原因有很多，但从根本上说，癫痫发作本质上是大脑中过度的兴奋。是由于大脑的一个小区域变得异常活跃，然后这种兴奋从这一小区域扩散开来，以一种相对非特异性的方式激发大量的神经元，导致身体出现类似抽搐的运动模式和大脑中的活动模式，这可能包括对周围环境失去感知和缺乏感知能力。

Sometimes there's aura. There's a whole discussion to be had about seizure. And by the way, seizure can occur in a lot of different contexts. Of course, it can occur in epilepsy, it can occur after head injury, etc. We'll cover seizure in a future episode of this podcast, of course. But one of the major causes of seizure, and by extension, lack of seizure, is that ordinarily, inhibitory neurons and excitatory neurons are in this kind of push-pull that for somebody that doesn't experience seizures, puts the brain in balance. So they don't have seizures, right? The inhibitory neurons are suppressing the activity of many neurons so that those many neurons don't get runaway excitation. You don't get seizures. The excitatory neurons are feeding back onto the inhibitory neurons, so everything is kept in balance. There isn't too much inhibition. There isn't too much excitation. Everything's in balance.

有时候会有先兆，对于癫痫这个话题有很多可以讨论的地方。顺便说一句，癫痫可以在很多不同的情况下发生。当然，它可以在癫痫病中出现，也可以在头部受伤后发生等等。当然，我们将在这个播客的未来一期中讨论癫痫。但癫痫发生的一个主要原因，也就是说没有癫痫发作的原因，是通常情况下，抑制性神经元和兴奋性神经元处于一种此消彼长的状态。对于那些不经历癫痫的人来说，这种状态让大脑保持平衡，所以他们不会癫痫发作。抑制性神经元会压制许多神经元的活动，以防止这些神经元过度兴奋，从而避免癫痫发作。而兴奋性神经元会反馈给抑制性神经元，使一切保持平衡。没有过多的抑制，也没有过多的兴奋，一切都在平衡中。

Okay, so now you understand that there are NMDA receptors, and these are critical for many forms of neuroplasticity. You also understand that there are excitatory neurons which stimulate the electrical activity of other neurons, and that there are inhibitory neurons in your brain, that inhibit or suppress the activity of other neurons, and that you need excitatory and inhibitory communication between neurons at all times, and that it has to remain in balance, and that the NMDA receptor is normally just sort of sitting there, not doing a whole lot, unless levels of neural activity are elevated above their normal baseline, and then you can get changes in the neural circuits, and those changes can be very long-lasting.

好的，现在你明白了，NMDA受体对于多种形式的神经可塑性是非常重要的。你也知道在大脑中，有兴奋性神经元，它们能够刺激其他神经元的电活动；还有抑制性神经元，它们会抑制或压制其他神经元的活动。兴奋性和抑制性神经元之间的交流是随时需要的，而且必须保持平衡。NMDA受体通常处于一种不怎么活跃的状态，除非神经活动水平高于正常的基线水平，这时候神经回路才会发生变化，并且这些变化可能会持续很长时间。

Let's not forget the piece of information, most pertinent to today's discussion, which is about ketamine, which is that ketamine blocks that NMDA receptor. There's the conundrum I keep coming back to, which is you need neuroplasticity in order to get relief from depression. What researchers have discovered is that, yes, ketamine blocks the NMDA receptor. It actually quiets down neurons. It prevents neurons from being as active as they normally would be, and yet somehow, almost paradoxically, it increases neuroplasticity in brain circuits that are involved in mood and reward, in self-reflection. We'll get into what those brain circuits are in a little bit.

让我们不要忘记今天讨论中最相关的一条信息，那就是关于氯胺酮（Ketamine）的。氯胺酮阻断了NMDA受体。这个问题让我一直回头思考，那就是你需要神经可塑性来缓解抑郁症。研究人员发现，氯胺酮确实阻断了NMDA受体。它实际上安静了神经元，防止神经元像平常一样活跃。然而，有些近乎矛盾的是，它在涉及情绪和奖励以及自我反思的大脑回路中增加了神经可塑性。稍后我们会详细讨论这些大脑回路是什么。

The way it works is that ketamine binds to the NMDA receptor present on inhibitory neurons, and in doing so, dramatically reduces the amount of inhibition coming from those inhibitory neurons onto excitatory neurons. When that happens, the excitatory neurons in specific circuits of the brain are allowed to increase their activity. They do what's called bursting. Bursting is a pattern of electrical activity whereby normally, one of these excitatory neurons is releasing glutamate in a pattern that might look or sound like this. It actually doesn't make a sound in the brain, but if you were to record from one of these neurons, which people have done many times over, and then you were to convert the electrical signal in those neurons to an audio monitor, you would hear the firing, the action potential of those neurons as that's what it actually sounds like on the audio monitor. It sounds like a little bit of static.

其原理是，氯胺酮会结合到抑制性神经元上的NMDA受体，从而大幅减少这些神经元对兴奋性神经元的抑制作用。这样一来，大脑中特定回路的兴奋性神经元就能增加活动。这个现象被称为"爆发"。爆发是一种电活动模式，通常情况下，一个兴奋性神经元释放谷氨酸的模式可能类似于某种声音形态。实际上，大脑中这些活动是无声的，但如果记录这些神经元的活动，并将这些电信号转换为音频信号，那么你会在音频监视器上听到这些神经元的放电活动，也就是动作电位。它听起来有点像静电噪音。

But if the normal firing of the neuron is, which is the pretty typical baseline firing of the neurons in the relevant circuits to mood that I'm going to be discussing, under conditions where ketamine has been brought into the system, binds that NMDA receptor, blocks the output of those inhibitory neurons onto the excitatory neuron. Now the excitatory neuron is firing in burst. And those bursting patterns of electrical activity are the absolute perfect patterns of activity that induce not just short term, but long term changes in the neural circuits associated with reward, with dopamine release, with disappointment, and with mood in ways that are directly relevant to suppressing or providing relief from the symptoms of major depression.

在正常情况下，神经元的发放是神经元在与情绪相关的电路中的典型基础活动。当将氯胺酮引入系统后，它会结合到NMDA受体上，阻止抑制性神经元对兴奋性神经元的输出。此时，兴奋性神经元开始以爆发的方式发放信号。这种爆发的电活动模式是绝对理想的，它不仅能够引起短期变化，还能在与奖励、多巴胺释放、失望和情绪相关的神经回路中引发长期变化。这些变化直接有助于缓解或减轻重度抑郁症的症状。

Now I realize what I just told you is a lot of information. In fact, what I just described represents essentially what I would teach to an advanced undergraduate, slash graduate course, medical school course on neuroplasticity and how ketamine works. So keep in mind that we're having a discussion here that is at a fairly high level. And if you could understand even a tiny fraction, even just one bit, what I just described, you're doing great. If you could understand more outstanding. Just to make sure that everyone's on the same page as we move forward, because I do want to make sure that everyone understands ketamine and how it works, because it does have these sort of cryptic functions of engaging neuroplasticity in ways that aren't obvious if you just ask, you know, what does ketamine do when you inject it? What is ketamine produced in terms of a feeling state? And then, you know, how does somebody get relief from depression? That can all start to get a little bit muddled unless you understand the following.

现在我意识到我刚才告诉你的是很多信息。事实上，我刚才描述的内容基本上是我会在高年级本科生、研究生课程或医学院关于神经可塑性和氯胺酮如何工作的课程中教授的。所以请记住，我们正在进行的讨论水平相当高。如果你能理解我刚才描述的哪怕一点点，你已经做得很好了。如果你能理解更多，那就更出色了。为了确保我们接下来讨论时大家都在同一层面，因为我确实希望每个人都能理解氯胺酮及其工作原理。因为它在激活神经可塑性方面有一些隐晦的功能，如果你只问氯胺酮注射后的作用是什么，氯胺酮产生了什么样的感觉状态，然后你知道，一个人如何从抑郁中获得缓解，这一切都可能会变得有些混乱，除非你理解以下内容。

So I'm going to tell it to you again in just very top contour terms. Somebody takes a pill or an injection or sublingual ketamine. It makes its way into the bloodstream and then it makes its way into the brain. Once it's in the brain, it binds to a particular category of receptors called the NMDA receptor. The NMDA receptor is a receptor that normally is quiescent. It's just kind of sitting there. It doesn't tend to do a lot under normal conditions of everyday life. However, the NMDA receptor's typical function, okay? So when there's no ketamine in the body or brain is to detect abnormal levels of neural activity and in doing so, recruit changes to cells, receptors, et cetera. Literally change the neurons in ways that allow them to respond to that activity in the future without having to be under such big metabolic demand.

所以，我要再用简单的方式告诉你。有人服用了一片药，或者接受了一次注射，或者舌下含服了氯胺酮。药物进入血液，然后进入大脑。在大脑中，它会结合到一种特定类型的受体上，叫做NMDA受体。NMDA受体通常是处于静止状态的。在日常生活的正常情况下，它不会有太多的活动。然而，NMDA受体的典型功能是检测异常的神经活动水平，并因此促使细胞、受体等发生变化。它实际上会改变神经元，使其在不需要承受大量代谢负担的情况下，能够在未来更好地响应这种活动。

And they do that by recruiting more receptors, et cetera. Much in the same way as when you overload a muscle in the gym, it will eventually recover, if you allow it to recover. And it will get stronger through the addition of a bunch of new proteins. The nerve communication of that muscle will change the muscle and the nerve to muscle connection change. It gets stronger and sometimes it gets bigger and stronger. In the same way, a neuron can change the way it functions in response to experience. And neurons don't know experience of life in any other way except the patterns of electrical activity and chemical activity that impinges on them, okay?

它们通过招募更多受体等方式来实现这一点。这与在健身房中过度训练肌肉的方式类似，如果你给它时间恢复，肌肉最终会恢复。通过添加许多新蛋白质，肌肉会变得更强壮。该肌肉的神经传导会改变肌肉和神经与肌肉的连接，它变得更强壮，有时还会变得更大更强。同样，神经元可以根据经验改变其功能。神经元并不知道生活的经验，除了它们所受的电活动和化学活动的模式以外，对其他方式一无所知。

Now ketamine the drug binds to and blocks that NMDA receptor. So the obvious conclusion would be that ketamine prevents neuroplasticity. And that's not what happens. We know that ketamine actually induces neuroplasticity. And it does so specifically in the brain circuits that control mood, the net consequence being improvements in mood. How does that happen? It happens because ketamine binds to and blocks those NMDA receptors on inhibitory neurons. The inhibitory neurons are the neurons that normally suppress the activity of other neurons. So when ketamine binds to the NMDA receptor, the activity of those inhibitory neurons is reduced and as a consequence, excitatory communication between neurons in those mood-related circuits increases.

现在，氯胺酮这种药物会结合并阻断NMDA受体。所以，显而易见的结论是氯胺酮阻止了神经可塑性。但实际情况并非如此。我们知道氯胺酮实际上会诱导神经可塑性，并且这种作用发生在控制情绪的大脑回路中，最终导致情绪改善。这是怎样做到的呢？这是因为氯胺酮结合并阻断了抑制性神经元上的NMDA受体。抑制性神经元通常会抑制其他神经元的活动。因此，当氯胺酮结合到NMDA受体上时，那些抑制性神经元的活动被减弱，结果就是，与情绪相关的回路中神经元之间的兴奋性交流增加。

And it increases in a way that recruits neuroplasticity that strengthens those connections and makes them more likely to be active in the future. Now it is not the case, at least at clinical doses, that ketamine induces seizures. It certainly can at higher doses. But at clinical doses, when ketamine suppresses the activity of those inhibitory neurons and the excitatory neurons ramp up their activity, they ramping up their activity a lot and enough to create changes in those neural circuits associated with mood. And the changes are in the direction of making those neural circuits more likely to generate positive mood and less likely to generate negative mood. We'll get into the specifics of those circuits in a little bit.

