- Maybe we could talk about bromocriptine a little bit, and I'm not encouraging people to run out and take bromocriptine. Bromocriptine, as you mentioned, is a dopamine agonist, relatively short acting. - Yeah, four or five hours, six hours. - So kicks in about 90 minutes after, as I recall you saying, I've never taken it.

How do people feel when they're on bromocriptine? I mean, when I hear dopamine agonist, I mean, there are a lot of illicit drugs like cocaine, methamphetamine that are increased dopamine, but then again, chocolate, sex and food increased dopamine, but the kinetics, the time course and the levels are different for each of those things.

Dopamine, of course, being a currency of motivation and reward, not directly related to any one compound. But I would think that based on the data you just described that, and given the fact that there are a number of people out there with challenges in working memory, attention, task switching, et cetera, that there would be a strong interest on the part of the pharmaceutical companies at least, and certainly the general public, in things like bromocriptine to increase dopamine, to increase working memory, given it is our superpower.

- Yeah, I mean, one of the most disappointing things to me in my career has been that pharmaceutical companies have not picked up on this idea that we could improve cognition and very specifically improve kind of process with very specific neuromodulators. The discovery that depletion of dopamine and not other transmitters impairs working memory was made in 1979.

When I heard Pat Gomer, he used to talk about this as a resident, I was just amazed that there could be a single transmitter can change a single behavior. I was seeing very complicated behavioral deficits and it just seemed impossible to me that there could be such a tight link between a single neuromodulator and a single cognitive process and just opened the door for me that this really could be an incredibly beneficial therapy for anyone with executive function or frontal lobe function.

So, but unfortunately there's never been a pharmaceutical company that's tried to develop a drug for improving cognition to this day. - And they, I mean, it's crazy for several reasons. One is that the data are clearly there. Two, these drugs are already established. It's not like they have to go through safety trials again, that's already been done.

But mostly because regardless of whether one is a fan of the pharmaceutical industry or hates it, the pharmaceutical industry in principle can make a ton of money doing this. So I would think that they'd be heavily incentivized to do it. So why have they turned a blind eye on this?

- I'm not sure. I mean, when I realized that I could test these drugs in healthy individuals, that they were, if I gave them in low enough doses, they were safe. And I had so much experience of them in patients that I felt comfortable doing it. Then I started asking pharmaceutical companies, do you want to get involved here?

We can, we can, this should be done. I can't do this by myself. We need to have real trials and real studies of how this will help, you know? And just, it was, you know, their eyes would always cross and never, never got any, any sort of traction. It always went back to sort of disease.

You know, what, what disease are you curing? You know, what, what's the market for it? Is it a Parkinson's disease thing? Is it Alzheimer's disease thing? And this has been a general problem with neurology. It's very disease centric. It's always sort of, and it's always focused on, you know, how can we develop a treatment for Alzheimer's or traumatic brain injury or stroke, as opposed to how can we develop a treatment for working memory dysfunction, which is a problem across diseases.

So the answer to your earlier question is these drugs are very safe. They, we give them in such low doses to healthy individuals. They don't even know, they can't even tell the difference between the placebo and the drug. - Really? - They don't even know which one they're on.

- So they're not buzzing, thinking like, "Oh, this feels good, and my working memory is better." - They have no idea. They don't even know their working memory is better. And so we show them that their working memory is better. - Love it. - Yeah. - So they're truly blind to what's going on.

Bromocriptine is but one of the dopamine agonists. Can think of a few other, cabergoline, like other things like that. Do any of these dopamine agonists exert this impact on working memory, or is it, does it vary by drug because different dopamine agonists sort of hit different receptor pathways and things like that?

- Yeah, no, it's not specifically the drug. I mean, the reason for bromocriptine is that it's the oldest, and it's the one I was most comfortable with. I had to be comfortable with it clinically before I'd give it to undergraduates at Penn or Berkeley. So there's nothing special, but other agonists work similarly.

There's a drug that's developed, which is a COMPT inhibitor, which actually inhibits this enzyme that we're talking about. And that also will improve, will have the same function. There's been some future work that norepinephrine also seems to be helpful with working memory. It's not as, maybe not as potent as the dopaminergic.

And that's the point I want to make. Another disappointing thing about this whole field with the pharmacology of cognition, I wrote a paper as a resident. Sometimes you're tending to say, "Hey, can you write this review paper for us?" And I wrote one as a resident called "The Pharmacology of Cognition," where I just looked at all the animal literature on giving neuromodulators, acetylcholine, bromodotamine or whatever.

And there was a lot of animal literature sort of supporting that this would work in humans, but what was more striking to me was that it wasn't always just a single neurotransmitter. There were studies where you'd give dopamine and it wouldn't do anything. You'd give acetylcholine and it wouldn't do anything.

But if you gave a low dose of both, it would be really effective. So these neurotransmitter systems don't act in isolation. So we need to also study sort of how the combinations work. And that's where another, where the pharmaceutical companies have the infrastructure to do these kinds of studies.

It's very hard to do in a single lab to do multiple drugs at one time, and then try and determine all the different interactions. - Maybe we could talk about a couple of other drugs that are legal and have FDA approval, are known to be safe in the right context that it seems would fit the bill here for improving working memory.

One is Welbutrin. Bupropiron, I can never pronounce that. As far as I know, it's a epinephrine or norepinephrine agonist. You just mentioned that increasing epinephrine may have a positive impact on working memory and to some extent, a dopamine agonist. Is there any evidence that Welbutrin can improve working memory?

- Yeah, anything that boosts norepinephrine can do it. The one that we've used, that's most used is Guanfacine, which is actually a blood pressure medication. So that's starting to gain some traction. In fact, I think there was a study with COVID, with brain fog for COVID, showing that improved symptoms with it.

So there's actually some trials now that are looking at Guanfacine. And so I would say anything that boosts norepinephrine would be helpful. But then again, I don't wanna leave out the other transmitters. Increasing serotonin, increasing acetylcholine boosts other cognitive processes. And then in a way, they can help working memory.

We talked about working memory being this foundation. Well, if you give acetylcholine and it kinda boosts memory, well, that can indirectly help your executive function. Or if you give a drug that improves your focus, then that can indirectly help working memory. So what I'm really pushing for is not just a single, it's gonna be one drug, it's gonna be a cocktail.

And we have to not only figure out what the cocktail is, but also figure out who we're giving it to, link it to the person's own makeup of their own neurochemistry. When we get to a point where we'll know, we can map out sort of everyone's dopamine, norepinephrine, serotonin levels, then we'll make real progress in helping them.

Because right now, I sort of say with my students, what we're doing is just like cutting open the skull and just sort of pouring it onto the brain. - We're not actually doing that. - We're not actually doing it, but it seems that way. The precision is not there yet.

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