Ketogenic Diets in Alcohol Addiction: Breakthrough Research with Dr. Wiers

Corinde: 
Ketones supplements are very quickly taken up by the brain. So, we very similarly see reductions in glucose metabolism that are similar to alcohol. So, also the brain seems to prefer ketones over glucose, which is a little bit against the dogma that’s glucose is a preferred energy source of the brain.

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.

Dr. Corinde Wiers, researcher at University of Pennsylvania School of Medicine and Assistant Professor of Psychiatry, is doing fascinating research on ketogenic therapy, ketosis as a potential treatment for alcohol use disorder. And specifically, she’s studying metabolic ketosis on brain energetics and alcohol consumption in alcohol use disorder.

And she has some incredibly interesting findings that may be showing that this is a very effective, and potentially the future of treating alcohol use disorder. Let’s hear what Dr. Wiers has to say.

Dr. Wiers, thank you so much for joining me today at Metabolic Mind. 

Corinde: 
Thank you. Thank you for having me. 

Bret: 
I’m excited to talk about all things related to alcohol use disorders, substance use disorders, the potential role for ketosis. But first start by just telling us more about you. Who are you?

What do you do? 

Corinde: 
Yeah, so my name is Corinde. I’m from the Netherlands. That’s where I grew up. I studied psychology and biology there. I had a gap year in the United Kingdom in Brighton and was fascinated by the level of alcohol consumed there. And after that, I went to Berlin, Germany, for for grad school where I primarily worked on alcohol use disorder and functional MRI.

And after that, I moved to the States. I joined the lab of Dr. Nora Volkow, who’s the Director of the National Institute on Drug Abuse in Bethesda, Maryland. And there it was, I was such a kid in a candy store with all different techniques and research questions related to alcohol use and and drug addiction and neuroimaging.

And there it was there that we picked up on low glucose metabolism in alcohol use disorder and seeing whether ketones or a ketogenic diet could be of potential therapeutic benefits for individuals with alcohol use disorder. 

Bret: 
Yeah, so you’re foreshadowing my next question here.

Curious how starting with alcohol use disorder research, you got into ketosis. And it sounds like from what you’re saying, it has to do with glucose utilization. So, tell us a little bit more about that. 

Corinde: 
Yeah, so it was actually Dr. Volkow for years found that when people drink alcohol acutely, that the brain levels of glucose utilization go down for about 20%.

And it was always interpreted like you can see, or how bad alcohol is for the brain. And also in chronic drinkers, glucose utilization is down for an extended period of time, could be a week or two even after alcohol abstinence, and also that was interpreted that alcohol very bad for the brain.

But what she actually found in around 2013 was that when you drink alcohol, the liver breaks down alcohol and converts it into acetates. Acetates goes through your bloodstream and gets taken up by the brain and is actually preferred by the brain as an energy metabolite. So is a shift from glucose to acetate as an energy source while you drink alcohol acutely but also chronically.

So yeah, I don’t really have a background in nutrition, but we thought acetoacetate, a ketone body, is very similar to acetate. So, could it be when people come in for alcohol detoxification, so when they quit drinking, they don’t have the source of acetates anymore, what their brain is so used to? Could it be that when we supplement people with ketones, could that help them during alcohol withdrawal and overcome alcohol withdrawal symptoms? 

Bret: 
Yeah, I mean that the mechanism there sounds fascinating, the reliance on acetate, the similarities to acetoacetate.

So, what is some of the background data that existed in this? Was it mostly like in mice and rats or had there been some human studies in this before you came along? 

Corinde: 
There have been no human studies in this, and we were actually very surprised. But then there was a group in Denmark that we partnered with by Dr. Anders Jensen, and he actually studied this for the first time in rats. So, he gave alcohol-dependent rats, he let them quit drinking or studied them during acute withdrawal, gave them either a ketogenic diets or standard 50% carb diets. And he saw improvements in body rigidity, or yeah, things that you can see as alcohol withdrawal signs in rats.

So, that was published in 2018. And that’s exactly when we started the first clinical trial in patients with AUD. 

Bret: 
Yeah, and so in this trial for inpatients with alcohol use disorder. I guess the conclusion was that the keto diet reduced the neurobiological craving signature.

So tell us about that. What is the neurobiological craving signature in alcohol use disorder? 