这段话翻译成中文如下：它通过增加神经可塑性来增强这些连接，使它们更可能在未来保持活跃。至少在临床剂量下，氯胺酮不会引发癫痫发作。当然，在更高剂量下可能会引发癫痫。但在临床剂量下，当氯胺酮抑制那些抑制性神经元的活动而兴奋性神经元活跃时，它们的活动大幅增强，足以引起与情绪相关的神经回路改变。这些改变是让这些神经回路更可能产生积极情绪，而不太可能产生消极情绪。我们稍后会具体探讨这些回路的细节。

But ketamine is not creating the kind of enormous increases in excitatory communication between neurons that leads to that runaway excitation. Now the point of the discussion we just had over the last 10 minutes or so was severalfold. First of all, I do believe it's important to understand the key components of neural plasticity, which is this remarkable feature of our brain and nervous system that we all have, right, this ability to change our own brain circuits. No other organ in the body, as far as we know, can direct its own changes. But we can direct our own brain changes. And the NMDA receptor is absolutely critical for that.

但是，氯胺酮并不会导致神经元之间兴奋性交流的极度增加，这种极度增加可能会导致失控的兴奋。我们刚才谈论的内容有几个要点。首先，我确实认为理解神经可塑性的关键要素很重要，因为这是一种我们大脑和神经系统的奇妙特性，这种特性让我们能够改变自己的大脑回路。据我们所知，身体的其他器官都无法自主改变，但我们可以主动改变自己的大脑。而NMDA受体在这个过程中至关重要。

I also think it's important to understand the difference between inhibitory and excitatory communication between neurons because that's just central to understanding brain function. Brain function is a series of accelerators and breaks. It's not all about neurons stimulating other neurons. It's also about neurons preventing the activation of other neurons. That's just central to everything, not just preventing seizures, but it's central to learning, it's central to vision, it's central to hearing, it's central to creativity. It is at the core of brain function.

我认为理解神经元之间抑制性和兴奋性交流的区别是非常重要的，因为这对于理解大脑功能至关重要。大脑功能就像是一系列的加速器和制动器。它不仅仅是关于神经元刺激其他神经元，还涉及到神经元抑制其他神经元的激活。这不仅对防止癫痫发作关键，对学习、视觉、听觉和创造力也是如此重要。它是大脑功能的核心所在。

And the other reason to have the discussion we just did is that ketamine has this incredible property. It can literally change the neural circuits that generate mood, that generate your feelings of well-being. But it does so through a somewhat convoluted pathway, right? It blocks the receptor that everyone thinks is involved in neuroplasticity and in doing so, it actually creates neuroplasticity. Now, even though I just described all of that to you over the last 10 minutes or so, keep in mind that what I just described to you as a process that actually occurs in the brain takes many, many days. It involves cells changing gene expression, making new proteins, new receptors.

我们刚才讨论的另一个原因是氯胺酮有一个非常特别的特性。它可以从根本上改变产生情绪和幸福感的神经回路。但是，它是通过一种稍微复杂的途径实现的。具体来说，它会阻断被认为与神经可塑性相关的受体，但通过这种方式，它实际上促进了神经可塑性。即使我刚才花了大约十分钟向你解释了这一过程，但请记住，这个在大脑中实际发生的过程需要很多天。它涉及细胞改变基因表达，制造新的蛋白质和受体。

Anytime we say neuroplasticity, even when you read about so-called short-term neuroplasticity, it is happening over the course of at least many, many hours and more likely many days or even weeks. So the process that I just described of how ketamine creates neuroplasticity through blockade of NMDA receptors is very likely to be the process that explains the longer-term changes in mood and affect that are associated with ketamine therapy for the treatment of depression.

每当我们提到神经可塑性时，即便是所谓的短期神经可塑性，也是在至少几个小时、更多时候是几天甚至几周的过程中发生的。我刚才描述的关于氯胺酮通过阻断NMDA受体来产生神经可塑性的过程，很可能就是解释氯胺酮治疗抑郁症如何带来长期情绪和心境变化的原因。

Now, it is possible that ketamine blocking the NMDA receptor is also responsible for some of the immediate effects of ketamine that people experience when they take the drug, the dissociation, in some cases euphoria, and that sort of dream-like state that it can put people into. That is possible, but it's very clear that the NMDA receptor blockade is critical for the neuroplastic changes that are going to occur over the days and weeks following ketamine treatment.

现在，有可能是氯胺酮（ketamine）阻断NMDA受体导致人们在服用这种药物时所体验到的一些直接效果，比如分离感、有时的愉悦感，以及那种仿佛置身梦境的状态。这是可能的，但非常明确的是，NMDA受体的阻断对于在氯胺酮治疗后几天或几周内发生的神经可塑性变化至关重要。

And if you think back to our earlier discussion when we were talking about the two-time a week over three-week type regimen of taking ketamine or some variant on that, now it might start to make sense as to why yes, there is immediate and short-term benefit of taking ketamine for depression in the clinically appropriate setting. Of course, I'm not talking about recreational use right now, but that also there's some durability of those effects that even after the three weeks of taking ketamine twice per week, people often will experience weeks or months of relief from depression when they're not doing the weekly ketamine therapy sessions.

回想一下我们之前讨论的内容，当时我们谈到每周两次、持续三周的氯胺酮治疗方案，现在可能开始理解为什么在临床合适的环境下，使用氯胺酮治疗抑郁症会有立竿见影和短期的效果。当然，我现在不是在谈论娱乐用途，而是说这种效果的持久性。即使在三周的氯胺酮治疗结束后，也就是每周两次的氯胺酮治疗结束后，人们通常会在没有进行每周氯胺酮治疗的情况下，享受数周或数月的抑郁缓解。

So that longer-term relief that I'm referring to as durability of the treatment is very likely to be the consequence of actual neural circuit rewiring. Now there's an additional and very important facet to this whole discussion about neuroplasticity in response to ketamine treatment for depression. If you recall the burst firing that induces that plasticity, I told you it induces plasticity but didn't tell you how. Now you already could imagine some of the mechanisms, it could be insertion of new glutamate receptors, those AMPA receptors that we talked about.

因此，我提到的治疗持久性带来的长期缓解，很可能是神经回路重新连接的结果。现在，关于对抑郁症进行氯胺酮治疗导致神经可塑性的反应，这整个讨论中还有一个非常重要的方面。你可能记得，诱发这种可塑性的爆发性放电。我告诉过你，它会诱发可塑性，但没告诉你具体原理。现在你可能已经想象得出一些机制，比如可能是插入新的谷氨酸受体，也就是我们之前提到过的AMPA受体。

However, even for that to happen, a bunch of other things have to happen first. But one of the key ones to understand is the thing I mentioned at the beginning of today's episode, BDNF, which stands for Brain Derived Neutrophic Factor. Brain Derived Neutrophic Factor is an incredible molecule. I should mention that it's one of many growth factors in the brain. And it has its own set of receptors. It binds to something called the Track B Receptor, TRKB, Track B Receptor.

然而，即便如此，在这发生之前，需要先发生许多其他事情。其中一个关键点就是我在今天节目一开始提到的BDNF，即脑源性神经营养因子。脑源性神经营养因子是一种非常了不起的分子。我需要提到的是，它是大脑中的众多生长因子之一，并且有自己的一套受体。它结合于一种称为Track B受体（TRKB，Track B受体）的东西。

When BDNF binds to Track B Receptors on neurons, it does a lot of things. It sets off a whole cascade of things, including the insertion of new glutamate receptors so that those neurons become extra sensitive to any input they get. So that's one form of change that BDNF can create. BDNF can also alter the overall shape of neurons. It can cause neurons to grow new branches so that it can receive new inputs from other neurons. Anytime BDNF is discussed in popular books or the popular press, people will talk about it as quote unquote fertilizer for neurons. I don't really like that term because it really undervalues the total number of things that BDNF can do. BDNF actually can act as its own kind of neurotransmitter. It can actually stimulate other neurons. And it does a bunch of other things.

当BDNF结合到神经元上的TrkB受体时，会引发一系列的反应。其中之一就是插入新的谷氨酸受体，使神经元对接收到的任何输入变得更加敏感。这是BDNF所能引起的一种变化。BDNF还可以改变神经元的整体形状，促使神经元生长出新的分支，以便接收来自其他神经元的新输入。每当BDNF在大众书籍或媒体中被讨论时，人们常常会用“神经元的肥料”来形容它。我不太喜欢这个说法，因为它低估了BDNF的多种作用。BDNF实际上可以作为一种神经递质，能够刺激其他神经元，并且还有很多其他的功能。

But for sake of this discussion about ketamine, understand that that burst firing of neurons, that very high frequency firing of neurons can invoke the release of BDNF in ways that make those circuits very plastic very quickly. And in addition to that, there's some evidence that ketamine itself may be able to cause release of BDNF directly without having to go through all of the mechanisms that I overwhelmed you with a few minutes ago or hopefully didn't overwhelm you with, but that I taught you a few minutes ago. Now what's especially exciting about BDNF in the context of ketamine therapy for depression is that it appears based on both preclinical and clinical studies that BDNF is in just one of the ways in which ketamine can invoke neuroplasticity and these improvements in mood.

为了讨论氯胺酮，我们需要了解，当神经元快速且高频率放电时，会以某种方式促进脑源性神经营养因子（BDNF）的释放，从而使神经回路变得非常迅速且具有可塑性。此外，有一些证据表明，氯胺酮本身可能直接引发BDNF的释放，而不需要经过之前提到的所有复杂机制。特别令人兴奋的是，结合氯胺酮治疗抑郁症的研究发现，不论是临床或是基础研究，都表明BDNF只是氯胺酮引发神经可塑性和情绪改善的众多途径之一。

It may actually be required. It may be the central process to all of that. Now it can still be downstream of all that NMDA receptor stuff that we talked about before. But there are several lines of evidence that suggest that ketamine-induced release of BDNF is one of the core mechanisms by which ketamine can relieve depression. Now there are several lines of evidence to support what I just said about BDNF in the context of ketamine. First of all, in mice that lack BDNF, they have no BDNF, they can't make BDNF because they don't have the gene for BDNF. We call those BDNF knockout mice. In those mice, if you give them ketamine and you put them into that learned helplessness task that we talked about a bit earlier where you put them in water and see how long they swim, normally ketamine would allow a mouse to swim longer, to fight for its life longer.

这可能确实是必要的。这可能是所有这一切的核心过程。现在，它仍然可能是我们之前讨论过的所有NMDA受体问题的下游过程。但有多方面的证据表明，氯胺酮诱导的BDNF（脑源性神经营养因子）释放是氯胺酮能够缓解抑郁症的核心机制之一。现在，关于BDNF在氯胺酮背景下的作用，有多方面的证据支持我刚才所说的。首先，在缺乏BDNF的小鼠中，它们没有BDNF，因为没有BDNF的基因，我们称这些小鼠为BDNF敲除小鼠。如果在这些小鼠中给予氯胺酮，并且让它们参与我们之前提到的学习性无助任务（即将它们放入水中，观察它们能游多久），通常情况下，氯胺酮会使小鼠游得更久、生命力更顽强。

Well, it no longer does that in a BDNF knockout mouse. And the only thing that's different about that mouse as far as we know is the lack of BDNF. And there are ways to make sure that lack of BDNF in the specific neurons that are relevant to everything we're talking about, not just that their limbs don't work as well, etc. In other words, all the appropriate control experiments have been done. That's preclinical data because it comes from animal models. In addition to that, depressed people who have a mutant form of BDNF. So these humans are not knockouts for BDNF. They can make BDNF, but the BDNF doesn't function normally. In those people, they have a very reduced response to ketamine treatment for depression.

