Meet the Solutionists, with Mark Scott

Addiction – substance abuse – is a wicked problem in our modern era. It robs potential, ruins lives.

Yet it isn’t a new problem. Over and over again, humans have tried to beat the scourge of addiction. And no matter the substance, or the treatment, every attempt at a cure has had limited success at best.

What if we’re thinking about it the wrong way? 

What if the solution to addiction isn't to focus on the addictive substance, but on the experience of addiction itself? What if focusing on cravings is the key? 

That’s the question Professor Michael Bowen is trying to answer.

Michael’s skills as a neuroscientist and psychopharmacologist give him unique insight into how substance abuse affects human brains and bodies. 

And right now Michael and his team are testing a single drug that could change the way we treat every addiction.

If listening to this episode raised any concerns for you, follow the below links to access assistance:

Australian Government National Alcohol and Other Drug Helpline – 1800 250 015

Turning Point – Treatment & Support

Mark Scott  00:01 

This podcast is recorded at the University of Sydney's Camperdown campus on the land of the Gadigal people of the Eora nation. They've been discovering and sharing knowledge here for tens of thousands of years. I pay my respects to elders past and present, and extend that respect to all Aboriginal and Torres Strait Islander people. 

Kellie R  00:24 

This episode contains discussion of substance use disorders and addiction. It may be triggering to some audiences. Please take care while listening. And if you need help, you can find resources in the show notes to this episode.  

Michael Bowen  00:47 

It's about having a strong, often uncontrollable urge to use a substance, despite negative consequences. 

Ritchie  01:00 

Cravings of addiction are the most horrible part. I remember waking up and I'd be feeling instantly sick. I'd be waking up in withdrawal. Especially around the heroin, there'd be, you know, stabbing pains in my stomach. There'd be pains that run all down my legs. My legs would be jittery and shaky. I’d wake up sweating and yet be freezing cold at the same time. The aches and the pains would come eventually all through my whole body. Every muscle would be taut and tight. Yeah, it was a until I knew that I could get something to make myself feel better, I'd be in a place where I could do anything, pretty much, to get what I needed to get, to not feel that horrible feeling.  

Michael Bowen  02:06 

So what we are trying to do is to help with those cravings, reduce the magnitude of them, stop them being triggered, and that will then reduce the risk of someone relapsing or increasing their use.  

Mark Scott  02:35 

As a society, we're dealing with addictions at scale. For as long as we've used addictive substances, we've been trying to understand and treat addiction itself. Psychologists, therapists, clinicians and researchers have all pursued different approaches for various addictions, and some of these interventions have worked to a certain degree, but still we haven't been able to deal with the overarching challenge of addiction. It just keeps happening. What if the way we think about addiction needs shaking up? What if we could identify the one thing that most addictions have in common and treat that? Professor Michael Bowen, wants to do just this. He is a neuroscientist and psychopharmacologist at the University of Sydney, and he's the co founder of Kinoxis Therapeutics. Michael, what do these terms mean? Neuroscientist, psychopharmacologist?  

Michael Bowen  03:36 

Well, apart from being quite a tongue twister, neuroscience is the study of the nervous system, how it functions normally and how it functions in disease and in various different disorders. Psychopharmacology is a study of how drugs affect the brain, behavior and cognition, and my specific focus area is in what's called translational neuroscience and psychopharmacology. So that's about taking discoveries in neuroscience and psychopharmacology and turning them into real world solutions that help people. 

Mark Scott  04:09 

So why is it so tough? What is it about addiction itself that's been so difficult to solve? What's the challenge at place here?  

Michael Bowen  04:18 

This is an incredibly complex phenomenon where parts of the brain that have evolved to motivate us to engage in activities that are essential for our survival essentially become hijacked. And understanding that complexity and figuring out ways to alter that trajectory is very scientifically challenging, but there's also an issue of stigma. It's an area that a lot of large pharmaceutical companies, for a very long time, just haven't wanted to go. It's not a patient population that they see as commercially attractive. A lot of people suffering from substance use disorders are doing it very tough, therefore paying for a treatment will be something that will be challenging, so the price point won't necessarily be a premium, but we are starting to see a shift in that and a shift in our conversations.  

