Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity

Welcome to the Huberman Lab podcast, where we discuss science and science-based tools for everyday life.

欢迎来到休伯曼实验室播客，我们在这里讨论科学和基于科学的日常生活工具。

I'm Andrew Huberman, and I'm a professor of neurobiology and ophthalmology at Stanford School of Medicine.

我是安德鲁·胡伯曼，斯坦福大学医学院神经生物学和眼科教授。

Today we are discussing ketamine.

今天我们讨论的是氯胺酮。

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.

氯胺酮是一种令人着迷的化合物，目前在临床上用于治疗抑郁症、自杀倾向和创伤后应激障碍，而且它也是一种经常被滥用的药物。

That is, ketamine is often used recreationally, and it has a high potential for abuse.

也就是说，氯胺酮经常用于娱乐目的，并且很可能被滥用。

So today, we are going to discuss both the research on the clinical benefits of ketamine as well as the risks of ketamine.

所以今天，我们将讨论氯胺酮的临床益处以及氯胺酮风险的研究。

We are going to discuss the mechanisms of action by which ketamine produces what are called dissociative states.

我们将讨论氯胺酮产生所谓解离状态的作用机制。

I will define for you what a so-called K hole is in scientific terms.

我用科学的术语给大家定义一下什么是所谓的K洞。

I will talk about dosages of ketamine.

我会谈谈氯胺酮的剂量。

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.

我将讨论氯胺酮的输送途径，并且自始至终，我将强调临床益处和风险，即在适当的临床背景下使用氯胺酮的潜在危害。

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.

因此，在今天的节目结束时，您将彻底了解氯胺酮是什么，它如何在大脑和身体中产生解离状态并缓解抑郁，并且您将了解它如何真正改变神经回路。

This is an important thing to understand about ketamine.

这是了解氯胺酮的重要一点。

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.

当一个人受到氯胺酮的影响时，氯胺酮所产生的急性或直接影响只是氯胺酮如何改变大脑以治疗抑郁症、自杀和创伤后应激障碍的一部分。

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.

推而广之，当人们娱乐性地使用氯胺酮时，氯胺酮会产生直接的急性影响，但大脑也会发生长期的变化，这一点值得了解。

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.

在今天的讨论中，我们还将大量讨论神经可塑性，即神经系统根据经验而变化的能力。

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.

我们将不仅在氯胺酮的背景下讨论神经可塑性，而且将其作为一个一般主题，说明您在学习任何东西时神经系统如何变化。

And in that discussion, you're going to hear a lot about BDNF, or brain-derived neurotrophic factor.

在这次讨论中，您将听到很多有关 BDNF（脑源性神经营养因子）的内容。

Brain-derived neurotrophic factor is a critical molecule for all forms of learning and memory and changes to your nervous system.

脑源性神经营养因子是所有形式的学习和记忆以及神经系统变化的关键分子。

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.

因此，除了了解氯胺酮及其临床作用及其与娱乐性使用和滥用的相关性之外，您还将了解很多有关神经可塑性和 BDNF 的知识，以及在学习过程中它现在在您大脑中的作用。

Before we begin, I'd like to emphasize that this podcast is separate from my teaching and research roles at Stanford.

在开始之前，我想强调一下，这个播客与我在斯坦福大学的教学和研究角色是分开的。

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.

然而，我的愿望和努力的一部分是向公众提供有关科学和科学相关工具的零成本消费者信息。

In keeping with that theme, I'd like to thank the sponsors of today's podcast.

为了与这个主题保持一致，我要感谢今天播客的赞助商。

Okay, let's talk about ketamine.

好吧，我们来谈谈氯胺酮。

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 phencyclidine, which goes by the street names angel dust or sherm.

我知道很多人都听说过氯胺酮，但大多数人没有意识到氯胺酮与另一种称为 PCP 或苯环己哌啶的药物非常相似，后者的街道名称为 Angel Dust 或 Sherm。

It has some other street names as well.

它还有一些其他街道名称。

When I was growing up, I heard a lot about PCP.

在我成长的过程中，我听说过很多关于 PCP 的事情。

They taught us about it in school.

他们在学校教过我们这一点。

You'd hear about it on cop shows on television, and the lore was that PCP would eliminate people's perception of pain and would make them violent.

你会在电视警察节目中听说过它，传说 PCP 会消除人们对疼痛的感知，并使他们变得暴力。

You'd hear these stories in drug education classes that when people are on PCP, they're punching light poles and breaking their hands.

您会在毒品教育课程中听到这些故事：当人们服用 PCP 时，他们会猛击灯杆并摔断双手。

They can fight off eight or 10 police officers who are trying to handcuff them.

他们可以击退八到十名试图给他们戴上手铐的警察。

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.

我不知道这些是否属实，但我们听说过很多有关五氯苯酚的信息，它与滥用药物有关，例如可卡因、甲基苯丙胺等。

It was lumped into that category.

它被归入该类别。

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?

如今，当我们听到氯胺酮时，很少有人提到氯胺酮和五氯苯酚实际上或多或少具有相同的作用方式，好吗？

I'm not talking about the specifics.

我不是在谈论具体细节。

I'm talking broadly they have the same mode of action in the brain, that both of them are dissociative anesthetics.

我广义地讲，它们在大脑中具有相同的作用模式，它们都是解离麻醉剂。

And nowadays, usually when we hear about ketamine, we are hearing about its benefits.

如今，通常当我们听到氯胺酮时，我们听到的是它的好处。

We are hearing that it can help cure depression.

我们听说它可以帮助治疗抑郁症。

We are hearing that it can help reduce or cure suicidality, that it can be used to treat PTSD.

我们听说它可以帮助减少或治愈自杀倾向，可以用来治疗创伤后应激障碍。

And indeed, all of that is true.

事实上，所有这些都是真的。

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.

在适当的临床背景下，以适当的剂量和适当的频率给药，氯胺酮已被证明对某些人（而非所有人）来说是治疗抑郁症、自杀和创伤后应激障碍的神奇药物。

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.

也就是说，氯胺酮也有很高的滥用可能性，因此，我们现在经常在聚会上使用氯胺酮，这也就不足为奇了。

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.

你听说过有人进入所谓的 K 洞，这是一种与过量服用氯胺酮（少量或大量）有关的特殊状态。

We'll get back to that a little bit later, what it is, how dangerous it is, et cetera.

我们稍后会再讨论它是什么、它有多危险等等。

In any case, ketamine is an incredible drug, very similar to PCP, phencyclidine, and it is a drug that nowadays there is crossover between the clinical uses of ketamine for treatment of depression, et cetera, and its recreational use.

无论如何，氯胺酮是一种令人难以置信的药物，与PCP、苯环己哌啶非常相似，并且目前氯胺酮用于治疗抑郁症等的临床用途与其娱乐用途之间存在交叉。

What do I mean by that?

我这么说是什么意思？

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.

我指的是人们为了治疗抑郁症而合法使用氯胺酮，但将氯胺酮带出诊所、医生办公室，这与大多数关于氯胺酮及其在抑郁症中的作用的研究截然不同。

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.

毫不奇怪，如果像氯胺酮这样的药物（实际上是任何有可能被滥用的药物）的使用机会增加，那么我们也会看到消遣性使用该药物的人数有所增加，其中一些人确实对氯胺酮上瘾。

So I know many of you are probably wondering, can you get addicted to ketamine?

所以我知道你们很多人可能想知道，你会对氯胺酮上瘾吗？

Indeed, people can get addicted to ketamine.

事实上，人们会对氯胺酮上瘾。

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, et cetera.

有些人非常喜欢它的效果，以至于他们发现自己不得不使用氯胺酮，尽管氯胺酮的使用会降低他们的整体生活表现，包括工作、学校、人际关系、财务等。

That said, ketamine does have these established clinical uses.

也就是说，氯胺酮确实具有这些既定的临床用途。

So nowadays, the landscape around ketamine is oh-so different than it was 10 or 20 years ago when it was lumped very closely with PCP, phencyclidine, and really just looked at as a drug of abuse.

因此，如今，氯胺酮周围的情况与 10 或 20 年前截然不同，当时它与 PCP、苯环己哌啶非常接近，实际上只是被视为一种滥用药物。

There were some early cases in the 1970s of the use of ketamine in order to treat PTSD.

20 世纪 70 年代有一些早期使用氯胺酮治疗 PTSD 的案例。

This was mainly in soldiers in Vietnam or people coming back from Vietnam.

这主要是在越南的士兵或从越南回来的人。

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.

但实际上，氯胺酮用于治疗抑郁症、自杀和创伤后应激障碍的临床应用在过去五到十年中才刚刚起步，这让我们对氯胺酮在临床和娱乐领域的兴趣、理解和使用产生了新的兴趣。

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?

那么，一种曾经被视为街头毒品、糟糕、糟糕、糟糕的药物现在为何被广泛使用，并引发了如此多的兴趣呢？

And really this has to do with our understanding of what depression is and what depression isn't.

这实际上与我们对什么是抑郁症、什么不是抑郁症的理解有关。

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.

所以我想花一两分钟向您解释一下抑郁症的历史及其治疗方法。

What we observed starting about the middle of the last century, so around 1950 But really taking off in the early 1980s and '90s is the so-called monoamine hypothesis of depression.

我们从上世纪中叶开始观察到，也就是 1950 年左右，但真正在 20 世纪 80 年代初和 90 年代兴起的是所谓的抑郁症单胺假说。

Monoamines, as the name suggests, are synthesized from amino acids.

一元胺，顾名思义，是由氨基酸合成的。

That's a good way to remember monoamines.

这是记住单胺的好方法。

Monoamines include things like serotonin, dopamine, and norepinephrine, although there are other monoamines as well.

单胺包括血清素、多巴胺和去甲肾上腺素，但也有其他单胺。

Monoamines are neurotransmitters, or more specifically, they are neuromodulators, meaning they change the activity of neural circuits in the brain and body.

单胺是神经递质，或更具体地说，它们是神经调节剂，这意味着它们改变大脑和身体神经回路的活动。

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.

它们可以提高许多不同大脑区域的活动水平，或者可以减少许多不同大脑区域以及体内神经回路的活动。

Right?

正确的？

Your gut has serotonin and needs serotonin.

您的肠道含有血清素并需要血清素。

Dopamine also plays important roles in the body, et cetera.

多巴胺在身体等方面也发挥着重要作用。

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.

抑郁症的单胺假说实际上围绕这样一种观点，即这些单胺的缺乏，无论是血清素、多巴胺、去甲肾上腺素还是这些单胺的某种组合，都会导致抑郁症。

Now, in reality, there is very little, if any, evidence that there is a deficiency of monoamines in any form of depression.

现在，实际上，几乎没有证据表明任何形式的抑郁症都缺乏单胺。

However, it is very clear that drugs that increase certain monoamines, so drugs like Prozac or Zoloft that increase serotonin, or drugs like bupropion, which is often called Wellbutrin, which is its commercial name, which increases dopamine and norepinephrine, can often provide relief for certain symptoms of depression in some people.

然而，很明显，增加某些单胺的药物，例如百忧解或左洛复等增加血清素的药物，或安非他酮（通常称为维布特林，这是其商业名称，可增加多巴胺和去甲肾上腺素）等药物，通常可以缓解某些人的某些抑郁症状。

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.

然而，我们在过去 30 或 40 年中了解到，旨在增加某些单胺水平以治疗抑郁症的药物仅对大约 40% 的抑郁症患者有效，而且有很多副作用。

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.

现在，有些人很幸运，他们可以使用足够低的剂量，甚至可能足够高的剂量，这可以缓解他们的抑郁症状，但不会产生副作用，使他们在使用该药物时感到不舒服，以至于他们宁愿选择不服用该药物。

However, a lot of people that do get depression relief from things like Zoloft or Paxil or from bupropion 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, et cetera, that those side effects really make it impossible or at least very uncomfortable for them to take those drugs.

然而，许多确实通过左洛复（Zoloft）、帕罗西汀（Paxil）或安非他酮等药物缓解抑郁症的人发现，副作用包括口干等，尽管更常见的是食欲下降或增加，或性欲大幅下降，或睡眠模式改变等，这些副作用确实使他们无法服用这些药物，或者至少非常不舒服。

And of course, there are the 60% of depressed people who do not respond to those drugs at all.

当然，有 60% 的抑郁症患者对这些药物根本没有反应。

Now, I want to be very clear.

现在，我想说得非常清楚。

Things like SSRIs, things like Wellbutrin, have helped a tremendous number of people get relief from depressive symptoms and in many cases have warded off suicidality as well.

像 SSRIs、维布特林这样的药物已经帮助大量的人缓解了抑郁症状，并且在许多情况下还避免了自杀倾向。

However, there are also a great number of people who have experienced a lot of side effects and problems from these drugs.

然而，也有很多人经历过这些药物的许多副作用和问题。

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.

因此，人们希望找到能够治疗抑郁症而不产生类似副作用的其他化合物，并且理想情况下不仅可以缓解 40% 的抑郁症患者的症状，还可以缓解所有抑郁症患者的症状。

So that's where ketamine enters the picture.

这就是氯胺酮发挥作用的地方。

Prior to the 1990s, they were mainly studied in neuroscience and pharmacology laboratories for their abuse properties and for their anesthetic properties.

20 世纪 90 年代之前，神经科学和药理学实验室主要研究它们的滥用特性和麻醉特性。

So ketamine is a dissociative anesthetic.

所以氯胺酮是一种解离麻醉剂。

It's actually used to induce certain forms of anesthesia for surgery.

它实际上用于诱导某些形式的手术麻醉。

It's not always used, but it's often used.

它并不总是使用，但经常使用。

This is something that if you've ever had a surgery, you might want to ask your anesthesiologist about.

如果您曾经做过手术，您可能想询问您的麻醉师。

What sorts of drugs are you giving me to go under?

你给我服用什么药物来治疗？

What sorts of drugs are you giving me to stay under?

你给我服用什么药物来让我保持清醒？

And maybe even what sorts of drugs are you giving me to bring me out of anesthesia?

也许你会给我服用什么药物来让我脱离麻醉状态？

Because it turns out that when you go into anesthesia, your anesthesiologist is rarely giving you just one drug.

因为事实证明，当您进行麻醉时，您的麻醉师很少只给您一种药物。

Typically, they're giving you one drug to 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.

通常，他们会给你一种药物来消除一点焦虑，有时可能消除一点疼痛，然后他们会给你另一种药物，让你进入更深的麻醉平面，然后现在有复杂的方法来监测你的麻醉平面，并且如果有必要，如果麻醉平面太深，也有复杂的方法可以让你脱离深层麻醉平面。

When I talk about a plane of anesthesia, I'm just talking about going from full wakefulness to a reduction in anxiety to falling asleep to asleep 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.

当我谈论麻醉平面时，我只是谈论从完全清醒到焦虑减少，再到入睡再入睡，直到即使有人捏你的脚趾或手臂，就像一个非常强烈的捏，你也不会从中醒来。

Okay.

好的。

So ketamine has the property of being an anesthetic.

所以氯胺酮具有麻醉剂的特性。

It kills the response to pain, and at certain doses, it can bring you into deep planes of anesthesia.

它会消除对疼痛的反应，在一定剂量下，它可以让你进入深度麻醉状态。

At lesser dosages, it can take you into transition points between awake and deeply anesthetized.

在较小的剂量下，它可以带您进入清醒和深度麻醉之间的过渡点。

And it's really that transition point between awake and deeply anesthetized, which we are going to call the dissociative state.

