In this episode, I explain how ketamine causes rewiring of brain circuits and dissociative states to relieve symptoms of depression and post-traumatic stress disorder (PTSD). I explain how ketamine impacts both the brain’s glutamate and its endogenous opioid pathways, which together regulate mood and well-being. I discuss how ketamine therapy is used clinically to treat major depression, bipolar depression, obsessive-compulsive disorder (OCD), suicidality and other psychiatric challenges. I also describe how ketamine causes the subjective effects of dissociation and euphoria and, at higher doses, is an anesthetic. I compare the different routes of ketamine administration, dosages and forms of ketamine, and if micro-dosing ketamine is effective. I also highlight the potential risks of recreational ketamine use (and the colloquial term ‘K-holes’). This episode should interest anyone interested in ketamine, treatments for depression, neuroplasticity mechanisms, psychiatry and mental health.
For the full show notes, visit hubermanlab.com.
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Timestamps
(00:00:00) Ketamine
(00:02:29) Sponsors: ROKA & Eight Sleep
(00:05:13) Ketamine & PCP; Clinical & Recreational Use
(00:09:00) Depression & Current Treatments
(00:15:17) Preclinical Models of Depression & Ketamine; “Learned Helplessness” 
(00:22:11) Ketamine & Clinical Uses; Depression & Suicidality 
(00:28:32) Ketamine & Other Psychiatric Challenges; Relief & Durability 
(00:33:24) Sponsor: AG1
(00:34:29) NMDA Receptor & Neuroplasticity
(00:41:36) Excitatory & Inhibitory Communication, Seizure, NMDA Receptors & Ketamine
(00:48:26) How Ketamine Functions in Brain; Acute & Long-Term Effects
(00:55:36) Brain-Derived Neurotrophic Factor (BDNF) & Ketamine Therapy
(01:02:28) Sponsor: LMNT
(01:03:40) Ketamine & Opioid Pathway 
(01:10:00) Divergent Mechanisms of Immediate & Long-Term Effects
(00:15:45) Habenula, Pro-Depressive Behaviors & Ketamine Therapy
(01:20:36) Ketamine & Context-Dependent Strategy; Reward Pathway
(01:22:45) Dissociative States
(01:26:04) Doses & Routes of Administration; “K-holes”; Risk & Caution
(01:32:25) Ketamine Forms; R-, S- vs R/S- Ketamine; Micro-Dosing
(01:38:24) Ketamine: Effects & Therapy
(01:40:40) Zero-Cost Support, YouTube Feedback, Spotify & Apple Reviews, Sponsors, Momentous, Social Media, Neural Network Newsletter
Title Card Photo Credit: Mike Blabac
Disclaimer

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

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

Ketamine is a fascinating compound, and it's 1 that nowadays is being used both clinically for the treatment of depression and suicidality and PTSD, and it is also a drug that is commonly abused.

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

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

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

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

I'll 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.

So by the end of today's episode, you will understand thoroughly what ketamine is, how it works in the brain and body to produce dissociative states and to relieve depression, and you will understand how it can actually change neural circuitry.

This is an important thing to understand about ketamine.

The acute or immediate effects of ketamine while 1 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.

And by extension, when people use ketamine recreationally, there are those immediate acute effects of ketamine, but there are also long-term changes in the brain that are important to understand.

During today's discussion, we will also be talking a lot about neuroplasticity or your nervous system's ability to change in response to experience.

And we will be talking about neuroplasticity, not just in the context of ketamine, but as a general theme for how your nervous system changes anytime you learn anything.

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

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

So in addition to learning about ketamine and how it works clinically and its relevance to recreational use and abuse, you will also learn a lot about neuroplasticity and BDNF and what it's doing in your brain right now as you learn.

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

It is however, part of my desire and effort to bring 0 cost to consumer information about science and science-related tools to the general public.

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

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I realized that many people have heard of ketamine, but most people don't realize that ketamine is very similar to another drug called PCP or fencyclidine, which goes by the street names Angel Dust or Sherm.

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

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.

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

You know, they can fight off 8 or 10 police officers who are trying to handcuff them.

I don't know whether or not any of that is true or not, but we heard a lot about PCP and it was associated with drugs of abuse, things like cocaine, methamphetamine.

Nowadays, when we hear about ketamine, rarely do people mention that ketamine and PCP actually have the same mode of action, more or less.

