Attacking Addiction at the Molecular Level: The Medicinal Chemistry of Dr. Amy Hauck Newman

Meg welcomes Dr. Amy Hauck Newman, the Scientific Director and the Chief of Molecular Targets and Medications Discovery Branch and Medicinal Chemistry Section of the National Institute on Drug Abuse’s Intramural Research Program also known as “NIDA” IRP. It is one of the 27 institutes and centers of the National Institutes of Health (NIH) and it is dedicated to understanding the causes, consequences and treatment of substance use disorders. 

On today’s show, Dr. Amy Hauck Newman discusses her work in developing novel medications to treat substance use disorders. She explains the lengthy process of drug development and the importance of intellectual property and partnerships. Dr. Newman also highlights the role of AI and machine learning in healthcare and drug design.

Amy shares her journey into chemistry and the challenges and rewards of starting and leading her own laboratory. The use of drugs like Ozempic is touched on as well as various aspects of substance use disorder and the challenges associated with its treatment. Amy talks about the challenges in treating cocaine and methamphetamine use disorder and the emotional weight of working in this field. Finally, the conversation gets into the challenges in engaging the pharmaceutical industry when it comes to fighting substance use disorders.

Further Reading:

Molecular Targets and Medications Discovery Branch at NIDA 

Presynaptic and Postsynaptic Mesolimbic Dopamine D3 Receptors Play Distinct Roles in Cocaine Versus Opioid Reward in Mice

NIH Postbac Program

NIH Summer Internship Program (SIP)

Episode Credits: 

The Game-Changing Women of Healthcare is a production of The Krinsky Company. 

Hosted by Meg Escobosa. 

Produced by Meg Escobosa, Calvin Marty, Chelsea Ho, Medina Sabic, Markala Comfort, and Wendy Nielsen.

Edited, engineered, and mixed by Calvin Marty. 

All music composed and performed by Calvin Marty. 

©2024 The Krinsky Company

Creators & Guests

Host

Meg Escobosa

Meg Escobosa has 15 years of innovation consulting experience, focusing on the unique challenges of healthcare since 2012. For The Krinsky Company, Meg leads client engagements overseeing advisory board design, creation and management. She also leads industry research, expert recruitment and trend analysis to support corporate innovation initiatives centered on the future of healthcare. Her background in innovation and strategy consulting began at IdeaScope Associates where she was involved all aspects of strategic innovation initiatives including understanding the voice of the customer, industry research and aligning the executive team to invest in promising strategic growth opportunities. Meg received her BA in Latin American Studies from Trinity College in Hartford and her MBA in sustainable management from the pioneering Master’s degree program, Presidio Graduate School. She is also on the board of a non-profit foundation focused on researching and developing technology to support a sustainable society. She lives in San Francisco with her husband and two teenage daughters.

Producer

Calvin Marty

A man of many hats, Calvin Marty is a Podcast Producer, Editor, Engineer, Voice Actor, Actor, Composer, Singer/Songwriter, Musician, and Tennis Enthusiast. Calvin produces, engineers, edits, mixes, and scores The Game-Changing Women of Healthcare. Calvin is also the creator of the 2020 podcast, irRegular People, among others. Find his music under the names Calvin Marty, Billy Dubbs, Nature Show, and The Sunken Ship. Over his long career as an actor, Calvin's has voiced many Radio and TV commercials for a wide-range of companies and products and has appeared in small on-camera roles on shows such as Chicago Fire and Empire.

What is The Game-Changing Women of Healthcare?

The Game-Changing Women of Healthcare is a podcast featuring exceptional women making an impact in healthcare today. We celebrate our guests’ accomplishments, setbacks, and the lessons they've learned throughout their careers. We dig into the many healthcare issues we face today and how these innovative leaders are working to solve them. Join host Meg Escobosa in conversation with some of the many brilliant, courageous women on the front lines of the future of health.

Dr. Amy Hauck Newman: Substance use disorders are a horrible neuropsychiatric disorder that's painful not only to the person but to their families, to our communities, and so forth. It is devastating. The neuroscience of addiction is fascinating. I have been doing this for more than 30 years and I never get tired of it. And every day I learn something new, I get more excited about something else that we can try.

That's what keeps me going because there's a lot of very smart people who are working in this field in all different disciplines. I just believe that the collective will be able to come up with medications and treatments for this population that will help in the future, and I will continue to believe that. It is extremely challenging.

Meg Escobosa: Welcome to the Game-Changing Women of Healthcare, featuring exceptional women making an impact in healthcare today. Together, we dig into the many healthcare issues we face today and how these innovative leaders are working to solve them. We celebrate our guests’ accomplishments, setbacks, and the lessons they've learned throughout their careers.