好的，在一种BDNF基因敲除的小鼠中，这种情况不再发生。就我们所知，该小鼠唯一的不同之处在于缺乏BDNF。我们可以通过特定的方法确保BDNF在相关神经元中的缺失是针对我们讨论的一切，而不仅仅是肢体的功能减退等等。换句话说，所有合适的对照实验都已完成。这些是源自动物模型的临床前数据。除此之外，那些带有BDNF突变形式的抑郁症患者——这些人并不是BDNF的敲除者，他们仍然可以产生BDNF，但其功能不正常。在这些人中，他们对氯胺酮治疗抑郁症的反应非常减弱。

Suggesting that BDNF action is at least one of the critical functions that allows ketamine to relieve depression. And as I mentioned earlier, ketamine can actually invoke the release of BDNF and get this. There's some evidence that ketamine itself can bind to the track B receptor. That is, it can bind to the BDNF receptor. It can mimic BDNF. So this is an entirely different way of thinking about ketamine than we normally hear about. Nowadays, we hear a lot about ketamine and ketamine therapy. We also hear, fortunately, about some of the problems of ketamine abuse.

这段话的意思是：有观点认为脑源性神经营养因子（BDNF）的作用至少是氯胺酮舒缓抑郁症的重要功能之一。如我之前提到的，氯胺酮实际上可以引发BDNF的释放。而且氯胺酮本身可能与TrkB受体结合，也就是说它可以与BDNF受体结合，模仿BDNF的作用。这是一种完全不同于我们平常听到的关于氯胺酮的看法。如今，我们常常听到关于氯胺酮及其治疗的讨论，同时也幸亏了解到一些关于氯胺酮滥用的问题。

And we will talk about some of those concerns a little bit later. And we hear about BDNF, this so-called brain fertilizer. But rarely, if ever, do we hear that ketamine itself can mimic the effects of BDNF in the brain. But researchers and clinicians are definitely paying attention to this. And it's starting to raise what I consider a very exciting model of how ketamine could provide relief for depression, which is that it's acting as a growth factor in the brain. Or at least it's mimicking the action of growth factors, allowing the specific neural circuits that control things like mood, outlook on the future, self-reflection, et cetera, allowing those circuits to change in ways that provide significant relief for major depression.

我们会稍后再谈论其中的一些担忧。我们常常听到有关 BDNF（被称为“脑肥料”）的讨论，但很少听到氯胺酮本身也可以在大脑中模拟 BDNF 的效果。不过，研究人员和临床专家已经开始关注这一点。这开始提出一个令我感到非常兴奋的模型，即氯胺酮如何可以通过扮演脑内生长因子的角色来缓解抑郁症。或者至少，它在模仿生长因子的作用，使得控制情绪、未来展望、自我反思等功能的神经回路发生变化，从而为重度抑郁症提供显著的缓解。

And in doing so, and this is a very important point, it appears that ketamine is relieving depression in ways that are entirely different from any other kind of treatment. Now, in an earlier episode about psilocybin and its potential role for the treatment of depression, I went into a lot of depth about how psilocybin can induce neuroplasticity to provide relief for major depression in certain individuals under certain conditions. I do want to highlight that because indeed it's another case where neuroplasticity is involved. But in that situation, as some of you may remember, or if you don't, don't worry, I'll tell you right now, it was a pretty straightforward model. Psilocybin looks a lot like serotonin chemically, except that psilocybin binds a particular receptor. When that receptor is bound, it allows these brain-wide changes, those brain-wide changes seem to change one's reflection on oneself, so-called ego-dissolution changes in mood that are stable over time, et cetera, et cetera. It was all pretty straightforward.

在这一过程中，这一点非常重要，氯胺酮似乎通过完全不同于其他任何治疗的方法来缓解抑郁。在之前一集关于迷幻药（psilocybin）及其在治疗抑郁症中的潜在作用的讨论中，我详细探讨了迷幻药如何通过诱导神经可塑性，为某些个体在特定条件下提供重度抑郁的缓解。我想强调这一点，因为确实这是另一个涉及神经可塑性的案例。但在那个情况下，正如有些人可能记得的，或者如果不记得也没关系，我现在告诉你，那是个相当直接的模式。迷幻药在化学结构上很像血清素，但它会结合到一个特定的受体上。当这个受体被结合时，它允许大脑发生全面的变化，这些变化似乎改变了人们对自我的反思，所谓的自我消融，稳定的情绪变化等，等等。这一切都相当直接。

With ketamine, it's clear there are multiple mechanisms involved. And perhaps most importantly, with ketamine, it's that immediate relief that occurs day of or close to day of treatment. And in the days afterwards, and it's that long-term relief that very likely is the consequence of NMDA receptor suppression, burst activity in neurons within these mood-related circuits, BDNF being released and changing neural circuits, strengthening them in order to give elevated mood as a consequence of that bursting activity, and ketamine mimicking BDNF. In other words, ketamine acting more or less like a growth factor in the brain in order to make sure that whatever changes occur in those neural circuits to elevate mood are durable, that they really are reinforced in last over time.

使用氯胺酮时，显然涉及多种机制。也许最重要的是，氯胺酮能够在治疗当天或接近当天提供立刻的缓解，并在接下来的几天内持续生效。这种长期的缓解很可能是由于NMDA受体抑制，情绪相关回路中的神经元爆发活动，以及BDNF（脑源性神经营养因子）的释放，从而改变和加强这些神经回路，进而提高情绪。氯胺酮在某种程度上模仿了BDNF的作用，类似于大脑中的一种生长因子，以确保这些神经回路中发生的变化能够持久，从而真正强化并延续提升情绪的效果。

I'd like to just take a brief break and thank one of our sponsors, which is Element. Element is an electrolyte drink that has everything you need and nothing you don't. That means plenty of salt, sodium, magnesium and potassium, the so-called electrolytes, and no sugar. Salt, magnesium and potassium are critical to the function of all the cells in your body, in particular to the function of your nerve cells, also called neurons. And we now know that even slight reductions in electrolyte concentrations or dehydration of the body can lead to deficits in cognitive and physical performance. Element contains a science-backed electrolyte ratio of 1000 milligrams, that's one gram of sodium, 200 milligrams of potassium, and 60 milligrams of magnesium. I typically drink Element first thing in the morning when I wake up in order to hydrate my body and make sure I have enough electrolytes. And while I do any kind of physical training and after physical training as well, especially if I've been sweating a lot, and certainly I drink Element in my water when I'm in the sauna and after going in the sauna because that causes quite a lot of sweating.

我想暂时休息一下，感谢我们的赞助商之一：Element。Element 是一种电解质饮料，包含你需要的一切，却没有你不需要的成分。它富含盐、钠、镁和钾，这些被称作电解质的物质，并且不含糖。盐、镁和钾对你身体所有细胞的功能至关重要，特别是对神经细胞（也叫神经元）的功能。而现在我们知道，即使是电解质浓度的轻微下降或身体脱水，也可能导致认知和身体表现的下降。Element 具有科学支持的电解质比例：每包含有1000毫克（也就是一克）的钠，200毫克的钾，还有60毫克的镁。我通常在早上醒来后第一时间喝Element，以补充身体水分并确保有足够的电解质。而在任何体能训练时、体能训练后，尤其是在大量出汗后，我也会饮用Element。此外，当我在桑拿房中以及桑拿后，我也会在水中加入Element，因为这时会出很多汗。

If you'd like to try Element, you can go to drinkelement. That's LMNT.com slash Huberman to claim a free Element sample pack with your purchase. Again, that's drinkelementlmnt.com slash Huberman. So basically, I've discussed two major mechanisms for how ketamine can induce neuroplasticity, leading to improvements in mood and affect that gives relief for depression. Those two mechanisms are linked, or at the very least are happening in parallel. They're happening at the same time in the brain. Now, just to make matters more interesting, there's an incredible twist into this whole thing of how ketamine works. And when I say how ketamine works, I'm not just talking about how ketamine provides relief for depression. I'm also talking about why people use ketamine for recreational purposes.

如果你想尝试 Element，可以访问 drinkelement。也就是 LMNT.com 斜杠 Huberman，购买时可以领取一个免费的 Element 试用包。再次强调，是 drinkelementlmnt.com 斜杠 Huberman。基本上，我已经讨论了氯胺酮如何通过两种主要机制诱导神经可塑性，从而改善情绪并缓解抑郁。这两种机制是相关的，或至少是同时在大脑中发生。现在，让事情变得更有趣的是，这整个氯胺酮作用机制里还有一个惊人的转折。当我说氯胺酮如何起作用时，我不仅仅指氯胺酮如何缓解抑郁症，我还在谈论为什么人们将其用于娱乐目的。

And it is the following. Yes, ketamine has all these impacts on excitatory neurons and inhibitory neurons, BDNF, etc., etc. But ketamine can also bind receptors in the opioid pathway. Now, what is the opioid pathway? Don't worry, here I'm not going to hit you with a lot of details. But we've all heard of the opioid crisis by now, or at least most of you have, the opioid crisis refers specifically to people taking exogenous opioids, taking opioids. So taking pills that activate particular receptors in the brain that lead to analgesia in some cases, so pain relief that lead to changes in mood. There's a lot to be said about the opioid crisis. It's called a crisis for a reason. Many, many people are addicted to those compounds. That's a discussion for another time.

翻译如下：是这样的。是的，氯胺酮对兴奋性神经元和抑制性神经元、脑源性神经营养因子（BDNF）等都有影响。但是，氯胺酮也可以结合到阿片类物质途径中的受体。那么，什么是阿片类物质途径呢？不用担心，我不会给你讲一大堆细节。但我们现在都听说过阿片类药物危机，至少大多数人都知道，这一危机特别指的是人们服用外源性阿片类药物，服用阿片类药物。也就是服用可以在大脑中特定受体上产生作用的药片，在某些情况下可以缓解疼痛，还可以改变情绪。关于阿片类药物危机有很多话题，它被称为危机是有原因的。许多人对这些化合物上瘾。不过，这个话题我们以后再讨论。

Keep in mind that the receptors those drugs bind to are opioid receptors. And those receptors that you and I all have, by the way, do not exist in order to bind drugs that are made by pharmaceutical companies. They exist in our brain and body to bind to the so-called endogenous, naturally made opioids that we all make. And those receptors have different names of the mu opioid receptor, the capa opioid receptor, etc. They tend to have the names of Greek letters to differentiate them.

请记住，那些药物结合的受体是阿片类受体。此外，你我体内都有这些受体，但它们的存在并不是为了与制药公司制造的药物结合。它们存在于我们的脑和身体中，是为了结合我们自己自然产生的所谓内源性阿片类物质。这些受体有不同的名称，比如μ（mu）阿片受体、κ（kappa）阿片受体等等。为了区分它们，它们通常用希腊字母命名。

Now, ketamine can bind to various opioid receptors. And when opioid receptors are bound, we know that creates certain effects, things like pain relief, things like changes in psychic states, dissociation, for example. If enough of them are bound, you can get you four states under certain conditions of high dose binding of ketamine to those opioid receptors. You can start getting into planes of anesthesia where people lose consciousness and actually have no response to pain whatsoever.

现在，氯胺酮可以结合到各种阿片受体上。当这些阿片受体被结合时，我们知道这会产生一些特定的效果，比如止痛、改变心理状态，或者出现解离现象。如果有足够多的阿片受体被结合，在特定情况下高剂量的氯胺酮结合到这些受体上，你可以进入麻醉状态，这时人们会失去意识，对疼痛完全没有反应。

If you recall the clinical studies we talked about earlier, where ketamine was used to relieve depression, well, the dosage used in that study as you recall was half a milligram per kilogram of body weight. That is the dosage that will induce these dissociative mild euphoria, those sorts of states of mind, but where people are still conscious. When you start getting to dosages of ketamine that are in the range of one to two milligrams per kilogram of body weight, now you're talking about anesthetic doses.