Okay, I'm not talking about the specifics.

They have the same mode of action in the brain, that both of them are dissociative anesthetics.

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

We are hearing that it can help cure depression.

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

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.

That said, ketamine also has a very high potential for abuse.

And so it may come as no surprise that we often hear about ketamine nowadays, also in the context of its use at parties.

You hear about people going into so-called K-holes, which is a particular state associated with overdoing the dosage of ketamine a little or a lot.

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

In any case, ketamine is an incredible drug, very similar to PCP, vencycladine, 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.

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.

And Not surprisingly, if there is increased access to a drug like ketamine, really any drug that has a potential for abuse, then we also see an increase in the number of people that are using that drug recreationally, and some of them do indeed get addicted to ketamine.

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

Indeed, people can get addicted to ketamine.

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.

That said, ketamine does have these established clinical uses.

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, fencyclidine, and really just looked at as a drug of abuse.

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

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

But really The clinical use of ketamine for the treatment of depression, suicidality, and PTSD has really just taken off in the last 5 to 10 years.

And that's what's brought us to this new landscape of interest and understanding and use of ketamine in the clinical and recreational context.

So how is it that a drug that at 1 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?

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

So I'd like to just take 1 or 2 minutes and explain to you a little bit about the history of depression and its treatment.

What we observe 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.

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

That's a good way to remember monoamines.

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

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

They can ramp up levels of activity in lots of different brain areas, or they can reduce the activity of neural circuits in lots of different brain areas, or they can reduce the activity of neural circuits in lots of different brain areas, as well as within the body, right?

Your gut has serotonin and needs serotonin.

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

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.

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

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

However, what we've learned over the last 30 or 40 years is that drugs that are designed to increase certain monoamines in order to treat depression only work in about 40% of depressed people that take them.

Now, some people are lucky enough that they can use a low enough dose or perhaps even a high enough dose that gives them relief from their depressive symptoms, but does not give them side effects that make it so uncomfortable for them to use that drug that they would choose rather to not take that drug.

However, a lot of people that do get depression relief from things like Zoloft or Paxil or from buprenorphine.

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.

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

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

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

Hence the desire to find other compounds that can treat depression without creating similar side effect profiles.

And that ideally can provide relief, not just for 40%, but for all people suffering from depression.

So that's where ketamine enters the picture.

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

So ketamine is a dissociative anesthetic.

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

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

This is something that if you've ever had a surgery, you might wanna ask your anesthesiologist about, you know, what sorts of drugs are you giving me to go under?

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

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

Because it turns out that when you go into anesthesia, your anesthesiologist is rarely giving you just 1 drug.

Typically, they're giving you 1 drug to, you know, kill off a little bit of anxiety and maybe eliminate a little bit of pain sometimes.

And then they'll give you another drug to drop you into a deeper plane of anesthesia.

And then nowadays there are sophisticated ways to monitor your plane of anesthesia.

And there are sophisticated ways to, if necessary, get you out of a deep plane of anesthesia if that plane of anesthesia is too deep.

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.

Okay, so ketamine has the property of being an anesthetic.

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

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

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

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

It can have some dreamlike qualities to it.

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

Which brings up a really important point, which is that when people use ketamine recreationally, it's not clear exactly what plane of anesthesia or dissociation they are actually seeking.

And this is why we hear about some of the desired effects of ketamine that are driving people to use it recreationally.

And why we also hear about people having some unpleasant or even very unpleasant or dangerous experiences when using ketamine recreationally.

Because we're talking about a drug that has a lot of different effects depending on the dosages.

And as we'll soon talk about, individuals vary tremendously in their response to different dosages of ketamine and the delivery route for ketamine, whether or not it's delivered 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, or then that's injected into the vein or intramuscularly, et cetera.

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.

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.

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.

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

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

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

I realize for some of you, this might be a bit of an aversive topic to hear about animal research, but this is 1 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.

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.

And then of course the researcher needs to rescue the rat or mouse, put it back into its home cage, dry it off, give it some food, et cetera.

This 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.

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

So we can only look at their behavior in order to understand whether or not they have a sense of happiness or a sense of depression.

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

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

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

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

So this thing of putting a rat or mouse into water and seeing how long it takes before they give up to save their own life is called the model of learned helplessness.