I'm Meg Escobosa. Join me in conversation with some of the many brilliant and courageous women on the front lines of the future of health.

Welcome back to The Game-Changing Women of Healthcare. I'm your host, Meg Escobosa. A quick note before we get into today's episode, we are currently looking for sponsors for the podcast. If supporting and encouraging female leadership in healthcare is important to you or your organization, help us do that by becoming a sponsor of the Game-Changing Women of Healthcare, reach our engaged audience with a mention by me in future episodes, or we'll produce a short audio spot for your organization. At The Krinsky Company, we believe in female and diverse leadership in healthcare. If that's important to you too, become a sponsor of the podcast and proudly share your values with the world. Reach out to us at [e-mail] and thank you.

Meg Escobosa: Hi everyone, today on the show we have Dr. Amy Hauck Newman. She is the Scientific Director and the Chief of Molecular Targets and Medications Discovery Branch and Medicinal Chemistry Section of the National Institute on Drug Abuse's Intramural Research Program, also known as NIDA IRP.

It is one of the 27 institutes and centers of National Institutes of Health and is dedicated to understanding the causes and consequences of treatment of substance use disorders. Amy is an inventor of several licensed NIH patents. She has also co-authored hundreds of original research papers, articles, and reviews on the design, synthesis, and evaluation in the role of the central nervous system active agents as potential treatments for substance use disorders.

And she has won several awards in the field of chemistry and science. She was the first woman to be awarded the Philip S. Portuguese Medicinal Chemistry Lectureship. She has demonstrated an unwavering commitment to science and continues to be recognized for all of her contributions and achievements in the industry.

Meg Escobosa: Hi Amy.

Dr. Amy Hauck Newman: Hi Meg.

Meg Escobosa: Welcome to the show.

Dr. Amy Hauck Newman: Thank you for inviting me.

Meg Escobosa: Can we start with what you are working on right now?

Dr. Amy Hauck Newman: Oh, sure. Always happy to talk about our work. So I'm a medicinal chemist, as you said. So we are at the very basic science end of this enterprise, and we are interested ultimately in developing novel medications to treat substance use disorders.

But in order to do that, we need to understand what mechanisms in the brain are associated with the development of addiction. And what might we be able to target to help people who do have substance use disorders, ultimately be able to live drug-free lives.

What we have discovered, we and many others in this field over decades, is that one of the brain chemicals or neurotransmitters that is critically involved with the development of addiction is dopamine. And dopamine binds to dopamine receptors in the brain, and it also is transported in and out of dopamine neurons via dopamine transporter. And so those targets have been the major focus of my research lab over the past many years. We have done other things, but we really have focused on the dopamine D3 receptor and the dopamine transporter as two targets that we are developing highly selective small molecules to interact with, in hopes of decreasing the reinforcing effects of substances that are abused.

The exciting thing that we are working on right now, there's a couple of things, but one is that one of our compounds, which is called an antagonist. This compound binds to the dopamine D3 receptors and blocks dopamine from interacting there, looks very promising in our animal models of opioid use disorder.

And although we have medications for the treatment of opioid use disorder, methadone, buprenorphine, naloxone for overdose, we believe that there should be more in the toolbox. Those are all compounds that actually work on opioid receptors and our hypothesis is that if we can develop medications that don't work directly through the opioid system, but can block those rewarding effects or prevent relapse to drug taking, that this would be an important advance.

And one of our compounds, we have been able to develop toward something called an investigational new drug, which is IND. This is the approval we need by our FDA to allow us to test compounds in humans. And something I often say is that I have cured opioid use disorder in rats, but I would really like to see whether these compounds, this compound, will work in humans.

And this will be the first opportunity that we hope to have to actually test everything that we've seen in animals to see if in fact, this drug will be helpful in humans who have opioid use disorder.

Meg Escobosa: Okay, so I see your lab as sort of the beginning of the relay race. If you're going to pass a baton, who is the next group that picks up your baton from where you are now to take it to the next level? Or do you drive that FDA piece of the puzzle?

Dr. Amy Hauck Newman: Yeah, that's a great question and I don't. And I actually, I'm learning all along. So the first thing that we do is synthesize these compounds and we do have a lot of in-house capabilities for testing to see if they bind to dopamine D3 receptors, for example, see what their selectivity is across other receptor systems.

We have numerous animal models that we can test our compounds in that suggest that they may be a useful medication. And we also can look at things like metabolic profile, whether they get into the brain, they have good blood-brain barrier penetration, all of those things we can do essentially in house, which give us good data to support that these could be developed toward medications.

