The Science of MDMA & Its Therapeutic Uses: Benefits & Risks

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

00:00:02.280 | where we discuss science and science-based tools

00:00:04.880 | for everyday life.

00:00:05.900 | I'm Andrew Huberman,

00:00:10.160 | and I'm a professor of neurobiology and ophthalmology

00:00:13.120 | at Stanford School of Medicine.

00:00:15.160 | Today, we are discussing MDMA,

00:00:17.620 | sometimes referred to as ecstasy or molly.

00:00:20.960 | MDMA stands for methylenedioxymethamphetamine.

00:00:24.540 | That's right, you heard the word methamphetamine in there.

00:00:27.560 | And MDMA has properties similar to methamphetamine,

00:00:30.840 | but also properties that are very distinct

00:00:33.460 | from methamphetamine.

00:00:35.160 | Just as a side note,

00:00:36.160 | methamphetamine is a commonly used drug of abuse.

00:00:40.300 | It is an illicit drug,

00:00:42.080 | and it produces some of the greatest and fastest increases

00:00:45.520 | in the neuromodulator dopamine

00:00:47.640 | of any available drugs on the street or in the clinic.

00:00:50.800 | And believe it or not,

00:00:51.640 | methamphetamine is prescribed as a prescription drug

00:00:54.360 | in some very limited clinical uses.

00:00:57.480 | MDMA, methylenedioxymethamphetamine,

00:01:00.440 | has properties similar to methamphetamine

00:01:02.900 | in that it powerfully promotes the release of dopamine,

00:01:07.060 | and it is a stimulant.

00:01:09.080 | And yet it also powerfully controls the release of serotonin,

00:01:13.160 | and in doing so, makes MDMA a distinct category of compound

00:01:18.160 | from either classic psychedelics like psilocybin or LSD,

00:01:23.240 | which largely work on the serotonin system,

00:01:25.800 | and tend to produce mystical experiences.

00:01:28.960 | And it's also distinct from pure stimulants

00:01:31.680 | such as methamphetamine,

00:01:33.580 | because MDMA, by producing big increases

00:01:36.720 | in both dopamine and serotonin,

00:01:39.740 | acts as what's called an empathogen.

00:01:42.080 | It actually can increase one's sense of social connectedness

00:01:45.660 | and empathy, not just for other people, but for oneself.

00:01:49.520 | And in that way, MDMA is commonly used

00:01:52.700 | as a recreational drug,

00:01:54.440 | but also is now being tested

00:01:56.740 | and is achieving incredible early results in clinical trials

00:02:01.000 | for its use as an empathogen for the treatment of PTSD

00:02:04.840 | in clinical therapeutic settings.

00:02:07.120 | I want to be very clear that at this point in time,

00:02:09.680 | June, 2023, MDMA is still a schedule one drug.

00:02:14.520 | That is, it is highly illegal to possess or sell

00:02:18.000 | in the United States.

00:02:19.700 | And today we are going to talk about

00:02:21.460 | some of the path to legality that's underway.

00:02:24.480 | We are also going to talk about the history of MDMA

00:02:26.920 | and why it became illegal.

00:02:28.800 | And we are going to talk about the key difference

00:02:31.040 | between recreational use and therapeutic use

00:02:33.740 | and the important components of the studies exploring MDMA

00:02:37.560 | in the clinical setting for the treatment of PTSD.

00:02:40.240 | So during today's discussion,

00:02:41.420 | we will talk about what MDMA really is,

00:02:44.100 | how it works at the level of neurons,

00:02:46.220 | which brain circuits it activates and deactivates.

00:02:50.500 | And in doing so, you will come to understand

00:02:52.240 | why it is so exciting as a treatment for PTSD.

00:02:55.060 | We will also, of course, talk about the results

00:02:57.200 | of these clinical trials using MDMA

00:03:00.120 | for the treatment of PTSD.

00:03:01.820 | They are incredibly exciting.

00:03:03.600 | In fact, the field of psychiatry has never before seen

00:03:06.800 | the kind of success in treatment of PTSD

00:03:09.680 | with any other compound that they are seeing and achieving

00:03:13.080 | with the appropriate safe use of MDMA.

00:03:17.040 | And when I say appropriate,

00:03:18.120 | that means in conjunction with nine therapy sessions.

00:03:21.740 | So this is an area that really deserves some time

00:03:24.260 | for us to discuss because again,

00:03:26.040 | there is a distinct difference between the recreational

00:03:28.300 | and the therapeutic use of MDMA.

00:03:30.060 | We will also talk about the toxicity of MDMA.

00:03:32.720 | This is a very important issue

00:03:35.500 | because many of you have perhaps heard that MDMA,

00:03:37.980 | quote unquote, puts holes in your brain

00:03:40.100 | or kills serotonin neurons or kills dopamine neurons.

00:03:43.340 | And indeed MDMA, because of its similarity

00:03:46.620 | to methamphetamine, which is highly neurotoxic,

00:03:49.420 | MDMA can be neurotoxic.

00:03:51.780 | However, there are ways to use MDMA therapeutically

00:03:56.660 | that avoid its toxicity.

00:03:58.220 | And yet there are still questions about its toxicity

00:04:02.080 | and its long-term effects, both after acute use,

00:04:04.380 | meaning just one to three times, as well as chronic use,

00:04:07.940 | meaning people who have taken it many, many times.

00:04:10.160 | We'll talk about the spacing between sessions of MDMA.

00:04:12.340 | We will talk about dosages.

00:04:13.820 | We will also talk about things that people do

00:04:16.520 | and that can be done to offset

00:04:18.600 | some of the potential toxicity of MDMA.

00:04:21.220 | So by the end of today's discussion,

00:04:23.540 | you will have a thorough understanding of what MDMA is,

00:04:26.500 | what it isn't, what is known about what it does,

00:04:30.080 | what is known about what it doesn't do,

00:04:32.160 | as well as some of the still outstanding questions

00:04:35.120 | about MDMA that remain to be resolved.

00:04:37.620 | Before we begin, I'd like to emphasize that this podcast

00:04:40.380 | is separate from my teaching and research roles at Stanford.

00:04:43.020 | It is, however, part of my desire and effort

00:04:44.980 | to bring zero cost to consumer information about science

00:04:47.640 | and science-related tools to the general public.

00:04:50.280 | In keeping with that theme,

00:04:51.400 | I'd like to thank the sponsors of today's podcast.

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00:08:18.760 | Let's talk about MDMA.

00:08:20.260 | MDMA, or ecstasy, is a fascinating compound.

00:08:24.420 | And I say fascinating from the perspective

00:08:26.860 | of its chemical structure, which is highly unusual.

00:08:30.380 | I say fascinating because it has an incredible set

00:08:32.840 | of subjective effects in terms of how it makes people feel,

00:08:36.440 | and it has a fascinating history.

00:08:38.140 | So let's just briefly start with the history of MDMA.

00:08:40.380 | MDMA was synthesized by the drug company Merck

00:08:43.400 | in the early 1900s, but it actually was never applied

00:08:46.340 | to any particular clinical use,

00:08:48.500 | and it wasn't really explored much

00:08:49.820 | in any laboratories at all.

00:08:51.700 | And then it was later rediscovered

00:08:54.220 | by a guy named Alexander Schulgen,

00:08:56.820 | who was a bit of a renegade drug chemist,

00:08:59.820 | who was designing different drugs

00:09:02.500 | for the purpose of understanding

00:09:03.900 | their subjective effects on humans.

00:09:06.180 | So there's a long history of Schulgen designing drugs.

00:09:09.580 | He was, after all, a chemist.

00:09:11.500 | And then taking those drugs himself,

00:09:14.020 | and then if he liked the effects of a particular drug,

00:09:17.580 | or rather, if he thought

00:09:18.900 | that it had potential clinical utility,

00:09:21.820 | he would give it to his wife.

00:09:23.480 | Then she would give him her notes about those drugs,

00:09:26.420 | and then they would share them with their friends.

00:09:28.360 | And it was a small group of friends

00:09:29.960 | who consisted of therapists and physicians.

00:09:33.540 | So this was a really underground kind of operation.

00:09:37.000 | It was technically not illegal when it started,

00:09:40.000 | because MDMA wasn't illegal when it started,

00:09:42.420 | but over the several decades

00:09:44.820 | that Schulgen and his wife and this group

00:09:46.900 | were doing this kind of exploration,

00:09:48.580 | MDMA did become illegal,

00:09:51.100 | and he fell under, let's just say, scrutiny by the DEA.

00:09:55.580 | Now, here's the important thing to understand

00:09:57.260 | about MDMA and its history.

00:09:59.300 | First of all, MDMA is a synthetic compound.

00:10:02.940 | As far as we know, it does not exist anywhere in nature.

00:10:06.260 | So unlike similar compounds, such as mescaline,

00:10:09.340 | because MDMA and mescaline are very similar

00:10:12.060 | in their chemical properties,

00:10:13.380 | and to some extent, their subjective properties,

00:10:16.480 | unlike mescaline, which can be found in the plant kingdom,

00:10:19.680 | or LSD, which comes from ergot,

00:10:22.220 | or psilocybin, which of course

00:10:23.500 | can be found in magic mushrooms,

00:10:24.980 | MDMA is a unique chemical in that,

00:10:27.540 | again, as far as we know, only exists in its synthetic form.

00:10:31.540 | It is human-made.

00:10:33.580 | And as we get into the chemical effects

00:10:35.440 | and the subjective effects of MDMA

00:10:37.180 | a little bit later in the episode,

00:10:38.820 | I think you'll understand why it is such a unique

00:10:41.620 | and to some extent exciting compound

00:10:43.640 | from the perspective of clinical treatment.

00:10:45.880 | Put differently, there's really no other compound

00:10:47.980 | that we know of in nature

00:10:49.940 | or in the pharmaceutical industry shelf

00:10:54.040 | or options of drugs that are prescription drugs

00:10:57.240 | that produce the kinds of effects that MDMA does.

00:11:00.260 | And by the way, if you're interested

00:11:01.700 | in the story of Alexander Shulgin

00:11:03.820 | and the drugs he synthesized

00:11:05.820 | and the group that he built up to take these drugs

00:11:08.640 | and try them and actually had several members of this group

00:11:12.140 | using these drugs in therapy with their patients

00:11:15.540 | for a long period of time,

00:11:16.540 | both before and after MDMA became illegal.

00:11:20.520 | There's a wonderful book called PIKAL.

00:11:23.080 | That stands for P-I-K-H-A-L.

00:11:26.220 | PIKAL is the title of the book which Shulgin wrote,

00:11:30.140 | which describes his discovery of MDMA.

00:11:32.900 | I confess it also describes the synthesis of MDMA.

00:11:36.220 | And for that reason was a book that for a long time

00:11:38.120 | was not available, but is now available again

00:11:40.840 | in audible form and in printed form.

00:11:44.340 | PIKAL stands for phenylethylamines, I have known and loved.

00:11:48.980 | Phenylethylamines is the category of drug

00:11:51.500 | for which MDMA belongs to.

00:11:53.740 | And it's a long book, but a very interesting one

00:11:56.780 | both from the perspective of understanding

00:11:58.580 | the history of MDMA and what MDMA is

00:12:01.380 | and the effects that it produces.

00:12:03.680 | But it's also an interesting book

00:12:04.860 | because it will teach you a lot

00:12:06.060 | about the history of the pharmaceutical industry,

00:12:08.420 | the war on drugs in the United States

00:12:10.380 | and the interaction between illegal drug exploration

00:12:14.420 | and drugs for clinical treatment of psychiatric challenges.

00:12:19.380 | So right now this is a very important issue

00:12:21.940 | because MDMA is currently granted breakthrough status,

00:12:26.680 | which means it's now something that scientists

00:12:29.640 | and clinicians can study

00:12:31.540 | if they have authorization to do that.

00:12:33.300 | It is, as I mentioned earlier, still a schedule one drug,

00:12:35.680 | so it's illegal to possess

00:12:37.300 | unless you are one of these scientists

00:12:38.640 | who has been granted permission to study it

00:12:41.280 | in the clinical setting or the laboratory setting.

00:12:43.660 | And right now we are on the cusp of MDMA becoming legal,

00:12:47.980 | but again, it is not yet legal.

00:12:50.100 | And this is something I'm going to touch back on

00:12:51.840 | a few times during today's episode.

00:12:54.440 | Later, for instance, when we talk about

00:12:56.700 | the potential toxicity of MDMA,

00:12:58.800 | its ability potentially to kill neurons,

00:13:01.960 | and the neurons it has been hypothesized to kill

00:13:05.620 | are neurons of the serotonin and dopamine type,

00:13:08.240 | so this is something you would not want.

00:13:09.740 | Let's just recall that killing off of

00:13:12.100 | or death of dopamine neurons

00:13:13.940 | is the underlying basis for Parkinson's disease,

00:13:16.940 | which is a movement disorder

00:13:18.120 | where people have difficulty generating smooth movements

00:13:20.800 | and in very severe form, they can't move at all.

00:13:24.420 | They sort of become locked in to some extent,

00:13:26.540 | and it also has cognitive effects,

00:13:28.180 | so you don't want to lose dopamine neurons,

00:13:29.980 | and loss of serotonergic neurons

00:13:31.660 | is known to impact mood negatively,

00:13:34.180 | mood regulation negatively, et cetera.

00:13:36.420 | The story of MDMA and its potential neurotoxicity

00:13:41.000 | comes slam right up against this issue of legality,

00:13:44.980 | and what we'll get into a little bit later is that

00:13:46.920 | there has been a sort of race in the scientific community

00:13:49.500 | consisting of two groups,

00:13:52.080 | one set of groups trying to establish the toxicity of MDMA

00:13:56.920 | so that it does not become legal again,

00:13:59.960 | and another group trying to establish the utility

00:14:03.160 | and the lack of toxicity in MDMA

00:14:05.220 | so that it does become legal again

00:14:07.020 | for the treatment of PTSD.

00:14:08.720 | So even though the story, PCAL,

00:14:11.560 | relates to events that took place

00:14:13.260 | largely in the 1970s, '80s, and '90s,

00:14:15.780 | right now MDMA and its toxicity or lack of toxicity,

00:14:21.880 | its legality or lack of legality are really key issues.

00:14:26.100 | So as you're listening to this,

00:14:27.600 | I'm giving you a real-time blow-by-blow

00:14:30.360 | of what led up to where we are now,

00:14:32.620 | but we will also want to think about

00:14:34.620 | how what's happening right now,

00:14:36.520 | including the description of these data on MDMA,

00:14:40.360 | may or may not impact the potential legal status of MDMA.

00:14:45.100 | Okay, so what is MDMA?

00:14:47.460 | MDMA is 3,4-methylenedioxymethamphetamine,

00:14:50.920 | but unless you're a chemist,

00:14:52.640 | that's not going to mean much to you, nor should it.

00:14:55.560 | MDMA has some very interesting properties,

00:14:58.520 | the first of which is that methamphetamine component,

00:15:01.640 | which, because it's a methamphetamine

00:15:04.400 | and acts like other amphetamines,

00:15:06.760 | what it does is it blocks the reuptake of dopamine

00:15:10.080 | from neurons after dopamine is released.

00:15:12.220 | So for those of you that heard the episode

00:15:13.840 | that I did on drugs to treat ADHD,

00:15:16.640 | I discussed the biology and mechanisms

00:15:18.660 | of drugs like Adderall and Vyvanse,

00:15:21.320 | which basically are either combinations of amphetamines

00:15:25.040 | or single types of amphetamines

00:15:27.380 | that have either a quick release or a long release.

00:15:30.360 | Now, MDMA, because it has this methamphetamine component,

00:15:35.360 | prevents the reuptake of dopamine,

00:15:37.900 | and in doing so, creates net increases in dopamine.

00:15:42.220 | So for those of you that don't have a background

00:15:43.940 | in neurobiology, let me just briefly explain.

00:15:45.740 | I'll make this very simple.

00:15:47.000 | Neurons or nerve cells release chemicals

00:15:50.360 | at their sites of communication, which are called synapses.

00:15:53.620 | Synapses are little gaps between neurons,

00:15:56.240 | and what happens is the neurons spit out

00:15:58.780 | these little spherical balls,

00:16:01.960 | which we call vesicles or vesicles,

00:16:04.040 | depending on where in the world you live.

00:16:05.240 | They'll either be called vesicles or vesicles,

00:16:07.600 | and those little vesicles contain neurotransmitter

00:16:09.740 | or what's technically referred to as a neuromodulator.

00:16:13.080 | Dopamine is a neuromodulator.

00:16:14.360 | It can modulate the activity of other neurons.

00:16:16.380 | It can either increase or decrease

00:16:18.100 | the activity of other neurons.

00:16:19.900 | Now, at the end of the neuron,

00:16:22.020 | what we call the axonal bouton, okay?

00:16:24.580 | Axon is kind of the wire component of the neuron

00:16:26.580 | that can reach to another site in the brain

00:16:28.420 | and then release the neurotransmitter

00:16:30.420 | or neuromodulator there.

00:16:31.660 | At those axonal boutons, which are the sites of release,

00:16:35.300 | the vesicles literally fuse with the edge of the neuron

00:16:39.060 | and vomit their neuromodulator out into the synapse,

00:16:43.060 | and then the neuromodulator, in this case,

00:16:45.140 | dopamine will bind to receptors on the postsynaptic side,

00:16:48.180 | that means to another neuron,

00:16:49.540 | and then depending on how much binds

00:16:51.580 | and depending on what else is going on

00:16:53.900 | in that local neighborhood of neuronal connections,

00:16:57.140 | the neuron will either increase its neural activity

00:16:59.780 | and itself release neuromodulator

00:17:02.420 | or neurotransmitter someplace else,

00:17:04.140 | so sort of a chain reaction,

00:17:05.780 | or else it will suppress its activity

00:17:08.140 | and the flow of communication from one neuron

00:17:10.860 | to the next will be stopped, okay?

00:17:13.020 | So MDMA doesn't prevent the release

00:17:15.340 | of dopamine at the synapse, it does quite the opposite.

00:17:18.340 | It actually prevents the sucking up

00:17:21.540 | of the dopamine that's been released

00:17:23.580 | and that does not bind to the receptors.

00:17:26.020 | So basically what it does is it blocks these things

00:17:28.180 | called dopamine transporters,

00:17:29.940 | and the transporters are the things that suck back up

00:17:33.300 | the dopamine that's been released

00:17:34.540 | that has not bound to receptors.

00:17:36.760 | So because it blocks that sucking up process,

00:17:40.580 | there's more dopamine around in the synapse

00:17:43.180 | to hang out and then bind to receptors

00:17:45.260 | once some become available, okay?

00:17:47.420 | The other thing that the methamphetamine component

00:17:50.220 | of MDMA does, just like methamphetamine,

00:17:53.180 | is that it actually gets into

00:17:55.580 | what we call the presynaptic neuron,

00:17:56.900 | the neuron that releases the dopamine,

00:17:58.940 | and it interferes with the repackaging

00:18:01.700 | of dopamine into those vesicles.

00:18:04.100 | Now you might think, oh, it interferes

00:18:05.340 | with the repackaging of dopamine into vesicles

00:18:07.460 | and therefore less will be released,

00:18:09.420 | but actually what happens is as a consequence of that,

00:18:13.020 | a bunch of dopamine builds up in the presynaptic neuron

00:18:15.940 | so that when an electrical impulse comes down that neuron

00:18:19.540 | and dopamine is released,

00:18:20.740 | a huge amount of dopamine is released.

00:18:23.260 | And this is one of the characteristic properties

00:18:25.460 | of methamphetamine and of MDMA,

00:18:28.400 | which is that it leads to enormous increases

00:18:31.260 | in the amount of dopamine released

00:18:33.300 | and the amount of dopamine that hangs around in the synapse

00:18:36.300 | and therefore it increases what we call dopaminergic tone

00:18:39.460 | or dopaminergic drive.

00:18:40.620 | That's just a bunch of different ways

00:18:42.040 | to describe increases in dopamine.

00:18:44.500 | Okay, so that's the main way that MDMA,

00:18:48.440 | and by extension methamphetamine, increase dopamine.

00:18:52.500 | However, MDMA is not just methamphetamine,

00:18:55.460 | it's methylenedioxymethamphetamine,

00:18:57.260 | and it has another incredible property,

00:18:59.820 | which is that it doesn't just lead

00:19:02.180 | to huge increases in dopamine,

00:19:03.780 | it also leads to huge increases in serotonin.

00:19:06.740 | And that's because there are other neurons

00:19:09.020 | that release serotonin and they have serotonin transporters,

00:19:13.020 | which are sometimes called Serts, S-E-R-T-S,

00:19:15.860 | serotonin transporters,

00:19:17.060 | and they work very much in the same way

00:19:18.860 | that dopamine transporters do, right?

00:19:20.620 | They basically control the sucking back up of serotonin

00:19:24.480 | that's been released into the synapse

00:19:26.940 | and that has not bound to serotonin receptors

00:19:31.700 | on the other neurons yet,

00:19:33.420 | and in doing so, allow more serotonin to hang out

00:19:37.080 | and have its effects as those receptors become available

00:19:40.380 | for serotonin to bind to them.

