Skin disease and alcohol use disorder may not be related conditions, but new research from Oregon Health & Science University suggests they could be treated with the same medication. Researchers ran animal studies and found that apremilast, which is normally used to treat psoriasis and psoriatic arthritis, had an effect on alcohol consumption. In human studies conducted at the Scripps Research Institute in California, participants who received apremilast reduced their alcohol intake from five to two drinks per day, on average.
Angela Ozburn is an associate professor of behavioral neuroscience at OHSU and a senior author of the study. She joins to tell us more.
This transcript was created by a computer and edited by a volunteer.
Dave Miller: From the Gert Boyle Studio at OPB, this is Think Out Loud. I’m Dave Miller. Skin disease and alcohol use disorder may not seem to have much in common, but new research from OHSU suggests they could be treated by the same medication. Scientists found that apremilast, which is normally used to treat things like psoriasis, led people to drink less. Angela Ozburn is an associate professor of behavioral neuroscience at OHSU and a senior author of a new study. She joins us with the details. It’s great to have you on Think Out Loud.
Angela Ozburn: Thank you. I’m honored to be here.
Miller: We have talked so much in recent years about opioid addiction and fentanyl overdoses. But can you just remind us first about the extent and the severity of alcohol use disorder in the U.S. right now?
Ozburn: Oh. That’s a great thing to start with. In recent years, deaths related to alcohol in the U.S. have gone over 140,000 per year. The costs to society are estimated to be over $250 million, where a quarter of people report binge drinking or drinking to intoxication in the last month. That accounts for 75% of the costs associated with it and alcohol related liver damage, cancer. It has multiple health consequences. This isn’t for the occasional drinker or a glass or two of wine. This is four drinks within a two hour period or more kind of drinking that is excessive and harmful. The deaths have risen since COVID – people have reported an increase in the amount they drink at a time. So it’s become a big problem.
Miller: What existing medications– we’re talking about the possibility of a new medication or existing medications used in a new way, but what existing medications are there for people who have problems with alcohol?
Ozburn: There are several. There are three FDA approved medications. Antabuse is one. It typically just makes people feel sick when they drink, so you can just choose to stop taking it in order to continue drinking. It doesn’t really do anything to help people want to reduce their drinking…
Miller: But if you do drink after you’ve taken it, you feel nauseous or…?
Ozburn: Very. Very sick.
Miller: Okay.
Ozburn: Yeah, immediately with less than one beverage. Other medications, there are two: naltrexone and acamprosate. They’re designed to help people increase the number of days sober, reduce the amount of drinking when it does occur. They work well, but they don’t work for everyone. We have a lot of medications for psoriasis, for acid reflux… So in searching for medications for more precision-based medicine for people, we want to find help for people suffering from alcohol use disorder symptoms. I mean, it severely affects their lives and their loved ones. So our goal is to provide additional options that may work better for some people.
Miller: How did you go about doing that, scientifically, in ways that we laypeople can understand? I mean, you basically set out to say there’s a hole here, there’s a gap in effective medication for people with this problem. So what did you do first?
Ozburn: I mean, really, it was a career goal. It wasn’t something that happened within a year or two.
Miller: You mean this is the focus of your career?
Ozburn: Yeah. Yeah. So, initially, I thought, oh if we can learn more about the brain regions important for drinking and using animal models and reading human studies. And then what’s special about those brain regions? How are they affected? Then learning more about particular symptoms. Alcohol is complex. It interacts with lots of different molecules. There’s no one gene, it’s what we call a polygenic disorder. So then I focused on genetics and how different constellations of genes can contribute to severity of alcohol use disorder or risk for alcohol use disorder. Really the more I learned about it, the more I learned how complex it was. So when I was starting my own research program at OHSU, I worked with a consortium of people on this problem. That was outstanding. This team science approach has really helped us move science from the bench – from studying gene expression or genes – to treatments. One of the ways I want to think about this is, if it takes multiple types of genes that contribute to the risk for alcohol use disorder, how can we leverage that? The first thing that we did was we used animal models. They were selectively bred to voluntarily drink to intoxication. That means that we captured a genetic signature of risk. Then we said, ‘what’s the opposite of that?’ We looked in databases where people had used cell lines and said, here’s the effects of different compounds on the gene expression of different cell lines. And we said, what could be opposite? In other words, if in our animals we see these changes and in humans we see these changes, what might do the opposite of that?
Miller: You mean, what compounds or existing drugs would counteract that inclination or desire in animals or humans?
Ozburn: Yes.
Miller: What animals are you talking about, by the way?
Ozburn: Mice.
Miller: So you have, you or others, have created in a sense, selected for mice that have a desire to drink too much alcohol or drink a lot of alcohol.
Ozburn: Yes. Behavioral geneticist and now Professor Emeritus John Crabbe developed those animal models. Again, this is, I’m standing on the shoulders of giants here and lots of teamwork. The study we’re talking about, you know, this is multiple papers, at least eight labs moving this forward. What we did was we identified some compounds. We prioritized them, and we said we think these will have the opposite effects. We tested them, and they worked. It was incredibly exciting. We call that our proof of concept. Here what we found were investigational compounds. We don’t know what they do. We don’t know if they’re safe. We don’t know if they harm the liver. Half of people with liver transplants, it’s due to alcohol. So we need to be really careful about how we move forward here.
Miller: Because a lot of drugs have to be processed by the liver.
Ozburn: Yes.
Miller: And if the liver is compromised, giving them a drug to help them stop drinking may not be the best thing for them because their livers don’t work very well.
Ozburn: Yes, thank you.
Miller: Okay. So, at what point did you find, did you zero in on, this existing drug, apremilast, that’s used for psoriasis?