您是否还记得我们之前讨论过的临床研究，在那些研究中，使用氯胺酮（ketamine）来缓解抑郁症？当时研究中使用的剂量是每公斤体重半毫克。这个剂量可以诱发轻微的解离感和愉悦感等状态，但人仍然是清醒的。当氯胺酮的剂量达到每公斤体重一到两毫克时，我们就进入了麻醉剂量的范围。

And when that happens, you're going to get full parking, full saturation of all the potential receptors that ketamine can bind to those NMDA receptors. It's going to block those. It's also going to bind to the so-called mu opioid receptors. And maybe this other type as well for those of you that want to know, you have a fissionato is also the capa type opioid receptors. And so what we've got here is a drug ketamine that is hitting two different systems, the glutamate related system and the endogenous opioid system.

当这种情况发生时，所有的停车位都会满员，你会看到所有能被氯胺酮结合的潜在受体也都饱和了。氯胺酮会阻断这些NMDA受体，还会结合到所谓的μ阿片受体。对于那些好奇的人来说，它可能也会结合到另一种κ型阿片受体。因此，我们这里有一种药物——氯胺酮，它同时作用于两个不同的系统：谷氨酸相关系统和内源性阿片系统。

And researchers and clinicians have logically started to ask whether or not some or all of the effects of ketamine are due to the opioid system. And they want to know which effects those are. Now this is where things start to get really interesting both in the context of clinical treatment of depression and recreational use. First of all, when people take ketamine, again it enters the bloodstream and it goes into the brain, but it is metabolized to something called HNK, which is hydroxy nor ketamine.

研究人员和临床医生已经开始探讨，氯胺酮的某些或全部效果是否归因于阿片类系统。他们想知道具体是哪些效果。现在，在抑郁症的临床治疗和娱乐用途的背景下，这个问题变得非常有趣。首先，当人们使用氯胺酮时，它会进入血液，再通过血液进入大脑，但在这个过程中会被代谢为一种叫做HNK（羟基去甲氯胺酮）的物质。

Now I don't expect you to know what hydroxy nor ketamine is and I don't expect you to care about it until I tell you what I'm about to tell you, which is that hydroxy nor ketamine has an incredible specificity for the new opioid receptor. And maybe that capa opioid receptor as well. In other words, when we talk about ketamine, that's the drug people take. But when it goes into the body, it's converted into yet another drug and that other drug, hydroxy nor ketamine is selectively activating the opioid system.

现在，我并不指望你知道什么是羟基去甲噻胺酮，也不期待你会关心这件事，直到我告诉你接下来我要说的内容——羟基去甲噻胺酮对新型阿片受体具有极强的特异性。也许对κ阿片受体也有类似作用。换句话说，我们通常提到的噻胺酮是人们服用的药物，但进入体内后，它会转化为另一种药物，而这种药物——羟基去甲噻胺酮，能够选择性地激活阿片系统。

So this led researchers to ask a very important question, which is when a human being takes ketamine in order to treat their depression and they get some relief from depression, is that the consequence of neuroplastic changes in all those NMDA glutamate, BDNF related circuits that we talked about before? Or is it the consequence of something happening in the opioid system? You can't ignore the fact that ketamine has this property of binding to these opioid receptors because they have such a powerful effect on our thinking, on our mood, on our state of consciousness.

因此，这让研究人员提出了一个非常重要的问题：当一个人服用氯胺酮以治疗抑郁症，并获得一定的缓解时，这种效果是由于之前提到的NMDA谷氨酸、BDNF相关神经回路发生的神经可塑性变化，还是源于阿片系统中发生的某种变化？我们不能忽视氯胺酮能够结合在这些阿片受体上的特性，因为它们对我们的思维、情绪和意识状态有着极大的影响。

It's entirely reasonable that the opioid system could be a major player, if not the major player, in this whole depression relief thing and maybe even in the creation of dissociative symptomology when people take ketamine recreationally. So what researchers slash clinicians did is they undertook a series of experiments where they gave people ketamine for the relief of depression, but they also blocked the opioid receptor system.

有理由相信，阿片系统在抑郁症缓解过程中可能是一个重要因素，甚至可能是最重要的因素，特别是在有人出于娱乐目的使用氯胺酮时，它还可能与解离症状的产生有关。所以研究人员和临床医生进行了一系列实验，在这些实验中，他们给抑郁症患者使用氯胺酮来缓解症状，但同时阻断了阿片受体系统。

And they did that using a drug called Naltrexone. So what I'm about to describe to you is a study done by my colleagues at Stanford School of Medicine, namely Dr. Nolan Williams and Alan Schatzberg and colleagues entitled attenuation of anti-depressant and anti-suicidal effects of ketamine by opioid receptor antagonism. And as a consequence of me reading you that title a moment ago, you now already have the conclusion of the study.

他们使用一种叫做纳曲酮（Naltrexone）的药物进行了这项研究。接下来我要向你介绍的是我的同事在斯坦福大学医学院进行的一项研究，这项研究由诺兰·威廉姆斯医生、艾伦·施茨伯格博士和他们的同事们完成，题目是《通过阿片受体拮抗作用削弱氯胺酮的抗抑郁和抗自杀效果》。刚才我念给你的标题实际上已经包含了这项研究的结论。

What they observed is that when people were given ketamine, they got relief from depression. That wasn't surprising. Again, many studies had shown that before since the early 2000s. If, however, individuals were given Naltrexone to block the opioid receptor pathway and they were given ketamine, well then the anti-depressant effects of ketamine were no longer observed. Now that suggests that it is the opioid receptor system that's responsible for the anti-depressant effects of ketamine.

他们观察到，当人们使用氯胺酮时，抑郁症状得到缓解。这并不令人惊讶，因为自2000年代初以来，许多研究已经证明了这一点。然而，如果给这些人使用纳曲酮来阻断阿片类受体通路，再给他们使用氯胺酮，那么氯胺酮的抗抑郁效果就不再出现了。这表明氯胺酮的抗抑郁效果可能是由阿片类受体系统引起的。

And perhaps this HNK, this hydroxene nor ketamine, which is the metabolite of ketamine, is the way in which ketamine normally relieves depression. Now a lot of people took note of these studies because after all there are probably dozens, if not hundreds of studies, looking at the effects of ketamine on all that NMDA receptor stuff. And indeed, neuroplasticity and mood-related circuits can't be discounted as one way in which ketamine provides relief from depression. But what was very interesting is that in people given ketamine and Naltrexone, those people still experienced the immediate effects of ketamine, the mild euphoria, the dissociation, the feelings that one would normally expect when people were under the effects of ketamine. But what they didn't get were the longer term changes in mood that we would call relief from depression.

或许这种HNK（羟基氢去甲氧氯胺），作为氯胺酮的代谢物，正是氯胺酮通常能缓解抑郁的原因。很多人注意到了这些研究，因为实际上可能有几十甚至几百项研究在观察氯胺酮对那些NMDA受体相关问题的影响。而且，神经可塑性和与情绪相关的神经回路也不能被忽视，这是氯胺酮缓解抑郁的另一个可能原因。但非常有趣的一点是，在使用氯胺酮和纳曲酮的人群中，这些人仍然感受到氯胺酮的即时效果，例如轻微的欣快感、解离感以及通常在使用氯胺酮时会期望出现的感觉。不过，他们并没有经历我们所称的缓解抑郁的长期情绪变化。

Now of course the goal of modern psychiatry is to treat depression, not to block the effects of these drugs that are capable of treating depression. Now what the study does, and by the way, there are several studies like it that support these general set of findings that part of the critical role of ketamine in providing relief from depression is to activate the opioid system. But what the study does is it really points to the fact that when we say ketamine treatment, or we talk about somebody taking ketamine recreationally for that matter, we have to pay attention to what's happening while they are under the influence of the drug.

现在，现代精神病学的目标当然是治疗抑郁症，而不是阻止那些能够治疗抑郁症的药物的效果。这个研究表明（顺便说一下，有多个研究支持这一结论），氯胺酮能够缓解抑郁症的一个关键作用部分是激活阿片系统。但研究真正指出的是，当我们谈论氯胺酮治疗或有人为了娱乐目的使用氯胺酮时，我们必须关注在药物影响下他们的状况。

We also have to pay attention to what's happening in the days and weeks after they're under the influence of the drug. And perhaps most importantly, this calls to mind a really important idea, which is that whether or not you're talking about ketamine-induced relief from depression, or psilocybin-induced relief for depression, or MDMA-induced relief for PTSD, a topic that I covered on a previous episode of this podcast. We have to step back and look at the idea that the effects of the drug that people experience, whatever those may be, because obviously it's going to depend on what particular drug they took. Those immediate effects may not actually be related to the long-term clinical benefit of those particular drugs.

我们还必须关注在药物影响后的几天或几周内发生的事情。或许更重要的是，这提醒了我们一个非常重要的概念：无论是凯他敏、迷幻蘑菇（psilocybin）还是摇头丸（MDMA）带来的抑郁症或创伤后应激障碍（PTSD）的缓解——这是我在之前一期播客中谈到的话题——我们都必须退后一步，审视这一想法：人们经历的药物效果，无论是什么药物，都会因具体的药物而异。这些药物的即时效果可能实际上与其长期的临床效益没有直接关系。

Now, I realize that many people might not like that idea. And frankly, I don't actually think that's the way that it works. I don't think it's going to be an either or situation. However, because drugs like ketamine, psilocybin, MDMA have such profound effects on people's psychic states when they are under the influence of them. And because at least in the proper clinical setting and use, they do seem to provide impressive relief from a lot of these psychiatric challenges, like depression and PTSD. People naturally correlate those two things. They couple those two things. In fact, they collapse those two things and presume that their experience of what they saw, what they heard, how they felt, while they were under the influence of the drug, was actually the stimulus that created the relief from their clinical condition, like depression.

现在，我意识到很多人可能不喜欢这个想法。坦率地说，我其实也不认为事情是这样运作的。我不认为这会是非此即彼的情况。然而，因为像氯胺酮、裸盖菇素和MDMA这样的药物在影响下对人的心理状态有极大的影响，并且至少在合适的临床环境和使用下，它们确实似乎能够有效缓解许多精神疾病问题，如抑郁症和创伤后应激障碍。人们自然而然地将这两者联系起来。他们将这两者结合在一起。实际上，他们将这两者混淆，并假设他们在药物影响下所看到、听到、感觉到的体验，实际上就是产生他们临床症状缓解的原因，比如抑郁症。

But what these data on combined treatment with ketamine and naltrexone to block the meopiod receptor really show us is that that may not actually be the way that it works. It may be that the effects of a drug like ketamine that one experiences, while interesting, perhaps even profound, perhaps great insight comes to one when they do that therapy in the proper context. It is not clear at all that it is that experience in the effects of those drugs in those immediate minutes and hours, that's actually what's causing the relief from depression.

这些关于联合使用氯胺酮和纳曲酮阻断阿片受体的研究数据显示，这可能并不是它们发挥作用的真正机制。可能的情况是，像氯胺酮这样的药物所带来的效果，尽管可能很有趣甚至深刻，或在合适的环境下进行治疗时带来重大的领悟，但尚不明确这种用药带来的短暂体验和药效发挥在几分钟或几小时内是否真正导致了抑郁症的缓解。

Now again, I don't think it's an either or. I like to view the whole situation more or less as a sort of wavefront that the experience that one has, subjectively, while they are under the influence of a drug like ketamine or psilocybin or MDMA, sets off a series. And in fact, multiple series, is that a word? Multiple types of processes in the brain, some of which rely on things like NMDA receptor, BDNF, et cetera, type neuroplasticity, others which rely on the opioid receptor pathway, and that each of these have different time courses such that some provide immediate relief in the days and hours after treatment, some in the weeks after treatment, and some more durable long-lasting changes that can occur over months or maybe even years.