00:19:42.180 | The other thing MDMA does is it also gets

00:19:44.700 | into the presynaptic neuron to impact the packaging

00:19:48.340 | of serotonin into something called

00:19:51.180 | the vesicle monoamine transporter for serotonin.

00:19:54.740 | And in doing so, it leads to a big buildup of serotonin

00:19:57.740 | in the presynaptic terminals

00:19:58.940 | and then massive increases in serotonin release.

00:20:01.940 | Okay, so what we've got with MDMA

00:20:03.980 | is a really interesting compound.

00:20:06.100 | Unlike methamphetamine or other amphetamines,

00:20:08.420 | such as Adderall, Vyvanse, et cetera,

00:20:10.420 | that cause increases in dopamine by blocking reuptake

00:20:14.460 | and increasing release of dopamine, MDMA does that,

00:20:17.580 | but it also does the same thing for serotonin.

00:20:20.020 | And here's a really key point.

00:20:21.760 | The increases in serotonin that MDMA creates

00:20:27.380 | are at least three times

00:20:29.220 | and maybe as much as eight times greater

00:20:32.180 | than the amount of dopamine release that MDMA causes.

00:20:37.180 | But when you put those two things together,

00:20:38.740 | what you basically have is a drug

00:20:40.060 | that causes huge increases in dopamine

00:20:42.900 | and even bigger increases in serotonin.

00:20:46.460 | And remember earlier when I said

00:20:48.340 | that MDMA is a purely synthetic compound,

00:20:50.740 | as far as we know, it does not exist in any plants

00:20:53.020 | or fungus or anything else in nature?

00:20:55.140 | Well, this is a very unusual circumstance

00:20:59.420 | of having big increases in dopamine

00:21:01.580 | and big increases in serotonin caused by the same compound.

00:21:05.740 | And that combination of big increases in dopamine

00:21:08.380 | and big increases in serotonin

00:21:10.480 | are what lead to these highly unusual

00:21:12.860 | and yet what seem to be potentially clinically

00:21:16.080 | very beneficial effects of having people feel

00:21:18.900 | a lot of mood elevation and a lot of stimulation

00:21:23.520 | from the stimulant properties of the methamphetamine

00:21:25.740 | component, so that's the dopamine effect.

00:21:28.260 | The dopaminergic tone goes way up.

00:21:30.440 | So it's a stimulant.

00:21:31.640 | People feel really alert.

00:21:32.940 | They feel like talking a lot.

00:21:34.660 | They feel very excited.

00:21:36.500 | They feel a lot of positive motivation.

00:21:39.980 | These are classic effects of drugs

00:21:41.560 | that promote the release of dopamine,

00:21:43.140 | including amphetamine, cocaine, et cetera.

00:21:45.940 | But ordinarily that's not such a good thing

00:21:48.900 | because what happens is there's then a crash

00:21:51.720 | in the dopamine levels

00:21:53.040 | and then people feel depressed.

00:21:54.260 | They feel lethargic.

00:21:56.140 | They don't feel good at all.

00:21:58.220 | MDMA seems to cause these increases in dopamine

00:22:01.420 | and all the accompanying effects I just described,

00:22:03.860 | but by also causing big increases in serotonin,

00:22:07.620 | it activates neural networks that are associated

00:22:11.180 | with feeling more socially connected.

00:22:13.980 | In fact, we'll talk about data in a little bit

00:22:15.660 | where people have had their brains imaged

00:22:18.120 | while under the influence of MDMA.

00:22:20.420 | And it's very clear that people who have taken MDMA

00:22:23.460 | look at faces that ordinarily they would rate as fearful

00:22:29.660 | and rate them as less fearful.

00:22:31.800 | They see faces that are smiling

00:22:33.740 | and they rate those smiling happy faces

00:22:35.960 | as more positive than they would off the drug.

00:22:39.560 | The big increases in serotonin

00:22:41.300 | create what we call a prosocial effect.

00:22:43.780 | And that combined with the dopaminergic increase in mood

00:22:47.800 | and the stimulation effect creates this thing

00:22:50.040 | that we call an empathogen where,

00:22:52.220 | and this is very important,

00:22:53.440 | the empathy isn't just for other people.

00:22:55.400 | It's also for oneself

00:22:57.080 | and one's own experiences happening in the moment,

00:22:59.860 | as well as empathy for experiences from the past,

00:23:03.480 | which as you can imagine could be very beneficial

00:23:05.940 | for the treatment of PTSD, okay?

00:23:07.780 | So hopefully the way I described the biology of MDMA

00:23:11.820 | makes some sense.

00:23:12.780 | If you didn't get anything out of the description

00:23:14.440 | I provided except the understanding that MDMA is unusual

00:23:18.720 | in that it causes big increases in dopamine

00:23:20.940 | and even bigger increases in serotonin

00:23:23.280 | then you have more in your knowledge base now

00:23:26.360 | about MDMA than you need

00:23:28.320 | in order to understand the rest of our discussion.

00:23:30.480 | Before we go any further,

00:23:32.140 | I do want to separate MDMA out from some other compounds

00:23:36.040 | which are referred to as psychedelics.

00:23:38.040 | And I recently did a podcast episode all about psilocybin

00:23:42.140 | and its therapeutic exploration

00:23:44.300 | and its chemical basis, et cetera.

00:23:46.960 | You can find that like all episodes at Hubermanlab.com.

00:23:49.640 | I also did an episode with expert guest,

00:23:52.120 | Dr. Robin Carthart-Harris,

00:23:54.160 | who's at University of California, San Francisco,

00:23:56.800 | who's pioneering a lot of the studies

00:23:58.420 | on the clinical application of psilocybin.

00:24:00.760 | Psilocybin and LSD

00:24:03.480 | are mainly going to increase

00:24:07.480 | serotonin activation in the brain.

00:24:10.560 | In fact, they very closely resemble serotonin itself

00:24:14.840 | and they activate what's called the 5-HT2A or serotonin,

00:24:19.040 | 5-HT just stands for serotonin,

00:24:20.540 | the 5-HT2A receptor

00:24:22.860 | to create very mystical type experiences.

00:24:25.640 | They are considered classic psychedelics

00:24:28.640 | and are very introspective.

00:24:30.060 | And as I described in those episodes

00:24:33.260 | are being explored extensively now

00:24:34.900 | for the treatment of major depression.

00:24:37.040 | A different compound that's being used

00:24:38.360 | for the treatment of depression is ketamine.

00:24:41.260 | I will do an entire episode all about ketamine.

00:24:43.360 | Ketamine is actually a N-methyl-D-aspartate receptor blocker,

00:24:48.040 | NMDA receptor blocker,

00:24:49.720 | that shouldn't mean anything to most of you,

00:24:51.680 | but it is a dissociative anesthetic, not unlike PCP,

00:24:55.600 | what used to be called angel dust on the street.

00:24:58.960 | Ketamine is being used as a treatment for depression.

00:25:01.880 | It is currently legal.

00:25:03.380 | So unlike psilocybin and LSD,

00:25:05.320 | which are granted breakthrough status

00:25:07.560 | for the study of depression, but are not yet legal,

00:25:11.040 | they are still illegal.

00:25:12.220 | And of course, as I mentioned earlier,

00:25:13.360 | MDMA has breakthrough status, but is still illegal.

00:25:17.360 | Ketamine is being used for the treatment of depression

00:25:20.240 | and it does so, as its name suggests,

00:25:22.760 | a dissociative anesthetic

00:25:24.300 | by creating a sense of dissociation from emotions, okay?

00:25:28.280 | Now I raised this distinction between psilocybin and LSD,

00:25:31.740 | which are mystical in their effects.

00:25:35.400 | Ketamine, which is dissociative in its effects,

00:25:38.280 | with MDMA, which is an empathogen

00:25:40.680 | or sometimes called an enactogen,

00:25:42.520 | but as an empathogen or an enactogen,

00:25:45.340 | it's creating more affiliation, it's affiliative, okay?

00:25:49.000 | So it's a very distinct compound.

00:25:51.420 | And I think this is important to understand

00:25:53.160 | because when we hear the word psychedelic,

00:25:55.080 | a lot of people tend to lump together

00:25:57.700 | LSD, psilocybin, and MDMA.

00:26:00.120 | If you talk to researchers in these areas,

00:26:02.820 | they will tell you that MDMA

00:26:04.800 | really isn't that much of a psychedelic.

00:26:07.780 | It's an empathogen with stimulant properties

00:26:10.340 | and it also has the serotonergic component

00:26:12.680 | that makes it an empathogen or an enactogen.

00:26:15.440 | So MDMA is very different than the other psychedelics

00:26:20.520 | and my hunch is that over the next few years,

00:26:23.720 | we will stop talking about MDMA as a psychedelic

00:26:26.760 | because it does not tend to produce visual hallucinations

00:26:30.200 | or auditory hallucinations of the sort

00:26:32.600 | that classic psychedelics do.

00:26:34.580 | And in general, it is more of a mood impacting drug

00:26:39.840 | than it is mystical, okay?

00:26:41.760 | So we'll get into some of the brain networks

00:26:43.620 | and which ones are activated

00:26:45.120 | while under the influence of MDMA,

00:26:47.180 | but I do think it's very important to segment out MDMA

00:26:50.220 | from the other so-called classic psychedelics

00:26:52.140 | and also segment it out from ketamine.

00:26:54.520 | Thanks to some really terrific studies,

00:26:56.040 | both in animal models and in humans,

00:26:58.420 | we now understand a lot of what makes MDMA

00:27:02.220 | produce these incredibly unique effects.

00:27:04.880 | And when I say unique,

00:27:05.720 | I mean unique from drugs like psilocybin

00:27:07.720 | and LSD and ketamine

00:27:10.040 | and from methamphetamine for that matter.

00:27:12.120 | And it's really the combination of big increases in dopamine

00:27:15.320 | and even bigger increases in serotonin

00:27:18.320 | that create a situation where people have more energy

00:27:22.240 | and yet despite having more energy,

00:27:25.160 | they don't feel irritated.

00:27:27.440 | They feel a lot of pleasure.

00:27:29.960 | They seem to want to be in the state

00:27:31.800 | of having a lot of energy.

00:27:33.340 | This will become important as we talk about anxiety

00:27:36.620 | and the anxiety symptoms of PTSD.

00:27:39.960 | It also, because of the big increases in serotonin,

00:27:42.540 | produces a sense of emotional warmth

00:27:44.980 | towards others and towards oneself.

00:27:46.680 | That's the empathogen component.

00:27:49.560 | And for reasons that we still don't understand,

00:27:51.880 | it seems to increase trust.

00:27:54.360 | And the increases in trust turn out to be vital

00:27:57.680 | because as you will also learn later

00:28:00.280 | when we look at the clinical trials

00:28:01.640 | exploring MDMA for the treatment of PTSD,

00:28:04.880 | the major effect of MDMA for the treatment of PTSD

00:28:08.780 | is not to cure PTSD,

00:28:11.460 | but rather to make the therapy,

00:28:13.660 | the talk therapy for PTSD much more effective.

00:28:17.420 | This is a very important point.

00:28:18.980 | In fact, so important I'm going to repeat it

00:28:20.400 | at least three times during today's episode.

00:28:22.520 | MDMA taken on its own does not cure PTSD.

00:28:26.160 | MDMA can augment or boost the effects

00:28:30.860 | of talk therapy for PTSD.

00:28:34.740 | And it does that through the engagement

00:28:36.420 | of specific neural circuits.

00:28:38.400 | But before we talk about what those neural circuits are,

00:28:41.460 | I want to emphasize that the increases in serotonin

00:28:44.100 | that MDMA produces seem to act on different receptors

00:28:49.100 | than the big increases in serotonin

00:28:51.420 | that LSD and psilocybin produce.

00:28:54.300 | So if you listen to the episode that I did on psilocybin,

00:28:57.220 | we haven't done yet one on LSD,

00:28:58.940 | but the mechanisms are very similar for psilocybin and LSD,

00:29:02.520 | whereby psilocybin and LSD very closely mimic

00:29:06.620 | the molecule serotonin itself,

00:29:08.300 | but seem to have a more selective activation

00:29:11.580 | of just the so-called serotonin 2A receptor,

00:29:15.020 | abbreviated 5-HT-2A.

00:29:16.940 | And that leads to more interconnectedness

00:29:20.080 | between different brain areas,

00:29:21.420 | more consideration of new possibilities

00:29:23.520 | about events from the past, present, and future,

00:29:26.580 | and also the opening of so-called neuroplasticity

00:29:29.660 | of rewiring of neural connections

00:29:31.620 | that persist long after the psilocybin

00:29:33.660 | or LSD effects have worn off.

00:29:36.140 | Now, MDMA can activate the serotonin 2A receptor,

00:29:41.140 | but it seems that it largely activates

00:29:44.500 | the serotonin 1B receptor.

00:29:46.920 | Now, what does that mean?

00:29:48.460 | Activation of the serotonin 1B receptor

00:29:51.420 | seems to be what gives MDMA its very strong impact

00:29:56.020 | on the neural circuits of the brain

00:29:57.860 | that relate to trust and to social engagement,

00:30:01.580 | not just the willingness to engage socially

00:30:03.780 | and to confide in a therapist or another person,

00:30:06.940 | but the intense desire to do so.

00:30:09.820 | And when I say intense desire,

00:30:11.600 | that takes us back to the dopamine system.

00:30:13.300 | Remember, dopamine, even though when increased in the brain,

00:30:17.740 | can increase our mood,

00:30:20.100 | it is largely responsible for increasing our sense

00:30:22.860 | of motivation and desire for something and to do something.

00:30:26.460 | So the increase in dopamine that's created by MDMA

00:30:29.580 | seems to make people what I call forward center of mass.

00:30:33.420 | They want to do something.

00:30:34.620 | They're very motivated to do something.

00:30:36.340 | And the increases in serotonin

00:30:38.600 | acting on the serotonin 1B receptor

00:30:41.460 | seems to be what creates this desire to bond

00:30:44.540 | or create trust or to have a discussion of real things,

00:30:47.740 | both things that are positive,

00:30:48.980 | but also to explore things that are difficult.

00:30:51.780 | And this, I realize,

00:30:53.220 | is going to be a little bit of a mind bend

00:30:54.940 | for people to understand.

00:30:56.900 | But one of the key things

00:30:59.100 | that quality MDMA therapy consists of

00:31:03.660 | is not just having a very good rapport

00:31:06.380 | and communication with a therapist

00:31:07.860 | that's guiding the PTSD treatment,

00:31:11.560 | but also rapport and a willingness

00:31:14.540 | to engage in conversations with oneself.

00:31:17.500 | And I think that most of us can relate to the fact

00:31:19.940 | that we have experiences, some of which are hard,

00:31:22.380 | some of which are great, and everything in between.

00:31:25.540 | Trauma is, I believe, best defined

00:31:28.060 | by the words that a former guest on this podcast,

00:31:30.320 | who's a world expert in trauma, Paul Conte,

00:31:32.860 | explained as trauma is an event

00:31:36.220 | that fundamentally changes the way that our brain works

00:31:40.020 | for the worse, okay?

00:31:41.180 | So not every bad event of our past is trauma,

00:31:44.220 | but events that change the way that we think,

00:31:48.060 | our emotional tone, or our behavior,

00:31:50.840 | in ways going forward that are not adaptive for us,

00:31:53.940 | they don't serve us well,

00:31:55.660 | either because they are highly distracting,

00:31:57.620 | or because they create anxiety,

00:32:00.060 | or because they disrupt sleep,

00:32:01.340 | or any number of different things

00:32:03.020 | that are maladaptive consequences,

00:32:05.160 | that's what really defines trauma.

00:32:07.500 | And when under the influence of MDMA,

00:32:09.460 | because of those parallel increases

00:32:11.580 | in dopamine and serotonin,

00:32:13.700 | people seem far more willing to both trust the therapist,

00:32:17.980 | that they're talking about that trauma with,

00:32:19.940 | but also to trust their own ability to, quote unquote,

00:32:23.800 | go internal and think about the challenging thing or things,

00:32:28.620 | 'cause oftentimes trauma can consist of many events,

00:32:30.980 | not just one event,

00:32:32.180 | and the thought patterns around that,

00:32:33.580 | and the context around that,

00:32:35.180 | and therein to be able to explore new possibilities

00:32:38.560 | to essentially rewire their relationship to that trauma.

00:32:42.260 | So I promised that a little bit later,

00:32:44.000 | we'll talk about the direct application of MDMA

00:32:46.940 | for the treatment of PTSD,

00:32:48.660 | but now I'd like to shift off of the chemical changes

00:32:51.220 | that MDMA produces and some of the subjective changes,

00:32:53.820 | these increases in trust and pleasure and energy

00:32:56.340 | and emotional warmth,

00:32:57.740 | to some of the brain circuits that are activated

00:32:59.980 | and modified by MDMA use,

00:33:02.660 | and then we will explore the toxicity issue,

00:33:05.340 | and then we will explore the clinical studies

00:33:07.680 | of which I can promise you are extremely exciting,

00:33:10.540 | but until we understand the neural circuit phenomena,

00:33:12.580 | and of course, until we consider the neurotoxicity issues,

00:33:16.320 | I don't think those clinical findings can be appreciated

00:33:18.960 | in their full value.

00:33:20.040 | But now I'd like to talk about what MDMA

00:33:22.000 | really does in the brain, both in the short term,

00:33:24.800 | while someone is under the influence of the drug,

00:33:27.100 | and in the long term,

00:33:28.380 | what sorts of neuroplastic or rewiring changes

00:33:31.180 | does MDMA produce, and how can those be beneficial

00:33:34.700 | or perhaps not beneficial?

00:33:37.040 | I'd like to take a quick break

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00:34:51.460 | So in order to understand what MDMA does to the human brain,

00:34:54.900 | we need to take a step back

00:34:56.940 | and really define the sorts of experiments

00:34:59.100 | that one could do.

00:35:00.640 | So for instance, you could take a person

00:35:02.020 | who's never ingested MDMA and put them into an fMRI machine,

00:35:06.620 | which is functional magnetic resonance imaging,

00:35:09.900 | put them into the fMRI machine,

00:35:11.860 | and just have them sit there with their eyes closed,

00:35:14.120 | what we would call resting functional connectivity

00:35:17.500 | or resting state functional connectivity,

00:35:19.760 | and simply look at how interconnected

00:35:22.600 | certain brain areas are, which brain areas are active,

00:35:25.600 | which brain areas are less active at rest.

00:35:28.740 | This is an important thing to do,

00:35:30.640 | not just to provide a baseline for understanding

00:35:33.060 | what the drug MDMA will subsequently do,

00:35:36.160 | but also because it addresses

00:35:37.500 | what's called the default mode network.

00:35:39.500 | The default mode network or DMN

00:35:42.100 | is the network that is active in our brains

00:35:44.700 | when we aren't really attending

00:35:45.980 | to anything specific outside us,

00:35:48.220 | and we're not trying to think about anything specific

00:35:50.660 | or accomplish anything specific.

00:35:52.620 | It actually relates to our sense of imagination

00:35:54.740 | and daydreaming.

00:35:56.180 | It has a lot to do with our self-referencing,

00:35:58.660 | what we're thinking about ourselves.

00:36:00.100 | This may come as no surprise,

00:36:01.260 | but if you're just sitting there on the bus

00:36:03.700 | or around the dinner table

00:36:06.260 | and you're not paying attention to what's going on,

00:36:08.100 | in large part, your brain is in this default mode network,

00:36:11.660 | and you're thinking about yourself, okay?

00:36:14.160 | So we can get a sense

00:36:15.420 | of what the default mode network activation is.

00:36:18.500 | We can get a sense of which brain areas

00:36:20.320 | are more or less active,

00:36:21.640 | simply by putting somebody into an fMRI machine.

00:36:25.580 | Then of course, you could give somebody MDMA

00:36:28.780 | while they are in the fMRI machine

00:36:30.880 | and see how the activation

00:36:32.660 | of different brain networks changes.

00:36:34.620 | And then of course,

00:36:35.460 | you could analyze how the default mode networks

00:36:38.220 | and other brain networks change in the days and weeks

00:36:42.340 | and even years after the drug has worn off,

00:36:45.420 | so-called neuroplasticity effects,

00:36:47.500 | what changed in a permanent or pervasive way.

00:36:50.100 | Okay, so that's sort of one basic paradigm

00:36:52.980 | for exploring the effects of drugs like MDMA on the brain.

00:36:56.100 | The other way that you can explore the effects

00:36:57.700 | of MDMA on the brain

00:36:59.220 | is to ask people in the general population,

00:37:01.860 | hey, who out there has taken MDMA?

00:37:04.380 | How many times have you taken it?

00:37:06.060 | And come on into the laboratory

00:37:07.700 | and we will image your brain

00:37:09.620 | and compare people who have,

00:37:11.420 | for instance, taken MDMA zero times

00:37:14.860 | to people who have taken MDMA one time or five times,

00:37:18.460 | or believe it or not,

00:37:19.740 | there's some studies sitting right here in front of me

00:37:22.140 | on my desk of people who have taken MDMA

00:37:25.560 | more than 200 times and ask the same sorts of questions,

00:37:28.940 | which brain areas are more or less active?

