Lorenzo Leggio, MD, PhD

This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity. 

Akshay B. Jain, MD: Today we are very excited to have Dr. Leggio join us all the way from the National Institutes of Health (NIH). He is an addiction physician scientist in the intramural research program at NIH. Welcome, Dr. Leggio. Thanks for joining us. 

Lorenzo Leggio, MD, PhD: Thank you so much. 

Dr. Jain: We’ll get right into this. Your session was, in my mind, extremely informative. The session looked at glucagon-like peptide 1 receptor agonist (GLP-1 RA) therapy and its potential effects on mitigating alcohol misuse syndrome, so, reduction of alcohol addiction potentially. 

We’ve seen in some previous clinical trials, including many from your group, that alcohol use is known to be reduced — the overall risk of incidence, as well as recurrence of alcohol use — in individuals who are on GLP-1 RA therapy.

Can you share more insights about the data already out there? 

Dr. Leggio: At the preclinical level, we have a very robust line of studies, experiments, and publications looking at the effect of GLP-1 RAs, starting from exenatide up to, more recently, semaglutide. They show that these GLP-1 RAs do reduce alcohol drinking. They used different animal models of excessive alcohol drinking, using different species — for example, mice, rats, nonhuman primates — models that reflect the excessive alcohol drinking behavior that we see in patients, like physical alcohol dependence or binge-like alcohol drinking, and other behaviors in animal models that reflect the human condition.

In addition to that, we recently have seen an increase in human evidence that GLP-1 RAs may reduce alcohol drinking. For example, there is some anecdotal evidence and some analyses using social media showing that people on GLP-1 RAs report drinking less alcohol. 

There are also some pharmacoepidemiology studies which are very intriguing and quite promising. In this case, people have been looking at electronic medical records; they have used the pharmacoepidemiology approaches to match patients on GLP-1 RAs because of diabetes or obesity, and have compared and matched to patients on different drugs as the controls.

A study was recently published Nature Communications by a group in Cleveland in collaboration with Dr. Nora Volkow from the National Institute on Drug Abuse. This study shows the association between being on a GLP-1 RA and the lower incidence of alcohol use disorder and lower drinking.

There is also some promise from prospective randomized clinical trials. In particular, there was one clinical trial from Denmark, a well-known and -conducted clinical trial where they looked at exenatide, and they didn’t see an effect of exenatide compared with placebo in the main analysis. But in a subanalysis, they did see that exenatide reduced alcohol drinking, but only in patients with alcohol use disorder and obesity.

This suggests that these medications may work for some patients and not for other patients. That’s fine, because just like in any other field in medicine, including diabetes, obesity, hypertension, Parkinson’s, and depression, not all medications work for everybody. If these medications will work for alcohol addiction, we do not expect that they will work for everybody.

One ongoing question in the field is to try to identify the phenotypes or the subgroup of people who may be more responsive to these medications. 

Dr. Jain: This is such a fascinating field, and all these studies are coming out. In your review of all the literature so far, do you think this is dose dependent? Also, we see that, for instance, with certain individuals, when they take GLP-1 RA therapy, they might have a lot of gastrointestinal (GI) side effects. Recent studies have shown that the rate of these GI side effects does not necessarily correlate with the amount of weight loss. In the alcohol addiction field, do you think that the GI side effects, things like nausea, could also have a potential role in mitigating the alcohol addiction?

Dr. Leggio: This is a great question. They may play a role; they may contribute, too, but we don’t think that they are the driving mechanism of why people drink less, for at least a couple of reasons. 

One is that, similar to the obesity field, the data we have so far don’t necessarily show a relationship between the GI side effects and the reduction in drinking. Plus, the reduction in drinking is likely to happen later when many GI side effects are gone or attenuated. 

The second reason is from the neuroscience field. We are starting to better understand the mechanism at the brain level as to how these medications work. We don’t see that the nausea or, more generally, not feeling well — malaise, etc. — are driving mechanisms for how these medications work.

Again, it’s not to discount completely that the GI side effects may play a role, but I would say that, if anything, they may be more contributing to. And if they do, that will not be unique to this class of medication. For example, we have three medications approved by the US Food and Drug Administration (FDA) for alcohol use disorder.

One challenge we have in the addiction field is that many people don’t know that these medications exist — many primary care providers don’t know — and they are completely underutilized. Everybody here who is listening to us knows that roughly 85% of people with diabetes receive a medication for diabetes. For alcohol use disorder, the number is 2%. These are medications approved by the FDA. 