这实际上是清醒和深度麻醉之间的过渡点，我们将其称为解离状态。

It's kind of this liminal state, a little bit like dreaming.

这是一种阈限状态，有点像做梦。

It can have some dreamlike qualities to it.

它可能具有一些梦幻般的品质。

That's the state that has most often been sought after or employed for the treatment of depression, suicidality, and PTSD.

这是最常被寻求或用于治疗抑郁症、自杀倾向和创伤后应激障碍的状态。

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.

这就提出了一个非常重要的观点，那就是当人们娱乐性地使用氯胺酮时，并不清楚他们真正寻求的麻醉或解离的具体平面。

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.

这就是为什么我们听说氯胺酮的一些预期效果促使人们娱乐性地使用它，为什么我们也听说人们在娱乐性使用氯胺酮时有一些不愉快甚至非常不愉快或危险的经历。

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 orally in the form of a pill or put sublingually in what's called a troche that dissolves under the tongue, or it's injected, whether or not it's injected into the vein or intramuscularly, et cetera.

因为我们谈论的是一种根据剂量而具有许多不同作用的药物，并且正如我们很快将讨论的那样，个体对不同剂量的氯胺酮和氯胺酮的输送途径的反应存在巨大差异，无论它是以药丸的形式口服还是以所谓的舌下溶解的含片形式舌下给药，或者注射，无论是否注射到静脉或肌内，等等。

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.

就药物起效速度及其在大脑和身体中产生的作用类型而言，每种药物都会产生非常不同的作用。

So what happened in the early '90s is that laboratories that were studying animal models, what we call preclinical 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.

所以在 90 年代初发生的事情是，研究动物模型的实验室，我们称之为抑郁症、学习和记忆等临床前模型，在某种程度上，氯胺酮，但主要关注学习、记忆和抑郁症，做出了一个有趣的发现。

There's a certain preclinical model of depression that's pretty common in laboratories that involves taking a rat or a mouse and putting it into a small container.

有一种抑郁症的临床前模型在实验室中很常见，该模型涉及将大鼠或小鼠放入一个小容器中。

It looks like a beaker or a jar.

它看起来像一个烧杯或一个罐子。

Sometimes it's a tray, and it has water in it.

有时它是一个托盘，里面有水。

And you might be surprised to learn, perhaps not, that if you put a rat or a mouse into water, it will swim.

你可能会惊讶地发现，也许不会，如果你把一只老鼠放入水中，它会游泳。

Okay?

好的？

So it's treading water in order to keep its head above water and not drown.

所以它踩水是为了保持头部露出水面而不被淹死。

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 preclinical models of depression, which is put a rat or a mouse into water, let it swim, and see at what point it gives up.

我意识到对于你们中的一些人来说，这可能是一个关于动物研究的令人厌恶的话题，但这是抑郁症的常见临床前模型之一，即将一只大鼠或小鼠放入水中，让它游泳，看看它什么时候放弃。

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.

因为如果你把一只老鼠放入水中，它会尝试通过游泳来拯救自己的生命，但在某些时候，它会放弃，然后开始下沉。

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.

然后，当然，研究人员需要营救老鼠，将其放回笼子里，擦干，给它一些食物，等等。

This preclinical model is called the model of learned helplessness, and it's become a prominent preclinical model of depression because, of course, we can't ask mice or rats if they are depressed or happy.

这种临床前模型被称为习得性无助模型，它已成为抑郁症的重要临床前模型，因为我们当然不能问老鼠是否抑郁或快乐。

I suppose you can ask them, but they're not going to answer in any kind of meaningful way.

我想你可以问他们，但他们不会以任何有意义的方式回答。

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.

所以我们只能通过他们的行为来了解他们是否有幸福感或抑郁感。

And of course, that's very hard to gauge in an animal model of any kind.

当然，在任何类型的动物模型中都很难衡量这一点。

You could make guesses based on other behaviors like are they grooming regularly, are they eating regularly?

您可以根据其他行为进行猜测，例如他们是否定期梳理毛发，是否定期饮食？

Things that more or less parallel what we think of as health or lack of health in a human who's happy or depressed.

或多或少与我们对快乐或抑郁的人的健康或缺乏健康的看法相似。

But in the context of trying to understand depression in these preclinical animal models, having a behavior that you can really quantify carefully across a lot of different animals and conditions is really beneficial.

但在试图了解这些临床前动物模型中的抑郁症的背景下，拥有一种可以在许多不同的动物和条件下仔细量化的行为确实是有益的。

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.

因此，将一只老鼠放入水中，看看它们需要多长时间才能放弃拯救自己的生命，这件事被称为习得性无助模型。

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.

它允许研究人员做的就是将大鼠和小鼠放入水中，看看它们需要多长时间才放弃，然后给它们不同的药物，看看这些药物是否会加速、加速或延长动物试图拯救自己生命的时间。

This actually has some meaningful parallels to human depression.

这实际上与人类抑郁症有一些有意义的相似之处。

One of the hallmarks of depression is that people stop thinking positively about their future.

抑郁症的标志之一是人们不再积极思考自己的未来。

Depression, of course, can include a lot of other symptoms.

当然，抑郁症还可能包括许多其他症状。

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.

例如，抑郁症最显着的症状之一就是总是在凌晨 2:30 或 3:30 左右醒来，并且无法再次入睡。

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.

现在请记住，如果您在凌晨 2:30 或 3:30 醒来并且无法再入睡，这并不是说您就绝对抑郁了。

That's simply not the case.

事实并非如此。

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, et cetera, are part of the key features of what we call a major depressive episode.

但这种睡眠不足的模式，加上其他一些事情，比如缺乏对积极未来的预期、无法以任何有意义或积极的方式想象未来等等，都是我们所说的重度抑郁发作的关键特征的一部分。

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.

因此，这种习得性无助的临床前模型使研究人员能够测试许多不同的药物，并确定哪些药物和剂量可以让动物在放入水中时能够更长时间地争取生命。

It's really that simple as a model, but it revealed some very interesting things, 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.

作为一个模型，它确实很简单，但它揭示了一些非常有趣的事情，至少其中之一是，当动物被注射氯胺酮（一种解离麻醉剂）时，但注射的氯胺酮剂量低于引起完全麻醉的剂量时，这些动物会游泳更长的时间。

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.

现在，在某种程度上，这应该令人惊讶，事实上，对研究人员来说也是令人惊讶的，因为氯胺酮是所谓的 NMDA 受体阻滞剂。

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.

现在，当我说阻断剂时，我不会详细说明它是什么具体形式，但我确实想提一下，阻断剂有时被称为拮抗剂，而促进受体活性的物质被称为激动剂。

Okay?

好的？

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.

因此，如果您只记得氯胺酮是一种 NMDA 受体拮抗剂或阻滞剂，那么您应该可以顺利完成今天剩下的对话。

Now, I haven't told you what NMDA is.

现在，我还没有告诉你 NMDA 是什么。

NMDA stands for N-methyl-D-aspartate, and you do not need to remember that.

NMDA 代表 N-甲基-D-天冬氨酸，您无需记住这一点。

But the surprise for researchers was that this drug, ketamine, is allowing animals to fight for their life for longer.

但令研究人员惊讶的是，氯胺酮这种药物可以让动物为自己的生命而奋斗更长时间。

So it has this sort of property of overcoming what we call learned helplessness or a sense of helplessness, AKA antidepressant effects.

因此，它具有克服我们所说的习得性无助或无助感的特性，又称抗抑郁作用。

And we also know that it's an NMDA receptor antagonist or blocker.

我们还知道它是一种 NMDA 受体拮抗剂或阻滞剂。

And that's perplexing because we also know that the NMDA receptor is critical for changing neural circuitry in the brain.

这令人困惑，因为我们也知道 NMDA 受体对于改变大脑神经回路至关重要。

It's critical for neuroplasticity.

这对于神经可塑性至关重要。

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.

换句话说，这是一种药物，它可以阻断对神经可塑性和大脑变化至关重要的受体，但不知何故，它却能让这些动物为自己的生命而奋斗得更久。

It's somehow giving them more of a sense of hope.

这在某种程度上给了他们更多的希望。

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.

至少这是对当小鼠或大鼠游泳更长时间时观察到的情况的主观解释，否则它只会放弃并沉入容器底部。

Now, in general, there are two kinds of scientists.

现在，一般来说，有两种科学家。

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.

有些科学家在研究了一系列类似的发现后说：“哦，这是一种对我们来说应该很糟糕的药物。

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." 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."

它是一种麻醉剂，可以阻断 NMDA 受体，而 NMDA 受体有利于神经可塑性，不知何故，它还可以让这些动物游得更久。”我想说，一类科学家只会看到这一点，然后说：“哇，这是一个大球或一团混乱的事实。”

How does one even reconcile that, right?

如何调和这一点，对吗？

Brain change ought to be good and perhaps even lie at the heart of our ability to recover from depression.

大脑的改变应该是好事，甚至可能是我们从抑郁症中恢复能力的核心。

This is a drug that blocks neuroplasticity, but somehow is relieving depression, I'm going to walk away from that.

这是一种阻碍神经可塑性的药物，但以某种方式可以缓解抑郁症，我将不再使用它。

I'm going to work on something far simpler.

我将做一些更简单的事情。

And then there's this other category of scientist, which thank goodness exists, who looks at that apparent contradiction of, okay, there's a drug which blocks plasticity.

然后还有另一类科学家，谢天谢地，他们的存在，他们看到了明显的矛盾，好吧，有一种药物可以阻止可塑性。

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.

可塑性被认为对于克服抑郁症很重要，但这种药物可以在一定程度上缓解抑郁症，至少在这些临床前动物模型中是这样。

And they say, "Hmm, I like a good puzzle." Right?

他们说：“嗯，我喜欢好的拼图。”正确的？

The more complex the puzzle, the more interesting.

谜题越复杂，就越有趣。

And they start digging in with preclinical studies, and they start talking to clinicians who are treating patients for depression.

他们开始深入进行临床前研究，并开始与治疗抑郁症患者的临床医生交谈。

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.

就像我说的，谢天谢地有这样的科学家存在，谢天谢地他们这么做了，因为事实证明，当临床医生在抑郁症患者身上尝试使用氯胺酮作为缓解抑郁症的方法时，它产生了显着的效果。

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.

因此，大约在 2000 年，第一批关于临床使用氯胺酮治疗抑郁症的论文开始出现。

Now, we have to remember the context in which all of this was happening.

现在，我们必须记住这一切发生的背景。

In 2000, drugs like Prozac and some of the similar SSRIs, selective serotonin reuptake inhibitors, things like Wellbutrin, were really hitting the market in full force.

2000 年，百忧解和一些类似的 SSRIs、选择性血清素再摄取抑制剂、维布特林等药物真正全面进入市场。

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.

正如我们之前谈到的，有些人得到了缓解，有些人得到了缓解，但有很多副作用，因此决定不服用这些药物，而很多人，大多数服用这些药物的人，没有得到缓解。

So there was a real urgent need to find other drugs for the treatment of depression.

因此，迫切需要寻找其他治疗抑郁症的药物。

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?

氯胺酮，至少从其作为解离麻醉剂的明显特征来看，似乎是您最不想用来治疗抑郁症的药物，对吗？

It dissociates people.

它使人们分离。

We even hear about dissociation as a symptom of depression.

我们甚至听说分离是抑郁症的症状。

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.

然而，少数非常具有开创性的临床医生开始探索在临床上使用氯胺酮治疗抑郁症，特别是对任何其他治疗都没有反应的抑郁症。

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.

因此，确实迫切需要找到其他化合物，并有更多的动力来测试其中的一些化合物，让我们称它们为治疗抑郁症的非典型化合物。

So one of the first landmark papers in the use of ketamine for the treatment of depression is entitled "Antidepressant Effects of Ketamine in Depressed Patients." This is a paper that I provided a link to in the show note captions.

因此，使用氯胺酮治疗抑郁症的最早具有里程碑意义的论文之一的标题是“氯胺酮对抑郁症患者的抗抑郁作用”。我在演出笔记标题中提供了这篇论文的链接。

It's a small study, okay?

这是一个小研究，好吗？

So it doesn't involve many subjects at all.

所以它根本不涉及很多科目。

It really just has seven subjects, all of whom had major depression.

它实际上只有七个受试者，所有人都患有重度抑郁症。

And they did intravenous injections with half a milligram per kilogram of body weight of ketamine.

他们静脉注射每公斤体重半毫克的氯胺酮。

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.

现在，每公斤体重半毫克的剂量对于今天的讨论非常重要，因为当我们讨论氯胺酮的其他给药方式（例如口服药丸形式的氯胺酮或舌下氯胺酮）时，它将作为后续讨论的参考点。

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.

因为它与 K 孔或解离状态等因素有关，或者氯胺酮根据剂量和输送途径可能产生的各种影响。

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.

同时，回到这项研究，他们发现，当他们给患有严重抑郁症的患者注射氯胺酮时，氯胺酮的作用在几分钟内、10或15分钟内就发生了。

And that they experienced a sort of peak euphoric state, okay?

他们经历了一种巅峰欣快状态，好吗？

So they're not inducing deep anesthesia.

所以它们不会引起深度麻醉。

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.

在这个剂量下，他们让人们进入一种欣快、梦幻、​​半解离的状态，这种状态在注射药物后 15 分钟内发生，并在大约 45 分钟到一个小时内达到峰值。

And that the total effects of the drug in terms of euphoria were effectively over by about two hours or so.

而且该药物在欣快感方面的总效果有效地超过了大约两个小时左右。

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, et cetera.

如果你看看氯胺酮的半衰期，即一半药物在系统中发挥作用所需的时间，等等，那么效果的时间进程就非常有意义。

But what was really interesting about this study, and others like it, is that the patients experienced relief from their depression almost immediately after taking the drug.

但这项研究以及其他类似研究的真正有趣之处在于，患者在服用药物后几乎立即感受到抑郁症的缓解。

So within minutes to hours.

所以在几分钟到几小时内。

And that it persisted for several days after taking the ketamine, okay?

服用氯胺酮后，这种情况持续了好几天，好吗？

So the dissociative, euphoric, dreamlike effects of ketamine take place very quickly.

因此，氯胺酮的解离、欣快、梦幻般的效果发生得非常快。

They're very, very salient, right?

它们非常非常突出，对吧？

The person basically is just lying there experiencing this euphoric, dreamlike, dissociative state, and they get some relief from their depression immediately.

这个人基本上只是躺在那里体验这种欣快、梦幻、​​分离的状态，他们的抑郁立即得到一些缓解。

And yet there's persistent relief from that depression, which lasted at least three days out from the treatment.

然而，治疗后至少持续了三天的抑郁症持续缓解。

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.

现在，今天讨论的一个关键主题是，氯胺酮的抗抑郁作用似乎相当短暂，至少在人们探索一种或两种氯胺酮治疗方法时是这样。

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.

换句话说，典型的轮廓是人们服用氯胺酮，获得这种欣快、梦幻、​​解离的效果，从那种感觉中立即摆脱抑郁的感觉。

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.

这使得氯胺酮成为治疗抑郁症非常有吸引力的药物，尤其是对其他形式的治疗没有反应的抑郁症，即人们非常非常快地得到缓解。

Indeed, the same day that they initiate the treatment.

事实上，就在他们开始治疗的同一天。

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, et cetera, those drugs often can provide support for people with depression.