再次说明，我不认为这是非此即彼的情况。我更倾向于把整个情况看作一种波前。当一个人在使用如氯胺酮、迷幻药或MDMA等药物时，他们主观体验到的感受会引发一系列变化。事实上，还会引发多种变化过程，这是个词吗？可能不是。这里有多种类型的大脑过程，其中一些依赖于NMDA受体、脑源性神经营养因子（BDNF）等相关的神经可塑性，另一些则依赖于阿片受体通路。每种过程的时间进程不同，有些在治疗后的几小时或几天内提供即时的缓解，有些在几周后产生效果，还有一些可以产生持续几个月甚至几年之久的长期变化。

And a really important thing to underscore in the context of all this is that throughout today's discussion, we've been talking about drugs and receptors and relief from depression. But what we're really talking about here are people who get relief from depression and almost with certainty, when they get relief from depression, they are also starting to do other things. They are going back to work. They are engaging in relationships again. They are viewing themselves differently again. Hopefully, they're getting morning sunlight and exercising and eating well and doing all the sorts of things that we would call anti-depressive behaviors.

在这一切的背景下，有一个非常重要的事情需要强调：在今天的讨论中，我们一直在谈论药物、受体以及如何缓解抑郁。但是，我们真正关心的话题是人们如何从抑郁中得到缓解。几乎可以肯定的是，当他们从抑郁中解脱出来时，他们也开始做其他事情。他们重返工作岗位，重新参与社交关系，再次以新的眼光看待自己。希望他们能够在早晨晒太阳、进行锻炼、饮食健康，并从事我们所谓的抗抑郁行为。

And it is impossible to separate the positive behavioral consequences of a drug treatment for depression from the drug itself in a way that lets us say, okay, ketamine-relieved depression. And then as a consequence, people went and did a bunch of behaviors that were healthy for them. We're stopped engaging in behaviors that were unhealthy for them. So we can think of behaviors as pro-depressive or anti-depressive.

将药物治疗抑郁症的积极行为后果与药物本身进行分离是不可行的，这样我们就不能简单地说，"好，氯胺酮缓解了抑郁症"。因为在这种情况下，人们可能因此去做了一些对他们健康有益的行为，或停止了一些对他们健康有害的行为。我们可以将行为视为具有促进抑郁或抗抑郁的效果。

In fact, we know that one particular behavior that is viewing blue light in the middle of the night between the hours of, say, 11 p.m. and 4 a.m. is known to invoke a pro-depressive circuit. It involves a structure called the Hebenula. I've talked about this on previous podcasts. It tends to lower dopamine and increase cortisol in the day is following that exposure to light, etc., etc. So there are pro-depressive behaviors and there are anti-depressive behaviors.

事实上，我们知道，有一种特定的行为，即在夜间11点到凌晨4点之间观看蓝光，会激活一种导致抑郁的神经回路。这涉及到一个叫做缰核的结构。我在以前的播客中谈到过这一点。这种行为倾向于降低多巴胺水平，并在之后的白天增加皮质醇水平。所以，的确存在一些易导致抑郁的行为和一些抗抑郁的行为。

We know that viewing morning sunlight, getting regular and sufficient amounts of quality sleep, proper nutrition, proper social engagement. There is now a plethora of quality research pointing to the fact that those are true anti-depressive behaviors. So we can never separate out the effects of a drug from the effects of a drug that feed back on and combine with the effects of the drug that one is hoping for in this case, depression relief.

我们知道，晒早晨的阳光、规律且充足的优质睡眠、适当的营养和良好的社交互动，这些都是有效的抗抑郁行为。现在有大量高质量的研究表明，这些行为确实有助于对抗抑郁。因此，我们无法将药物的效果与其反馈并结合了我们所期望的药物效果（在这个例子中是缓解抑郁的效果）分开来看待。

Okay, so I've been bookending this conversation about ketamine at two very divergent levels, meaning we've been talking about high-level stuff, relief from depressive symptoms. We haven't been going into a lot of detail about that, but that's pretty high level. We're talking about thought changes, behavioral changes that we're calling anti-depressive, right? Changes in mood and affect that are positive, positive anticipation of the future, etc., etc.

好的，我已经从两个非常不同的层面来谈论有关氯胺酮的对话。我们讨论了一些高层次的内容，比如缓解抑郁症状。我们没有深入探讨其中的细节，但这些都是较高层次的东西。我们在谈论思维变化、行为变化，这些变化我们称之为抗抑郁，对吗？还有情绪和感受的积极变化，充满对未来的积极期待，等等。

And then we've also been talking a lot at this other end, which is very reductionist down at the cellular and molecular level. We're talking about receptors and binding of receptors and neuroplasticity and TrkB and all that stuff. We completely neglected, meaning I've completely neglected until now, what bridges those two levels of understanding?

然后我们也在讨论另一个层面，非常简化地深入到细胞和分子层面。我们谈论受体、受体结合、神经可塑性、TrkB以及所有那些东西。但我们完全忽略了，也就是说我到现在为止完全忽略了，是哪些东西将这两个理解层面连接起来的。

And what bridges those two levels of understanding are the neural circuits that actually change when one takes ketamine, whether or not those changes occur quickly, whether or not they take a longer period of time, whether or not they involve NMDA receptors or the opioid receptor systems or both. We know that certain neural circuits change when people take ketamine in these patterns of dosage and frequency of about half a milligram per kilogram. And again, that's the injected form twice per week over three weeks. And then they get some durable resistance to depression.

连接这两种理解层次的是神经回路的变化，这些回路会在服用氯胺酮时发生改变，无论这些变化是快速发生还是需要较长时间，以及它们是否涉及NMDA受体或阿片受体系统，或者两者都有。我们知道，特定的神经回路会在服用约每公斤体重半毫克剂量的氯胺酮时发生变化。通常以注射形式，每周两次，持续三周。这种方式可以有效地增强对抑郁症的抵抗力。

Fortunately, we can talk about those neural circuits without having to bring about a lot more nomenclature, a lot of new language. And I say fortunately because I realized today you've been hit with a lot of new terms. Now, I've already mentioned one of the key brain structures and that's the habanula. A few moments ago, I talked about the habanula in the context of people who get too much bright light exposure in the middle of the night.

幸运的是，我们可以讨论这些神经回路，而无需引入大量的新名词或新语言。我说幸运是因为我意识到今天你们已经接触了很多新术语。现在，我已经提到过一个关键的大脑结构，那就是缰核。刚才，我在谈论那些在半夜暴露在过多强光下的人时，提到了缰核。

That activates the habanula. It's a sort of a disappointment circuit. We can call it that because we know that it leads to pro-depressive symptoms in animal models and very likely in humans as well. And it does so, we know, by reducing dopamine and increasing cortisol. There is evidence that when people undergo ketamine therapy, connections between the habanula, what we can broadly just talk about as a structure involved in generating a feeling of disappointment.

这激活了缰核，它是一种“失望回路”。我们可以这样称呼它，因为在动物模型中，它会导致类似抑郁的症状，极有可能在人类中也是如此。这是因为缰核通过减少多巴胺和增加皮质醇来产生这些效应。有证据表明，当人们接受氯胺酮治疗时，缰核与某些大脑结构的连接（这些结构总体上与失望感的产生有关）会发生变化。

The connections between the habanula and the reward circuitry of the brain, which I've talked about several times before on this podcast. But for those of you that aren't familiar with it, this is a so-called mesolimbic reward pathway as areas like the ventral tegmental area, the nucleus accumbens. Don't worry at all about those names. Just know that this is a brain area that is chocoblock full of neurons that release dopamine, which is a molecule that tends to increase mood, increase motivation.

我在这个播客中多次提到过大脑中的缰核与奖赏回路之间的联系。对于不太了解这些的人来说，这所谓的中脑边缘系统奖赏通路，包括腹侧被盖区、伏隔核等区域。不用担心这些名称，只需要知道这是一个充满了释放多巴胺的神经元的大脑区域。多巴胺是一种通常能提升情绪和增加动力的分子。

In many ways, we can think about it at least for sake of this discussion as anti-depressive. So what we've got is a structure, the habanula, that normally provides inhibitory, and now you know what that means, inhibitory input to this reward pathway that releases dopamine. And when people take ketamine, that inhibition is lessened such that the reward pathway is more available for engagement through daily life activities. Now I say available for engagement through daily life activities for a very specific purpose, which is that all of the changes in neural circuits that we're talking about, they can come about from taking a drug. Well, those changes don't actually do a whole lot unless those circuits are reinforced by particular behaviors.

在很多方面，为了便于讨论，我们可以将其视为抗抑郁的作用。我们所谈论的是一种结构——缰核，它通常会对释放多巴胺的奖赏通路提供抑制性输入。现在你知道了这意味着什么。当人们服用氯胺酮时，这种抑制作用减弱，使得奖赏通路更容易通过日常生活活动得到激活。我特别提到通过日常生活活动进行激活的原因是，因为所有这些我们所谈论的神经回路变化，可以通过药物来实现。然而，这些变化实际上很难起作用，除非通过特定的行为来强化这些回路。

So this relates back to what I said just a few minutes ago about pro-depressive and anti-depressive behaviors. Somebody can take ketamine and potentially get relief from depression. But if they continue to engage in pro-depressive behaviors, they are not going to get much of any relief from depression. Conversely, if somebody takes ketamine and they are reducing the amount of output from this disappointment circuit, this habanula, to the reward circuitry of the brain, and they do engage in behaviors such as seeking out work that stimulates them, seeking out social engagement, taking good care of their body, their mental health, their physical health, etc.

这与我几分钟前提到的关于促进抑郁和抗抑郁行为的内容有关。有人服用氯胺酮可能会暂时缓解抑郁症状，但如果他们继续从事那些促进抑郁的行为，抑郁并不会得到很大缓解。相反，若某人服用了氯胺酮后，能够减少大脑中称为缰核（habanula）的失望回路对奖赏系统的负面输出，并积极参与一些活动，比如寻找能激励自己的工作、参加社交活动、悉心照料自己的身体和精神健康，他们的抑郁可能会得到更有效的改善。

Well, those circuits are not designed to respond to ketamine. They are designed to respond to particular patterns of thinking and behavior. So again, we can't forget that when we hear that a drug causes plasticity in a given neural circuit, what it's doing is it's biasing the balance or the probability that those neural circuits will be engaged by certain activities. But one still has to engage in those activities. Now, fortunately, when people tend to have elevations in mood, they tend to move around more. When they tend to move around more, they tend to engage in more things. When they tend to engage in more things, if they have a positive outlook on life presumably, they are engaging in adaptive things, things like social relationships, job related, school related, go related behavior.

这些神经回路并不是为了响应氯胺酮而设计的，它们是为了响应特定的思维和行为模式而设计的。因此，当我们听到某种药物在某个神经回路中引起可塑性时，我们不能忘记，它实际上是在影响这些神经回路被某些活动激活的平衡或概率。但我们仍然需要参与这些活动。幸运的是，当人们的情绪高涨时，他们往往会更加活跃。当他们更加活跃时，他们往往会参与更多的事情。如果他们对生活持积极态度，他们参与的通常是有益的活动，比如社交关系、工作、学校或个人目标相关的行为。

So it's important to understand that a discussion of neural circuit changes in response to ketamine is really a discussion of neural circuit changes in response to ketamine that shift one's overall system toward having yet further neural circuit changes in response to daily activities and thereby bolstering health, or in this case mental health. Now, it's also important to understand that rarely if ever does a drug provide relief for some sort of clinical challenge in just a one track kind of way. The way to think about this is that most mental processes and certainly things like depression are a two way road. You have pro depressive behaviors in circuits and you have anti depressive behaviors in circuits.

因此，重要的是要理解，当我们讨论神经回路对氯胺酮反应的变化时，其实是在讨论这些变化如何使整个系统更容易对日常活动产生进一步的神经回路变化，从而增强健康状况，特别是心理健康。还需要明白的是，很少有药物能够仅通过一个途径就解决临床问题。我们应该这样来看待这个问题：大多数心理过程，尤其是像抑郁这样的情况，都是双向的。神经回路中既有促使抑郁的行为，也有抗抑郁的行为。

And so perhaps it won't be surprising to you that there's evidence that ketamine treatment can reduce the output from the habenula to the reward pathway, this disappointment to reward pathway weakening that making the reward pathway more available for engagement through thoughts and behaviors that are anti depressive. And in addition to that, it can further bolster the neural plasticity within the reward pathway itself, in particular with connections with the frontal cortex. And for those of you that aren't familiar with the frontal cortex, your frontal cortex does a lot of things. But one of the things that your frontal cortex is absolutely critical for is for establishing context dependent strategy, meaning for allowing you to say, okay, in a given circumstance, what should I do to get the results I want?