00:37:30.900 | Those studies have been done as well.

00:37:32.700 | And of course, one can do studies

00:37:34.140 | where you give people different dosages of MDMA

00:37:36.740 | as well as giving people MDMA

00:37:38.840 | and then giving them specific stimuli,

00:37:41.300 | meaning not just asking them to sit there

00:37:43.220 | in the fMRI scanner with eyes closed,

00:37:45.060 | looking at the resting state functional connectivity,

00:37:47.840 | but also how the brain responds

00:37:50.580 | to the presentation of happy faces or sad faces

00:37:53.340 | or images of oneself or even images that recall memories

00:37:57.260 | of traumatic events and so on.

00:37:59.300 | So fortunately, all of those sorts of studies

00:38:02.060 | have been done in humans

00:38:04.020 | and there are also a large number of studies

00:38:06.420 | in animal models exploring how the social activity

00:38:09.800 | of laboratory mice changes

00:38:11.840 | when they are under the effects of MDMA.

00:38:14.220 | There are even studies, believe it or not,

00:38:15.980 | on the effects of MDMA in cephalopods.

00:38:18.900 | Cephalopods include octopuses as well as cuttlefish

00:38:23.900 | and other aquatic animals that are known

00:38:26.620 | for having complex behavior.

00:38:28.340 | Some people believe that the cephalopods

00:38:29.980 | are extremely intelligent.

00:38:32.320 | The obsession with cephalopods

00:38:33.620 | is something that really intrigues me.

00:38:35.060 | I actually used to have cuttlefish in my laboratory.

00:38:37.320 | We did not put them on MDMA,

00:38:39.060 | but there is a study that's been published

00:38:40.580 | in the journal Current Biology.

00:38:42.540 | It's a cell press journal, excellent journal.

00:38:44.340 | This is from Gould Dolan's laboratory

00:38:46.060 | at Johns Hopkins School of Medicine,

00:38:48.420 | showing that if you give octopuses MDMA,

00:38:51.220 | they like to spend more time with other octopuses

00:38:54.260 | than they do if they are not on MDMA.

00:38:56.640 | And that might sound like kind of a playful experiment

00:39:00.740 | just done in order to entertain oneself

00:39:04.300 | and the octopuses, perhaps.

00:39:05.780 | But actually in that study,

00:39:07.300 | they identified the serotonin transporter in octopuses

00:39:11.420 | and showed that it has a lot of homology similarity

00:39:14.460 | to human serotonin transporter receptors.

00:39:17.180 | And so what that really speaks to is the fact

00:39:18.580 | that the prosocial effects of MDMA

00:39:20.300 | that are observed in mice and in humans and in octopuses

00:39:24.700 | all have a common basis,

00:39:26.060 | which is the activation of more serotonin release

00:39:30.140 | in particular brain networks.

00:39:31.900 | Okay, so that interesting study on octopuses aside,

00:39:34.940 | I think what most of us are interested in

00:39:36.500 | is how MDMA impacts the brain.

00:39:38.940 | And so I'm going to spell out the three major ways

00:39:41.500 | in which MDMA changes the activation of the brain

00:39:45.220 | in the short and long-term.

00:39:46.660 | And here I'm pooling across a number of different studies.

00:39:49.540 | But one of the key sets of studies in this area

00:39:51.860 | comes from what I consider very beautiful work

00:39:54.780 | of Harriet DeWitt.

00:39:56.100 | Harriet DeWitt runs

00:39:57.360 | the Human Behavioral Pharmacology Laboratory

00:40:00.300 | in the Department of Psychiatry and Behavioral Neuroscience

00:40:02.800 | at the University of Chicago.

00:40:04.040 | And her laboratory has a long history

00:40:06.700 | of giving people certain drugs in very specific dosages

00:40:10.020 | and then measuring their effects on the brain

00:40:12.500 | using different types of imaging, including fMRI.

00:40:16.200 | And one particular study that I'll highlight

00:40:19.120 | is entitled Effects of MDMA on Sociability

00:40:21.660 | and Neural Responses to Social Threat and Social Reward.

00:40:25.440 | So what this study looked at is how MDMA impacts

00:40:27.820 | people's perceptions of others' emotional expressions

00:40:32.140 | on their face.

00:40:33.720 | What they found is that when people are on MDMA,

00:40:36.780 | their response to threatening faces

00:40:39.080 | or other threatening stimuli is reduced.

00:40:41.340 | And it's reduced in a very specific way,

00:40:43.160 | which is reductions in activity of the amygdala.

00:40:45.740 | The amygdala is a structure

00:40:47.340 | that some of you may be familiar with.

00:40:49.380 | It is known to be involved in the threat detection systems

00:40:53.060 | or networks of the brain.

00:40:54.460 | It is sometimes called the fear area of the brain,

00:40:57.300 | although I want to caution people

00:40:59.180 | against assigning any one particular subjective experience

00:41:02.420 | to any one particular brain area.

00:41:04.160 | The amygdala is actually a complex.

00:41:05.920 | It's actually called the amygdaloid complex

00:41:08.120 | and has a lot of different sub areas.

00:41:09.920 | And it's involved in a lot of things

00:41:11.300 | besides fear and threat detection.

00:41:13.340 | Nonetheless, when people are under the influence of MDMA

00:41:16.020 | and you show them a face that is grimacing

00:41:19.480 | or would otherwise be rated as quite threatening,

00:41:22.900 | they tend to rate it as less threatening.

00:41:25.060 | In addition, they tend to respond to happy faces

00:41:28.580 | or even slightly happy faces as more kind

00:41:33.460 | or more generous or happier than they would

00:41:36.700 | when they are not on MDMA.

00:41:39.060 | Again, the faces that are being shown

00:41:41.340 | are not of people on MDMA.

00:41:43.120 | That would be an interesting experiment,

00:41:44.340 | but that's not what they did here.

00:41:45.840 | What's happening here is people are being given MDMA

00:41:48.100 | and then they are rating in a subjective way

00:41:51.420 | the friendliness or the level of threat

00:41:54.540 | that they detect in these facial expressions.

00:41:56.920 | And of course, they have extremes

00:41:59.380 | of friendly and threatening,

00:42:01.660 | but then they also grade them, right?

00:42:03.700 | They titrate them so that they also have mildly threatening

00:42:06.100 | and mildly happy faces, et cetera.

00:42:08.620 | So everything from a grin to a smirk to a giant smile,

00:42:12.060 | everything from a sort of somebody looking

00:42:15.420 | a little bit askance at somebody to really wide-eyed

00:42:18.260 | and looking angry like they're going to attack you

00:42:20.380 | and things of that sort.

00:42:21.920 | So what's discovered in the study is that MDMA

00:42:24.220 | has a bi-directional effect

00:42:26.500 | on our perception of others' emotions,

00:42:29.220 | making people more likely to rate something as positive

00:42:33.340 | if it's initially positive or even a little bit positive

00:42:35.880 | and less likely to rate a threatening face

00:42:39.900 | as more threatening.

00:42:41.860 | Now, one thing I have not mentioned thus far

00:42:43.860 | are the dosages of MDMA used in this and in other studies.

00:42:47.860 | And fortunately, despite the studies

00:42:49.300 | that we're going to talk about,

00:42:50.620 | using a lot of different types of people,

00:42:52.380 | different ages, different sexes, so male and female,

00:42:55.620 | located in different parts of the world even,

00:42:57.300 | some with PTSD, some not with PTSD, et cetera,

00:43:00.720 | there's been fairly tight dosage control

00:43:03.740 | of MDMA in these studies.

00:43:05.340 | It's not perfectly matched from study to study,

00:43:07.260 | but it's pretty darn close,

00:43:09.660 | which makes interpreting results across studies

00:43:12.340 | a lot easier for me and therefore for you.

00:43:16.780 | The typical dosages of MDMA used in these neuroimaging

00:43:20.220 | studies and in the clinical studies of PTSD

00:43:24.280 | that we're going to talk about later

00:43:26.220 | range anywhere from 0.75 milligrams per kilogram

00:43:30.000 | of body weight to 1.5 milligrams per kilogram of body weight.

00:43:34.360 | So for somebody like me, I weigh 220 pounds,

00:43:37.120 | that's 100 milligrams.

00:43:38.420 | 1.5 milligrams per kilogram of body weight

00:43:41.800 | would therefore be 150 milligrams in a single dose, okay?

00:43:47.160 | A dosage of one milligram per kilogram of body weight

00:43:50.800 | would mean 100 milligrams for my 100 kilograms, okay?

00:43:55.200 | Somebody lighter than 100 kilograms

00:43:58.120 | would obviously take less MDMA in one of these studies.

00:44:01.480 | But in general, the range of MDMA that's been explored

00:44:05.080 | is 0.75 to 1.5 milligrams per kilogram of body weight.

00:44:09.700 | The exception being in the clinical studies

00:44:12.300 | that we'll talk about a little bit later,

00:44:14.000 | there's a tendency to explore both an initial dose

00:44:17.440 | of 1.5 milligrams per kilogram of body weight.

00:44:20.960 | So again, for a 100 kilogram person,

00:44:23.520 | that'd be 150 milligrams or so.

00:44:25.480 | And then a so-called booster of half that amount,

00:44:29.340 | about 90 minutes to two and a half hours into the session.

00:44:32.980 | So another 75 milligrams later.

00:44:35.040 | And I should point out that there is not always

00:44:36.960 | the inclusion of the so-called booster.

00:44:38.720 | And in some cases, lower doses of MDMA,

00:44:41.240 | such as the 0.75 milligrams per kilogram dosages are used.

00:44:45.420 | Why am I getting so into the details of dosages?

00:44:48.220 | Well, if we are going to talk about toxicity of MDMA,

00:44:51.880 | we absolutely have to talk about dosages.

00:44:54.600 | Because like any drug, the toxicity of MDMA

00:44:59.600 | does scale with the dosage that's applied,

00:45:02.280 | not just the frequency of MDMA use.

00:45:05.680 | We hear a lot about that.

00:45:07.040 | Someone has taken MDMA one time or four times or 200 times.

00:45:11.080 | We hear about frequency of use,

00:45:12.720 | but rarely do we hear about the specific dosages

00:45:16.780 | that are taken in any one particular session.

00:45:19.640 | So when we talk about the subjective effects

00:45:21.240 | or the brain networks that are activated

00:45:22.920 | when people take MDMA, in general,

00:45:25.460 | we're talking about dosages somewhere

00:45:28.320 | between 0.75 milligrams per kilogram of body weight

00:45:31.000 | and 1.5 milligrams per kilogram of body weight.

00:45:34.000 | Although typically you're going to see studies,

00:45:37.400 | both clinical and more research explorative,

00:45:40.940 | using anywhere from one to 1.5 milligrams

00:45:44.360 | of MDMA per kilogram of body weight.

00:45:46.880 | So that's important to highlight.

00:45:48.200 | I told you about the subjective effects

00:45:49.840 | of MDMA engaging the responses of people's faces,

00:45:53.780 | but I didn't tell you about the brain areas

00:45:55.240 | that are responsible,

00:45:56.760 | except for the reduction in amygdala activity.

00:46:00.120 | Now, one of the key features of PTSD

00:46:03.780 | seems to be that there is a heightened connectivity

00:46:06.640 | between the amygdala and a brain area called the insula.

00:46:10.060 | The insula is a brain area that's very important

00:46:12.000 | for something that's called interoception.

00:46:14.480 | Interoception is one's perception of our feelings,

00:46:18.980 | both pure sensations, but also our emotional states

00:46:23.560 | and our feelings of wellbeing or lack of wellbeing

00:46:26.280 | for everything from our skin inward, okay?

00:46:29.080 | So that's interoception.

00:46:30.860 | You actually can interocept now,

00:46:33.600 | even though you're always interocepting a little bit,

00:46:35.400 | you can interocept now to a great degree

00:46:37.420 | if you were to, for instance, close your eyes

00:46:39.440 | or simply focus on the contact points between your body

00:46:42.820 | and any surface that you happen to be contacting.

00:46:44.980 | So maybe the backs of your legs against a chair

00:46:47.300 | or your feet against the floor

00:46:49.620 | or the bottoms of your shoes or sandals.

00:46:51.920 | Your nervous system is constantly sensing

00:46:53.800 | those contact points,

00:46:55.380 | but normally they're not under your conscious awareness

00:46:58.880 | unless you direct your interoceptive capacity to them,

00:47:02.660 | which is just fancy nerd speak for saying,

00:47:05.300 | you normally don't notice what's going on

00:47:07.160 | from your skin inward unless you focus on it.

00:47:10.020 | That focus is interoception.

00:47:13.380 | It can be about the fullness of your gut.

00:47:15.380 | It can be about how happy or sad you are.

00:47:17.500 | It can be about how tired or alert you happen to feel,

00:47:20.660 | but that's interoception.

00:47:21.820 | And it is distinctly different from exteroception,

00:47:25.020 | which is your ability and tendency to focus on things

00:47:28.480 | beyond the confines of your skin.

00:47:30.100 | So this could be visual attention, auditory attention.

00:47:33.020 | It could be paying attention to events like birds flying by,

00:47:37.780 | whether or not your Uber is showing up,

00:47:39.500 | these kinds of things.

00:47:40.620 | And we are always in a balance,

00:47:42.480 | a push-pull of interoception and exteroception.

00:47:45.200 | The insula is a brain area that is absolutely critical

00:47:47.960 | for interoception, so much so that it has a map

00:47:51.840 | of the complete body surface, including our internal organs.

00:47:55.220 | In other words, if you put somebody into an fMRI machine

00:48:00.040 | or you were to record from the insula with electrodes,

00:48:03.280 | as has been done in humans many times now

00:48:06.000 | during the course of neurosurgery for other purposes,

00:48:08.580 | what you would find is that if you stimulate neurons

00:48:10.560 | in one end of the insula, the person will say,

00:48:12.040 | "Oh, you know, I feel something going on in my gut

00:48:15.780 | and on my left side."

00:48:16.800 | And then as you were to march that stimulation

00:48:18.880 | across the insula, you would find that they would now

00:48:21.920 | be paying attention to their legs or just to one leg

00:48:24.820 | or to their whole body or to the sensations in their face

00:48:28.760 | or their head.

00:48:29.600 | There's a systematic map of interoception in the insula,

00:48:33.760 | and there are direct connections between the amygdala

00:48:37.080 | and the insula, and the amygdala,

00:48:39.660 | despite getting this reputation as just being a fear center

00:48:43.860 | or a threat detection center, is actually part

00:48:45.800 | of a much larger set of networks that include inputs

00:48:48.080 | from the hippocampus, an area of the brain that's involved

00:48:50.520 | in memory formation and storage, and what is observed

00:48:54.680 | is that people who have PTSD tend to have greater

00:48:58.600 | or rather stronger connections between the amygdala

00:49:01.680 | and the insula than is normally observed in people

00:49:05.540 | who do not have PTSD, okay?

00:49:07.880 | So there seems to be heightened input

00:49:10.400 | from the threat detection centers of the brain

00:49:13.100 | to this area of the brain, the insula that is responsible

00:49:16.200 | for our sense of interoception,

00:49:17.880 | which provides a logical explanation for why people

00:49:20.780 | with PTSD often will feel the memory or sense the discomfort

00:49:26.860 | or just feel agitation or even other types

00:49:30.560 | of bodily sensations like back pain,

00:49:32.380 | or just perhaps just a sense within their body

00:49:35.400 | that's more generalized.

00:49:36.420 | It doesn't even have to be pain,

00:49:37.500 | doesn't even have to be negative,

00:49:38.900 | but that's associated with the negative memory

00:49:41.540 | of some traumatic event or series of events, okay?

00:49:44.180 | So this is a really interesting brain network

00:49:46.120 | that I should mention exists in everybody,

00:49:48.860 | but that in people with PTSD seems

00:49:51.580 | to have heightened connectivity,

00:49:53.360 | and those brain networks can be revealed

00:49:55.760 | by putting people with PTSD into functional imaging machines,

00:50:00.700 | getting them to recall a traumatic event,

00:50:02.800 | or even looking at the resting state of connectivity

00:50:05.160 | between the amygdala and the insula.

00:50:07.080 | So those experiments have been done,

00:50:08.700 | and what's also been done is to give people 1.5 milligrams

00:50:12.540 | per kilogram of MDMA and to look at the connectivity

00:50:16.040 | between the amygdala and the insula

00:50:18.180 | and between the hippocampus, the amygdala and the insula.

00:50:21.200 | And so what's observed over time in people

00:50:23.400 | that have been given MDMA and, this is a very important and,

00:50:28.080 | and have done therapy for PTSD,

00:50:31.920 | both before, during, and after the drug,

00:50:36.760 | there's a weakening of connections

00:50:38.300 | between the amygdala and the insula,

00:50:41.220 | and that scales very directly

00:50:43.660 | with the relief of symptoms from PTSD.

00:50:46.300 | So this is really exciting because it's one thing

00:50:48.740 | to see a brain network get activated or inactivated,

00:50:51.420 | or you say, okay, in one person,

00:50:52.620 | a certain connection between threat centers

00:50:55.100 | and the interoceptive centers of the brain was,

00:50:57.860 | let's say, arbitrary units.

00:50:59.300 | Let's say it was level eight out of 10 for that person, right?

00:51:02.540 | These things are normalized for a particular person.

00:51:04.580 | And then after taking MDMA and doing PTSD therapy,

00:51:07.660 | it was five out of 10 or four out of 10.

00:51:10.260 | That's a good experiment,

00:51:11.940 | but what's far more powerful is to observe that

00:51:15.480 | in that patient or that person,

00:51:18.380 | and then to see a change that's perhaps less dramatic.

00:51:22.380 | So a shift from eight out of 10 to seven out of 10

00:51:26.300 | in another person, and to see less shift

00:51:30.100 | in brain connectivity in the same network.

00:51:32.420 | And then perhaps in the person

00:51:33.940 | that went from full-blown PTSD to full remission of PTSD,

00:51:37.520 | something that, believe it or not,

00:51:38.740 | has been observed in single sessions with MDMA,

00:51:41.620 | if that person demonstrates an even greater reduction

00:51:46.580 | in the connections between the amygdala and the insula,

00:51:49.180 | well, then that gives even more confidence

00:51:51.300 | that this connection between the amygdala and the insula

00:51:54.380 | is actually perhaps causally related

00:51:57.260 | to the reduction in symptoms of PTSD.

00:52:00.220 | Or even if it's just correlated

00:52:01.540 | with reduction in symptoms of PTSD,

00:52:03.300 | the fact that the degree of reduction

00:52:05.860 | of connection of this circuit scales with the reduction

00:52:10.020 | in clinically relevant symptoms,

00:52:12.060 | that's a very powerful finding

00:52:13.500 | because it moves things away from pure correlation of,

00:52:16.460 | oh, this brain area is active or less active over time,

00:52:19.180 | and this person has more or fewer symptoms of PTSD,

00:52:22.420 | to something that starts to look like a mechanistic

00:52:25.240 | and logical framework for understanding PTSD,

00:52:29.080 | as well as the effects of MDMA,

00:52:30.980 | and for understanding how changes in the brain

00:52:34.100 | underlie relief from PTSD.

00:52:36.380 | Okay, so again, even if you just could grasp the idea

00:52:39.620 | that you have a brain area, the amygdala,

00:52:42.340 | that's involved in threat detection,

00:52:43.740 | and it provides inputs to another brain area

00:52:45.780 | called the insula, which is involved in this thing

00:52:47.520 | called interoception, and that reductions in those connections

00:52:51.340 | between the amygdala and the insula scale with

00:52:53.980 | or correlate with reductions in PTSD symptoms

00:52:56.980 | as a consequence of people taking MDMA.

00:52:59.660 | So if you have that under your mental belt,

00:53:01.300 | I promise you, you understand far more

00:53:02.980 | about how MDMA impacts the brain in the short and long term

00:53:06.140 | than 99.9% of people out there.

00:53:08.380 | However, it's also important that you understand

00:53:10.840 | a few other things that MDMA does to the brain,

00:53:13.420 | as well as what it doesn't do to the brain.

00:53:15.300 | First of all, classic psychedelics like psilocybin and LSD,

00:53:20.300 | as I mentioned earlier, are known to create

00:53:22.800 | more lateral connectivity between different areas

00:53:25.980 | of the so-called neocortex.

00:53:27.500 | And these are long-lasting changes

00:53:29.080 | that are thought to underlie both some of the relief

00:53:32.560 | from major depression,

00:53:33.740 | but also some of the enhanced creativity

00:53:36.080 | and some of the other things that have been observed

00:53:38.180 | with psilocybin treatment.

00:53:39.720 | And again, if you're interested in psilocybin treatments

00:53:42.360 | and psilocybin itself, please check out the episode

00:53:44.320 | I did on psilocybin and the guest episode

00:53:46.180 | with Dr. Robin Carthart-Harris.

00:53:48.640 | Those episodes, like all other episodes

00:53:50.520 | of the Huberman Lab podcast can be found

00:53:51.980 | at hubermanlab.com.