现在，当你想到抑郁症的单胺假说推动了 SSRIs、Wellbutrin 等所有药物的发现和开发这一事实时，这一点尤其重要，这些药物通常可以为抑郁症患者提供支持。

Again, only 40% of people get true relief from their depression.

同样，只有 40% 的人的抑郁症得到真正的缓解。

And again, there are some side effect issues or major side effect issues in some cases that have to be dealt with.

再说一遍，在某些情况下存在一些副作用问题或主要副作用问题需要处理。

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.

但即使是积极的效果，即使在最好的条件下，这些效果通常也不会在人们开始服用药物后几周或几个月内显现出来。

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.

现在，对于你们中的一些人来说，等待的时间似乎并不长，但如果你是一个患有抑郁症的人，那么即使再过一天，甚至再过一个小时，抑郁症似乎也几乎难以控制。

And sadly, many people who have these forms of depression will go on to commit suicide.

可悲的是，许多患有这些形式抑郁症的人会继续自杀。

So it is ever so important that there be rapid treatments for depression, even same-day treatments for depression.

因此，快速治疗抑郁症，甚至当日治疗抑郁症，是非常重要的。

And based on this study, it appeared that ketamine was, and indeed still remains, that drug.

根据这项研究，氯胺酮似乎曾经是而且实际上仍然是这种药物。

Now, I certainly don't want to position ketamine in your mind as a miracle drug for depression.

现在，我当然不想将氯胺酮定位为治疗抑郁症的灵丹妙药。

In fact I don't actually believe in miracle drugs.

事实上，我并不相信有神奇药物。

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.

我认为没有任何一种化合物能够单独产生人们想要的所有预期效果，而不会产生任何负面影响，足以被称为奇迹药物。

That's just not how biology works.

生物学不是这样运作的。

There's always an interplay between pharmacology, between our behaviors, and what we choose to do or not do.

药理学之间、我们的行为之间以及我们选择做什么或不做什么之间总是存在相互作用。

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.

当我们稍后讨论抗抑郁行为以及氯胺酮在产生抗抑郁行为以缓解抑郁方面的作用时，我们将讨论这个话题。

Now, with that said, the study that I just mentioned, as well as many, many other studies that followed, emphasized 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.

话虽如此，我刚才提到的研究以及随后的许多其他研究都强调，氯胺酮不仅可以显着降低抑郁症和自杀率，还可以显着降低与重度抑郁症相关的无助感和无价值感。

And again, it could do that in people that also were not responding to other forms of depression treatment, such as SSRIs, et cetera.

再说一次，它可以对那些对其他形式的抑郁症治疗（如 SSRIs 等）没有反应的人起到同样的作用。

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.

因此，虽然我们不想称其为神奇药物，但事实证明，氯胺酮在某些情况下是并且仍然是治疗抑郁症的令人难以置信的药物。

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, right?

现在，除此之外，临床研究表明氯胺酮不仅可以缓解重度抑郁症类型的难治性抑郁症，对吗？

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.

抑郁症有许多不同的形式，但当我们谈论抑郁症时，我们通常会想到或提到重度抑郁症。

But ketamine has also been shown to be effective in treating bipolar depression, sometimes called bipolar disorder, although more commonly nowadays called bipolar depression.

但氯胺酮也被证明可以有效治疗双相抑郁症，有时称为双相情感障碍，尽管现在更常见的是双相抑郁症。

I did an entire episode, by the way, on bipolar depression.

顺便说一句，我拍了一整集关于双相抑郁症的节目。

If you want to know what it is and what it isn't, how it differs from borderline personality disorder, et cetera, you can go to hubermanlab.com, just put into the search function "bipolar," and it will take you to that episode.

如果你想知道它是什么、不是什么、它与边缘性人格障碍有何不同等等，你可以访问 hubermanlab.com，只需输入搜索功能“双相情感障碍”，它就会带你到那一集。

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.

氯胺酮还被证明可用于治疗创伤后应激障碍 (PTSD)、强迫症、强迫症、焦虑症和各种形式的物质成瘾。

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.

因此，氯胺酮并不是一种神奇药物，但它似乎确实具有广泛的应用，并且在治疗许多重大精神疾病方面非常成功。

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.

现在，正因为氯胺酮已经展示了这些令人难以置信的应用，它也存在一些严重的问题，这些问题与其在大脑中的工作方式直接相关，或者至少从我们对它在大脑中的工作方式的理解来看是这样。

And what I'm referring to here is, yes, ketamine is very rapid acting.

我在这里指的是，是的，氯胺酮起效非常快。

It can often provide relief from depression almost immediately, meaning same day.

它通常可以几乎立即（即同一天）缓解抑郁情绪。

However, it is very short-lived.

然而，它的寿命非常短暂。

After about three days or a week or so, the antidepressant effects of ketamine often wear off.

大约三天或一周左右后，氯胺酮的抗抑郁作用通常会消失。

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.

因此，这就造成了一种情况，人们可能需要每周服用氯胺酮，但它却造成了足够的分离状态，这意味着它使人们充分脱离了正常的日常生活，以至于人们每周服用氯胺酮的前景实际上不太可行。

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.

而且由于氯胺酮有成为滥用药物的倾向，即它会形成习惯和/或成瘾，人们还担心，如果人们每周服用氯胺酮来治疗抑郁症，他们可能会对氯胺酮上瘾。

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.

幸运的是，现在已经有关于氯胺酮及其作用的研究，不仅是短期的，而且是长期的，这导致了一些非常重要的临床研究，这些研究探索了，例如，人们每周服用氯胺酮两次，总共持续三周，他们发现，是的，在第一次服用后，他们的抑郁症得到了一些缓解。

They take it a second time that week, they get some relief from depression.

他们在那一周第二次服用，他们的抑郁症得到了一些缓解。

And they do the same thing the next week and the next week.

他们在下周和下周都做同样的事情。

And when they do that, they get relief from depression the whole way through that entire three weeks.

当他们这样做时，他们会在整个三周内从抑郁中得到缓解。

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 the twice a week for three weeks regimen.

但事实证明，这种效果也有一些所谓的持久性，例如，如果人们每周两次进行这种给药方案，即每周两次氯胺酮，总共三周，他们发现当三周结束时，他们的抑郁症状会得到一些持续的缓解，这种缓解可能会持续几个月或更长时间，然后他们必须重复每周两次，持续三周的方案。

Now, certainly not all studies of using ketamine for the treatment of depression have used that exact dosage regimen, twice a week for three weeks, then take some time off, repeat.

现在，当然并不是所有使用氯胺酮治疗抑郁症的研究都使用了精确的剂量方案，每周两次，持续三周，然后休息一段时间，重复。

Twice a week for three weeks, take some time off, repeat.

每周两次，持续三周，休息一段时间，重复。

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.

有些人尝试每周给予氯胺酮一次甚至每周三次，或者每周给予一次氯胺酮，持续五周，然后在重复治疗计划之前休息较长一段时间。

There are a bunch of different studies out there, but when one looks at all of those studies en masse together, it's very clear that ketamine is providing relief from depressive symptoms immediately and in the days after the treatment.

有很多不同的研究，但是当我们把所有这些研究放在一起时，很明显氯胺酮可以立即以及在治疗后的几天内缓解抑郁症状。

But that when those treatments are stacked fairly closely together, that there is some durability, some ongoing relief from depression.

但当这些治疗方法相当紧密地结合在一起时，就会有一定的持久性，并能持续缓解抑郁症。

And what this tells us is very important.

这告诉我们非常重要。

In fact, I hope everybody really highlight this in their minds as they're hearing it.

事实上，我希望每个人在听到这句话时都能在脑海中真正强调这一点。

It's very likely that ketamine is acting by at least two and probably three different mechanisms in order to provide relief from depression.

氯胺酮很可能通过至少两种甚至三种不同的机制发挥作用，以缓解抑郁症。

One of those mechanisms induces relief from depression very quickly and seems to be associated with that euphoric, dissociative, dreamlike state that one experiences when they are under the influence of ketamine.

其中一种机制可以很快缓解抑郁症，并且似乎与人们在氯胺酮影响下所经历的欣快、解离、梦幻般的状态有关。

The second mechanism seems to provide relief from depression in the days and weeks that follow the ketamine treatment.

第二种机制似乎可以在氯胺酮治疗后的几天或几周内缓解抑郁症。

And there also appears to be a third mechanism by which ketamine can induce long-lasting changes in the nervous system.

氯胺酮似乎还有第三种机制可以引起神经系统的持久变化。

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.

正是这三种机制，即短期、中期和长期机制，产生了神经化学的变化，更重要的是，实际神经回路接线的变化，使氯胺酮能够令人难以置信地缓解抑郁症。

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.

接下来，我们将讨论这些机制是什么，因为在了解这些机制时，您将了解氯胺酮如何缓解抑郁症，但您还将了解更重要的更广泛的主题，即抑郁症在神经回路层面的真正含义以及抑郁症的缓解如何与神经可塑性有关。

So how is ketamine really working?

那么氯胺酮到底是如何发挥作用的呢？

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.

我们已经确定氯胺酮会阻断 NMDA 受体，并且 NMDA 受体对于多种形式（不是全部）但多种形式的神经可塑性至关重要。

Now, I realize some of you might be familiar with so-called ligands and receptors, but most of you probably are not.

现在，我意识到你们中的一些人可能熟悉所谓的配体和受体，但你们中的大多数人可能并不熟悉。

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.

配体是一种与受体结合的化学物质，而受体就像细胞外部的一个小停车位。

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.

细胞内部也可能存在受体，但大多数时候，当我们谈论神经细胞、神经元时，您听到受体这个词时，您听到的是细胞外部的受体。

So the NMDA receptor does not exist in our neurons in order to bind ketamine.

因此，我们的神经元中不存在用于结合氯胺酮的 NMDA 受体。

It's there actually to bind all sorts of other things that are endogenous, that are naturally made by us.

它实际上是为了结合我们自然产生的各种其他内生事物。

But ketamine has a very high, what's called affinity.

但氯胺酮具有非常高的亲和力。

It has a very high probability of binding to the NMDA receptor if it's introduced to our bloodstream.

如果它被引入我们的血液中，它就有非常高的概率与 NMDA 受体结合。

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, the so-called BBB, blood-brain barrier.

因此，当氯胺酮以药丸形式、舌下形式（即舌下）服用时，当将其注射到肌肉或静脉中时，它会进入血液，然后能够轻松穿过血脑屏障，即所谓的 BBB，血脑屏障。

The blood-brain barrier keeps a lot of things out of the brain, but ketamine can very readily pass across the blood-brain barrier.

血脑屏障将很多东西挡在大脑之外，但氯胺酮很容易穿过血脑屏障。

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.

一旦进入大脑，它就具有非常高的亲和力，这意味着它知道如何寻找并结合那些 NMDA 受体。

Now, the simplest way to explain how NMDA receptors ordinarily contribute to neuroplasticity is that they represent what's called an AND gate.

现在，解释 NMDA 受体通常如何促进神经可塑性的最简单方法是它们代表所谓的“与”门。

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.

顾名思义，与门是细胞或系统中必须存在两个事物的函数。

In fact, for those of you that have a bit of an engineering or computer programming background, you'll be familiar with AND gates.

事实上，对于那些有一点工程或计算机编程背景的人来说，您会熟悉“与”门。

For those of you that don't, don't worry about it, I'm going to explain what an AND gate is right now.

对于那些不知道的人，不用担心，我现在将解释什么是“与”门。

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.

神经系统功能中的“与”门是指当存在两种物质时，例如化学物质 A 和化学物质 B 都必须存在，才能发生某些过程（例如神经可塑性）。

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.

正如我之前提到的，NMDA 受体是神经元表面的受体，它与谷氨酸（我们大脑中产生的一种分子）结合，并激活其他神经元。

It's what's called an excitatory neurotransmitter.

这就是所谓的兴奋性神经递质。

Now, there are lots of different receptors for glutamate, and those receptors are binding glutamate all the time.

现在，谷氨酸有很多不同的受体，并且这些受体始终与谷氨酸结合。

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.

然而，为了激活 NMDA 受体，必须存在大量谷氨酸，并且必须在很短的时间内发生。

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.

因此，NMDA 受体是一个与门，谷氨酸必须存在并与其结合，并且它必须获得大量的电活动、大量的输入才能发生这种情况。

So it's a receptor that responds primarily to unusually high or frequent levels of electrical activity.

因此，它是一种主要对异常高或频繁的电活动水平做出反应的受体。

Let's place this in real-world context so that it makes a bit more sense.

让我们把它放在现实世界中，这样它就更有意义了。

I like most all of you in moving my arms around a lot throughout the day.

我最喜欢你们所有人全天频繁地活动手臂。

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.

现在，作为一个成年人，我的运动皮层，即控制四肢运动协调的大脑区域，从我的大脑到我的脊髓，从我的脊髓到我的肌肉都有连接，这就是我能够移动四肢的原因。

Under conditions of just moving my limbs and doing things throughout the day, drinking a cup of coffee or yerba mate, 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.

在整天活动我的四肢、做一些事情、喝一杯咖啡或马黛茶、早上到外面散步看看阳光、做我每天都会做的事情以及我已经知道该怎么做的事情的情况下，谷氨酸肯定参与了这个过程。

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.

谷氨酸与其其他受体类型（称为 AMPA 受体）结合，对于那些想知道的人来说，它参与了该过程。

It's typical levels of activity.

这是典型的活动水平。

If, however, I were to sit down at this desk and be commanded to or decide to do some specific motor limb movement.

然而，如果我坐在这张桌子前并被命令或决定做一些特定的运动肢体运动。

Let's say move my hand in a three-dot sequence.

假设以三点顺序移动我的手。

For those of you watching, you can see this.

对于那些正在观看的人来说，您可以看到这一点。

For those of you that are listening, don't worry about it, it's not very interesting to watch.

对于那些正在听的人，不要担心，观看起来并不是很有趣。

The point is just that I'm going to put my finger down in one, two, three points on the desk in front of me, and then three, two, one points coming back to me.

重点是我要把手指放在我面前的桌子上一、二、三点，然后三、二、一点回到我身上。

Now, that's obviously a motor sequence that I can perform.

现在，这显然是我可以执行的运动序列。

I just did it, so clearly I can perform it.

我刚刚做到了，所以很明显我可以执行它。

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.

但如果我这样做一个小时，会发生的情况是，参与生成一、二、三、三、二、一、一、二、三、三、二、一运动序列的神经元将一遍又一遍地活跃。

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, 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.

坦率地说，由于这种不寻常的运动行为，可能会发生的情况是，负责产生这种运动行为的神经元将能够检测到产生这种行为的回路中异常频繁、异常高水平的活动，并且影响该回路中神经元的谷氨酸的增加会与 NMDA 受体结合，使其改变一些重要的事情。

The first of which is that your nervous system is capable of changing, but that's an energetically demanding process.

首先，你的神经系统能够改变，但这是一个需要精力的过程。

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.

因此，关于神经可塑性的令人难以置信的事情是，当你产生异常高或只是一种不寻常的活动模式、运动活动时，或者你正在听到一种新语言，你正在尝试学习它，或者你正在探索一个新城市时，神经元会以非典型的方式放电，而且放电的次数要多得多。

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.

因此，神经元将结合谷氨酸，NMDA 受体将被激活，然后 NMDA 受体激活的下游是一系列我们所说的细胞内过程，细胞中发生的一系列事情，试图在需要时一次又一次地发生这种行为，但不需要巨大的能量需求。

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.

