Medications That May Improve Memory & Brain Function | Dr. Mark D'Esposito & Dr. Andrew Huberman
00:00:00.000 | - Maybe we could talk about bromocriptine a little bit,
00:00:04.820 | and I'm not encouraging people to run out
00:00:06.860 | and take bromocriptine.
00:00:08.100 | Bromocriptine, as you mentioned, is a dopamine agonist,
00:00:12.980 | relatively short acting.
00:00:15.900 | - Yeah, four or five hours, six hours.
00:00:17.940 | - So kicks in about 90 minutes after,
00:00:20.340 | as I recall you saying, I've never taken it.
00:00:23.380 | How do people feel when they're on bromocriptine?
00:00:25.380 | I mean, when I hear dopamine agonist,
00:00:27.660 | I mean, there are a lot of illicit drugs
00:00:29.020 | like cocaine, methamphetamine that are increased dopamine,
00:00:32.740 | but then again, chocolate,
00:00:34.580 | sex and food increased dopamine,
00:00:36.100 | but the kinetics, the time course and the levels
00:00:38.900 | are different for each of those things.
00:00:41.340 | Dopamine, of course, being a currency of motivation
00:00:43.780 | and reward, not directly related to any one compound.
00:00:48.000 | But I would think that based on the data
00:00:52.460 | you just described that,
00:00:55.460 | and given the fact that there are a number of people
00:00:57.100 | out there with challenges in working memory,
00:00:59.220 | attention, task switching, et cetera,
00:01:00.900 | that there would be a strong interest
00:01:03.700 | on the part of the pharmaceutical companies at least,
00:01:06.060 | and certainly the general public,
00:01:07.780 | in things like bromocriptine to increase dopamine,
00:01:12.260 | to increase working memory, given it is our superpower.
00:01:15.880 | - Yeah, I mean, one of the most disappointing things to me
00:01:18.580 | in my career has been that pharmaceutical companies
00:01:21.060 | have not picked up on this idea
00:01:23.220 | that we could improve cognition
00:01:25.020 | and very specifically improve kind of process
00:01:27.000 | with very specific neuromodulators.
00:01:29.640 | The discovery that depletion of dopamine
00:01:31.760 | and not other transmitters impairs working memory
00:01:33.860 | was made in 1979.
00:01:36.660 | When I heard Pat Gomer, he used to talk about this
00:01:40.020 | as a resident, I was just amazed
00:01:41.860 | that there could be a single transmitter
00:01:44.220 | can change a single behavior.
00:01:46.400 | I was seeing very complicated behavioral deficits
00:01:49.540 | and it just seemed impossible to me
00:01:50.980 | that there could be such a tight link
00:01:52.700 | between a single neuromodulator
00:01:55.820 | and a single cognitive process
00:01:57.080 | and just opened the door for me
00:01:58.320 | that this really could be an incredibly beneficial therapy
00:02:02.160 | for anyone with executive function or frontal lobe function.
00:02:05.920 | So, but unfortunately there's never been
00:02:08.760 | a pharmaceutical company that's tried to develop a drug
00:02:11.500 | for improving cognition to this day.
00:02:15.080 | - And they, I mean, it's crazy for several reasons.
00:02:17.120 | One is that the data are clearly there.
00:02:19.480 | Two, these drugs are already established.
00:02:21.440 | It's not like they have to go through safety trials again,
00:02:24.040 | that's already been done.
00:02:25.080 | But mostly because regardless of whether one is a fan
00:02:28.560 | of the pharmaceutical industry or hates it,
00:02:30.720 | the pharmaceutical industry in principle
00:02:32.520 | can make a ton of money doing this.
00:02:33.760 | So I would think that they'd be heavily incentivized
00:02:35.600 | to do it.
00:02:36.420 | So why have they turned a blind eye on this?
00:02:39.240 | - I'm not sure.
00:02:40.080 | I mean, when I realized that I could test these drugs
00:02:44.880 | in healthy individuals, that they were,
00:02:47.720 | if I gave them in low enough doses, they were safe.
