Viloxazine ER: A New Era in ADHD Treatment?

Join Greg Mattingly, MD, as he discusses the evolving ADHD treatment landscape. An associate clinical professor at Washington University School of Medicine, president of the American Professional Society of ADHD and Related Disorders, and co-chair for Psych Congress, Dr Mattingly provides expert insight into the clinical promise of viloxazine extended-release (ER)—a nonstimulant recently recognized by the US Food and Drug Administration for its unique dual mechanism of action involving both norepinephrine and serotonin modulation. He highlights key clinical trial findings showing rapid symptom improvement, enhanced executive function, and improved quality of life, along with practical guidance on dosing, titration, and the use of viloxazine in combination with stimulants. Whether treating children, adolescents, or adults, this episode offers essential insights into a potential new standard in ADHD care. 

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Dr Greg Mattingly: Welcome to an episode on viloxazine XR and the evolving nature of ADHD. I'm Dr Greg Mattingly, an associate clinical professor at the Washington University School of Medicine, president of the American Professional Society of ADHD and Related Disorders, and co-chair for Psych Congress.   

I'd like to talk a little bit today about the evolving nature of ADHD. We know that ADHD is no longer just a childhood condition. We know it's no longer just a condition affecting boys. We know that ADHD is a condition which has an almost equal prevalence between boys and girls. And we know that 90% of children will not outgrow their functional issues, their symptomatic issues of ADHD.  

What we do know is that the field of ADHD has emerged. We know that girls even now are less likely to be picked up during childhood. They may not get picked up until those adult years. We know the average age of diagnosis for many women in our country is 25, 30, 35 years old. Why that's important is ADHD is not just a set of symptoms, but it's a set of symptoms that cause functional impairment within your life. And like any other health condition, the longer someone goes without recognition, the longer someone goes without treatment, the more that those functional impairments take root within their life.  

So, my new terminology when I think about untreated ADHD is that untreated ADHD goes from being simple ADHD to being complicated, comorbid, metastatic ADHD. And by the definition of metastatic what I mean is the symptoms of ADHD no longer just affect cognition and concentration in grades. But they start affecting relationships, impulse control, risky behavior, self-esteem, and unfortunately, deaths of illnesses of despair.  

So, when we think about ADHD, it's a set of symptoms that cause impairments, but it's also a condition that has a dramatically higher mortality rate when left untreated. Data from here around the United States, from around the world, have all shown very similar findings that untreated ADHD has about a 400% higher mortality rate than individuals who do not have ADHD. We also know that untreated ADHD, as it becomes more complicated—as you start picking up problems with anxiety, depression, insomnia—becomes even more lethal. So, by the time you have ADHD plus 1 or 2 other health conditions, your mortality rate is now 800% higher than the general population.  

If we think about many of the limitations of standard ADHD, a lot of those limitations come to us about the treatment options we've had to offer. Our treatment options have traditionally been around the world of stimulants and stimulant medications. Taking a short-acting medicine and making it a long-acting medicine, we helped to get rid of the gaps in treatment between each of the doses, but we still have the limitations of being a stimulant molecule. Issues around the possibilities of abuse, misuse, and diversion. Issues around the possibility of unwanted side effects such as appetite suppression, sleep issues, rebound when coming off your medicine. So, when we think about the limitations there, part of that's been the limitations of the very treatments we've had to offer for our patients.  

What's exciting about the world of ADHD is here in the United States and around the world, we see new innovations coming forward. Today, I'd like to focus on one of those innovations that I've been a part of, both as a clinical researcher, having been a part of many of the trials, and as a clinician using it with my patients. And that is viloxazine XR. Viloxazine XR comes to us, is a compound that was originally approved in Europe. It was approved over there for other health conditions. It was brought to the United States, turned into a sustained release, once-daily medication, and was studied in children, adolescents, and adults with ADHD.  

Having been a part of those trials, what we found is viloxazine felt different in the brain. We knew that viloxazine was helping not just with core ADHD symptoms, but we studied it for things like executive function. Can I plan? Can I control my impulsivity? Can I think about strategies to be successful in the future? Can I be present in a relationship? So, we saw that viloxazine was not only helping core ADHD symptoms, but it was helping issues around executive function.  

In addition to that, we looked at areas around quality of life. Not only is it helping your symptoms, but is it helping the very inherent nature of your quality of your life? And we studied that with a scale called the AAQoL, where we looked at quality of life improvements with viloxazine use. What we also found is, both in the long-term pediatric trials, but then in the adult trials, we found consistent findings. And that was the longer you stayed on viloxazine, the more your symptoms continued to improve. So, it wasn't a short-term fix. It wasn't something you pop it once and tomorrow you wake up better. But with consistent, ongoing use, we saw consistent, significant improvement in ADHD symptoms and related impairments within people's lives.  