因此，或许你并不会感到意外，有证据表明氯胺酮治疗可以减少来自缰核对奖励途径的输出，从而削弱失望对奖励途径的影响，使奖励途径在通过抗抑郁的思维和行为进行参与时更为活跃。此外，它还可以进一步增强奖励途径本身的神经可塑性，特别是与前额叶皮层的连接。对前额叶皮层不太了解的朋友，前额叶皮层的功能很多，其中一个非常重要的功能就是帮助我们根据情境制定策略，也就是说，让我们在特定环境下能够判断应该采取什么行动来达到想要的结果。

In another circumstance, what should I do to get the results I want? It's not strategizing of the manipulative type, although I suppose it could be it's strategizing of how do I get what I need from this social connection? How do I get what I need from my goals and exercise? How do I get what I need from my goals in terms of work or school, etc? Your frontal cortex is that part of your cortex that's always churning ideas. It's always wondering, am I doing well? Am I not doing well? And is it adjusting your behavior accordingly?

在另一种情况下，我应该怎么做才能得到我想要的结果？这并不是那种带有操控性质的策略，虽然我想它也可以被这样看待。这里的策略其实是指我如何从这段社交关系中获取我需要的东西？我如何在健身目标中得到我所需的结果？在工作或学习目标中，我又如何实现自我需求？你的前额皮层是大脑中不停闪现各种想法的部分。它总是在探究：我做得好吗？我做得不好吗？并根据情况不断调整你的行为。

So it's now established that ketamine can improve connectivity. That is, it can strengthen the connections between areas of the brain that are associated with context dependent strategy building and these reward pathways. In other words, it makes people more sensitive to whether or not they are getting the results they want from their efforts and to how to adjust their efforts so that they do get the results they want from those efforts. And there's other evidence that NMDA receptor blockade is not the way that ketamine provides relief from depression.

现在已经确定，氯胺酮可以改善大脑的联结。也就是说，它能够强化大脑中与情境依赖策略构建以及奖励路径相关的区域之间的连接。换句话说，氯胺酮可以让人们更敏感地察觉到他们的努力是否得到了想要的结果，并且能够调整他们的努力以实现预期的结果。此外，还有证据表明，氯胺酮缓解抑郁症的功效并非通过阻断NMDA受体实现。

Namely, there's a drug called Mementin. It's used actually to treat Alzheimer's and it too is an NMDA receptor blocker and it has no anti-depressant effects. Now, as you recall, ketamine is a dissociative anesthetic and one of its primary effects is to create this feeling of dissociation. For those of you that aren't familiar with what dissociation is, dissociation is where people feel separate from their body. They can still think, but it's as if they are observing themselves. In fact, in anticipation for this episode, I consulted with several different colleagues in the Department of Psychiatry at Stanford School of Medicine and one of them described the effects of ketamine as described by a patient there who had taken ketamine for the treatment of depression.

这段文字用中文表达如下：有一种名为美金刚的药物，它实际上用于治疗阿尔茨海默症，它也是一种NMDA受体阻断剂，不过它没有抗抑郁效果。您可能还记得，氯胺酮是一种解离性麻醉药，其主要效果之一是引发解离感。对于不熟悉解离的人来说，解离是指人们感到与身体分离，他们仍然可以思考，但感觉就像在观察自己。事实上，为了准备这一集节目，我与斯坦福医学院精神科的几位同事进行了咨询，其中一位描述了使用氯胺酮治疗抑郁症的患者所描述的效果。

And that patient described it as observing themselves, thinking, observing themselves, doing things, even though they were lying completely still. And perhaps, most importantly, describing themselves as being above their body and actually looking down on themselves from the third person perspective. Now, that, I realize, is a foreign experience to most people, but of course, there are people who experience dissociation, even while not on ketamine. And as many of you know, dissociation is actually one of the primary symptoms of PTSD and trauma. So, this raises a sort of conundrum. You know, why is it that a particular state of mind that's associated with PTSD and trauma?

那位患者描述自己的经验是，仿佛在观察自己，思考、观察自己在做事情，尽管他们实际上完全静止不动。也许更重要的是，他们形容自己仿佛身在体外，从第三人称视角俯视着自己。我知道，对大多数人来说，这是一个陌生的体验，但当然，也有一些人在没有使用氯胺酮的情况下也会经历这种解离状态。如许多人所知，解离实际上是创伤后应激障碍（PTSD）和创伤的主要症状之一。所以，这引发了一个疑问，为什么这种心理状态会与PTSD和创伤联系在一起呢？

And in some cases, depression itself, which is induced by a drug like ketamine, can provide relief from depression. And that all goes back to the neuroplastic changes that we talked about earlier and more likely that changes in the new opioid receptor system that we talked about earlier. But nonetheless, the dissociative effects of ketamine are so profound for people that take them that I thought I'd spend a minute or two explaining what likely causes that dissociative third-personning of self-effect. And in so far as we know, it has to do with an uncoupling of certain brain circuits.

在某些情况下，由药物如氯胺酮引发的抑郁症本身，可以缓解抑郁症。这与我们之前提到的神经可塑性变化有关，更可能涉及到我们之前提到的新阿片受体系统的变化。然而，氯胺酮的分离效果对使用者来说是如此明显，所以我想花一两分钟解释可能导致这种自我第三人称分离感的原因。就我们所知，这与某些大脑回路的解耦有关。

In particular, neocortical brain circuits, the neocortex is the part of the brain, the lumpy outside part of the brain that's associated with action planning. It does a lot of things, really. It's involved in sensory perception, it's involved in speech generation, many, many things. But the neocortex has connections to other regions, which are called subcortical regions. And it seems that when people take ketamine or fan-cycletine PCP, there's an uncoupling of those networks, a quieting of those networks, that starts to create a different dominant rhythm in the brain. Some of you may be familiar with rhythms in the brain, so-called alpha rhythms or alpha patterns of activity.

特别是大脑的新皮层回路，新皮层是大脑的一部分，是大脑外表凹凸不平的区域，与行动计划有关。实际上，它的功能非常多，涉及到感官感知、语言生成等许多方面。然而，新皮层与其他被称为皮层下区域的大脑区域有联系。研究表明，当人们摄入氯胺酮或天使尘（PCP）时，这些网络的连接会被削弱或静止，从而在大脑中产生一种不同的主导节律。你们中的一些人可能对大脑节律有所了解，比如所谓的阿尔法节律或阿尔法活动模式。

That's just dominant patterns of activity associated with particular brain states. So for instance, alpha brain ways are associated with an alert but calm, relaxed state of mind, where thoughts are sort of free-flowing. It's a little bit dreamlike, but it isn't really like a dream where anything can happen. It has a structure to it. When people take ketamine, the alpha pattern of activity is completely abolished, at least for the duration of time that they're under the influence of the drug, which typically is about an hour to two hours or so.

这只是与特定大脑状态相关的主要活动模式。例如，阿尔法脑波与一种警觉但平静、放松的心理状态有关，此时思绪自由流动。这个状态有点像梦境，但并不是任何事情都可能发生的那种梦，它有一定的结构。当人们服用氯胺酮时，阿尔法活动模式会完全消失，至少在药物影响下的持续时间内是这样，通常大约持续一到两个小时。

And a different pattern of brain activity, which is called the theta pattern of brain activity, starts to really emerge. It's as if it gets unveiled. And that theta pattern of activity is the one that's associated with a dreamlike state. It's the one that resides more or less at that liminal border between wakefulness and sleep. If you've ever been falling asleep and you were thinking something like you were running and you kicked your leg, it's very likely that you were in theta pattern of activity in your brain at that moment, just prior to when you woke up.

一种不同的脑活动模式，称为脑活动的θ模式，开始真正显现出来。就像它被揭示出来一样。这个θ活动模式与梦境状态有关，位于清醒与睡眠之间的临界边缘。如果你曾在快要入睡时，脑海中想象自己在跑步，并伴随有实际的腿部抽动，很可能那一刻你的大脑正处于θ活动模式。这通常发生在你即将醒来之前。

Whereas when you were more alert, you see patterns of activity that are higher frequency, things like alpha, beta rhythms, and so forth. So ketamine produces particular patterns of brain activity and this sense of dissociation when it's taken at sub-anesthetic doses. If you recall the clinical studies we talked about earlier, they injected half a milligram per kilogram of body weight in order to provide depression relief for those patients. When people take ketamine, they will take it by different routes of delivery.

当你比较清醒时，大脑活动的频率会更高，比如会出现阿尔法波、贝塔波等模式。而氯胺酮在以次麻醉剂量使用时，会产生特定的大脑活动模式以及一种分离感。你可能还记得我们早些讨论过的临床研究中，为了缓解患者的抑郁症，他们注射了每公斤体重半毫克的氯胺酮。人们使用氯胺酮时，可能会通过不同的途径摄入。

And now here we have to expand our conversation to include both the clinical context, research studies, and recreational use. Now I do that because typically when people take ketamine in a study, in a clinical study, they will get an intravenous into the vein or an intramuscular into the muscle injection of half a milligram per kilogram of body weight ketamine. However, when people are taking ketamine recreationally or when they are accessing ketamine legally by prescription and taking it at home, which is becoming a more common practice, they will often take it orally in pill form or they will take it sub-lingually by putting it under the tongue or in their cheek and then that so-called trosh dissolves and the ketamine goes into their system.

现在，我们需要拓展讨论范围，包括临床背景、研究研究和娱乐用途。我这样做是因为通常在临床研究中，人们会通过静脉注射或肌肉注射的方式，注入每公斤体重半毫克的氯胺酮。然而，当人们在娱乐环境中使用氯胺酮，或者合法获得处方并在家自行服用时（这种情况越来越普遍），他们通常会口服药片，或者通过舌下含服，即将其放在舌头下或颊部，这样所谓的“含片”就会溶解，氯胺酮进入体内。

Now an important thing to understand is that when people take ketamine orally, only 25% of the active form of ketamine makes it into the blood stream. And when they take it sub-lingually, typically only about 35% of the total amount of ketamine they take is converted into metabolically active ketamine that acts on the neurons in their brain. So when you hear about the dosages used in studies, they are going to generally involve injections of ketamine and far lower doses of ketamine than when you hear about people taking ketamine orally or sub-lingually.

现在需要理解一个重要的事情是，当人们口服氯胺酮时，只有25%的活性氯胺酮进入血液。而当他们舌下含服时，通常只有大约35%的氯胺酮被转换为对大脑神经元有作用的代谢活性形式。因此，当你听到研究中使用的剂量时，通常会涉及氯胺酮的注射，剂量要远远低于人们口服或舌下含服氯胺酮的剂量。

So for instance, I weigh 220 pounds, that's 100 kilograms. So if I were to be in one of these studies, which I have not been, but if I were, I would be given 50 milligrams of ketamine by way of injection. However, if I were going to try to achieve the same amount of active ketamine in my bloodstream and brain as I would through injection, I would need to ingest three times as much ketamine by way of pill and perhaps a little bit more by way of sub-lingual ketamine if I wanted to get the same effects.

比如说，我的体重是220磅，大约是100千克。如果我参加一个这样的研究（虽然我没有参加过），那么我会通过注射的方式获得50毫克的氯胺酮。然而，如果我想通过口服药片达到与注射相同的血液和大脑中的氯胺酮活性含量，我需要摄入三倍的氯胺酮。如果我想通过舌下含服的方式达到同样的效果，可能还需要更多一点。

So if I were to take 50 milligrams by way of injection in a study and I went to a different study and they said, okay, we want to recreate that effect. We're going to give you a pill. Typically, they're going to give me 150 milligrams of ketamine in the pill form or 200 milligrams of ketamine in the trosh sub-lingual form. Now, it's really important to understand this dose dependence according to delivery business because I realize that nowadays, especially a lot of people are taking ketamine through legal sources.