Mark Scott  05:09 

But I can imagine it's a difficult area in which to do research. This would be a challenging area to pull together the patient population.  

Michael Bowen  05:20 

So if you take for instance, people with methamphetamine use disorder or opioid use disorder, many of them are living rough, so getting in contact with them can be very challenging. The nature of the disorder can lead to unreliable behaviors where they're not necessarily focusing on showing up to sessions at the hospital or at the clinic that can make it very challenging for them to maintain reliability over the course of, say, a 24-week clinical trial. 

Mark Scott  05:52 

How should we define an addiction? How's it different to just doing a lot of something?  

Michael Bowen  05:58 

Yeah, so I mean, if it was just about doing a lot of something, then we'd all be addicted to toothpaste. So it's certainly not about that. It's about having a strong, often uncontrollable urge to use a substance or engage in a behavior that's harmful despite negative consequences. And that's really the key component of it, that someone with an addiction is continuing to drink alcohol despite the harms it's having on their health, on their relationships, on their professional life and so on. So, feeling like they have to use even though they don't want to, and also using more than than they intended to. 

Mark Scott  06:42 

People who haven't experienced addiction might think beating it is just about determination, about strong will and commitment, but your research is saying, actually, there's something different going on in the brains of people who have substance use disorders. What's happening to them? 

Michael Bowen  06:58 

In terms of the changes in the brain in addiction, they're complex and multifaceted, but let's focus on it on a few key areas. So firstly, addiction hijacks and alters the parts of the brain that are key for reward and motivation. So early on in substance use, dopamine floods the mesolimbic dopamine circuit in the brain, which is a circuit that's evolved a long, long time ago, well before humans came along to motivate animals to engage in activities that are critical for survival and for passing on genes. Think feeding, mating, those sorts of things. But as someone starts to use a substance chronically, those circuits become desensitised, so as this system becomes dysregulated, and the person needs to take more of the substance to get the same effect. Now something else happens as someone continues to use a substance chronically, and it develops an addiction, and that's that another dopamine circuit in a part of the brain called the dorsal striatum, starts to respond to cues that are associated with the drug. So, this is people, places, things that are associated with the drug taking, and those things actually start to elicit dopamine release more effectively than the drug itself, and the release of dopamine triggers craving and drug seeking in that brain region. Now another part of the brain, if we move a little bit forward in the brain, to the prefrontal cortex, is also really key. So, this is the part of the brain that allows us to control our behavior and engage in effective decision making. So, what are sometimes referred to as executive functions, these higher order functions that are very human. Now, this part of the brain becomes really dysregulated over the course of chronic substance use, and that means that people really struggle to resist these urges and these cravings, because that's the part of the brain that really drives that willpower and that determination. Now finally, one last part of the brain, or parts of the brain, that are really key, that start to play a key role in really severe addiction are the stress and emotional regulation systems, so parts of the amygdala and the extended amygdala, these become severely dysregulated in the more severe cases of substance use disorder, this leads to mood dysregulation, socio emotional dysfunctioning, and a shift from positive reinforcement driving drug use, which is, I'm seeking the drug because it makes me feel good to negative reinforcement driving drug use, which is I'm seeking this drug to escape feeling horrible for a little while. And that's what we call the dark side of addiction, and that's what my team and I really focused on targeting.  

Mark Scott  09:57 

And the payoff for that escape comes with the anticipation that that relief is about to come. It becomes almost before partaking of the substance that you're addicted to, rather than what happens to you once it has its impact on you. 

Michael Bowen  10:12 

Yeah, it's about anticipating the relief so, and that's where you know, when we talk about craving, that's something else, where people think about craving, they think, oh, the craving is because they really want to feel good. There is craving that's driven by positive reinforcement, that desire to consume something because it's going to make you feel good. But craving can also be driven by more sinister things, by that desire for relief, and that's where it can become particularly challenging, where someone is craving a substance because they know that it's going to give them a temporary escape from that intense dysphoria that they're experiencing when they're not on the drug, and that mood dysregulation and all of those aspects of the dark side of addiction.  