你以前经历过这种情况，当你试图学习某样东西时，感觉缓慢、困难、令人沮丧，然后最终你学会了，它非常轻松、非常容易。

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 AMPA 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, et cetera.

原因之一是，当 NMDA 受体被这些不常见或不寻常的活动模式激活时，它可以招募其他谷氨酸受体，更典型的一种，即 AMPA 型受体到细胞表面，然后这些受体可以简单地结合谷氨酸，并允许这种行为发生，而无需参与神经可塑性的整个过程，并进行诸如在细胞中构建新蛋白质、构建新机器等事情。

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.

因此，退一步来说，思考 NMDA 受体的方法是，NMDA 受体的激活仅发生在异常高或异常活动模式的条件下，NMDA 受体，是的，直接控制神经活动，就像当它被激活时，它肯定会改变神经元的活动模式。

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.

但它也可以参与基因表达并向细胞引入新的受体，基本上使细胞能够重新创建相同的活动模式，而不必以如此代谢要求高的方式进行。

In fact, a good analogy for all of this is the way that muscles can hypertrophy.

事实上，所有这一切的一个很好的类比就是肌肉肥大的方式。

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 innervate, that control the contraction of those muscles, and then those muscles grow, they get stronger, et cetera, and they're able to function and use that new strength and new growth.

如果你通过任何类型的阻力训练适当地使肌肉超负荷，然后让它们休息一段时间，就会向肌肉纤维募集特定的物质，并募集神经支配的变化，控制这些肌肉的收缩，然后这些肌肉就会生长，变得更强，等等，并且它们能够发挥作用并利用新的力量和新的生长。

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.

而且你不必损害这些肌肉纤维或一遍又一遍地触发这些适应来维持它们，因为你拥有这种新能力。

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 important forms of neuroplasticity, it would be the NMDA receptor and its functions that I just told you about.

现在，我意识到关于 NMDA 受体和神经可塑性的细节很多，但实际上，如果我们需要选择一种位于许多重要神经可塑性形式中心的生物机制，那就是我刚才告诉你的 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.

因此，既然您已经了解了这些 NMDA 受体对于检测异常活动、对细胞进行改变以便这些细胞能够在未来对该活动做出反应至关重要，那么您就已经了解了了解氯胺酮如何发挥作用的概念基础。

Because as I've mentioned several times already, ketamine is an NMDA receptor blocker, antagonist.

因为正如我已经多次提到的，氯胺酮是一种 NMDA 受体阻滞剂、拮抗剂。

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.

然而我们知道，大脑从抑郁状态向非抑郁状态转变的许多变化都涉及神经可塑性。

So what's going on there?

那么那里发生了什么？

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.

嗯，事实证明，那里发生的事情非常有趣，如果您了解大脑中本质上有两种主要类型的神经元，您就可以很容易地理解它。

You have those excitatory neurons, meaning neurons that when they are activated electrically, they activate or excite other neurons.

你有那些兴奋性神经元，这意味着当它们被电激活时，它们会激活或兴奋其他神经元。

At least they try to.

至少他们尝试这样做。

They release neurotransmitter into the synapse, which is the little gap between neurons.

它们将神经递质释放到突触中，突触是神经元之间的小间隙。

The neurons on the other side have receptors.

另一侧的神经元有受体。

They bind those neurotransmitters, in this case, glutamate, which is the major excitatory neurotransmitter in the brain, and then there's a high probability that those other neurons will be excited, that they will be electrically active.

它们与这些神经递质结合，在这种情况下，谷氨酸是大脑中主要的兴奋性神经递质，然后其他神经元很可能会被兴奋，它们会产生电活动。

That's one major type of so-called neurotransmission in the brain.

这是大脑中所谓的神经传递的一种主要类型。

The other major type of neurotransmission in the brain is called inhibitory neurotransmission.

大脑中另一种主要的神经传递类型称为抑制性神经传递。

Inhibitory neurotransmission involves neurons that release the neurotransmitter GABA, or sometimes also another molecule called glycine, but mostly GABA.

抑制性神经传递涉及释放神经递质 GABA 的神经元，有时也释放另一种称为甘氨酸的分子，但主要是 GABA。

When GABA is released, it has the property of reducing the probability that the next neuron will be electrically active.

当 GABA 被释放时，它具有降低下一个神经元电活动概率的特性。

In fact, GABA's job is to bind to receptors on the next cell and to make it less electrically active.

事实上，GABA 的作用是与下一个细胞上的受体结合并降低其电活性。

So we've got excitatory neurotransmission, and we have inhibitory neurotransmission.

所以我们有兴奋性神经传递，也有抑制性神经传递。

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.

为了将抑制性和兴奋性神经传递放在背景中，如果你考虑一下像癫痫这样的疾病，这种疾病涉及较小类型的癫痫发作，称为小癫痫发作或大癫痫发作，这是人们全身抽搐的类型。

They are often disengaged from whatever's going on around them in those moments.

在那些时刻，他们常常脱离周围发生的一切。

They're shaking quite a lot, et cetera.

他们摇晃得很厉害，等等。

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.

癫痫发作的原因有很多，但要深入了解癫痫发作的本质，它本质上是大脑失控的兴奋。

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.

大脑的一小部分区域变得特别电活跃，然后它从那个焦点（兴奋的焦点）扩散开来，它以一种相当非特定的方式招募大量神经元，在身体中产生这些类似癫痫发作的运动模式和大脑中的活动模式，这些模式可能涉及脱离直接经验和缺乏感知。

Sometimes there's aura.

有时候还有灵气。

There's a whole discussion to be had about seizure.

关于癫痫发作有一个完整的讨论。

And by the way, seizure can occur in a lot of different contexts.

顺便说一下，癫痫发作可能发生在许多不同的情况下。

Of course, it can occur in epilepsy, it can occur after a head injury, et cetera.

当然，它可以发生在癫痫症中，也可以发生在头部受伤后等等。

We'll cover seizure in a future episode of this podcast, of course.

当然，我们将在本播客的下一集中介绍癫痫发作。

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.

但癫痫发作以及缺乏癫痫发作的主要原因之一是，通常情况下，抑制性神经元和兴奋性神经元处于这种推拉状态，对于没有经历过癫痫发作的人来说，使大脑保持平衡，因此他们不会癫痫发作。

The inhibitory neurons are suppressing the activity of many neurons so that those many neurons don't get runaway excitation.

抑制性神经元抑制许多神经元的活动，这样许多神经元就不会受到失控的兴奋。

You don't get seizures.

你不会癫痫发作。

The excitatory neurons are feeding back onto the inhibitory neurons, so everything is kept in balance.

兴奋性神经元反馈到抑制性神经元，因此一切都保持平衡。

There isn't too much inhibition.

没有太多的抑制。

There isn't too much excitation.

没有太多的兴奋。

Everything's in balance.

一切都处于平衡状态。

Okay, so now you understand that there are NMDA receptors, and these are critical for many forms of neuroplasticity.

好的，现在您了解了 NMDA 受体的存在，它们对于多种形式的神经可塑性至关重要。

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.

您还了解，兴奋性神经元会刺激其他神经元的电活动，大脑中存在抑制性神经元，会抑制或抑制其他神经元的活动，神经元之间始终需要兴奋性和抑制性通信，并且必须保持平衡，并且 NMDA 受体通常只是坐在那里，不会做很多事情，除非神经活动水平升高到高于其正常基线，然后您可以在神经回路中发生变化，这些变化可能是非常大的。持久。

And 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.

我们不要忘记与今天的讨论最相关的一条信息，它是关于氯胺酮的，即氯胺酮会阻断 NMDA 受体。

And there's the conundrum I keep coming back to, which is you need neuroplasticity in order to get relief from depression.

我不断回到一个难题，那就是你需要神经可塑性才能缓解抑郁症。

So what researchers have discovered is that, yes, ketamine blocks the NMDA receptor.

研究人员发现，氯胺酮确实可以阻断 NMDA 受体。

It actually quiets down neurons.

它实际上可以让神经元安静下来。

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, in reward, in self-reflection.

它阻止神经元像平常一样活跃，但不知何故，几乎自相矛盾的是，它增加了涉及情绪、奖励和自我反思的大脑回路的神经可塑性。

We'll get into what those brain circuits are in a little bit.

我们将稍微了解一下这些大脑回路。

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.

它的工作原理是氯胺酮与抑制性神经元上的 NMDA 受体结合，从而显着减少抑制性神经元对兴奋性神经元的抑制量。

When that happens, the excitatory neurons in specific circuits of the brain are allowed to increase their activity.

当这种情况发生时，大脑特定回路中的兴奋性神经元就会增加其活动。

They do what's called bursting.

他们所做的就是所谓的爆裂。

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.

爆发是一种电活动模式，通常这些兴奋性神经元之一会以看起来或听起来像这样的模式释放谷氨酸。

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 a .

它实际上不会在大脑中发出声音，但如果你要从这些神经元之一进行记录（人们已经做过很多次了），然后你将这些神经元中的电信号转换为音频监视器，你会听到放电，这些神经元的动作电位作为.

That's what it actually sounds like on the audio monitor.

这就是音频监视器上实际听起来的样子。

It sounds like a little bit of static .

听起来有点静电。

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.

但是，如果神经元的正常放电是 ，这就是我将要讨论的与情绪相关的电路中神经元的非常典型的基线放电。

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.

在氯胺酮进入系统的情况下，它会与 NMDA 受体结合，阻止这些抑制性神经元向兴奋性神经元的输出。

Now the excitatory neuron is firing in bursts .

现在兴奋性神经元正在爆发性放电。

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.

这些爆发性的电活动模式是绝对完美的活动模式，它不仅会引起与奖励、多巴胺释放、失望以及情绪相关的神经回路的短期变化，而且会导致长期变化，这些变化与抑制或缓解重度抑郁症的症状直接相关。

Now, I realize what I just told you is a lot of information.

现在，我意识到我刚才告诉你的信息量很大。

In fact, what I just described represents essentially what I would teach to an advanced undergraduate/graduate course, medical school course on neuroplasticity and how ketamine works.

事实上，我刚才描述的基本上代表了我将向高级本科生/研究生课程、医学院神经可塑性课程以及氯胺酮如何发挥作用所教授的内容。

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 of what I just described, you're doing great.

所以请记住，我们在这里进行的讨论是相当高水平的，如果你能理解我刚才描述的哪怕一小部分，哪怕只是一点点，你就做得很好了。

If you could understand more, outstanding.

如果你能理解更多，那就太棒了。

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.

只是为了确保每个人都在我们前进的同一页面上，因为我确实想确保每个人都了解氯胺酮及其工作原理，因为它确实具有以不明显的方式参与神经可塑性的神秘功能。

If you just ask, what does ketamine do when you inject it?

如果你问，注射氯胺酮会起什么作用？

What does ketamine produce in terms of a feeling state?

氯胺酮会产生什么感觉状态？

And then, how does somebody get relief from depression?

那么，人们如何摆脱抑郁症呢？

That can all start to get a little bit muddled unless you understand the following.

除非您理解以下内容，否则这一切可能会开始变得有点混乱。

So I'm going to tell it to you again in just very top contour terms.

因此，我将用非常重要的轮廓术语再次告诉您。

Somebody takes a pill or an injection or sublingual ketamine.

有人服用药丸、注射剂或舌下含服氯胺酮。

It makes its way into the bloodstream, and then it makes its way into the brain.

它进入血液，然后进入大脑。

Once it's in the brain, it binds to a particular category of receptors called the NMDA receptor.

一旦进入大脑，它就会与一种称为 NMDA 受体的特定受体结合。

The NMDA receptor is a receptor that normally is quiescent.

NMDA 受体是一种通常处于静止状态的受体。

It's just kind of sitting there.

它只是坐在那里。

It doesn't tend to do a lot under normal conditions of everyday life.

在日常生活的正常情况下，它往往不会做很多事情。

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.

然而，NMDA 受体的典型功能是，当身体或大脑中没有氯胺酮时，NMDA 受体的典型功能是检测神经活动的异常水平，并在此过程中招募细胞、受体等的变化。

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.

从字面上改变神经元，使它们能够在未来对这种活动做出反应，而不必承受如此大的代谢需求。

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.

他们通过招募更多的受体来做到这一点，等等，就像你在健身房里超负荷的肌肉一样，如果你允许它恢复，它最终会恢复，并且通过添加一堆新的蛋白质，它会变得更强。

The nerve communication of that muscle will change.

该肌肉的神经通讯将会改变。

The muscle and the nerve to muscle connection change.

肌肉和神经与肌肉的连接发生变化。

It gets stronger, and sometimes it gets bigger and stronger.

它变得越来越强，有时它变得越来越大、越来越强。

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.

同样，神经元可以根据经验改变其功能方式，而神经元除了影响它们的电活动和化学活动模式外，不以任何其他方式了解生活经验。

Okay?

好的？

Now, ketamine the drug binds to and blocks that NMDA receptor.

现在，氯胺酮这种药物可以结合并阻断 NMDA 受体。

So the obvious conclusion would be that ketamine prevents neuroplasticity, and that's not what happens.

因此，显而易见的结论是氯胺酮可以防止神经可塑性，但事实并非如此。

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.

我们知道氯胺酮实际上会诱导神经可塑性，而且它特别是在控制情绪的大脑回路中发挥作用，最终结果是情绪的改善。

How does that happen?

这是怎么发生的？

It happens because ketamine binds to and blocks those NMDA receptors on inhibitory neurons.

发生这种情况是因为氯胺酮与抑制性神经元上的 NMDA 受体结合并阻断这些受体。

The inhibitory neurons are the neurons that normally suppress the activity of other neurons.

抑制性神经元是通常抑制其他神经元活动的神经元。

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.

因此，当氯胺酮与 NMDA 受体结合时，这些抑制性神经元的活性就会降低，结果，这些情绪相关回路中的神经元之间的兴奋性通讯就会增加。

And it increases it in a way that recruits neuroplasticity, that strengthens those connections, and makes them more likely to be active in the future.

它以一种招募神经可塑性的方式增加这种联系，加强这些联系，并使它们在未来更有可能活跃起来。

Now, it is not the case, at least at clinical doses, that ketamine induces seizures.

现在，至少在临床剂量下，氯胺酮不会引起癫痫发作。

It certainly can at higher doses.

在更高剂量下当然可以。

But at clinical doses, when ketamine suppresses the activity of those inhibitory neurons and the excitatory neurons ramp up their activity, they're ramping up their activity a lot and enough to create changes in those neural circuits associated with mood.

但在临床剂量下，当氯胺酮抑制这些抑制性神经元的活动而兴奋性神经元增强其活动时，它们的活动会大量增强，足以在与情绪相关的神经回路中产生变化。

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.

这些变化的方向是使这些神经回路更有可能产生积极情绪，而不太可能产生消极情绪。

We'll get into the specifics of those circuits in a little bit.

我们将稍微了解这些电路的细节。

But ketamine is not creating the kind of enormous increases in excitatory communication between neurons that leads to that runaway excitation.

但氯胺酮并没有大幅增加神经元之间的兴奋性通讯，从而导致失控的兴奋。

Now, the point of the discussion we just had over the last 10 minutes or so was severalfold.

现在，我们在过去 10 分钟左右的时间里进行的讨论有几个要点。

First of all, I do believe it's important to understand the key components of neuroplasticity, which is this remarkable feature of our brain and nervous system that we all have This ability to change our own brain circuits.

首先，我确实认为了解神经可塑性的关键组成部分很重要，这是我们大脑和神经系统的显着特征，我们所有人都具有这种改变我们自己的大脑回路的能力。

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.