But the next step is a huge one. Well, first of all, we always try to protect everything, our intellectual property because we know that eventually, although we do pretty good basic and preclinical science, eventually, we will need a pharmaceutical company to pick up this technology and take it, take that baton all the way to the end game, and they won't do it if there's no intellectual property protection so we make sure that we have patent protection. And then in the case that I just mentioned, we were very fortunate to work with another center, which is one of the other centers of the NIH, called the National Center for Advancing Translational Science. This is a center that's unique because it’s NIH’s little mini drug company.

Most of the scientists there have drug company experience, and they really have all the capabilities to do what the FDA requires for that investigational new drug approval, which is a lot of work and a lot of money for to determine, mostly toxicology, determine is this compound, it works in your rats, but is it going to be safe in humans?

And then formulation, we just inject our rats with a solution of our compound. But obviously that's not going to be useful for people. So figuring out the formulation is this going to be a capsule, how many times a day will they have to take it and so forth. So this is where we do hand the baton off to, in this case, NCATS, sometimes in the case of a pharmaceutical company who also clearly has those capabilities.

And then of course, the ultimate goal is if we do get this approval and we can do clinical studies, we will be able to do the very early human studies at NIDA. But eventually, again, we would have to have an industrial partner to move these forward and hopefully get it into the clinic.

Meg Escobosa: That's great. I was going to ask you about these 27 other centers. So that's fascinating to think that one of the other centers is actually a key enabler to that next step. And what would prevent it from carrying it all the way through to its own clinical studies? Can they do clinical studies?

Dr. Amy Hauck Newman: They can't. They really do. They do all the way up to this IND approval, and they really depend on their partners, like me, to take it to the next step, whether we do it in our own institute or we find a partner who can do it first in human studies. It’s just a safety study and it's actually in people in our case who don't have opioid use disorder and it's really a dose escalation study to see how is this drug tolerated in someone who doesn't have this disease. Those are typically done by contract research organizations, CROs, and NIDA has a contract research organization that they will work with if we get that far.

And then, assuming, and hopefully, our compound is safe in that population, what we can do is what's called a Phase 1A, which is the same safety study, but now in the patient population that we hope to treat. So these people will have opioid use disorder, and we'll see how they tolerate the drug. And if they tolerate it, and there's no real adverse events, then that opens the door to the clinical studies that go into Phase 2.

The phase one is really just to see if it's safe. The phase two clinical studies will really start to see whether it's effective. And then by then we will have to hand it off to a company because those studies become very expensive and it's not really our purview.

Meg Escobosa: How many years have you been at this particular research just to give us all a reality check on what it really takes to get to this clarity of a potential treatment.

Dr. Amy Hauck Newman: Yeah, it's a long time. And not that we're super slow at this, but I know we are slow at it. And the reason that first of all, we are, we're a research organization and I have a relatively small team of people to do this work and they're not just working on this particular project and that's different than in industry where they have, they choose a target and they put a team on it, but it can, even in pharma, it can take a decade.

We have been working on the dopamine D3 receptor for more than 20 years, but in the beginning, we didn't know whether it was really going to be a target or not. So it took years just to make compounds that were highly selective that we could use as tools to really study and we're still using those compounds as tools because it's not just, “Oh, this blocks the reinforcing effects in rats,” there's many more levels that we are always continuing to attempt to understand. So we've been working on it for a long time. One of the challenges with this particular target is that most of the compounds that we and others have made over the years, were great tools, but they weren't great drugs. So that's the other thing.

You can get a compound that has high affinity for your target and doesn't have off target effects, but it's metabolized super fast or it doesn't get into the brain very well. Or there was a compound from a company a few years ago that turned out to have cardio toxicity, which you don't really learn until much later in the game, at least in my laboratory.

In pharma, they do things a little bit differently. They look at safety before they really look at efficacy and we're the opposite because we have the capability of looking at these models first. But those are the kinds of caveats that have really prevented us and any other lab from getting compounds into the clinic. But right now, at least our compound looks like it's checked all those boxes in the models that we've tested.

Meg Escobosa: Well, you can't see me, but I'm touching wood.

Dr. Amy Hauck Newman: Yeah, all the time.

Meg Escobosa: Okay, good luck with that. That is, it's phenomenal.

Dr. Amy Hauck Newman: Thank you.

Meg Escobosa: Congrats on getting to this point and we'll just sort of wish you the best on the next leg.

Meg Escobosa: We know that AI, machine learning, those are tools that are increasingly being used in healthcare and certainly in life sciences research. Can it be useful to you? Is it being, playing a role at all in your center?

Dr. Amy Hauck Newman: That's a wonderful question and it is, I would say that in some of the work that's being done in my institute, it has already played a role.

This is more in the clinical studies and using large language and using social media and all those kinds of tools to understand our patient population, who's vulnerable, who may be about to relapse and so forth. And so we have a fantastic tenure-track investigator, Dr. Brenda Curtis, who's working on that and using all the AI machine learning tools on our side.