Corinde: 
Yeah, so we did actually a variety of testing. The neurobiological craving signature, it’s a functional MRI response. So ,what we did is we randomized people to receive a ketogenic diet or a control diet for three weeks during alcohol detoxification.

And our main outcome actually was alcohol withdrawal and the need for a benzodiazepine. So, alcohol withdrawal is always very high in those first five days to a week of alcohol detoxification. It’s treated with benzodiazepines or GABAergic drugs, and they’re really required, some people really need these drugs to not have seizures, not have really severe anxiety. And a severe withdrawal could even be lethal in some cases.

First, we really wanted to see, does alcohol withdrawal, is that reduced with the ketogenic diets? And we saw reductions in alcohol withdrawal as well as the need for benzodiazepines. But then back to your neurobiological craving score, we were also interested in could it be if we change this source of energy that people crave alcohol less because maybe they’re low level of glucose is supplemented with ketones?

So, maybe they don’t crave alcohol that much because they’re not in this energy deficit state? So, we developed an alcohol cure activity test where people were, they were in an. MRI scanner, they were seeing cues of alcohol and food and neutral cues that elicits brain responses in brain reward areas such as the striatum, the medial prefrontal cortex.

And we actually used the neurobiological craving score, was developed by a group at Yale that they used machine learning to look at which brain areas really light up or are involved in cue-induced craving. They just looked over a larger data sets and compiled these brain areas that’s correlated well with behavioral craving.

So, we basically used the technique and then saw does it apply to our intervention? And we saw that those individuals on the ketogenic diet showed lower behavioral craving. So, they said, oh yeah, no, I don’t want alcohol as much. But also these brain responses were lower in those reward related area. 

Bret: 
Yeah, such interesting findings. On the one hand, the clinical benefits of less withdrawal, less benzodiazepines and then for maybe potentially the long-term behavioral changes and brain changes of not craving so much. So really like a powerful one-two approach there.

But tell us about the less withdrawal and the less need for benzodiazepines. That sounds pretty significant because that, like you said, that can be a very dangerous period for someone to go through that type of withdrawal. So, how clinically significant was that difference? 

Corinde: 
it was very clinically significant.

It was a strong reduction. Oh, I don’t remember the percentage difference, but it was definitely stronger than we ever expected it to be. But we, what was important for our trial was that it wasn’t randomized and blinded study, which is quite difficult to do for a nutritional intervention. If you provide people with real food, it’s very easy to guess if you eat chicken and oil, and maybe a leaf of lettuce for a ketogenic diets versus pasta with chicken, for example.

So what we did is that. We gave people a largely liquid diet. We gave people a shake for a breakfast, lunch, and dinner that was either ketogenic or standards American, namely 50% of carbs. And because of that, we also asked after those three weeks, which diet did you think you were on? And most people actually thought around the ketone diet. So, the blinding actually worked.

So that was good. Our effects were not due to people expecting to be in a novel dietary intervention that may have helped their alcohol withdrawal. So, yeah, we’ve found strong reductions in alcohol withdrawal symptoms as well as the need for benzodiazepine. 

Bret: 
Yeah, and that’s so important to be able to treat, use it as a acute treatment, but also as a potential long-term preventative treatment.

And I guess we should take a step back and tell us a little bit about the landscape for current treatments for alcohol use disorders. Because if there are wonderful treatments that everybody gets and it’s not much of a problem, then maybe you don’t need innovative therapies?

But, I’m guessing that’s not the case here. 

Corinde: 
Yeah, so most treatment for, I mean, for acute alcohol withdrawal would be benzodiazepine, but for reductions of drinking would all be also more pharmacological treatments such as Naltrexone and Topiramate. They’re all FDA-approved for alcohol use disorder.

But still there’s a strong gap between those treatments that are available and clearly effective, and people actually getting them. I think it’s less than 8% of people who would benefit from treatments actually do, or with an alcohol use disorder actually getting the treatment that they need.

And i’m not sure, but it might be that stigma is associated with it, too. That no, I can do this on my own. I don’t need in pharmacological intervention. Of course, access to healthcare is something, particularly in the United States that’s, it may not be optimal for an accessible for everyone.

So, something that is more simple as a dietary intervention and maybe less stigmatizing as well, and potentially also being seen as more of a health benefits beyond the alcohol use disorders. Your group also shows that it’s the ketone diet may be beneficial. So, for mood disorders for, and in general, like feeling better, weight loss it may improve overall metabolic health and not only focusing on alcohol. 