据我们所知，身体中没有其他器官可以指导自己的变化，但我们可以指导自己的大脑变化，而 NMDA 受体对此绝对至关重要。

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.

我还认为了解神经元之间的抑制性和兴奋性通讯之间的差异很重要，因为这对于理解大脑功能至关重要。

Brain function is a series of accelerators and brakes.

大脑功能是一系列的加速器和刹车。

It's not all about neurons stimulating other neurons.

这并不全是神经元刺激其他神经元的问题。

It's also about neurons preventing the activation of other neurons.

它还涉及神经元阻止其他神经元激活的问题。

That's just central to everything.

这是一切的核心。

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.

它不仅可以预防癫痫发作，而且对于学习、视觉、听力和创造力都至关重要。

It is at the core of brain function.

它是大脑功能的核心。

And the other reason to have the discussion we just did is that ketamine has this incredible property.

我们刚才进行讨论的另一个原因是氯胺酮具有这种令人难以置信的特性。

It can literally change the neural circuits that generate mood, that generate your feelings of wellbeing, but it does so through a somewhat convoluted pathway, right?

它确实可以改变产生情绪、产生幸福感的神经回路，但它是通过一个有点复杂的途径实现的，对吗？

It blocks the receptor that everyone thinks is involved in neuroplasticity, and in doing so, it actually creates neuroplasticity.

它阻断了每个人都认为与神经可塑性有关的受体，这样做实际上创造了神经可塑性。

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.

现在，尽管我刚刚在过去 10 分钟左右向您描述了所有这些，但请记住，我刚才向您描述的过程实际上在大脑中发生需要很多很多天。

It involves cells changing gene expression, making new proteins, new receptors.

它涉及细胞改变基因表达、制造新蛋白质、新受体。

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.

每当我们谈到神经可塑性时，即使你读到所谓的短期神经可塑性，它也至少在许多、许多小时、更有可能是许多天甚至几周的过程中发生。

So the process 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.

因此，我刚才描述的氯胺酮如何通过阻断 NMDA 受体产生神经可塑性的过程很可能是解释与氯胺酮治疗抑郁症相关的情绪和情感的长期变化的过程。

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.

现在，氯胺酮阻断 NMDA 受体也可能是人们服用氯胺酮时所经历的一些直接影响的原因。

The dissociation, the, in some cases, euphoria, and that sort of dreamlike state that it can put people into.

分离，在某些情况下，欣快感，以及它可以让人进入的那种梦幻般的状态。

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.

这是可能的，但很明显，NMDA 受体阻断对于氯胺酮治疗后数天或数周内将发生的神经塑性变化至关重要。

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.

如果你回想一下我们之前的讨论，当时我们正在讨论每周两次或三周以上的服用氯胺酮的方案或其他方案，那么现在可能开始明白为什么在临床适当的情况下服用氯胺酮治疗抑郁症会产生直接和短期的益处。

I'm not talking about recreational use right now.

我现在不是在谈论娱乐用途。

But that also there's some durability of those effects.

但这些影响也有一定的持久性。

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.

即使在每周服用两次氯胺酮三周后，当人们不进行每周一次的氯胺酮治疗时，抑郁症通常也会得到数周或数月的缓解。

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.

因此，我所说的治疗持久性的长期缓解很可能是实际神经回路重新布线的结果。

Now there's an additional and very important facet to this whole discussion about neuroplasticity in response to ketamine treatment for depression.

现在，关于氯胺酮治疗抑郁症的神经可塑性的整个讨论还有一个非常重要的额外方面。

If you recall the burst firing that induces that plasticity, I told you it induces plasticity, but I didn't tell you how.

如果你还记得引发可塑性的爆发射击，我告诉过你它会引发可塑性，但我没有告诉你如何引发。

Now you already could imagine some of the mechanisms.

现在你已经可以想象一些机制了。

It could be insertion of those new glutamate receptors, those AMPA receptors that we talked about.

它可能是插入那些新的谷氨酸受体，即我们谈到的 AMPA 受体。

However, even for that to happen, a bunch of other things have to happen first.

然而，即使要实现这一点，也必须先发生许多其他事情。

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 neurotrophic factor.

但要理解的关键之一是我在今天节目开始时提到的 BDNF，它代表脑源性神经营养因子。

Brain-derived neurotrophic factor is an incredible molecule.

脑源性神经营养因子是一种令人难以置信的分子。

I should mention that it's one of many growth factors in the brain, and it has its own set of receptors.

我应该提到，它是大脑中的众多生长因子之一，并且有自己的一组受体。

It binds to something called the TrkB receptor, T-R-K-B, TrkB receptor.

它与 TrkB 受体、T-R-K-B、TrkB 受体结合。

When BDNF binds to TrkB receptors on neurons, it does a lot of things.

当 BDNF 与神经元上的 TrkB 受体结合时，它会做很多事情。

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.

它引发了一系列的事情，包括插入新的谷氨酸受体，使这些神经元对它们获得的任何输入变得格外敏感。

And so that's one form of change that BDNF can create.

这就是 BDNF 可以创造的一种改变形式。

BDNF can also alter the overall shape of neurons.

BDNF 还可以改变神经元的整体形状。

It can cause neurons to grow new branches so that it can receive new inputs from other neurons.

它可以导致神经元长出新的分支，以便它可以接收来自其他神经元的新输入。

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.

每当流行书籍或大众媒体讨论 BDNF 时，人们都会将其称为“神经元肥料”。我不太喜欢这个词，因为它确实低估了 BDNF 可以做的事情的总数。

BDNF actually can act as its own kind of neurotransmitter.

BDNF 实际上可以充当自己的神经递质。

It can actually stimulate other neurons, and it does a bunch of other things.

它实际上可以刺激其他神经元，并且可以做很多其他事情。

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.

但为了讨论氯胺酮，请了解神经元的突发放电，神经元的高频放电可以引发 BDNF 的释放，从而使这些电路非常快速地具有可塑性。

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 to you a few minutes ago.

除此之外，有一些证据表明氯胺酮本身可能能够直接导致 BDNF 的释放，而无需经历我几分钟前让您不知所措的所有机制，或者希望没有让您不知所措，但我几分钟前教给您的。

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 isn't just one of the ways in which ketamine can invoke neuroplasticity and these improvements in mood, it may actually be required.

现在，在氯胺酮治疗抑郁症的背景下，BDNF 特别令人兴奋的是，根据临床前和临床研究，BDNF 似乎不仅仅是氯胺酮引发神经可塑性和情绪改善的方式之一，它实际上可能是必需的。

It may be the central process to all of that.

这可能是所有这一切的核心过程。

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.

现在它仍然可以是我们之前讨论过的所有 NMDA 受体物质的下游，但有几条证据表明氯胺酮诱导的 BDNF 释放是氯胺酮缓解抑郁症的核心机制之一。

Now there are several lines of evidence to support what I just said about BDNF in the context of ketamine.

现在有几条证据可以支持我刚才所说的关于氯胺酮背景下的 BDNF 的内容。

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.

首先，缺乏BDNF的小鼠，它们没有BDNF，它们不能制造BDNF，因为它们没有BDNF的基因，我们称之为BDNF敲除小鼠。

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 into water and see how long they swim.

在这些小鼠中，如果你给它们氯胺酮，然后将它们放入我们之前讨论过的习得性无助任务中，将它们放入水中，看看它们游了多长时间。

Normally, ketamine would allow a mouse to swim longer to fight for its life longer.

通常情况下，氯胺酮可以让老鼠游得更久，以争取更长的寿命。

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.

嗯，在 BDNF 敲除小鼠中，它不再这样做，据我们所知，该小鼠唯一不同的是缺乏 BDNF。

And there are ways to make sure that its 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, et cetera.

有一些方法可以确保与我们正在谈论的一切相关的特定神经元中缺乏 BDNF，而不仅仅是它们的四肢不能正常工作等等。

In other words, all the appropriate control experiments have been done.

换句话说，所有适当的对照实验都已经完成。

That's preclinical data because it comes from animal models.

这是临床前数据，因为它来自动物模型。

In addition to that, depressed people who have a mutant form of BDNF.

除此之外，患有 BDNF 突变型的抑郁症患者。

So these humans are not knockouts for BDNF.

所以这些人并没有被 BDNF 淘汰。

They can make BDNF, but the BDNF doesn't function normally.

它们可以产生 BDNF，但 BDNF 不能正常发挥作用。

In those people, they have a very reduced response to ketamine treatment for depression, suggesting that BDNF action is at least one of the critical functions that allows ketamine to relieve depression.

在这些人中，他们对氯胺酮治疗抑郁症的反应非常低，这表明 BDNF 作用至少是氯胺酮缓解抑郁症的关键功能之一。

And as I mentioned earlier, ketamine can actually invoke the release of BDNF.

正如我之前提到的，氯胺酮实际上可以引发 BDNF 的释放。

And get this, there's some evidence that ketamine itself can bind to the TrkB receptor.

明白了，有一些证据表明氯胺酮本身可以与 TrkB 受体结合。

That is, it can bind to the BDNF receptor.

也就是说，它可以与BDNF受体结合。

It can mimic BDNF.

它可以模仿 BDNF。

So this is an entirely different way of thinking about ketamine than we normally hear about.

因此，这是一种与我们通常听到的完全不同的思考氯胺酮的方式。

Nowadays, we hear a lot about ketamine and ketamine therapy.

如今，我们听到很多关于氯胺酮和氯胺酮疗法的信息。

We also hear, fortunately, about some of the problems of ketamine abuse, and we will talk about some of those concerns a little bit later.

幸运的是，我们也听说了氯胺酮滥用的一些问题，稍后我们将讨论其中的一些问题。

And we hear about BDNF, this so-called brain fertilizer.

我们听说过 BDNF，这种所谓的大脑肥料。

But rarely, if ever, do we hear that ketamine itself can mimic the effects of BDNF in the brain.

但我们很少听说氯胺酮本身可以模仿大脑中 BDNF 的作用。

But researchers and clinicians are definitely paying attention to this.

但研究人员和临床医生肯定正在关注这一点。

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.

它开始提出一个我认为非常令人兴奋的模型，说明氯胺酮如何缓解抑郁症，即它作为大脑中的生长因子，或者至少它模仿生长因子的作用，允许控制情绪、未来展望、自我反思等的特定神经回路，使这些回路以显着缓解重度抑郁症的方式发生变化。

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.

在这样做的过程中，这是非常重要的一点，氯胺酮似乎正在以与任何其他治疗方法完全不同的方式缓解抑郁症。

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.

现在，在关于裸盖菇素及其治疗抑郁症的潜在作用的早期剧集中，我深入探讨了裸盖菇素如何诱导神经可塑性，从而在某些条件下缓解某些个体的重度抑郁症。

I do want to highlight that because indeed, it's another case where neuroplasticity is involved.

我确实想强调这一点，因为事实上，这是涉及神经可塑性的另一个案例。

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.

但在那种情况下，正如你们中的一些人可能还记得的那样，或者如果你们不记得的话，别担心，我现在就告诉你们，这是一个非常简单的模型。

Psilocybin looks a lot like serotonin chemically, except that psilocybin binds a particular receptor.

裸盖菇素在化学上看起来很像血清素，只是裸盖菇素结合特定的受体。

When that receptor is bound, it allows these brain-wide changes.

当该受体被结合时，它就会允许这些大脑范围内的变化。

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.

这些大脑范围的变化似乎改变了一个人对自己的反思，所谓的自我消解，随着时间的推移稳定的情绪变化等等。

It was all pretty straightforward.

一切都很简单。

With ketamine, it's clear there are multiple mechanisms involved.

对于氯胺酮，很明显涉及多种机制。

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.

也许最重要的是，对于氯胺酮，治疗当天或接近当天以及治疗后几天会立即出现缓解。

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.

这种长期缓解很可能是 NMDA 受体抑制、这些情绪相关回路中神经元的爆发活动、BDNF 被释放并改变神经回路、强化它们以因爆发活动而带来情绪升高以及氯胺酮模仿 BDNF 的结果。

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 and last over time.

换句话说，氯胺酮或多或少就像大脑中的生长因子一样，以确保这些神经回路中发生的任何提升情绪的变化都是持久的，并且它们确实会随着时间的推移而得到加强和持续。

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.

基本上，我已经讨论了氯胺酮如何诱导神经可塑性的两种主要机制，从而改善情绪和情感，从而缓解抑郁症。

Those two mechanisms are linked, or at the very least, are happening in parallel.

这两种机制是相互关联的，或者至少是并行发生的。

They're happening at the same time in the brain.

它们在大脑中同时发生。

Now, just to make matters more interesting, there's an incredible twist into this whole thing of how ketamine works.

现在，为了让事情变得更有趣，氯胺酮的作用原理发生了令人难以置信的转变。

And when I say how ketamine works, I'm not just talking about how ketamine provides relief for depression.

当我说氯胺酮如何发挥作用时，我不仅仅是在谈论氯胺酮如何缓解抑郁症。

I'm also talking about why people use ketamine for recreational purposes.

我还谈到了为什么人们使用氯胺酮进行娱乐。

And it is the following.

如下。

Yes, ketamine has all these impacts on excitatory neurons, inhibitory neurons, BDNF, et cetera.

是的，氯胺酮对兴奋性神经元、抑制性神经元、BDNF 等都有所有这些影响。

But ketamine can also bind receptors in the opioid pathway.

但氯胺酮也可以结合阿片途径中的受体。

Now, what is the opioid pathway?

现在，阿片类途径是什么？

Don't worry.

不用担心。

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.

在这里，我不会向你们提供太多细节，但我们现在都听说过阿片类药物危机，或者至少你们大多数人都听说过。

The opioid crisis refers specifically to people taking exogenous opioids, taking opioids.

阿片类药物危机特指人们服用外源性阿片类药物、服用阿片类药物。

Right?

正确的？

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.

因此，服用能够激活大脑中特定受体的药物，在某些情况下会产生镇痛作用，从而缓解疼痛，从而导致情绪变化。

There's a lot to be said about the opioid crisis.

关于阿片类药物危机有很多话要说。

It's called a crisis for a reason.

它被称为危机是有原因的。

Many, many people are addicted to those compounds.

很多很多人对这些化合物上瘾。

That's a discussion for another time.

这是下次再讨论的事。

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.

请记住，这些药物结合的受体是阿片类受体，顺便说一句，你和我都拥有的那些受体并不存在于结合制药公司生产的药物。

They exist in our brain and body to bind to the so-called endogenous, naturally made opioids that we all make.

它们存在于我们的大脑和身体中，与我们所有人都会产生的所谓内源性、自然产生的阿片类药物结合。

And those receptors have different names, the mu opioid receptor, the kappa opioid receptor, et cetera.

这些受体有不同的名称，μ阿片受体、κ阿片受体等等。

They tend to have the names of Greek letters to differentiate them.

它们往往使用希腊字母的名称来区分它们。

Now, ketamine can bind to various opioid receptors.

现在，氯胺酮可以与各种阿片受体结合。

And when opioid receptors are bound, we know that creates certain effects.

我们知道，当阿片受体结合时，会产生一定的效果。

Things like pain relief, things like changes in psychic states, dissociation, for example.

例如缓解疼痛、改变精神状态、解离等。

If enough of them are bound, you can get euphoric states.

如果有足够多的物质被束缚，你就能获得欣快的状态。

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.

在高剂量氯胺酮与阿片受体结合的某些条件下，您可以开始进入麻醉状态，人们会失去意识，实际上对疼痛没有任何反应。

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.

