How Ketamine Works & Its Potential for Depression Relief

00:00:00.000 | [silence]

00:00:02.520 | We've all heard of the opioid crisis by now,

00:00:04.600 | or at least most of you have.

00:00:06.520 | The opioid crisis refers specifically

00:00:08.800 | to people taking exogenous opioids, taking opioids, right?

00:00:12.140 | So taking pills that activate particular receptors

00:00:14.840 | in the brain that lead to analgesia in some cases,

00:00:18.800 | so pain relief that lead to changes in mood.

00:00:21.680 | There's a lot to be said about the opioid crisis.

00:00:24.480 | It's called a crisis for a reason.

00:00:27.120 | Many, many people are addicted to those compounds.

00:00:30.400 | That's a discussion for another time.

00:00:32.840 | Keep in mind that the receptors those drugs bind to

00:00:35.180 | are opioid receptors.

00:00:36.880 | And those receptors that you and I all have, by the way,

00:00:40.400 | do not exist in order to bind drugs

00:00:42.180 | that are made by pharmaceutical companies.

00:00:44.160 | They exist in our brain and body

00:00:46.000 | to bind to the so-called endogenous,

00:00:48.080 | naturally made opioids that we all make.

00:00:50.640 | And those receptors have different names.

00:00:52.120 | The mu-opioid receptor, the kappa-opioid receptor, et cetera.

00:00:55.840 | They tend to have the names of Greek letters

00:00:57.880 | to differentiate them.

00:00:59.800 | Now, ketamine can bind to various opioid receptors.

00:01:04.800 | And when opioid receptors are bound,

00:01:08.180 | we know that creates certain effects,

00:01:10.600 | things like pain relief,

00:01:12.440 | things like changes in psychic states,

00:01:15.120 | dissociation, for example.

00:01:17.120 | If enough of them are bound, you can get euphoric states.

00:01:19.340 | Under certain conditions of high dose binding of ketamine

00:01:23.480 | to those opioid receptors,

00:01:25.000 | you can start getting into planes of anesthesia

00:01:28.140 | where people lose consciousness

00:01:29.520 | and actually have no response to pain whatsoever.

00:01:32.120 | If you recall the clinical studies we talked about earlier

00:01:34.960 | where ketamine was used to relieve depression,

00:01:38.440 | well, the dosage used in that study, as you recall,

00:01:41.620 | was half a milligram per kilogram of body weight.

00:01:44.940 | That is the dosage that will induce these dissociative,

00:01:48.140 | mild euphoria, those sorts of states of mind,

00:01:51.600 | but where people are still conscious.

00:01:53.760 | When you start getting to dosages of ketamine

00:01:55.700 | that are in the range of one to two milligrams

00:01:57.840 | per kilogram of body weight,

00:01:59.200 | now you're talking about anesthetic doses.

00:02:02.200 | And when that happens, you're going to get full parking,

00:02:06.080 | full saturation of all the potential receptors

00:02:09.520 | that ketamine can bind to.

00:02:10.520 | Those NMDA receptors, it's going to block those.

00:02:13.080 | It's also going to bind

00:02:13.920 | to the so-called mu-opioid receptors,

00:02:16.240 | and maybe this other type as well,

00:02:17.660 | for those of you that want to know, uficionados,

00:02:19.640 | also the kappa-type opioid receptors.

00:02:22.200 | And so what we've got here is a drug, ketamine,

00:02:25.480 | that is hitting two different systems,

00:02:27.160 | the glutamate-related system

00:02:29.200 | and the endogenous opioid system.

00:02:32.880 | And researchers and clinicians

00:02:34.320 | have logically started to ask whether or not

00:02:37.000 | some or all of the effects of ketamine

00:02:39.120 | are due to the opioid system,

00:02:41.720 | and they want to know which effects those are.

00:02:43.760 | Now, this is where things start to get really interesting,

00:02:45.880 | both in the context of clinical treatment of depression

00:02:48.280 | and recreational use.

00:02:50.320 | First of all, when people take ketamine,

00:02:54.280 | again, it enters the bloodstream and it goes into the brain,

00:02:57.280 | but it is metabolized to something called HNK,

00:03:00.700 | which is hydroxynorketamine.

00:03:03.360 | Now, I don't expect you to know

00:03:04.440 | what hydroxynorketamine is,

00:03:06.080 | and I don't expect you to care about it

00:03:07.600 | until I tell you what I'm about to tell you,

00:03:09.560 | which is that hydroxynorketamine

00:03:12.520 | has an incredible specificity for the mu-opioid receptor,

00:03:17.400 | and maybe that kappa-opioid receptor as well.

00:03:19.960 | In other words, when we talk about ketamine,

00:03:21.800 | that's the drug people take,

00:03:23.480 | but when it goes into the body,

00:03:24.920 | it's converted into yet another drug,

00:03:27.520 | and that other drug, hydroxynorketamine,

00:03:29.780 | is selectively activating the opioid system.

00:03:32.920 | So this led researchers to ask it a very important question,

00:03:36.260 | which is when a human being takes ketamine

00:03:39.000 | in order to treat their depression

00:03:41.080 | and they get some relief from depression,

00:03:42.680 | is that the consequence of neuroplastic changes

00:03:45.300 | and all those NMDA, glutamate, BDNF-related circuits

00:03:48.040 | that we talked about before?

00:03:49.580 | Or is it the consequence of something happening

00:03:51.420 | in the opioid system?

00:03:52.920 | You can't ignore the fact that ketamine has this property

00:03:56.600 | of binding to these opioid receptors

00:03:58.720 | because they have such a powerful effect on our thinking,

00:04:01.640 | on our mood, on our state of consciousness.

00:04:04.480 | It's entirely reasonable that the opioid system

00:04:07.000 | could be a major player, if not the major player,

00:04:10.200 | in this whole depression relief thing,

00:04:12.160 | and maybe even in the creation of dissociative symptomology

00:04:15.160 | when people take ketamine recreationally.

00:04:17.280 | So what researchers/clinicians did

00:04:20.260 | is they undertook a series of experiments

00:04:22.860 | where they gave people ketamine

00:04:24.180 | for the relief of depression,

00:04:25.820 | but they also blocked the opioid receptor system.

00:04:28.880 | And they did that using a drug called naltrexone.

00:04:31.740 | So what I'm about to describe to you

00:04:33.100 | is a study done by my colleagues

00:04:34.580 | at Stanford School of Medicine,

00:04:36.260 | namely Dr. Nolan Williams and Alan Schatzberg

00:04:39.500 | and colleagues, entitled "Attenuation of Antidepressant

00:04:43.180 | and Antisuicidal Effects of Ketamine

00:04:45.580 | by Opioid Receptor Antagonism."

00:04:48.080 | And as a consequence of me reading you

00:04:49.400 | that title a moment ago,

00:04:50.800 | you now already have the conclusion of the study.

00:04:54.680 | What they observed is that when people were given ketamine,

00:04:56.680 | they got relief from depression.

00:04:57.920 | That wasn't surprising.

00:04:58.880 | Again, many studies had shown that before,

00:05:00.700 | since the early 2000s.

00:05:03.060 | If, however, individuals were given naltrexone

00:05:05.800 | to block the opioid receptor pathway,

00:05:08.360 | and they were given ketamine,

00:05:10.680 | well, then the antidepressant effects of ketamine

00:05:12.880 | were no longer observed.

00:05:14.560 | Now, that suggests that it is the opioid receptor system

00:05:18.000 | that's responsible for the antidepressant effects

00:05:21.620 | of ketamine.

00:05:22.460 | And perhaps this HNK, this hydroxynorketamine,

00:05:25.520 | which is the metabolite of ketamine,

00:05:27.400 | is the way in which ketamine normally relieves depression.

00:05:31.280 | Now, a lot of people took note of these studies

00:05:34.200 | because after all, there are probably dozens,

00:05:37.660 | if not hundreds of studies looking at the effects

00:05:39.440 | of ketamine on all that NMDA receptor stuff.

00:05:42.120 | And indeed, neuroplasticity and mood-related circuits

00:05:45.160 | can't be discounted as one way in which ketamine

00:05:48.880 | provides relief from depression.

00:05:51.360 | But what was very interesting is that in people given

00:05:54.760 | ketamine and naltrexone,

00:05:57.200 | those people still experienced the immediate effects

00:05:59.960 | of ketamine, the mild euphoria, the dissociation,

00:06:03.480 | the feelings that one would normally expect

00:06:05.560 | when people were under the effects of ketamine.

00:06:08.120 | But what they didn't get were the longer term changes

00:06:11.880 | in mood that we would call relief from depression.

00:06:15.400 | Now, of course, the goal of modern psychiatry

00:06:17.440 | is to treat depression, not to block the effects

00:06:20.120 | of these drugs that are capable of treating depression.

00:06:22.520 | Now, what this study does, and by the way,

00:06:23.860 | there are several studies like it

00:06:25.440 | that support these general set of findings

00:06:27.400 | that part of the critical role of ketamine

00:06:30.040 | in providing relief from depression

00:06:31.600 | is to activate the opioid system.

00:06:33.460 | But what this study does is it really points to the fact

00:06:35.600 | that when we say ketamine treatment,

00:06:37.320 | or we talk about somebody taking ketamine recreationally,

00:06:40.000 | for that matter, we have to pay attention

00:06:42.000 | to what's happening while they are under the influence

00:06:43.740 | of the drug.

00:06:45.280 | We also have to pay attention to what's happening

00:06:47.000 | in the days and weeks after they're under the influence

00:06:49.280 | of the drug.

00:06:50.120 | And perhaps most importantly, this calls to mind

00:06:53.040 | a really important idea, which is that whether or not

00:06:55.520 | you're talking about ketamine induced relief

00:06:57.140 | from depression, or psilocybin induced relief

00:07:00.360 | for depression, or MDMA induced relief for PTSD,

00:07:03.440 | a topic that I covered on a previous episode

00:07:05.400 | of this podcast, we have to step back

00:07:08.640 | and look at the idea that the effects of the drug

00:07:11.680 | that people experience, whatever those may be,

00:07:14.560 | because obviously it's going to depend

00:07:15.940 | on what particular drug they took,

00:07:18.500 | those immediate effects may not actually be related

00:07:22.000 | to the long-term clinical benefit

00:07:23.800 | of those particular drugs.

00:07:25.760 | Now, I realize that many people might not like that idea.

00:07:28.040 | And frankly, I don't actually think

00:07:29.640 | that's the way that it works.

00:07:30.600 | I don't think it's going to be an either or situation.

00:07:32.920 | However, because drugs like ketamine, psilocybin, MDMA

00:07:37.120 | have such profound effects on people's psychic states

00:07:40.320 | when they are under the influence of them.

00:07:42.040 | And because at least in the proper clinical setting and use,

00:07:45.600 | they do seem to provide impressive relief

00:07:47.840 | from a lot of these psychiatric challenges

00:07:50.500 | like depression and PTSD.

00:07:52.720 | People naturally correlate those two things.

00:07:55.360 | They couple those two things.

00:07:56.480 | In fact, they collapse those two things

00:07:59.160 | and presume that their experience of what they saw,

00:08:02.240 | what they heard, how they felt

00:08:03.640 | while they were under the influence of the drug

00:08:05.680 | was actually the stimulus that created the relief

00:08:08.900 | from their clinical condition like depression.

00:08:11.920 | But what these data on combined treatment

00:08:14.720 | with ketamine and naltrexone

00:08:16.320 | to block the mu opioid receptor really show us

00:08:19.480 | is that that may not actually be the way that it works.

00:08:22.640 | It may be that the effects of a drug like ketamine

00:08:25.520 | that one experiences, while interesting,

00:08:27.800 | perhaps even profound, perhaps great insight comes to one

00:08:31.120 | when they do that therapy in the proper context,

00:08:34.900 | it is not clear at all that it is that experience

00:08:38.160 | and the effects of those drugs

00:08:39.560 | in those immediate minutes and hours

00:08:41.600 | that's actually what's causing the relief from depression.

00:08:45.480 | Now, again, I don't think it's an either or.

00:08:48.400 | I like to view the whole situation more or less

00:08:50.840 | as a sort of wave front

00:08:52.760 | that the experience that one has subjectively

00:08:55.900 | while they are under the influence of a drug

00:08:57.600 | like ketamine or psilocybin or MDMA sets off a series.

00:09:01.400 | And in fact, multiple series, is that a word?

00:09:05.100 | Multiple types of processes in the brain,

00:09:08.660 | some of which rely on things like NMDA receptor,

00:09:11.500 | BDNF, et cetera, type neuroplasticity,

00:09:14.300 | others which rely on the opioid receptor pathway.

00:09:17.380 | And that each of these have different time courses

00:09:20.260 | such that some provide immediate relief

00:09:22.800 | in the days and hours after treatment,

00:09:24.460 | some in the weeks after treatment,

00:09:26.540 | and some more durable, long-lasting changes

00:09:29.260 | that can occur over months or maybe even years.

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How Ketamine Works & Its Potential for Depression Relief | Dr. Andrew Huberman

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