Bret: 
Yeah, that is really interesting, especially the overlap with substance use disorders, alcohol use disorders and mood disorders. There’s a significant overlap there, and serious mental illness.

So, you wonder if helping one helps the other as well. And so, we’ve been talking about alcohol use disorder, specifically with the mechanism involving acetate. Do you think it would also apply to narcotics use or other addictions?

Corinde: 
It might, we don’t quite know yet. There was one study in cocaine, cocaine-dependent rats, where the ketogenic diet was helpful also during cocaine withdrawal.

And then the group in d Denmark also tried the diet for heroin, heroin withdrawal, but it wasn’t so successful. One of my colleagues, Pete Menza, he is moving to the University of Maryland right now. And he’s actually setting up a trial at the Care and Treatment Center to see whether ketone supplements, yeah, withdrawal in opioid use disorder patients. And that’s really in parallel to an alcohol trial that we’re running there, too.

Bret: 
Yeah, so really interesting. Next question then about a ketogenic diet versus exogenous ketones, ketone supplements. Does it matter if you know your livers the one producing the ketones and you’re burning fat for fuel and improving your metabolic health? Or does it just matter that your ketone levels in your blood are at a certain level and how you get there doesn’t matter so much?

it sounds like you’re studying it, but what do you think? 

Corinde: 
Yeah, that was really the research question that made me jump out of the NIH. And now I’ve set up my lab at the University of of Pennsylvania to study exactly that. We found in animals that the keto supplements is sufficient to reduce alcohol withdrawal.

So very comparable results with the ketogenic diet. And we’ve started now neuroimaging experiments and also alcohol lab experiments with the ketones supplements, but we haven’t done really a longer clinical trial. So one of them is the treatment trial at Care and Treatment Center, where for five days, we give ketones supplements for breakfast, lunch, and dinner, just in as an add-on to their regular standard American diets.

But we don’t have the results yet. So, the trial’s ongoing. So, I can’t really say anything yet about the human results, but we see already in the, in a lab setting that ketones supplements are very quickly taken up by the brain. So, we very similarly see reductions in glucose metabolism that are similar to alcohol.

So, also the brain seems to prefer ketones over glucose, which is a little bit against the dogma that’s glucose is a preferred energy source of the brain. And what we also see, we gave healthy volunteers a ketone supplement, and then around three shots of vodka. And we saw that people do not like the effects of alcohol that much when they have the ketones on board.

But there might be two different mechanisms there. On the one hand, it might be this brain energy as the brain is already working on ketones and maybe the alcohol effects are not as fun? Also there is a pharmacokinetic effect.

And we were really surprised by, that If you drink ketone, the ketone supplements, and then half an hour later drink alcohol, alcohol blood and breath levels were very flat. So. People don’t get the immediate rush from drinking alcohol. And we followed up a little bit on that. Hey, this effects of that alcohol gets broken down faster or is it an absorption effect?

And it looks like it’s an absorption effect. So, when you drink ketones supplements, and then alcohol, ketones sorry, the alcohol doesn’t get absorbed as quickly. So, people don’t have the rush that we usually feel when we, when we drink alcohol. 

Bret: 
Wow. Yeah, super interesting. Another mechanism for how it can help chronically.

So we, I think we’ve uncovered three, at least three, different mechanisms, potential mechanisms here so far. But I want to go back to a statement that you said that the brain prefers ketone. Now, this is something that people throw around all the time, that no brain prefers glucose, brain prefers ketones, and here’s why.

And they usually will cite some maybe historical or evolutionary, but not like real, not I don’t want to say real, but not like evidence that actually studied, which does it actually prefer. So, I want to hear more about what leads you to conclude that the brain prefers ketones. 

Corinde: 
Yeah, so we ran a pilot PET study in both healthy volunteers and people with an alcohol use disorder where we brought people into the lab twice. Once at baseline when people didn’t drink a supplement, and once after drinking the supplement.

We didn’t give a placebo here because we were, we didn’t think that people could influence their brain glucose metabolism that much. But basically, we studied the glucose, or the metabolic grades of glucose, in their brain as well as in the rest of their body.

We still need to work with the cardiologist. We were looking at glucose utilization in the heart as well. But in the brain, the effects were very drastic. When you drink a ketones supplement, I think we gave us about half an hour before the PET scan, glucose utilization is reduced by 17%.