所以，如果我在一个研究中通过注射方式摄入了50毫克的药物，然后去到另一个研究，他们说想要重现这种效果，并打算给我一粒药丸。通常，他们会给我150毫克的氯胺酮药片，或者200毫克的氯胺酮舌下含片。现在，了解药物剂量与给药方式的关系是非常重要的，因为我意识到如今，特别是很多人通过合法渠道获取氯胺酮。

So they're accessing it legally, but they're taking it outside the clinic and more typically they're taking it not by way of injection, meaning they're taking higher dose ketamine and they're taking it sub-lingually or orally. So it's very important to understand this dose dependence according to mode of delivery business. Now, in anticipation of this episode, I put out a request for questions about ketamine on Twitter and I got many, many questions. It's some excellent ones therein. But one of the more common questions was what is a K-hole in scientific terms?

他们合法地获取了它，但他们把它带出了诊所，更常见地是他们不是通过注射的方式服用，而是摄入更高剂量的氯胺酮，并通过舌下或口服的方式服用。因此，根据给药方式来理解剂量依赖性非常重要。为了准备这期节目，我在推特上征集了有关氯胺酮的问题，收到了一堆问题，其中有些非常好。但其中一个较为常见的问题是：用科学术语来说，什么是“K洞”？

A K-hole is what's used to describe the subjective experience of when somebody takes ketamine typically recreationally and they end up in basically a pseudo anesthetized state. What that means is that they took a dosage that for them put them beyond the boundary of the sub-anesthetic dose and has them transitioning into the anesthesia level dose of ketamine. Now, I mentioned everything I did about dosages before because it's very important to know that different people, even if they are of equivalent body weight, are going to respond to ketamine differently depending on how quickly and how thoroughly they metabolize ketamine.

K洞是用来描述一个人在娱乐性使用氯胺酮时的主观体验，他们基本上会处于一种类似麻醉的状态。这意味着他们服用了一个超过亚麻醉剂量的剂量，进入了氯胺酮的麻醉剂量级别。我之前提到剂量的原因是，因为了解这一点非常重要：即使体重相似的人，也会因为他们新陈代谢氯胺酮的速度和程度不同而对其有不同的反应。

In the clinical context, injections of ketamine into the vein or into the muscle are done at this half a milligram per kilogram dose and they have clinicians there. They have researchers there who are paying attention to whether or not the person is in a dissociative state if they're still conscious and to see whether or not the person is going into full-blown anesthesia. Now, that's one of the values of doing ketamine in the context of a legal clinical setting.

在临床环境中，注射氯胺酮通常是通过静脉或肌肉注射，剂量为每公斤体重半毫克。在这种情况下，会有临床医生和研究人员在场，他们会关注使用者是否处于解离状态、是否仍然清醒，并观察他们是否进入完全的麻醉状态。这就是在合法的临床环境中使用氯胺酮的一个重要价值。

However, I'd be remiss if I didn't acknowledge that a lot of people are getting ketamine legally but then taking it at home, hopefully not alone. Hopefully, there's someone there to monitor them or they're in session with their physician over Zoom. That's actually happening more and more these days through telehealth. But that itself also has certain risks, right? Because if the person needs something and they don't have someone there immediately in the room to take care of it, that could be a very problematic situation.

然而，如果我不承认这一点，那就有些失职了。很多人合法地获得氯胺酮后，会在家里使用，希望他们不是独自一人。希望有其他人在旁边监督，或者他们正在通过Zoom与医生进行远程会诊。如今，通过远程医疗进行这样的操作变得越来越普遍。但是，这也带来了某些风险，对吧？因为如果患者需要帮助，而身边没有人能立即提供帮助，那可能会导致非常麻烦的情况。

And of course, there are situations where people are taking ketamine recreationally. Regardless of how they're acquiring it, they're taking it and they are guessing how they are going to respond to it based on some crude understanding of dosages. But when people talk about a K-hole, what they're talking about is taking ketamine at a dose that for them takes them beyond the mild or perhaps even an extreme dissociation and starts placing them into full-blown anesthesia. And that itself actually can be dangerous. Going into anesthesia like planes of consciousness, while not always deadly, can be deadly. And it certainly can be and has been deadly when people start to combine it with other drugs, in particular drugs like barbituates or alcohol.

当然，也有些人是出于娱乐目的使用氯胺酮。无论他们是如何获得这种药物的，他们正在使用它，并且是根据自己对剂量的一些粗略理解来猜测他们会有什么反应。当人们提到"K洞"时，他们是在说服用氯胺酮的剂量已经超出了轻微或极端的解离状态，进入到了全身麻醉的状态。这本身是有危险的。进入类似麻醉的意识状态，虽然并不总是致命的，但确实可能是致命的。当人们开始将氯胺酮与其他药物一起使用时，尤其是像巴比妥类药物或酒精这样的药物，危险性更大，而且确实已经导致过死亡。

So I want to be very clear that the dosage ranges that you hear about when hearing about ketamine are extremely broad. And so is the variability to anyone given dose. And so too is the response to a given dose in a given person depending on the route of delivery. You need to be very careful about the ability of ketamine to take you into deep, deep planes of unconsciousness. And in some cases death. And of course, as with any sedative, one needs to be extremely cautious about doing anything like driving or even walking in traffic or walking anywhere in some cases if one is under the influence of ketamine.

我想要明确说明，当你听到关于氯胺酮的剂量范围时，这个范围是非常广泛的。同样，每个人对特定剂量的反应也有很大的差异，具体反应还取决于给药方式。你需要非常小心，因为氯胺酮可能会让你进入深度的无意识状态，甚至导致死亡。当然，和任何镇静剂一样，如果你在氯胺酮影响下进行任何活动，比如开车，或者甚至在有交通的地方走路，甚至在某些情况下的任何走动，都需要极其谨慎。

Additionally, for those of you that are seizure prone either due to epilepsy or prior head injury or maybe you're seizure prone and you don't know it, ketamine can induce seizures and it should be completely obvious to you now why that's the case. Ketamine blocks NMDA receptors on inhibitory neurons and quads their activity, which of course can lead to runaway excitation in the brain if you are seizure prone. When I put out the request for questions about ketamine on social media, I also got a lot of questions about the different forms of ketamine. When I say different forms, that included questions about whether or not intranasal was better than oral, was better than sublingual, etc, etc.

对于那些因为癫痫、头部受伤等原因而容易发生癫痫的人，或者那些潜在的癫痫患者来说，氯胺酮（Ketamine）可能会诱发癫痫发作。现在应该很明显为什么会这样：氯胺酮会阻断抑制性神经元上的NMDA受体，抑制它们的活性，这当然可能导致大脑过度兴奋，如果你本身容易发生癫痫的话。当我在社交媒体上征集关于氯胺酮的问题时，我也收到了很多关于氯胺酮不同形式的问题。所谓不同形式，包括对于鼻用、口服、舌下含服哪种更好的问题等等。

To be fair, with one exception, the different modes of delivery probably relate more to dosage that actually gets metabolized than to anything else. What I mean by that is most people don't know how to equate the clinical dose of half a milligram per kilogram of body weight into a dosage to take orally or sublingually or in some cases, by the way, people will take it rectally and the reason people take ketamine rectally is that rectal administration bypasses the liver and indeed ketamine can be hard on the liver to metabolize. It can dramatically increase liver enzymes. Oftentimes people that are taking ketamine frequently and don't want to create damage to the liver, they will opt for rectal administration.

公平地说，除了一个例外，不同的给药方式可能更多地与被代谢的剂量有关，而不是其他因素。我的意思是，大多数人不知道如何将每公斤体重半毫克的临床剂量转换成口服剂量或舌下含服剂量。有些情况下，人们会选择肛门给药，这是因为这样可以绕过肝脏，而肝脏处理氯胺酮可能比较困难，容易导致肝酶显著增加。通常情况下，那些经常使用氯胺酮但不想对肝脏造成损害的人会选择肛门给药。

Now, I realize that unless it's somehow related to your profession, anytime somebody says intra-rectally, it raises a few eyebrows and people lean back a little bit and I get it. In a future episode of the podcast, I promise to distinguish between the different modes of drug metabolism depending on whether or not people take something orally, sublingually, by injection or rectally. Another common question I got when I solicited for questions about ketamine on social media was about the R versus S versus RS forms of ketamine.

现在，我意识到，除非这个话题与你的职业相关，否则每当有人提到“肛门内”时，人们总会惊讶，稍微往后倾。我理解这种反应。在未来的播客节目中，我会详细解释不同的药物代谢方式，无论是口服、舌下含服、注射还是肛门给药。我在社交媒体上征集关于氯胺酮的问题时，常被问到的另一个问题是关于氯胺酮的R型、S型和RS型形式。

And I must tell you, that sent me down a deep, deep rabbit hole of research in which I discovered very contradictory evidence. For instance, I could find papers, I did find papers that said that the R form of ketamine had a much greater affinity for the NMDA receptor than did the S form of ketamine. I also found reviews that said the exact opposite. And there I was sitting with the two reviews in front of one another, wondering if there was something wrong with my visual system until I called a colleague, Dr. Nolan Williams, who's a triple board certified neurologist psychiatrist at Stanford School of Medicine, who's laboratory specializes in the use of ketamine for studies of treating depression and for treating depression in the clinical population.

我必须告诉你，这让我开始了一段深入的研究过程，在这个过程中我发现了很多互相矛盾的证据。例如，我找到了有论文指出，相比S型氯胺酮，R型氯胺酮对NMDA受体的亲和力要强得多。我也发现了一些综述却说正好相反。我就这样坐在那里，看着这两份截然不同的综述，怀疑是不是自己的视觉系统出了问题。最后我打电话给我的同事，斯坦福医学院的Nolan Williams博士，他是三重认证的神经学家兼精神病学家，他的实验室专注于使用氯胺酮进行抑郁症治疗的研究。

So I asked him, what's the deal here? I'm getting very contradictory evidence. And he spelled it all out for me. It appears based on the clinical data in humans and on binding studies, that the S form of ketamine is more potent, that is, it can more robustly bind to the NMDA receptor. And in addition to that, the S form of ketamine tends to produce less dissociation at a given dosage, then does the combined SR form of ketamine or pure R ketamine. He also added and sent me a study that I'll link in the show note captions that there was recently a clinical trial of R ketamine, so pure R ketamine alone. And it failed to relieve depressive symptoms.

所以我问他，这到底是怎么回事？我收到的信息非常矛盾。他给我详细解释了。根据人体临床数据和结合研究显示，S型氯胺酮的效力比较强，也就是说，它可以更有力地与NMDA受体结合。而且，在相同剂量下，S型氯胺酮比联合的SR型氯胺酮或纯R型氯胺酮更不容易引起解离反应。他还补充说，最近有一项关于R型氯胺酮（即纯R型氯胺酮）的临床试验，他会把这项研究的链接附在节目的备注中。但试验显示，R型氯胺酮未能缓解抑郁症状。

So I said, great, thank you so much. This is now all made very clear to me that S ketamine is the preferred form. It produces less dissociation and it provides better depression relief. And then he said, no, actually, it's a little more complicated than that. It appears the situation is the following. The combined SR form of ketamine seems to be the most potent for relieving depressive symptoms. The S form of ketamine is second best in terms of providing relief from depressive symptoms and is the one that's most commonly prescribed nowadays by nasal spray, by oral dosing, by sublingual dosing, and it's what is typically given by way of injection in clinical studies where they do injections. And it appears that the R form of ketamine is the least potent and effective in treating depression.