00:53:53.020 | It's a fully searchable site.

00:53:54.620 | You can put keywords into the search function.

00:53:56.620 | It will take you to specific timestamps.

00:53:58.980 | Every episode is timestamped so you can navigate

00:54:01.100 | to topics of particular interest to you.

00:54:03.180 | Feel free to go there and listen to those episodes

00:54:06.380 | about psilocybin.

00:54:08.060 | MDMA, by contrast, does not seem to produce

00:54:10.940 | long-lasting increases in lateral connectivity

00:54:13.900 | between those same brain networks,

00:54:15.300 | probably because it impacts different serotonin receptors.

00:54:18.680 | It does, however, seem to change resting state

00:54:21.100 | functional connectivity within these limbic structures

00:54:24.500 | like the amygdala and related structures

00:54:26.820 | that are associated with threat detection.

00:54:28.960 | Now, this is interesting,

00:54:29.920 | and it actually was highlighted very nicely

00:54:31.440 | in a study I'll provide a link to in our show note caption,

00:54:33.820 | which actually has Dr. Robin Carthart-Harris

00:54:36.560 | as the first author.

00:54:37.400 | So not only has he done incredible work on psilocybin

00:54:40.760 | and LSD and DMT and ayahuasca in his laboratory,

00:54:43.560 | but also on MDMA.

00:54:45.980 | And the particular study I have in mind here

00:54:48.940 | showed that people who take MDMA

00:54:52.700 | at more or less the dosage that we talked about earlier

00:54:55.860 | report marked increases in positive mood,

00:54:58.580 | as well as decreased blood flow

00:55:00.960 | to the amygdala and hippocampus.

00:55:02.600 | So again, these threat detection centers of the brain

00:55:04.660 | and brain areas associated with memory.

00:55:08.580 | And those changes are seen

00:55:10.460 | both while under the influence of MDMA

00:55:13.000 | and afterwards when the brain is simply at rest.

00:55:16.080 | So it really does appear that MDMA creates neuroplasticity

00:55:19.920 | that changes the overall level of activation

00:55:22.740 | of these threat detection networks

00:55:24.560 | and their connections to memory systems

00:55:26.920 | in a way that's pervasive over time

00:55:28.780 | and that doesn't require any particular probe

00:55:31.040 | with a negative stimulus.

00:55:34.280 | Translated to English,

00:55:35.220 | what that means is that during the MDMA session,

00:55:39.420 | people report feeling less threatened,

00:55:42.700 | more pro-social towards others,

00:55:45.420 | more empathic towards others and themselves.

00:55:47.940 | And then after the session,

00:55:49.620 | they have less of a threat response to memories

00:55:51.940 | that before the session were more troubling.

00:55:54.220 | And those changes in the brain do seem to be pervasive.

00:55:57.500 | So there are both short-term and long-term effects of MDMA,

00:56:01.500 | all of which point in the direction

00:56:03.160 | of lowered levels of threat detection,

00:56:05.740 | heightened levels of positivity,

00:56:07.620 | pro-social components of the brain,

00:56:10.020 | more active threat detection centers of the brain,

00:56:12.860 | less active.

00:56:14.340 | Now, earlier we talked about MDMA as a drug

00:56:17.540 | that potently increases dopamine

00:56:19.500 | and even more potently increases serotonin,

00:56:23.300 | largely acting through this serotonin 1B receptor.

00:56:28.100 | Now, without getting into too many more details

00:56:30.220 | before moving on to issues of toxicity around MDMA,

00:56:33.460 | I do want to touch on what I think is perhaps the finest

00:56:36.620 | of the animal model studies of MDMA

00:56:39.720 | that explored which brain networks

00:56:41.940 | and which chemical, that is serotonin or dopamine,

00:56:46.020 | is responsible for, say, the motivational components of MDMA

00:56:50.420 | versus the pro-social effects of MDMA.

00:56:52.680 | And then it also raises a really important point,

00:56:55.240 | which I haven't mentioned yet in this episode,

00:56:57.800 | which is the role of oxytocin,

00:57:00.300 | something that many of you have perhaps heard of.

00:57:03.180 | The paper that I'm going to describe

00:57:05.700 | is from the laboratory of Dr. Robert Malanka.

00:57:08.980 | He's a colleague of mine at Stanford University

00:57:10.840 | School of Medicine, Psychiatry and Behavioral Sciences.

00:57:13.740 | He is both a pioneer and luminary

00:57:16.800 | in the field of neuroplasticity,

00:57:18.240 | of how the brain wires and forms memories

00:57:20.580 | and can change itself over time in response to experience,

00:57:23.560 | as well as the study of drugs of abuse,

00:57:25.880 | as well as the study of drugs like MDMA

00:57:29.000 | and now additional compounds

00:57:31.020 | that can provide therapeutic support in certain conditions.

00:57:35.720 | The study, which I will provide a link to

00:57:37.700 | in the show note caption,

00:57:39.120 | is entitled Distinct Neural Mechanisms

00:57:41.120 | for the Pro-Social and Rewarding Properties of MDMA.

00:57:43.880 | And I'm just going to summarize

00:57:45.380 | the major results of this study.

00:57:46.600 | It's a study that was done on mice,

00:57:48.460 | and I realize that a lot of people will hear that

00:57:50.240 | and think, ah, what relevance does that have to humans?

00:57:52.300 | But when thinking about the effects of dopamine and serotonin

00:57:55.180 | in the types of circuits

00:57:56.440 | that we've been talking about thus far,

00:57:58.600 | these circuits that are subcortical, as we refer to them,

00:58:01.540 | so these are limbic circuits, these are hypothalamic circuits,

00:58:04.180 | these are what are called mesolimbic circuits,

00:58:06.100 | these are all names for circuits that are highly conserved

00:58:09.020 | between mice and humans.

00:58:11.120 | And so results in mice really do translate quite well

00:58:14.780 | to results in humans,

00:58:16.340 | at least in so far as the effects of MDMA

00:58:19.260 | and which neurochemicals are involved is concerned.

00:58:22.000 | So what they found in this study,

00:58:23.460 | using a huge array of beautiful techniques,

00:58:26.460 | such as inactivation of specific brain areas,

00:58:28.660 | activation of specific brain areas,

00:58:30.840 | drug antagonist to prevent oxytocin function,

00:58:34.360 | or drug antagonist to prevent specific receptors

00:58:37.240 | involved in the serotonin pathway,

00:58:38.700 | lots and lots of tools in their toolkit.

00:58:41.220 | What they found is that MDMA causing the release of dopamine

00:58:46.100 | is what really establishes the rewarding effects

00:58:49.200 | of an experience.

00:58:50.300 | This isn't really a surprise.

00:58:52.080 | We've known that MDMA, just like cocaine or methamphetamine

00:58:57.940 | or Adderall for that matter, or Vyvanse for that matter,

00:59:01.880 | creates big increases in dopamine that tend to couple

00:59:06.380 | an experience with a sense of reward

00:59:09.360 | and lead to changes in the neural circuitry

00:59:11.700 | that make the animal or human more likely

00:59:13.500 | to seek out that same experience again.

00:59:15.900 | Okay, these are the rewarding

00:59:17.080 | or sometimes called reinforcing properties of dopamine

00:59:19.620 | that take place in the so-called mesolimbic reward pathway.

00:59:23.140 | If you want to learn about mesolimbic reward pathways

00:59:25.140 | and dopamine and how they control everything

00:59:26.740 | from your level of motivation

00:59:28.140 | to your tendency to procrastinate

00:59:29.580 | or overcome procrastination,

00:59:31.180 | I've done two episodes about dopamine.

00:59:33.540 | You can simply go to hubermanlab.com,

00:59:35.080 | put dopamine into the search function,

00:59:36.940 | and you'll find at least two episodes on that topic.

00:59:40.200 | And you'll also find a number of different tools

00:59:42.200 | related to how one can better regulate

00:59:44.860 | their own patterns of dopamine release

00:59:47.140 | for sake of motivation, et cetera.

00:59:48.900 | So MDMA is increasing dopamine to increase reward

00:59:53.140 | to a particular experience.

00:59:55.020 | What's the experience?

00:59:55.960 | Well, this paper beautifully parses the fact

00:59:59.700 | that it is serotonin release

01:00:01.860 | within a structure called the nucleus accumbens,

01:00:03.700 | which is part of the reward pathway,

01:00:05.620 | which is rewarding the experience of social interaction.

01:00:09.420 | They do this by putting mice in arenas

01:00:11.860 | where they have the option

01:00:12.700 | of either spending time with other mice

01:00:13.980 | or not spending time with other mice

01:00:15.260 | and blocking the activation of certain brain areas,

01:00:17.400 | and again, using drug antagonists, et cetera.

01:00:19.860 | And what they find is that it really is the activation

01:00:22.740 | of the serotonin 1B receptor

01:00:25.380 | in the nucleus accumbens by MDMA

01:00:27.900 | that leads to this prosocial effect of MDMA.

01:00:32.620 | So that's really nice to know

01:00:33.920 | because there's always been this conundrum of,

01:00:36.480 | okay, psilocybin and LSD are basically like serotonin.

01:00:40.400 | They activate the serotonin 2A receptor.

01:00:42.580 | MDMA has this huge serotonergic component,

01:00:45.540 | tons of serotonin released when one takes MDMA,

01:00:48.820 | but very different effects in the short and long term,

01:00:51.960 | very different subjective effects,

01:00:53.220 | very different patterns of change activity in the brain

01:00:56.380 | in the short and long term.

01:00:57.920 | Well, that's because MDMA is activating

01:01:00.100 | the serotonin 1B receptor, not the serotonin 2A receptor,

01:01:03.060 | and it's doing so in a completely different set

01:01:04.900 | of brain networks as is LSD and psilocybin.

01:01:08.180 | So what happens when an animal or a person takes MDMA

01:01:11.940 | is that social connection is strongly rewarded

01:01:15.300 | and reinforced, making social connection more likely

01:01:18.700 | after the drug wears off.

01:01:21.540 | Now, that's one component of social connection,

01:01:24.100 | but in addition, people who take MDMA

01:01:26.940 | in the clinical therapeutic setting

01:01:29.040 | for the treatment of PTSD often report feeling more empathy

01:01:33.220 | and compassion for themselves during the session,

01:01:36.120 | but also for long periods of time,

01:01:37.940 | maybe even indefinitely after the session.

01:01:41.040 | So it really seems that the addition

01:01:43.720 | of this huge release of serotonin by MDMA

01:01:47.380 | on top of the release of dopamine

01:01:50.780 | sets in motion two parallel circuits,

01:01:52.640 | one for rewarding something, anything,

01:01:55.140 | that's the dopamine component.

01:01:56.460 | And then fortunately,

01:01:57.640 | because the increase in serotonin caused by MDMA

01:02:00.960 | increases empathy and sociability for and with others,

01:02:06.340 | but also for oneself,

01:02:08.620 | the motivation that's reinforced,

01:02:10.640 | that's wired into the brain seems to be a motivation

01:02:13.960 | to perceive others as more kind,

01:02:15.780 | but also to be kinder to oneself.

01:02:18.400 | Now, I realize that for some of you

01:02:19.940 | who are listening to this, you're probably saying,

01:02:21.780 | well, of course, right?

01:02:23.600 | You know, serotonin is pro-social and dopamine is motivation,

01:02:26.820 | so you put the two together

01:02:28.000 | and people become more motivated to be social

01:02:30.620 | and kinder to themselves.

01:02:32.580 | Ah, but it didn't necessarily have to be that way, right?

01:02:36.880 | It is very hard to go from a statement

01:02:40.060 | like drug A produces effects B, C, and D

01:02:44.900 | to neurochemicals B, C, and D

01:02:47.960 | cause motivation and sociability,

01:02:49.980 | and therefore, when you take that drug,

01:02:51.980 | you're going to get all of that stuff.

01:02:53.500 | In fact, we have to go back to our understanding

01:02:55.420 | that MDMA, despite causing a big increase in serotonin,

01:03:00.300 | also causes huge increases in dopamine,

01:03:03.540 | and it does so with this molecule that is methamphetamine.

01:03:07.520 | Now, methamphetamine is not known to be a pro-social drug.

01:03:11.240 | In fact, the study I just referred to,

01:03:12.740 | as well as some human studies,

01:03:14.580 | have explored how the application of methamphetamine,

01:03:17.820 | so not MDMA, but pure methamphetamine,

01:03:20.620 | impacts social interactions,

01:03:23.100 | and what it does to social interactions is very profound.

01:03:26.080 | It dramatically reduces one's tendency

01:03:28.420 | to engage in social interaction.

01:03:31.020 | So this really speaks to the polypharmacology,

01:03:33.680 | as it's called, of MDMA,

01:03:35.500 | the fact that serotonin and dopamine are released together

01:03:39.580 | has distinctly different effects

01:03:41.900 | than if just dopamine or just serotonin is increased,

01:03:46.840 | so much so that it's worth taking a step back

01:03:49.620 | and talking about another class of drugs

01:03:51.480 | which dramatically increases serotonin,

01:03:53.960 | which are the SSRIs,

01:03:55.600 | the selective serotonin reuptake inhibitors.

01:03:58.500 | SSRIs, such as fluoxetine, Prozac, as well as Zoloft,

01:04:02.940 | and of course, there are many other SSRIs out there,

01:04:05.340 | citalopram, et cetera,

01:04:07.340 | they block the reuptake of serotonin

01:04:09.760 | and thereby lead to net increases

01:04:12.100 | in the amount of serotonin,

01:04:13.260 | and yet those drugs are not known to create

01:04:16.960 | even close to the same sorts of effects as MDMA.

01:04:21.740 | In fact, there have been human and animal studies showing

01:04:25.360 | that if you give somebody an SSRI

01:04:27.840 | prior to them taking MDMA,

01:04:30.200 | you actually block the prosocial

01:04:32.280 | and empathogenic effects of MDMA.

01:04:35.200 | Now, you might say, why in the world would that be?

01:04:37.800 | Aren't these drugs just increasing serotonin

01:04:40.080 | and the increase in serotonin is prosocial, et cetera?

01:04:43.200 | Ah, well, that speaks to the complexity

01:04:45.960 | of all this polypharmacology

01:04:47.460 | and the fact that it's really the activation

01:04:50.200 | of serotonin at particular receptors,

01:04:53.000 | in this case, the serotonin 1B receptor,

01:04:55.300 | in particular brain areas.

01:04:57.040 | In this case, the nucleus accumbens,

01:04:59.160 | a brain area associated with motivation and reward

01:05:02.740 | that largely explains the effects of MDMA

01:05:06.240 | in making people and animals,

01:05:08.120 | and octopuses included for that matter,

01:05:11.640 | more prosocial and more empathic towards themselves.

01:05:16.040 | It's not just an issue of raising

01:05:19.040 | the levels of one neurochemical.

01:05:20.960 | It's really about raising levels

01:05:22.960 | of a particular neurochemical

01:05:24.440 | acting in particular receptors, in particular brain areas.

01:05:27.420 | And in the case of MDMA,

01:05:29.520 | the fact that there's also dopamine increased

01:05:31.680 | in those very same brain areas, right?

01:05:33.760 | I don't think I mentioned this before,

01:05:35.040 | but the nucleus accumbens

01:05:36.360 | is part of that mesolimbic reward pathway

01:05:38.820 | that is essentially establishing a reward

01:05:40.820 | for whatever is happening at the moment.

01:05:43.500 | So the way to conceptualize MDMA

01:05:45.640 | and its effects on the brain,

01:05:47.460 | both subjectively and mechanistically,

01:05:50.080 | is that it's an empathogen

01:05:52.040 | for which empathy and social connection

01:05:54.840 | is very strongly reinforced

01:05:56.800 | while under the influence of the drug,

01:05:58.900 | and in a way so intense and powerful

01:06:02.300 | that those neural networks get stronger

01:06:04.280 | and persist in being more active

01:06:06.840 | for long periods of time after the drug has worn off.

01:06:10.200 | I'd like to just take a brief break

01:06:11.800 | and thank one of our sponsors, which is Element.

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01:06:16.080 | that has everything you need and nothing you don't.

01:06:18.300 | That means plenty of salt, sodium, magnesium, and potassium,

01:06:21.940 | the so-called electrolytes, and no sugar.

01:06:24.760 | Now, salt, magnesium, and potassium

01:06:26.920 | are critical to the function of all the cells in your body,

01:06:29.440 | in particular to the function of your nerve cells,

01:06:32.100 | also called neurons.

01:06:33.280 | And we now know that even slight reductions

01:06:35.920 | in electrolyte concentrations or dehydration of the body

01:06:39.120 | can lead to deficits in cognitive and physical performance.

01:06:42.720 | Element contains a science-backed electrolyte ratio

01:06:45.240 | of 1,000 milligrams, that's one gram, of sodium,

01:06:48.360 | 200 milligrams of potassium, and 60 milligrams of magnesium.

01:06:51.860 | I typically drink Element first thing in the morning

01:06:53.920 | when I wake up in order to hydrate my body

01:06:56.040 | and make sure I have enough electrolytes.

01:06:57.820 | And while I do any kind of physical training

01:07:00.080 | and after physical training as well,

01:07:01.600 | especially if I've been sweating a lot,

01:07:03.400 | and certainly I drink Element in my water

01:07:06.240 | when I'm in the sauna and after going in the sauna,

01:07:08.700 | because that causes quite a lot of sweating.

01:07:10.380 | If you'd like to try Element, you can go to Drink Element,

01:07:13.360 | that's lmnt.com/huberman,

01:07:15.940 | to claim a free Element sample pack with your purchase.

01:07:18.240 | Again, that's drinkelementlmnt.com/huberman.

01:07:22.460 | Now, one of the things that's been explored

01:07:24.680 | in both the animal literature and the human literature

01:07:27.420 | is that MDMA doesn't just increase dopamine

01:07:30.900 | and doesn't just increase serotonin,

01:07:32.500 | but it also profoundly increases levels

01:07:35.440 | of oxytocin release in the brain.

01:07:37.840 | Now, oxytocin is considered what's called a neurohormone

01:07:41.160 | because it acts as both a neurotransmitter,

01:07:44.240 | or I guess if we were going to be really specific,

01:07:46.700 | we'd say a neuromodulator

01:07:48.040 | because it tends to modulate the activity

01:07:49.840 | of a bunch of other circuits, and a hormone.

01:07:52.080 | How can we say it's a hormone or a modulator or a transmitter?

01:07:55.800 | Well, hormonal effects tend to be effects

01:07:57.920 | that act not just locally,

01:07:59.420 | but on many sites within the brain and body as well.

01:08:02.360 | And oxytocin is known to do that as well as to work locally.

01:08:05.300 | So that's what we call a neurohormone.

01:08:08.020 | It activates neurons and is associated with neural networks

01:08:11.260 | related to pair bonding, both between parent and child,

01:08:14.400 | both mother and child, and father and child,

01:08:17.180 | or caretaker and child, not just biological parent,

01:08:21.340 | as well as bonding between friends, bonding between lovers.

01:08:26.080 | And it's thought to actually be involved in the process,

01:08:29.820 | that is the painful process of breaking of bonds

01:08:32.940 | when people are no longer available to us as caretakers

01:08:37.000 | or as partners, either by way of breakup,

01:08:40.160 | death, departure, et cetera.

01:08:41.800 | In fact, there are even data suggesting

01:08:43.500 | that humans can have strong oxytocin responses

01:08:46.100 | to their pets, in particular dogs,

01:08:48.220 | and their dogs can have strong oxytocin patterns of release

01:08:52.140 | in response to their owners.

01:08:54.000 | I think for any dog lovers or dog owners,

01:08:56.640 | certainly includes me, I'm raising my hand,

01:08:59.180 | that comes as no surprise.

01:09:00.420 | Anyone that's ever had to put down a dog

01:09:02.240 | or has lost a dog and here, no disrespect to the cat owners,

01:09:05.580 | but I'm just referring to the studies

01:09:07.000 | that have been done on humans and dogs,

01:09:09.540 | you can certainly relate to the incredible pain

01:09:13.280 | of that loss.

01:09:14.600 | Oxytocin is thought to be involved in bonding

01:09:17.220 | between people and other creatures,

01:09:19.180 | as well as the breaking of those bonds.

01:09:22.280 | MDMA is known to powerfully increase oxytocin release.

01:09:26.940 | In fact, there's a really nice study on this done in humans.

01:09:30.220 | This is a study I'll provide a link to

01:09:31.620 | in the show note captions entitled

01:09:32.860 | Plasma Oxytocin Concentrations Following MDMA

01:09:36.220 | or Intranasal Oxytocin in Humans.

01:09:39.160 | Nowadays, oxytocin is available by nasal inhaler.

01:09:42.900 | To be honest, I don't know the legality around it.

01:09:44.940 | I don't know if it's gray market or,

01:09:47.120 | but what I'm about to tell you will basically discourage you

01:09:49.540 | from wanting to take it,

01:09:50.500 | because what they found in this study was

01:09:53.580 | people given either 0.75 or 1.5 milligrams per kilogram

01:09:59.900 | of body weight of MDMA experienced increases in oxytocin.