So, even though glucose is available when ketones are present, too, the glucose utilization goes down. We still want to follow-up with this with more fancy dual tracer techniques that in combination with glucose metabolism, that you study with PETs in FDG, that we will also look at ketones metabolism in the same session because then you can really look at regional shifts in brain, brain energetics.

So, where in the brain does glucose goes down? And is that also where acetoacetate or other ketones go up? 

Bret: 
Yeah. Okay, very interesting. And we know that chronic alcohol use disorder can lead to so many other cognitive or mental health complications. And you wonder if fuel utilization and brain energy has a component to that as well.

And if it does, if ketones can help a ameliorate that, too. I’m sure there are lots of areas to be studied around this. So, what kind of projects are you working on now? 

Corinde: 
So, ideally, I’d like to set up longer clinical trials both with ketone supplements as well as a ketogenic diet and treatment seeking people with alcohol use disorder.

And we can use, for example, telephones where we ask them every day, or phone data where people report how much they drink or how much they want to drink. So, where we can see maybe for 6 to 12 weeks, does this actually lead to a reduction in alcohol craving and alcohol consumption in a natural setting?

And then we can also look before and after it’s, for example, neurocognitive performance, did that improve? But currently, we’re still we’re working primarily with the spectroscopy team on various brain metabolism outcomes, including GABA. So, one of the ideas as well, if people require fewer benzodiazepine, could it be that these ketones elevate GABA, and therefore, people experience lower withdrawal symptoms?

Something else is that we’re looking at mitochondrial health, some measures of nicotinamide adenine dinucleotides, which rapidly goes down with age and also goes down with alcohol use disorder, which somewhat accelerates brain aging.

So, there we’d also like to see whether ketones could actually elevate the mitochondrial health in the brain. So, there’s lots and lots to study, and I feel I can spend my whole life doing this. 

Bret: 
Well, yeah, you might have to, you might have to answer all these questions. Now, before we wrap, I can just think of one sort of clinical concern some people may have in that people with chronic alcohol use disorder are more prone to ketoacidosis.

Still not common, but that’s one of the subtypes of people without type I diabetes, who could develop ketoacidosis. So, if someone is actively abusing alcohol and malnourished and supplementing ketones, that could potentially be a dangerous combination. Now, I don’t know that many people would be in that combination.

But is there any concern clinically among your colleagues about this combination? 

Corinde: 
Yeah, there definitely the IRB has also raised this concern also with the alcohol-dependent patients coming in for alcohol withdrawal. But it looks from animal research that ketones alone do not increase the alcoholic ketoacidosis.

So, it’s really more the alcohol and the lack of vitamins, particular B1, B2 that may lead to the alcohol ketoacidosis. So, more poor nutritional health in combination with alcohol. But what is of concern is that in an animal study where we gave rats the ketogenic diets, and then we learned them to self-administer alcohol, they self-administered a lot less.

But also they were much, much more sensitive to alcohol. So the rest, on a ketogenic diet for six weeks, and this was in partnership with Dr. Leandro Vendruscolo at NIDA in Baltimore. And they have an alcohol drinking or alcohol consumption paradigm in that they lets rats vape alcohol for 14 hours overnight.

So, their alcohol levels are really high and very high for very long. But what he saw was that the rats on the ketogenic diet at five times higher alcohol levels in their blood. So what we do not want, of course, is to put people on the ketogenic diets and then they overdose with their regular six pack that they’re drinking because suddenly it’s, their levels are five times higher.

So, right now we’re still looking at that factor in a lab setting, all very well standardized before we move to the next phase of providing a ketogenic diet to patients with alcohol use disorder in a setting where they can actually drink. 

Bret: 
Oh, very good. it’s clear you have a very good grasp on the knowledge base in this field and are doing some really interesting work.

So, I can’t wait to hear more about what you find in the future projects you embark on. If people did want to learn more about your work or hear more from you, where could they go to find more? 

Corinde: 
Ooh, they can go to my website. But yeah, we always post all our recent findings on the alcohol use disorder there.

Bret: 
Alright, thank you so much for your time. I really appreciate you joining me and sharing all your knowledge with us here at Metabolic Mind. 

Corinde: 
Sure. Thank you. 

Bret: 
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