如果您还记得我们之前讨论过的临床研究，其中氯胺酮用于缓解抑郁症，那么，正如您所记得的那样，该研究中使用的剂量是每公斤体重半毫克。

That is the dosage that will induce these dissociative, mild euphoria, those sorts of states of mind, but where people are still conscious.

这个剂量会引发这些解离的、轻微的欣快感，这些精神状态，但人们仍然有意识。

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.

当您开始使用每公斤体重一到两毫克的氯胺酮剂量时，现在您正在谈论麻醉剂量。

And when that happens, you're going to get full parking, full saturation of all the potential receptors that ketamine can bind to.

当这种情况发生时，你将完全停车，氯胺酮可以结合的所有潜在受体完全饱和。

Those NMDA receptors, it's going to block those.

那些 NMDA 受体，它会阻断它们。

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 aficionados, also the kappa type opioid receptors.

它还将与所谓的 mu 阿片受体结合，也许还有其他类型的阿片受体，对于那些想知道的人，你们的爱好者，还有 kappa 型阿片受体。

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.

所以我们这里有一种药物，氯胺酮，它会影响两个不同的系统，即谷氨酸相关系统和内源性阿片类系统。

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.

研究人员和临床医生已经合乎逻辑地开始询问氯胺酮的部分或全部作用是否是由阿片类药物系统引起的，他们想知道这些作用是什么。

Now, this is where things start to get really interesting, both in the context of clinical treatment of depression and recreational use.

现在，事情开始变得真正有趣，无论是在抑郁症的临床治疗还是娱乐用途方面。

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 hydroxynorketamine.

首先，当人们服用氯胺酮时，它会再次进入血液并进入大脑，但它会代谢成一种称为 HNK 的物质，即羟基去甲氯胺酮。

Now, I don't expect you to know what hydroxynorketamine 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 hydroxynorketamine has an incredible specificity for the mu opioid receptor, and maybe that kappa opioid receptor as well.

现在，我不希望您知道羟基去甲氯胺酮是什么，也不希望您关心它，直到我告诉您我要告诉您的事情，即羟基去甲氯胺酮对 mu 阿片受体（也许还有 kappa 阿片受体）具有令人难以置信的特异性。

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, hydroxynorketamine, is selectively activating the opioid system.

换句话说，当我们谈论氯胺酮时，人们服用的药物是氯胺酮，但当它进入体内时，它会转化为另一种药物，而另一种药物羟基去甲氯胺酮会选择性地激活阿片类药物系统。

So this led researchers to ask it 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?

因此，这导致研究人员提出了一个非常重要的问题，即，当一个人服用氯胺酮来治疗抑郁症并从抑郁中得到一些缓解时，这是我们之前讨论过的所有 NMDA、谷氨酸、BDNF 相关回路中神经塑性变化的结果，还是阿片系统中发生的某些事情的结果？

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.

你不能忽视氯胺酮具有与这些阿片受体结合的特性，因为它们对我们的思维、我们的情绪和我们的意识状态有如此强大的影响。

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.

在整个缓解抑郁症的过程中，甚至在人们消遣性服用氯胺酮时，甚至可能在产生解离症状的过程中，阿片类药物系统即使不是主要参与者，也可能是主要参与者，这是完全合理的。

So what researchers/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, and they did that using a drug called naltrexone.

因此，研究人员/临床医生所做的是，他们进行了一系列实验，他们给人们服用氯胺酮来缓解抑郁症，但他们也阻断了阿片受体系统，他们使用一种名为纳曲酮的药物来做到这一点。

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 Antidepressant and Antisuicidal Effects of Ketamine by Opioid Receptor Antagonism."

因此，我要向您介绍的是我在斯坦福大学医学院的同事诺兰·威廉姆斯 (Nolan Williams) 博士和艾伦·沙茨伯格 (Alan Schatzberg) 及其同事所做的一项研究，题为“阿片受体拮抗作用减弱氯胺酮的抗抑郁和抗自杀作用”。

And as a consequence of me reading you that title a moment ago, you now already have the conclusion of the study.

由于我刚才给你们读了这个标题，你们现在已经有了这项研究的结论。

What they observed is that when people were given ketamine, they got relief from depression.

他们观察到，当人们服用氯胺酮时，他们的抑郁症得到了缓解。

That wasn't surprising.

这并不奇怪。

Again, many studies had shown that before, since the early 2000s.

同样，自 2000 年代初以来，许多研究都表明了这一点。

If, however, individuals were given naltrexone to block the opioid receptor pathway and they were given ketamine, well, then the antidepressant effects of ketamine were no longer observed.

然而，如果个体服用纳曲酮来阻断阿片受体途径，然后服用氯胺酮，那么就不再观察到氯胺酮的抗抑郁作用。

Now, that suggests that it is the opioid receptor system that's responsible for the antidepressant effects of ketamine, and perhaps this HNK, this hydroxynorketamine, which is the metabolite of ketamine, is the way in which ketamine normally relieves depression.

现在，这表明阿片受体系统负责氯胺酮的抗抑郁作用，也许这种 HNK，这种羟基去甲氯胺酮，它是氯胺酮的代谢产物，是氯胺酮通常缓解抑郁症的方式。

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.

现在，很多人都注意到了这些研究，因为毕竟可能有数十项甚至数百项研究关注氯胺酮对所有 NMDA 受体物质的影响。

And indeed, neuroplasticity and mood related circuits can't be discounted as one way in which ketamine provides relief from depression.

事实上，神经可塑性和情绪相关回路不能被视为氯胺酮缓解抑郁症的一种方式。

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.

但非常有趣的是，在服用氯胺酮和纳曲酮的人中，这些人仍然经历了氯胺酮的直接影响，轻微的欣快感，解离感，以及人们在氯胺酮作用下通常会预期的感觉。

But what they didn't get were the longer term changes in mood that we would call relief from depression.

但他们没有得到的是情绪的长期变化，我们称之为抑郁症的缓解。

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.

当然，现在现代精神病学的目标是治疗抑郁症，而不是阻止这些能够治疗抑郁症的药物的作用。

Now, what this 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.

现在，这项研究的作用是，顺便说一句，有几项类似的研究支持这些一般性的发现，即氯胺酮在缓解抑郁症方面的关键作用部分是激活阿片类药物系统。

But what this 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.

但这项研究确实指出了这样一个事实：当我们说氯胺酮治疗，或者我们谈论某人出于娱乐目的服用氯胺酮时，我们必须注意他们在药物影响下发生的情况。

We also have to pay attention to what's happening in the days and weeks after they're under the influence of the drug.

我们还必须关注他们受到药物影响后几天或几周内发生的情况。

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.

也许最重要的是，这让人想起一个非常重要的想法，那就是，无论你是否在谈论氯胺酮引起的抑郁症缓解，或裸盖菇素引起的抑郁症缓解，或 MDMA 引起的 PTSD 缓解（我在本播客的前一集中讨论过这个主题），我们都必须退后一步，看看人们经历的药物的影响，无论这些影响是什么，因为显然这将取决于他们服用的特定药物，这些直接影响实际上可能与这些特定药物的长期临床益处。

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.

现在，我意识到很多人可能不喜欢这个想法，坦率地说，我实际上并不认为它是这样运作的。

I don't think it's going to be an either/or situation.

我认为这不会是一个非此即彼的情况。

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.

然而，由于氯胺酮、裸盖菇素、摇头丸等药物在人们受到影响时会对他们的精神状态产生如此深远的影响，并且因为至少在适当的临床环境和使用下，它们似乎确实可以令人印象深刻地缓解抑郁症和创伤后应激障碍等许多精神挑战，所以人们自然地将这两件事联系起来。

They couple those two things.

他们将这两件事结合起来。

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.

事实上，他们推翻了这两件事，并假设他们在药物影响下看到的、听到的、感受到的经历实际上是刺激，使他们的临床症状（如抑郁症）得到缓解。

But what these data on combined treatment with ketamine and naltrexone to block the mu-opioid receptor really show us is that that may not actually be the way that it works.

但这些关于用氯胺酮和纳曲酮联合治疗来阻断 mu-阿片受体的数据真正向我们展示的是，这实际上可能不是它的作用方式。

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.

人们可能会体验到氯胺酮等药物的作用，虽然有趣，甚至可能是深刻的，但当人们在适当的环境中进行这种治疗时，也许会产生伟大的洞察力。

It is not clear at all that it is that experience and the effects of those drugs in those immediate minutes and hours, that's actually what's causing the relief from depression.

根本不清楚的是，这些药物在这几分钟和几小时内的经历和作用实际上是导致抑郁症缓解的原因。

Now, again, I don't think it's an either/or.

现在，我再次认为这不是一个非此即彼的问题。

I like to view the whole situation more or less as a sort of wave front, 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 serieses, is that a word?

我喜欢将整个情况或多或少地视为一种波前，即一个人在受到氯胺酮、裸盖菇素或摇头丸等药物影响时的主观体验，引发了一系列，事实上，多个系列，这是一个词吗？

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.

大脑中存在多种类型的过程，其中一些依赖于 NMDA 受体、BDNF 等类型的神经可塑性，另一些则依赖于阿片受体途径，并且每种过程都有不同的时间进程，例如有些在治疗后数天和数小时内立即缓解，有些在治疗后数周内缓解，而有些则可能在数月甚至数年内发生更持久的变化。

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.

在这一切的背景下，需要强调的一件非常重要的事情是，在今天的讨论中，我们一直在谈论药物和受体以及抑郁症的缓解。

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.

但我们在这里真正谈论的是那些从抑郁中得到缓解的人，几乎可以肯定，当他们从抑郁中得到缓解时，他们也开始做其他事情。

They are going back to work.

他们要回去工作了。

They are engaging in relationships again.

他们再次建立关系。

They are viewing themself differently again.

他们再次以不同的方式看待自己。

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.

希望他们能享受早晨的阳光、锻炼身体、吃得好，并做各种我们称之为抗抑郁行为的事情。

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 or stopped engaging in behaviors that were unhealthy for them.

而且不可能将药物治疗抑郁症的积极行为后果与药物本身分开，让我们说，好吧，氯胺酮缓解了抑郁症，然后结果，人们去做了一堆对他们健康的行为，或者停止了对他们不健康的行为。

So we can think of behaviors as pro-depressive or anti-depressive.

因此，我们可以将行为视为促抑郁或抗抑郁的行为。

In fact, we know that one particular behavior, that is viewing blue light in the middle of the night between the hours of, say, 11:00 PM and 4:00 AM, is known to invoke a pro-depressive circuit.

事实上，我们知道一种特殊的行为，即在半夜（例如晚上 11:00 到凌晨 4:00）之间观看蓝光，会引发促抑郁回路。

It involves a structure called the habenula.

它涉及一种称为缰核的结构。

I've talked about this on previous podcasts.

我在之前的播客中谈到过这个问题。

It tends to lower dopamine and increase cortisol in the days following that exposure to light, et cetera.

在暴露于光线等之后的几天里，它往往会降低多巴胺并增加皮质醇。

So there are pro-depressive behaviors, and there are anti-depressive behaviors.

因此，有促抑郁行为，也有抗抑郁行为。

We know that viewing morning sunlight, getting regular and sufficient amounts of quality sleep, proper nutrition, proper social engagement.

我们知道，观看早晨的阳光、定期充足的优质睡眠、适当的营养、适当的社交活动。

There is now a plethora of quality research pointing to the fact that those are true anti-depressive behaviors.

现在有大量的高质量研究表明这些是真正的抗抑郁行为。

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.

因此，我们永远无法将药物的作用与药物的作用区分开来，而药物的作用又会反馈并与人们所希望的药物的作用相结合，在这种情况下，就是缓解抑郁症。

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.

好的，所以我一直在两个非常不同的层面上结束这次关于氯胺酮的对话，这意味着我们一直在谈论高层面的东西，即缓解抑郁症状。

We haven't been going into a lot of detail about that, but that's pretty high level.

我们还没有详细讨论这一点，但这已经是相当高的水平了。

We're talking about thought changes, behavioral changes that we're calling anti-depressive.

我们谈论的是思想改变、行为改变，我们称之为抗抑郁。

Changes in mood and affect that are positive, positive anticipation of the future, et cetera.

情绪和影响的变化是积极的，对未来的积极预期等等。

And then we've also been talking a lot at this other end, which is very reductionist, down at the cellular and molecular level.

然后我们在另一端也进行了很多讨论，这是非常还原论的，在细胞和分子水平上。

We've talked about receptors and binding of receptors and neuroplasticity and TrkB and all that stuff.

我们讨论了受体和受体结合、神经可塑性和 TrkB 等等。

We've completely neglected, meaning I've completely neglected until now, what bridges those two levels of understanding.

我们完全忽视了，也就是说我到现在为止完全忽视了，是什么在这两个层面的理解之间架起桥梁。

And what bridges those two levels of understanding are the neural circuits that actually change when one takes ketamine.

连接这两个层面的理解的是，当人们服用氯胺酮时，神经回路实际上会发生变化。

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.

无论这些变化是否很快发生，无论它们是否需要更长的时间，无论它们是否涉及 NMDA 受体或阿片受体系统或两者，我们都知道，当人们以每公斤约半毫克的剂量和频率服用氯胺酮时，某些神经回路会发生变化，而且，这是注射形式，每周两次，持续三周，然后他们获得了对抑郁症的持久抵抗力。

Fortunately, we can talk about those neural circuits without having to bring about a lot more nomenclature, a lot of new language.

幸运的是，我们可以讨论这些神经回路，而不必引入更多的术语和新的语言。

And I say fortunately because I realize today you've been hit with a lot of new terms.

我说幸运是因为我意识到今天你受到了很多新术语的影响。

Now, I've already mentioned one of the key brain structures, and that's the habenula.

现在，我已经提到了关键的大脑结构之一，那就是缰核。

A few moments ago, I talked about the habenula in the context of people who get too much bright light exposure in the middle of the night.

不久前，我在半夜接受过多强光照射的人的背景下谈到了缰核。

That activates the habenula.

这会激活缰核。

It's a sort of a disappointment circuit.

这是一种失望循环。

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.

我们可以这样称呼它，因为我们知道它会在动物模型中导致促抑郁症状，并且很可能在人类中也会导致抑郁症状，而且我们知道，它是通过减少多巴胺和增加皮质醇来实现的。

There's evidence that when people undergo ketamine therapy, connections between the habenula, what we can broadly just talk about as a structure involved in generating a feeling of disappointment, the connections between the habenula 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 the so-called mesolimbic reward pathway.

有证据表明，当人们接受氯胺酮治疗时，缰核之间的联系，我们可以广泛地谈论作为一种涉及产生失望感的结构，缰核和大脑奖励回路之间的联系，我之前在这个播客中已经多次谈到过，但对于那些不熟悉它的人来说，这就是所谓的中脑边缘奖励通路。

It has areas like the ventral tegmental area, the nucleus accumbens.

它具有腹侧被盖区、伏隔核等区域。

Don't worry at all about those names.

完全不用担心这些名字。

Just know that this is a brain area that is chock-a-block full of neurons that release dopamine, which is a molecule that tends to increase mood, increase motivation.

只要知道这个大脑区域充满了释放多巴胺的神经元，多巴胺是一种往往会增加情绪、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.

在很多方面，我们可以将其视为抗抑郁药物，至少在本次讨论中是如此。

So what we've got is a structure, the habenula, 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.