01:10:04.460 | However, it was only the group that took 1.5 milligrams

01:10:08.160 | per kilogram of body weight of MDMA

01:10:11.340 | that experienced the really big significant changes

01:10:14.140 | in oxytocin.

01:10:15.060 | And when I say really big,

01:10:16.360 | really highly statistically significant,

01:10:18.960 | what they observed is that in the placebo group,

01:10:21.860 | because of course they include a placebo group,

01:10:24.260 | the amount of circulating oxytocin

01:10:27.540 | was 18.6 picograms per milliliter,

01:10:31.020 | which to you probably means nothing.

01:10:32.940 | And to me also sort of means nothing

01:10:34.620 | because those units of oxytocin can't be directly related

01:10:38.000 | to any kind of direct experience of feeling bonded

01:10:40.840 | or not bonded.

01:10:41.680 | That's just a number, but nonetheless,

01:10:43.180 | it provides a baseline to compare to the average levels

01:10:47.540 | of oxytocin in the bloodstream of people

01:10:49.740 | that were given 1.5 milligrams per kilogram of MDMA,

01:10:52.780 | which is 83.7 picograms per milliliter.

01:10:57.020 | That equates to nearly a five-fold increase

01:10:59.400 | in the amount of circulating oxytocin

01:11:01.340 | when people are under the influence of MDMA.

01:11:04.220 | Now, this study had a bunch of different conditions,

01:11:07.340 | not just MDMA of different doses, not just placebo.

01:11:12.200 | They also had people take oxytocin by nasal spray,

01:11:16.300 | which we know can change levels of circulating oxytocin.

01:11:19.900 | And indeed when measured in the study,

01:11:21.500 | it did change levels of circulating oxytocin.

01:11:24.660 | And the end point in the study was to have people

01:11:27.660 | give subjective ratings of their feelings

01:11:29.940 | of connectedness to one another, as well as rate.

01:11:33.860 | And here I'm just drawing directly from the paper

01:11:35.460 | of how much they like the feeling, how much they felt high.

01:11:39.260 | They measure their heart rate, their systolic pressure,

01:11:41.300 | their diastolic blood pressure, et cetera.

01:11:43.660 | And they looked at how social people felt.

01:11:47.020 | They looked at how insightful people felt.

01:11:49.540 | And the key takeaway from this study

01:11:52.020 | for sake of our discussion here today

01:11:54.440 | is that it does not, again, it does not appear

01:11:58.900 | that the increases in oxytocin produced by taking MDMA

01:12:03.700 | are the source of the prosocial effects of MDMA.

01:12:07.800 | And that's also what was found in the animal studies of MDMA

01:12:12.020 | where in those studies, mice were given MDMA

01:12:15.680 | at comparable doses.

01:12:17.360 | The doses were a little bit higher

01:12:18.820 | than used in the human studies.

01:12:20.660 | But at comparable doses, big increases in oxytocin

01:12:24.620 | were observed, increases in sociability

01:12:28.300 | of those mice were observed,

01:12:29.460 | just as they are in humans that take MDMA.

01:12:32.060 | But in those mice, they were also given a drug

01:12:35.260 | to block the oxytocin receptor.

01:12:37.420 | And lo and behold, no changes in sociability were observed.

01:12:41.640 | In humans that take oxytocin by nasal spray,

01:12:44.660 | you can see big increases in oxytocin.

01:12:47.020 | That's not surprising, gets across the blood brain barrier.

01:12:49.960 | Oxytocin goes up and levels of sociability do not increase.

01:12:54.960 | So what this points to is a situation

01:12:57.400 | where MDMA is increasing dopamine to increase motivation

01:13:01.240 | and to reward something, what gets rewarded?

01:13:03.920 | Well, what gets rewarded is the serotonin activation

01:13:07.340 | of particular brain networks associated with sociability.

01:13:10.640 | And the dramatic increases in oxytocin

01:13:13.760 | that are very, very real when people take MDMA

01:13:17.980 | do not appear to underlie any of the known short

01:13:21.920 | or long-term subjective effects of MDMA.

01:13:24.900 | Now, a conclusion like that needs to have a caveat.

01:13:28.500 | And the caveat is that as far as we know,

01:13:31.260 | the big increases in oxytocin that are produced by MDMA

01:13:34.740 | aren't doing anything for the sorts of effects

01:13:37.260 | that we've been talking about here,

01:13:38.440 | sociability, empathy, et cetera,

01:13:41.120 | but there could be other effects of oxytocin

01:13:42.980 | that we're just not aware of.

01:13:44.600 | That said, the data from both animal models and in humans

01:13:48.120 | really point to the fact that the increases in oxytocin

01:13:50.860 | that are produced by MDMA are not directly related

01:13:54.060 | to any of the short and long-term effects of MDMA

01:13:56.680 | that we are most familiar with,

01:13:58.020 | namely motivation, sociability, increased empathy,

01:14:02.440 | or the longstanding changes in neural circuitry

01:14:05.760 | that underlie, for instance, reduced threat detection

01:14:08.640 | or reduced connectivity between threat detection centers

01:14:11.160 | of the brain and interoception.

01:14:13.240 | So is the big increase in oxytocin produced by MDMA

01:14:16.920 | completely irrelevant in the context of this discussion?

01:14:20.580 | We don't know.

01:14:21.500 | It appears that it's not very relevant.

01:14:24.860 | Is oxytocin a meaningless molecule, right?

01:14:27.800 | After all, they gave these people

01:14:29.000 | nasal infusions of oxytocin.

01:14:31.240 | Oxytocin went way up.

01:14:33.060 | It didn't observe anything very interesting or significant

01:14:36.440 | in the context of sociability,

01:14:38.240 | but we do know that oxytocin can play a powerful role

01:14:40.880 | in pair bonding and in human-human-human-animal bonding

01:14:44.320 | of various kinds from other experiments that have been done.

01:14:46.900 | So I don't want to diminish the incredible power

01:14:49.560 | that oxytocin has in our brains and bodies,

01:14:51.960 | but it doesn't appear that the MDMA-induced increases

01:14:56.640 | in oxytocin, which are enormous,

01:14:59.480 | have much to do with anything related to the value of MDMA

01:15:03.120 | as a treatment for PTSD or for its subjective effects

01:15:06.480 | on empathy, sociability,

01:15:08.360 | or any of those other factors either.

01:15:10.560 | Now, perhaps the one caveat to that

01:15:12.520 | is that Harriet DeWitt's laboratory,

01:15:14.400 | which I referred to earlier,

01:15:15.840 | has looked at how variations in oxytocin receptor genes

01:15:20.840 | vary between people.

01:15:22.940 | So it turns out that some people have an allele,

01:15:25.860 | basically a version of the oxytocin receptor

01:15:29.280 | that is different from other people

01:15:30.480 | that makes oxytocin work differently

01:15:32.920 | and actually less effectively

01:15:34.280 | in activating certain brain networks.

01:15:35.920 | And it does appear that when those people take MDMA,

01:15:39.800 | they actually experience less of a prosocial effect

01:15:44.700 | of the drug.

01:15:46.000 | Now, that spits in the face of everything I just said

01:15:48.400 | about oxytocin not being involved in the effects of MDMA

01:15:51.320 | on prosociability and empathy.

01:15:53.160 | I think the bulk of the data really point to the fact

01:15:56.800 | that it's the serotonin increases

01:15:59.160 | combined with the dopamine increases caused by MDMA

01:16:02.320 | that lead to most of the understood effects.

01:16:05.160 | And that oxytocin, if it's playing a role,

01:16:07.280 | is going to play a more minor role.

01:16:10.280 | Let's talk about the safety

01:16:11.680 | and potential neurotoxicity of MDMA.

01:16:14.340 | And here, I really want to highlight

01:16:16.280 | that our discussion today is couched

01:16:18.800 | in a discussion about the application of pure MDMA

01:16:23.740 | to animals or humans in the context of laboratory

01:16:27.320 | or clinical studies.

01:16:29.140 | This is really important to point out

01:16:30.520 | because I would be remiss if I didn't note

01:16:33.560 | that there is a lot of recreational use of MDMA.

01:16:37.760 | In fact, it was the recreational use of MDMA in the 1980s,

01:16:42.360 | but really that took off,

01:16:44.760 | even exploded in the 1990s with so-called rave culture

01:16:48.380 | that created the massive attention on illegality of MDMA

01:16:53.380 | and put the drug enforcement agencies onto MDMA

01:16:57.040 | as a drug that they wanted to and indeed do restrict.

01:17:00.500 | In fact, just today, in anticipation of this episode,

01:17:03.760 | I put MDMA into the search function on Google

01:17:07.280 | and clicked news, and there were at least two reports

01:17:10.200 | of major MDMA seizures and busts.

01:17:12.880 | So again, I want to highlight the fact

01:17:14.320 | that MDMA is still illegal to possess or sell

01:17:17.640 | and certainly to traffic.

01:17:19.480 | I also want to highlight the fact that nowadays,

01:17:22.400 | all recreational drugs, but certainly MDMA included,

01:17:26.080 | are often, in fact, very often contaminated with fentanyl

01:17:30.320 | and while fentanyl has certain clinical uses,

01:17:33.000 | fentanyl is highly deadly.

01:17:35.040 | The current estimates are as much as 60%,

01:17:38.200 | maybe even 80% of drugs that are sold on the gray market

01:17:41.680 | are being repackaged or reformulated with fentanyl,

01:17:44.900 | and there have been a lot of fentanyl-related deaths,

01:17:47.200 | both in kids and adults.

01:17:48.900 | So the sourcing of MDMA is extremely important

01:17:51.640 | and the safety issues simply cannot be overlooked.

01:17:54.980 | And I say that not to protect me,

01:17:57.500 | I say that to protect you, right?

01:17:59.820 | The last thing any of us want is for someone

01:18:02.340 | to take a compound thinking it's one compound

01:18:04.640 | and it contains another compound

01:18:06.240 | and them getting hurt or even dying,

01:18:09.160 | and that is happening a lot, a lot,

01:18:11.080 | and it is certainly happening a lot for people

01:18:13.240 | that think that they're buying MDMA.

01:18:15.040 | The use of MDMA in the laboratory or in the clinical setting

01:18:21.080 | with pure MDMA has also been explored

01:18:25.000 | for the potential neurotoxicity of MDMA.

01:18:27.380 | So how would methamphetamine and MDMA be neurotoxic?

01:18:30.240 | Well, that's because they increase dopamine

01:18:32.400 | in the case of methamphetamine

01:18:34.320 | and dopamine and serotonin in the case of MDMA,

01:18:36.780 | and they do so to a very high degree.

01:18:39.000 | The big increases in dopamine and serotonin,

01:18:42.880 | but in particular, the big increases in dopamine

01:18:45.060 | tend to promote electrical activity of other neurons.

01:18:48.080 | Remember, these are after all neuromodulators,

01:18:50.480 | they modulate up or down the activity of other neurons

01:18:52.880 | and dopamine tends to modulate

01:18:54.360 | the activity of other neurons up.

01:18:56.920 | So dopamine itself is not neurotoxic,

01:18:59.160 | but when a lot of dopamine is released, it is neurotoxic.

01:19:02.140 | And it's well known that even a single dose of methamphetamine

01:19:05.780 | can be neurotoxic, not just for dopamine neurons,

01:19:09.000 | but for other types of neurons as well,

01:19:10.580 | including serotonergic neurons.

01:19:12.880 | Put differently, we know that the brains of people

01:19:15.200 | that take methamphetamine degenerate to a small

01:19:18.660 | or to a large degree, depending on how often

01:19:20.900 | they take the drug, how potent the drug is,

01:19:22.680 | and whether or not they combine it with other drugs.

01:19:24.540 | And yes, if you heard that combining caffeine

01:19:28.380 | with amphetamines can increase the neurotoxicity

01:19:31.500 | of amphetamines, such as methamphetamine, that is true.

01:19:33.660 | If you've heard that taking caffeine within the hours

01:19:36.420 | or same day as MDMA can increase the toxicity of MDMA,

01:19:40.940 | that does appear to be true based on animal studies.

01:19:44.460 | Now, there are not a lot of studies looking

01:19:46.740 | at the toxicity of MDMA in humans, but there are a few.

01:19:50.640 | There are also studies looking at the toxicity of MDMA

01:19:53.080 | in animal models, including non-human primate models.

01:19:56.580 | Now, this is a very complex literature, a lot of results,

01:19:59.700 | not all over the place, but they're scattered

01:20:02.380 | in a number of ways.

01:20:03.220 | First of all, some of the animal studies have used dosages

01:20:05.940 | of MDMA as high as two milligrams per kilogram

01:20:08.880 | of body weight, as high as three milligrams per kilogram

01:20:12.820 | of body weight, and even an upwards of that.

01:20:15.540 | But even for the animal studies that used a range

01:20:19.420 | of dosages from 0.75 to 1.5 milligrams per kilogram

01:20:22.780 | of body weight, there is some evidence

01:20:25.380 | that in laboratory mice or rats, there can be some loss

01:20:29.560 | of serotonergic tone in the brains of animals

01:20:33.720 | that have been administered MDMA.

01:20:35.480 | Now, notice I said serotonergic tone,

01:20:37.560 | I didn't say serotonin neurons.

01:20:39.580 | Because of the way that MDMA works in encouraging

01:20:44.080 | or promoting big releases in dopamine,

01:20:46.180 | big releases in serotonin, it's not surprising

01:20:48.740 | that if the animals that were given MDMA

01:20:50.580 | are subsequently sacrificed, say later that day

01:20:53.220 | or the next day, maybe even a week or two weeks later,

01:20:56.380 | and those brains are stained for proteins

01:20:58.580 | that are related to the synthesis or release of serotonin,

01:21:01.740 | it's not surprising that there would be reductions

01:21:03.980 | in those sorts of proteins, right?

01:21:06.140 | After all, a lot of dopamine and serotonin is released

01:21:09.220 | and it can be depleted.

01:21:11.380 | But I should point out, depletion of a neuromodulator

01:21:14.600 | in the short term is not the same thing

01:21:16.500 | as depletion of that neuromodulator in the long-term,

01:21:19.220 | nor is it the same as loss of the neurons

01:21:21.780 | that release dopamine and serotonin itself.

01:21:24.620 | So there are data pointing to the fact

01:21:26.500 | that repeated administration of MDMA

01:21:30.140 | at dosages that are very much within lines

01:21:32.500 | with what we're talking about today,

01:21:33.780 | 1.5 milligrams per kilogram of body weight,

01:21:36.460 | can lower total amounts of serotonin

01:21:39.140 | or other proteins in the serotonin synthesis pathway

01:21:42.060 | or dopamine or proteins that are

01:21:44.360 | in the dopamine synthesis pathway in specific areas

01:21:46.900 | of the brain related to reinforcement, related to mood,

01:21:50.300 | related to motivation, et cetera.

01:21:52.500 | However, the primate studies,

01:21:55.120 | or I should say the non-human primate studies,

01:21:56.980 | which are the sorts of animal studies

01:21:58.660 | that most closely mimic what one expects to see

01:22:01.580 | in the human brain, because after all,

01:22:03.620 | mice and the effects of these drugs in mice

01:22:05.860 | do translate to humans, but it's thought

01:22:07.780 | that non-human primates provide a model

01:22:09.460 | that's far more similar to humans.

01:22:12.620 | There, the data start to get kind of complicated

01:22:16.460 | in a way that suggests that MDMA might not be as neurotoxic

01:22:21.060 | as is thought based on the rodent studies.

01:22:23.460 | And this gets into a whole history of back and forth

01:22:27.180 | between different laboratories and governing bodies

01:22:30.260 | who are trying to keep MDMA illegal,

01:22:32.080 | as well as people such as the Sasha Shulgans of the world

01:22:35.940 | and people in the therapy community that are excited

01:22:38.240 | about the potential for MDMA becoming legal

01:22:40.500 | for the treatment of PTSD.

01:22:42.220 | And it really centers around one or two studies,

01:22:46.020 | both of which were published in very high profile journals.

01:22:48.720 | And the one that I'll highlight,

01:22:50.620 | because the results are now very clear and conclusive,

01:22:54.740 | is a study that was published back in 2002,

01:22:58.780 | which was entitled

01:22:59.820 | Severe Dopaminergic Neurotoxicity in Primates

01:23:02.660 | After a Common Recreational Dose Regimen of MDMA or Ecstasy.

01:23:07.660 | This paper was published in the journal Science,

01:23:10.260 | which is one of the three apex journals

01:23:12.300 | for publishing scientific research.

01:23:14.180 | So there's Science, Nature, and Cell.

01:23:17.240 | Those are the top, top journals,

01:23:18.460 | the most stringent journals

01:23:19.460 | to get scientific manuscripts into.

01:23:21.820 | The paper received a lot of attention

01:23:25.020 | because as you can imagine, based on the title,

01:23:27.020 | it suggested that even recreational doses of ecstasy,

01:23:29.400 | even if it's pure ecstasy

01:23:30.700 | and it doesn't have contamination

01:23:32.260 | from additional methamphetamine or other things in it,

01:23:35.660 | is neurotoxic to serotonergic and/or dopaminergic neurons.

01:23:39.700 | This is largely where MDMA got the reputation

01:23:42.060 | for "putting holes in your brain."

01:23:44.760 | However, this study came under a lot of scrutiny

01:23:49.260 | for a couple of reasons.

01:23:50.280 | First of all, and I'm certainly not saying this,

01:23:52.340 | but it was argued that the authors of the study

01:23:56.220 | were perhaps trying to prevent the legalization of MDMA

01:23:59.700 | for the treatment of PTSD.

01:24:02.220 | As far as I know, there's no direct evidence

01:24:04.320 | that that statement is true,

01:24:05.380 | but you will actually find that

01:24:06.900 | in some of the scientific journals.

01:24:08.180 | In fact, I was able to find an editorial

01:24:10.800 | that was published in the Biomedical Journal in 2003,

01:24:14.120 | which argued somehow that Dr. Ricarte was accused

01:24:19.120 | of "rushing his results into print

01:24:22.540 | because of legislation designed to curb ecstasy use

01:24:25.340 | before U.S. Congress."

01:24:26.400 | So, you know, there were some connotations,

01:24:29.260 | or rather there were some strong suggestions

01:24:31.340 | that there was a political backing

01:24:32.660 | to trying to get this study done quickly

01:24:34.420 | and into print and so forth.

01:24:36.400 | I don't think that ever really got resolved.

01:24:38.180 | What did get resolved, however,

01:24:40.380 | is that the very study in question was retracted, okay?

01:24:45.340 | So the authors themselves published a letter of retraction

01:24:49.440 | that unfortunately is not as well recognized

01:24:52.140 | as the paper that stimulated this idea

01:24:55.300 | that MDMA is neurotoxic in primates.

01:24:57.820 | And keep in mind that we are human primates,

01:25:00.000 | non-human primates being the closest model

01:25:01.740 | to human primates that we are aware of.

01:25:03.540 | But to make a long story short,

01:25:05.500 | there were some issues of labeling of MDMA

01:25:09.660 | versus other drugs in the laboratory.

01:25:11.640 | There were some issues of mislabeling,

01:25:13.380 | all of which were eventually acknowledged

01:25:15.260 | by the authors of the study.

01:25:16.940 | And they concluded, in fact,

01:25:18.540 | they verified based on some very detailed analysis

01:25:22.200 | that what these monkeys were injected with

01:25:25.500 | was not actually MDMA,

01:25:27.780 | but rather was methamphetamine itself.

01:25:31.220 | So what's not often acknowledged

01:25:32.740 | is the retraction of the paper on neurotoxicity.

01:25:36.060 | And unfortunately, the neurotoxicity issue

01:25:39.000 | is often what's mentioned.

01:25:40.220 | Now, keep in mind,

01:25:41.380 | there are studies in rodents showing neurotoxicity of MDMA,

01:25:44.820 | perhaps even at recreational doses.

01:25:47.140 | But to date, at least to my knowledge,

01:25:49.600 | there don't seem to be any data

01:25:51.180 | in either non-human primates or in humans

01:25:54.300 | showing toxicity of MDMA at clinically relevant doses,

01:25:58.060 | provided it is pure MDMA.

01:26:00.820 | I want to be very clear.

01:26:01.820 | I'm not saying that if you can get pure MDMA

01:26:04.860 | that you should take it or that it won't be neurotoxic.

01:26:07.460 | Certainly, we can expect

01:26:09.020 | that because of the huge known variation

01:26:11.760 | in dopamine receptors, in serotonin receptors,

01:26:14.860 | and of course, because of the known interactions

01:26:17.440 | between MDMA and other compounds, in particular caffeine,

01:26:21.300 | but also drugs such as cocaine or other stimulants,

01:26:26.140 | that some people might experience more toxicity

01:26:28.740 | to a given dose of MDMA compared to somebody else.

01:26:32.060 | And there's really no way

01:26:32.900 | to detect that susceptibility to neurotoxicity.

01:26:36.120 | Now, what we do know is that there are people

01:26:38.280 | in the general population that have taken a lot of MDMA,

01:26:42.020 | anywhere from one to 200

01:26:44.360 | or sometimes even in excess of 400 doses of MDMA.