所以我说：好的，非常感谢你。这让我非常清楚地了解了S型氯胺酮是首选形式。它产生的分离感更少，并且能更好地缓解抑郁症。然后他说，实际上，情况比这稍微复杂一些。看起来现在这样的情况：SR型氯胺酮的联合形式在缓解抑郁症状方面似乎是最有效的。S型氯胺酮在缓解抑郁症状方面效果次佳，目前是最常通过鼻喷、口服和舌下使用的药物，也是临床研究中使用注射的常见方式。而R型氯胺酮在治疗抑郁症方面的效力和效果似乎是最低的。

Now I realized that by putting this out into the larger world and assuming that there are experts in ketamine out there, either by way of use or by clinical study of their own, that I will get a lot of comments back saying, no, actually the R form was more effective for me than the S form versus the SR form, et cetera, just to reiterate from the clinical trials that have been done. We know that the combined SR form is more potent and effective than the pure S form, which is still more effective than the pure R form. So that's what we know now based on the clinical studies. But of course, I acknowledge that any time a drug is out there as a clinical tool and it's being used recreationally, that people are going to explore and they're going to experiment and they're going to find what works best for them.

现在我明白了，当我把这个信息放到更广泛的世界中，并假设有专家对氯胺酮有研究，无论是通过使用经验还是自己的临床研究时，我将会收到很多反馈。有些人可能会说，对他们而言，R型比S型更有效，或者和SR型有不同的效果等等。根据已完成的临床试验，我们知道SR型的组合形式比纯S型更强效，而S型又比纯R型更有效。这是我们目前从临床研究中了解到的情况。当然，我也意识到，当一种药物作为临床工具被使用，且也有人将其用于娱乐用途时，人们会进行探索和试验，寻找对自己最有效的方法。

So I certainly invite feedback about what has worked best for you, hopefully in the clinical context. So whether or not people have used ketamine prescription from their doctor, whether or not they participated in a clinical study, or whether or not they're doing it recreationally, I imagine that I will hear about those experiences and I will take note of them. Another commonly asked question I received was, what about microdosing of ketamine? There's a lot of interest in microdosing nowadays. People are microdosing psilocybin, people are microdosing all sorts of things, hoping to get some of the same effects as the macrodoses, but by using dosages of compounds that are below what would induce say, in the case of psilocybin hallucinations, or in the case of ketamine below what would induce the kind of dissociation and euphoric effects that one would have to lie down for a few hours and disengage for the rest of the day.

我非常欢迎大家给我反馈，告诉我在临床环境中对你最有效的方法。无论是有人从医生那里获得氯胺酮处方，参与临床研究，还是以娱乐方式使用，我都希望能听到这些经历，并加以记录。另一个常被问及的问题是关于氯胺酮的微剂量（microdosing）使用。如今，微剂量使用的兴趣很高。人们在微剂量使用迷幻蘑菇（psilocybin），以及各种其他物质，希望能够获得与大剂量类似的效果，但使用的剂量却低于引发幻觉（如迷幻蘑菇）或低于氯胺酮导致的那种解离和欣快感的剂量，这些效果可能让人需要躺下几个小时并整天无法参与其他活动。

I consulted with my clinician colleagues about this, and they told me that at present, meaning as of yesterday, there is zero published clinical evidence that they are aware of and by way of extension that I am aware of in which microdosing ketamine has been effective for the treatment of depression. All of the positive effects on depression that I've talked about during this episode are gleaned from studies where people used this half milligram per kilogram dosage of ketamine or its equivalent by way of some other route of administration not injected but oral or sublingual. So are there any benefits to microdosing ketamine as far as the scientific and clinical literature that's published as of today is concerned? The answer is no.

我咨询了我的临床医生同事，他们告诉我，截至昨天，目前没有他们知道的，也就是说我知道的，任何有关微剂量使用氯胺酮有效治疗抑郁症的已发表临床证据。我们在这次讨论中提到的所有关于抑郁症的积极效果，都是来自于研究中使用每公斤半毫克剂量氯胺酮或其它非注射而是口服或舌下含服途径的研究。那么，截止到今天为止的科学和临床文献中，是否有任何支持微剂量使用氯胺酮有益的证据呢？答案是否定的。

Okay, so today we covered a lot of information. We talked about what ketamine is. Remember, ketamine and PCP, angel dust, very similar compounds, both block the NMDA receptor. We also talked about what sorts of subjective effects that produces? Dissociation and mild euphoria and third-personing of self, that's the dissociation when taken at low dosages and when taken at higher dosages, it can induce full-blown anesthesia and put people into subconscious states and there's actually a potential even for seizure and death if the dosage is high enough for that person.

好的，今天我们讨论了很多信息。我们讲到什么是氯胺酮。记住，氯胺酮和天使尘（PCP）是非常相似的化合物，都能够阻断NMDA受体。我们还讨论了这会产生什么样的主观效果？在低剂量情况下，会导致分离感、轻度欣快感，以及一种第三视角看自己的感觉，这就是所谓的“分离”。如果服用更高剂量，可能引发完全的麻醉状态，使人进入潜意识状态。而且，如果剂量大到一定程度，还有引发癫痫和死亡的潜在风险。

Again, I want to emphasize that people's dosage sensitivity varies tremendously. Route of delivery will impact that and on and on. We also talked about how the NMDA receptor itself and the activation of this incredible molecule, BDNF, brain-derived neurotrophic factor, seemed to be important for at least some of the antidepressant effects of ketamine, both in the days and weeks following ketamine administration. In addition to that, I described how ketamine impacts the opioid receptor system and how we simply cannot overlook the involvement of the opioid receptor system in producing the antidepressant effects of ketamine.

再次，我想强调，人们对剂量的敏感性有很大的不同。给药途径也会对此产生影响。此外，我们还讨论了NMDA受体本身，以及这种神奇分子——脑源性神经营养因子（BDNF）的激活，似乎在至少部分的抗抑郁效果中发挥着重要作用，这些效果可以在服用氯胺酮后的几天和几周内显现。除此之外，我还描述了氯胺酮对阿片受体系统的影响，而我们绝不能忽视阿片受体系统在产生氯胺酮的抗抑郁作用中所起的作用。

We also talked about the brain circuits and the brain waves associated with dissociative states and the depression relief that seems to arrive for many people who take ketamine. I tried to highlight some of the unique features of ketamine. First of all, that it does seem to provide depression relief where other approaches have not, but that the depression relief tends to be pretty short-lived unless it's applied in this multi-times per week over multiple weeks kind of fashion to produce what I call durable changes, which almost certainly involve changes in neuroplasticity, that is rewiring of brain circuits.

我们还讨论了与解离状态相关的大脑回路和脑电波，以及许多人在服用氯胺酮后似乎获得的抑郁症缓解。我试图强调氯胺酮的一些独特特征。首先，它似乎能够在其他方法无效时提供抑郁症的缓解，但这种缓解往往比较短暂，除非采用一种在多个星期内每周多次使用的方法，以产生我所谓的持久性变化，这几乎可以肯定涉及神经可塑性变化，也就是大脑回路的重组。

Another key point that I highlighted is that we always have to remember that when thinking about how chemicals like ketamine or any other substance for that matter can modify brain circuits in order to change them and provide relief from depression or some other psychiatric challenge that always, always, always there is a requirement for engaging in antidepressant behaviors as a way to further reinforce whatever positive changes have come about through the drug treatment. As a friend and colleague of mine who is expert in this area once so aptly said, better living through chemistry still requires better living.

我强调的另一个关键点是，我们必须始终记住，当考虑像氯胺酮或任何其他物质如何修饰大脑回路以带来改变，并缓解抑郁症或其他精神问题时，总是需要通过参与抗抑郁行为来进一步巩固药物治疗带来的积极变化。正如我在这一领域的专家朋友兼同事曾恰当地说过的，通过化学改善生活仍然需要良好的生活方式。

Thank you for joining me for today's discussion about ketamine. If you're learning from Endora and enjoying this podcast, please subscribe to our YouTube channel. That's a terrific zero cost way to support us. In addition, please subscribe to the podcast on both Spotify and Apple. And on both Spotify and Apple, you can leave us up to a five-star review. If you have questions for me or comments about the podcast or guests that you'd like me to consider hosting on the Huberman Lab podcast, please put those in the comment section on YouTube. I do read all the comments.

感谢您参加我今天关于氯胺酮的讨论。如果您正在从Endora学习并喜欢这个播客，请订阅我们的YouTube频道。这是支持我们的一个绝佳免费的方式。此外，请在Spotify和Apple上订阅这个播客。在Spotify和Apple上，您可以给我们留下最高五星的评价。如果您对我有问题，或者对播客或希望我在Huberman Lab播客中邀请的嘉宾有意见，请在YouTube的评论区留言。我会阅读所有评论。

Please also check out the sponsors mentioned at the beginning and throughout today's episode. That's the best way to support this podcast. Not on today's podcast, but on many previous episodes of the Huberman Lab podcast, we discuss supplements. While supplements aren't necessary for everybody, many people derive tremendous benefit from them for things like sleep support, hormone support, and improving focus.

请您关注在今天节目开头及过程中提到的赞助商。这是支持我们播客的最好方式。在今天的节目中没有提到，但在许多之前的 Huberman Lab 播客集中，我们讨论过补充剂。虽然补充剂不是每个人都必需的，但对于很多人来说，它们在帮助睡眠、激素支持和提高注意力方面有很大帮助。

The Huberman Lab podcast has partnered with momentous supplements. If you'd like to learn more about the supplements discussed on the Huberman Lab podcast, you can go to live momentous spelled OUS, so it's livemomentous.com slash Huberman. If you're not already following me on social media, I am Huberman Lab on all platforms. So Instagram, Twitter, Threads, Facebook, and LinkedIn.

Huberman Lab 播客与 Momentous 营养补剂合作。如果你想了解更多在 Huberman Lab 播客中讨论的补剂，可以访问网站：livemomentous.com/Huberman（请注意，"momentous"的拼写结尾是"OUS"）。如果你还没有在社交媒体上关注我，我在所有平台上的账号都是 Huberman Lab，包括 Instagram、Twitter、Threads、Facebook 和 LinkedIn。

And on all of those platforms, I cover science and science-based tools, some of which overlap with the content of the Huberman Lab podcast, but much of which is distinct from the content of the Huberman Lab podcast. So again, it's Huberman Lab on all social media platforms. If you haven't already subscribed to our neural network newsletter, our neural network newsletter is a free monthly newsletter that includes podcast summaries and protocols in the form of brief one to three page PDFs.

在所有这些平台上，我讨论科学和基于科学的工具，其中一些内容和Huberman Lab博客的内容有重叠，但很多内容都是Huberman Lab博客中没有的。因此，再次提醒大家，我们在所有社交媒体平台上的账号都是Huberman Lab。如果你还没有订阅我们的神经网络通讯，现在可以考虑订阅。我们的神经网络通讯是一份每月免费的简报，里面包括播客总结和简短的1到3页的PDF格式的协议说明。

Those protocols include things like a tool kit to enhance the quality and duration of your sleep, tool kits to improve learning and neural plasticity, tool kits for deliberate cold exposure, exercise, focus, dopamine, and on and on. To sign up for the neural network newsletter, you simply go to Huberman Lab.com, go to the menu, scroll down to newsletter. You sign up using your email, but I want to emphasize that we do not share your email with anybody.

这些协议包括一些工具包，用于提升你的睡眠质量和时间，工具包也可以用来提高学习能力和神经可塑性，还有用于有意识的冷暴露、锻炼、专注力、多巴胺等的工具包，等等。如果你想订阅神经网络新闻简报，只需访问Huberman Lab.com，进入菜单，向下滚动至新闻简报。使用你的电子邮箱进行注册，但我想强调的是，我们不会与任何人分享你的电子邮箱。

Thank you once again for joining me for today's discussion. And last, but certainly not least, thank you for your interest in science.

再次感谢您参与今天的讨论。同时，我也特别感谢您对科学的兴趣。