00:02:50.520 | And I had so much experience of them in patients
00:02:53.040 | that I felt comfortable doing it.
00:02:54.940 | Then I started asking pharmaceutical companies,
00:02:58.960 | do you want to get involved here?
00:03:00.120 | We can, we can, this should be done.
00:03:02.080 | I can't do this by myself.
00:03:03.720 | We need to have real trials and real studies
00:03:06.280 | of how this will help, you know?
00:03:07.640 | And just, it was, you know, their eyes would always cross
00:03:10.800 | and never, never got any, any sort of traction.
00:03:13.440 | It always went back to sort of disease.
00:03:15.680 | You know, what, what disease are you curing?
00:03:18.880 | You know, what, what's the market for it?
00:03:20.580 | Is it a Parkinson's disease thing?
00:03:21.880 | Is it Alzheimer's disease thing?
00:03:23.600 | And this has been a general problem with neurology.
00:03:25.880 | It's very disease centric.
00:03:27.480 | It's always sort of, and it's always focused on, you know,
00:03:30.080 | how can we develop a treatment for Alzheimer's
00:03:32.020 | or traumatic brain injury or stroke,
00:03:33.400 | as opposed to how can we develop a treatment
00:03:35.160 | for working memory dysfunction,
00:03:37.440 | which is a problem across diseases.
00:03:40.560 | So the answer to your earlier question
00:03:42.520 | is these drugs are very safe.
00:03:44.080 | They, we give them in such low doses to healthy individuals.
00:03:47.080 | They don't even know, they can't even tell the difference
00:03:50.000 | between the placebo and the drug.
00:03:52.520 | - Really?
00:03:53.360 | - They don't even know which one they're on.
00:03:54.680 | - So they're not buzzing, thinking like,
00:03:55.920 | "Oh, this feels good, and my working memory is better."
00:03:58.840 | - They have no idea.
00:03:59.680 | They don't even know their working memory is better.
00:04:01.000 | And so we show them that their working memory is better.
00:04:03.560 | - Love it.
00:04:04.400 | - Yeah.
00:04:05.220 | - So they're truly blind to what's going on.
00:04:07.480 | Bromocriptine is but one of the dopamine agonists.
00:04:11.040 | Can think of a few other, cabergoline,
00:04:14.320 | like other things like that.
00:04:16.460 | Do any of these dopamine agonists
00:04:19.380 | exert this impact on working memory,
00:04:22.000 | or is it, does it vary by drug
00:04:24.500 | because different dopamine agonists
00:04:26.740 | sort of hit different receptor pathways
00:04:29.020 | and things like that?
00:04:30.060 | - Yeah, no, it's not specifically the drug.
00:04:31.780 | I mean, the reason for bromocriptine
00:04:33.700 | is that it's the oldest,
00:04:34.960 | and it's the one I was most comfortable with.
00:04:36.720 | I had to be comfortable with it clinically
00:04:38.380 | before I'd give it to undergraduates at Penn or Berkeley.
00:04:41.620 | So there's nothing special, but other agonists work similarly.
00:04:45.500 | There's a drug that's developed,
00:04:47.820 | which is a COMPT inhibitor,
00:04:49.260 | which actually inhibits this enzyme
00:04:51.420 | that we're talking about.
00:04:52.420 | And that also will improve, will have the same function.
00:04:57.420 | There's been some future work that norepinephrine
00:05:01.500 | also seems to be helpful with working memory.
00:05:04.200 | It's not as, maybe not as potent as the dopaminergic.
00:05:09.200 | And that's the point I want to make.
00:05:11.260 | Another disappointing thing about this whole field
00:05:13.740 | with the pharmacology of cognition,
00:05:15.740 | I wrote a paper as a resident.
00:05:18.980 | Sometimes you're tending to say,
00:05:20.060 | "Hey, can you write this review paper for us?"
00:05:21.980 | And I wrote one as a resident
00:05:23.660 | called "The Pharmacology of Cognition,"
00:05:25.020 | where I just looked at all the animal literature
00:05:26.780 | on giving neuromodulators,
00:05:31.100 | acetylcholine, bromodotamine or whatever.