01:26:47.340 | And there now are studies

01:26:48.640 | that have explored the neurotoxicity

01:26:51.460 | and perhaps even more importantly,

01:26:53.560 | the neurocognitive and behavioral effects

01:26:56.400 | of taking MDMA either zero times, one time, five times,

01:27:01.400 | 40 times, 200 times, et cetera, et cetera.

01:27:05.980 | And one of the,

01:27:07.220 | what I would consider landmark studies in this area

01:27:10.240 | is a study entitled residual neurocognitive features

01:27:12.900 | of long-term ecstasy users

01:27:14.500 | with minimal exposure to other drugs.

01:27:17.220 | And those words with minimal exposure to other drugs

01:27:20.120 | is really key in the context of this conversation.

01:27:23.300 | Because as I mentioned before, interactions between drugs,

01:27:27.320 | what's called polypharmacology, can create neurotoxicity.

01:27:31.000 | It's unclear if MDMA is neurotoxic,

01:27:33.420 | but we know methamphetamine on its own is neurotoxic.

01:27:37.280 | We also know that people often will combine MDMA

01:27:41.060 | and methamphetamine.

01:27:42.100 | We also know that a lot of so-called MDMA out there

01:27:45.240 | is mostly methamphetamine with only a little bit of MDMA.

01:27:48.760 | So a study of the sort that I'm about to describe

01:27:51.900 | where it is essentially confirmed

01:27:54.200 | that people were taking pure MDMA

01:27:56.080 | and not taking any other drugs is of immense value.

01:27:59.720 | This study has been a little bit controversial.

01:28:03.540 | In fact, I've talked about it before.

01:28:05.320 | I talked about it on the Joe Rogan podcast.

01:28:06.940 | I've talked about it briefly with a guest on this podcast,

01:28:09.640 | Dr. Nolan Williams, who's a triple board certified physician,

01:28:12.460 | psychiatrist and neurologist

01:28:13.680 | at Stanford School of Medicine.

01:28:15.520 | And it's an interesting study and a little bit controversial

01:28:17.840 | because it relied on a population of people

01:28:20.800 | who have taken MDMA anywhere from one to 200 times

01:28:26.200 | and who've not taken any other drugs, including caffeine.

01:28:31.200 | And the population in mind here

01:28:34.420 | is a population of people living in Utah

01:28:38.040 | who self-identify as members

01:28:40.480 | of the Church of Latter-day Saints,

01:28:42.120 | sometimes referred to as Mormons,

01:28:43.520 | sometimes referred to as LDS

01:28:44.960 | or of the Church of Latter-day Saints.

01:28:47.040 | The Church of Latter-day Saints, as I understand,

01:28:50.140 | does not allow for taking of certain compounds,

01:28:53.980 | certain drugs, certainly most recreational drugs,

01:28:57.920 | alcohol, even caffeine.

01:29:00.100 | And I'm sure there's some variation on some of those themes,

01:29:02.540 | depending on where people live

01:29:04.440 | and the certain communities that they happen to be in.

01:29:06.460 | I am in no way, shape or form declaring

01:29:09.100 | that I'm an expert on Latter-day Saints.

01:29:12.780 | I have a couple of friends who are LDS.

01:29:15.260 | I happen to be very nice people.

01:29:16.300 | As far as I know, they were not the people in this study,

01:29:19.100 | but this study really emphasized ecstasy users,

01:29:22.700 | as they're called, who have not taken other drugs,

01:29:25.260 | who self-identify as LDS.

01:29:27.240 | And the major takeaway of this study was that for moderate,

01:29:32.780 | meaning people who have taken ecstasy

01:29:35.740 | anywhere from 22 to 50 times in their lifetime,

01:29:40.680 | as well as heavy users of MDMA,

01:29:42.580 | so these are people who have taken MDMA

01:29:44.240 | anywhere from 60 to 450 times in their lifetime,

01:29:49.380 | there was little evidence of decreased cognitive performance

01:29:53.460 | in standard assays for cognitive performance.

01:29:57.460 | Now, there were some effects showing poor,

01:30:01.040 | here I'm quoting from the findings,

01:30:02.980 | poor strategic self-regulation,

01:30:05.700 | quote, "Possibly reflecting increased impulsivity."

01:30:08.340 | However, when you see a conclusion like that,

01:30:11.380 | you should immediately be thinking chicken versus egg,

01:30:13.940 | right, it could be that people that are more impulsive

01:30:16.540 | and that have less strategic self-regulation

01:30:20.900 | are more likely to take ecstasy 450 times,

01:30:24.140 | you could conclude that,

01:30:25.060 | or you could conclude that people who have taken ecstasy

01:30:28.260 | 75 times or 25 times, et cetera,

01:30:31.940 | are degrading their levels of self-control

01:30:35.620 | and thereby increasing impulsivity.

01:30:37.160 | The direction of the effect is not known,

01:30:39.040 | these are purely correlations.

01:30:40.380 | Nonetheless, this study and a few others like it

01:30:43.900 | really stand as our best evidence,

01:30:46.380 | believe it or not, as to how ecstasy taken many times,

01:30:51.380 | because after all these people are taken anywhere

01:30:53.620 | from 22 to 450 doses of ecstasy in their lifetime,

01:30:57.460 | is producing severe detriments in cognitive performance

01:31:00.660 | and that simply does not appear to be the case.

01:31:02.940 | Now, unfortunately, there are no data

01:31:04.980 | looking at the brains of these individuals,

01:31:08.020 | looking at, for instance,

01:31:09.120 | which brain structures are active or less active,

01:31:11.100 | or perhaps even looking at levels of serotonin or dopamine,

01:31:14.460 | all things that can be done with

01:31:16.460 | positron emission tomography imaging,

01:31:18.180 | functional MRI, et cetera.

01:31:20.500 | Hopefully those studies will be done

01:31:21.640 | in the not too distant future.

01:31:23.220 | But if we were to just take a step back from all the data,

01:31:25.820 | the data in mice, in rats, in non-human primates,

01:31:28.240 | the retraction of the study in non-human primates,

01:31:31.100 | which showed that the primates

01:31:33.460 | that showed neurodegeneration were not given MDMA

01:31:36.340 | as it was thought by the researchers,

01:31:37.740 | but rather as later was acknowledged,

01:31:39.420 | were actually given methamphetamine.

01:31:41.460 | And we take into account these moderate and heavy users

01:31:44.860 | of MDMA who, as far as we know,

01:31:46.660 | are being honest and haven't taken any other drugs.

01:31:49.580 | And we look at the clinical studies

01:31:52.140 | where people who have never taken MDMA

01:31:54.500 | are given one or two or three defined doses of pure MDMA.

01:31:58.700 | We'll talk about those studies in a moment.

01:32:00.580 | I think the gestalt, the top contour,

01:32:04.140 | the overall view of those studies is that

01:32:07.900 | provided it is pure MDMA

01:32:10.540 | and provided the individual is not consuming other drugs

01:32:14.500 | which have the potential to be neurotoxic

01:32:17.180 | and provided that it's being done

01:32:18.860 | in a controlled clinical setting,

01:32:21.740 | the risk for toxicity seems quite a bit lower

01:32:25.140 | than the popular press has promoted.

01:32:27.860 | And yet there is still the risk of neurotoxicity

01:32:31.540 | if people are taking high doses of MDMA

01:32:33.820 | or taking it very frequently,

01:32:35.500 | or certainly if they are taking it

01:32:37.660 | in conjunction with other drugs

01:32:40.060 | or, or I should say, and/or taking MDMA in settings

01:32:45.060 | that can promote neurotoxicity.

01:32:47.020 | And the settings I'm referring to are any settings

01:32:49.380 | in which blood pressure or body temperature

01:32:52.420 | have the propensity to be greatly increased.

01:32:55.300 | Every study in mice and non-human primates and in humans

01:32:58.980 | in which MDMA is administered

01:33:00.540 | has observed significant increases

01:33:02.860 | in blood pressure and heart rate.

01:33:04.140 | MDMA is after all a psychostimulant.

01:33:07.340 | It's a sympathomimetic.

01:33:09.100 | Talk about sympathomimetics and what that means

01:33:10.820 | in the episode on Adderall and Vyvanse and ADHD.

01:33:13.940 | But basically it's ramping up the activity

01:33:15.980 | of the sympathetic nervous system,

01:33:17.280 | which is your fight or flight system, okay?

01:33:19.820 | This is why people who take these drugs get big pupils,

01:33:22.260 | you know, big pupils of the eyes.

01:33:23.820 | This is why they feel agitated, they want to talk a lot.

01:33:25.540 | They feel like they want to move a lot.

01:33:27.220 | This is why people take it to dance at raves, et cetera.

01:33:29.620 | But when people take sympathomimetics,

01:33:31.620 | whether or not it's MDMA or amphetamine or cocaine

01:33:34.700 | or even caffeine,

01:33:35.980 | there's an increase in blood pressure and heart rate,

01:33:38.220 | but also body temperature.

01:33:40.180 | And if that's done in an environment

01:33:41.980 | in which there's very little temperature regulation,

01:33:44.520 | so people aren't, for instance,

01:33:46.260 | drinking enough fluids and electrolytes,

01:33:48.660 | it's very hot in the room,

01:33:50.540 | you can get neurotoxicity based on temperature effects.

01:33:53.460 | And that's because serotonin and dopamine

01:33:55.720 | also act on the so-called medial pre-optic area

01:33:57.980 | of the hypothalamus,

01:33:58.820 | which is involved in temperature regulation.

01:34:00.620 | If you're curious about temperature regulation,

01:34:02.260 | I covered a lot of that in the episodes

01:34:04.060 | of the Huberman Lab Podcast on deliberate cold exposure

01:34:06.100 | and deliberate heat exposure.

01:34:07.700 | This is an area I used to work on many years ago

01:34:10.320 | as a research scientist before moving on to other topics

01:34:13.320 | to research in my laboratory.

01:34:14.780 | Big increases in body temperature are not good.

01:34:19.540 | The body, and in particular your brain,

01:34:21.420 | can tolerate decreases in body temperature

01:34:24.180 | that are pretty robust and you can still stay safe.

01:34:29.180 | You're not going to kill neurons,

01:34:30.360 | but even an increase of three or four degrees

01:34:33.500 | in body temperature can start to kill off neurons.

01:34:36.340 | So when thinking about the potential neurotoxicity of MDMA,

01:34:39.260 | the conditions, that is the environmental conditions,

01:34:42.820 | the behavioral conditions under which somebody takes MDMA

01:34:46.340 | are vitally important, at least important, I would argue,

01:34:49.620 | as any other compounds they might be ingesting with MDMA.

01:34:52.620 | So that's something really serious to consider.

01:34:55.200 | So if somebody says MDMA puts holes in your brain,

01:34:58.020 | you would be correct in being skeptical

01:35:00.940 | or at least giving them some counterarguments

01:35:03.260 | for that statement.

01:35:04.400 | But if somebody says MDMA is not toxic,

01:35:07.080 | well then you would be equally valid in saying,

01:35:10.200 | ah, wait, but we need to think about the conditions

01:35:12.180 | under which MDMA is being taken.

01:35:14.040 | Is it pure MDMA or is it mostly methamphetamine?

01:35:16.320 | In which case it would be very toxic.

01:35:17.640 | Is it MDMA alone or in conjunction with caffeine

01:35:22.040 | within that same 24 hour period?

01:35:23.600 | Is it MDMA while moving around a lot or being outdoors

01:35:27.700 | or being in an environment,

01:35:28.920 | perhaps a rave or dance type environment

01:35:30.600 | where temperature is going up?

01:35:31.520 | Well, in that case, it could be very neurotoxic.

01:35:34.220 | So pharmacology of MDMA counts,

01:35:37.100 | but so does polypharmacology,

01:35:38.920 | the ingestion of other compounds,

01:35:41.020 | not just during the MDMA session,

01:35:43.200 | but also in the 24 hours before and after that MDMA session.

01:35:47.060 | And behaviors will certainly impact temperature,

01:35:51.080 | which will impact whether or not MDMA is neurotoxic or not.

01:35:54.940 | And despite my efforts,

01:35:55.900 | I couldn't find out whether or not the LDS community

01:35:59.360 | has officially sanctioned the use of MDMA.

01:36:02.480 | Certainly that's one possibility,

01:36:03.760 | but I have no evidence for that.

01:36:05.180 | Or rather whether or not certain people

01:36:07.840 | within the LDS community have allowed themselves,

01:36:10.920 | given themselves permission to use MDMA

01:36:13.680 | and they are not using other drugs.

01:36:15.500 | What I do understand to be the case

01:36:17.720 | is that people within the LDS community

01:36:19.760 | are discouraged from using drugs

01:36:22.060 | like caffeine or cocaine or alcohol.

01:36:24.620 | And this particular population of people

01:36:26.840 | that was explored in this study self-identify as LDS

01:36:31.680 | and self-identify as having taken MDMA

01:36:34.320 | anywhere from 22 to 450 times.

01:36:37.280 | But where they got permission for that,

01:36:38.960 | whether or not it was from someone else or from themselves,

01:36:41.260 | I do not know.

01:36:42.100 | What I do know is that

01:36:43.760 | within the acknowledgements of the paper,

01:36:45.920 | there's actually a thank you to the person

01:36:49.220 | that identified this "unique population" for our study.

01:36:53.600 | So I welcome you to take a look at the paper.

01:36:56.220 | And if any of you know more about

01:36:59.400 | if and how a particular subgroup within the LDS community

01:37:03.020 | is allowed to take MDMA,

01:37:04.720 | perhaps you want to put those

01:37:05.680 | in the comment section on YouTube.

01:37:07.520 | Before moving to our discussion about what MDMA is doing

01:37:12.220 | and the effects that people are seeing

01:37:13.600 | in the clinical studies for the treatment of PTSD,

01:37:16.400 | which by the way, are extremely exciting.

01:37:18.160 | I can't wait to share these data with you.

01:37:20.160 | I do want to touch on something that

01:37:22.360 | anyone who's heard about MDMA

01:37:24.360 | or perhaps used MDMA is familiar with.

01:37:27.600 | And that's the so-called crash that people experience

01:37:30.120 | after MDMA.

01:37:31.780 | There are a lot of myths about the post MDMA crash.

01:37:35.200 | And there's a lot of lore out there on the internet

01:37:37.080 | about how to offset the crash

01:37:39.520 | and a lot of lore about how to prevent

01:37:41.320 | the potential neurotoxicity of MDMA.

01:37:43.820 | Earlier, we talked about some of the major points

01:37:45.880 | around offsetting neurotoxicity.

01:37:48.200 | So certainly making sure that any MDMA that one takes

01:37:51.660 | is in the legal clinical setting,

01:37:54.360 | that it's therefore pure MDMA, right?

01:37:56.840 | That it's not cut with other things,

01:37:59.240 | which certainly can increase toxicity,

01:38:01.200 | controlling the temperature of one's environment,

01:38:04.060 | restricting caffeine intake,

01:38:06.600 | at least on the day of MDMA ingestion,

01:38:11.600 | but certainly the day before and the day after

01:38:14.160 | would be advantageous as well,

01:38:15.400 | simply because of the way that caffeine

01:38:17.680 | and activation of the adenosine receptor,

01:38:19.780 | as well as caffeine's effects on dopamine receptors

01:38:22.000 | can interact with the potential,

01:38:24.040 | again, potential neurotoxicity of MDMA.

01:38:26.660 | But the crash that one experiences after MDMA

01:38:29.780 | is actually a phenomenon very common

01:38:32.220 | to the crash that one experiences

01:38:33.800 | after ingestion of any type of stimulant,

01:38:36.280 | cocaine, amphetamine, et cetera.

01:38:38.660 | And the crash that we're referring to is a drop in mood,

01:38:42.160 | increase in lethargy, feelings of lack of motivation.

01:38:46.100 | Many people have wrongly assumed

01:38:48.760 | that the crash was due to quote unquote,

01:38:51.260 | depletion of serotonin or depletion of dopamine,

01:38:54.140 | or maybe even death of serotonergic and dopaminergic neurons.

01:38:57.240 | And while certainly that could be the case,

01:38:59.320 | it's very unlikely that that would be the case

01:39:01.440 | in the immediate 24 or 48 hours after MDMA ingestion.

01:39:06.100 | That said, you will see protocols

01:39:10.000 | that people have put out on the internet such as,

01:39:11.700 | oh, you know, after taking MDMA,

01:39:13.600 | you should take a bunch of, you know,

01:39:15.120 | 5-HTP or other precursors to serotonin or dopamine,

01:39:19.800 | which come in amino acid form.

01:39:21.580 | So L-tryptophan, for instance, is the amino acid precursor

01:39:26.480 | to serotonin, it's in the serotonin synthesis pathway.

01:39:29.860 | You'll hear that people will take L-tyrosine,

01:39:32.040 | which is the amino acid precursor to dopamine

01:39:34.160 | as a way to try and buffer or increase dopamine

01:39:37.260 | during the so-called period of the crash.

01:39:39.700 | There's really no evidence

01:39:41.260 | that any of those things can be beneficial.

01:39:43.960 | And there is actually some reason to believe

01:39:46.700 | that it might be detrimental

01:39:48.200 | because if anything, taking L-tryptophan

01:39:51.080 | and taking L-tyrosine

01:39:53.360 | would actually further deplete serotonin and dopamine.

01:39:56.000 | So the logic there is simply not very good.

01:39:59.480 | What is clear, however, is that MDMA can cause

01:40:03.800 | not just profound increases

01:40:05.180 | in dopamine, serotonin, and oxytocin,

01:40:07.800 | but that anytime there's a big increase in dopamine,

01:40:11.320 | there is going to be a post dopaminergic increase

01:40:14.600 | in prolactin release.

01:40:16.440 | And prolactin is a hormone,

01:40:18.640 | sometimes considered a neurohormone,

01:40:20.160 | but it's really a hormone that's involved in a lot of things,

01:40:22.360 | milk let down in lactating women.

01:40:24.880 | It's involved in setting the refractory period

01:40:27.240 | to sexual arousal and erection and ejaculation in males

01:40:32.160 | after ejaculation.

01:40:34.000 | It's involved in lots of different functions

01:40:36.780 | in the brain and body,

01:40:37.720 | including the laying down of body fat stores.

01:40:40.160 | And it's also associated with increases in lethargy,

01:40:43.500 | decreases in dopamine.

01:40:45.480 | This is why drugs that increase dopamine

01:40:48.800 | are known to decrease prolactin,

01:40:51.120 | at least in the short term.

01:40:52.960 | This is why drugs like cabergoline, for instance,

01:40:56.740 | that increase dopamine are used

01:40:58.680 | as ways to suppress prolactin.

01:41:00.820 | Now, MDMA ingestion is known

01:41:02.440 | to dramatically increase prolactin,

01:41:05.480 | and people are starting to realize

01:41:07.760 | that it perhaps is the increase in prolactin

01:41:11.080 | that occurs both during and for some period of time,

01:41:14.080 | probably hours or days after ingestion of MDMA

01:41:18.040 | that leads to at least some components

01:41:20.120 | of the so-called crash,

01:41:21.200 | that feeling of lethargy and lack of motivation,

01:41:24.640 | maybe diminished mood, et cetera.

01:41:26.440 | And for that reason,

01:41:27.740 | some people have started to explore the use of things

01:41:29.860 | like P5P, which is essentially a metabolite of vitamin B6,

01:41:34.860 | which is known to suppress prolactin

01:41:38.000 | as a way to try and buffer some of that crash.

01:41:40.840 | To my knowledge, there are no human data yet exploring

01:41:45.000 | the use of P5P or other vitamin B6 derivatives

01:41:48.760 | or cabergoline or things of that sort

01:41:50.960 | to reduce prolactin in a controlled,

01:41:54.640 | standardized clinical trial kind of manner.

01:41:57.000 | But I've spoken to some of the clinicians

01:41:59.100 | that are using MDMA legally

01:42:01.640 | within the context of the treatment of PTSD.

01:42:04.680 | And this is an area that's starting

01:42:06.480 | to receive some additional attention.

01:42:08.360 | So I just mention it briefly here because, for instance,

01:42:11.040 | there's a lot of ideas out there

01:42:12.260 | that people should be taking L-tryptophan,

01:42:14.880 | they should be taking L-tyrosine,

01:42:16.320 | they should be taking magnesium, other things, et cetera,

01:42:19.000 | after taking MDMA in order to recover

01:42:21.320 | from the post-MDMA crash more quickly.

01:42:24.120 | But it's really the increase in prolactin,

01:42:26.520 | which speaks most directly to the subjective effects

01:42:30.260 | of the so-called crash.

01:42:31.560 | So by my read of the mechanisms of MDMA,

01:42:34.280 | the neurochemicals it releases,

01:42:35.760 | the neurohormones that it promotes the release of,

01:42:38.520 | prolactin in particular,

01:42:40.040 | this P5P suppression of prolactin

01:42:43.000 | is perhaps the one that's most intriguing

01:42:44.600 | and that really has any kind of mechanistic basis.