One of them is naltrexone, which does give GI symptoms — in particular, nausea and vomiting. The other medication is acamprosate, which does give diarrhea.

You have medications approved for alcohol disorder where you do have some GI symptoms, but they are not the mechanism either for how these medications help people to curb craving and reduce alcohol drinking.

Dr. Jain: What about the dose-dependent action? Do you think that GLP-1 RAs, at a lower dose, may not have an effect on alcohol use disorder vs at a higher dose, or is everyone a little different? 

Dr. Leggio: That’s a wonderful question. The short answer is, we don’t know, to be honest. Now, in some of the animal studies — my team has been in collaboration with other scientists in the NIH intramural research program, and also with scientists in academia, for example, at Scripps, UCLA — we see a dose response where the higher the dose, the higher the effect of the drug. In this case, semaglutide reduced binge drinking in a rat model of a physical alcohol dependence.

That said, I would be very cautious about claiming, based on the rodent data, that humans will have a dose response. It’s an open question. We really don’t know. Some of the pharmacoepidemiology data suggested that even lower doses — for example, using semaglutide for diabetes without going up to the obesity dose — may be just as effective as a higher dose in reducing the incidence of alcohol use disorder. 

It’s important also to keep in mind that the pharmacoepidemiology data are always an association. Reduction in alcohol disorder is associated with the prescription GLP-1 RA, but they don’t really replace the more gold-standard, double-blind, placebo-controlled randomized clinical trial. Nonetheless, with the pharmacoepidemiology data, I think there is an argument to at least hypothesize that people may respond well, even to lower doses. 

This also may be important from a safety standpoint. 

Basically, we need to wait for results in the next years to come from randomized clinical trials to better unfold the question about doses. For example, just anecdotally, I will tell you that in the clinical trial we are conducting right now at the NIH Intramural Research Program, for which I’m the principal investigator (PI), we are going up to 2.4 mg — the highest dose of semaglutide.

We are collaborating with Kyle Simmons, PhD, from Oklahoma State University. Our two studies are not like a two-site clinical trial, but they are harmonized. In Dr. Simmons’ clinical trial, they’re going up to 1.0 mg. We are excited about this team approach because the trials are slightly different, but they’re harmonized to the point that, once the studies are done, we’ll be able to combine and compare data to better answer the question about dosing, and many other questions.

Dr. Jain: From a clinical perspective, we see that many people who are battling alcohol use disorder may not have obesity. They might actually be on the leaner side, and hence, we may not want to use a high dose of GLP-1 RA therapy. It’ll be very exciting to see when these results come out.

This brings me to the next question. I think everyone would love to know why this happens. Why is GLP-1 RA having this effect on alcohol use disorder? I know that your group has done many animal studies, as you pointed out, and one of the postulated theories was the effect on the GABA neurotransmission pathway.

Can you tell us more about what you feel is the underlying mechanism of action here?

Dr. Leggio: I will start by saying that we don’t fully know. There are many open questions. If I can sidetrack for one second: We come up with the idea that, first of all, alcohol use disorder and substance use disorder are addictive behaviors, addictive disorders. We define addiction as a brain disease. 

Granted that addiction is a brain disease, it doesn’t mean that addiction works just in the brain in isolation. As we all know, the brain works in concert with the rest of the body. One specific approach my team has been taking is working on the analogy and the similarities between obesity and addiction to try to understand how the body-brain connection, such as the gut-brain-neuroendocrine pathway, may play a role in patients with addiction.

With that in mind, a large amount of work in my lab in the past 20 years — since I’ve been a PI — has been focused on studying this neuroendocrine pathways related to the gut-brain axis. For example, we have done work on insulin and leptin, primarily; we had done work on ghrelin, and since 2015 on the GLP-1 RAs.

With that in mind, the framework we are working on, which is also substantiated by many studies done by our team and other teams in the neuroscience field, kind of supports the idea that, similar to what we see in obesity, these medications may work by affecting what we call reward processing, or the seeking for addictive drugs, such as alcohol, and also the drugs such as the stimulants, opioids, nicotine, and so on.

The idea is that the mechanism is driven by the ability of the medication — semaglutide and all the GLP-1 RAs — to reduce the rewarding properties of alcohol and drugs. To maybe make the example more pragmatic, what does that mean? It means, for example, that a patient who typically has 10 drinks per day in the afternoon and night, while they are on the medication they may feel the lack of need to drink up to 10 to feel the same reward. 

They may be able to stop after two or three drinks, which means a significant harm reduction and a beneficial outcome. This also brings us to another mechanism, which may be related to society. We don’t fully understand how much the society mechanism, including society mechanism related to GI motility, may also play a role.

With that said, we don’t think that the effect of the GLP-1 RAs is merely due to alcohol being a calorie-based nutrient because, in fact, we see alcohol as an addictive drug, not as a nutrient. Also, the GLP-1 RAs, at least in animal models, seem to work on other addictive drugs that don’t have calories, such as nicotine, and possibly with cannabis, opioids, and stimulants.

Then on the molecular level, our team recently showed, in collaboration with Dr. Marisa Roberto from Scripps in La Jolla, California, that semaglutide may in fact change the GABA transmission at the level of some brain regions, such as the amygdala and the prefrontal cortex. These are brain regions that are well-established hubs that play a role in the mechanism underlying addiction. 

There are also some very exciting recent data showing how these medications may work not just on GABA or just on dopamine, which is the canonical way we conceive of reward processing, but by working on both by modulating GABA transmission — for example, at the ventral tegmental area and dopamine transmission at the nucleus accumbens.

Bottom line, if I summarize all of this, is that the mechanism is not fully understood, but there is definitely a contribution of this medication to effect and reward processing, possibly by altering the balance between GABA and dopamine. There are still some unknown questions, such as, are these mechanisms all brain driven or are they signaling from the periphery to the brain, or maybe both?

Also, as we all know, there are many differences across all these GLP-1 analogs in brain penetrance. Whether the drug needs to go to the brain to have an effect on alcohol drinking, cocaine seeking, or smoking is really an open question.

Dr. Jain: This is so thought-provoking. I guess the more we uncover, the more mesmerized we get with all the potential crosstalk. There is a large amount of overlap in the brain with each of these different things and how it all interplays with each other. 

Speaking of interplay, I’m thinking about how many people prone to having alcohol use disorder can potentially develop complications, one of these being chronic pancreatitis. This is a well-known complication that can occur in people having alcohol addiction. Along that same line, we know that previous history of pancreatitis is considered a use-with-caution, or we don’t want to use GLP-1 RA therapy in people who have had pancreatitis. 

Now it becomes this quagmire where people may have chronic pancreatitis, but we may want to consider GLP-1 RA therapy for management of alcohol use disorder. What are your thoughts about this, and the safety, potentially, in using it in these patients? 

Dr. Leggio: This is another wonderful question. That’s definitely a top priority in our mind, to address these kinds of questions. For example, our RCT does have, as core primary outcomes, not only the efficacy defined as a reduction in alcohol drinking, but also safety.

The reason is exactly what you just explained. There are many unanswered questions, including whether giving a GLP-1 RA and alcohol together may have synergistic effects and increase the likelihood of having pancreatitis. 

The good news is that, so far, based on the published literature, including the RCT done with exenatide in Denmark and published in 2022 and also the ongoing clinical trials — including my own clinical trial, but of course we are blind — pancreatitis has not been coming out as an adverse event.

However, it’s also true that it often happens in clinical medication development. Of course, we screen and select our population well. For example, we do exclude people who have a history of pancreatitis. We exclude people with high lipase or with any of the clinical symptomatology that makes us concerned about these people having pancreatitis. 

As often happens when you move a medication from clinical trials to clinical practice, we still need to understand whether this medication works in patients. I’m just speculating, but even if the clinical trials do not raise red flags in terms of increased risk for some side effects such as pancreatitis, I think it will be very important for practitioners to keep a close eye on the death risk regardless. 

It’s very interesting that it’s similar to alcohol liver disease. With pancreatitis, not every single patient with alcohol addiction has pancreatitis. We don’t really fully understand why some people develop pancreatitis and some people do not. The point being that there are many patients with alcohol addiction who don’t have pancreatitis and may benefit from these medications if they work. Again, we have to prove that in patients.

On the other side, as we all know, pancreatitis is a potentially life-threatening condition for those people who either have it or are at risk for it. I think we have to be very careful before we consider giving them a GLP-1 RA.

One could argue that alcohol is the leading cause of mortality and morbidity in the world. For example, right now, alcohol is the leading cause of liver disease. It’s the main reason for liver transplantation in our country. Alcohol is affecting thousands of people in terms of death and emergency room visits.

You could argue that the downside is not treating these people and they die because of alcohol addiction. A GLP-1 RA is not going to be for everybody. I will remind everybody that (1) we do have FDA-approved medications for alcohol addiction; and (2) there are also other medications not approved by the FDA, but with a proven efficacy in some clinical trials — for example, topiramate and gabapentin — and they’ve been endorsed by the American Psychiatric Association. 

There is also some evidence for another medication, baclofen, which has been endorsed by the American College of Gastroenterology for patients with alcohol addiction and liver disease.

The point I’m making is that it’s not that either we use the GLP-1 RAs or we have no other tools. We have other tools. I think we have to personalize the treatment based on the patient’s profile from a safety standpoint and from a phenotypic standpoint. 

Dr. Jain: I love that thought. I think individualization is the key here.

We know that people with diabetes have a higher risk for pancreatitis by virtue of having diabetes. People with obesity also have a higher risk for pancreatitis by virtue of having obesity. These are the two conditions where we are using a large amount of GLP-1 RA therapy. Again, the idea is looking at the person in front of us and then deciding, based on their past medical history and their current risk, whether or not a medication is a right fit for them.

I think more individualization here will come as we start using these medications that might be having potential effects on different organ systems. You mentioned a little bit about the liver, so a thought came in my mind. We know that people with diabetes who have alcohol use disorder are at a higher risk for potential hypoglycemia. If they have events when they have increased consumption of alcohol, there can be more hypoglycemia.

We now could potentially be using semaglutide or other GLP-1 RA therapy for management of alcohol use disorder. In your own experience in the studies that you’ve done or the literature that’s out there, has that been associated with an even higher risk for hypoglycemia? 

Dr. Leggio: It’s a wonderful question. I’m not aware of any formal and published report of that association. That said, your thinking from a physiopathologist standpoint makes total sense. I could not agree more. The fact that nothing has been published, at least to my knowledge, doesn’t mean that the death risk doesn’t exist. In fact, I agree with you that it does exist. 

Alcohol use disorder is interesting and tricky clinically because chronically, alcohol addiction or alcohol use disorder is associated with an increased risk for diabetes. Acutely, as you point out; and this could be with or without alcohol use disorder. An episode of a high volume of binge drinking may lead to hypoglycemia.

This is one of the reasons why people may show up to the emergency room with intoxication, and one of the symptoms detected at the emergency room is that they also have hypoglycemia in addition to vomiting, nausea, and everything else that we see in patients with acute intoxication.

Similar to the discussion about pancreatitis, as we work on understanding the possible role of GLP-1 RA in patients with alcohol use disorder, we do have to keep a close eye on the risk for hypoglycemia. The short answer is that this is not well established, but based on the simple concept of “first, do no harm,” I think we need to track that very carefully. 

In the ongoing clinical trial we’re doing in Maryland in my program at the NIH, we do just that. We are tracking glucose levels. Of course, patients come to clinic weekly, so unless they have symptoms, typically we don’t see anything at the time.

More important, we educate our patients when they go through the consent process. We tell them that this medication per se does not give hypoglycemia. In fact, we’re including people with diabetes, so for people on other medications like metformin, we explain to them that technically such a risk should not exist, but because you’re drinking alcohol in excessive amounts, you do have a potential higher risk. We just don’t know how significant that risk could be. 

We do a large amount of education at baseline when they enroll in our study. We also educate our patients on how to recognize early on the potential risk for hypoglycemia, exactly for the reasons you said. We explain to them the unknown potential that the GLP-1 RAs and alcohol together may synergize and give hypoglycemia.

Dr. Jain: I don’t know if you got this feeling at the ADA conference, but I felt, when attending all these sessions, that it seems like GLP-1 RA is the gift that keeps giving. We see the effect on diabetes, obesity, metabolic-associated steatotic liver disease, possibly with Alzheimer’s, chronic obstructive pulmonary disease, and so many things.

Now, of course, there’s potential use in alcohol use disorder. Do you think that using GLP-1 RA therapy is ready for prime time? Do you think we are now ready to prescribe this in people with alcohol use disorder?

Dr. Leggio: I would say we’re not there yet. As I mentioned at the beginning, the evidence keeps on growing. It’s getting stronger and stronger because the positive data keep on coming up. We have data from animal models, including the different species, ranging from rodents to nonhuman primates. We have anecdotal evidence and machine-learning approaches using, for example, big data and social media data. Now we have pharmacoepidemiology data and some small, initial, but still good randomized clinical trials.

What we are missing is the final step of having a substantial number of prospective, double-blind, placebo-controlled clinical trials to really prove or disprove whether these medications work, and to also better understand which patients may respond to these medications.

The good news is that there are many ongoing clinical trials. We are conducting a clinical trial in Maryland at the NIH. Dr. Simmons is doing a clinical trial at Oklahoma State University. Dr. Christian Hendershot at UNC is conducting a study at Chapel Hill. Dr. Josh Gowin is doing a study in Colorado. Dr. Anders Fink-Jensen is doing a study in Denmark. The momentum is very high. 

I’m only mentioning those people who are doing alcohol-semaglutide clinical trials. There are also people doing clinical trials on smoking, stimulants, and opioids. There are actually some very fresh, still unpublished data from Penn State that were presented publicly at conferences, showing how these drugs may reduce opioid craving, which is, of course, critically important, given that we’re in the middle of a fentanyl pandemic that is killing one person every 7 minutes, for example, in Baltimore. It’s very alarming and we need more treatments.

The bottom line is that it’s very promising, but we need to wait for these clinical trials to have a definitive answer. I would say that if you have a patient with diabetes, obesity, and also alcohol addiction, and they are on semaglutide or any other GLP-1 RA, and in addition to using the medication for diabetes and obesity, they also have a beneficial effect on their alcohol drinking, then that’s fantastic. At the end of the day, that’s the mission we all share: helping people. 

If it’s someone without obesity and diabetes, personally, at this stage, I will go with other medications that either have FDA approval or at least very solid evidence of efficacy from RCTs rather than going with the GLP-1 RA, at least until I see more definitive data from randomized clinical trials. 

There is a large amount of hope. We are hoping that these clinical trials will be positive. We are very enthusiastic and we’re also very thrilled to see that Novo Nordisk recently launched a gigantic multisite clinical trial with — I forgot how many sites, but it’s very large across Europe, America, and maybe other continents as well.

Their primary outcome is improvement in alcohol-related liver disease, but they’re also looking at alcohol drinking as a secondary outcome. That’s very important because, unlike in the diabetes field, in the addiction field, we do struggle to build partnership with the private sector because sometimes the addiction field is not seen as an appetitive field from pharma. 

We all know that the best success in any medication development story is when you put academia, the government, and pharma together. Think about the COVID-19 vaccine development. That’s unfortunately the exception rather than rule in the addiction field. 

With the company doing a large clinical trial in the alcohol field, although they focus more on the liver but they also looked at drinking, I really hope we’ll see more and more companies in the private sector take more and more interest in addiction. Also, I hope to see more and more partnership between the private sector, the government, and academia. 

Dr. Jain: Such exciting times, indeed. We can’t wait enough for the results of these and many other trials to come out. Dr. Leggio, it was an absolute delight chatting with you today. Thank you so much for joining us from ADA 2024.

Akshay B. Jain, MD, Clinical Instructor, Department of Endocrinology, University of British Columbia; Endocrinologist, TLC Diabetes and Endocrinology, Vancouver, British Columbia, Canada, has disclosed the following relevant financial relationships: Serve(d) as a speaker or a member of a speakers bureau for: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Care to Know; CCRN; Connected in Motion; CPD Network; Dexcom; Diabetes Canada; Eli Lilly; GSK; HLS Therapeutics; Janssen; Master Clinician Alliance; MDBriefcase; Merck; Medtronic; Moderna; Novartis; Novo Nordisk; Partners in Progressive Medical Education; Pfizer; Sanofi Aventis; Timed Right; WebMD. Received research grants/research support from: Abbott; Amgen; Novo Nordisk. Received consulting fees from: Abbott; Acerus; AstraZeneca; Amgen; Bausch Healthcare; Bayer; Boehringer Ingelheim; Dexcom; Eli Lilly; Gilead Sciences; GSK; HLS Therapeutics; Insulet; Janssen; Medtronic; Novo Nordisk; Partners in Progressive Medical Education; PocketPills; Roche; Sanofi Aventis; Takeda. Lorenzo Leggio, MD, PhD, Clinical Director, Deputy Scientific Director, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, Maryland, has disclosed the following relevant financial relationships: Serve(d) as a US federal employee for: National Institutes of Health. He had received income in an amount equal to or greater than $250 from: UK Medical Council on Alcohol for his service as editor-in-chief for Alcohol and Alcoholism and received royalties from Rutledge as an editor for a textbook.

A version of this article first appeared on Medscape.com.