Mark Scott  10:57 

And despite the fact that addiction can have such a wide array of causes or triggers, it's that, it's that search for the craving. That's the area that's driving your research. 

Michael Bowen  11:10 

That's right, yeah, we really want to go after craving. Interestingly, it's not yet an approved indication with the major regulatory bodies. It's an aspect of the criteria for diagnosing a substance use disorder, but it's not, yeah, there's not yet what's called a primary endpoint that's been approved. We're hoping that our drug is going to be at the forefront of that, and that it's going to be a real innovator in this space, and hopefully the first approved treatment that's targeting drug craving, specifically one exceptions in nicotine, where craving does come into the description of some of the products but in alcohol, opioid, cocaine, there's not yet been a product that's specifically targeting craving, and we think it's really key, and the research shows that it's really key. 

Michael Bowen  12:03 

So there was a fantastic meta-analysis, which is where whole bunch of different studies are taken, Iin this case, hundreds of hundreds of studies conducted all over the world. The data was pulled together by a colleague of mine, Hedy Kober, at Yale, and it was data from over 55,000 different patients. And they looked at sort of what are the key triggers of relapse, and the key triggers of increased substance use and craving was number one. It would triple the risk of someone relapsing or escalating their drug use when they were exposed to things that increased craving. So, if we can come up with a treatment that manages that craving, it could have a profound impact on the treatment of substance use disorders. 

Ritchie  12:53 

Hi, my name is Ritchie. I’ve struggled in addiction for 35 years. I have used substances like marijuana to start off with, and then that quickly advanced to amphetamines and also heroin and alcohol. I reached recovery via rehab services, and I had five different days of rehab, and I have achieved some maintainable success since COVID. Reflecting back now, I started off with a sugar addiction. It was a comfort that I saw when I was really young, and that followed with extreme behavior, I suppose. And you know, from the from the high of the sugar, I got to the park, and I'd play in an extreme manner. I was adopted as a child into a loving, great family. But nonetheless, it impacted myself worked quite heavily. I felt really alone and isolated as a child, found really hard to fit in, and didn't feel that I belonged anywhere. So that was the gateway to my substance use. So it wasn't long before I discovered alcohol, and that was a really good method of self-soothing and not feeling the things that I didn't want to feel. That was followed up by marijuana. Of course, I used those two substances together into my late teens, amphetamine was quite a big thing then, and that soon became my next drug of choice. And all along I was lending them together, it's around that time that I became an IV user. I enjoyed the subculture. I enjoyed the thrill. I enjoyed escaping from what I thought about myself and the feelings that I had around not belonging. 

Ritchie  15:17 

I was quite a as they say, functioning addict up until my mid 20s. I achieved an apprenticeship and a qualification in a trade. I joined the army when I was in my late teens as well. That was my first attempt to get off drugs. And of course, that's where I learned how to drink even heavier. When I was high functioning, and that was mostly an early addiction as far as still being a part time, upstanding member of society and holding a job, I was always thinking about knock off time and so I could get something into my system. During the day you know, I sneak drinks, and I'd do all that while I was while I was working. Obviously, I didn't hold down many jobs at that stage. Sooner or later, I'd hit a crisis. Until I knew that I could get something to make myself feel better, I'd be in a place where I could do anything, pretty much, to get what I needed to get to not feel that horrible feeling. Yeah, and in that desperation of done some pretty, pretty nasty things, and I paid the price, many times. The longer my addiction went on, the better I got at doing it, the more efficient, the better, the more connections I'd made. The ability to get credit. No, I was that well enabled in the end, that I didn't have to try hard to get to get drugs.  

Mark Scott  17:07 

So if you were successful with a drug like this, what impact would that have on treatment for specific addictions like opioids or alcohol? 