01:42:47.080 | So I promise that going forward,

01:42:48.800 | as the scientists and clinicians that are using MDMA

01:42:51.180 | for the treatment of PTSD and other conditions,

01:42:53.540 | such as alcohol use disorder, et cetera,

01:42:56.200 | start to explore the use of post-MDMA session P5P

01:43:00.560 | and other modes of suppressing prolactin

01:43:03.200 | for the hours and days after MDMA,

01:43:05.340 | promise to update you on those findings.

01:43:07.320 | Throughout today's episode,

01:43:08.440 | I've been referring to clinical studies,

01:43:10.720 | that is clinical trials,

01:43:12.840 | exploring the use of MDMA

01:43:15.160 | in order to augment treatment for PTSD.

01:43:18.760 | So let's just take a moment and talk about what PTSD is.

01:43:22.320 | PTSD is post-traumatic stress disorder.

01:43:25.600 | Trauma is anything that modifies the brain

01:43:29.900 | to function less well going forward.

01:43:33.240 | You can have physical trauma,

01:43:34.240 | you can have emotional trauma.

01:43:35.840 | Typically PTSD is used to refer to emotional trauma

01:43:40.200 | caused by either single events.

01:43:42.400 | So you can imagine car accident, sexual assault.

01:43:46.320 | These could be first person experiences.

01:43:49.000 | So things that happened to somebody

01:43:50.800 | that leads to trauma and then PTSD.

01:43:53.960 | These can also be third person events

01:43:56.640 | where someone observes something that is traumatic to them.

01:44:00.480 | Maybe somebody being killed, dismembered,

01:44:02.520 | any number of different things

01:44:03.760 | that could be very traumatic in the immediate and longterm.

01:44:06.840 | And of course, PTSD need not be caused

01:44:10.400 | only by single event traumas,

01:44:12.440 | but by multiple event traumas,

01:44:14.640 | entire relationships, entire childhoods,

01:44:17.760 | wartime experiences, combinations of different traumas

01:44:21.460 | and on and on.

01:44:22.520 | There are so many different forms of trauma.

01:44:24.880 | If any of you are interested in trauma and its treatment,

01:44:27.920 | I highly recommend the book "Trauma" by Dr. Paul Conte.

01:44:31.280 | He's an MD, medical doctor, psychiatrist.

01:44:33.680 | He was featured as a guest on this podcast.

01:44:35.800 | He's been on a number of other prominent podcasts.

01:44:38.240 | We will provide a link in our show note captions

01:44:40.640 | to the book "Trauma."

01:44:41.880 | I consider that book to be the best book

01:44:45.160 | in terms of describing what trauma is and isn't

01:44:47.880 | and how it leads to PTSD.

01:44:49.200 | It also describes some of Dr. Paul Conte's own experiences

01:44:52.640 | with trauma and his own treatment of trauma

01:44:55.840 | in his patient population,

01:44:57.140 | which is quite wide ranging men, women, young people,

01:45:00.000 | older people, and a variety of traumatic experiences.

01:45:02.960 | So excellent book for those of you interested in trauma.

01:45:06.240 | Now, the treatment of trauma has been met

01:45:08.920 | with some degree of success through quality talk therapy.

01:45:12.820 | Let's define quality talk therapy

01:45:15.560 | in the way that Dr. Paul Conte did on this episode.

01:45:18.180 | That's talk therapy for which the patient,

01:45:20.820 | sometimes referred to as the client,

01:45:22.340 | but more traditionally referred to as the patient,

01:45:24.820 | and the therapist, so a psychologist or psychiatrist,

01:45:27.720 | has good rapport.

01:45:30.000 | And as a consequence of that rapport,

01:45:32.260 | there is the feeling of support,

01:45:34.060 | that there is a safe place in which to explore the trauma

01:45:37.860 | and what's happening in one's current life

01:45:40.000 | in order to understand how that trauma

01:45:41.720 | is fitting into adaptive and maladaptive behaviors

01:45:44.800 | and emotional states.

01:45:46.600 | Now, in addition to rapport and support being critical,

01:45:49.580 | there's a third component of effective talk therapy

01:45:53.540 | for trauma, which is insight,

01:45:55.280 | where one's ability to come to an understanding

01:45:58.020 | of why one feels the way they do

01:46:01.220 | and to link that to some larger context,

01:46:04.000 | that brings about some degree of relief.

01:46:06.620 | And that's where things start to get a little bit abstract.

01:46:09.820 | And that's also where we start to see that

01:46:13.060 | while trauma therapy in the form of talk therapy

01:46:16.320 | can be very effective,

01:46:18.020 | about half of people that undergo talk therapy

01:46:22.140 | and talk therapy alone for the treatment of PTSD

01:46:25.120 | achieve no long lasting relief of symptoms,

01:46:28.420 | and an even smaller number of them

01:46:30.740 | undergo complete remittance of their PTSD, okay?

01:46:35.640 | So their symptoms can lessen,

01:46:39.460 | they can get some improvement,

01:46:41.320 | but that improvement is often slight or is transient.

01:46:45.520 | And for those that do achieve relief,

01:46:47.460 | it's often not complete remission of the PTSD itself.

01:46:52.460 | Now, in addition to talk therapy for PTSD,

01:46:55.480 | there is of course prescription drug therapies.

01:46:58.440 | And most often these fall under the category of SSRIs,

01:47:01.400 | selective serotonin reuptake inhibitors.

01:47:03.820 | And it's well known that SSRIs can be

01:47:07.680 | in limited circumstances effective for the treatment of PTSD.

01:47:10.680 | It has been shown, for instance, that as many as 40,

01:47:14.220 | maybe as many as 60% of people that take SSRIs

01:47:17.080 | for the treatment of PTSD get some symptom relief.

01:47:20.300 | Now, that is not to say that SSRIs don't have side effects.

01:47:23.440 | They can have side effects.

01:47:25.020 | Some of you are probably familiar with these side effects.

01:47:27.700 | Things like blunting of libido, blunting of appetite,

01:47:30.640 | or increases in appetite in some cases,

01:47:32.600 | disruption of sleep-wake rhythms, motivation, et cetera.

01:47:35.880 | So there's often an exploration

01:47:37.320 | for the so-called minimal effective dose

01:47:39.120 | that provides some symptom relief to PTSD,

01:47:42.200 | but that doesn't introduce unwanted side effects.

01:47:45.840 | And of course, there's a third situation

01:47:47.360 | where people are taking SSRIs

01:47:48.960 | and doing talk therapy for PTSD.

01:47:51.400 | And what's very clear is that anytime you add

01:47:53.560 | quality talk therapy to a drug treatment,

01:47:56.360 | you're going to improve the outcomes for that drug treatment.

01:47:59.960 | The reverse is not always true.

01:48:01.460 | It's not always the case

01:48:02.440 | that adding prescription drug treatment to talk therapy

01:48:04.700 | improves outcomes for talk therapy,

01:48:06.300 | although that has been observed in a number of studies.

01:48:09.120 | Now, the whole idea of exploring the use of MDMA

01:48:12.140 | for the treatment of PTSD stemmed from the fact

01:48:15.280 | that even in people who are getting quality talk therapy,

01:48:18.320 | and again, we can define quality talk therapy

01:48:20.480 | as good rapport between patient and clinician,

01:48:25.740 | as well as feelings of support,

01:48:27.780 | as well as potential insight.

01:48:30.640 | And even when SSRIs are combined

01:48:33.280 | with that quality talk therapy,

01:48:34.960 | there's still a large number of people

01:48:36.760 | who simply do not achieve significant

01:48:39.800 | or long-lasting relief from their PTSD,

01:48:42.780 | and an even fewer number

01:48:44.600 | who go into full remittance of their PTSD.

01:48:47.760 | That is despite being diligent

01:48:49.280 | and hardworking in their talk therapy,

01:48:51.080 | despite the therapist being very committed,

01:48:53.000 | despite the use of SSRIs in conjunction

01:48:55.140 | with that talk therapy,

01:48:56.840 | those people often still qualify as having PTSD.

01:49:00.840 | And the goal of course is for somebody

01:49:02.480 | to receive treatment that allows them

01:49:05.000 | to no longer meet the criteria for having PTSD,

01:49:08.820 | not just in terms of a clinical evaluation,

01:49:11.160 | but that they themselves report feeling much better,

01:49:13.820 | not feeling overwhelmed with the symptomology of PTSD.

01:49:17.520 | Now, the symptomology for PTSD is vast,

01:49:20.120 | and it's far too vast to go into

01:49:21.720 | into a lot of detail right now.

01:49:24.140 | I think most people are familiar

01:49:25.580 | with the stereotyped example of PTSD.

01:49:27.680 | This is the soldier that comes back from overseas

01:49:31.260 | that has been in gunfights or in battles of different kinds,

01:49:35.080 | has likely seen casualties and severe injuries,

01:49:38.160 | and that upon return to a safe environment

01:49:41.040 | is still experiencing a lot of anxiety,

01:49:43.640 | and sometimes panic attacks that occur seemingly at random,

01:49:46.320 | or that can be sparked by the classic stereotyped example

01:49:49.560 | is a car backfires,

01:49:50.840 | and then the person suddenly feels

01:49:52.200 | as if they're back in battle.

01:49:53.860 | That sort of thing does happen, certainly,

01:49:56.280 | but there are a whole other category of symptoms of PTSD,

01:50:00.580 | which include dissociative symptoms of PTSD,

01:50:03.080 | people who have PTSD from very intensely

01:50:06.520 | traumatic experiences that are checked out.

01:50:09.940 | They don't feel like they can engage.

01:50:11.520 | They have brain fog.

01:50:12.840 | They are distracted.

01:50:14.980 | They go from feeling anxious to feeling exhausted.

01:50:18.160 | They have sleep issues.

01:50:19.900 | Not surprisingly then,

01:50:21.000 | people with PTSD of either the dissociative type

01:50:24.400 | or other symptomology of PTSD,

01:50:26.920 | and keep in mind that one can have both dissociative

01:50:29.440 | and non-dissociative symptoms of PTSD,

01:50:31.620 | such as anxiety and panic,

01:50:33.120 | are at a far greater risk of substance abuse.

01:50:37.700 | So the current estimates are that people with PTSD,

01:50:40.240 | no matter what type of PTSD, dissociative symptoms,

01:50:43.520 | or otherwise, you know, panic attacks or both,

01:50:46.580 | are at a much greater risk of having addictions

01:50:50.680 | to either illicit drugs or prescription drugs or both.

01:50:54.480 | So things like alcohol use disorder

01:50:57.000 | is very common in people with PTSD.

01:50:58.900 | Opioid use disorder is very common.

01:51:01.160 | Stimulant use disorder, and on and on.

01:51:04.280 | So people with PTSD suffer at a number of different levels,

01:51:07.320 | and there are all these what are called comorbidities

01:51:10.640 | with PTSD, including addiction, but also depression, anxiety.

01:51:15.240 | And so you can start to see how PTSD

01:51:16.800 | sets up a whole cascade of things

01:51:19.200 | that make living life extremely problematic

01:51:21.880 | at the level of basic relationships,

01:51:23.800 | functioning in the workplace.

01:51:25.420 | And even when mental health appears to be in check,

01:51:28.760 | oftentimes people are holding a lot in,

01:51:30.800 | so they have cardiovascular and cerebral vascular deficits

01:51:34.480 | that cause a lot of problems

01:51:35.760 | in their immediate and long-term physical health.

01:51:38.240 | So PTSD is a very serious issue.

01:51:40.720 | The current estimates are that as many as 8% of people

01:51:43.560 | in the United States have PTSD.

01:51:46.460 | And again, the estimates around comorbidities

01:51:49.380 | range anywhere from 17 to 46 or as high as 65% of people

01:51:54.220 | with PTSD having comorbidities

01:51:55.860 | for other mental health issues and addiction in particular.

01:51:59.140 | So finding lasting relief to PTSD is extremely important

01:52:03.120 | and made even more important by the fact

01:52:05.280 | that many people with PTSD sadly end up committing suicide.

01:52:08.700 | So suicide rates are far greater in people with PTSD.

01:52:12.340 | The exact rates of increase in suicidality

01:52:14.980 | in people with PTSD are a little bit hard to arrive at

01:52:18.760 | in the statistics because of all the comorbidities,

01:52:21.240 | but suffice to say that suicide is far more likely

01:52:24.340 | in people with PTSD,

01:52:25.720 | along with all the other issues that PTSD brings about.

01:52:28.920 | Now, PTSD creates all the problems that it does,

01:52:31.840 | largely through changes in brain circuitry,

01:52:35.060 | as well as neural communication between the brain and body.

01:52:38.160 | Many people have perhaps heard of the book,

01:52:40.400 | "The Body Keeps the Score,"

01:52:41.760 | which is a very successful and popular book

01:52:44.740 | about the idea that trauma can be, quote unquote,

01:52:46.860 | "Stored in the body."

01:52:48.500 | To be clear, traumas can't actually be stored in the body.

01:52:52.000 | You don't actually store memories in the body.

01:52:54.840 | What you store are activation of neural circuits

01:52:57.940 | that include brain and body,

01:52:59.940 | and they all seem to center back into the insula,

01:53:04.340 | that structure that we talked about earlier,

01:53:05.820 | this structure in our brain

01:53:06.880 | that has a map of our body surface.

01:53:09.140 | So contrary to popular belief,

01:53:11.420 | we don't store memories in the body or trauma in the body

01:53:14.500 | in a way that, for instance,

01:53:16.100 | working out a knot or a pain in one's lower back

01:53:18.460 | will relieve the trauma.

01:53:19.980 | It sometimes can activate a memory of the trauma,

01:53:22.500 | but when one is doing that,

01:53:23.820 | what you're really doing is activating neural circuits

01:53:26.500 | that reside within the brain, within the insula,

01:53:29.340 | that correspond to sensations within the body.

01:53:32.160 | Now, I don't want to diminish the role of the body

01:53:33.940 | in the formation and the persistence of PTSD,

01:53:36.500 | and I certainly think the book,

01:53:37.460 | "The Body Keeps the Score" is a pioneering book.

01:53:40.420 | It's, in fact, an important book,

01:53:43.220 | but I want to emphasize that the modern neuroscience

01:53:45.820 | really points to the fact that PTSD

01:53:48.940 | is caused by the exact sorts of brain network activations

01:53:52.740 | that we were discussing earlier,

01:53:54.460 | things like heightened levels of activation

01:53:56.580 | in the amygdala to insula pathway,

01:53:58.900 | which, of course, would exacerbate bodily sensations

01:54:02.140 | related to the trauma,

01:54:03.740 | or heightened activation of the hippocampus,

01:54:05.860 | this memory center in the brain,

01:54:07.040 | to amygdala to insula circuitry.

01:54:09.460 | Now, therefore, it should come as no surprise

01:54:12.320 | that if MDMA can reduce the levels of activity

01:54:16.700 | in the hippocampal to amygdala to insula circuitry,

01:54:19.580 | and can do so both while someone

01:54:21.380 | is under the effects of MDMA,

01:54:22.700 | but then lead to persistent, long-lasting reductions

01:54:26.020 | in the activation of those brain networks,

01:54:27.980 | well, then it stands to reason

01:54:29.300 | that MDMA could be a valid therapeutic

01:54:32.740 | for the treatment of PTSD,

01:54:34.080 | and, of course, this has been explored,

01:54:36.840 | and here we can really give a nod

01:54:39.260 | and a large debt of gratitude to the so-called MAPS group.

01:54:43.860 | The MAPS group is a group that's operating

01:54:46.340 | mainly out of Santa Cruz, California,

01:54:48.040 | but they have a number of different satellite laboratories

01:54:50.120 | and clinical groups, both in the US, in Canada, and abroad,

01:54:54.060 | where they've worked with government organizations

01:54:56.020 | to get legal authorization to give MDMA

01:55:00.860 | to patients who have PTSD, to also give them talk therapy,

01:55:04.880 | and then to compare the effects of talk therapy with MDMA

01:55:08.560 | to talk therapy with placebo alone,

01:55:11.180 | and there are about three to five studies in this area now

01:55:14.780 | that stand as large-scale clinical trials

01:55:17.240 | that are showing what can only be described

01:55:19.820 | as remarkable results for the treatment of PTSD,

01:55:23.100 | so rather than going to any one of those studies

01:55:24.920 | in immense detail, I'm going to summarize

01:55:26.480 | across those studies.

01:55:27.320 | I will provide links to those in the show note captions.

01:55:30.580 | The two that I think are most interesting

01:55:33.920 | are the study entitled "MDMA-Assisted Therapy

01:55:37.000 | for Severe PTSD, a Randomized, Double-Blind,

01:55:39.420 | Placebo-Controlled Phase 3 Study,"

01:55:42.120 | as well as the study entitled

01:55:43.700 | "The Effects of MDMA-Assisted Therapy

01:55:45.560 | on Alcohol and Substance Use in a Phase 3 Trial

01:55:48.740 | for the Treatment of Severe PTSD."

01:55:50.660 | So as the title suggests, both clinical trials

01:55:52.620 | involve giving people talk therapy and MDMA,

01:55:55.340 | or talk therapy and placebo.

01:55:58.060 | Talk about exactly how that was done in a moment,

01:56:00.340 | and then to look at relief of PTSD symptoms,

01:56:03.100 | but also relief of some of the addictive symptoms

01:56:05.460 | that are commonly associated with PTSD.

01:56:08.160 | So just to give you an overview

01:56:09.760 | of what's happening with these trials

01:56:12.900 | and why there's so much excitement

01:56:14.680 | and why we really are on the cusp of legalization of MDMA

01:56:18.820 | for the treatment of PTSD

01:56:20.680 | in the sorts of clinical context I described,

01:56:23.240 | when people are given just talk therapy alone

01:56:28.360 | or talk therapy with SSRIs,

01:56:31.280 | they will often, as I mentioned earlier,

01:56:33.680 | experience reductions in their severity of PTSD symptoms,

01:56:38.220 | and rarely they will experience

01:56:39.960 | complete remittance of their PTSD.

01:56:43.020 | That is, they will no longer qualify for PTSD

01:56:45.160 | after receiving a number of talk therapy sessions.

01:56:48.000 | So let's compare that to what happens

01:56:49.580 | when people do talk therapy in conjunction with MDMA.

01:56:52.740 | And I'll explain exactly what that means in a moment,

01:56:54.760 | but it essentially means taking MDMA

01:56:57.420 | while doing talk therapy.

01:56:59.360 | However, this is a very important however,

01:57:02.180 | the people who are taking MDMA in these trials

01:57:04.100 | have already done talk therapy without MDMA,

01:57:07.840 | then they're doing talk therapy under the influence of MDMA,

01:57:11.320 | and then they are doing sessions of talk therapy

01:57:13.780 | not under the influence of MDMA,

01:57:15.800 | and the entire time they're doing that

01:57:17.200 | with the same two therapists, okay?

01:57:19.240 | In the placebo group,

01:57:20.680 | people are doing talk therapy with two therapists,

01:57:23.760 | but they're not taking MDMA, okay?

01:57:25.560 | So they're doing the same number of therapy sessions,

01:57:27.200 | but they're not taking MDMA.

01:57:28.600 | So to just get to the key numbers first,

01:57:31.880 | the overall rate for clinically effective response

01:57:34.180 | to MDMA assisted therapy is 88%.

01:57:37.820 | That's what's emerging from these trials,

01:57:40.580 | versus 60% for the placebo and therapy alone.

01:57:45.280 | So on the face of it, you might say,

01:57:47.140 | okay, wow, 88% of people who do talk therapy,

01:57:50.740 | and here I might as well just finally explain

01:57:52.580 | how this is done.

01:57:53.720 | Patients are selected because they have PTSD.

01:57:56.780 | They meet the clinical criteria for PTSD.

01:57:59.620 | They do three 90 minute therapy sessions with two therapists

01:58:04.280 | talking about their PTSD symptoms,

01:58:06.280 | talking about to the extent that they can,

01:58:08.380 | the incident or incidents,

01:58:10.820 | the life events that led to that PTSD.

01:58:12.900 | None of that is done under the influence of any drug, okay?

01:58:17.000 | So everyone in the experiment does that.

01:58:18.980 | Then the group divides into two,

01:58:22.760 | where half are taking MDMA.

01:58:26.580 | They take that three times.

01:58:29.480 | During those three times,

01:58:32.060 | they are also receiving therapy sessions

01:58:34.480 | with the same therapists that they were working with

01:58:36.780 | before they took MDMA.

01:58:38.100 | The first session, they're taking 80 milligrams of MDMA

01:58:42.220 | and then a 40 milligram booster

01:58:43.660 | about an hour and a half to two hours in.

01:58:46.160 | The second session, they are taking a higher dose of MDMA.

01:58:48.660 | It's 120 milligrams.

01:58:50.980 | And then if they elect to,

01:58:52.920 | they can take a 60 milligram booster

01:58:55.200 | about an hour and a half to two hours into the session.

01:58:59.240 | And then there's a third session

01:59:01.320 | where they take, again, 120 milligrams of MDMA

01:59:04.640 | and have the option to take a 60 milligram booster

01:59:08.000 | about an hour and a half to two hours into the session.