00:05:34.540 | And there was a lot of animal literature
00:05:37.740 | sort of supporting that this would work in humans,
00:05:40.140 | but what was more striking to me
00:05:42.340 | was that it wasn't always just a single neurotransmitter.
00:05:47.300 | There were studies where you'd give dopamine
00:05:49.620 | and it wouldn't do anything.
00:05:50.740 | You'd give acetylcholine and it wouldn't do anything.
00:05:52.620 | But if you gave a low dose of both,
00:05:54.980 | it would be really effective.
00:05:56.940 | So these neurotransmitter systems don't act in isolation.
00:06:00.760 | So we need to also study sort of how the combinations work.
00:06:04.380 | And that's where another,
00:06:05.460 | where the pharmaceutical companies have the infrastructure
00:06:08.340 | to do these kinds of studies.
00:06:09.540 | It's very hard to do in a single lab
00:06:11.140 | to do multiple drugs at one time,
00:06:15.220 | and then try and determine all the different interactions.
00:06:18.820 | - Maybe we could talk about a couple of other drugs
00:06:22.220 | that are legal and have FDA approval,
00:06:26.140 | are known to be safe in the right context
00:06:28.660 | that it seems would fit the bill here
00:06:33.020 | for improving working memory.
00:06:34.060 | One is Welbutrin.
00:06:37.060 | Bupropiron, I can never pronounce that.
00:06:41.500 | As far as I know, it's a epinephrine
00:06:44.900 | or norepinephrine agonist.
00:06:46.620 | You just mentioned that increasing epinephrine
00:06:48.700 | may have a positive impact on working memory
00:06:50.980 | and to some extent, a dopamine agonist.
00:06:53.060 | Is there any evidence that Welbutrin
00:06:55.580 | can improve working memory?
00:06:57.460 | - Yeah, anything that boosts norepinephrine can do it.
00:07:00.380 | The one that we've used, that's most used is Guanfacine,
00:07:03.700 | which is actually a blood pressure medication.
00:07:05.560 | So that's starting to gain some traction.
00:07:07.500 | In fact, I think there was a study with COVID,
00:07:09.780 | with brain fog for COVID,
00:07:11.180 | showing that improved symptoms with it.
00:07:13.780 | So there's actually some trials now
00:07:15.980 | that are looking at Guanfacine.
00:07:17.860 | And so I would say anything that boosts norepinephrine
00:07:20.340 | would be helpful.
00:07:22.340 | But then again, I don't wanna leave out
00:07:25.100 | the other transmitters.
00:07:26.260 | Increasing serotonin, increasing acetylcholine
00:07:30.700 | boosts other cognitive processes.
00:07:32.580 | And then in a way, they can help working memory.
00:07:35.600 | We talked about working memory being this foundation.
00:07:38.200 | Well, if you give acetylcholine and it kinda boosts memory,
00:07:41.920 | well, that can indirectly help your executive function.
00:07:44.440 | Or if you give a drug that improves your focus,
00:07:47.840 | then that can indirectly help working memory.
00:07:50.560 | So what I'm really pushing for is not just a single,
00:07:54.040 | it's gonna be one drug, it's gonna be a cocktail.
00:07:57.560 | And we have to not only figure out what the cocktail is,
00:08:00.820 | but also figure out who we're giving it to,
00:08:02.880 | link it to the person's own makeup
00:08:06.480 | of their own neurochemistry.
00:08:08.160 | When we get to a point where we'll know,
00:08:10.200 | we can map out sort of everyone's dopamine,
00:08:12.440 | norepinephrine, serotonin levels,
00:08:14.120 | then we'll make real progress in helping them.
00:08:16.960 | Because right now, I sort of say with my students,
00:08:19.840 | what we're doing is just like cutting open the skull
00:08:22.520 | and just sort of pouring it onto the brain.
00:08:24.400 | - We're not actually doing that.
00:08:26.080 | - We're not actually doing it, but it seems that way.
00:08:28.920 | The precision is not there yet.
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