And what it allowed researchers to do was to take rats and mice, put them into water, see how long it took before they gave up, and then to give them different drugs to see whether or not any of those drugs either hastened, sped up, or prolonged the duration over which the animal would attempt to save its own life.

This actually has some meaningful parallels to human depression.

You know, 1 of the hallmarks of depression is that people stop thinking positively about their future.

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

You know, 1 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.

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.

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.

So this preclinical model of learned helplessness allowed researchers to test a lot of different drugs and establish which drugs at which dosages allowed animals to fight for their life longer when placed into water.

It's really that simple as a model, but it revealed some very interesting things, at least 1 of which is that when animals were injected with ketamine, this dissociative anesthetic, but they were injected with dosages of ketamine that were below what would induce full anesthesia, these animals would swim for their life for a lot longer.

Now, to some extent, that ought to be surprising, and in fact, was surprising to researchers because ketamine is what's called an NMDA receptor blocker.

Now, when I say blocker, I'm not getting into the details of what specific form of blocker it is, but I do want to mention that a blocker is sometimes referred to as an antagonist, whereas something that promotes the activity of a receptor is called an agonist, okay?

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.

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

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

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

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

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

So put differently, here's a drug that blocks the receptor that's critical for neuroplasticity, for changes in the brain, and yet somehow it's allowing these animals to fight for their life longer.

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

At least that's the subjective interpretation of what 1 observes when a mouse or rat is swimming for much longer when it would otherwise just give up and sink to the bottom of the vessel.

Now, in general, there are 2 kinds of scientists.

There are scientists that take a look at a set of findings like that and say, oh, here's a drug that's supposed to be terrible for us.

It's an anesthetic and it blocks NMDA receptors and NMDA receptors are good for neuroplasticity.

And somehow it's also allowing these animals to swim longer.

And I would say 1 category of scientists would just look at that and just say, wow, that is a big ball or tangle of confused facts.

Like how does 1 even reconcile that, right?

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

This is a drug that blocks neuroplasticity, but somehow is relieving depression.

And then there's this other category of scientists, which thank goodness exists, who looks at that apparent contradiction of, okay, there's a drug which blocks plasticity, plasticity is thought to be important for getting over depression, and yet the drug can provide some relief from depression, at least in these preclinical animal models, and they say, I like a good puzzle, right?

The more complex the puzzle, the more interesting.

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

And like I said, thank goodness these sorts of scientists exist and thank goodness they did that because it turned out that when clinicians tried ketamine in depressed patients as a means to relieve depression, it had remarkable effects.

So it was about the year 2000, when the first sets of papers about the clinical use of ketamine for the treatment of depression started to emerge.

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

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

And as we talked about earlier, some people were getting relief, some people were getting relief with a lot of side effects and therefore deciding not to take those drugs.

And a lot of people, the majority of people that were taking those drugs were not getting relief.

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

And ketamine, at least based on its apparent profile of being a dissociative anesthetic, would seem like the last drug that you'd want to use to treat depression, right?

It dissociates people, you even hear about dissociation as a symptom of depression.

And yet what happened was a small number of very pioneering clinicians started to explore the use of ketamine in the clinic for the treatment of depression.

And in particular for depression that did not respond to any other treatment.

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.

So 1 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.

So it doesn't involve many subjects at all.

Really just has 7 subjects, all of whom had major depression.

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

Now that dosage, half a milligram per kilogram of body weight turns out to be very important for today's discussion, because it's going to serve as a reference point for later discussions when we get into other modes of delivery of ketamine, such as oral pill form ketamine or sublingual ketamine.

And as it relates to things like the K-hole or the dissociative state, or the various effects that ketamine can have depending on the dosage and the delivery route.

Meanwhile, going back to this study, what they found is that when they injected patients with severe depression with ketamine, the effects of ketamine took place within minutes, within 10 or 15 minutes, and that they experienced a sort of peak euphoric state.

Okay, so they're not inducing deep anesthesia, right?

At this dosage, they're getting people into a kind of euphoric, dreamy, semi-dissociative state.

That occurred within 15 minutes and really peaked about 45 minutes to an hour after they were injected with the drug.

And that the total effects of the drug in terms of euphoria were effectively over by about 2 hours or so.

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.

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.

So within minutes to hours, and that it persisted for several days after taking the ketamine.

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Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity