Amity Addrisi 

Drug and alcohol abuse are the leading cause of preventable illness and death across the U.S.

In 2023, more than one hundred thousand people in the U.S. died of an overdose – roughly the population of Ventura, California.

Liz Dueweke 

In cities like Seattle, drug addiction is a public health crisis as fentanyl, a synthetic opioid 100 times stronger than morphine, has flooded the illegal drug market.

Amity Addrisi 

In 2024, the toxic drug supply killed more than one thousand people in King County.

While first responders fight this public health crisis on the streets, scientists around the globe are waging their own kind of battle.

Amity Addrisi
I’m Amity Addrisi.

Liz Dueweke
I’m Liz Dueweke – and this – is Lab Notes.

Christian Luscher
Contrary to many other diseases, addiction is not a disease where people are sick because they lost cells…

Liz Dueweke
That’s Doctor Christian Luscher, an addiction expert and neuroscientist at the University of Geneva.

Christian Luscher
…they are changing their behavior because the circuits are changing their function and the cellular mechanism by which this occurs is synaptic plasticity.

Liz Dueweke
Synaptic plasticity: That is – the brain’s ability to adapt and modify neural connections.

Christian Luscher
That is, the plasticity of the transmission from one neuron to the next is the crucial mechanism by which the circuits change their function and eventually lead to this compulsive use despite negative consequences. There are now investigations to directly target the addiction circuits themselves; however, we’re still in an experimental stage, mostly in animal research.

John Wilson
When I was steeped in my addiction, it was just like automatic compulsive, you know, I—I didn’t have any defense against it. There is no defense. There is no defense. That’s the power. That’s the power and the pull that drugs or alcohol has on people. There is no defense. I mean, there just isn’t.

Liz Dueweke
John Wilson is in recovery from addiction and now helps others fight the same battle at the Recovery Café in downtown Seattle—an organization that offers support and resources for addiction, homelessness, and mental health.

John Wilson
When I worked right down the street right here at the antique store, I’ve, I’ve worked all day and I obsessed about, I couldn’t wait to get off. I couldn’t wait to get off. I used to have a drug dealer meet me right at the bus stop right across the street from the Recovery Cafe. You know, I worked my, you know, you think somebody that works hard for their money, you know, they would want to make some kind of valuable use of it. But when you’re in your addiction, that’s where that money’s going. There’s no intervention there. 

Liz Dueweke
We invited John and Recovery Café founder Killian Noe to provide first-hand insight into addiction, overdose… and what they believe are solutions to this public health crisis. 

John Wilson
Every Sunday when I come to the Recovery Cafe, I always have to move some cardboard boxes. I always have to move some aluminum foil lighters. It’s, you know, yeah, the same thing you guys probably would see all the time. It is personal, you know, (Killian says a few words) and we have to be careful not to demonize the people dying of fentanyl because it’s no, it, it’s, it’s deadly because, you know, for all the reasons that we understand. But it’s to the person who is craving that high, it’s no different than the person craving that drink at, at the end of the day or whatever. It’s just that this is a drug that has been unleashed that can kill you just like that. 

Amity Addrisi
And that is what happened to a friend of John’s shortly before he sat down with us. Over the years, he has lost many friends to overdose and is grateful for his own life and sobriety. John started using drugs and alcohol when he was a teenager in New Jersey. He remembers growing up in a supportive home and believes his relationship with drugs started by trying to fit in with his peers… 

John Wilson
We used to all hang together, but I didn’t feel a part of them because I wasn’t doing what they were doing. But the minute I picked up a drink, I felt like I was a part of them. 

Amity Addrisi
Once the addiction took hold … it changed his life and his sense of right and wrong. 

John Wilson
There was one particular time back in, oh, I can’t remember when my father passed away, but you know, I was sitting in my parent’s house, the house that I was raised in and physically I was being tortured and I was sitting on the spiral staircase crying because I was getting ready to stage a robbery in the house. You know, I was getting ready to, they was going to bury my parent, my father. And the reason I was crying is because I couldn’t stop myself. Whatever moral value I had, I couldn’t stop myself. And that’s the disease factor right there. 