所以我们得到的是一种结构，缰核，通常提供抑制作用，现在你知道这意味着什么，抑制输入到释放多巴胺的奖励途径，当人们服用氯胺酮时，抑制作用减弱，使得奖励途径更容易参与日常生活活动。

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 that 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.

现在，我说可以为了一个非常具体的目的而参与日常生活活动，也就是说，我们正在谈论的神经回路的所有变化都可以通过服用药物来实现，好吧，这些变化实际上并没有多大作用，除非这些回路被特定的行为所强化。

So this relates back to what I said just a few minutes ago about pro-depressive and anti-depressive behaviors.

所以这与我几分钟前所说的关于促抑郁和抗抑郁行为有关。

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.

有人可以服用氯胺酮，并有可能从抑郁症中得到缓解，但如果他们继续从事促抑郁行为，他们就不会从抑郁症中得到太多缓解。

Conversely, if somebody takes ketamine and they are reducing the amount of output from this disappointment circuit, this habenula, 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, et cetera, well, those circuits are not designed to respond to ketamine.

相反，如果有人服用氯胺酮，他们会减少从这个失望回路、这个缰核到大脑奖励回路的输出量，并且他们确实从事一些行为，例如寻找刺激他们的工作、寻求社会参与、照顾好自己的身体、心理健康、身体健康等等，那么，这些回路并不是为了对氯胺酮做出反应而设计的。

They are designed to respond to particular patterns of thinking and behavior.

它们旨在响应特定的思维和行为模式。

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.

因此，我们不能忘记，当我们听说某种药物会导致特定神经回路的可塑性时，它所做的就是使平衡或这些神经回路参与某些活动的概率产生偏差。

But one still has to engage in those activities.

但人们仍然必须参与这些活动。

Now fortunately, when people tend to have elevations in mood, they tend to move around more.

幸运的是，当人们情绪高涨时，他们往往会更多地四处走动。

When they tend to move around more, they tend to engage in more things.

当他们倾向于四处走动时，他们往往会参与更多的事情。

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, goal-related behavior.

当他们倾向于从事更多的事情时，如果他们对生活有积极的看法，那么他们可能会从事适应性的事情，比如社会关系、与工作相关的、与学校相关的、与目标相关的行为。

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.

因此，重要的是要理解，对氯胺酮反应引起的神经回路变化的讨论实际上是对氯胺酮反应引起的神经回路变化的讨论，这种变化使一个人的整个系统朝着对日常活动作出反应的进一步神经回路变化的方向发展，从而促进健康，或者在这种情况下，促进心理健康。

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-trap kind of way.

现在，了解这一点也很重要：一种药物很少（如果有的话）仅以一种单一的方式缓解某种临床挑战。

The way to think about this is that most mental processes, and certainly things like depression, are a two-way road.

思考这个问题的方法是，大多数心理过程，尤其是抑郁症，都是双向的。

You have pro-depressive behaviors and circuits, and you have anti-depressive behaviors and circuits.

你有促抑郁的行为和回路，也有抗抑郁的行为和回路。

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.

因此，有证据表明氯胺酮治疗可以减少从缰核到奖赏途径的输出，这种失望到奖赏途径，削弱它，使奖赏途径更容易通过抗抑郁的思想和行为参与，也许你不会感到惊讶。

And in addition to that, it can further bolster the neuroplasticity within the reward pathway itself, in particular, with connections with the frontal cortex.

除此之外，它还可以进一步增强奖励通路本身的神经可塑性，特别是与额叶皮层的连接。

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?

对于那些不熟悉额叶皮层的人来说，你的额叶皮层做了很多事情，但你的额叶皮层绝对关键的一件事是建立上下文相关的策略，这意味着让你可以说，“好吧，在特定情况下，我应该做什么才能得到我想要的结果？

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.

在另一种情况下，我该怎么做才能得到我想要的结果？”这不是操纵类型的战略，尽管我认为它可能是。

It's strategizing of, how do I get what I need from this social connection?

它的策略是，我如何从这种社交联系中获得我需要的东西？

How do I get what I need from my goals in exercise?

我如何从锻炼目标中获得所需的东西？

How do I get what I need from my goals in terms of work or school, et cetera?

我如何从工作或学校等方面的目标中获得所需的东西？

Your frontal cortex is that part of your cortex that's always churning ideas.

额叶皮层是大脑皮层中始终搅动想法的部分。

It's always wondering, am I doing well?

总是在想，我做得好吗？

Am I not doing well?

难道是我做得不好吗？

And is adjusting your behavior accordingly.

并相应地调整你的行为。

So it's now established that ketamine can improve connectivity.

因此现在已经确定氯胺酮可以改善连通性。

That is, it can strengthen the connections between areas of the brain that are associated with context-dependent strategy building and these reward pathways.

也就是说，它可以加强与情境相关策略构建相关的大脑区域和这些奖励途径之间的联系。

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.

换句话说，它使人们更加敏感地意识到他们是否从自己的努力中得到了他们想要的结果，以及如何调整他们的努力，以便他们确实从这些努力中得到他们想要的结果。

And there's other evidence that NMDA receptor blockade is not the way that ketamine provides relief from depression.

还有其他证据表明，氯胺酮并非通过阻断 NMDA 受体来缓解抑郁症。

Namely, there's a drug called memantine.

也就是说，有一种药物叫做美金刚。

It's used actually to treat Alzheimer's, and it too is an NMDA receptor blocker, and it has no antidepressant effects.

它实际上用于治疗阿尔茨海默氏症，也是一种 NMDA 受体阻滞剂，并且没有抗抑郁作用。

Now, as you recall, ketamine is a dissociative anesthetic, and one of its primary effects is to create this feeling of dissociation.

现在，正如您所记得的，氯胺酮是一种解离性麻醉剂，其主要作用之一就是产生这种解离感。

For those of you that aren't familiar with what dissociation is, dissociation is where people feel separate from their body.

对于那些不熟悉什么是分离的人来说，分离是指人们感到与自己的身体分离。

They can still think, but it's as if they are observing themselves.

他们仍然可以思考，但就好像他们在观察自己一样。

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 of theirs who had taken ketamine for the treatment of depression.

事实上，为了预测这一事件，我咨询了斯坦福大学医学院精神病学系的几位同事，其中一位描述了氯胺酮的作用，正如他们的一位服用氯胺酮治疗抑郁症的患者所描述的那样。

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.

那位患者将其描述为观察自己的思考、观察自己的做事，即使他们完全静止地躺着，也许最重要的是，将自己描述为高于自己的身体，实际上从第三人称的角度俯视自己。

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.

现在，我意识到这对大多数人来说都是一种陌生的经历，但当然，有些人即使在不服用氯胺酮的情况下也会经历分离。

And as many of you know, dissociation is actually one of the primary symptoms of PTSD and trauma.

正如你们许多人所知，分离实际上是创伤后应激障碍和创伤的主要症状之一。

So this raises a sort of conundrum.

所以这就提出了一个难题。

Why is it that a particular state of mind that's associated with PTSD and trauma, and in some cases depression itself, which is induced by a drug like ketamine, can provide relief from depression?

为什么与创伤后应激障碍（PTSD）和创伤相关的特定精神状态，以及在某些情况下由氯胺酮等药物引起的抑郁症本身，可以缓解抑郁症？

And that all goes back to the neuroplastic changes that we talked about earlier, and more likely, the changes in the mu opioid receptor system that we talked about earlier.

这一切都可以追溯到我们之前讨论过的神经塑性变化，更有可能的是我们之前讨论过的 mu 阿片受体系统的变化。

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-personing-of-self effect.

但尽管如此，氯胺酮的解离效应对于服用氯胺酮的人来说是如此深远，以至于我想我应该花一两分钟解释一下是什么可能导致解离性第三人称自我效应。

And insofar as we know, it has to do with an uncoupling of certain brain circuits, in particular neocortical brain circuits.

据我们所知，这与某些大脑回路，特别是新皮质大脑回路的解耦有关。

The neocortex is the part of the brain, the lumpy outside part of the brain that's associated with action planning.

新皮质是大脑的一部分，是与行动计划相关的大脑外部的块状部分。

It does a lot of things really.

它确实做了很多事情。

It's involved in sensory perception.

它涉及感官知觉。

It's involved in speech generation, many, many things.

它涉及语音生成等很多很多事情。

But the neocortex has connections to other regions which are called subcortical regions, and it seems that when people take ketamine or phencyclidine, PCP, there's an uncoupling of those networks, a quieting of those networks that starts to create a different dominant rhythm in the brain.

但新皮质与其他被称为皮质下区域的区域有联系，似乎当人们服用氯胺酮或苯环己哌啶（PCP）时，这些网络会解耦，这些网络会安静下来，开始在大脑中产生不同的主导节律。

Some of you may be familiar with rhythms in the brain, so-called alpha rhythms or alpha patterns of activity.

你们中的一些人可能熟悉大脑的节律，即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.

这只是与特定大脑状态相关的主要活动模式。

So for instance, alpha brain waves are associated with an alert but calm, relaxed state of mind, where thoughts are sort of free-flowing.

例如，阿尔法脑电波与警觉但平静、放松的心态有关，在这种状态下，思想是自由流动的。

It's a little bit dreamlike, but it isn't really like a dream where anything can happen.

有点像做梦，但又不像梦，什么事情都有可能发生。

It has a structure to it.

它有一个结构。

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.

当人们服用氯胺酮时，阿尔法活性模式被完全消除，至少在他们受到药物影响的时间内，通常是大约一小时到两小时左右。

And a different pattern of brain activity, which is called the theta pattern of brain activity, starts to really emerge.

一种不同的大脑活动模式，即大脑活动的θ模式，开始真正出现。

It's as if it gets unveiled.

仿佛揭开了面纱。

And that theta pattern of activity is the one that's associated with a dreamlike state.

θ 活动模式与梦幻状态相关。

It's the one that resides more or less at that liminal border between wakefulness and sleep.

它或多或少地处于清醒和睡眠之间的界限。

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 a theta pattern of activity in your brain at that moment just prior to when you woke up.

如果您曾经在入睡时想着类似跑步并踢腿的事情，那么在您醒来之前的那一刻，您的大脑很可能处于 θ 活动模式。

Whereas when you're more alert, you see patterns of activity that are higher frequency, things like alpha, beta rhythms and so forth.

而当您更加警觉时，您会看到频率更高的活动模式，例如阿尔法、贝塔节奏等。

So ketamine produces particular patterns of brain activity and this sense of dissociation when it's taken at sub-anesthetic doses.

因此，当服用亚麻醉剂量的氯胺酮时，它会产生特定的大脑活动模式和这种分离感。

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.

如果您还记得我们之前讨论过的临床研究，他们每公斤体重注射半毫克，以缓解这些患者的抑郁症。

When people take ketamine, they will take it by different routes of delivery.

当人们服用氯胺酮时，他们会通过不同的输送途径服用。

And now here we have to expand our conversation to include both the clinical context, research studies, and recreational use.

现在我们必须扩大我们的谈话范围，包括临床背景、研究和娱乐用途。

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.

现在，我这样做是因为通常当人们在临床研究中服用氯胺酮时，他们会静脉注射，或肌肉注射，每公斤体重注射半毫克氯胺酮。

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 sublingually by putting it under the tongue or in their cheek, and then that so-called troche dissolves and the ketamine goes into their system.

然而，当人们为了消遣而服用氯胺酮时，或者当他们通过处方合法获得氯胺酮并在家服用时（这已成为一种更常见的做法），他们通常会以药丸的形式口服氯胺酮，或者将其放在舌下或脸颊上舌下服用，然后所谓的锭剂溶解，氯胺酮进入他们的系统。

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 bloodstream.

现在需要了解的重要一点是，当人们口服氯胺酮时，只有 25% 的氯胺酮活性形式会进入血液。

And when they take it sublingually, 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.

当他们舌下服用氯胺酮时，通常只有大约 35% 的氯胺酮总量会转化为具有代谢活性的氯胺酮，作用于大脑中的神经元。

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 sublingually.

因此，当您听说研究中使用的剂量时，它们通常涉及注射氯胺酮，并且氯胺酮的剂量远低于您听说人们口服或舌下服用氯胺酮时的剂量。

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.

举例来说，我的体重为 220 磅，即 100 公斤，所以如果我参加其中一项研究（我没有参加过），但如果我参加了，我会通过注射的方式注射 50 毫克氯胺酮。

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 sublingual ketamine if I wanted to get the same effects.

然而，如果我想尝试在血液和大脑中获得与通过注射相同量的活性氯胺酮，我需要通过药丸摄入三倍量的氯胺酮，如果我想获得相同的效果，则可能需要通过舌下含服氯胺酮摄入更多的氯胺酮。

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.

因此，如果我在一项研究中通过注射的方式服用 50 毫克，然后我去了另一项研究，他们说：“好吧，我们想重现这种效果。

We're going to give you a pill." Typically, they're going to give me 150 milligrams of ketamine in a pill form, or 200 milligrams of ketamine in the troche sublingual form.

我们会给你一颗药。”通常，他们会给我 150 毫克药丸形式的氯胺酮，或 200 毫克舌下含片形式的氯胺酮。

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, 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 sublingually or orally.

现在，根据交付业务了解这种剂量依赖性非常重要，因为我意识到，尤其是现在，很多人通过合法来源服用氯胺酮，因此他们是合法获取的，但他们在诊所外服用，更常见的是，他们不是通过注射方式服用，这意味着他们服用更高剂量的氯胺酮，并且是舌下或口服服用。

So it's very important to understand this dose dependence according to mode of delivery business.

因此，根据业务的交付方式了解这种剂量依赖性非常重要。

Now in anticipation of this episode, I put out a request for questions about ketamine on Twitter, and I got many, many questions.

现在，为了这一集的预期，我在 Twitter 上提出了有关氯胺酮的问题请求，我收到了很多很多问题。

Some excellent ones therein.

其中有一些优秀的。

But one of the more common questions was what is a K hole in scientific terms?

但更常见的问题之一是科学术语中的 K 孔是什么？

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.

K 孔用于描述某人服用氯胺酮（通常是为了娱乐）时的主观体验，他们最终基本上处于伪麻醉状态。

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.

这意味着他们服用的剂量超出了亚麻醉剂量的范围，并转变为氯胺酮的麻醉水平剂量。

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.

现在，我提到了我之前所做的关于剂量的所有事情，因为重要的是要知道不同的人，即使他们体重相同，也会根据他们代谢氯胺酮的速度和彻底程度而对氯胺酮产生不同的反应。

So in the clinical context, injections of ketamine into the vein or into the muscle are done at this half a milligram per kilogram dose.

因此，在临床上，氯胺酮注射到静脉或肌肉中的剂量为每公斤半毫克。

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.

他们那里有临床医生，那里有研究人员，他们正在关注这个人是否处于解离状态，是否仍然有意识，并观察这个人是否进入全面麻醉。

Now, that's one of the values of doing ketamine in the context of a legal clinical setting.

现在，这是在合法临床环境下使用氯胺酮的价值之一。

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.

然而，如果我不承认很多人合法获得氯胺酮，然后在家服用，那就是我的失职。

Hopefully not alone.

希望不是一个人。

Hopefully, there's someone there to monitor them, or they're in session with their physician over Zoom.

希望有人在那里监视他们，或者他们正在通过 Zoom 与医生会面。

That's actually happening more and more these days through telehealth.

如今，通过远程医疗，这种情况实际上越来越多地发生。

But that itself also has certain risks, right?

但这本身也存在一定的风险不是吗？

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.

