This Molecule Might Be the Key to Beating Addiction

Susan: 
I’ve actually had people reach out to me who said they were addicted to cocaine and went on a ketogenic diet or a low carb diet, and it resolved it. And same thing with people who have had problems with alcohol. And I really hope more work could be done on this because as we know, if you have healthy metabolism, you can solve a lot of different problems at once.

Bret: 
Welcome to the Metabolic Mind Podcast. I’m your host, Dr. Bret Scher. Metabolic Mind is a nonprofit initiative of Baszucki Group where we’re providing information about the intersection of metabolic health and mental health and metabolic therapies such as nutritional ketosis as therapies for mental illness.

Thank you for joining us. Although our podcast is for informational purposes only and we aren’t giving medical advice, we hope you will learn from our content and it will help facilitate discussions with your healthcare providers to see if you could benefit from exploring the connection between metabolic and mental health.

Could what you eat impact whether or not you have addictions to drugs, addictions to food, carb addiction, sugar addictions, addiction to gambling, cell phones, et cetera? We hear about the role of dopamine in addictions. Today, we’re gonna hear about the role of diet, ketogenic diets, adenosine, and how that impacts dopamine in addiction.

So maybe it could be something people can do to help stem the risk of addictions. I’m joined by Dr. Susan Masino, who’s a distinguished professor of applied sciences at Trinity College and also has an appointment in neuroscience and psychology. And she’s done a tremendous amount of work and research on adenosine.

And she had a paper published in a very special issue of Frontiers in Nutrition. It was all about ketogenic diets and their potential impact, and she wrote a paper about its potential role in modulating adenosine, dopamine and addiction. So here’s the interview with Dr. Susan Macino.

Hi Susan. Thanks so much for joining me at Metabolic Mind. 

Susan: 
Thank you so much, Bret. It’s an honor to be here today. 

Bret: 
Yeah. And I’m really interested to talk to you about the concepts of Adenosine, dopamine addiction, ketosis. And I saw the paper that was published in Frontiers in Nutrition, Ketogenic diet, adenosine, and dopamine in addiction, psychiatry, and there’s a lot in there.

There’s so much talk now about addiction, about dopamine, whether it’s your social media, your cell phone, or whether it’s alcohol, drugs, et cetera. There’s so much talk about addiction and dopamine and to think how we eat could potentially impact that is really revolutionary.

But before we get into the details, let’s rewind for a second and talk us about dopamine. What is dopamine? How does that impact addiction? And then from there, we’ll go to adenosine and then we’ll draw the two together. 

Susan: 
Alright, great. My career has not been spent as a dopamine person, but many people know dopamine is a neurotransmitter that’s associated with addiction.

And particularly the craving and preceding addictive behaviors, and dopamine’s also really critical for learning and pathologies. And dopamine are associated with serious neurological disorders like Parkinson’s disease. And behaviorally, dopamine is interesting because it’s in parts of the brain that are associated with habit learning.

And so habit learning is one of the most powerful things that you can take advantage of with our big brains, but also one of the most dangerous things in terms of learning bad habits. So when I teach behavioral neuroscience to my students at Trinity College, the first couple of classes, we talk about learning and habits. And I try and explain to them that curating your brain and your habits is one of the most powerful lifelong things that you can do.

Bret: 
Yeah, I really like that explanation. And the way you’re talking about, it’s clear we need dopamine. Dopamine has beneficial effects and beneficial habits and so forth. Like a lot of things in the body, it can go haywire and something that’s has a positive impact can turn negative.

But then you also talk a lot about adenosine and that’s something you’ve studied for years, your an expert in. And it’s funny as a cardiologist, when I hear adenosine, I think of, we used to, well not used to, we still do push adenosine as a medication that actually stops the heart, right?

Someone’s in a bad arrhythmia and we push a bolus of adenosine and it stops the heart. So the heart can reset. But adenosine is much more than that. So tell us, your short take on what Adenosine is and why it’s important, when we talk about addiction. 

Susan: 
Yeah, I’d like to give a full overview of that.