Christian Luscher
Addiction is not a disease where people are sick because they lost cells, because cells died. This is simply not the case. They are changing their behavior because the circuits change their function, and the cellular mechanism through which this occurs is synaptic plasticity. 

Liz Dueweke
Along with specializing in addiction research at the University of Geneva – Christian Luscher works with patients suffering from addiction… He began looking at this through the lens of neuroscience when he was a post doc in California—specifically, the role synaptic plasticity plays in chemical dependency. 

Christian Luscher
So the neural plasticity, or more specifically, synaptic plasticity, that is the plasticity of the transmission from one neuron to the next is the crucial mechanism through which the circuits change their function and eventually lead to this compulsive use despite negative consequences that defines addiction. 

Christian Luscher
The quantities are so small, and of course, that also has an effect on the market, which means, in order to get this, the substance across the border, it’s much easier, because you need lower quantities. And there’s estimations that a couple of trucks actually are sufficient for the entire supply of the US for an entire year. 

Amity Addrisi
In 2022 the Centers for Disease Control identified fentanyl as the leading cause of drug overdose deaths in the country. In April of 2024, an average of 30 people died of drug overdose per week in Seattle alone… more than 80% of those deaths involved fentanyl. 

Amity Addrisi
Right now, the current treatments for opioids are to reverse overdose and help people survive withdrawal and cravings through medications. But to truly treat addiction, Luscher says we must investigate how the brain processes drug withdrawal. 

Christian Luscher
So we understand how the fentanyl activates the dopamine system. So this is a crucial element, and one study that we have recently published suggests that this is very different on how fentanyl induces the aversive state of withdrawal. That is when someone takes fentanyl. Obviously, this is a pleasurable experience, but when the fentanyl is no longer available, they go into withdrawal. And up until now, people believe that this is just sort of the flip side of the same coin. That is, you stimulated the reward system so strongly that when the drug is no longer available, that leads to this aversive state. And our research now suggests that it is a separate pathway, that there are other parts of the brain that are recruited and responsible for this withdrawal aversive step. 

Amity Addrisi
But what if you could avoid withdrawal… and stop addiction at its source? According to Luscher’s research – the answer may lie in studying the addiction circuitry in the mouse brain. Through a process called optogenetics, researchers use light fed directly in the brain to turn neurons ‘on’ or ‘off’ in a specific cell or cells, reversing compulsion. 

Christian Luscher, Ph.D.
The good news is if, because the good news is that, since addiction is governed by synaptic plasticity and no cells die. In theory, it’s all reversible, and we have been able to show in animal models that indeed you can restore normal transmission and through that, also restore baseline behavior. That is the animal, the mice that have changes in their behavior. When synaptic transmission is normalized, they will reverse their behavior and behave as if they’ve never seen the drug before. 

Liz Dueweke
While research into optogenetics for treating addiction in mice has been successful – actually finding ways to manipulate the circuits in the human brain is a long way off. Dr. Luscher believes continued study of these genetic interventions is a promising step to finding successful treatment for humans. 

Christian Luscher
What I’m always arguing is that through optogenetics, in an animal model, you know what you should be doing, then the question becomes, can you do it in humans with the technique, techniques that are available? So it helps you focus on a more specific goal. 

One of the questions is whether we can actually translate optogenetic approaches to the human and there are many questions that are associated to that which slowly people are now trying to address. And there are, on the other hand, FDA approved circuit therapies in humans, such as deep brain stimulation, transcranial magnetic stimulation and focal ultrasound. And these techniques, while much less specific than optogenetics, could possibly be refined to do the job. 

Liz Dueweke
Let’s go back to our conversation with John Wilson from Seattle’s Recovery Café. We asked how much he believes genetics and personal history led him down the road to addiction. 

John Wilson
There was never no neglect in my household while I grew up at. So it wasn’t a matter of being abused or, or I don’t, I don’t believe it was traumatic for me to leave my siblings and go. I did feel isolated. I did feel like special. I was a special need kid, you know, being adopted by I was adopted by my aunt and uncle now in the house, since they weren’t my biological mom and dad. Maybe there was a missing link there that caused something in my brain. 