因为如果这个人需要某些东西，而房间里没有人立即照顾它，那么这可能是一个非常有问题的情况。

And of course, there are situations where people are taking ketamine recreationally.

当然，在某些情况下人们会为了娱乐而服用氯胺酮。

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.

不管他们如何获得它，他们都会服用它，并且根据对剂量的一些粗略了解来猜测他们将如何应对它。

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.

但当人们谈论 K 孔时，他们谈论的是服用氯胺酮，其剂量对他们来说可以使他们超越轻度甚至极端的解离，并开始使他们进入全面的麻醉状态。

And that itself actually can be dangerous.

这本身实际上可能是危险的。

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.

进入类似麻醉的意识层面，虽然并不总是致命的，但可能是致命的，当人们开始将其与其他药物结合使用时，它肯定可以而且已经是致命的。

In particular, drugs like barbiturates or alcohol.

特别是巴比妥类药物或酒精。

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 any one given dose, and so too is the response to a given dose in a given person, depending on the route of delivery.

因此，我想非常清楚地表明，您在听到氯胺酮时听到的剂量范围非常广泛，任何给定剂量的变异性也是如此，并且特定人对给定剂量的反应也是如此，具体取决于给药途径。

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.

您需要非常小心氯胺酮会带您进入深深的无意识状态，在某些情况下甚至导致死亡。

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.

当然，与任何镇静剂一样，在某些情况下，如果一个人受到氯胺酮的影响，那么在做任何事情时都需要极其谨慎，例如开车，甚至在交通中行走或在任何地方行走。

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.

此外，对于那些容易癫痫发作的人来说，无论是由于癫痫或先前的头部受伤，还是您有癫痫发作倾向但您不知道，氯胺酮可以诱发癫痫发作，现在您应该完全清楚为什么会出现这种情况。

Ketamine blocks NMDA receptors on inhibitory neurons and quiets their activity, which of course, can lead to runaway excitation in the brain if you are seizure-prone.

氯胺酮会阻断抑制性神经元上的 NMDA 受体并使其活动安静下来，如果您有癫痫发作倾向，这当然会导致大脑失控兴奋。

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.

当我在社交媒体上提出有关氯胺酮的问题请求时，我也收到了很多关于不同形式的氯胺酮的问题。

When I say different forms, that included questions about whether or not intranasal was better than oral, was better than sublingual, et cetera.

当我说不同的形式时，其中包括鼻内是否优于口服、是否优于舌下等等的问题。

To be fair, with one exception, the different modes of delivery probably relate more to dosage that actually gets metabolized than to anything else.

公平地说，除了一个例外，不同的给药方式可能更多地与实际代谢的剂量相关，而不是其他任何因素。

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.

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等同于口服或舌下服用的剂量，或者顺便说一句，在某些情况下，人们会直肠服用。

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.

人们直肠服用氯胺酮的原因是直肠给药绕过了肝脏，事实上，氯胺酮很难让肝脏代谢。

It can dramatically increase liver enzymes.

它可以显着增加肝酶。

So oftentimes, people that are taking ketamine frequently and don't want to create damage to the liver, they will opt for rectal administration.

通常，经常服用氯胺酮且不想对肝脏造成损害的人会选择直肠给药。

Now, I realize that unless it's somehow related to your profession, anytime somebody says intrarectally, it raises a few eyebrows and people kind of lean back a little bit, and I get it.

现在，我意识到，除非它与你的职业有某种关系，否则任何时候有人在直肠内说话，都会引起一些人的眉毛，人们会稍微向后靠，我明白了。

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.

在播客的未来一集中，我承诺根据人们是否口服、舌下、注射或直肠服用某种药物来区分不同的药物代谢模式。

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.

当我在社交媒体上征求有关氯胺酮的问题时，我得到的另一个常见问题是关于氯胺酮的 R、S 和 RS 形式。

And I must tell you, that sent me down a deep rabbit hole of research in which I discovered very contradictory evidence.

我必须告诉你，这让我陷入了研究的深渊，在其中我发现了非常矛盾的证据。

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.

例如，我可以找到一些论文，我确实找到了一些论文，其中提到氯胺酮的 R 形式对 NMDA 受体的亲和力比氯胺酮的 S 形式大得多。

I also found reviews that said the exact opposite.

我还发现评论的说法完全相反。

Okay?

好的？

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, whose laboratory specializes in the use of ketamine for studies of treating depression and for treating depression in the clinical population.

我坐在一起，看着两篇评论，想知道我的视觉系统是否有问题，直到我打电话给同事诺兰·威廉姆斯博士，他是斯坦福大学医学院的三重委员会认证的神经病学家和精神科医生，他的实验室专门研究使用氯胺酮治疗抑郁症和临床人群中的抑郁症。

So I asked him, "What's the deal here?

于是我问他：“这是怎么回事？

I'm getting very contradictory evidence." And he spelled it all out for me.

我得到了非常矛盾的证据。”他为我详细说明了一切。

It appears based on the clinical data in humans and on binding studies that the S form of ketamine is more potent.

根据人类临床数据和结合研究，S 型氯胺酮似乎更有效。

That is, it can more robustly bind to the NMDA receptor.

也就是说，它可以更牢固地结合NMDA受体。

And in addition to that, the S form of ketamine tends to produce less dissociation at a given dosage than does the combined SR form of ketamine or pure R ketamine.

除此之外，在给定剂量下，S 形式的氯胺酮往往比 SR 形式的氯胺酮或纯 R 氯胺酮的组合产生更少的解离。

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.

他还添加并向我发送了一项研究，我将在节目注释标题中链接该研究，最近进行了 R 氯胺酮的临床试验，因此仅使用纯 R 氯胺酮，但它未能缓解抑郁症状。

So I said, "Great.

所以我说：“太好了。

Thank you so much.

非常感谢。

This is now all made very clear to me that S ketamine is the preferred form.

现在我已经非常清楚，S 氯胺酮是首选形式。

It produces less dissociation, and it provides better depression relief." And then he said, "No, actually, it's a little more complicated than that.

它产生更少的解离，并且可以更好地缓解抑郁症。”然后他说：“不，实际上，情况比这更复杂一点。

It appears the situation is the following.

看来情况如下。

The combined SR form of ketamine seems to be the most potent for relieving depressive symptoms.

氯胺酮的复合 SR 形式似乎是缓解抑郁症状最有效的方法。

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.

S 型氯胺酮在缓解抑郁症状方面排名第二，是当今最常通过鼻喷雾剂、口服给药、舌下给药方式开具的氯胺酮，在临床研究中通常通过注射给药。

And it appears that the R form of ketamine is the least potent and effective in treating depression." Now, I realize 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.

看来 R 形式的氯胺酮在治疗抑郁症方面的效力和效果最差。”现在，我意识到，通过将其推广到更大的世界，并假设那里有氯胺酮方面的专家，无论是通过使用还是通过他们自己的临床研究，我都会收到很多评论说，“不，实际上 R 形式对我来说比 S 形式与 SR 形式更有效，”等等。

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.

重申一下，从已经完成的临床试验来看，我们知道联合 SR 形式比纯 S 形式更有效，而纯 S 形式仍然比纯 R 形式更有效。

So that's what we know now based on the clinical studies.

这就是我们现在根据临床研究所知道的。

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.

但当然，我承认，只要有一种药物作为临床工具出现并被娱乐性地使用，人们就会去探索，他们会进行实验，他们会找到最适合他们的药物。

So I certainly invite feedback about what has worked best for you, hopefully in the clinical context.

因此，我当然会邀请您反馈最适合您的方法，希望是在临床环境中。

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.

因此，无论人们是否使用了医生开出的氯胺酮处方，无论他们是否参加了临床研究，或者他们是否只是为了娱乐而这样做，我想我都会听到这些经历，并且我会记下它们。

Another commonly asked question I received was, what about microdosing of ketamine?

我收到的另一个常见问题是，微剂量氯胺酮怎么样？

And there's a lot of interest in microdosing nowadays.

如今人们对微剂量很感兴趣。

People are microdosing psilocybin.

人们正在服用微量裸盖菇素。

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.

人们正在服用各种微剂量药物，希望能获得与大剂量相同的效果，但使用的化合物剂量要低于裸盖菇素、幻觉或氯胺酮等所引起的解离和欣快效果，使人必须躺上几个小时，然后在一天中的其余时间里放松下来。

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.

我就此咨询了我的临床医生同事，他们告诉我，目前，即截至昨天，他们所知道的已发表的临床证据为零，并且据我所知，微剂量氯胺酮对治疗抑郁症有效。

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.

我在这一集中谈到的所有对抑郁症的积极作用都是从研究中收集到的，在这些研究中，人们使用每公斤半毫克剂量的氯胺酮，或通过其他一些给药途径（不是注射，而是口服或舌下含服）的等效剂量。

So are there any benefits to microdosing ketamine?

那么微剂量氯胺酮有什么好处吗？

As far as the scientific and clinical literature that's published as of today is concerned, the answer is no. Okay, so today we covered a lot of information.

就目前发表的科学和临床文献而言，答案是否定的。好的，今天我们涵盖了很多信息。

We talked about what ketamine is.

我们讨论了氯胺酮是什么。

Remember, ketamine and PCP, angel dust, very similar compounds.

请记住，氯胺酮和五氯苯酚、天使之尘是非常相似的化合物。

Both block the NMDA receptor.

两者都会阻断 NMDA 受体。

We also talked about what sorts of subjective effects that produces.

我们还讨论了会产生什么样的主观效果。

Dissociation and mild euphoria, and third-personing of self, that's the dissociation, when taken at low dosages.

当低剂量服用时，会产生解离和轻微的欣快感，以及第三人称的自我，这就是解离。

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.

当服用较高剂量时，它可以引起全面麻醉并使人进入潜意识状态，如果剂量足够高，实际上甚至有可能导致癫痫发作和死亡。

Again, I want to emphasize that people's dosage sensitivity varies tremendously, route of delivery will impact that, and on and on.

我想再次强调，人们的剂量敏感性差异很大，给药途径也会影响这一点，等等。

We also talked about how the NMDA receptor itself and the activation of this incredible molecule, BDNF, brain-derived neurotrophic factor, seem to be important for at least some of the antidepressant effects of ketamine, both in the days and weeks following ketamine administration.

我们还讨论了 NMDA 受体本身以及这种令人难以置信的分子 BDNF（脑源性神经营养因子）的激活，在氯胺酮给药后的几天和几周内，似乎对氯胺酮的至少一些抗抑郁作用很重要。

And 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.

除此之外，我还描述了氯胺酮如何影响阿片受体系统，以及我们如何不能忽视阿片受体系统在产生氯胺酮抗抑郁作用中的作用。

And 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.

我们还讨论了与解离状态相关的大脑回路和脑电波，以及许多服用氯胺酮的人似乎可以缓解抑郁症。

And I tried to highlight some of the unique features of ketamine.

我试图强调氯胺酮的一些独特功能。

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.

首先，它似乎确实能缓解抑郁症，而其他方法则不能，但抑郁症的缓解往往是相当短暂的，除非它以每周多次、持续数周的方式应用，以产生我所说的持久变化，这几乎肯定涉及神经可塑性的变化，即大脑回路的重新布线。

And 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 there is a requirement for engaging in antidepressive behaviors as a way to further reinforce whatever positive changes have come about through the drug treatment.

我强调的另一个关键点是，我们始终必须记住，当考虑氯胺酮或任何其他相关物质等化学物质如何改变大脑回路以改变它们并缓解抑郁或其他精神挑战时，总是需要进行抗抑郁行为，以进一步强化通过药物治疗所带来的任何积极变化。

As a friend and colleague of mine who's expert in this area once so aptly said, "Better living through chemistry still requires better living." Thank you for joining me for today's discussion about ketamine.

正如我的一位该领域专家的朋友和同事曾经恰当地说的那样：“通过化学实现更好的生活仍然需要更好的生活。”感谢您参加今天有关氯胺酮的讨论。

If you're learning from and/or enjoying this podcast, please subscribe to our YouTube channel.

如果您正在学习和/或喜欢此播客，请订阅我们的 YouTube 频道。

That's a terrific zero-cost way to support us.

这是支持我们的绝佳零成本方式。

In addition, please subscribe to the podcast on both Spotify and Apple.

此外，请在 Spotify 和 Apple 上订阅该播客。

And on both Spotify and Apple, you can leave us up to a five-star review.

在 Spotify 和 Apple 上，您都可以给我们五星级的评价。

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 comments section on YouTube.

如果您对我有疑问或对您希望我考虑在 Huberman Lab 播客上主持的播客或嘉宾有意见，请将这些意见放在 YouTube 的评论部分。

I do read all the comments.

我确实阅读了所有评论。

Please also check out the sponsors mentioned at the beginning and throughout today's episode.

另请查看今天节目开头和整个节目中提到的赞助商。

That's the best way to support this podcast.

这是支持这个播客的最佳方式。

Not on today's podcast, but on many previous episodes of the Huberman Lab podcast, we discuss supplements.

不是在今天的播客中，而是在 Huberman Lab 播客的许多先前剧集中，我们讨论了补充剂。

While supplements aren't necessary for everybody, many people derive tremendous benefit from them for things like sleep support, hormone support, and improving focus.

虽然补充剂并不是每个人都需要的，但许多人从它们中获得了巨大的益处，例如睡眠支持、激素支持和提高注意力。

The Huberman Lab podcast has partnered with Momentous Supplements.

Huberman Lab 播客与 Momentous Supplements 合作。

If you'd like to learn more about the supplements discussed on the Huberman Lab podcast, you can go to Live Momentous, spelled O-U-S, so it's livemomentous.com/huberman.

如果您想了解有关 Huberman Lab 播客上讨论的补充剂的更多信息，您可以访问 Live Momentous，拼写为 O-U-S，即 livemomentous.com/huberman。

If you're not already following me on social media, I am hubermanlab on all platforms, so Instagram, Twitter, Threads, Facebook, and LinkedIn.

如果您还没有在社交媒体上关注我，我是所有平台上的 hubermanlab，例如 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.

在所有这些平台上，我介绍了科学和基于科学的工具，其中一些与胡伯曼实验室播客的内容重叠，但其中大部分与胡伯曼实验室播客的内容不同。

So again, it's hubermanlab on all social media platforms.

再说一遍，所有社交媒体平台上都是 hubermanlab。

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.

如果您还没有订阅我们的神经网络新闻通讯，我们的神经网络新闻通讯是一份免费的每月新闻通讯，其中包括一到三页 PDF 形式的播客摘要和协议。

Those protocols include things like a toolkit to enhance the quality and duration of your sleep, toolkits to improve learning and neuroplasticity, toolkits for deliberate cold exposure, exercise, focus, dopamine, and on and on.

这些协议包括诸如提高睡眠质量和持续时间的工具包、改善学习和神经可塑性的工具包、用于故意冷暴露、锻炼、专注、多巴胺等等的工具包。

To sign up for the Neural Network Newsletter, you simply go to hubermanlab.com, go to the menu, scroll down to Newsletter.

要注册神经网络新闻通讯，您只需访问 hubermanlab.com，进入菜单，向下滚动到新闻通讯。

You sign up using your email, but I want to emphasize that we do not share your email with anybody.

您使用您的电子邮件进行注册，但我想强调的是，我们不会与任何人分享您的电子邮件。

Thank you once again for joining me for today's discussion.

再次感谢您参加今天的讨论。

And last but certainly not least, thank you for your interest in science.

最后但并非最不重要的一点是，感谢您对科学的兴趣。