I have a wonderful collaboration with a computational biophysicist, big words, but yeah, very smart guy. And he has been able to do for us, which is great, going to really be extremely useful for us. And we're already using it as he's created bioinformatics tools that will predict certain activities that are difficult to test for us.

And so, for example, one target that we always try to avoid is something called the hERG channel. It is associated with cardiotoxicity. And if your compound binds to the hERG channel, it's an automatic red flag that it might have cardiotoxicity and it's not going to go anywhere. Compounds that penetrate the blood-brain barrier and bind to dopamine receptors often bind to hERG.

And it's something that's been really hard to separate and it's not something I have set up in my own laboratory. It's a kind of a specialty thing. Pharma has it, but drug compound institutes like mine, we don't. And it's an expensive thing to have tested so we can't send all our compounds to someone to test.

So my colleague has developed a bioinformatics tool using all the data out there to be able to predict hERG activity. And now we're using that in our drug design. So before we even make a compound, we throw it into his system. His test and it says, “Oh, ding, ding, this is going to have high hERG activity,” we don't even make it, but if we can see that it's going to have relatively low affinity for hERG, then that gives us reason to move forward with it and that's been really useful. And I think we're going to be doing a lot more of that. And that's just an example where even at my level, we are using this. The other thing is, there's a lot more computational models that are using AI for even drug design. And now we have a lot more data and even with our own compounds with structural data, how do these compounds actually bind to the dopamine D3 receptor, for example, and being able to use those data to create computational models that then you can feed in millions of structures that no one's ever made before, but then you can come out with, “Oh, this structure looks like it's going to have the activity that you want,” and that gives us a whole new template to work with. So those are two examples, which I think will be a breakthrough over the next decade or more.

Meg Escobosa: Oh, so exciting. Just, I can sense the speed that you're saving so much time.

Dr. Amy Hauck Newman: And resources.

Meg Escobosa: Just that learning process.

Dr. Amy Hauck Newman: And in fact, we published a paper where we used this bioinformatics model to prevent us from moving forward with compounds, which in some ways is a negative data, but it's important.

We didn't waste animals. We didn't waste the time to test compounds because even though they hit our target. They look like they are going to have this cardiac toxicity and we decided we need to improve this before we sacrifice the resources and animals to test them.

Meg Escobosa: That's amazing. I'm loving also just how collaborative your group is and you're recognizing that you need to tap into the other resources around the institute and elsewhere. So kudos to you.

Dr. Amy Hauck Newman: Medicinal chemistry is only successful if it's collaborative and that is my opinion. I'm sticking to it. I can't do everything. And so what we want to do is be very good at our drug design, our synthesis, make sure our compounds are pure and they have the structures that we say they do and so forth.

But we really rely on our collaborators to do the other things and to work with us and to come in with other ideas and us to propose hypotheses to those. And to be honest, that is the most fun part of our job. That's one of the things I love the most is tapping into other people's ideas and being able to implement them and then see where it goes because that's how science often sends us in a completely new direction that we wouldn't have had any idea about if we didn't have that collaboration with someone who could do these things that we can.

Meg Escobosa: Right, and to me and to our work in innovation, to me, it's sort of the seed of creativity. It's that cross pollination of thinking and another perspective and expanding the way you think about it. So yeah, I love that.

Dr. Amy Hauck Newman: Yeah, me too.

Meg Escobosa: What exactly? When you're building a structure, like what do you do at your bench? I've never been in a chemistry lab, so I must admit I am a novice. What's happening at your bench?

Dr. Amy Hauck Newman: It's a little bit like cooking. And we actually use that verb, like what are you cooking today? Cause, cause it's a little bit like that, but the front end of it is actually designing the compound that you want to make or the series of compounds that you want to make. And we always have a starting block. Often in my lab, we start with a drug that's already out there. But it doesn't quite have the activity that we want, but there are structural reasons why we think we can make it better for what we're looking for.

And we use a lot of different tools to design that new series of compounds that no one's ever made before. And we always check because if someone's already made it, then we can either follow their recipe or go in a different direction, but the vast majority of what we do are compounds that no one's ever made before or thought of before.

And we then design those molecules with modifications that we think are going to get us to our target activity. And then we have to figure out how to make them. And we can't just buy them in a store. They don't just fall and so we do something called retrosynthesis.

So we basically, on paper, break this molecule down into pieces that are commercially available. And then we figure out how to build them back up. So this is your flour, sugar, eggs, butter of your cake. And then we have to figure out which ones to go first. And sometimes that doesn't always work. So you think, “Oh, I'm going to do it this way,” and then you run into a roadblock that didn't work. So then you have to go back and say, “Okay, what's another route to get to this.” And it's literally putting chemicals together with. solvent. And maybe you're cooking them. Maybe they're zero degrees. There's lots of different ways that we put them together and we monitor them to see if something's happening.