And just by the way, adenosine is an amazing molecule and, in terms of what it has been known for historically, has been a molecule that’s released when neurons, or any cells really, are under a severe amount of metabolic stress. Over excitation in the brain releases adenosine and that adenosine is known to be neuroprotective from neurons dying from the stress.

Adenosine is also known to be a sleep promoter. Adenosine actively promotes sleep and many people may be familiar with that because caffeine is an adenosine receptor antagonist and the most widely used psychoactive drug worldwide. So, many of us are regulating our adenosine tone in our brains pretty regularly.

Adenosine is also able to relieve pain. And I’ve done some work on adenosine in autism and Huntington’s disease. So it’s really a pan, I would say a pan-disease molecule. And the reason why it’s so powerful is it’s a link among neuronal activity, cell metabolism, and actually we now know epigenetic changes.

So it’s linking these three powerful, acute and long-term changes. So in that sense, it’s really uniquely poised to respond to changes and help the cell adapt immediately and on a more long-term basis. It acts at a number of different receptors even though it’s not a traditional neurotransmitter.

And whenever we have ATP cell energy molecule, ATP in the extracellular space, it’s pretty rapidly dephosphorylated into adenosine, and specifically that happens at neuronal synapses. There’s almost a specific channeling of released ATP, it’s dephosphorylated, and then it can target the adenosine receptor.

So it’s cells can even have their own kind of feedback loop. I’m under stress, let me clamp things down a little bit. 

Bret: 
Yeah, so real quick, just to expand upon that. So ATP is basically adenosine with three phosphates on it. And when you say dephosphorylate, the phosphates come off. So you’re left with adenosine.

Which then has all these potential impacts on the brain cells, the neurons that you’re talking about. So, interesting how a medication, which seems so simple, is actually much more intricate and has so many different effects. So, then what is the relationship between adenosine and dopamine in the brain?

Susan: 
Yeah, adenosine binds to a number of different receptors. Basically there’s a couple sub forms, but we found out that adenosine A1 receptors form functional heteromers. And what happens is that as adenosine activation of that functional heteromer goes up, dopamine activation will go down. So, they almost have this kind of gas break relationship with each other.

So, when I first started working on adenosine and ketogenic diet, I realized this is interesting. All the behavioral implications of a hypothesis about adenosine and ketogenic diet would extend to hypotheses about sleep, hypotheses, about neuroprotection hypotheses, about dopamine related behaviors and activity.

And just going back briefly to your original point about addiction, the reason why drugs are so addictive is they produce an increase in dopamine that is so far beyond what can happen with your endogenous mechanisms of transmitter regulation. So, there’s a huge burst of dopamine that’s way out of the norm.

And that’s probably what promotes a lot of the fierce habits in our habit part of the brain. One of the things that promotes these very difficult behaviors to remit from. 

Bret: 
Yeah. So when you get such a spike in dopamine, I guess that’s when the mechanism of the adenosine is being, like you said, the gas and the break. That if the adenosine can blunt that spike a little bit or lower that spike a little bit, it could help with the addictive potential.

So is that sort of the connection there with adenosine and addiction and how it impacts dopamine? 

Susan: 
Yeah. So that’s one mechanism, but I actually think there’s several mechanisms related to adenosine ketogenic diet and addiction. And another one is one of the precipitators of drug relapse is stress.

So stress induced relapse, and this in adenosine is related to stress, but the other thing that’s related to stress is hyperglycemia. So, is that hyperglycemic signal also initiating higher risk for drug relapse? And so I think both adenosine and the ketogenic diet have common mechanisms and maybe individual mechanisms that could be helping with preventing and treating addiction and helping people maintain their sobriety or drug-free state. 

Bret: 
Yeah, now you’ve mentioned adenosine and ketogenic diet together a couple of times. So, I want to get into how those are related. And I had an interview with Dr. Wiers, where she talked about her research about ketogenic diets for alcohol addiction and alcohol withdrawal, and a definite potential connection there. So one question is could adenosine be part of that mechanism? But tell us the connection then between ketogenic diets and adenosine. How does one lead to the other? 

Susan: 
Yeah, so I don’t think we’ve a hundred percent nailed down exactly all the possible ways that a ketogenic diet could increase adenosine.