Michael Bowen  17:14 

Yeah, so how it's used may differ slightly in different substance use disorders in alcohol, we could envisage it being used as a standalone treatment, where as the sort of common mode of use for the for the treatment where someone is prescribed it to help manage their cravings, so that they can go about their day to day life, not having to do battle with those cravings that can be triggered by by so many different things. Internal things, you know, stresses in one's life can trigger craving in a really significant way. External things can trigger craving. You're at a party, you're trying not to drink. Everyone around you is drinking. You surrounded by those cues that you associate they trigger craving in a really significant way. So that's what we call cue induced craving, that kind of scenario where there's a specific trigger for the craving. Another example would be, if there's a stressful life event, relationship breaks down, they lose their job. That's another thing where there's a very specific trigger that increases the craving. But there's also what's called baseline craving, which is a lot of people just experience some level of craving all the time, and they're constantly having to try and use that part of the brain, the prefrontal cortex, to to reduce those cravings, suppress it. So what we are trying to do is to help with those cravings, reduce the magnitude of them, stop them being triggered, you know, at all ideally, but, you know, reducing the magnitude of the craving that's triggered if they are and that will then reduce the risk of someone relapsing or increasing their use.  

Mark Scott  18:51 

Does it target the craving, or is it just reducing the overall stimulus that they are receiving in a range of areas?  

Michael Bowen  19:00 

Yeah. So our data suggests that we are reducing the negative affect that's experienced during substance use disorder. So there's negative affective components, the emotional dysregulation, which is a key feeder of craving in that more severe form of addiction that we've been talking about. And our data also suggests that it just directly reduces the drug seeking response to cues that are associated with a drug and other things that trigger craving. So it's likely all tied in together, and the mechanism of the drug helps us understand how it's having these effects. 

Mark Scott  19:42 

So you're at work on a treatment like this. Now, can you talk a little bit about KNX100 and where you're up to in the development of that treatment? 

Michael Bowen  19:50 

So KNX100 is a small molecule that I discovered with colleagues here at the University of Sydney 15 years ago, spun out Kinoxis Therapeutics to take this compound through the development path. It was a very early stage compound, still in the discovery stage, you know, pre-clinical testing when Kinoxis was founded in 2018. Since then, we've taken it through that pre-clinical development, figured out how the compound is working, where it can be best used in terms of the therapeutic application. Have done all the safety testing, gone through the first of two major regulatory hurdles with the USFDA, and we're now in phase two clinical trials. So we've completed the first phase of clinical trials. We're in the second phase, and then there's phase three. Phase three goes, well, yeah, you're on the market. We are looking to complete our phase two testing over the next few years, then phase three will be another few years on top of that. 

Mark Scott  20:46 

Are there any challenges in treating drug addiction with another drug? 

Michael Bowen  20:51 

Yeah? Sure, yeah. There's always complexities that can come along with that. You have to consider things that you might not have to as much in other areas. So for instance, there's always the risk that someone is going to take the drug to which they're addicted while they're taking the treatment. So you have to understand, is there a potential threat interaction, you know, when those substances are both in the body at the same time, are they going to play nice together? So we're doing some work with the NI AAA, which is the National Institute on Alcohol and Alcohol Abuse, where before you can even go into a phase two clinical trial to look at your drug in patients with alcohol use disorder, you have to run what's called a phase 1b study, where you give alcohol and the treatment at the same time and make sure that there's no unintended consequences, because alcohol is just known to not play nice with so many different substances. 

Mark Scott  21:44 

I'm interested on a drug like this, would you anticipate you'd need to be on this drug for the rest of your life? Because those cravings can emerge at any time, or do they fade and wane, and the risk fundamentally diminish over time?  

Michael Bowen  21:59 

So we know that the majority of people will relapse within a year of entering into a period of sobriety. We know if people can get to five years, they're more likely not to relapse than to relapse. So will they need to be on the treatment once they enter into abstinence? Almost certainly how long will that be? I would say it would likely be years. Will it need to be for the rest of their life? Potentially not. And it really depends on where they're up to in their treatment path, what's going on in their life, how confident they feel in going off of the substance and and taking the risk that it could increase their chances of relapsing. 