If those things are just looking in the oven to see if that cake is rising. And then at some point, when it looks like it's good and we have reasons to know that, then we work it up. We just like you take it out of the oven, put it on, take it out of its pan and so forth. And so that's our next piece. And then we have a number of analytical tools that we use to characterize that to see if it does have the structure.

This new compound has a structure for, we have to do a lot of purifications, a lot of tough work in there because it's back and forth and purifying and characterizing, and then going to the next step until you get to your final compound, there's a number of steps, even at that level to get to that compound. We might have to make a salt so it's water soluble because if it doesn't go into solution, we're not going to be able to test it in our models. So it's really about this kind of iterative process, but it is the closest thing I can tell you is that it is a little bit like cooking, which I think for most chemists, including me, we all really like to cook at home. That's just something about it. And at least at home we can taste what we eat, not like in the lab.

Meg Escobosa: Exactly. Yeah. No, don't do that. That's an awesome example and a very nice, clear description. So that's helpful. It’s very grounding to hear that. You prompted me to think of the character - did you ever read Lessons in Chemistry?

Dr. Amy Hauck Newman: Oh, I did, and not too long ago and really enjoyed it and have recommended it to a bunch of people because it was actually, my husband gave it to me as a birthday present. Someone had recommended it to him and I read it and I did really enjoy it.

Meg Escobosa: Same here. I just thought it was a really great story, but I love the connection to cooking. Obviously the character is a big cook, a very effective cook. And but I also was thinking about her example as a young scientist, chemist in the 50s, so it was a different era. But that kind of brings us to your journey as a young chemist or soon-to-be chemist. You were maybe going to be a pediatrician, from what I've read, or even a poet perhaps.

Tell us about that journey into chemistry and did you feel like you faced any barriers in particular? Were they self-created barriers, if there were any, or was it the industry or? I would love to hear that story.

Dr. Amy Hauck Newman: You know, Meg, I received a Christmas card this year from my best friend growing up. She and I were in nursery school together and in her card, she said, “I remember when we were five and you told me you were going to be a doctor.” And so I always had it in my head, but speaking of pediatrician, what else did I know? I only knew what a pediatrician was. And I had that in my mind from the time I was a little girl until I was a senior in college. And I became a chemistry major as opposed to a biology major. I was pre-med, but I just like chemistry.

I like to think about chemistry. Chemistry is much more, for me, problem solving. And I was, I think I was a better problem solver than a memorizer and it was my senior year. I wasn't really thinking about being a chemist, but I really got excited and interested about using organic chemistry to make biologically active compounds, which is essentially the definition of medicinal chemistry.

I had some senior level courses where I was reading the Journal of Medicinal Chemistry, and at that time I had thought that it might be useful to take a year off before I go to medical school, maybe do research because I hadn't really had any experience doing that. And I had this amazing opportunity to go up to the NIH in Bethesda. It was close to where I was in college. I had an alumna from my college who was there at the National Cancer Institute, and it just blew me away. I had never been in a big research institution and it just was so interesting and so exciting and what she was doing that I came back to my advisor and said, “I think I don't want to go to medical school anymore. I want to go into medicinal chemistry and I want to go back to the NIH and run my own laboratory.”

Meg Escobosa: Oh my gosh.

Dr. Amy Hauck Newman: I know. It's so weird. It's strange what I.

Meg Escobosa: You manifested it.

Dr. Amy Hauck Newman: Yeah. It's so funny that actually did happen. But so he, he just raked his hands through his hair and said, “Well, I guess we need to get you into graduate school.” I hadn't really thought of that part. So I was really fortunate to get into a terrific med chem program at the Virginia Commonwealth University. Again, not really having any idea what I was doing, but just had the concept that this would be something I'd be interested to do. And I also thought I'd go into cancer research because that's where there's a lot of medicinal chemistry.

All the papers in JMedChem that I was reading were cancer.

Meg Escobosa: We need help there. Yes.

Dr. Amy Hauck Newman: It's an obvious area, but I had a lecture from one of the faculty early on. And he was actually looking at studying hallucinogens, interestingly, amphetamine and tryptamine analogs, which have now really had a resurgence in medicine, but gave this fascinating lecture about how these compounds are binding in the brain and how they interact with neurotransmitters like serotonin and dopamine.

And I, it just, I was like, “I have to do this. This is the coolest thing I've ever heard of this idea that drug molecules bind to receptors in the brain, and they have this crazy effect.” And he took me to his lab. I was the first woman in his lab. That was tough for me and him. I'm sure.

Meg Escobosa: Really?