But the most obvious way is ketogenic diet increasing mitochondrial function, increasing ATP. And as we talked previously, ATP is the precursor to adenosine, basically, and part of cell energy charge. And cells have a fairly high level of ATP compared to adenosine, and it’s actually an incredibly efficient.

Mechanism whereby a cell, even if it’s under stress, could use a little bit of its ATP and gain a lot of leverage adenosine pretty dramatically to help to mitigate, more stress or a more serious situation. So I think it’s largely due to the increased aTP pools, although there are also, perhaps, changes in intracellular pH, I think could be critical.

There’s other kind of enzyme related regulation mechanisms that may be important in sub compartments of neurons that are very metabolically active, like the particularly the synaptic domain, pre-synaptic synapse, post-synaptic synapse, but particularly pre-synaptic synapse, which are just these are very energetically demanding parts of neurons that have a lot of flux of cell energy through the whole ATP adenosine cycle. And in that whole kind of regulation, it’s not just the neurons, it’s also the astrocytes that are part of every synapse, and the astrocytes are very actively regulating this adenosine tone in the synapse as well.

So, there’s a lot of possible puzzle pieces that can help between the ketogenic diet, regulating the enzymes that regulate adenosine, increasing ATP and changing the metabolic milieu related to pH and other things like that. 

Bret: 
You can tell you’re a professor and that you teach this stuff. You’re very good at explaining it. So, that’s good.

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It’s fascinating to talk about the potential, about the theory, about how keto ketogenic diets can impact adenosine, which could potentially impact dopamine in addiction. But if we want to make recommendations or talk to patients about it or make changes for ourselves, it’s important to know what level of research is out there.

So from the broader perspective, where does the research stand, in terms of adenosine impact on addiction? Is it just in rodents and mice? Is there some human data? Is it causative or correlative? How would you sum up where the data is? 

Susan: 
I would say it’s not as far as it could be at this point.

So, I’m delighted to be on the podcast. I have a small lab. I can only do so much, and I have a lot of ideas. I love to share them and have other people work on them, and that’s how science should work. And as a tiny aside, I don’t want to forget to tell you how impressed I am with all the work that you’re doing at Metabolic Mind and really pushing forward this field of metabolic health and metabolic brain health, which has really been my passion for so long. So, I just want to thank you deeply for that. In terms of the research, I did a couple of papers on cocaine. We actually thought about doing an alcohol study way back, but I had a colleague join Trinity College, Luis Martinez, and he has done some cocaine work, and we worked with my colleague, David Ruskin, to look at the effect of ketogenic diet on cocaine place preference.

Animals will prefer a place where they got that addictive substance that shot of dopamine. So, we’ve looked a little bit at Male and female mice in this cocaine determined place preference. And there are some other kind of hints in the literature and there’s a lot of things that you could pull together.

Like, oh, we would predict this and this is what we see in the literature. If this is true, we would predict this. But there’s, and I’ve actually had people reach out to me who said they were addicted to cocaine, went on a ketogenic diet or a low carb diet and it resolved it. And same thing with people who have had problems with alcohol.

This is a number of many years ago. So, I feel like it’s almost at the point where other fields have started with just snippets in the literature, a solid mechanistic rationale, for the hypothesis, some anecdotal work, et cetera. And I really hope more work could be done on this because, as we know, if you have healthy metabolism, you can solve a lot of different problems at once.

So, people who have problems with addiction may also have problems with sleep or attention or other kind of issues that they may think are unrelated to their addiction. And they may be unrelated to their addiction, but they could all be solved by better metabolic health. 

Bret: 
Yeah. So you’ve talked about cocaine.

You’ve talked about alcohol, some obviously very addictive substances. But we’re now learning a lot more about food addiction, carb addiction, sugar addiction. I think we still need to learn exactly how to define it and what the components are. But do you think whatever we learn in the addiction world for cocaine would translate to food addiction or the same thing? Cell phone addiction or whatever the case may be?

Do you think they’re transferable, basically because the mechanisms are very similar? 

Susan: 
I absolutely think it’s transferable. And I think what I spoke about before in terms of kind of stress induced hyperglycemia or stress induced changes in blood sugar or the changes in blood sugar that happen when someone may have an eating disorder of various ilk, right?

