Ketamine: Benefits and Risks for Depression, PTSD & Neuroplasticity

00:00:00.000 | - Welcome to the Huberman Lab Podcast,

00:00:02.300 | where we discuss science and science-based tools

00:00:04.920 | for everyday life.

00:00:05.940 | I'm Andrew Huberman,

00:00:10.680 | and I'm a professor of neurobiology and ophthalmology

00:00:13.600 | at Stanford School of Medicine.

00:00:15.500 | Today, we are discussing ketamine.

00:00:17.940 | Ketamine is a fascinating compound,

00:00:20.280 | and it's one that nowadays is being used both clinically

00:00:23.480 | for the treatment of depression and suicidality and PTSD,

00:00:28.820 | and it is also a drug that is commonly abused.

00:00:31.800 | That is, ketamine is often used recreationally,

00:00:35.020 | and it has a high potential for abuse.

00:00:37.480 | So today, we are going to discuss both the research

00:00:39.840 | on the clinical benefits of ketamine,

00:00:41.900 | as well as the risks of ketamine.

00:00:44.060 | We are going to discuss the mechanisms of action

00:00:46.760 | by which ketamine produces

00:00:48.340 | what are called dissociative states.

00:00:50.560 | I will define for you what a so-called K-hole is

00:00:53.280 | in scientific terms.

00:00:54.760 | I will talk about dosages of ketamine.

00:00:56.620 | I'll talk about delivery routes of ketamine,

00:00:58.980 | and throughout, I will be emphasizing

00:01:00.780 | both the clinical benefits and the risks,

00:01:03.220 | that is, the potential harms of using ketamine

00:01:05.860 | out of the appropriate clinical context.

00:01:08.080 | So by the end of today's episode,

00:01:09.520 | you will understand thoroughly what ketamine is,

00:01:12.340 | how it works in the brain and body

00:01:14.060 | to produce dissociative states and to relieve depression,

00:01:17.680 | and you will understand

00:01:19.060 | how it can actually change neural circuitry.

00:01:21.700 | This is an important thing to understand about ketamine.

00:01:24.260 | The acute or immediate effects of ketamine,

00:01:26.620 | while one is under the influence of ketamine,

00:01:29.440 | are just part of the story of how ketamine modifies the brain

00:01:32.940 | for the treatment of depression, suicidality, and PTSD.

00:01:36.620 | And by extension, when people use ketamine recreationally,

00:01:39.460 | there are those immediate acute effects of ketamine,

00:01:42.100 | but there are also long-term changes in the brain

00:01:44.660 | that are important to understand.

00:01:46.460 | During today's discussion,

00:01:47.420 | we will also be talking a lot about neuroplasticity,

00:01:50.500 | or your nervous system's ability to change

00:01:52.560 | in response to experience.

00:01:54.100 | And we will be talking about neuroplasticity,

00:01:56.060 | not just in the context of ketamine,

00:01:58.200 | but as a general theme for how your nervous system changes

00:02:01.220 | anytime you learn anything.

00:02:03.340 | And in that discussion, you're going to hear a lot

00:02:05.680 | about BDNF, or brain-derived neutrophic factor.

00:02:09.900 | Brain-derived neutrophic factor is a critical molecule

00:02:13.220 | for all forms of learning and memory

00:02:15.140 | and changes to your nervous system.

00:02:17.060 | So in addition to learning about ketamine

00:02:18.820 | and how it works clinically

00:02:19.960 | and its relevance to recreational use and abuse,

00:02:22.740 | you will also learn a lot about neuroplasticity and BDNF

00:02:26.400 | and what it's doing in your brain right now as you learn.

00:02:29.720 | Before we begin, I'd like to emphasize that this podcast

00:02:32.460 | is separate from my teaching and research roles at Stanford.

00:02:35.380 | It is, however, part of my desire and effort

00:02:37.380 | to bring zero cost to consumer information

00:02:39.340 | about science and science-related tools

00:02:41.420 | to the general public.

00:02:42.840 | In keeping with that theme,

00:02:44.060 | I'd like to thank the sponsors of today's podcast.

00:02:46.980 | Our first sponsor is Roca.

00:02:49.040 | Roca makes eyeglasses and sunglasses

00:02:51.140 | that are of the absolute highest quality.

00:02:53.020 | The company was founded by two all-American swimmers

00:02:55.140 | from Stanford, and everything about Roca eyeglasses

00:02:57.820 | and sunglasses were designed with performance in mind.

00:03:01.000 | I've spent a lifetime working on the biology

00:03:02.740 | of the visual system, and I can tell you

00:03:03.960 | that your visual system has to contend

00:03:05.880 | with an enormous number of different challenges

00:03:07.940 | in order for you to be able to see clearly

00:03:10.020 | when, for instance, you go from a shady area to a sunny area

00:03:13.180 | when you look at something up close or off in the distance.

00:03:16.180 | Roca understands all of that

00:03:17.740 | and have designed their eyeglasses and sunglasses

00:03:20.180 | so that regardless of conditions,

00:03:21.620 | you always see with perfect clarity.

00:03:24.020 | Their glasses are also extremely lightweight,

00:03:26.500 | and they won't slip off your face if you get sweaty.

00:03:28.960 | In fact, initially, Roca eyeglasses and sunglasses

00:03:31.500 | were designed for use in sports,

00:03:33.040 | things like running and cycling, et cetera,

00:03:34.660 | and they still can be used for that,

00:03:36.140 | but really, their eyeglasses and sunglasses

00:03:37.840 | are designed to be worn anytime.

00:03:39.280 | I wear readers at night or when I drive at night,

00:03:41.720 | and I'll sometimes wear sunglasses in the middle of the day,

00:03:44.080 | although, of course, I do not wear sunglasses

00:03:46.400 | when I do my morning sunlight exposure,

00:03:48.580 | which everyone should be doing

00:03:49.500 | to set their circadian rhythm.

00:03:51.260 | If you'd like to try Roca eyeglasses or sunglasses,

00:03:53.920 | simply go to Roca, that's R-O-K-A, dot com,

00:03:56.980 | and enter the code Huberman to save 20% off

00:03:59.620 | your first order.

00:04:00.460 | Again, that's R-O-K-A dot com

00:04:02.140 | and enter the code Huberman at checkout.

00:04:04.660 | Today's episode is also brought to us by Eight Sleep.

00:04:07.340 | Eight Sleep makes smart mattress covers

00:04:09.240 | with cooling, heating, and sleep tracking capacity.

00:04:12.300 | Now, I've spoken many times before on this podcast

00:04:14.440 | and elsewhere about the fact that sleep is the foundation

00:04:17.440 | of mental health, physical health, and performance.

00:04:19.620 | When we're sleeping well and enough,

00:04:21.520 | all of those things are improved,

00:04:22.940 | and when we are not sleeping well or enough,

00:04:25.100 | all of those things, mental health, physical health,

00:04:26.940 | and performance all get worse.

00:04:29.040 | Now, a key component to getting a great night's sleep

00:04:31.460 | is that the temperature of your sleeping environment

00:04:33.900 | has to be such that your body temperature drops

00:04:36.540 | by one to three degrees in order to fall

00:04:38.700 | and stay deeply asleep,

00:04:40.380 | and that your body temperature increase

00:04:42.380 | by about one to three degrees in order to wake up

00:04:44.600 | feeling refreshed.

00:04:45.880 | With Eight Sleep mattress covers,

00:04:47.420 | you can customize the temperature

00:04:48.700 | of your sleeping environment

00:04:49.860 | such that you always get the best possible night's sleep.

00:04:52.840 | I've been sleeping on an Eight Sleep mattress cover

00:04:54.540 | for about two years now,

00:04:55.880 | and I must say it has vastly improved my sleep.

00:04:58.660 | If you'd like to try Eight Sleep,

00:04:59.920 | you can go to EightSleep.com/Huberman

00:05:02.440 | and save $150 off off their Pod 3 cover.

00:05:05.500 | They currently ship in the USA, Canada, UK,

00:05:07.720 | select countries in the EU, and Australia.

00:05:10.220 | Again, that's EightSleep.com/Huberman.

00:05:13.100 | Okay, let's talk about ketamine.

00:05:14.940 | I realize that many people have heard of ketamine,

00:05:17.340 | but most people don't realize

00:05:18.980 | that ketamine is very similar to another drug

00:05:21.660 | called PCP or fencyclidine,

00:05:24.120 | which goes by the street names angel dust or sherm.

00:05:26.840 | It has some other street names as well.

00:05:28.940 | When I was growing up, I heard a lot about PCP.

00:05:31.340 | They taught us about it in school.

00:05:33.020 | You'd hear about it on cop shows, on television,

00:05:36.380 | and the lore was that PCP

00:05:38.300 | would eliminate people's perception of pain

00:05:40.700 | and would make them violent.

00:05:42.020 | You'd hear these stories in drug education classes

00:05:45.120 | that when people are on PCP,

00:05:46.660 | they're punching light poles and breaking their hands.

00:05:48.980 | They can fight off eight or 10 police officers

00:05:51.420 | who are trying to handcuff them.

00:05:53.140 | I don't know whether or not any of that is true or not,

00:05:55.740 | but we heard a lot about PCP

00:05:58.200 | and it was associated with drugs of abuse,

00:06:01.340 | things like cocaine, methamphetamine.

00:06:03.020 | It was lumped into that category.

00:06:04.940 | Nowadays, when we hear about ketamine,

00:06:06.740 | rarely do people mention that ketamine and PCP

00:06:09.620 | actually have the same mode of action, more or less.

00:06:12.340 | Okay, I'm not talking about the specifics.

00:06:13.680 | I'm talking broadly.

00:06:14.820 | They have the same mode of action in the brain.

00:06:17.180 | The both of them are dissociative anesthetics.

00:06:20.100 | And nowadays, usually when we hear about ketamine,

00:06:22.620 | we are hearing about its benefits.

00:06:24.140 | We are hearing that it can help cure depression.

00:06:25.920 | We are hearing that it can help reduce or cure suicidality,

00:06:29.240 | that it can be used to treat PTSD.

00:06:30.860 | And indeed, all of that is true

00:06:32.860 | in the appropriate clinical context,

00:06:34.460 | at the appropriate dosages,

00:06:35.620 | and given at the appropriate frequency,

00:06:37.580 | ketamine has proven to be a miraculous drug

00:06:40.920 | for some people, not all people,

00:06:43.600 | for the treatment of depression, suicidality, and PTSD.

00:06:47.820 | That said, ketamine also has a very high potential for abuse.

00:06:51.940 | And so it may come as no surprise

00:06:53.240 | that we often hear about ketamine nowadays,

00:06:55.540 | also in the context of its use at parties.

00:06:58.580 | You hear about people going into so-called K holes,

00:07:00.860 | which is a particular state

00:07:02.040 | associated with overdoing the dosage of ketamine

00:07:06.020 | a little or a lot.

00:07:07.780 | We'll get back to that a little bit later,

00:07:09.180 | what it is, how dangerous it is, et cetera.

00:07:12.380 | In any case, ketamine is an incredible drug,

00:07:15.320 | very similar to PCP, fencyclidine.

00:07:18.640 | And it is a drug that nowadays there is crossover

00:07:22.400 | between the clinical uses of ketamine

00:07:24.480 | for treatment of depression, et cetera,

00:07:26.160 | and its recreational use.

00:07:27.640 | What do I mean by that?

00:07:29.120 | What I'm referring to is people accessing ketamine legally

00:07:32.300 | for the purpose of treating depression,

00:07:34.740 | but taking that ketamine out of the clinic,

00:07:36.960 | out of the doctor's office,

00:07:38.400 | which is a very different set of conditions

00:07:40.520 | than most of the studies that have been done on ketamine

00:07:42.900 | and its role in depression.

00:07:44.440 | And not surprisingly,

00:07:45.760 | if there's increased access to a drug like ketamine,

00:07:48.880 | really any drug that has a potential for abuse,

00:07:52.080 | then we also see an increase in the number of people

00:07:53.920 | that are using that drug recreationally,

00:07:56.240 | and some of them do indeed get addicted to ketamine.

00:07:59.540 | So I know many of you are probably wondering,

00:08:01.020 | can you get addicted to ketamine?

00:08:02.560 | Indeed, people can get addicted to ketamine.

00:08:05.160 | There are some people who like its effects enough

00:08:07.860 | that they find themselves compelled to use ketamine

00:08:10.200 | even though the use of ketamine

00:08:12.320 | is degrading their overall life performance.

00:08:14.720 | So work, school, relationships, finances, et cetera.

00:08:18.680 | That said, ketamine does have

00:08:21.000 | these established clinical uses.

00:08:22.760 | So nowadays the landscape around ketamine

00:08:24.640 | is oh so different than it was 10 or 20 years ago,

00:08:28.380 | when it was lumped very closely with PCP, fencyclidine,

00:08:31.520 | and really just looked at as a drug of abuse.

00:08:34.400 | There were some early cases in the 1970s

00:08:36.800 | of the use of ketamine in order to treat PTSD.

00:08:40.040 | This was mainly in soldiers in Vietnam

00:08:42.240 | or people coming back from Vietnam.

00:08:44.260 | But really the clinical use of ketamine

00:08:46.940 | for the treatment of depression, suicidality, and PTSD

00:08:50.620 | has really just taken off in the last five to 10 years.

00:08:53.600 | And that's what's brought us to this new landscape

00:08:56.120 | of interest and understanding and use of ketamine

00:08:58.720 | in the clinical and recreational context.

00:09:01.040 | So how is it that a drug that at one time

00:09:02.780 | was really just viewed as a street drug

00:09:05.160 | that was bad, bad, bad is now being prescribed widely

00:09:08.860 | and has all this interest surrounding it?

00:09:11.200 | And really this has to do with our understanding

00:09:13.480 | of what depression is and what depression isn't.

00:09:16.360 | So I'd like to just take one or two minutes

00:09:18.400 | and explain to you a little bit

00:09:19.760 | about the history of depression and its treatment.

00:09:22.400 | What we observed starting about the middle

00:09:24.080 | of the last century, so around 1950,

00:09:26.640 | but really taking off in the early 1980s and 90s

00:09:30.360 | is the so-called monoamine hypothesis of depression.

00:09:33.960 | Monoamines, as the name suggests,

00:09:35.900 | are synthesized from amino acids.

00:09:38.440 | That's a good way to remember monoamines.

00:09:41.040 | Monoamines include things like serotonin,

00:09:44.120 | dopamine, and norepinephrine,

00:09:46.160 | although there are other monoamines as well.

00:09:49.240 | Monoamines are neurotransmitters, or more specifically,

00:09:52.680 | they are neuromodulators, meaning they change the activity

00:09:56.080 | of neural circuits in the brain and body.

00:09:58.400 | They can ramp up levels of activity

00:10:00.280 | in lots of different brain areas,

00:10:01.920 | or they can reduce the activity of neural circuits

00:10:04.760 | in lots of different brain areas,

00:10:06.560 | as well as within the body, right?

00:10:08.320 | Your gut has serotonin and needs serotonin.

00:10:11.180 | Dopamine also plays important roles in the body,

00:10:13.800 | et cetera, et cetera.

00:10:14.880 | The monoamine hypothesis of depression

00:10:16.920 | is really centered around the idea

00:10:18.400 | that it is deficiencies in these monoamines,

00:10:21.300 | either serotonin or dopamine or norepinephrine,

00:10:24.320 | or some combination of those that gives rise to depression.

00:10:27.840 | Now, in reality, there is very little, if any, evidence

00:10:31.360 | that there is a deficiency of monoamines

00:10:34.300 | in any form of depression.

00:10:36.320 | However, it is very clear that drugs

00:10:38.920 | that increase certain monoamines,

00:10:41.240 | so drugs like Prozac or Zoloft that increase serotonin,

00:10:44.720 | or drugs like bupren, which is often called Welbutrin,

00:10:48.120 | which is its commercial name,

00:10:49.700 | which increases dopamine and norepinephrine,

00:10:52.200 | can often provide relief

00:10:54.080 | for certain symptoms of depression in some people.

00:10:57.640 | However, what we've learned over the last 30 or 40 years

00:11:00.700 | is that drugs that are designed

00:11:02.160 | to increase certain monoamines

00:11:03.880 | in order to treat depression only work

00:11:06.360 | in about 40% of depressed people that take them,

00:11:09.560 | and they have a lot of side effects.

00:11:12.720 | Now, some people are lucky enough

00:11:14.120 | that they can use a low enough dose,

00:11:16.540 | or perhaps even a high enough dose

00:11:18.100 | that gives them relief from their depressive symptoms,

00:11:20.780 | but does not give them side effects

00:11:22.200 | that make it so uncomfortable for them to use that drug

00:11:24.880 | that they would choose rather to not take that drug.

00:11:27.560 | However, a lot of people that do get depression relief

00:11:30.680 | from things like Zoloft or Paxil or from bupren,

00:11:35.600 | find that the side effects,

00:11:37.140 | which include things like dry mouth,

00:11:39.460 | although more commonly reductions or increases in appetite,

00:11:43.100 | or vast reductions in libido,

00:11:45.420 | or changes in their sleep patterns, et cetera,

00:11:48.180 | that those side effects really make it impossible,

00:11:51.380 | or at least very uncomfortable for them to take those drugs.

00:11:54.600 | And of course, there are the 60% of depressed people

00:11:57.400 | who do not respond to those drugs at all.

00:12:00.240 | Now, I want to be very clear.

00:12:02.420 | Things like SSRIs, things like Wellbutrin

00:12:04.840 | have helped a tremendous number of people

00:12:06.700 | get relief from depressive symptoms,

00:12:08.560 | and in many cases have warded off suicidality as well.

00:12:11.800 | However, there are also a great number of people

00:12:14.840 | who have experienced a lot of side effects

00:12:16.520 | and problems from these drugs,

00:12:18.220 | hence the desire to find other compounds

00:12:20.460 | that can treat depression

00:12:21.740 | without creating similar side effect profiles,

00:12:24.160 | and that ideally can provide relief not just for 40%,

00:12:27.680 | but for all people suffering from depression.

00:12:30.360 | So that's where ketamine enters the picture.

00:12:32.240 | Prior to the 1990s, they were mainly studied in neuroscience

00:12:35.340 | and pharmacology laboratories for their abuse properties

00:12:39.400 | and for their anesthetic properties.

00:12:41.720 | So ketamine is a dissociative anesthetic.

00:12:44.920 | It's actually used to induce

00:12:46.840 | certain forms of anesthesia for surgery.

00:12:49.020 | It's not always used, but it's often used.

00:12:51.400 | This is something that if you've ever had a surgery,

00:12:53.860 | you might want to ask your anesthesiologist about,

00:12:56.680 | what sorts of drugs are you giving me to go under?

00:12:59.080 | What sorts of drugs are you keeping me to stay under?

00:13:01.440 | And maybe even what sorts of drugs are you giving me

00:13:03.400 | to bring me out of anesthesia?

00:13:04.680 | 'Cause it turns out that when you go into anesthesia,

00:13:06.900 | your anesthesiologist is rarely giving you just one drug.

00:13:09.480 | Typically, they're giving you one drug

00:13:10.780 | to kill off a little bit of anxiety

00:13:13.300 | and maybe eliminate a little bit of pain sometimes.

00:13:16.360 | And then they'll give you another drug

00:13:17.600 | to drop you into a deeper plane of anesthesia.

00:13:19.960 | And then nowadays, there are sophisticated ways

00:13:21.780 | to monitor your plane of anesthesia,

00:13:23.760 | and there are sophisticated ways to, if necessary,

00:13:26.540 | get you out of a deep plane of anesthesia

00:13:28.360 | if that plane of anesthesia is too deep.

00:13:30.340 | When I talk about a plane of anesthesia,

00:13:31.860 | I'm just talking about going from full wakefulness

00:13:34.440 | to a reduction in anxiety, to falling asleep, to asleep,

00:13:38.360 | to the point where even if someone were to pinch your toe

00:13:41.260 | or your arm, like a really intense pinch,

00:13:43.800 | that you wouldn't wake up from that.

00:13:45.420 | Okay, so ketamine has the property of being an anesthetic.

00:13:50.280 | It kills the response to pain, and at certain doses,

00:13:53.500 | it can bring you into deep planes of anesthesia.

00:13:55.960 | At lesser dosages, it can take you into transition points

00:13:59.480 | between awake and deeply anesthetized.

00:14:02.000 | And it's really that transition point

00:14:03.480 | between awake and deeply anesthetized,

00:14:05.700 | which we are going to call the dissociative state.

00:14:08.060 | It's kind of this liminal state, a little bit like dreaming.

00:14:10.480 | It can have some dream-like qualities to it.

00:14:12.920 | That's the state that has most often been sought after

00:14:16.040 | or employed for the treatment of depression,

00:14:18.120 | suicidality, and PTSD,

00:14:20.060 | which brings up a really important point,

00:14:21.560 | which is that when people use ketamine recreationally,

00:14:24.320 | it's not clear exactly what plane of anesthesia

00:14:28.440 | or dissociation they are actually seeking.

00:14:30.740 | And this is why we hear about some of the desired effects

00:14:33.400 | of ketamine that are driving people to use it recreationally

00:14:36.200 | and why we also hear about people having some unpleasant

00:14:40.000 | or even very unpleasant or dangerous experiences

00:14:42.800 | when using ketamine recreationally.

00:14:45.140 | Because we're talking about a drug

00:14:46.520 | that has a lot of different effects,

00:14:48.300 | depending on the dosages, and as we'll soon talk about,

00:14:51.520 | individuals vary tremendously in their response

00:14:54.560 | to different dosages of ketamine

00:14:56.080 | and the delivery route for ketamine,

00:14:58.300 | whether or not it's delivered orally in the form of a pill

00:15:01.360 | or put sublingually in what's called a troche

00:15:03.300 | that dissolves under the tongue or it's injected.

00:15:05.960 | Whether or not it's injected into the vein

00:15:07.380 | or intramuscularly, et cetera.

00:15:09.160 | Each of those can produce very different effects

00:15:11.960 | in terms of the speed of onset of the drug

00:15:14.280 | and the type of effects that it produces

00:15:15.980 | in the brain and body.

00:15:17.200 | So what happened in the early '90s

00:15:19.120 | is that laboratories that were studying animal models,

00:15:21.880 | what we call preclinical models of things like depression

00:15:25.560 | and learning and memory, and to some extent ketamine,

00:15:29.200 | but mainly focusing on learning and memory and depression,

00:15:32.340 | made an interesting discovery.

00:15:34.060 | There's a certain preclinical model of depression

00:15:36.100 | that's pretty common in laboratories

00:15:38.140 | that involves taking a rat or a mouse

00:15:40.340 | and putting it into a small container,

00:15:43.060 | like it looks like a beaker or a jar,

00:15:44.980 | sometimes it's a tray and it has water in it.

00:15:47.220 | And you might be surprised to learn, perhaps not,

00:15:49.680 | that if you put a rat or a mouse into water, it will swim.

00:15:53.100 | Okay, so it's treading water

00:15:54.220 | in order to keep its head above water and not drown.

00:15:57.060 | I realize for some of you,

00:15:58.540 | this might be a bit of an aversive topic

00:16:00.380 | to hear about animal research,

00:16:01.600 | but this is one of the common preclinical models

00:16:04.200 | of depression, which is put a rat or a mouse into water,

00:16:08.060 | let it swim and see at what point it gives up.

00:16:11.160 | Because what happens is if you put a rat or mouse into water,

00:16:15.000 | it will attempt to save its own life by swimming,

00:16:17.840 | but at some point it will just give up

00:16:20.140 | and it will just start sinking.

00:16:21.280 | And then of course, the researcher needs to rescue

00:16:23.700 | the rat or mouse, put it back into its home cage,

00:16:25.580 | dry it off, give it some food, et cetera.

00:16:28.020 | This preclinical model is called

00:16:29.600 | the model of learned helplessness,

00:16:31.580 | and it's become a prominent preclinical model of depression,

00:16:34.680 | because of course we can't ask mice or rats

00:16:38.140 | if they are depressed or happy.

00:16:39.900 | I suppose you can ask them,

00:16:41.660 | but they're not going to answer

00:16:42.800 | in any kind of meaningful way.

00:16:44.300 | So we can only look at their behavior

00:16:46.260 | in order to understand whether or not

00:16:47.980 | they have a sense of happiness or a sense of depression.

00:16:50.920 | And of course, that's very hard to gauge

00:16:52.780 | in an animal model of any kind.

00:16:54.920 | You could make guesses based on other behaviors,

00:16:57.020 | like are they grooming regularly?

00:16:58.340 | Are they eating regularly?

00:16:59.780 | Things that more or less parallel

00:17:01.580 | what we think of as health or lack of health

00:17:03.480 | in a human who's happy or depressed.

00:17:06.400 | But in the context of trying to understand depression

00:17:08.360 | in these preclinical animal models,

00:17:10.140 | having a behavior that you can really quantify carefully

00:17:13.460 | across a lot of different animals and conditions

00:17:15.960 | is really beneficial.

00:17:17.040 | So this thing of putting a rat or mouse into water

00:17:20.420 | and seeing how long it takes

00:17:21.580 | before they give up to save their own life

00:17:24.140 | is called the model of learned helplessness.

00:17:26.800 | And what it allowed researchers to do

00:17:29.420 | was to take rats and mice, put them into water,

00:17:31.700 | see how long it took before they gave up,

00:17:33.620 | and then to give them different drugs

00:17:35.660 | to see whether or not any of those drugs

00:17:37.720 | either hastened, sped up, or prolonged

00:17:41.600 | the duration over which the animal would attempt

00:17:43.440 | to save its own life.

00:17:44.740 | This actually has some meaningful parallels

00:17:46.900 | to human depression.

00:17:48.100 | You know, one of the hallmarks of depression

00:17:50.140 | is that people stop thinking positively about their future.

00:17:53.820 | Depression, of course, can include a lot of other symptoms.

00:17:56.440 | You know, one of the most prominent symptoms of depression,

00:17:58.520 | for instance, is consistently waking up

00:18:01.140 | around 2.30 or 3.30 in the morning

00:18:03.480 | and not being able to fall back asleep again.

00:18:05.380 | Now, keep in mind, it is not the case

00:18:08.280 | that if you're waking up at 2.30 or 3.30 in the morning

00:18:11.060 | and you can't fall back asleep,

00:18:12.280 | that you are absolutely depressed.

00:18:14.300 | That's simply not the case.

00:18:16.400 | But that pattern of lack of sleep

00:18:19.980 | plus some other things like lack of anticipation

00:18:22.620 | of a positive future, inability to imagine the future

00:18:25.180 | in any kind of meaningful or positive way, et cetera,

00:18:28.860 | are part of the key features

00:18:31.140 | of what we call a major depressive episode.

00:18:33.700 | So this preclinical model of learned helplessness

00:18:36.140 | allowed researchers to test a lot of different drugs

00:18:38.660 | and establish which drugs at which dosages

00:18:42.220 | allowed animals to fight for their life longer

00:18:45.020 | when placed into water.

00:18:46.160 | It's really that simple as a model,

00:18:48.520 | but it revealed some very interesting things,

00:18:51.060 | at least one of which is that

00:18:52.060 | when animals were injected with ketamine,

00:18:54.260 | this dissociative anesthetic,

00:18:56.040 | but they were injected with dosages of ketamine

00:18:58.160 | that were below what would induce full anesthesia,

00:19:02.460 | these animals would swim for their life for a lot longer.

00:19:05.860 | Now, to some extent, that ought to be surprising,

00:19:08.980 | and in fact was surprising to researchers

00:19:10.820 | because ketamine is what's called an NMDA receptor blocker.

00:19:15.820 | Now, when I say blocker, I'm not getting into the details

00:19:18.420 | of what specific form of blocker it is,

00:19:20.700 | but I do want to mention that a blocker

00:19:23.140 | is sometimes referred to as an antagonist,

00:19:25.820 | whereas something that promotes the activity of a receptor

00:19:29.260 | is called an agonist, okay?

00:19:30.940 | So if you can just remember

00:19:32.660 | that ketamine is an NMDA receptor antagonist or blocker,

00:19:37.500 | then you should be fine

00:19:38.340 | for the rest of today's conversation.

00:19:40.360 | Now, I haven't told you what NMDA is.

00:19:42.940 | NMDA stands for N-methyl-D-aspartate,

00:19:45.780 | and you do not need to remember that,

00:19:47.600 | but the surprise for researchers was that this drug, ketamine,

00:19:51.860 | is allowing animals to fight for their life for longer,

00:19:55.420 | so it has this sort of property

00:19:57.180 | of overcoming what we call learned helplessness

00:19:59.700 | or a sense of helplessness, AKA antidepressant effects,

00:20:04.460 | and we also know

00:20:06.480 | that it's an NMDA receptor antagonist or blocker,

00:20:10.100 | and that's perplexing because we also know

00:20:13.500 | that the NMDA receptor is critical

00:20:16.460 | for changing neural circuitry in the brain.

00:20:19.900 | It's critical for neuroplasticity.

00:20:22.060 | So put differently, here's a drug that blocks the receptor

00:20:25.660 | that's critical for neuroplasticity for changes in the brain,

00:20:28.460 | and yet somehow it's allowing these animals

00:20:31.220 | to fight for their life longer.

00:20:33.280 | It's somehow giving them more of a sense of hope.

00:20:35.500 | At least that's the subjective interpretation

00:20:38.220 | of what one observes when a mouse or rat

00:20:40.480 | is swimming for much longer

00:20:41.780 | when it would otherwise just give up

00:20:43.340 | and sink to the bottom of the vessel.

00:20:45.300 | Now, in general, there are two kinds of scientists.

00:20:47.480 | There are scientists that take a look at a set of findings

00:20:50.080 | like that and say, oh, here's a drug

00:20:51.740 | that's supposed to be terrible for us.

00:20:53.120 | It's an anesthetic, and it blocks NMDA receptors,

00:20:56.320 | and NMDA receptors are good for neuroplasticity,

00:20:59.640 | and somehow it's also allowing these animals to swim longer,

00:21:02.880 | and I would say one category of scientists

00:21:05.300 | would just look at that and just say,

00:21:06.480 | wow, that is a big ball or tangle of confused facts.

00:21:11.600 | How does one even reconcile that, right?

00:21:13.520 | Brain change ought to be good

00:21:15.000 | and perhaps even lie at the heart of our ability

00:21:17.720 | to recover from depression.

00:21:19.140 | This is a drug that blocks neuroplasticity,

00:21:21.680 | but somehow is relieving depression.

00:21:23.620 | I'm going to walk away from that.

00:21:24.600 | I'm going to work on something far simpler.

00:21:26.400 | And then there's this other category of scientists,

00:21:28.240 | which, thank goodness, exists,

00:21:29.940 | who looks at that apparent contradiction of,

00:21:32.160 | okay, there's a drug which blocks plasticity.

00:21:34.440 | Plasticity is thought to be important

00:21:36.600 | for getting over depression,

00:21:37.640 | and yet the drug can provide some relief from depression,

00:21:40.760 | at least in these preclinical animal models,

00:21:42.800 | and they say, hmm, I like a good puzzle, right?

00:21:46.020 | The more complex the puzzle, the more interesting,

00:21:48.280 | and they start digging in with preclinical studies,

00:21:50.920 | and they start talking to clinicians

00:21:52.640 | who are treating patients for depression.

00:21:54.740 | And like I said, thank goodness

00:21:56.800 | these sorts of scientists exist,

00:21:58.200 | and thank goodness they did that,

00:22:00.160 | because it turned out that when clinicians tried ketamine

00:22:05.160 | in depressed patients as a means to relieve depression,

00:22:08.640 | it had remarkable effects.

00:22:10.640 | So it was about the year 2000

00:22:13.600 | when the first sets of papers

00:22:15.640 | about the clinical use of ketamine

00:22:17.400 | for the treatment of depression started to emerge.

00:22:19.980 | Now, we have to remember the context

00:22:21.480 | in which all of this was happening.

00:22:23.220 | You know, in 2000, drugs like Prozac

00:22:25.500 | and some of the similar SSRIs,

00:22:27.400 | selective serotonin reuptake inhibitors,

00:22:29.520 | things like Wellbutrin,

00:22:31.000 | were really hitting the market in full force.

00:22:33.760 | And as we talked about earlier,

00:22:34.860 | some people were getting relief,

00:22:36.360 | some people were getting relief with a lot of side effects

00:22:38.800 | and therefore deciding not to take those drugs,

00:22:40.380 | and a lot of people,

00:22:41.220 | the majority of people that were taking those drugs

00:22:43.200 | were not getting relief.

00:22:44.500 | So there was a real urgent need to find other drugs

00:22:47.440 | for the treatment of depression.

00:22:48.720 | And ketamine, at least based on its apparent profile

00:22:52.840 | of being a dissociative anesthetic,

00:22:54.440 | would seem like the last drug

00:22:56.080 | that you'd want to use to treat depression, right?

00:22:58.560 | It dissociates people.

00:22:59.800 | You even hear about dissociation as a symptom of depression.

00:23:02.640 | And yet what happened was

00:23:04.520 | a small number of very pioneering clinicians

00:23:07.200 | started to explore the use of ketamine in the clinic

00:23:09.920 | for the treatment of depression,

00:23:11.280 | and in particular for depression

00:23:13.420 | that did not respond to any other treatment.

00:23:15.600 | So there was a real critical need to find other compounds

00:23:18.680 | and a bit more motivation to test some of these,

00:23:21.140 | let's call them atypical compounds

00:23:22.600 | for the treatment of depression.

00:23:24.320 | So one of the first landmark papers

00:23:26.960 | in the use of ketamine for the treatment of depression

00:23:28.880 | is entitled "Antidepressant Effects of Ketamine

00:23:31.600 | in Depressed Patients."

00:23:32.960 | This is a paper that I've provided a link to

00:23:34.600 | in the show note captions.

00:23:35.840 | It's a small study, okay?

00:23:37.480 | So it doesn't involve many subjects at all,

00:23:39.360 | really just has seven subjects,

00:23:41.040 | all of whom had major depression.

00:23:42.760 | And they did intravenous injections

00:23:46.100 | with half a milligram per kilogram

00:23:48.380 | of body weight of ketamine.

00:23:50.580 | Now that dosage,

00:23:51.420 | half a milligram per kilogram of body weight

00:23:53.160 | turns out to be very important for today's discussion

00:23:55.540 | because it's going to serve as a reference point

00:23:58.000 | for later discussions

00:23:59.320 | when we get into other modes of delivery of ketamine,

00:24:01.880 | such as oral pill form ketamine or sublingual ketamine.

00:24:05.440 | And as it relates to things like the K-hole

00:24:07.920 | or the dissociative state

00:24:09.360 | or the various effects that ketamine can have

00:24:12.160 | depending on the dosage and the delivery route.

00:24:14.920 | Meanwhile, going back to this study,

00:24:16.320 | what they found is that when they injected patients

00:24:18.440 | with severe depression with ketamine,

00:24:21.640 | the effects of ketamine took place within minutes,

00:24:24.920 | within 10 or 15 minutes,

00:24:26.640 | and that they experienced a sort of peak euphoric state,

00:24:29.880 | okay, so they're not inducing deep anesthesia,

00:24:32.440 | right, at this dosage.

00:24:33.280 | They're getting people into a kind of euphoric, dreamy,

00:24:36.440 | semi-dissociative state.

00:24:38.440 | That occurred within 15 minutes and really peaked

00:24:41.600 | about 45 minutes to an hour

00:24:44.180 | after they were injected with the drug.

00:24:45.920 | And that the total effects of the drug in terms of euphoria

00:24:49.960 | were effectively over by about two hours or so.

00:24:54.100 | And that time course of effects makes perfect sense

00:24:56.420 | if you look at, say, the half-life of ketamine,

00:24:58.320 | which is how long it takes for half of the drug

00:25:00.300 | to be active in the system, et cetera.

00:25:02.340 | But what was really interesting about this study

00:25:05.720 | and others like it is that the patients experienced relief

00:25:08.980 | from their depression almost immediately

00:25:12.040 | after taking the drug, so within minutes to hours,

00:25:15.240 | and that it persisted for several days

00:25:18.280 | after taking the ketamine, okay?

00:25:20.040 | So the dissociative euphoric, dreamlike effects of ketamine

00:25:24.040 | take place very quickly.

00:25:25.540 | They're very, very salient, right?

00:25:27.200 | The person basically is just lying there,

00:25:30.020 | experiencing this euphoric, dreamlike dissociative state,

00:25:34.220 | and they get some relief from their depression immediately.

00:25:37.380 | And yet there's persistent relief from that depression,

00:25:40.160 | which lasted at least three days out from the treatment.

00:25:43.680 | Now, a key theme of today's discussion is going to be

00:25:46.120 | that the antidepressant effects of ketamine

00:25:48.240 | appear to be fairly short-lived,

00:25:50.680 | at least when one is exploring

00:25:52.520 | one or two treatments with ketamine.

00:25:54.500 | In other words, the typical contour

00:25:56.820 | is that people will take ketamine,

00:25:58.560 | get this euphoric, dreamlike dissociative effect,

00:26:01.220 | come out of that feeling some immediate relief

00:26:03.680 | from their depression.

00:26:04.520 | This is one of the things that makes ketamine

00:26:06.060 | an incredibly attractive drug

00:26:07.920 | for the treatment of depression,

00:26:09.700 | especially depression that hasn't responded

00:26:11.500 | to other forms of treatment,

00:26:13.020 | which is that people get relief very, very quickly,

00:26:16.640 | indeed the same day that they initiate the treatment.

00:26:19.720 | Now, this is especially important

00:26:21.120 | when you think about the fact

00:26:22.580 | that the monoamine hypothesis of depression,

00:26:25.520 | which drove the discovery and development

00:26:27.840 | of all these drugs like SSRIs, wellbutrin, et cetera,

00:26:31.360 | those drugs often can provide support

00:26:33.640 | for people with depression.

00:26:34.680 | Again, only 40% of people get true relief

00:26:37.800 | from their depression.

00:26:39.080 | And again, there are some side effect issues

00:26:40.680 | or major side effect issues in some cases

00:26:42.420 | that have to be dealt with.

00:26:43.940 | But even the positive effects,

00:26:45.940 | even under the best conditions,

00:26:47.200 | oftentimes those effects don't kick in for weeks or months

00:26:50.400 | after somebody initiates taking the drug.

00:26:52.880 | Now, that might not seem like a long time to wait

00:26:55.600 | for some of you,

00:26:56.940 | but if you are somebody suffering from depression,

00:26:59.500 | even another day, even another hour with depression

00:27:02.520 | seems almost unmanageable.

00:27:04.160 | And sadly, many people who have these forms of depression

00:27:07.440 | will go on to commit suicide.

00:27:08.900 | So it is ever so important

00:27:10.600 | that there be rapid treatments for depression,

00:27:12.780 | even same day treatments for depression.

00:27:15.040 | And based on this study, it appeared that ketamine was,

00:27:17.380 | and indeed still remains, that drug.

00:27:20.100 | Now, I certainly don't want to position ketamine in your mind

00:27:22.720 | as a miracle drug for depression.

00:27:24.620 | In fact, I don't actually believe in miracle drugs.

00:27:27.940 | I don't think that there is any compound

00:27:29.760 | that alone can produce all the desired effects

00:27:32.360 | that one wants without any negative effects

00:27:35.100 | in a way that could warrant calling it a miracle drug.

00:27:38.600 | That's just not how biology works.

00:27:40.360 | There's always an interplay between pharmacology,

00:27:43.240 | between our behaviors and what we choose to do or not do.

00:27:46.120 | This is a topic we'll get into a little bit later

00:27:47.800 | when we talk about antidepressant behaviors

00:27:50.000 | and the role of ketamine

00:27:50.960 | in bringing about antidepressant behaviors

00:27:53.680 | for the relief of depression.

00:27:55.280 | Now, with that said, the study that I just mentioned,

00:27:57.480 | as well as many, many other studies that followed,

00:28:01.380 | emphasized that ketamine could provide

00:28:03.500 | significant decreases in not just depression and suicidality,

00:28:08.060 | but also the feelings of helplessness and worthlessness

00:28:11.580 | that are associated with major depression.

00:28:14.000 | And again, it could do that in people

00:28:15.660 | that also were not responding

00:28:18.020 | to other forms of depression treatment,

00:28:20.160 | such as SSRIs, et cetera.

00:28:22.740 | So while we don't want to call it a miracle drug,

00:28:25.840 | ketamine turned out to be and remains an incredible drug

00:28:29.480 | for the treatment of depression in certain cases.

00:28:32.240 | Now, in addition to that,

00:28:33.240 | ketamine has been shown in clinical studies

00:28:35.440 | to provide relief not just for treatment-resistant

00:28:38.380 | depression of the major depression type, right?

00:28:40.880 | There's many different forms of depression,

00:28:42.800 | but major depression is the one

00:28:44.760 | that we're normally thinking about or referring to

00:28:47.340 | when we talk about depression.

00:28:49.040 | But ketamine has also been shown to be effective

00:28:51.220 | in treating bipolar depression,

00:28:53.400 | sometimes called bipolar disorder,

00:28:55.160 | although more commonly nowadays called bipolar depression.

00:28:58.240 | I did an entire episode, by the way,

00:28:59.600 | on bipolar depression.

00:29:00.720 | If you want to know what it is and what it isn't,

00:29:02.800 | how it differs from borderline personality disorder,

00:29:05.080 | et cetera, you can go to Hubermanlab.com,

00:29:07.340 | just put into the search function bipolar,

00:29:09.320 | and it will take you to that episode.

00:29:11.560 | Ketamine has also been shown to be useful

00:29:13.080 | for the treatment of PTSD

00:29:14.760 | and for OCD, obsessive compulsive disorder,

00:29:18.000 | and for anxiety and for various forms of substance addiction.

00:29:21.800 | So ketamine is not a miracle drug,

00:29:23.560 | but it does seem to have broad application

00:29:26.280 | and to be very successful for the treatment

00:29:28.460 | of a lot of major psychiatric challenges.

00:29:31.100 | Now, just because ketamine has shown

00:29:32.600 | these incredible applications,

00:29:34.500 | it also has some serious problems

00:29:36.560 | that are directly related to how it works in the brain,

00:29:39.540 | or at least from what we understand

00:29:40.920 | of how it works in the brain.

00:29:42.480 | And what I'm referring to here is,

00:29:44.240 | yes, ketamine is very rapid acting.

00:29:46.520 | It can often provide relief from depression

00:29:48.920 | almost immediately, meaning same day.

00:29:51.640 | However, it is very short-lived.

00:29:54.060 | After about three days or a week or so,

00:29:57.480 | the antidepressant effects of ketamine often wear off.

00:30:01.320 | So that creates a situation

00:30:02.640 | where people perhaps need to take ketamine every week,

00:30:06.180 | and yet it creates enough of a dissociative state,

00:30:08.740 | meaning it takes people enough

00:30:10.500 | out of their normal daily routine,

00:30:12.520 | that the prospect of people taking ketamine every week

00:30:15.800 | is actually not that feasible.

00:30:17.480 | And also because of some of the propensity

00:30:19.280 | for ketamine to become a drug of abuse,

00:30:20.960 | that is for it to be habit forming and/or addicting.

00:30:23.840 | One also worries that if people are doing ketamine

00:30:26.740 | every week to treat their depression,

00:30:28.260 | that they can become so-called hooked on ketamine.

00:30:31.700 | Now, fortunately, there have been studies of ketamine

00:30:33.960 | and how it works, not just in the short term,

00:30:36.120 | but in the longer term,

00:30:37.780 | that have led to some very important clinical studies

00:30:40.800 | that have explored, for instance,

00:30:42.360 | people taking ketamine twice per week

00:30:44.960 | for a duration of three weeks total.

00:30:47.680 | And what they find is that,

00:30:49.260 | yes, after the first time they take it,

00:30:51.100 | they get some relief from depression.

00:30:52.740 | They take it a second time that week,

00:30:53.940 | they get some relief from depression.

00:30:55.400 | And they do the same thing the next week and the next week.

00:30:58.840 | And when they do that,

00:30:59.680 | they get relief from depression the whole way through,

00:31:01.580 | that entire three weeks.

00:31:03.560 | But it turns out that there's also

00:31:05.500 | some so-called durability to the effect,

00:31:08.000 | such that if people do this twice a week dosing regimen,

00:31:12.020 | so ketamine twice a week for three weeks total,

00:31:14.700 | they find that when they end that three weeks,

00:31:17.060 | they get some ongoing relief from their depressive symptoms,

00:31:20.120 | which can extend months or more

00:31:22.520 | before they have to repeat the twice a week

00:31:25.320 | for three weeks regimen.

00:31:27.040 | Now, certainly not all studies of using ketamine

00:31:29.480 | for the treatment of depression

00:31:30.600 | have used that exact dosage regimen.

00:31:32.400 | Twice a week for three weeks and take some time off, repeat.

00:31:35.020 | Twice a week for three weeks, take some time off, repeat.

00:31:37.320 | Some have explored giving ketamine once per week

00:31:39.480 | or even three times per week,

00:31:41.280 | or doing it once a week for five weeks

00:31:44.000 | and then taking an extended period of time off

00:31:46.200 | before repeating the treatment schedule.

00:31:48.160 | There are a bunch of different studies out there,

00:31:50.200 | but when one looks at all of those studies

00:31:52.360 | and mass together, it's very clear

00:31:55.660 | that ketamine is providing relief from depressive symptoms

00:31:58.820 | immediately and in the days after the treatment,

00:32:02.040 | but that when those treatments

00:32:03.100 | are stacked fairly closely together,

00:32:05.160 | that there is some durability,

00:32:06.540 | some ongoing relief from depression.

00:32:08.740 | And what this tells us is very important.

00:32:10.940 | In fact, I hope everybody really highlight this

00:32:13.660 | in their minds as they're hearing it.

00:32:15.420 | It's very likely that ketamine is acting by at least two

00:32:19.040 | and probably three different mechanisms

00:32:21.680 | in order to provide relief from depression.

00:32:24.260 | One of those mechanisms induces relief from depression

00:32:27.000 | very quickly and seems to be associated

00:32:29.440 | with that euphoric dissociative dreamlike state

00:32:31.880 | that one experiences

00:32:32.980 | when they are under the influence of ketamine.

00:32:35.380 | The second mechanism seems to provide relief from depression

00:32:38.540 | in the days and weeks that follow the ketamine treatment.

00:32:41.900 | And there also appears to be a third mechanism

00:32:44.720 | by which ketamine can induce long-lasting changes

00:32:47.480 | in the nervous system.

00:32:48.420 | And it is those three mechanisms,

00:32:50.180 | short, medium, and long-term mechanisms

00:32:53.480 | that produce the kinds of changes in neurochemistry

00:32:55.900 | and more importantly,

00:32:57.340 | changes in actual neural circuit wiring

00:33:00.300 | that allows ketamine to provide

00:33:02.220 | this incredible relief from depression.

00:33:04.340 | So next, we're going to turn to what those mechanisms are

00:33:06.700 | because in understanding those mechanisms,

00:33:09.320 | you will understand how ketamine

00:33:10.980 | provides this relief from depression,

00:33:12.900 | but you'll also come to understand

00:33:14.460 | the more important broader theme

00:33:16.520 | of what depression is really all about

00:33:19.080 | at a neural circuit level

00:33:20.420 | and how relief from depression is all about neuroplasticity.

00:33:24.820 | As many of you know,

00:33:25.720 | I've been taking AG1 daily since 2012.

00:33:28.400 | So I'm delighted that they're sponsoring the podcast.

00:33:30.860 | AG1 is a vitamin mineral probiotic drink

00:33:33.160 | that's designed to meet

00:33:34.000 | all of your foundational nutrition needs.

00:33:36.220 | Now, of course, I try to get enough servings

00:33:37.860 | of vitamins and minerals through whole food sources

00:33:40.140 | that include vegetables and fruits every day,

00:33:42.400 | but oftentimes I simply can't get enough servings.

00:33:45.060 | But with AG1, I'm sure to get enough vitamins and minerals

00:33:48.040 | and the probiotics that I need

00:33:49.800 | and it also contains adaptogens to help buffer stress.

00:33:52.980 | Simply put, I always feel better when I take AG1.

00:33:55.780 | I have more focus and energy and I sleep better

00:33:58.300 | and it also happens to taste great.

00:34:00.540 | For all these reasons, whenever I'm asked,

00:34:02.400 | if you could take just one supplement, what would it be?

00:34:05.100 | I answer AG1.

00:34:06.680 | If you'd like to try AG1,

00:34:08.180 | go to drinkag1.com/huberman to claim a special offer.

00:34:12.320 | From now until August 12th, 2023,

00:34:14.860 | AG1 is giving away 10 free travel packs

00:34:17.220 | plus a year supply of vitamin D3K2.

00:34:19.940 | Again, if you go to drinkag1.com/huberman,

00:34:23.360 | you can claim the special offer of 10 free travel packs

00:34:26.380 | plus a year supply of vitamin D3K2.

00:34:29.340 | So how is ketamine really working?

00:34:31.460 | We already established that ketamine blocks

00:34:33.660 | the NMDA receptor and that the NMDA receptor is critical

00:34:38.000 | for many forms, not all, but many forms of neuroplasticity.

00:34:41.620 | Now I realize some of you might be familiar

00:34:43.360 | with so-called ligands and receptors,

00:34:45.740 | but most of you probably are not.

00:34:47.660 | A ligand is a chemical that binds to a receptor

00:34:51.160 | and a receptor is like a little parking spot

00:34:53.780 | on the outside of a cell.

00:34:55.080 | There can also be receptors inside of cells,

00:34:57.520 | but most of the time when we're talking about nerve cells,

00:34:59.980 | neurons, and you hear the word receptors,

00:35:02.500 | you're hearing about receptors on the outside of the cell.

00:35:05.360 | So the NMDA receptor does not exist in our neurons

00:35:08.980 | in order to bind ketamine.

00:35:10.560 | It's there actually to bind all sorts of other things

00:35:13.640 | that are endogenous, that are naturally made by us.

00:35:16.720 | But ketamine has a very high, what's called affinity,

00:35:19.240 | has a very high probability of binding to the NMDA receptor

00:35:23.240 | if it's introduced to our bloodstream.

00:35:25.280 | So when ketamine is taken in pill form,

00:35:27.880 | sublingual form, meaning under the tongue,

00:35:30.720 | when it's injected into the muscle or the vein,

00:35:33.260 | it gets into the bloodstream and then it's able

00:35:35.220 | to cross easily across the blood brain barrier,

00:35:38.660 | the so-called BBB, blood brain barrier.

00:35:40.920 | The blood brain barrier keeps a lot of things

00:35:42.700 | out of the brain, but ketamine can very readily pass

00:35:45.500 | across the blood brain barrier.

00:35:47.540 | Once it's in the brain, it has a very high affinity for,

00:35:50.480 | meaning it knows how to seek out

00:35:52.460 | and bind to those NMDA receptors.

00:35:54.980 | Now, the simplest way to explain how NMDA receptors

00:35:57.340 | ordinarily contribute to neuroplasticity

00:35:59.960 | is that they represent what's called an AND gate.

00:36:03.440 | And an AND gate, as the name suggests,

00:36:06.000 | is a function in a cell or in a system

00:36:09.420 | where two things have to be present.

00:36:10.960 | In fact, for those of you that have a bit of an engineering

00:36:13.460 | or computer programming background,

00:36:15.120 | you'll be familiar with AND gates.

00:36:16.460 | For those of you that don't, don't worry about it.

00:36:18.340 | I'm going to explain what an AND gate is right now.

00:36:20.820 | An AND gate in the context of nervous system function

00:36:23.860 | is when two things are present,

00:36:25.540 | like chemical A and chemical B both have to be present

00:36:28.700 | in order for some process, say neuroplasticity, to occur.

00:36:32.380 | The NMDA receptor, as I mentioned earlier,

00:36:34.460 | is a receptor on the surface of neurons

00:36:36.340 | and it binds glutamate,

00:36:37.560 | which is a molecule that we all make in our brain,

00:36:39.860 | and it activates other neurons.

00:36:41.460 | It's what's called an excitatory neurotransmitter.

00:36:44.660 | Now, there are lots of different receptors for glutamate

00:36:47.620 | and those receptors are binding glutamate all the time.

00:36:50.660 | However, in order to activate the NMDA receptor,

00:36:54.020 | there has to be a lot of glutamate present

00:36:56.160 | and it has to happen over a very brief period of time.

00:36:59.080 | So the NMDA receptor is an AND gate

00:37:01.620 | in the sense that glutamate has to be present

00:37:04.420 | and to bind it,

00:37:05.260 | and it has to get a lot of electrical activity,

00:37:08.380 | a lot of input in order for that to happen.

00:37:10.480 | So it's a receptor that responds primarily

00:37:12.340 | to unusually high or frequent levels of electrical activity.

00:37:17.340 | Let's place this in real-world context

00:37:19.280 | so that it makes a bit more sense.

00:37:20.820 | I, like most all of you,

00:37:21.980 | am moving my arms around a lot throughout the day.

00:37:24.520 | Now, as an adult, my motor cortex,

00:37:26.620 | the area of my brain that controls

00:37:28.540 | motor coordination in my limbs,

00:37:30.300 | has connections from my brain to my spinal cord,

00:37:32.760 | from my spinal cord to my muscles,

00:37:33.900 | and that's what allows me to move my limbs.

00:37:36.660 | Under conditions of just moving my limbs

00:37:38.460 | and doing things throughout the day,

00:37:39.500 | drinking a cup of coffee or yerba mate,

00:37:42.340 | walking outside to view some sunlight in the morning,

00:37:44.940 | doing the things that I do every single day

00:37:46.620 | and that I already know how to do,

00:37:49.000 | glutamate is definitely involved in that process.

00:37:51.860 | Glutamate binding to its other receptor types,

00:37:54.660 | which are called AMPA receptors,

00:37:56.060 | for those of you that want to know,

00:37:57.420 | that's involved in that process.

00:37:59.000 | It's typical levels of activity.

00:38:01.480 | If, however, I were to sit down at this desk

00:38:04.560 | and be commanded to, or decide to,

00:38:07.540 | do some specific motor limb movement,

00:38:09.960 | let's say move my hand in a three-dot sequence,

00:38:12.900 | for those of you watching, you can see this,

00:38:14.200 | for those of you that are listening, don't worry about it,

00:38:15.960 | it's not very interesting to watch.

00:38:17.440 | The point is just that I'm going to put my finger down

00:38:20.080 | in one, two, three points on the desk in front of me,

00:38:22.800 | and then three, two, one points coming back to me.

00:38:25.200 | Now, that's obviously a motor sequence that I can perform,

00:38:27.360 | I just did it, so clearly I can perform it.

00:38:29.720 | But if I were to do that for, let's say, an hour,

00:38:33.120 | what would happen is the neurons that are involved

00:38:35.760 | in generating that motor sequence of one, two, three,

00:38:38.080 | three, two, one, one, two, three, three, two, one,

00:38:40.340 | would be active over and over and over again.

00:38:42.960 | And what would likely happen, because of that unusual,

00:38:46.000 | frankly, motor behavior, is that the neurons responsible

00:38:49.080 | for generating that motor behavior would be able

00:38:51.800 | to detect it as unusually frequent,

00:38:54.060 | unusually high levels of activity in the circuits

00:38:56.280 | that generate that behavior.

00:38:57.600 | And the increase in glutamate that's impinging

00:39:00.680 | on the neurons in that circuit would bind the NMDA receptor,

00:39:04.760 | making it change several important things.

00:39:06.800 | The first of which is that your nervous system

00:39:09.240 | is capable of changing,

00:39:10.360 | but that's an energetically demanding process.

00:39:12.840 | So the incredible thing about neuroplasticity

00:39:15.160 | is that when you generate an unusually high

00:39:17.660 | or just an unusual pattern of activity,

00:39:20.040 | motor activity, or you're hearing a new language,

00:39:22.160 | you're trying to learn that,

00:39:22.980 | or you're navigating a new city,

00:39:24.760 | the neurons are firing in ways that are atypical for them,

00:39:28.680 | and they are firing a lot more.

00:39:30.840 | And so the neurons are going to bind glutamate,

00:39:32.960 | the NMDA receptor is going to be activated,

00:39:35.580 | and then downstream of NMDA receptor activation

00:39:39.480 | are a bunch of what we call intracellular processes,

00:39:42.240 | a bunch of things that happen in the cells

00:39:43.840 | to try and make that behavior occur again and again,

00:39:47.240 | if needed, but without the huge energetic demand.

00:39:50.320 | You've experienced this before

00:39:51.380 | when you're trying to learn something and it feels sluggish,

00:39:54.080 | it feels hard, it's frustrating,

00:39:55.540 | and then eventually you learn it and it's very facile,

00:39:57.960 | it's very easy.

00:39:59.600 | One of the reasons for that

00:40:01.000 | is that when the NMDA receptor is activated

00:40:03.200 | by these infrequent or unusual patterns of activity,

00:40:06.360 | it can then recruit other glutamate receptors,

00:40:09.240 | the more typical kind,

00:40:10.240 | the AMPA-type receptors to the cell surface,

00:40:12.880 | and then those receptors can simply bind the glutamate

00:40:15.220 | and allow that behavior to occur

00:40:17.440 | without this whole process

00:40:19.840 | that's involved in neuroplasticity having to engage

00:40:22.560 | and do things like build new proteins in the cell,

00:40:25.280 | build new machinery, et cetera.

00:40:27.060 | So to just step back from this,

00:40:28.440 | the way to think about the NMDA receptor

00:40:30.720 | is that activation of the NMDA receptor

00:40:33.200 | only occurs under conditions of unusually high

00:40:36.080 | or simply unusual patterns of activity,

00:40:38.600 | that the NMDA receptor, yes, controls neural activity

00:40:42.040 | in the immediate sense, like when it's activated,

00:40:44.900 | it's changing the patterns of activity in the neuron, sure,

00:40:47.900 | but it also can engage gene expression

00:40:51.640 | and introduce new receptors to the cell,

00:40:54.060 | basically giving the cell the ability

00:40:55.920 | to then recreate the same patterns of activity

00:40:58.360 | without having to do it

00:40:59.600 | in such a metabolically demanding way.

00:41:01.540 | In fact, a good analogy for all of this

00:41:03.640 | is the way that muscles can hypertrophy, right?

00:41:06.120 | If you overload muscles properly

00:41:08.540 | through resistance training of any kind

00:41:10.440 | and then give them a period of rest,

00:41:12.000 | there's recruitment of specific things to the muscle fibers

00:41:15.620 | as well as recruitment of changes in the nerves

00:41:18.600 | that innervate, that control the contraction of those muscles

00:41:21.640 | and then those muscles grow, they get stronger, et cetera,

00:41:25.520 | and they're able to function

00:41:26.800 | and use that new strength and new growth

00:41:29.360 | and you don't have to damage those muscle fibers

00:41:31.920 | or trigger those adaptations over and over again

00:41:34.040 | to maintain them because you have this new capability.

00:41:36.800 | Now, I realize that's a lot of details

00:41:38.200 | about NMDA receptors and neuroplasticity,

00:41:40.720 | but really if we needed to pick one biological mechanism

00:41:43.320 | that resides at the center

00:41:45.000 | of many, many important forms of neuroplasticity,

00:41:48.280 | it would be the NMDA receptor

00:41:49.920 | and its functions that I just told you about.

00:41:52.160 | So now that you have that in mind

00:41:53.800 | that these NMDA receptors are critical

00:41:55.720 | at detecting unusual activity, making changes to cells

00:41:58.500 | so the cells can then respond to that activity in the future,

00:42:01.560 | you have in mind the conceptual basis

00:42:03.300 | for understanding how ketamine works

00:42:05.840 | because as I've mentioned several times already,

00:42:08.080 | ketamine is an NMDA receptor blocker, antagonist,

00:42:12.600 | and yet we know that a lot of the changes in the brain

00:42:16.280 | that underlie the transition from a depressed state

00:42:19.080 | to a non-depressed state involve neuroplasticity.

00:42:22.640 | So what's going on there?

00:42:24.220 | Well, what's going on there turns out

00:42:25.920 | to be extremely interesting

00:42:27.640 | and you can understand it very easily

00:42:29.280 | if you understand that there are essentially

00:42:31.220 | two major types of neurons in the brain.

00:42:34.260 | You have those excitatory neurons,

00:42:36.200 | meaning neurons that when they are activated electrically,

00:42:39.060 | they activate or excite other neurons,

00:42:42.800 | at least they try to.

00:42:43.720 | They release neurotransmitter into the synapse,

00:42:46.000 | which is the little gap between neurons.

00:42:48.360 | The neurons on the other side have receptors.

00:42:50.400 | They bind those neurotransmitters, in this case, glutamate,

00:42:52.880 | which is the major excitatory neurotransmitter in the brain,

00:42:55.360 | and then there's a high probability

00:42:57.580 | that those other neurons will be excited,

00:42:59.280 | that they will be electrically active.

00:43:00.860 | That's one major type

00:43:02.320 | of so-called neurotransmission in the brain.

00:43:04.760 | The other major type of neurotransmission in the brain

00:43:07.300 | is called inhibitory neurotransmission.

00:43:09.940 | Inhibitory neurotransmission involves neurons

00:43:12.720 | that release the neurotransmitter GABA,

00:43:15.400 | or sometimes also another molecule called glycine,

00:43:17.900 | but mostly GABA.

00:43:19.920 | When GABA is released,

00:43:21.000 | it has the property of reducing the probability

00:43:23.900 | that the next neuron will be electrically active.

00:43:26.360 | In fact, GABA's job is to bind to receptors on the next cell

00:43:29.920 | and to make it less electrically active.

00:43:32.920 | So we've got excitatory neurotransmission

00:43:35.240 | and we have inhibitory neurotransmission.

00:43:37.360 | And just to place inhibitory

00:43:38.880 | and excitatory neurotransmission into context,

00:43:41.960 | if you think about a condition like epilepsy,

00:43:44.720 | which involves seizures of either the smaller type

00:43:48.000 | called petit mal seizures or grand mal seizures,

00:43:50.440 | which are the type in which people have

00:43:52.640 | body-wide convulsions.

00:43:54.660 | They are often disengaged from whatever's going on

00:43:57.720 | around them in those moments.

00:43:58.720 | They're shaking quite a lot, et cetera.

00:44:00.640 | There are many causes of seizures,

00:44:02.080 | but to get to the heart of what a seizure is,

00:44:04.840 | it is essentially runaway excitation in the brain.

00:44:08.480 | A small region of the brain

00:44:09.760 | becomes especially electrically active,

00:44:11.920 | and then it spreads out from that foci,

00:44:14.140 | that focus of the excitation.

00:44:16.440 | And it recruits a lot of neurons

00:44:18.680 | in a fairly nonspecific way,

00:44:20.120 | creating these seizure-like motor patterns in the body

00:44:23.920 | and patterns of activity in the brain

00:44:26.400 | that can involve disengagement from immediate experience

00:44:28.880 | and lack of perception.

00:44:29.920 | Sometimes there's aura.

00:44:31.040 | There's a whole discussion to be had about seizure.

00:44:33.880 | And by the way, seizure can occur

00:44:35.300 | in a lot of different contexts.

00:44:36.800 | Of course, it can occur in epilepsy,

00:44:38.360 | it can occur after a head injury, et cetera.

00:44:40.520 | We'll cover seizure in a future episode

00:44:42.320 | of this podcast, of course.

00:44:43.960 | But one of the major causes of seizure,

00:44:46.220 | and by extension, lack of seizure,

00:44:48.580 | is that ordinarily inhibitory neurons

00:44:50.900 | and excitatory neurons are in this kind of push-pull

00:44:53.620 | that for somebody that doesn't experience seizures

00:44:55.900 | puts the brain in balance.

00:44:57.280 | So they don't have seizures, right?

00:44:58.460 | The inhibitory neurons are suppressing the activity

00:45:00.820 | of many neurons so that those many neurons

00:45:03.960 | don't get runaway excitation.

00:45:06.540 | You don't get seizures.

00:45:08.020 | The excitatory neurons are feeding back

00:45:09.760 | onto the inhibitory neurons,

00:45:11.060 | so everything is kept in balance.

00:45:12.580 | There isn't too much inhibition.

00:45:13.780 | There isn't too much excitation.

00:45:15.060 | Everything's in balance.

00:45:16.300 | Okay, so now you understand that there are NMDA receptors,

00:45:19.720 | and these are critical for many forms of neuroplasticity.

00:45:23.280 | You also understand that there are excitatory neurons,

00:45:26.940 | which stimulate the electrical activity of other neurons,

00:45:30.900 | and that there are inhibitory neurons in your brain

00:45:33.740 | that inhibit or suppress the activity of other neurons,

00:45:36.980 | and that you need excitatory and inhibitory communication

00:45:39.940 | between neurons at all times,

00:45:41.500 | and that it has to remain in balance,

00:45:43.460 | and that the NMDA receptor is normally

00:45:45.940 | just sort of sitting there, not doing a whole lot,

00:45:48.660 | unless levels of neural activity are elevated

00:45:52.540 | above their normal baseline,

00:45:54.560 | and then you can get changes in the neural circuits,

00:45:58.380 | and those changes can be very long-lasting.

00:46:01.220 | And let's not forget the piece of information

00:46:02.780 | most pertinent to today's discussion,

00:46:04.660 | which is about ketamine,

00:46:06.020 | which is that ketamine blocks that NMDA receptor.

00:46:10.080 | And there's the conundrum I keep coming back to,

00:46:11.980 | which is you need neuroplasticity

00:46:14.000 | in order to get relief from depression.

00:46:16.740 | So what researchers have discovered is that,

00:46:20.020 | yes, ketamine blocks the NMDA receptor.

00:46:22.980 | It actually quiets down neurons.

00:46:25.400 | It prevents neurons from being as active

00:46:28.400 | as they normally would be,

00:46:29.680 | and yet somehow, almost paradoxically,

00:46:32.540 | it increases neuroplasticity in brain circuits

00:46:35.480 | that are involved in mood, in reward, in self-reflection.

00:46:40.200 | We'll get into what those brain circuits are

00:46:41.720 | in a little bit.

00:46:43.340 | The way it works is that ketamine binds

00:46:46.440 | to the NMDA receptor present on inhibitory neurons,

00:46:50.540 | and in doing so, dramatically reduces the amount

00:46:54.640 | of inhibition coming from those inhibitory neurons

00:46:57.780 | onto excitatory neurons.

00:47:00.080 | When that happens, the excitatory neurons

00:47:02.080 | in specific circuits of the brain

00:47:04.040 | are allowed to increase their activity.

00:47:05.900 | They do what's called bursting.

00:47:07.600 | Bursting is a pattern of electrical activity

00:47:09.760 | whereby normally one of these excitatory neurons

00:47:12.400 | is releasing glutamate in a pattern

00:47:14.160 | that might look or sound like this.

00:47:16.320 | It actually doesn't make a sound in the brain,

00:47:18.560 | but if you were to record from one of these neurons,

00:47:21.360 | which people have done many times over,

00:47:23.180 | and then you were to convert the electrical signal

00:47:25.440 | in those neurons to an audio monitor,

00:47:27.480 | you would hear the firing,

00:47:28.580 | the action potential of those neurons as a kk.

00:47:31.240 | That's what it actually sounds like on the audio monitor.

00:47:33.200 | It sounds like a little bit of static, kk,

00:47:35.640 | but if the normal firing of the neuron is kk, kk, kk,

00:47:40.140 | which is the pretty typical baseline firing

00:47:42.540 | of the neurons and the relevant circuits to mood

00:47:44.920 | that I'm going to be discussing,

00:47:46.700 | under conditions where ketamine

00:47:48.200 | has been brought into the system,

00:47:49.680 | binds that NMDA receptor,

00:47:52.040 | blocks the output of those inhibitory neurons

00:47:55.040 | onto the excitatory neuron,

00:47:56.720 | now the excitatory neuron is firing in bursts.

00:47:59.800 | [imitates burst]

00:48:02.560 | And those bursting patterns of electrical activity

00:48:07.840 | are the absolute perfect patterns of activity

00:48:10.920 | that induce not just short-term,

00:48:12.800 | but long-term changes in the neural circuits

00:48:15.160 | associated with reward, with dopamine release,

00:48:18.040 | with disappointment, and with mood

00:48:20.360 | in ways that are directly relevant to suppressing

00:48:23.760 | or providing relief from the symptoms of major depression.

00:48:27.080 | Now, I realize what I just told you is a lot of information.

00:48:29.680 | In fact, what I just described represents

00:48:32.200 | essentially what I would teach

00:48:33.580 | to an advanced undergraduate/graduate course,

00:48:36.440 | medical school course on neuroplasticity

00:48:39.360 | and how ketamine works.

00:48:40.780 | So keep in mind that we're having a discussion here

00:48:42.820 | that is at a fairly high level.

00:48:44.780 | And if you could understand even a tiny fraction,

00:48:47.420 | even just one bit of what I just described,

00:48:49.640 | you're doing great.

00:48:50.480 | If you could understand more, outstanding.

00:48:53.680 | Just to make sure that everyone's on the same page

00:48:55.600 | as we move forward, because I do want to make sure

00:48:57.960 | that everyone understands ketamine and how it works,

00:49:00.880 | because it does have these sort of cryptic functions

00:49:03.480 | of engaging neuroplasticity in ways that aren't obvious.

00:49:06.660 | If you just ask, what does ketamine do when you inject it?

00:49:10.260 | What does ketamine produce in terms of a feeling state?

00:49:13.420 | And then how does somebody get relief from depression?

00:49:16.000 | That can all start to get a little bit muddled

00:49:18.160 | unless you understand the following.

00:49:19.500 | So I'm going to tell it to you again

00:49:20.800 | in just very top contour terms.

00:49:23.500 | Somebody takes a pill or an injection or sublingual ketamine.

00:49:27.200 | It makes its way into the bloodstream,

00:49:28.880 | and then it makes its way into the brain.

00:49:30.840 | Once it's in the brain, it binds to a particular category

00:49:34.720 | of receptors called the NMDA receptor.

00:49:37.220 | The NMDA receptor is a receptor

00:49:39.240 | that normally is quiescent.

00:49:41.080 | It's just kind of sitting there.

00:49:42.120 | It doesn't tend to do a lot under normal conditions

00:49:44.760 | of everyday life.

00:49:45.840 | However, the NMDA receptor's typical function, okay,

00:49:48.360 | so when there's no ketamine in the body or brain,

00:49:51.760 | is to detect abnormal levels of neural activity.

00:49:57.000 | And in doing so, recruit changes to cells,

00:50:01.200 | receptors, et cetera, literally change the neurons

00:50:04.080 | in ways that allow them to respond to that activity

00:50:07.360 | in the future without having to be

00:50:10.560 | under such big metabolic demand.

00:50:13.120 | And they do that by recruiting more receptors, et cetera,

00:50:15.800 | much in the same way as when you overload a muscle

00:50:18.300 | in the gym, it will eventually recover

00:50:20.880 | if you allow it to recover,

00:50:22.200 | and it will get stronger through the addition

00:50:24.240 | of a bunch of new proteins, the nerve communication

00:50:27.360 | of that muscle will change,

00:50:28.840 | the muscle and the nerve to muscle connection change.

00:50:31.160 | It gets stronger, and sometimes it gets bigger and stronger.

00:50:33.720 | In the same way, a neuron can change the way it functions

00:50:36.480 | in response to experience,

00:50:38.320 | and neurons don't know experience of life in any other way

00:50:41.720 | except the patterns of electrical activity

00:50:43.880 | and chemical activity that impinges on them, okay?

00:50:47.480 | Now, ketamine, the drug, binds to

00:50:49.240 | and blocks that NMDA receptor.

00:50:51.460 | So the obvious conclusion would be that ketamine

00:50:54.780 | prevents neuroplasticity, and that's not what happens.

00:50:57.460 | We know that ketamine actually induces neuroplasticity,

00:51:00.620 | and it does so specifically in the brain circuits

00:51:03.400 | that control mood,

00:51:05.260 | the net consequence being improvements in mood.

00:51:07.980 | How does that happen?

00:51:08.860 | It happens because ketamine binds to and blocks

00:51:11.200 | those NMDA receptors on inhibitory neurons.

00:51:14.900 | The inhibitory neurons are the neurons

00:51:16.500 | that normally suppress the activity of other neurons.

00:51:19.600 | So when ketamine binds to the NMDA receptor,

00:51:23.020 | the activity of those inhibitory neurons is reduced,

00:51:25.900 | and as a consequence, excitatory communication

00:51:29.160 | between neurons in those mood-related circuits increases.

00:51:32.440 | And it increases it in a way that recruits neuroplasticity,

00:51:35.660 | that strengthens those connections,

00:51:37.820 | and makes them more likely to be active in the future.

00:51:41.140 | Now, it is not the case, at least at clinical doses,

00:51:43.880 | that ketamine induces seizures.

00:51:45.300 | It certainly can at higher doses.

00:51:47.400 | But at clinical doses, when ketamine suppresses

00:51:51.500 | the activity of those inhibitory neurons

00:51:53.180 | and the excitatory neurons ramp up their activity,

00:51:55.920 | they're ramping up their activity a lot

00:51:58.020 | and enough to create changes

00:52:00.620 | in those neural circuits associated with mood.

00:52:02.700 | And the changes are in the direction

00:52:04.060 | of making those neural circuits

00:52:05.620 | more likely to generate positive mood

00:52:07.860 | and less likely to generate negative mood.

00:52:10.000 | We'll get into the specifics

00:52:10.980 | of those circuits in a little bit.

00:52:13.180 | But ketamine is not creating the kind of enormous increases

00:52:16.220 | in excitatory communication between neurons

00:52:18.320 | that leads to that runaway excitation.

00:52:20.720 | Now, the point of the discussion we just had

00:52:22.320 | over the last 10 minutes or so was several-fold.

00:52:24.600 | First of all, I do believe it's important to understand

00:52:27.580 | the key components of neuroplasticity,

00:52:29.980 | which is this remarkable feature

00:52:31.680 | of our brain and nervous system that we all have, right?

00:52:34.580 | This ability to change our own brain circuits.

00:52:37.260 | No other organ in the body, as far as we know,

00:52:39.200 | can direct its own changes,

00:52:40.500 | but we can direct our own brain changes.

00:52:42.820 | And the NMDA receptor is absolutely critical for that.

00:52:45.900 | I also think it's important to understand the difference

00:52:47.660 | between inhibitory and excitatory communication

00:52:50.260 | between neurons, because that's just central

00:52:52.100 | to understanding brain function.

00:52:53.940 | Brain function is a series of accelerators and breaks.

00:52:56.540 | It's not all about neurons stimulating other neurons.

00:52:58.980 | It's also about neurons preventing

00:53:00.620 | the activation of other neurons.

00:53:02.140 | That's just central to everything,

00:53:03.660 | not just preventing seizures, but it's central to learning.

00:53:07.260 | It's central to vision.

00:53:08.780 | It's central to hearing.

00:53:09.780 | It's central to creativity.

00:53:10.860 | It is at the core of brain function.

00:53:13.500 | And the other reason to have the discussion we just did

00:53:16.280 | is that ketamine has this incredible property.

00:53:19.140 | It can literally change the neural circuits

00:53:22.040 | that generate mood,

00:53:23.560 | that generate your feelings of wellbeing,

00:53:25.760 | but it does so through a somewhat convoluted pathway, right?

00:53:28.900 | It blocks the receptor

00:53:30.100 | that everyone thinks is involved in neuroplasticity,

00:53:32.180 | and in doing so, it actually creates neuroplasticity.

00:53:35.460 | Now, even though I just described all of that to you

00:53:37.740 | over the last 10 minutes or so,

00:53:40.080 | keep in mind that what I just described to you

00:53:43.060 | as a process that actually occurs in the brain

00:53:46.120 | takes many, many days.

00:53:47.780 | It involves cells changing gene expression,

00:53:50.060 | making new proteins, new receptors.

00:53:52.620 | Anytime we say neuroplasticity,

00:53:54.560 | even when you read about so-called

00:53:56.620 | short-term neuroplasticity,

00:53:58.440 | it is happening over the course of at least many, many hours

00:54:01.460 | and more likely many days or even weeks.

00:54:04.200 | So the process I just described

00:54:05.620 | of how ketamine creates neuroplasticity

00:54:07.980 | through blockade of NMDA receptors

00:54:11.100 | is very likely to be the process

00:54:13.080 | that explains the longer-term changes in mood and affect

00:54:18.020 | that are associated with ketamine therapy

00:54:20.500 | for the treatment of depression.

00:54:22.360 | Now, it is possible that ketamine

00:54:23.660 | blocking the NMDA receptor is also responsible

00:54:27.220 | for some of the immediate effects of ketamine

00:54:29.340 | that people experience when they take the drug,

00:54:31.900 | the dissociation, in some cases, euphoria,

00:54:35.180 | and that sort of dream-like state

00:54:36.940 | that it can put people into.

00:54:38.880 | That is possible,

00:54:40.180 | but it's very clear that the NMDA receptor blockade

00:54:42.700 | is critical for the neuroplastic changes

00:54:45.720 | that are going to occur over the days and weeks

00:54:47.860 | following ketamine treatment.

00:54:49.420 | And if you think back to our earlier discussion,

00:54:51.940 | when we were talking about the two-time-a-week,

00:54:54.540 | over three-week-type regimen of taking ketamine

00:54:57.580 | or some variant on that,

00:54:59.500 | now it might start to make sense as to why,

00:55:02.440 | yes, there is immediate and short-term benefit

00:55:06.300 | of taking ketamine for depression

00:55:07.900 | in the clinically appropriate setting.

00:55:09.580 | Of course, I'm not talking about recreational use right now,

00:55:12.440 | but that also there's some durability of those effects

00:55:15.820 | that even after the three weeks

00:55:17.600 | of taking ketamine twice per week,

00:55:19.700 | people often will experience weeks or months

00:55:22.680 | of relief from depression

00:55:23.880 | when they're not doing the weekly ketamine therapy sessions.

00:55:27.460 | So that longer-term relief

00:55:28.660 | that I'm referring to as durability of the treatment

00:55:31.560 | is very likely to be the consequence

00:55:33.320 | of actual neural circuit rewiring.

00:55:35.820 | Now, there's an additional and very important facet

00:55:37.960 | to this whole discussion about neuroplasticity

00:55:40.220 | in response to ketamine treatment for depression.

00:55:43.060 | If you recall the, [imitates explosion]

00:55:44.700 | the burst firing that induces that plasticity,

00:55:47.760 | I told you it induces plasticity, but I didn't tell you how.

00:55:51.940 | Now, you already could imagine some of the mechanisms.

00:55:54.320 | It could be insertion of those new glutamate receptors,

00:55:57.060 | those AMPA receptors that we talked about.

00:55:59.140 | However, even for that to happen,

00:56:01.020 | a bunch of other things have to happen first.

00:56:03.260 | But one of the key ones to understand

00:56:05.460 | is the thing I mentioned at the beginning of today's episode,

00:56:07.960 | BDNF, which stands for brain-derived neutrophic factor.

00:56:11.520 | Brain-derived neutrophic factor is an incredible molecule.

00:56:14.860 | I should mention that it's one of many growth factors

00:56:17.280 | in the brain, and it has its own set of receptors.

00:56:21.040 | It binds to something called the TRKB receptor,

00:56:23.360 | T-R-K-B, TRKB receptor.

00:56:26.360 | When BDNF binds to TRKB receptors on neurons,

00:56:29.360 | it does a lot of things.

00:56:30.840 | It sets off a whole cascade of things,

00:56:32.760 | including the insertion of new glutamate receptors

00:56:36.740 | so that those neurons become extra sensitive

00:56:39.460 | to any input they get.

00:56:41.000 | And so that's one form of change that BDNF can create.

00:56:44.540 | BDNF can also alter the overall shape of neurons.

00:56:48.020 | It can cause neurons to grow new branches

00:56:50.960 | so that it can receive new inputs from other neurons.

00:56:54.320 | Anytime BDNF is discussed in popular books

00:56:56.900 | or the popular press, people will talk about it

00:56:59.080 | as quote unquote fertilizer for neurons.

00:57:01.200 | I don't really like that term because it really undervalues

00:57:05.440 | the total number of things that BDNF can do.

00:57:07.560 | BDNF actually can act as its own kind of neurotransmitter.

00:57:11.240 | It can actually stimulate other neurons,

00:57:12.960 | and it does a bunch of other things.

00:57:14.560 | But for sake of this discussion about ketamine,

00:57:16.840 | understand that that burst firing of neurons,

00:57:19.220 | that very high frequency firing of neurons

00:57:23.800 | can invoke the release of BDNF in ways

00:57:27.120 | that make those circuits very plastic very quickly.

00:57:30.840 | And in addition to that, there's some evidence

00:57:33.480 | that ketamine itself may be able to cause release

00:57:37.160 | of BDNF directly without having to go through

00:57:40.200 | all of the mechanisms that I overwhelmed you with

00:57:43.400 | a few minutes ago, or hopefully didn't overwhelm you with,

00:57:45.440 | but that I taught to you a few minutes ago.

00:57:48.240 | Now, what's especially exciting about BDNF

00:57:50.280 | in the context of ketamine therapy for depression

00:57:53.360 | is that it appears based on both preclinical

00:57:56.220 | and clinical studies that BDNF isn't just one of the ways

00:58:00.800 | in which ketamine can invoke neuroplasticity

00:58:03.320 | and these improvements in mood.

00:58:05.100 | It may actually be required.

00:58:06.840 | It may be the central process to all of that.

00:58:10.000 | Now, it can still be downstream of all that NMDA receptor

00:58:12.760 | stuff that we talked about before,

00:58:14.760 | but there are several lines of evidence that suggest

00:58:17.300 | that ketamine-induced release of BDNF

00:58:20.600 | is one of the core mechanisms by which ketamine

00:58:24.040 | can relieve depression.

00:58:25.480 | Now, there are several lines of evidence to support

00:58:27.340 | what I just said about BDNF in the context of ketamine.

00:58:30.120 | First of all, in mice that lack BDNF,

00:58:33.640 | they have no BDNF, they can't make BDNF

00:58:36.300 | because they don't have the gene for BDNF.

00:58:37.880 | We call those BDNF knockout mice.

00:58:41.240 | In those mice, if you give them ketamine

00:58:43.860 | and you put them into that learned helplessness task

00:58:46.080 | that we talked about a bit earlier,

00:58:47.780 | where you put them into water and see how long they swim,

00:58:50.220 | normally ketamine would allow a mouse to swim longer,

00:58:53.600 | to fight for its life longer.

00:58:55.200 | Well, it no longer does that in a BDNF knockout mouse.

00:58:59.100 | And the only thing that's different about that mouse,

00:59:00.860 | as far as we know, is the lack of BDNF.

00:59:03.560 | And there are ways to make sure that it's lack of BDNF

00:59:06.400 | in the specific neurons that are relevant

00:59:08.120 | to everything we're talking about,

00:59:09.240 | not just that their limbs don't work as well, et cetera.

00:59:11.660 | In other words, all the appropriate control experiments

00:59:13.460 | have been done.

00:59:14.420 | That's preclinical data because it comes from animal models.

00:59:17.640 | In addition to that, depressed people

00:59:20.640 | who have a mutant form of BDNF.

00:59:23.060 | So these humans are not knockouts for BDNF,

00:59:25.800 | they can make BDNF, but the BDNF doesn't function normally.

00:59:29.840 | In those people, they have a very reduced response

00:59:34.120 | to ketamine treatment for depression,

00:59:36.640 | suggesting that BDNF action is at least

00:59:40.160 | one of the critical functions that allows ketamine

00:59:42.400 | to relieve depression.

00:59:44.040 | And as I mentioned earlier, ketamine can actually invoke

00:59:47.600 | the release of BDNF and get this,

00:59:49.400 | there's some evidence that ketamine itself

00:59:52.120 | can bind to the TRKB receptor.

00:59:54.600 | That is, it can bind to the BDNF receptor,

00:59:57.260 | it can mimic BDNF.

01:00:00.320 | So this is an entirely different way

01:00:01.800 | of thinking about ketamine than we normally hear about.

01:00:04.600 | Nowadays, we hear a lot about ketamine

01:00:06.080 | and ketamine therapy.

01:00:07.220 | We also hear, fortunately, about some of the problems

01:00:09.880 | of ketamine abuse, and we will talk about

01:00:11.540 | some of those concerns a little bit later.

01:00:14.280 | And we hear about BDNF, this so-called brain fertilizer,

01:00:18.320 | but rarely, if ever, do we hear that ketamine itself

01:00:21.220 | can mimic the effects of BDNF in the brain.

01:00:23.980 | But researchers and clinicians are definitely

01:00:25.920 | paying attention to this, and it's starting to raise

01:00:28.140 | what I consider a very exciting model

01:00:30.500 | of how ketamine could provide relief for depression,

01:00:33.300 | which is that it's acting as a growth factor in the brain,

01:00:36.600 | or at least it's mimicking the action of growth factors,

01:00:39.520 | allowing the specific neural circuits that control things

01:00:42.100 | like mood, outlook on the future, self-reflection, et cetera,

01:00:45.440 | allowing those circuits to change in ways

01:00:47.180 | that provide significant relief for major depression.

01:00:50.320 | And in doing so, and this is a very important point,

01:00:53.240 | it appears that ketamine is relieving depression

01:00:55.480 | in ways that are entirely different

01:00:57.440 | from any other kind of treatment.

01:00:59.380 | Now, in an earlier episode about psilocybin

01:01:02.040 | and its potential role for the treatment of depression,

01:01:04.680 | I went into a lot of depth about how psilocybin

01:01:07.140 | can induce neuroplasticity to provide relief

01:01:09.300 | for major depression in certain individuals

01:01:11.360 | under certain conditions.

01:01:13.060 | I do want to highlight that because, indeed,

01:01:14.800 | it's another case where neuroplasticity is involved.

01:01:17.360 | But in that situation, as some of you may remember,

01:01:20.240 | or if you don't, don't worry, I'll tell you right now,

01:01:22.720 | it was a pretty straightforward model.

01:01:24.400 | Psilocybin looks a lot like serotonin chemically,

01:01:27.240 | except that psilocybin binds a particular receptor.

01:01:29.380 | When that receptor is bound,

01:01:30.680 | it allows these brain-wide changes.

01:01:32.280 | Those brain-wide changes seem to change

01:01:34.560 | one's reflection on oneself, so-called ego dissolution,

01:01:37.160 | changes in mood that are stable over time,

01:01:39.500 | et cetera, et cetera.

01:01:40.440 | It was all pretty straightforward.

01:01:42.040 | With ketamine, it's clear

01:01:43.240 | there are multiple mechanisms involved.

01:01:45.480 | And perhaps most importantly, with ketamine,

01:01:47.240 | it's that immediate relief that occurs day of

01:01:49.680 | or close to day of treatment and in the days afterwards,

01:01:52.280 | and it's that long-term relief that very likely

01:01:55.680 | is the consequence of NMDA receptor suppression,

01:01:59.720 | burst activity in neurons within these mood-related circuits,

01:02:03.760 | BDNF being released and changing neural circuits,

01:02:06.600 | strengthening them in order to give elevated mood

01:02:10.200 | as a consequence of that bursting activity,

01:02:12.520 | and ketamine mimicking BDNF.

01:02:16.000 | In other words, ketamine acting more or less

01:02:18.220 | like a growth factor in the brain

01:02:19.880 | in order to make sure that whatever changes occur

01:02:22.440 | in those neural circuits to elevate mood are durable,

01:02:25.240 | that they really are reinforced and last over time.

01:02:28.360 | I'd like to just take a brief break

01:02:29.940 | and thank one of our sponsors, which is Element.

01:02:32.800 | Element is an electrolyte drink that has everything you need

01:02:35.400 | and nothing you don't.

01:02:36.460 | That means plenty of salt, sodium, magnesium, and potassium,

01:02:40.080 | the so-called electrolytes, and no sugar.

01:02:42.920 | Now, salt, magnesium, and potassium are critical

01:02:45.740 | to the function of all the cells in your body,

01:02:47.600 | in particular to the function of your nerve cells,

01:02:50.280 | also called neurons.

01:02:51.480 | And we now know that even slight reductions

01:02:54.080 | in electrolyte concentrations or dehydration of the body

01:02:57.320 | can lead to deficits in cognitive and physical performance.

01:03:00.880 | Element contains a science-backed electrolyte ratio

01:03:03.420 | of 1,000 milligrams, that's one gram of sodium,

01:03:06.520 | 200 milligrams of potassium, and 60 milligrams of magnesium.

01:03:10.040 | I typically drink Element first thing in the morning

01:03:12.080 | when I wake up in order to hydrate my body

01:03:14.240 | and make sure I have enough electrolytes.

01:03:16.000 | And while I do any kind of physical training

01:03:18.240 | and after physical training as well,

01:03:19.740 | especially if I've been sweating a lot,

01:03:21.540 | and certainly I drink Element in my water

01:03:24.360 | when I'm in the sauna and after going in the sauna

01:03:26.840 | because that causes quite a lot of sweating.

01:03:28.520 | If you'd like to try Element, you can go to Drink Element,

01:03:31.500 | that's lmnt.com/huberman,

01:03:34.080 | to claim a free Element sample pack with your purchase.

01:03:36.400 | Again, that's drinkelementlmnt.com/huberman.

01:03:40.640 | So basically I've discussed two major mechanisms

01:03:43.240 | for how ketamine can induce neuroplasticity,

01:03:45.580 | leading to improvements in mood and affect

01:03:49.020 | that gives relief for depression.

01:03:51.260 | Those two mechanisms are linked,

01:03:53.060 | or at the very least are happening in parallel,

01:03:54.960 | they're happening at the same time in the brain.

01:03:57.260 | Now, just to make matters more interesting,

01:03:59.360 | there's an incredible twist into this whole thing

01:04:02.340 | of how ketamine works.

01:04:03.560 | And when I say how ketamine works,

01:04:04.860 | I'm not just talking about how ketamine provides relief

01:04:07.500 | for depression, I'm also talking about

01:04:10.060 | why people use ketamine for recreational purposes.

01:04:13.200 | And it is the following.

01:04:14.940 | Yes, ketamine has all these impacts on excitatory neurons,

01:04:18.960 | inhibitory neurons, BDNF, et cetera, et cetera,

01:04:21.760 | but ketamine can also bind receptors in the opioid pathway.

01:04:26.560 | Now, what is the opioid pathway?

01:04:28.200 | Don't worry, here I'm not going to hit you

01:04:29.460 | with a lot of details,

01:04:30.460 | but we've all heard of the opioid crisis by now,

01:04:33.280 | or at least most of you have.

01:04:35.200 | The opioid crisis refers specifically

01:04:37.480 | to people taking exogenous opioids, taking opioids, right?

01:04:40.820 | So taking pills that activate particular receptors

01:04:43.520 | in the brain that lead to analgesia in some cases,

01:04:47.500 | so pain relief that lead to changes in mood.

01:04:50.360 | There's a lot to be said about the opioid crisis.

01:04:53.160 | It's called a crisis for a reason.

01:04:55.800 | Many, many people are addicted to those compounds.

01:04:59.100 | That's a discussion for another time.

01:05:01.520 | Keep in mind that the receptors those drugs bind to

01:05:03.860 | are opioid receptors.

01:05:05.560 | And those receptors that you and I all have, by the way,

01:05:09.100 | do not exist in order to bind drugs

01:05:10.860 | that are made by pharmaceutical companies.

01:05:12.840 | They exist in our brain and body

01:05:14.680 | to bind to the so-called endogenous,

01:05:16.780 | naturally made opioids that we all make.

01:05:19.320 | And those receptors have different names,

01:05:20.840 | the Mu opioid receptor, the Kappa opioid receptor, et cetera.

01:05:24.520 | They tend to have the names of Greek letters

01:05:26.580 | to differentiate them.

01:05:28.480 | Now, ketamine can bind to various opioid receptors.

01:05:33.480 | And when opioid receptors are bound,

01:05:36.880 | we know that creates certain effects,

01:05:39.280 | things like pain relief,

01:05:41.120 | things like changes in psychic states,

01:05:43.800 | dissociation, for example.

01:05:45.800 | If enough of them are bound, you can get euphoric states.

01:05:48.020 | Under certain conditions of high dose binding of ketamine

01:05:52.160 | to those opioid receptors,

01:05:53.680 | you can start getting into planes of anesthesia,

01:05:56.820 | where people lose consciousness

01:05:58.200 | and actually have no response to pain whatsoever.

01:06:00.820 | If you recall the clinical studies we talked about earlier,

01:06:03.640 | where ketamine was used to relieve depression,

01:06:07.120 | well, the dosage used in that study, as you recall,

01:06:10.280 | was half a milligram per kilogram of body weight.

01:06:13.640 | That is the dosage that will induce these dissociative,

01:06:16.840 | mild euphoria, those sorts of states of mind,

01:06:20.300 | but where people are still conscious.

01:06:22.440 | When you start getting to dosages of ketamine

01:06:24.400 | that are in the range of one to two milligrams

01:06:26.540 | per kilogram of body weight,

01:06:27.880 | now you're talking about anesthetic doses.

01:06:30.880 | And when that happens, you're going to get full parking,

01:06:34.800 | full saturation of all the potential receptors

01:06:38.200 | that ketamine can bind to those NMDA receptors.

01:06:40.840 | It's going to block those.

01:06:41.760 | It's also going to bind to the so-called

01:06:43.160 | mu-opioid receptors and maybe this other type as well,

01:06:46.360 | for those of you that want to know,

01:06:47.460 | you aficionados, also the kappa type opioid receptors.

01:06:50.880 | And so what we've got here is a drug, ketamine,

01:06:54.160 | that is hitting two different systems,

01:06:55.840 | the glutamate-related system

01:06:57.880 | and the endogenous opioid system.

01:07:01.560 | And researchers and clinicians have logically

01:07:04.160 | started to ask whether or not

01:07:05.680 | some or all of the effects of ketamine

01:07:07.800 | are due to the opioid system.

01:07:10.400 | And they want to know which effects those are.

01:07:12.440 | Now, this is where things start to get really interesting,

01:07:14.560 | both in the context of clinical treatment of depression

01:07:16.960 | and recreational use.

01:07:19.000 | First of all, when people take ketamine,

01:07:22.960 | again, it enters the bloodstream and it goes into the brain,

01:07:25.960 | but it is metabolized to something called HNK,

01:07:29.360 | which is hydroxy nor ketamine.

01:07:32.040 | Now, I don't expect you to know what hydroxy nor ketamine is

01:07:34.760 | and I don't expect you to care about it

01:07:36.280 | until I tell you what I'm about to tell you,

01:07:38.280 | which is that hydroxy nor ketamine

01:07:41.200 | has an incredible specificity for the mu opioid receptor

01:07:46.080 | and maybe that kappa opioid receptor as well.

01:07:48.660 | In other words, when we talk about ketamine,

01:07:50.480 | that's the drug people take,

01:07:52.160 | but when it goes into the body,

01:07:53.620 | it's converted into yet another drug.

01:07:56.200 | And that other drug, hydroxy nor ketamine,

01:07:58.480 | is selectively activating the opioid system.

01:08:01.600 | So this led researchers to ask a very important question,

01:08:04.940 | which is when a human being takes ketamine

01:08:07.700 | in order to treat their depression

01:08:09.760 | and they get some relief from depression,

01:08:11.360 | is that the consequence of neuroplastic changes

01:08:13.980 | in all those NMDA glutamate BDNF-related circuits

01:08:16.740 | that we talked about before?

01:08:18.260 | Or is it the consequence of something happening

01:08:20.100 | in the opioid system?

01:08:21.620 | You can't ignore the fact that ketamine has this property

01:08:25.280 | of binding to these opioid receptors

01:08:27.400 | because they have such a powerful effect on our thinking,

01:08:30.320 | on our mood, on our state of consciousness.

01:08:33.160 | It's entirely reasonable that the opioid system

01:08:35.680 | could be a major player, if not the major player,

01:08:38.880 | in this whole depression relief thing

01:08:40.840 | and maybe even in the creation of dissociative symptomology

01:08:43.840 | when people take ketamine recreationally.

01:08:45.960 | So what researchers/clinicians did

01:08:48.920 | is they undertook a series of experiments

01:08:51.540 | where they gave people ketamine

01:08:52.860 | for the relief of depression,

01:08:54.500 | but they also blocked the opioid receptor system.

01:08:57.560 | And they did that using a drug called naltrexone.

01:09:00.440 | So what I'm about to describe to you

01:09:01.780 | is a study done by my colleagues

01:09:03.280 | at Stanford School of Medicine,

01:09:04.940 | namely Dr. Nolan Williams and Alan Schatzberg and colleagues

01:09:09.180 | entitled "Attenuation of Antidepressant

01:09:11.880 | and Antisuicidal Effects of Ketamine

01:09:14.260 | by Opioid Receptor Antagonism."

01:09:16.760 | And as a consequence of me reading you

01:09:18.080 | that title a moment ago,

01:09:19.500 | you now already have the conclusion of the study.

01:09:23.360 | What they observed is that when people were given ketamine,

01:09:25.360 | they got relief from depression.

01:09:26.600 | That wasn't surprising.

01:09:27.580 | Again, many studies had shown that before

01:09:29.380 | since the early 2000s.

01:09:31.740 | If, however, individuals were given naltrexone

01:09:34.500 | to block the opioid receptor pathway

01:09:36.960 | and they were given ketamine,

01:09:39.380 | well then the antidepressant effects of ketamine

01:09:41.580 | were no longer observed.

01:09:43.260 | Now that suggests that it is the opioid receptor system

01:09:46.700 | that's responsible for the antidepressant effects

01:09:50.300 | of ketamine.

01:09:51.140 | And perhaps this HNK, this hydroxynorketamine,

01:09:54.220 | which is the metabolite of ketamine,

01:09:56.100 | is the way in which ketamine normally relieves depression.

01:09:59.980 | Now, a lot of people took note of these studies

01:10:02.900 | because, after all, there are probably dozens,

01:10:06.340 | if not hundreds of studies,

01:10:07.420 | looking at the effects of ketamine

01:10:08.640 | on all that NMDA receptor stuff.

01:10:10.820 | And indeed, neuroplasticity and mood-related circuits

01:10:13.860 | can't be discounted as one way

01:10:16.340 | in which ketamine provides relief from depression.

01:10:20.060 | But what was very interesting is that

01:10:22.680 | in people given ketamine and naltrexone,

01:10:25.900 | those people still experienced

01:10:27.700 | the immediate effects of ketamine,

01:10:29.460 | the mild euphoria, the dissociation,

01:10:32.160 | the feelings that one would normally expect

01:10:34.260 | when people were under the effects of ketamine,

01:10:36.800 | but what they didn't get were the longer-term changes in mood

01:10:41.200 | that we would call relief from depression.

01:10:44.100 | Now, of course, the goal of modern psychiatry

01:10:46.140 | is to treat depression,

01:10:47.620 | not to block the effects of these drugs

01:10:49.380 | that are capable of treating depression.

01:10:51.220 | Now, what this study does,

01:10:52.180 | and by the way, there are several studies like it

01:10:54.120 | that support these general set of findings

01:10:56.100 | that part of the critical role of ketamine

01:10:58.700 | in providing relief from depression

01:11:00.280 | is to activate the opioid system.

01:11:02.140 | But what this study does is it really points to the fact

01:11:04.300 | that when we say ketamine treatment,

01:11:06.000 | or we talk about somebody taking ketamine recreationally,

01:11:08.680 | for that matter, we have to pay attention

01:11:10.700 | to what's happening

01:11:11.520 | while they are under the influence of the drug.

01:11:13.940 | We also have to pay attention to what's happening

01:11:15.700 | in the days and weeks

01:11:16.720 | after they're under the influence of the drug.

01:11:18.620 | And perhaps most importantly,

01:11:20.780 | this calls to mind a really important idea,

01:11:23.320 | which is that whether or not you're talking

01:11:24.540 | about ketamine-induced relief from depression

01:11:26.880 | or psilocybin-induced relief for depression

01:11:29.720 | or MDMA-induced relief for PTSD,

01:11:32.140 | a topic that I covered on a previous episode

01:11:34.100 | of this podcast,

01:11:35.480 | we have to step back and look at the idea

01:11:38.820 | that the effects of the drug that people experience,

01:11:41.760 | whatever those may be,

01:11:43.260 | because obviously it's going to depend

01:11:44.640 | on what particular drug they took,

01:11:47.180 | those immediate effects may not actually be related

01:11:50.700 | to the long-term clinical benefit of those particular drugs.

01:11:54.460 | Now, I realize that many people might not like that idea,

01:11:56.720 | and frankly, I don't actually think

01:11:58.340 | that's the way that it works.

01:11:59.300 | I don't think it's going to be an either/or situation.

01:12:01.620 | However, because drugs like ketamine, psilocybin, MDMA

01:12:05.800 | have such profound effects on people's psychic states

01:12:09.020 | when they are under the influence of them,

01:12:10.700 | and because at least in the proper clinical setting and use,

01:12:14.280 | they do seem to provide impressive relief

01:12:16.520 | from a lot of these psychiatric challenges

01:12:19.180 | like depression and PTSD,

01:12:21.420 | people naturally correlate those two things.

01:12:24.060 | They couple those two things.

01:12:25.160 | In fact, they collapse those two things

01:12:27.820 | and presume that their experience of what they saw,

01:12:30.940 | what they heard, how they felt

01:12:32.320 | while they were under the influence of the drug

01:12:34.380 | was actually the stimulus that created the relief

01:12:37.580 | from their clinical condition like depression.

01:12:40.620 | But what these data on combined treatment

01:12:43.380 | with ketamine and naltrexone

01:12:45.020 | to block the mu opioid receptor really show us

01:12:48.160 | is that that may not actually be the way that it works.

01:12:51.320 | It may be that the effects of a drug like ketamine

01:12:54.220 | that one experiences, while interesting,

01:12:56.460 | perhaps even profound, perhaps great insight

01:12:59.020 | comes to one when they do that therapy

01:13:01.420 | in the proper context,

01:13:03.580 | it is not clear at all that it is that experience

01:13:06.840 | and the effects of those drugs

01:13:08.220 | in those immediate minutes and hours

01:13:10.280 | that's actually what's causing the relief from depression.

01:13:14.160 | Now, again, I don't think it's an either/or.

01:13:17.080 | I like to view the whole situation

01:13:18.580 | more or less as a sort of wave front

01:13:21.460 | that the experience that one has subjectively

01:13:24.580 | while they are under the influence of a drug

01:13:26.280 | like ketamine or psilocybin or MDMA

01:13:28.480 | sets off a series, and in fact, multiple serieses.

01:13:33.020 | Is that a word?

01:13:33.860 | Multiple types of processes in the brain,

01:13:37.360 | some of which rely on things like NMDA receptor,

01:13:40.180 | BDNF, et cetera, type neuroplasticity,

01:13:42.980 | others which rely on the opioid receptor pathway,

01:13:46.140 | and that each of these have different time courses

01:13:48.960 | such that some provide immediate relief

01:13:51.480 | in the days and hours after treatment,

01:13:53.160 | some in the weeks after treatment,

01:13:55.240 | and some more durable, long-lasting changes

01:13:57.960 | that can occur over months or maybe even years.

01:14:00.940 | And a really important thing to underscore

01:14:02.740 | in the context of all this

01:14:04.340 | is that throughout today's discussion,

01:14:06.360 | we've been talking about drugs and receptors

01:14:08.640 | and relief from depression,

01:14:10.280 | but what we're really talking about here

01:14:11.960 | are people who get relief from depression

01:14:15.180 | and almost with certainty,

01:14:17.680 | when they get relief from depression,

01:14:19.180 | they are also starting to do other things.

01:14:21.220 | They are going back to work.

01:14:22.660 | They are engaging in relationships again.

01:14:24.320 | They are viewing themselves differently again.

01:14:26.260 | Hopefully they're getting morning sunlight

01:14:27.680 | and exercising and eating well

01:14:29.920 | and doing all the sorts of things

01:14:31.660 | that we would call anti-depressive behaviors.

01:14:34.880 | And it is impossible to separate

01:14:37.100 | the positive behavioral consequences

01:14:39.600 | of a drug treatment for depression

01:14:41.740 | from the drug itself in a way that lets us say,

01:14:44.120 | okay, ketamine relieved depression,

01:14:46.440 | and then as a consequence,

01:14:47.700 | people went and did a bunch of behaviors

01:14:49.140 | that were healthy for them

01:14:49.980 | or stopped engaging in behaviors

01:14:51.240 | that were unhealthy for them.

01:14:52.480 | So we can think of behaviors

01:14:53.740 | as pro-depressive or anti-depressive.

01:14:56.120 | In fact, we know that one particular behavior

01:14:58.720 | that is viewing blue light in the middle of the night

01:15:01.380 | between the hours of say 11 p.m. and 4 a.m.

01:15:04.160 | is known to invoke a pro-depressive circuit.

01:15:06.720 | It involves a structure called the habenula.

01:15:08.360 | I've talked about this on previous podcasts.

01:15:10.640 | It tends to lower dopamine and increase cortisol,

01:15:12.940 | and the day is following that exposure to light, et cetera.

01:15:16.420 | So there are pro-depressive behaviors

01:15:18.940 | and there are anti-depressive behaviors.

01:15:20.520 | We know that viewing morning sunlight,

01:15:22.280 | getting regular and sufficient amounts of quality sleep,

01:15:25.680 | proper nutrition, proper social engagement,

01:15:27.800 | there is now a plethora of quality research

01:15:30.000 | pointing to the fact

01:15:30.960 | that those are true anti-depressive behaviors.

01:15:33.360 | So we can never separate out the effects of a drug

01:15:36.800 | from the effects of a drug that feed back on

01:15:40.640 | and combine with the effects of the drug

01:15:42.260 | that one is hoping for, in this case, depression relief.

01:15:45.720 | Okay, so I've been bookending this conversation

01:15:47.720 | about ketamine at two very divergent levels,

01:15:51.560 | meaning we've been talking about high-level stuff,

01:15:54.840 | relief from depressive symptoms, right?

01:15:56.620 | We haven't been going into a lot of detail about that,

01:15:58.540 | but that's pretty high level.

01:15:59.400 | We're talking about thought changes, behavioral changes

01:16:01.960 | that we're calling anti-depressive, right?

01:16:04.000 | Changes in mood and affect that are positive,

01:16:06.440 | positive anticipation of the future, et cetera, et cetera.

01:16:09.140 | And then we've also been talking a lot at this other end,

01:16:11.740 | which is very reductionist,

01:16:12.960 | down at the cellular and molecular level.

01:16:14.680 | We're talking about receptors and binding of receptors

01:16:17.240 | and neuroplasticity and TracB and all that stuff.

01:16:20.480 | We've completely neglected,

01:16:21.720 | meaning I've completely neglected until now,

01:16:25.260 | what bridges those two levels of understanding?

01:16:27.960 | And what bridges those two levels of understanding

01:16:30.200 | are the neural circuits that actually change

01:16:32.320 | when one takes ketamine.

01:16:33.940 | Whether or not those changes occur quickly,

01:16:35.640 | whether or not they take a longer period of time,

01:16:37.800 | whether or not they involve NMDA receptors

01:16:39.800 | or the opioid receptor systems or both,

01:16:42.760 | we know that certain neural circuits change

01:16:44.880 | when people take ketamine in these patterns of dosage

01:16:48.600 | and frequency of about half a milligram per kilogram.

01:16:51.880 | And again, that's the injected form,

01:16:53.480 | twice per week over three weeks,

01:16:55.760 | and then they get some durable resistance to depression.

01:16:58.640 | Fortunately, we can talk about those neural circuits

01:17:00.680 | without having to bring about a lot more nomenclature,

01:17:03.120 | a lot of new language.

01:17:04.520 | And I say fortunately, because I realized today

01:17:06.840 | you've been hit with a lot of new terms.

01:17:09.100 | Now I've already mentioned one of the key brain structures,

01:17:11.560 | and that's the habenula.

01:17:13.040 | A few moments ago, I talked about the habenula

01:17:14.720 | in the context of people who get too much

01:17:17.320 | bright to light exposure in the middle of the night.

01:17:19.440 | That activates the habenula.

01:17:20.900 | It's a sort of a disappointment circuit.

01:17:23.000 | We can call it that because we know that it leads

01:17:25.160 | to pro depressive symptoms in animal models

01:17:28.300 | and very likely in humans as well.

01:17:30.160 | And it does so we know by reducing dopamine

01:17:32.960 | and increasing cortisol.

01:17:34.520 | There's evidence that when people undergo ketamine therapy,

01:17:37.200 | connections between the habenula,

01:17:39.440 | what we can broadly just talk about as a structure involved

01:17:42.360 | in generating a feeling of disappointment,

01:17:44.520 | the connections between the habenula

01:17:47.460 | and the reward circuitry of the brain,

01:17:49.480 | which I've talked about several times before

01:17:51.300 | on this podcast,

01:17:52.140 | but for those of you that aren't familiar with it,

01:17:53.800 | this is the so-called mesolimbic reward pathway

01:17:56.280 | as areas like the ventral tegmental area,

01:17:58.480 | the nucleus accumbens.

01:17:59.540 | Don't worry at all about those names.

01:18:01.640 | Just know that this is a brain area

01:18:03.720 | that is chock-a-block full of neurons that release dopamine,

01:18:08.020 | which is a molecule that tends to increase mood,

01:18:11.420 | increase motivation.

01:18:12.820 | In many ways, we can think about it,

01:18:14.380 | at least for sake of this discussion, as anti-depressive.

01:18:17.260 | So what we've got is a structure, the habenula,

01:18:20.480 | that normally provides inhibitory,

01:18:22.960 | and now you know what that means, inhibitory input

01:18:25.800 | to this reward pathway that releases dopamine.

01:18:28.760 | And when people take ketamine,

01:18:30.560 | that inhibition is lessened such that the reward pathway

01:18:34.160 | is more available for engagement

01:18:36.020 | through daily life activities.

01:18:37.800 | Now I say available for engagement

01:18:40.240 | through daily life activities for a very specific purpose,

01:18:43.720 | which is that all of the changes in neural circuits

01:18:46.740 | that we're talking about

01:18:47.580 | that can come about from taking a drug,

01:18:49.800 | well, those changes don't actually do a whole lot

01:18:54.200 | unless those circuits are reinforced

01:18:56.100 | by particular behaviors.

01:18:57.300 | So this relates back to what I said just a few minutes ago

01:19:00.040 | about pro-depressive and anti-depressive behaviors.

01:19:04.180 | Somebody can take ketamine

01:19:05.560 | and potentially get relief from depression,

01:19:07.440 | but if they continue to engage in pro-depressive behaviors,

01:19:11.120 | they are not going to get much,

01:19:12.480 | if any, relief from depression.

01:19:14.240 | Conversely, if somebody takes ketamine

01:19:16.640 | and they are reducing the amount of output

01:19:18.820 | from this disappointment circuit, this habenula,

01:19:21.520 | to the reward circuitry of the brain,

01:19:23.760 | and they do engage in behaviors

01:19:26.280 | such as seeking out work that stimulates them,

01:19:28.860 | seeking out social engagement,

01:19:30.760 | taking good care of their body, their mental health,

01:19:32.600 | their physical health, et cetera,

01:19:34.240 | well, those circuits are not designed to respond to ketamine.

01:19:37.720 | They are designed to respond

01:19:39.080 | to particular patterns of thinking and behavior.

01:19:41.680 | So again, we can't forget that when we hear

01:19:45.000 | that a drug causes plasticity in a given neural circuit,

01:19:48.320 | what it's doing is it's biasing the balance

01:19:50.560 | or the probability that those neural circuits

01:19:52.800 | will be engaged by certain activities,

01:19:55.000 | but one still has to engage in those activities.

01:19:58.000 | Now, fortunately, when people tend to have elevations

01:20:01.300 | in mood, they tend to move around more.

01:20:03.280 | When they tend to move around more,

01:20:05.000 | they tend to engage in more things.

01:20:06.500 | When they tend to engage in more things,

01:20:08.720 | if they have a positive outlook on life,

01:20:10.480 | presumably they are engaging in adaptive things,

01:20:13.160 | things like social relationships, job-related,

01:20:15.120 | school-related, goal-related behavior.

01:20:17.600 | So it's important to understand that a discussion

01:20:19.480 | of neural circuit changes in response to ketamine

01:20:22.060 | is really a discussion of neural circuit changes

01:20:24.760 | in response to ketamine that shift one's overall system

01:20:28.540 | toward having yet further neural circuit changes

01:20:31.140 | in response to daily activities

01:20:32.840 | and thereby bolstering health,

01:20:34.720 | or in this case, mental health.

01:20:36.440 | Now, it's also important to understand that rarely, if ever,

01:20:39.840 | does a drug provide relief

01:20:41.580 | for some sort of clinical challenge

01:20:43.680 | in just a one-track kind of way.

01:20:45.680 | The way to think about this is that most mental processes

01:20:48.240 | and certainly things like depression are a two-way road.

01:20:51.160 | You have pro-depressive behaviors in circuits

01:20:53.360 | and you have anti-depressive behaviors in circuits.

01:20:56.400 | And so perhaps it won't be surprising to you

01:20:58.340 | that there's evidence that ketamine treatment

01:21:00.540 | can reduce the output from the habenula

01:21:02.360 | to the reward pathway,

01:21:03.280 | this disappointment to reward pathway, weakening that,

01:21:05.680 | making the reward pathway more available for engagement

01:21:08.680 | through thoughts and behaviors that are anti-depressive.

01:21:11.680 | And in addition to that,

01:21:13.520 | it can further bolster the neuroplasticity

01:21:16.340 | within the reward pathway itself,

01:21:18.720 | in particular with connections with the frontal cortex.

01:21:21.360 | And for those of you that aren't familiar

01:21:22.800 | with the frontal cortex,

01:21:23.980 | your frontal cortex does a lot of things,

01:21:25.740 | but one of the things that your frontal cortex

01:21:27.400 | is absolutely critical for

01:21:29.300 | is for establishing context-dependent strategy,

01:21:32.880 | meaning for allowing you to say,

01:21:35.020 | okay, in a given circumstance,

01:21:36.540 | what should I do to get the results I want?

01:21:38.960 | In another circumstance,

01:21:40.140 | what should I do to get the results I want?

01:21:41.880 | It's not strategizing of the manipulative type,

01:21:44.660 | although I suppose it could be,

01:21:46.040 | it's strategizing of how do I get what I need

01:21:48.760 | from this social connection?

01:21:50.300 | How do I get what I need from my goals in exercise?

01:21:54.100 | How do I get what I need from my goals

01:21:56.200 | in terms of work or school, et cetera?

01:21:58.940 | Your frontal cortex is that part of your cortex

01:22:01.000 | that's always churning ideas.

01:22:02.440 | It's always wondering, am I doing well?

01:22:03.880 | Am I not doing well?

01:22:04.720 | And is adjusting your behavior accordingly.

01:22:07.120 | So it's now established

01:22:08.220 | that ketamine can improve connectivity.

01:22:10.120 | That is, it can strengthen the connections

01:22:12.200 | between areas of the brain that are associated

01:22:14.140 | with context-dependent strategy building

01:22:16.760 | and these reward pathways.

01:22:18.160 | In other words, it makes people more sensitive

01:22:20.680 | to whether or not they are getting the results they want

01:22:22.800 | from their efforts and to how to adjust their efforts

01:22:26.080 | so that they do get the results they want from those efforts.

01:22:29.240 | And there's other evidence

01:22:30.220 | that NMDA receptor blockade is not the way

01:22:33.100 | that ketamine provides relief from depression.

01:22:35.420 | Namely, there's a drug called memantine.

01:22:38.060 | It's used actually to treat Alzheimer's

01:22:39.800 | and it too is an NMDA receptor blocker

01:22:43.140 | and it has no antidepressant effects.

01:22:45.740 | Now, as you recall, ketamine is a dissociative anesthetic.

01:22:48.700 | And one of its primary effects

01:22:50.060 | is to create this feeling of dissociation.

01:22:52.700 | For those of you that aren't familiar

01:22:53.980 | with what dissociation is,

01:22:55.460 | dissociation is where people feel separate from their body.

01:22:59.120 | They can still think,

01:23:00.600 | but it's as if they are observing themselves.

01:23:03.140 | In fact, in anticipation for this episode,

01:23:05.260 | I consulted with several different colleagues

01:23:07.160 | in the Department of Psychiatry

01:23:08.300 | at Stanford School of Medicine.

01:23:09.660 | And one of them described the effects of ketamine

01:23:11.740 | as described by a patient of theirs

01:23:13.260 | who had taken ketamine for the treatment of depression.

01:23:15.980 | And that patient described it as observing themselves,

01:23:20.080 | thinking, observing themselves, doing things,

01:23:22.960 | even though they were lying completely still.

01:23:25.220 | And perhaps most importantly,

01:23:27.020 | describing themselves as being above their body

01:23:29.460 | and actually looking down on themselves

01:23:31.380 | from the third person perspective.

01:23:33.820 | Now that I realize is a foreign experience to most people,

01:23:36.500 | but of course there are people who experience dissociation

01:23:38.640 | even while not on ketamine.

01:23:40.140 | And as many of you know,

01:23:41.940 | dissociation is actually one of the primary symptoms

01:23:44.240 | of PTSD and trauma.

01:23:46.260 | So this raises a sort of conundrum.

01:23:48.060 | Why is it that a particular state of mind

01:23:50.540 | that's associated with PTSD and trauma,

01:23:52.700 | and in some cases depression itself,

01:23:55.220 | which is induced by a drug like ketamine,

01:23:57.520 | can provide relief from depression?

01:23:58.820 | And that all goes back to the neuroplastic changes

01:24:00.880 | that we talked about earlier,

01:24:02.280 | and more likely the changes in the mu-opioid receptor system

01:24:06.220 | that we talked about earlier.

01:24:07.520 | But nonetheless, the dissociative effects of ketamine

01:24:10.880 | are so profound for people that take them

01:24:13.180 | that I thought I'd spend a minute or two

01:24:14.620 | explaining what likely causes

01:24:16.560 | that dissociative third-personing of self-effect.

01:24:19.620 | And in so far as we know,

01:24:21.760 | it has to do with an uncoupling of certain brain circuits,

01:24:25.560 | in particular, neocortical brain circuits.

01:24:27.680 | The neocortex is the part of the brain,

01:24:29.100 | the lumpy outside part of the brain

01:24:30.940 | that's associated with action planning.

01:24:32.720 | It does a lot of things, really.

01:24:34.020 | It's involved in sensory perception.

01:24:36.640 | It's involved in speech generation, many, many things.

01:24:39.400 | But the neocortex has connections to other regions

01:24:42.880 | which are called subcortical regions.

01:24:45.080 | And it seems that when people take ketamine

01:24:47.380 | or phencyclidine PCP,

01:24:48.980 | there's an uncoupling of those networks,

01:24:50.780 | a quieting of those networks

01:24:52.700 | that starts to create a different dominant rhythm

01:24:55.160 | in the brain.

01:24:56.280 | Some of you may be familiar with rhythms in the brain,

01:24:58.760 | so-called alpha rhythms or alpha patterns of activity.

01:25:01.320 | That's just dominant patterns of activity

01:25:03.500 | associated with particular brain states.

01:25:05.540 | So for instance, alpha brain waves are associated

01:25:07.940 | with an alert but calm, relaxed state of mind

01:25:11.640 | where thoughts are sort of free flowing.

01:25:13.420 | It's a little bit dreamlike,

01:25:14.940 | but it isn't really like a dream where anything can happen.

01:25:18.060 | It has a structure to it.

01:25:19.800 | When people take ketamine,

01:25:20.940 | the alpha pattern of activity is completely abolished,

01:25:23.700 | at least for the duration of time

01:25:24.840 | that they're under the influence of the drug,

01:25:26.300 | which typically is about an hour to two hours or so.

01:25:29.500 | And a different pattern of brain activity,

01:25:31.340 | which is called the theta pattern of brain activity,

01:25:33.780 | starts to really emerge.

01:25:35.380 | It's as if it gets unveiled.

01:25:37.100 | And that theta pattern of activity

01:25:38.720 | is the one that's associated with a dreamlike state.

01:25:41.460 | It's the one that resides more or less at that liminal border

01:25:44.500 | between wakefulness and sleep.

01:25:46.980 | If you've ever been falling asleep

01:25:48.700 | and you were thinking something like you were running

01:25:50.300 | and you kicked your leg,

01:25:51.500 | it's very likely that you were in theta pattern of activity

01:25:54.220 | in your brain at that moment,

01:25:56.260 | just prior to when you woke up.

01:25:58.020 | Whereas when you're more alert,

01:25:59.200 | you see patterns of activity that are higher frequency,

01:26:01.720 | things like alpha, beta rhythms, and so forth.

01:26:04.580 | So ketamine produces particular patterns of brain activity

01:26:07.260 | and this sense of dissociation

01:26:09.220 | when it's taken at subanesthetic doses.

01:26:12.380 | If you recall the clinical studies we talked about earlier,

01:26:14.880 | they injected half a milligram per kilogram of body weight

01:26:18.540 | in order to provide depression relief for those patients.

01:26:21.820 | When people take ketamine,

01:26:23.420 | they will take it by different routes of delivery.

01:26:25.740 | And now here we have to expand our conversation

01:26:27.860 | to include both the clinical context,

01:26:30.180 | research studies and recreational use.

01:26:33.540 | Now I do that because typically when people take ketamine

01:26:36.900 | in a study, in a clinical study,

01:26:38.940 | they will get an intravenous into the vein

01:26:41.420 | or an intramuscular into the muscle injection

01:26:44.140 | of half a milligram per kilogram of body weight ketamine.

01:26:48.060 | However, when people are taking ketamine recreationally

01:26:51.180 | or when they are accessing ketamine legally by prescription

01:26:54.640 | and taking it at home,

01:26:55.820 | which is becoming a more common practice,

01:26:58.280 | they will often take it orally in pill form

01:27:00.860 | or they will take it sublingually

01:27:02.760 | by putting it under the tongue or in their cheek.

01:27:04.740 | And then that so-called troche dissolves

01:27:07.460 | and the ketamine goes into their system.

01:27:09.620 | Now, an important thing to understand is that

01:27:11.460 | when people take ketamine orally,

01:27:13.500 | only 25% of the active form of ketamine

01:27:16.620 | makes it into the bloodstream.

01:27:18.420 | And when they take it sublingually,

01:27:19.740 | typically only about 35% of the total amount of ketamine

01:27:23.140 | they take is converted into metabolically active ketamine

01:27:26.140 | that acts on the neurons in their brain.

01:27:28.580 | So when you hear about the dosages used in studies,

01:27:31.100 | they are going to generally involve injections of ketamine

01:27:34.140 | and far lower doses of ketamine

01:27:35.940 | than when you hear about people taking ketamine orally

01:27:38.440 | or sublingually.

01:27:39.660 | So for instance, I weigh 220 pounds, that's 100 kilograms.

01:27:43.160 | So if I were to be in one of these studies,

01:27:44.940 | which I have not been, but if I were,

01:27:47.500 | I would be given 50 milligrams of ketamine

01:27:50.340 | by way of injection.

01:27:51.580 | However, if I were going to try to achieve

01:27:54.060 | the same amount of active ketamine

01:27:55.780 | in my bloodstream and brain as I would through injection,

01:27:59.700 | I would need to ingest three times as much ketamine

01:28:02.440 | by way of pill and perhaps a little bit more

01:28:06.460 | by way of sublingual ketamine

01:28:08.500 | if I wanted to get the same effects.

01:28:10.380 | So if I were to take 50 milligrams

01:28:12.500 | by way of injection in a study

01:28:14.420 | and I went to a different study and they said,

01:28:16.280 | "Okay, we want to recreate that effect.

01:28:18.520 | We're going to give you a pill."

01:28:19.620 | Typically, they're going to give me 150 milligrams

01:28:22.540 | of ketamine in a pill form

01:28:24.620 | or 200 milligrams of ketamine in the troche sublingual form.

01:28:29.100 | Now, it's really important to understand this dose dependence

01:28:31.780 | according to delivery business,

01:28:33.700 | because I realized that nowadays, especially,

01:28:36.640 | a lot of people are taking ketamine through legal sources.

01:28:40.540 | So they're accessing it legally,

01:28:42.260 | but they're taking it outside the clinic

01:28:43.960 | and more typically, they're taking it

01:28:45.140 | not by way of injection,

01:28:46.740 | meaning they're taking higher dose ketamine

01:28:48.660 | and they're taking it sublingually or orally.

01:28:51.360 | So it's very important to understand this dose dependence

01:28:54.220 | according to mode of delivery business.

01:28:56.620 | Now, in anticipation of this episode,

01:28:58.260 | I put out a request for questions about ketamine on Twitter

01:29:01.280 | and I got many, many questions,

01:29:03.700 | some excellent ones therein.

01:29:05.580 | But one of the more common questions was,

01:29:07.660 | what is a K-hole in scientific terms?

01:29:10.980 | A K-hole is what's used to describe

01:29:14.160 | the subjective experience of when somebody takes ketamine,

01:29:17.580 | typically recreationally,

01:29:19.100 | and they end up in basically a pseudoanesthetized state.

01:29:22.780 | What that means is that they took a dosage that for them,

01:29:27.820 | put them beyond the boundary of the subanesthetic dose

01:29:31.420 | and has them transitioning

01:29:32.660 | into the anesthesia level dose of ketamine.

01:29:36.900 | Now, I mentioned everything I did about dosages before

01:29:40.060 | because it's very important to know that different people,

01:29:43.460 | even if they are of equivalent body weight,

01:29:46.100 | are going to respond to ketamine differently

01:29:48.380 | depending on how quickly

01:29:49.900 | and how thoroughly they metabolize ketamine.

01:29:52.760 | So in the clinical context,

01:29:55.900 | injections of ketamine into the vein or into the muscle

01:29:59.260 | are done at this half a milligram per kilogram dose.