Dr. Amy Hauck Newman: Yes. It was the eighties, early eighties. I was the only woman in my class in that med chem class and the only woman in his lab until later, of course he brought in others. So I didn't ruin it for the rest of the women. It was a steep slope. It was a steep slope for a number of reasons. One is I didn't have research experience.

I'd gone to a small undergraduate liberal arts college and I didn't have research experience. So I really started slow and I had a tough project for me at the time, but I never stopped loving it. And when I had the opportunity to put my compounds into rats and see what they did. I was totally hooked.

I really wanted to continue to do this, but my research advisor, Richard Glennon, taught me many things. And one was resilience. And one was always looking at the structure and thinking about what is going to answer this question? What modification can I make that really makes sense. Not just do anything.

And then what does it do in the animal? What does it do? What is the biological activity, this compound and that was something that I will forever be grateful for. And then writing the story, which he was a terrific writer and a really good presenter. And that was something that got me hooked. So I wanted to be able to do that to others.

I felt like my synthetic chemistry expertise was not as strong as I wanted it to be. And I had another wonderful opportunity to this now go to the NIH, go to the National Institute on Diabetes and Digestive and Kidney Diseases, another one of the institutes for Dr. Kenner Rice who is a medicinal chemist, also a terrific organic chemist.

And I knew that I would learn a great deal from him on the synthetic organic chemistry side. So he really taught me how to make compounds. He taught me how to cook and how to very careful about characterizing our molecules and so forth and continued to fan that flame. I worked mostly on opioids with him.

I did a little bit of other things, but it kept me still very interested in this area of substance use disorders. And eventually I was able to join the National Institute on Drug Abuse. They were looking for a medicinal chemist. They didn't have medicinal chemistry at the time. They thought it was important to have someone who was dedicated to synthesizing these targeted small molecules, but someone who also had the experience of putting those molecules into animals and understanding pharmacology. And so I was able to join there in the early nineties and ultimately started running my own laboratory and moving up the ladder and now becoming the scientific director of the institute.

Meg Escobosa: That's amazing. Congrats on that. It's a great story.

Dr. Amy Hauck Newman: Thank you. I had a fun run.

Meg Escobosa: Well, and a lot of hard work, obviously. What was it like to start your lab? And do you see your leadership borrowing from those mentors and adding to it? And what's that extra thing that you bring to your leadership?

Dr. Amy Hauck Newman: Yeah, I did bring certain things to that table.

I always wanted to - I don't know. I always wanted to be the leader. And I even, that's one thing that I really had the opportunity to do when I was in college, a small liberal arts college. It was all women. I was president of my class for three out of the four years. I always liked to have that ability to take the lead.

So it was going to be a natural transition for me to run a lab. What I took from my PhD advisor is what I said - really following your nose on the structures and medicinal chemistry, making sure that you're testing your compounds and biological assays, always thinking about the story, writing it, presenting it, moving it forward.

My postdoc advisor, Kenner Rice - be a meticulously good organic chemist, be very careful about how you do all those things. And also just continue the love of working in the substance use disorder arena.

I have had other really peer mentors, I think now to the people that I really admire - one is my institute director, Dr. Nora Volkow. What a brilliant mind. So excited about what she does every single day, has an incredible breadth of knowledge and is always challenging us to, to work hard, to get to the next step. And I really admire her and I'm really fortunate because I get to talk to her all the time. Another person who I consider as a peer mentor is Susan Amara.

She's Scientific Director for the National Institute on Mental Health. I've known Susan for many years. She's a brilliant mind and a strong leader, but she has a very quiet way of handling things. I'm sure she feels stressed. You'd never know it. And I really admire that in her about not letting it get to you.

There are sleepless nights in these jobs and to try to just step back and say, “Look, one foot in front of the other, one step at a time, you'll get there.” And I have to remind myself of that, and I really appreciate Susan's demeanor in that way.

Meg Escobosa: Right now, I'm thinking about drugs that are out there right now that everyone's all excited. I'm excited about, like Ozempic, and I wonder, I don't expect you to have like an answer to this, but it made me wonder what your thoughts are about how it's being used. This is obviously now a developed prescribed drug that was intended to help people with obesity. Now it's being widely used for weight loss and perhaps with people not necessarily at risk of obesity. And I'm just curious when you see something like that, does it excite you because you see how the drug can be deployed in a wider way that's helping more people? Or I wonder if it's like as a scientist, you're like, “Yikes, what is happening out there?” The way it gets used in the public.

Dr. Amy Hauck Newman: Yeah, no, it's a super important question and it's all around us. My husband, who's a scientist at the National Institute on Aging, worked on these types of compounds years ago and they were ultimately developed for diabetes. They're effective in obesity. We have a clinical study going on at NIDA right now with semaglutide and alcohol use disorder.