A low carb ketogenic diet could help to smooth out those things, which may be a precipitator of, let’s say, binge eating disorder, for example, or could be one of the underlying issues with other kinds of eating disorders. And there is literature on ketogenic diet and anorexia. I believe there’s one on bulimia recently.

And, this what I was saying, solve multiple problems at once. This would be a huge way to address especially problems that are very difficult to treat and serious psychiatric conditions that result in lifelong disability, basically. 

Bret: 
Yeah, and I think it’s so interesting when we talk about addiction or when we talk about mental illness, we talk about them as they’re separate, but they coincide with each other so often. So, if you can find something that could potentially address both of those concepts, both of those disorders, then that’s a huge win for the individual to be able to address that because it’s really hard to improve the symptoms of your depression or your bipolar disorder if you have significant addiction.

And it’s hard to kick that addiction if you are living with the ups and downs of major depression or bipolar disorder. Do you see that as an important interaction that research needs to address going forward? How those interact with each other and how they can be addressed together?

Susan: 
I think we should address them together, and we should do a better job of tracking these kind of comorbid symptoms. So, for example, with epilepsy so many of your viewers might know that the ketogenic diet was his a long history with epilepsy. And so I didn’t grow up in the epilepsy field. I grew up in kind of behavior and synaptic plasticity and physiology.

But when I started working on adenosine, of course epilepsy was a natural area because adenosine will stop any kind of a seizure. And it turns out that sleep disruption often precedes someone having a seizure or depression often precedes someone having a seizure. And similarly with someone who may develop cognitive impairment with Alzheimer’s disease, there’s often preceding morbidities and sleep and depression particularly that, I think, can be helped significantly with better metabolic health and lower carbohydrates, maybe even a ketogenic diet if needed, and maybe that kind of intervention could even stave off transitioning to a full-blown, seizure or, at least slow the mild cognitive impairment decline if you’re headed on a decline and maybe even reverse it.

Bret: 
Yeah. So I just want to circle back to something you said that adenosine will stop any seizure. I think that’s so interesting because when we look at how ketogenic diets can impact epilepsy, there are a number of proposed mechanisms, right? It’s not a razor’s edge drug that focuses on one mechanism, but it really is multifactorial.

So, adenosine could be another one of those potential mechanisms, which then translate to why maybe it’s effective in so many other areas as well, beyond just seizures because of the brain effects of adenosine. And we also talk about GABA and glutamate and neuroinflammation and just having a different fuel source.

Yes. And all those, but so interesting to see how adenosine could, also play into that. 

Susan: 
Yes, and inflammation, I think, is a key point that I forgot to mention earlier because that’s associated with depression, drug addiction, all kinds of disorders have inflammation as a another partner in crime.

And so the point you made initially about adenosine being in the operating room in case someone’s heart stops that you can, in case someone runs into tachycardia, you could stop it, it’ll restart again. That’s great for the heart, but people don’t really, that was considered a non-starter in terms of drug development for neurological conditions.

So, that’s why I’ve always been looking for like, how can we alter adenosine endogenously? And that’s how I got into the ketogenic diet work, actually. 

Bret: 
Yeah. If you’re giving it as a medication, you have to give a big dose and it has to be in a big vein. It can’t be in a little vein.

It’s gotta get there fast, but that’s if you want the cardiac effects. If you don’t want the cardiac effects and looking how to stimulate it endogenously at smaller doses with a longer tail and not such a big peak. Yeah, that makes a lot of sense. And nutrition is a great way to do that.

But now I’ve also heard you talk about some theories about this, I don’t know, you could say hermetic stress, theories or the little bits of stress to actually help us in the long runs. And you can explain it much better than I can, but tell us about that general concept and how adenosine and ketosis play into that.

Susan: 
Yeah, so this backs up to like my first days in graduate school when I was very interested in evolution and how our big brains can learn. And I started thinking about how evolutionarily there were all these sort of different stresses in the environment. Even the daily circadian rhythms of light and dark and temperature, changes in pH, changes in osmolality, all the kind of environmental stresses that the, let’s just call it the primordial soup, was under.