Ozburn: We worked our way down that list, that prioritized list of compounds. Since the first few worked, we thought, okay, well, those are great. That’s investigational though. That’s going to take a lot of effort. Maybe there’s something on there that’s already FDA approved for another purpose and that’s safe and well tolerated. Well, what we found next on the list was really promising, but it’s not well tolerated. It’s called rolipram. It’s a phosphodiesterase type 4 inhibitor like apremilast, but it often induces nausea. We thought, well, there’s alternatives that are currently in use for psoriasis and psoriatic arthritis. Let’s try that. And there was another team: Dr. Blednov at UT Austin – University of Texas, Austin. He had said, okay, which kinds of medicines might be working best and have the least side effects. So, again, a lot of teamwork, a lot of different labs involved, different animal models, different strains. That way, when we did bring it to Dr. Barbara Mason at Scripps and say we think this is a strong candidate for human laboratory testing, we were standing on a strong foundation of generalizable findings, robust findings.
Miller: So let’s zoom ahead to what they found with humans. And maybe you can tell us the population of people that they were working with.
Ozburn: These were folks in Southern California. There were 51 people that they recruited to the study. It’s what we call a double-blind, placebo-controlled study. It’s the gold standard for a really good, ‘Is this gonna work?’
Miller: Meaning the people who took the medicine didn’t know if they were getting placebo or not, and the people who gave them the medicine didn’t know either.
Ozburn: That’s correct.
Miller: Okay.
Ozburn: Another condition that was unique was that these people were not treatment seeking.
Miller: What does that mean?
Ozburn: That means that they weren’t looking to get sober. They weren’t looking to change their drinking habits. They were paid participants in a study. They took a pill – active or inactive – for 11 days, and they agreed to come in for visits to discuss their drinking. They also provided samples so we could measure things in their blood and filled out questionnaires about whether there were side effects.
Miller: And what were the main effects of the actual drug?
Ozburn: It was exceptional and totally astonishing. I’ve never seen effects like this. People who weren’t even looking to change their behavior reduced their drinking by half. So, if they were drinking five or six drinks a day, they were now drinking two or three.
Miller: When you’re saying that you’ve never seen an effect like this, what effects have you seen in the past for other interventions, whether it’s talk therapy or pharmaceuticals?
Ozburn: In people who are actually seeking treatment, you’re looking at folks who are getting cognitive behavioral therapy, support groups, wellness counseling. So we see large placebo effects there in combination with medicines. The effect size of the medicine in those cases seems to go down because we see such a large change or increase in days sober or decrease in heavy drinking days for people who are seeking treatment. In studies where people weren’t seeking treatment, we haven’t seen anything like this before.
Miller: You haven’t seen a decrease in behavior of this size.
Ozburn: No. It was very robust.
Miller: Do you imagine that if this were to go forward that this would be an off-label prescription or would there actually be FDA approval specifically for a prescription for alcohol use disorder?
Ozburn: What I really want to see is I want to see it covered by insurance for people who want this option to try if the other currently available options don’t work. However that looks like, because the drug will go off patent… I just want to note, I have no, I declare no conflict of interest financially. But the company has this compound on patent through 2028.
Miller: And it could be $6,000 a month.
Ozburn: Oh yes. Yes. I have no interactions with the company, but I don’t think there’s enough time for them to do clinical trials with this compound, get FDA approval – that takes like 10 years – before this thing goes off patent. So I’m hopeful that the generic will become available, and it will be off-label use. Or maybe the American Psychiatric Association can help provide this as… like there are two compounds, gabapentin and topiramate, that they recommend. They’re not FDA approved for alcohol use disorder, but they are successful in helping treat it. So clinicians have access to other compounds that are recommended but not necessarily FDA approved.
Miller: I did skip us ahead a little bit to actual prescriptions in some way for this. But what would have to happen first? What are the next research steps?
Ozburn: For FDA approval?
Miller: For people who have alcohol use disorder to actually be taking this to make their lives better?
Ozburn: I think they can just request it.
Miller: Right now?
Ozburn: Right now.
Miller: It could happen right now?
Ozburn: Yeah, I think they can just request it. I don’t know that doctors will offer that.
Miller: And based on the research that’s already been done, I mean, because it’s already safe. People are taking this for psoriasis.
Ozburn: Yes, it’s very well tolerated.
Miller: But then again, I guess then it becomes a question of what would it take for a doctor to prescribe it?
Ozburn: That’s, I feel like that’s a little bit out of my realm of expertise because I don’t know. I mean, I think that depends on their specific, sort of rules around this like…
Miller: Or their comfort level looking at the basic research and what it takes to have that turn to prescribe in practice.
Ozburn: Yeah, and also the individual’s ability to afford it currently. I mean, especially if gabapentin could be helpful – it is available in a generic – or acamprosate or naltrexone. Those would probably be first line. More work is definitely needed. I’m excited for what the future holds though.
Miller: Angela Ozburn, thanks very much.
Ozburn: Oh, can I just make another plug?
Miller: Please.
Ozburn: Okay. I just want to say that this work wasn’t possible without the effort of multiple labs and multiple trainees in the labs. And I just want to thank Dr. Kolter Grigsby – he’s a postdoctoral fellow in my lab – for leading this and helping to get it across the finish line so we can share it with the public. So, thank you.
Miller: I have to say, I don’t think I’ve ever talked to a scientist who has acknowledged as clearly and effusively as you have the extent to which science is almost always a collaborative effort, so I appreciate that. Angela Ozburn, it was a pleasure talking with you. Thank you.
Ozburn: Thank you.
Miller: Angela Ozburn is an associate professor of behavioral neuroscience at OHSU. She joined us to talk about a new skin drug that could curb problem drinking.
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