I think that there are obviously some very exciting paths that we can take with this drug, but I don't believe - no drug works for everybody and every cause. And of course we worry because for people who are taking it for weight loss and may or may not be under real medical attention, that can be problematic on many different levels.

And I think what I am not aware of in a patient population that doesn't have diabetes, for example, what are the long term effects? And is this really the only answer to weight loss? And I'm a bigger advocate of eating well and exercising and all that kind of thing that doesn't always work for everyone.

But taking a pill is an American thing. And I worry that's the easiest thing, take a pill and not be hungry. And I think that for some, that's maybe the only answer to their obesity and their other real health problems. It may be the answer for substance use disorder, alcohol use disorder. These studies are ongoing and it could be super exciting to have that as a completely different drug molecule in our toolbox, but I do think that I'm a research scientist - I feel like we need to have data to support that and we need to be thoughtful about everybody jumping in and taking these drugs because they won't be safe for everyone for long periods of time. And I just hate to replace one disorder with another.

Meg Escobosa: Absolutely. Yeah. And I was thinking, can you use, like, could you imagine Ozempic being potentially an area of research for substance use?

Dr. Amy Hauck Newman: Absolutely true. And how it works, because actually we know at one level is a GLP agonist. We know a lot about how that is, but how does it work in reducing rewarding effects of food or alcohol or other substances? That is still a big question in the basic research side, but then what else is it doing?

What is it doing to other organs and other processes and systems, in humans and with comorbid, other comorbid diseases or disorders or age, when there's so many questions that we don't have answers to and we need to get there.

And one thing you read about, and this is not my expertise, but people who are taking this for weight loss, they're on it for life. If they take, if they are off of it, they go right back, which is of course disappointing, but taking any drug like this for life is going to have consequences. There's no question. So what are those consequences?

Meg Escobosa: And if you're diabetic taking this drug to avoid your diabetes is obviously beneficial. And so, yeah, but if you're not diabetic, there may not be as many benefits.

Dr. Amy Hauck Newman: Right, right. Exactly.

Meg Escobosa: Yeah. I was just thinking about cannabis use disorder, intensity of the toxicity or the intensity of the presence of THC is greater nowadays than the early. So are you seeing that also, I guess with fentanyl, that's what's happening with the opioid?

Dr. Amy Hauck Newman: Yes. No, I think that the more drug that you take and you don't know what the concentration is of cannabis, of THC. Certainly with fentanyl.

This is the huge driver of opioid overdose is that people are either taking fentanyl because they want it because they like it, They think that it's a better high for them or a longer high now. This is with combination with xylazine, which is a whole other horrible story that is happening in many studies - so xylazine is contaminated - the fentanyl at least in Baltimore or in Philadelphia is largely contaminated with this drug called xylazine.

It's an anesthetic. It's an animal anesthetic. What I've read about is that it makes the fentanyl last longer. Fentanyl is pretty short acting, so it makes it last longer and people like that, but it's a terrible drug and it has all kinds of awful side effects that I won't say here.

The other group are people who are getting fentanyl inadvertently. So people who normally wouldn't take opioids, they like cocaine or methamphetamine and their drug is contaminated with fentanyl. And those people die because they have no tolerance to fentanyl. It's super potent and it is a super potent respiratory depressant. So if you've never really taken opioids, you won't have a tolerance to that and you may think you're taking methamphetamine and you get a little fentanyl in there and you die of respiratory depression. And that's a really big problem. And now the other area that we've always been working in and we're going back to is the psychostimulants, is cocaine and methamphetamine.

Really tough use disorder to attack, and that's why we don't have any medications because it's not that no one has tried. There's lots of drugs that have been tested for cocaine and methamphetamine use disorder and nothing has really been helpful in people. We continue to work in this area as well.

That's really driving. Some of the opioid overdose as well because these people are getting fentanyl in their drug inadvertently and then they overdose. So it's really problematic and fentanyl, what I understand in Baltimore, which used to not have, we used to have the reputation, which is an unfortunate reputation of being the heroin capital of the United States. There's no heroin on the street in Baltimore anymore. It's all fentanyl and a lot of contaminated with xylazine, which is just a terrible combination.

Meg Escobosa: Yeah. Well, this is a very difficult field to work in. I can see how someone could feel very depressed and challenged. Just how to pick up every day and keep going and feel the inspiration to work. Tell us, how do you deal with that? Does it feel heavy sometimes? And how do you address that?

Dr. Amy Hauck Newman: Yes. What I often say is that substance use disorders are a horrible neuropsychiatric disorder that's painful not only to the person, but to their families, to our communities and so forth. It is devastating.