01:59:10.080 | Again, anytime they're on MDMA,

01:59:13.440 | they have therapists there

01:59:16.140 | that they're talking to about their trauma.

01:59:18.580 | They are either spending time

01:59:20.840 | with their eyes closed, lying down,

01:59:22.760 | sometimes in an eye mask and thinking about the trauma,

01:59:25.080 | thinking about their current state and experience,

01:59:28.140 | also thinking about what happened before.

01:59:30.160 | Then they're exiting the eye mask

01:59:31.960 | or talking to the therapist.

01:59:34.200 | The therapist is taking notes, asking questions.

01:59:36.200 | Remember, they've established a strong rapport,

01:59:39.300 | supportive relationship with these therapists

01:59:41.440 | prior to taking MDMA in the therapy session.

01:59:45.200 | And then they also undergo three 90-minute therapy sessions

01:59:49.360 | with the two therapists spaced one week apart

01:59:52.280 | after the final MDMA session.

01:59:55.400 | Now, those that were placed into the placebo condition

01:59:58.560 | do everything exactly the same as I just described.

02:00:01.100 | So three 90-minute sessions as prep,

02:00:03.040 | then three eight-hour sessions with those two therapists,

02:00:07.920 | and then three 90-minute follow-up sessions one week apart,

02:00:11.100 | but they take a placebo, not MDMA.

02:00:15.620 | So you can see that in these so-called MAPS studies,

02:00:17.720 | these clinical trials for PTSD,

02:00:20.040 | the conditions are very similar

02:00:21.480 | except for the inclusion of the drug MDMA.

02:00:25.480 | So those rates of success with talk therapy and MDMA,

02:00:29.720 | again, overall rate for clinically effective response

02:00:31.840 | to MDMA-assisted therapy was 88%

02:00:34.080 | compared to 60% for therapy and placebo.

02:00:38.040 | What's even more impressive, however,

02:00:41.240 | is that 67% of the people in the MDMA

02:00:45.860 | plus therapy treatment group

02:00:47.880 | no longer met the criteria for PTSD

02:00:50.660 | by the end of the treatment.

02:00:52.200 | So in other words, their PTSD went into remittance.

02:00:55.100 | Now, we could say they are quote-unquote cured,

02:00:58.360 | but typically for things like PTSD,

02:01:01.300 | that's not the language that's used.

02:01:03.160 | Rather, what's used is statistical evaluation

02:01:05.640 | of how the different symptoms like dissociation or anxiety

02:01:09.440 | or sleep disorders are explored.

02:01:12.520 | So while to some of you, a difference between 60% success

02:01:17.460 | with talk therapy and placebo versus 88% success

02:01:21.160 | with talk therapy plus MDMA

02:01:23.000 | might not seem like that big of a difference.

02:01:24.840 | It is indeed quite an enormous difference.

02:01:27.160 | In fact, to my knowledge, there is no other example

02:01:30.880 | of a treatment for a psychiatric disorder

02:01:33.740 | that is successful to the same magnitude.

02:01:36.840 | I could be wrong about that.

02:01:37.880 | I'm sure some psychiatrists out there

02:01:39.200 | are going to jump on me about this, and please do.

02:01:42.120 | I would encourage you, if you are aware of any therapy

02:01:45.600 | plus drug treatment that is effective

02:01:47.940 | at rates of greater than 88%

02:01:50.420 | for the treatment of a major psychiatric disorder,

02:01:53.620 | please do put that information in the comments on YouTube,

02:01:56.820 | and perhaps a reference to a study would be even better,

02:01:58.960 | but even if not, just put a reference to that.

02:02:01.400 | That would be great for sake of future episodes, et cetera.

02:02:04.280 | But nonetheless, an 88% success rate,

02:02:08.480 | and here I'm referring to success rate

02:02:09.920 | as a significant reduction in clinical symptoms for PTSD,

02:02:12.840 | and 67% of those people going into full remittance for PTSD

02:02:17.480 | by the end of the treatment is pretty spectacular,

02:02:20.760 | which is why you're hearing so much these days

02:02:22.620 | about the potential transition of MDMA

02:02:25.360 | from a schedule one drug for which there are, quote unquote,

02:02:27.940 | no clinical applications to potentially a legal

02:02:31.400 | within the context of clinical use application of MDMA,

02:02:36.400 | which it does appear the legislature is at least considering

02:02:39.880 | for as early as 2024, maybe even later in 2023.

02:02:44.720 | It remains to be seen.

02:02:46.680 | Now, a number of other important results have emerged

02:02:48.720 | from this and other clinical trials.

02:02:50.600 | For instance, remember earlier,

02:02:53.840 | I talked about how many people with PTSD

02:02:56.120 | also suffer from alcohol use disorder.

02:02:59.000 | What's interesting is that for people

02:03:01.160 | that were in the MDMA plus talk therapy group

02:03:04.560 | in this and other studies

02:03:06.880 | who also had patterns of alcohol use disorder

02:03:09.860 | and even some other substance use disorders,

02:03:12.080 | the MDMA plus talk therapy treatment

02:03:14.720 | in many cases resolved their addiction to alcohol

02:03:18.480 | or other symptoms as well,

02:03:20.480 | and perhaps that shouldn't be surprising

02:03:22.520 | if we think about the addictions

02:03:23.980 | as stemming directly from their PTSD,

02:03:26.940 | but it is surprising if you think about the fact

02:03:29.480 | that alcohol use disorder and some other addictive disorders

02:03:32.480 | oftentimes will stem from disruptions

02:03:36.360 | in neural circuitry that are the same disruptions

02:03:39.880 | in neural circuitry that occur in PTSD,

02:03:41.560 | but often are the consequence

02:03:43.460 | of entirely other brain wiring phenomenon.

02:03:46.440 | What I'm saying here is that just because addiction

02:03:48.600 | and PTSD are often comorbid with one another,

02:03:51.660 | it was not necessarily the case

02:03:53.680 | that treating and resolving PTSD would resolve the alcohol

02:03:57.480 | or substance abuse disorder,

02:03:58.840 | and yet that seems to be the case often, not always,

02:04:01.240 | but often in these successful treatments of PTSD.

02:04:03.780 | So that's very exciting.

02:04:05.400 | Some of the other particularly exciting results

02:04:07.520 | from these clinical trials on MDMA plus talk therapy

02:04:11.400 | is that the dissociative form of PTSD

02:04:14.840 | has traditionally proved to be especially hard to treat,

02:04:18.240 | and that's thought to stem from the fact

02:04:19.660 | that successful treatment of PTSD,

02:04:21.680 | whether or not it's by talk therapy

02:04:23.060 | or talk therapy combined with SSRIs

02:04:25.520 | or talk therapy combined with any drug treatment

02:04:28.520 | or behavioral treatment like EMDR,

02:04:30.920 | eye movement desensitization reprogramming,

02:04:33.080 | or other forms of treatments

02:04:35.940 | that are designed to rewire neural circuitry

02:04:39.320 | almost always involve the patient getting very close to,

02:04:44.120 | or at least reporting the traumatic experiences

02:04:47.160 | in a lot of detail.

02:04:48.680 | And you can imagine why for somebody

02:04:50.080 | who's dissociating from that very experience,

02:04:52.200 | who's "checked out" and can't really seem

02:04:55.200 | to access the emotional states and the memories

02:04:58.240 | because they're blocked off from them

02:04:59.740 | or because they're unwilling to access those memories

02:05:01.920 | and really think about the full emotional capacity

02:05:04.120 | of those memories,

02:05:05.560 | that it would be particularly hard to bring them

02:05:07.600 | through any kind of treatment for PTSD.

02:05:10.600 | So it appears that MDMA

02:05:12.240 | in providing this pro-social empathic,

02:05:15.320 | again, empathic for others and empathic for self,

02:05:18.400 | chemical and mental environment,

02:05:21.680 | as well as the presence of two trusted therapists,

02:05:24.480 | which one has a really good rapport,

02:05:27.580 | allows patients with PTSD to really get close

02:05:31.820 | to those experiences that were traumatic,

02:05:33.700 | to talk about them and to think about them,

02:05:36.140 | and in many ways to reframe them in a context

02:05:39.240 | that often involves empathy for others

02:05:41.940 | and empathy for self.

02:05:43.340 | Now here, we're not necessarily talking about

02:05:45.360 | forgiveness of perpetrators,

02:05:46.720 | although that's sometimes the case,

02:05:48.500 | that people will forgive the person

02:05:49.820 | that inflicted the trauma on them,

02:05:51.900 | but more often than not,

02:05:53.480 | it's about tying their feelings of trauma

02:05:56.420 | and their feelings of depression,

02:05:57.880 | anxiety, dissociation, et cetera,

02:06:00.540 | to some sort of larger context

02:06:02.200 | that allows them to see themselves in the role of agency,

02:06:06.480 | to be in the role of knowing that,

02:06:09.760 | yes, these things happened,

02:06:11.520 | and yet by getting close to the emotional load

02:06:14.800 | of those things and really being, in many ways,

02:06:18.060 | unafraid to get close to the emotional load of that

02:06:20.120 | and having support around that,

02:06:21.860 | that the emotional load seems diminished

02:06:24.220 | and that they experience the emotional load

02:06:26.160 | of those experiences as diminished

02:06:27.940 | both within the MDMA treatment session

02:06:29.940 | and afterwards for long periods of time.

02:06:32.580 | So essentially what happens is these people feel

02:06:35.060 | that once burdened them, they can still remember,

02:06:38.460 | but it no longer burdens them.

02:06:39.780 | It no longer feels like it's in their body

02:06:41.920 | and in their mind or on loop or on repeat

02:06:44.340 | in a way that's invasive,

02:06:46.140 | in a way that interferes with other aspects

02:06:48.580 | of normal functioning.

02:06:50.280 | So when one hears about these kinds of results,

02:06:52.680 | and when you hear about some of the patient reports,

02:06:55.120 | and I invite you to do that,

02:06:56.060 | you can go to the MAPS site,

02:06:57.820 | which by the way is recruiting subjects

02:06:59.500 | for these clinical trials.

02:07:00.700 | And you'll also find reports of individuals

02:07:04.160 | who participated in these clinical trials.

02:07:06.540 | And of course, we will provide links

02:07:07.900 | to these incredible clinical trials

02:07:10.060 | that MAPS has spearheaded.

02:07:12.320 | What you find is that the combination of MDMA

02:07:16.460 | and talk therapy in many ways

02:07:19.300 | is not about the drug having a particular effect.

02:07:23.100 | It's really about the drug having a particular effect

02:07:25.700 | that allows the motivations and the results of talk therapy

02:07:29.780 | to really be heightened.

02:07:31.580 | And I think that's a really key point to make

02:07:33.400 | because up until now,

02:07:34.240 | we've really been talking about the neurochemistry of MDMA,

02:07:36.780 | the potential toxicity or lack thereof of MDMA.

02:07:40.060 | We've been talking about the brain networks, et cetera.

02:07:42.860 | But when one thinks about the valid clinical use of MDMA

02:07:46.700 | for the treatment of PTSD,

02:07:48.620 | and I should mention it also had some success

02:07:52.180 | in dealing with not only alcohol use disorders

02:07:54.700 | and other use disorders associated with PTSD,

02:07:56.900 | but also relieving the depression associated with PTSD.

02:08:00.340 | So now MDMA is being explored for treatment of not just PTSD,

02:08:03.780 | but also for depression, for alcohol use disorder

02:08:05.820 | and for eating disorders as well.

02:08:07.460 | MDMA seems to be a compound

02:08:10.800 | that produces the right kind of subjective

02:08:13.320 | and neurochemical milieu in the brain

02:08:15.480 | that allows therapy to be that much more potent

02:08:18.640 | within a limited number of sessions.

02:08:20.580 | And when one thinks about the cost of mental health care,

02:08:23.580 | how expensive it is to get therapy

02:08:25.180 | over and over and over again,

02:08:26.340 | which in ideal circumstances, people are able to do that

02:08:29.740 | either by way of insurance or by their own finances,

02:08:32.320 | or I don't want to say that the cost of therapy

02:08:35.940 | should be reduced because of course,

02:08:37.260 | therapists have to survive also.

02:08:40.560 | But the idea here is that people who are suffering

02:08:43.320 | would be able to achieve relief from their PTSD,

02:08:46.080 | their depression, their addiction,

02:08:47.420 | and to be able to do so by hopefully

02:08:50.720 | persisting in their therapy

02:08:51.940 | over whatever period of time is required,

02:08:53.860 | but also to assume a circumstance

02:08:56.080 | in which somebody only has 10 or 15,

02:09:00.100 | or maybe even just three opportunities

02:09:02.860 | to undergo treatment for PTSD,

02:09:04.940 | and nonetheless is able to achieve tremendous relief

02:09:08.260 | during the session and after the session.

02:09:10.660 | And it really does seem to be the case

02:09:12.460 | that for reasons that you now understand,

02:09:15.620 | the activation of particular brain networks,

02:09:17.320 | the suppression of other brain networks,

02:09:19.300 | in particular this amygdala to insula pathway,

02:09:22.060 | that when people are under the influence of MDMA

02:09:24.680 | in these very safe and therapeutic supportive settings,

02:09:27.880 | they're able to look at traumatic events

02:09:30.020 | and the ways that those traumatic events impact them

02:09:32.980 | in ways that really allow them

02:09:34.420 | to cognitively reframe those events

02:09:36.340 | and somatically reframe those events,

02:09:38.940 | to really change the way that it lives in their body and mind

02:09:41.860 | so that it's no longer invasive,

02:09:43.700 | and then they can go on and lead productive, adaptive lives.

02:09:47.180 | And as a final point related to these clinical studies,

02:09:49.620 | I of course would be remiss

02:09:50.900 | if I didn't touch on some of the so-called adverse effects,

02:09:54.180 | because anytime there's a drug or talk therapy

02:09:56.580 | for a mental health issue,

02:09:59.180 | adverse events have to be considered.

02:10:01.780 | And I think it's quite reassuring

02:10:04.040 | that in the case of MDMA therapy,

02:10:06.660 | there were no increases in the number of suicide attempts

02:10:10.560 | or suicidality or obsession with suicide.

02:10:14.140 | Contrast that with the group that received placebo,

02:10:17.220 | where there were a certain number of baseline

02:10:20.140 | and predicted obsessions with suicide.

02:10:23.740 | Fortunately, at least to my knowledge,

02:10:25.160 | there was no actual suicide attempt

02:10:27.480 | or successful suicide, thankfully.

02:10:29.540 | But the point being that the addition of MDMA drug therapy

02:10:32.980 | to PTSD talk therapy does not seem to increase

02:10:36.700 | the quote unquote side effects

02:10:38.380 | that are sometimes associated with PTSD talk therapy,

02:10:40.900 | because indeed there can be side effects

02:10:42.940 | to exploring PTSD and trauma as one would expect.

02:10:46.700 | So overall, I would say it's very exciting times

02:10:48.940 | for the exploration of MDMA as an augment to talk therapy

02:10:52.340 | for the treatment of PTSD and these other conditions.

02:10:55.220 | Again, I think the MAPS group has done a remarkable job

02:10:59.020 | of keeping this within the realm of legal

02:11:01.480 | and trying to move things forward in terms of legislation

02:11:04.380 | to make sure that MDMA isn't simply made legal

02:11:07.120 | and then abused recreationally.

02:11:08.740 | I know people out there have different views

02:11:10.220 | on whether or not drugs like MDMA should be legal

02:11:12.860 | or not, that's not what this episode is about.

02:11:15.500 | What I am very excited about, as you can probably tell,

02:11:18.020 | and what I think a lot of people in the psychology

02:11:20.140 | and psychiatry community are very excited about,

02:11:22.500 | you say the mental health community at large,

02:11:24.740 | is that these compounds that for many years

02:11:28.080 | were only associated with their recreational uses

02:11:30.700 | and therefore were not well understood

02:11:33.740 | because they were often contaminated

02:11:35.440 | or taken in combination with other things

02:11:37.180 | or by people that never should have been taking them

02:11:39.660 | in the first place, taken by young kids,

02:11:42.920 | which is a whole other matter,

02:11:44.900 | lot of issues and problems associated with these compounds.

02:11:47.560 | And yet we're now seeing from these clinical trials

02:11:51.140 | when used say properly,

02:11:54.260 | because really when safety protocols are obeyed,

02:11:58.180 | when there's clinical support,

02:12:00.060 | it is very clear that when MDMA is combined

02:12:02.140 | with quality talk therapy,

02:12:04.300 | that the outcomes are looking tremendously positive.

02:12:07.540 | It's by no means a miracle cure,

02:12:09.540 | it is by no means perfect,

02:12:11.660 | and time will tell what problems if any arise

02:12:15.800 | from the short or long-term use of MDMA in this context.

02:12:19.060 | But I think it's remarkable

02:12:20.620 | that anywhere from two to three sessions with MDMA

02:12:23.140 | and talk therapy have been shown

02:12:24.980 | to significantly reduce PTSD symptoms,

02:12:28.140 | and in some cases completely eliminate PTSD symptoms

02:12:31.940 | in such a wide range of patients

02:12:33.940 | and in patients that have experienced both PTSD

02:12:37.100 | and these other comorbid disorders.

02:12:38.780 | I think it's really remarkable.

02:12:39.980 | It's very exciting.

02:12:40.980 | And I look forward to seeing

02:12:42.060 | what the next round of data produce.

02:12:44.160 | So as is often the case on this podcast,

02:12:46.720 | today we went into a lot of detail about a subject.

02:12:49.860 | MDMA is this incredible compound synthesized,

02:12:52.900 | as far as we know, first by humans,

02:12:54.620 | not by plants, not by aliens, but by humans.

02:12:57.980 | And that produces big increases in dopamine and serotonin

02:13:02.060 | to create these highly motivated pro-social empathic states,

02:13:07.180 | meaning both empathy for others and for self,

02:13:10.060 | and that when applied in the context

02:13:12.400 | of psychiatric challenges like PTSD and addiction

02:13:16.380 | is proving to create a lot of relief for a lot of people

02:13:19.760 | where other forms of drug therapy

02:13:22.100 | or combination drug and talk therapy had failed before.

02:13:26.400 | We talked about some of the potential neurotoxicity issues.

02:13:29.460 | I don't think that is a resolved issue just yet,

02:13:33.380 | although the bulk of data in humans and non-human primates

02:13:36.380 | point to the fact that at reasonable doses,

02:13:39.340 | and we talked earlier about what those are,

02:13:41.560 | at reasonable doses, when not combined with other drugs,

02:13:45.400 | does not appear that MDMA is exceedingly neurotoxic

02:13:49.020 | and it may not be neurotoxic at all.

02:13:51.380 | Of course, one needs to be exceedingly cautious

02:13:53.420 | when thinking about the use of any sympathomimetic.

02:13:57.260 | They, of course, can be neurotoxic.

02:14:00.260 | Anything with methamphetamine in it

02:14:01.700 | has the potential to be neurotoxic.

02:14:03.980 | But of course, dosage matters, context matters,

02:14:06.380 | we talked about that.

02:14:07.700 | And of course, the purity of drug matters.

02:14:11.020 | And again, I just want to reemphasize

02:14:12.840 | the fentanyl contamination of MDMA that's sold on the street

02:14:16.580 | and that is being used recreational

02:14:18.540 | is of very serious, potentially lethal concern.

02:14:21.860 | I also expect that there will be a lot of interest

02:14:23.680 | in these clinical trials that MAPS is doing.

02:14:25.540 | So again, you can find links to that

02:14:27.200 | in the show note captions.

02:14:28.860 | And I think in general, we should acknowledge

02:14:31.840 | that we are a very interesting and important time

02:14:34.700 | in human history for the treatment of psychiatric disorders

02:14:39.320 | and for neuroscience generally,

02:14:41.200 | because whether or not we're talking about psilocybin

02:14:43.000 | or LSD or ayahuasca or ketamine or today's topic of MDMA,

02:14:48.000 | regardless of what drug and neurotransmitter

02:14:51.360 | and neuromodulator systems are involved,

02:14:53.620 | what we're really talking about

02:14:54.880 | are ways to access neuroplasticity,

02:14:57.320 | the nervous system's incredible ability to modify itself

02:15:00.200 | in response to experience.

02:15:01.740 | Ideally to be modified in adaptive ways

02:15:05.120 | that make it function better.

02:15:06.400 | So that's really the crux of what talk therapy

02:15:08.460 | and drug therapies are about.

02:15:09.740 | That's what the goal of using MDMA

02:15:12.160 | as a clinical tool is all about.

02:15:14.520 | And in that sense, I find MDMA to be

02:15:17.200 | an incredibly interesting and important topic.

02:15:20.000 | And I hope you did as well.

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02:17:21.320 | Thank you again for joining me for today's discussion,

02:17:23.600 | all about MDMA.

02:17:25.400 | And last, but certainly not least,

02:17:27.640 | thank you for your interest in science.

02:17:29.440 | [upbeat music]

02:17:32.020 | (guitar strumming)

The Science of MDMA & Its Therapeutic Uses: Benefits & Risks | Huberman Lab Podcast

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