As different species evolved and differentiated and how are those stresses relevant to our brains? Being able to adapt and learn basically. And so early on in my career, I had looked at behavioral plasticity in rodents. And then when I started working on adenosine, the first experiments I wanted to do were these kind of, because I was now working in brain slices in dishes, is I started looking at changes in temperature, changes in pH, changes in osmolarity, slight metabolic poisons, excitatory stress, like all the different things I could think of. And I found that adenosine was a common denominator to all of those different things. And I was like, wow, that’s really interesting.

And that’s how I started trying to think about adenosine because these were very mild things that I was doing. So adenosine was always thought to be a neuroprotective agent in case you hit your head or have a seizure or have a stroke. It would help to protect your neurons, but it didn’t seem to me that something would be around all over evolutionarily conserved just in case you get hit on the head sometime. Because hopefully that would never happen. I started thinking about how is that used now because it’s all over the place and how is it used to help our brains learn? And how are those mechanisms that can mobilize adenosine how could they be taken advantage of therapeutically?

And that’s how I got into the ketogenic diet work. And I still think as an aside, this is, and I think there’s some evidence for this now, there was some evidence for acupuncture that adenosine is one of the key mechanisms of acupuncture or brain stimulation. So all the different kinds of brain stimulation they have for epilepsy or Parkinson’s disease or, for example, electroconvulsive shock therapy.

Is that one of the key things that you’re just going bam, hitting the brain with that and giving it a reset mechanism like the heart? 

Bret: 
Yeah. So that concept is so interesting about how it can have different effects and I like the idea of the evolution component to it, right?

Like, why do we have this to sit and think about it? Like why is this here? What are the benefits of it? And how can we capitalize on that? But also from your standpoint, how can we research it more? So you mentioned how you have a small lab, you have a lot of ideas, but only so much you can do.

So what are some of the other studies that you’re doing, and I guess the other question is how can other people help? Like how can there be more collaborations? How can we get other people interested in doing some of the studies that you have on your plate for the future? 

Susan: 
Wow. I’ve done a lot of work on autism that hasn’t been funded, and I think there’s a very significant link between autism and adenosine, and there’s very significant metabolic components and metabolic genes that are associated with autism. I’d love to have this addiction work take off. And you mentioned also eating disorders. In terms of other kinds of things that I think may be able to mobilize, adenosine exercise may be one, something like hot yoga. Like you’re not gonna give your body like an pH shock or some of the other things that I said, but think about the physiological things that we could do and maybe we can combine. These kind of physiological interventions with other interventions to promote the kind of epigenetic changes you would need to resolve situations. So, those are some of the things that I’ve been working on, would love to see more people work on. And I want to have more people think about how adenosine is really uniquely poised as something that can affect neuronal activity very powerfully and directly is also a metabolic feedback mechanism for cell metabolism and can mobilize epigenetic changes.

So, you’re getting all of those things stacked in one molecule. And one of the ways that I think adenosine plays a role is like a signal to noise ratio in the brain. So, if you have a little bit more adenosine, you’re getting the stronger signals through. You’re maybe able to learn more effectively.

You can maybe reshape what you’ve learned and made it make it more efficient, and I think that’s one of the things that’s happening during sleep. To prevent our brains from being more and more metabolically demanding, we need to like reshape our synapses and our memories to be more efficient, and I think adenosine is really critical for that.

Bret: 
Yeah. I really appreciate you joining me to talk about this, and I can only hope that somebody listening wants to fund some of your work or a research assistant wants to come help or other research facilities want to pile onto what you’re doing and add more to it because it seems like there’s such a wealth of opportunity there to learn more. And with addiction being such an important concept, and just neuroprotection being such an important concept, to really double down on adenosine and learn more, I think, would be so important. So if somebody did want to help or wanted to contact you or learn more about your work, where can we direct them to go?

Susan: 
Oh, thank you. So I’m easily Googleable at Trinity College and my last name is masino, which is spelled like casino, but starts with an M. 

Bret: 
Thank you for all your work and I definitely look forward to hearing more from you in the future. 

Susan: 
Thank you, Bret. 

Bret: 
Thanks for listening to the Metabolic Mind Podcast.

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