Ritchie  22:51 

In my darkest days in addiction, the discipline and the hard work and the fear that's ever present becomes a groundhog day experience, becomes a cycle that displays that day after day. I've escaped some really, some really dangerous situations and some I haven't escaped. Quite a few scars for me to prove it. Some of the hardest days in addiction, or just about all of the days in addiction, you don't want to live, I didn't want to live. I didn’t care if I overdosed, actually hoped for it sometimes. Only to be, you know, frustrated in the end, to be, you know, brought back to life by paramedics and services. I, of course, I would have loved a magic pill that, and I suppose that's why I would call it a magic pill that just when there you go, you don't crave anymore, you're not dulled, you're able to think clearly. Well, it'll be a miracle. I think it'll take a while for the drug culture to trust it, but yeah, the sooner the better. That'd be absolutely amazing. 

Mark Scott  24:11 

We've talked about alcohol addiction, opioid addiction, drug addictions, but cravings can apply to other forms of addiction as well. You know, gambling, pornography, other forms of almost social addiction. Would this drug be applicable to those kinds of addictions as well? 

Michael Bowen  24:30 

I can't count how many times I've gotten that question, and it's a really fascinating one. The short answer is we don't know, because we haven't been looking into that at yet. Our focus is really on on substance addiction, but our understanding of behavioral addictions like gambling is really improving. It's still, you know, probably at least a decade or two behind in terms of our understanding of the neuroscience behind it. But what we are learning is that there's certainly significant commonalities. The reward circuits that are dysregulated are common changes in the prefrontal cortex that executive function region I was talking about, changes in stress systems in the brain, can also become dysregulated, and there's no approved pharmacotherapy for behavioral addiction, but there is evidence to suggest that some of the treatments that work for some people with substance use disorders, like Naltrexone, which is approved for the treatment of alcohol and opioid use disorder, may also work for people with gambling disorder, for instance. So I think this is an area where if KNX100 gets to the market for treating a substance use disorder, it's probably inevitable that it's going to be examined in the context of behavioral addictions, and I certainly hope that that will happen, because there are enough commonalities there to suggest that the way that we treat behavioral addictions can, in part, be guided by breakthroughs in how we treat substance use disorders and vice versa.  

Mark Scott  26:08 

Thank you to Ritchie for so generously sharing his very personal insights from his experiences of addiction and recovery. Michael mentioned that we need more precise medicine if we're going to treat addiction properly, and if you want to know more about precision medicine and how it's changing the healthcare system, you'll like our conversation with David James. 

David James  26:27 

What I would like to see is if we could do a test on people right at the get go, and that test would tell us you should be taking drug y, so that you immediately prescribe drug y, save all those problems, and you save the potential dangerous adverse effects from taking four medications instead of one 

Mark Scott  26:50 

You can listen to that episode of The Solutionist right now and make sure you're following the show so you don't miss an episode. The Solutionist is a podcast from the University of Sydney, produced by Deadset Studios. This episode was recorded at the Faculty of Arts and Social Sciences media room, and our thanks to the technical staff here.  

The Solutionists is podcast from the University of Sydney, produced by Deadset Studios. Keep up to date with The Solutionists by following @sydney_uni on Twitter, Facebook, and Instagram. 

This episode was produced by Liam Riordan with sound design by Jeremy Wilmot. Supervising producer is Andrea Ho. Executive editors are Kellie Riordan, Jen Peterson-Ward, and Mark Scott. Strategist is Ann Chesterman. Thanks to the technical staff at the Faculty of Arts and Social Sciences Media Room.

This podcast was recorded on the land of the Gadigal people of the Eora nation. For thousands of years, across innumerable generations, knowledge has been taught, shared and exchanged here. We pay respect to Elders past and present and extend that respect to all Aboriginal and Torres Strait Islander people.