And I just, you know, when you’re in an urban city, you know, you’re influenced by a lot of things. And, and the environment that I was in, you know, there’s bars and, you know, just all kind of, it’s totally different from the, the West Coast, you know, totally different. I believe that may have played a part in it. But the bottom line is that I was just curious. 

Amity Addrisi
So, we know that our genes play a big role in addiction – but how do those addictive tendencies get activated? Dr. Luscher says those genes can be turned “on” or “off” because of epigenetics. 

Amity Addrisi
That means external factors like environment, exposure, stress – even your upbringing can affect what genes are active in your brain, and therefore addiction vulnerability. But with thousands of genes how do you know which ones to target? 

Christian Luscher
So we need to have better understanding of the epigenetic mechanisms and the genes that are turned on that confer this addiction vulnerability. So I think that’s one of the crucial elements to understand why someone is really at risk when taking a drug, and someone is less at risk, because that also applies for drugs that are legally available. I mean, the same holds true for alcohol: Some people can use, most people actually, alcohol in their entire adult life and never lose control. So yet, some people do, and it is a major health problem. If we knew how to better understand the individual vulnerability, that would be a big step forward. 

Liz Dueweke
Luscher hopes our understanding of the neuroscience behind addiction will help change public perceptions and policies… 

Christian Luscher
If you understand how it happens, that will help reduce stigma, because people with fentanyl addiction and addiction in general still face a huge amount of moral judgment and knowing what exactly is going on will help reduce that. So, I think that’s the first and foremost goal that we have and with our research. And then obviously, beyond that, it inspires new therapies. It helps us understand the relative changes, or the relative differences between different types of drugs, and it helps us understand how addiction vulnerability comes about, and that may have impact on policy. 

You know, I mean, of course, I mean, a lot of the limitations that we face still has to do with the stigma associated with addiction, which touches, of course, people who are affected by addiction, but it also affects the research and the foundations and companies that are willing to get involved. And so, this is still an issue that many of the big drug companies are very reluctant to develop programs for efficient treatments of drug addiction, because they don’t want to have their name associated with a disease that has this connotation of moral failure. 

Amity Addrisi
Stigma is not just a barrier to research … it is also a barrier to kindness… Recovery Café’s founder Killian Noe says sadly, it’s part of our culture to look at people struggling with substance use with disdain. 

Killian, Recovery Café
I think that there are addictions that are celebrated in our society and addictions that are stigmatized and despised. And it just breaks my heart that for drugs like fentanyl, you don’t get many mistakes, if any. I think that’s what breaks my heart. And if we truly can move as a society, and this is where stigma comes in, I think ’cause it allows us to not move to this place of claiming that we belong to each other. 

Liz Dueweke
If it weren’t for Killian’s compassion and understanding of addiction, many people like John would have had nowhere to go. 

John Wilson
Oh, life is what it looks like today. It’s a transformation, a total transformation and the Recovery Café has played a vital part in that. And I’ll be more specific about it, you know, just coming to the Recovery itself, learning how to be social, learning to care about somebody else. My form of giving back is that I try to get with guys one-on-one, not the women, just the guys and try to help uplift them and give them some hope. 

So it’s a big transformation. I mean, I don’t need to. That’s just, that’s all I need to say as far as that goes, you know. 

Christian Luscher, Ph.D.
We can actually look at addiction without any moral judgment. It is a disease like another or two, and some people are more vulnerable than others, and they have the misfortune that they actually, in the end, suffer from that, and we need to do something for them. 

Amity Addrisi
For a public health crisis as dire as addiction and overdose… it will take a team approach… a battle that can be fought and won on multiple fronts: from the compassion and support of social services, to the insight and innovation of science. 

I’m Amity Addrisi… 

Liz Dueweke
I’m Liz Dueweke… 

Thank you to Dr. Christian Luscher, Killian Noe, and John Wilson for sharing their stories and insight… 

Amity Addrisi
This episode of Lab Notes was produced by Amity Addrisi, Peter Kim, Liz Dueweke and Rob Piercy. 

Liz Dueweke
For more episodes and science research news – visit our website: alleninstitute.org… 

Amity Addrisi
Thanks for listening.