The neuroscience of addiction is fascinating. It is so interesting and such a cool area to be involved with and I have been doing this for more than 30 years and I never get tired of it. And every day I learn something new, I get more excited about something else that we can try. And so that's what keeps me going because I just believe, there's a lot of very smart people who are working in this field in all different disciplines, obviously not just medicinal chemistry and I just believe in this is that the collective will be able to come up with things that medications and treatments for this population that will help in the future. And I will continue to believe that. I think that it is extremely challenging. Another big challenge is that we have these comorbidities talking about schizophrenia or bipolar disorder, where people who have those disorders, which are tough enough, have very high comorbidities with substance use disorder, bipolar disorder, 60% of people have bipolar disorder, take cocaine or alcohol, and that makes it much more complicated to treat them. But we can't turn our backs on them. We have to know about it. These are people that have life to live and things to contribute, and I really feel strongly about helping us as much as we possibly can and moving the - and I'm, of course, I'm a big, proponent of moving basic science is the way to do it. Get that basic things understood so that we can then go to those steps and pass those batons like you mentioned earlier.

The thing that I think is frustrating to me, and I get it, but it's really disappointing so far, is that we've had a really hard time getting pharmaceutical industry interested in treating addiction. And there's a lot of good reasons for it. This is a tough population. By the time they need treatment, they don't have jobs, they don't have health insurance, who's going to vote for this? And frankly, with opioid use disorder, they got us into this. With a whole oxycontin thing. Are we going to, are we going to pay them to get us out?

I think that is a really frustrating thing. And I think that the stigma associated with addiction is still a real thing. And drug companies don't really want to go down that road. And yet we have to have them. We have to partner with them. We have to convince them that this is a population that needs our help and that there is frankly money to be made.

That pharma has to make money. I don't. But pharma does. Partner with us. We at the NIH, we're using taxpayer dollars to do the work that we do so that you don't have to, so you can take what we have learned and move it to the next stage. And I really feel strongly that those partnerships should be forged more easily.

We've had several over the years. Most of them have been broken because the company was small and they ran out of money. And that's probably the thing that is most frustrating to me. The science is always exciting. And the scientists that I have the privilege to work with are phenomenal. I really enjoy that every single day.

Meg Escobosa: We're coming to the end of our conversation, but I wanted to ask just to our listeners, what might you say to anyone who is thinking, “Wow, I didn't even know that this was a possibility. This was a path in a career.” What would you say to the young person out there who might be interested in getting into medicinal chemistry?

Dr. Amy Hauck Newman: Yeah, do it. You obviously, you have to like science and math and have some propensity toward that. But as a young person in, even in, you know, maybe high school. I don't take high school students because of the danger of what happens in my laboratory. There has to be expertise, but the NIH and many universities around the country have summer programs.

We have a terrific summer program at NIDA, as do all the institutes at the NIH. We also have a terrific program. post-baccalaureate program where people come from universities after they've received their bachelor's degrees and they're in between college and graduate student medical school and they can come and work in our laboratories and see, dip their foot in and decide.

And I've had many postbacs, for example, have come to my lab and some of them go to medical school and some of them go on to get their PhDs in chemistry. And some of them say, “Yeah, this is not what I thought it was going to be, but I'm really interested in the public health aspects, but I don't want to do this.”

And so those are great opportunities to take a look and see whether this is something that you want to do. And it's hard work, but it's really, I always say I have the privilege every day of working with super smart people. Asking questions, being able to go in the lab and try to answer them. I have chemists who all they did was do chemistry and they didn't really appreciate the biology and they're like, “I don't care about the biology. I just want to make compounds.” But then once they see their compounds have an effect, block cocaine self administration in a rat or increase locomotor activity in a mouse or those things are like, “Oh, wow. This is so cool.” The new thing that we're, we're, we have with these was x-ray crystal structures, now these cryo-EM structures, which give us actually a picture of how our drugs are binding in that receptor and being able to actually see that it's the cool thing. And I think that if you have an interest in that you could definitely become addicted to becoming a medicinal chemist.

Meg Escobosa: Oh, Amy, this has been so much fun. I really appreciate talking to you and hearing about your world and learning from you today. So thank you so much for doing this.

Dr. Amy Hauck Newman: Thank you, Meg. It's been a pleasure. It's really been a very enjoyable time. Thanks.

Meg Escobosa: Thanks for joining us for the Game Changing Women of Healthcare, a production of The Krinsky Company. Today's episode was produced by Calvin Marty, Chelsea Ho Medina Sabich, Wendy Nielsen, and me, Meg Escobosa. This podcast is engineered, edited, mixed and scored by Calvin Marty. If you enjoy the show, please consider leaving a rating and review wherever you get your podcasts. It really does make a difference and share the show with your friends and colleagues. If you have any questions, comments, or guest suggestions, please email us at [e-mail] and visit us on the web at www.thekrinskyco.com.

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