01:30:02.720 | And they have clinicians there,

01:30:03.760 | they have researchers there who are paying attention

01:30:05.500 | to whether or not the person is in a dissociative state

01:30:08.560 | if they're still conscious,

01:30:10.160 | and to see whether or not the person

01:30:11.340 | is going into full-blown anesthesia.

01:30:13.640 | Now, that's one of the values of doing ketamine

01:30:15.460 | in the context of a legal clinical setting.

01:30:17.920 | However, I'd be remiss if I didn't acknowledge

01:30:20.160 | that a lot of people are getting ketamine legally,

01:30:22.640 | but then taking it at home, hopefully not alone.

01:30:25.640 | Hopefully there's someone there to monitor them

01:30:27.780 | where they're in session with their physician over Zoom.

01:30:30.920 | That's actually happening more and more these days

01:30:32.620 | through telehealth.

01:30:33.940 | But that itself also has certain risks, right?

01:30:35.940 | Because if the person needs something

01:30:37.960 | and they don't have someone there immediately in the room

01:30:40.000 | to take care of it,

01:30:40.960 | that could be a very problematic situation.

01:30:42.960 | And of course, there are situations

01:30:44.620 | where people are taking ketamine recreationally.

01:30:47.280 | Regardless of how they're acquiring it,

01:30:48.820 | they're taking it and they are guessing

01:30:50.760 | how they're going to respond to it

01:30:52.360 | based on some crude understanding of dosages.

01:30:55.180 | But when people talk about a K-hole,

01:30:56.800 | what they're talking about is taking ketamine at a dose

01:31:00.000 | that for them takes them beyond the mild

01:31:01.960 | or perhaps even an extreme dissociation

01:31:04.880 | and starts placing them into full-blown anesthesia.

01:31:07.760 | And that itself actually can be dangerous.

01:31:10.920 | Going into anesthesia like planes of consciousness,

01:31:13.620 | while not always deadly, can be deadly.

01:31:16.320 | And it certainly can be and has been deadly

01:31:18.720 | when people start to combine it with other drugs,

01:31:21.240 | in particular drugs like barbiturates or alcohol.

01:31:24.360 | So I want to be very clear that the dosage ranges

01:31:27.080 | that you hear about when hearing about ketamine

01:31:29.240 | are extremely broad.

01:31:30.640 | And so is the variability to any one given dose.

01:31:33.820 | And so too is the response to a given dose in a given person,

01:31:38.820 | depending on the route of delivery.

01:31:41.340 | You need to be very careful about the ability of ketamine

01:31:44.440 | to take you into deep, deep planes of unconsciousness

01:31:47.860 | and in some cases, death.

01:31:50.060 | And of course, as with any sedative,

01:31:52.240 | one needs to be extremely cautious about doing anything

01:31:54.880 | like driving or even walking in traffic

01:31:58.080 | or walking anywhere in some cases,

01:32:00.380 | if one is under the influence of ketamine.

01:32:02.660 | Additionally, for those of you that are seizure-prone,

01:32:05.660 | either due to epilepsy or prior head injury,

01:32:07.920 | or maybe you're seizure-prone and you don't know it,

01:32:10.460 | ketamine can induce seizures

01:32:11.840 | and it should be completely obvious to you now

01:32:14.000 | why that's the case.

01:32:15.440 | Ketamine blocks NMDA receptors on inhibitory neurons

01:32:19.300 | and quiets their activity,

01:32:20.700 | which of course can lead to runaway excitation in the brain

01:32:23.200 | if you are seizure-prone.

01:32:24.720 | When I put out the request for questions

01:32:26.360 | about ketamine on social media,

01:32:27.880 | I also got a lot of questions

01:32:29.520 | about the different forms of ketamine.

01:32:31.760 | When I say different forms that included questions

01:32:33.800 | about whether or not intranasal was better than oral,

01:32:36.840 | was better than sublingual, et cetera, et cetera.

01:32:39.980 | To be fair, with one exception,

01:32:41.780 | the different modes of delivery probably relate more

01:32:44.720 | to dosage that actually gets metabolized

01:32:47.200 | than to anything else.

01:32:48.020 | What I mean by that is most people don't know

01:32:50.720 | how to equate the clinical dose

01:32:52.760 | of half a milligram per kilogram of body weight

01:32:55.600 | into a dosage to take orally or sublingually,

01:32:58.660 | or in some cases, by the way, people will take it rectally.

01:33:01.480 | And the reason people take ketamine rectally

01:33:03.680 | is that rectal administration bypasses the liver,

01:33:06.280 | and indeed ketamine can be hard on the liver to metabolize.

01:33:10.120 | It can dramatically increase liver enzymes.

01:33:12.760 | So oftentimes people that are taking ketamine frequently

01:33:15.440 | and don't want to create damage to the liver,

01:33:18.040 | they will opt for a rectal administration.

01:33:20.440 | Now, I realize that unless it's somehow related

01:33:22.520 | to your profession,

01:33:23.340 | anytime somebody says intra rectally,

01:33:25.320 | it raises a few eyebrows

01:33:26.600 | and people kind of lean back a little bit, and I get it.

01:33:30.200 | In a future episode of the podcast,

01:33:31.720 | I promise to distinguish

01:33:33.080 | between the different modes of drug metabolism,

01:33:35.360 | depending on whether or not people take something orally,

01:33:38.060 | sublingually, by injection, or rectally.

01:33:41.760 | Another common question I got

01:33:43.080 | when I solicited for questions about ketamine

01:33:45.360 | on social media was about the R versus S

01:33:49.280 | versus RS forms of ketamine.

01:33:51.720 | And I must tell you that sent me down

01:33:53.880 | a deep, deep rabbit hole of research

01:33:57.000 | in which I discovered very contradictory evidence.

01:34:00.400 | For instance, I could find papers,

01:34:02.440 | I did find papers that said that the R form of ketamine

01:34:05.960 | had a much greater affinity for the NMDA receptor

01:34:08.360 | than did the S form of ketamine.

01:34:10.820 | I also found reviews that said the exact opposite, okay?

01:34:15.520 | And there I was sitting with the two reviews

01:34:17.300 | in front of one another,

01:34:18.140 | wondering if there was something wrong with my visual system

01:34:21.600 | until I called a colleague, Dr. Nolan Williams,

01:34:23.880 | who's a triple board certified neurologist psychiatrist

01:34:26.480 | at Stanford School of Medicine,

01:34:27.560 | whose laboratory specializes in the use of ketamine

01:34:31.160 | for studies of treating depression

01:34:32.700 | and for treating depression in the clinical population.

01:34:36.300 | So I asked him, what's the deal here?

01:34:38.040 | I'm getting very contradictory evidence,

01:34:39.920 | and he spelled it all out for me.

01:34:41.680 | It appears, based on the clinical data in humans

01:34:45.920 | and on binding studies,

01:34:47.640 | that the S form of ketamine is more potent.

01:34:51.520 | That is, it can more robustly bind to the NMDA receptor.

01:34:55.440 | And in addition to that, the S form of ketamine

01:34:58.480 | tends to produce less dissociation at a given dosage

01:35:03.480 | than does the combined SR form of ketamine or pure R ketamine.

01:35:08.480 | He also added, and sent me a study

01:35:11.560 | that I'll link in the show note captions,

01:35:13.400 | that there was recently a clinical trial of R ketamine,

01:35:17.040 | so pure R ketamine alone,

01:35:19.520 | and it failed to relieve depressive symptoms.

01:35:22.900 | So I said, great, thank you so much.

01:35:24.460 | This is now all made very clear to me

01:35:26.940 | that S ketamine is the preferred form,

01:35:29.180 | it produces less dissociation,

01:35:31.100 | and it provides better depression relief.

01:35:33.780 | And then he said, no, actually,

01:35:36.300 | it's a little more complicated than that.

01:35:38.860 | It appears the situation is the following.

01:35:41.380 | The combined SR form of ketamine

01:35:44.160 | seems to be the most potent

01:35:46.040 | for relieving depressive symptoms.

01:35:48.300 | The S form of ketamine is second best

01:35:53.100 | in terms of providing relief from depressive symptoms,

01:35:55.680 | and is the one that's most commonly prescribed nowadays

01:35:59.000 | by nasal spray, by oral dosing, by sublingual dosing,

01:36:03.680 | and it's what is typically given by way of injection

01:36:06.380 | in clinical studies where they do injections.

01:36:09.320 | And it appears that the R form of ketamine

01:36:11.680 | is the least potent and effective in treating depression.

01:36:15.300 | Now, I realize that by putting this out

01:36:16.780 | into the larger world,

01:36:18.320 | and assuming that there are experts in ketamine out there,

01:36:21.360 | either by way of use or by clinical study of their own,

01:36:24.720 | that I will get a lot of comments back saying,

01:36:26.360 | no, actually the R form was more effective for me

01:36:28.640 | than the S form versus the SR form, et cetera.

01:36:31.100 | Just to reiterate from the clinical trials

01:36:33.280 | that have been done,

01:36:34.120 | we know that the combined SR form

01:36:36.100 | is more potent and effective than the pure S form,

01:36:39.200 | which is still more effective than the pure R form.

01:36:42.580 | So that's what we know now based on the clinical studies.

01:36:45.640 | But of course, I acknowledge that anytime a drug is out there

01:36:48.060 | as a clinical tool and it's being used recreationally,

01:36:50.620 | that people are going to explore

01:36:52.920 | and they're going to experiment

01:36:54.060 | and they're going to find what works best for them.

01:36:55.840 | So I certainly invite feedback

01:36:57.240 | about what has worked best for you,

01:36:59.300 | hopefully in the clinical context.

01:37:00.780 | So whether or not people have used ketamine prescription

01:37:03.140 | from their doctor,

01:37:03.980 | whether or not they participated in a clinical study

01:37:06.060 | or whether or not they're doing it recreationally,

01:37:07.780 | I imagine that I will hear about those experiences

01:37:10.040 | and I will take note of them.

01:37:11.520 | Another commonly asked question I received was,

01:37:13.960 | what about microdosing of ketamine?

01:37:15.940 | And there's a lot of interest in microdosing nowadays.

01:37:17.920 | People are microdosing psilocybin,

01:37:20.440 | people are microdosing all sorts of things,

01:37:22.760 | hoping to get some of the same effects as the macro doses,

01:37:25.720 | but by using dosages of compounds

01:37:28.220 | that are below what would induce say,

01:37:31.060 | in the case of psilocybin, hallucinations,

01:37:32.820 | or in the case of ketamine,

01:37:34.540 | below what would induce the kind of dissociation

01:37:37.340 | and euphoric effects that one would have to lie down

01:37:40.140 | for a few hours and disengage for the rest of the day.

01:37:42.960 | I consulted with my clinician colleagues about this

01:37:45.380 | and they told me that at present, meaning as of yesterday,

01:37:49.240 | there is zero published clinical evidence

01:37:52.160 | that they are aware of, and by way of extension,

01:37:54.700 | that I am aware of, in which microdosing ketamine

01:37:58.700 | has been effective for the treatment of depression.

01:38:01.040 | All of the positive effects on depression

01:38:02.660 | that I've talked about during this episode

01:38:04.800 | are gleaned from studies where people used

01:38:07.060 | this half milligram per kilogram dosage of ketamine

01:38:10.060 | or its equivalent by way of some other route

01:38:12.360 | of administration, not injected, but oral or sublingual.

01:38:15.420 | So are there any benefits to microdosing ketamine

01:38:18.240 | as far as the scientific and clinical literature

01:38:20.760 | that's published as of today is concerned?

01:38:22.840 | The answer is no.

01:38:24.320 | Okay, so today we covered a lot of information.

01:38:26.820 | We talked about what ketamine is.

01:38:28.080 | Remember, ketamine and PCP, angel dust,

01:38:31.200 | very similar compounds, both block the NMDA receptor.

01:38:34.880 | We also talked about what sorts of subjective effects

01:38:37.760 | that produces, dissociation and mild euphoria

01:38:40.960 | and third-personing of self, that's the dissociation,

01:38:43.860 | when taken at low dosages.

01:38:46.300 | And when taken at higher dosages, it can induce

01:38:48.660 | full-blown anesthesia and put people

01:38:50.280 | into subconscious states.

01:38:51.700 | And there's actually a potential even for seizure and death

01:38:54.900 | if the dosage is high enough for that person.

01:38:58.280 | Again, I want to emphasize that people's dosage sensitivity

01:39:01.280 | varies tremendously, route of delivery will impact that,

01:39:04.100 | and on and on.

01:39:05.100 | We also talked about how the NMDA receptor itself

01:39:08.460 | and the activation of this incredible molecule, BDNF,

01:39:12.040 | brain-derived neutrophic factor, seem to be important

01:39:15.300 | for at least some of the antidepressant effects of ketamine,

01:39:18.260 | both in the days and weeks

01:39:20.220 | following ketamine administration.

01:39:22.360 | And in addition to that, I described how ketamine impacts

01:39:24.960 | the opioid receptor system and how we simply cannot overlook

01:39:28.360 | the involvement of the opioid receptor system

01:39:30.960 | in producing the antidepressant effects of ketamine.

01:39:33.420 | And we also talked about the brain circuits

01:39:35.320 | and the brain waves associated with dissociative states

01:39:37.840 | and the depression relief that seems to arrive

01:39:40.680 | for many people who take ketamine.

01:39:42.400 | And I tried to highlight some of the unique features

01:39:44.260 | of ketamine.

01:39:45.100 | First of all, that it does seem to provide depression relief

01:39:48.020 | where other approaches have not,

01:39:50.160 | but that the depression relief tends to be pretty short-lived

01:39:53.020 | unless it's applied in this multi-times per week

01:39:56.300 | over multiple weeks kind of fashion

01:39:58.460 | to produce what I call durable changes,

01:40:00.540 | which almost certainly involve changes in neuroplasticity,

01:40:03.980 | that is rewiring of brain circuits.

01:40:06.180 | And another key point that I highlighted

01:40:08.180 | is that we always have to remember

01:40:10.440 | that when thinking about how chemicals like ketamine

01:40:12.760 | or any other substance for that matter

01:40:14.640 | can modify brain circuits in order to change them

01:40:17.880 | and provide relief from depression

01:40:19.860 | or some other psychiatric challenge,

01:40:22.000 | that always, always, always there is a requirement

01:40:25.540 | for engaging in antidepressant behaviors

01:40:28.320 | as a way to further reinforce whatever positive changes

01:40:31.060 | have come about through the drug treatment.

01:40:32.940 | As a friend and colleague of mine

01:40:34.240 | who's expert in this area once so aptly said,

01:40:37.340 | "Better living through chemistry

01:40:38.840 | still requires better living."

01:40:40.900 | Thank you for joining me for today's discussion

01:40:42.700 | about ketamine.

01:40:43.900 | If you're learning from and/or enjoying this podcast,

01:40:46.120 | please subscribe to our YouTube channel.

01:40:47.860 | That's a terrific zero-cost way to support us.

01:40:50.540 | In addition, please subscribe to the podcast

01:40:52.720 | on both Spotify and Apple.

01:40:54.400 | And on both Spotify and Apple,

01:40:55.720 | you can leave us up to a five-star review.

01:40:57.960 | If you have questions for me or comments about the podcast

01:41:00.280 | or guests that you'd like me to consider hosting

01:41:02.300 | on the Huberman Lab Podcast,

01:41:03.740 | please put those in the comments section on YouTube.

01:41:05.860 | I do read all the comments.

01:41:07.860 | Please also check out the sponsors mentioned

01:41:09.600 | at the beginning and throughout today's episode.

01:41:11.600 | That's the best way to support this podcast.

01:41:13.880 | Not on today's podcast,

01:41:15.000 | but on many previous episodes of the Huberman Lab Podcast,

01:41:17.340 | we discussed supplements.

01:41:18.360 | While supplements aren't necessary for everybody,

01:41:20.420 | many people derive tremendous benefit from them

01:41:22.360 | for things like sleep support, hormone support,

01:41:24.800 | and improving focus.

01:41:26.280 | The Huberman Lab Podcast

01:41:27.320 | has partnered with Momentous Supplements.

01:41:28.960 | If you'd like to learn more about the supplements

01:41:30.560 | discussed on the Huberman Lab Podcast,

01:41:32.380 | you can go to Live Momentous, spelled O-U-S,

01:41:34.460 | so it's livemomentous.com/huberman.

01:41:37.200 | If you're not already following me on social media,

01:41:39.200 | I am @hubermanlab on all platforms.

01:41:41.160 | So Instagram, Twitter, Threads, Facebook, and LinkedIn.

01:41:45.300 | And on all of those platforms,

01:41:46.560 | I cover science and science-based tools,

01:41:48.280 | some of which overlap with the content

01:41:49.720 | of the Huberman Lab Podcast,

01:41:50.840 | but much of which is distinct from the content

01:41:52.940 | of the Huberman Lab Podcast.

01:41:54.000 | So again, it's Huberman Lab on all social media platforms.

01:41:57.160 | If you haven't already subscribed

01:41:58.260 | to our neural network newsletter,

01:41:59.480 | our neural network newsletter is a free monthly newsletter

01:42:02.320 | that includes podcast summaries and protocols

01:42:04.560 | in the form of brief one to three page PDFs.

01:42:07.560 | Those protocols include things like a toolkit

01:42:09.480 | to enhance the quality and duration of your sleep,

01:42:12.160 | toolkits to improve learning and neuroplasticity,

01:42:14.400 | toolkits for deliberate cold exposure,

01:42:16.120 | exercise, focus, dopamine, and on and on.

01:42:19.040 | To sign up for the neural network newsletter,

01:42:20.600 | you simply go to HubermanLab.com,

01:42:22.240 | go to the menu, scroll down to newsletter.

01:42:24.400 | You sign up using your email,

01:42:25.580 | but I want to emphasize that we do not share your email

01:42:27.880 | with anybody.

01:42:29.040 | Thank you once again for joining me for today's discussion.

01:42:31.560 | And last, but certainly not least,

01:42:33.680 | thank you for your interest in science.

01:42:35.480 | (upbeat music)

01:42:38.060 | (upbeat music)

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

Chapters