When we think about some of the limitations of prior nonstimulants, part of that is the only other nonstimulant approved for adult ADHD quite often took weeks to a month or two to really show that it was taking effect. In the case of viloxazine, we wanted to say this is a nonstimulant molecule. It has no addiction potential. But how fast did we see improvement of symptoms? So, I think one of the key messages here is with the viloxazine molecule, we saw improvement not after weeks to months, but in the pediatric trials we saw significant improvement within the very first week. In the adolescent and the adult trials, we saw significant improvement after 2 weeks. So, I think one of the taglines when it comes to viloxazine is “Give me 2 weeks.” Give me 2 weeks to see this medicine start to improve your symptoms. In the children, as fast as 1 week. In the adolescents and adults, within 2 weeks.  

One of the mistakes I see clinicians make is they don't titrate the dose to get an optimal response. Just like most other medicines, I wouldn't stop with a blood pressure pill when you still had mild hypertension. I would titrate the dose of that medicine until I either ran into side effects or I normalized your blood pressure control. The same thing is true when we talk about using viloxazine. The starting dose for children is 100 milligrams. The starting dose for adolescents and adults is 200 milligrams. But for the majority of your patients, that will not be the optimal dose. For children, the dose range goes up to 400 milligrams. For adolescents, up to 400 milligrams. For adults, you can go as high as 600 milligrams, if needed, for your patients. In my clinical experience, what I’ve found is many of my children have their optimal experience starting at 100 milligrams but then working your way up to about 300 milligrams. Similarly, with adolescents, 300 to 400 mg. For my adults, I think right around 400 mg has been the most common optimal dose.  

One of the questions that came up with viloxazine is the original mechanism of action that we talked about was blocking the norepinephrine reuptake pump. So, blocking the norepinephrine reuptake transporter raises both norepinephrine and, to a lesser extent, dopamine in the prefrontal cortex. So, we see elevations of norepinephrine. We see elevations of dopamine in the prefrontal cortex. What many of us asked is, viloxazine feels different. What is it about the pharmacology that makes it feel different in our clinical experience with our patients? That led to a number of studies, historic studies, which said let's take a look at the true pharmacology of viloxazine in both animal models and in primate models to take a look at what's happening.  

And there, we found something that was really quite exceptional. We found that viloxazine not only raised norepinephrine and dopamine in the prefrontal cortex, but we found that unlike any other ADHD treatment, viloxazine also raised serotonin in the prefrontal cortex. We all know that serotonin modulation tends to help with things such as emotional frustration, impulse control, being able to tolerate stress, potentially being more resilient under stressful conditions, things that are quite often issues within our ADHD patients. That led to some very elegant research saying what is it about the nature of viloxazine that’s modulating serotonin? Because viloxazine is not a serotonin reuptake inhibitor. It wasn't working through the same mechanism as our serotonin antidepressants that block reuptake. But yet, it was raising serotonin in the prefrontal cortex, and it seemed to be helping with these associated symptoms of ADHD.  

That led to the people at Supernus going back and doing some historic studies, spending the time, spending the effort to come back and say, we want to understand this molecule to its best extent. They did a number of studies, both here in the United States, but also by some of our colleagues in the United Kingdom, looking at the basic pharmacology of viloxazine on neuroimaging studies and micropipette pharmacology studies. And what they found is viloxazine doesn't just hit the norepinephrine transporter, but it hits an array of serotonin receptors specifically and directly.  

That led to the FDA in January of 2025, making a historic decision. They came back and changed the pharmacodynamic section of the viloxazine package insert to include not just norepinephrine reuptake as its mechanism of action, but also including the fact that  viloxazine is a partial agonist of serotonin 2C receptors. That finding came because when they looked in various models of serotonin 2C modulation, serotonin 2C had primary efficacy, had specific efficacy on helping with impulsivity, impulse control. So, the FDA said we have convincing evidence that this molecule truly is unique in the way that it touches the brain. It touches the brain in a way that's different than other ADHD treatments. We think this is an important set of knowledge for clinicians to understand. And they did something they had never done before in the field of neuroscience. They changed the pharmacodynamic section of a package insert to include a new update.  

So, we now have a pathway going forward where the FDA said if we can have important new findings when it comes to pharmacodynamics, we'll adjust the package insert to be more educational, to be more holistic for the understanding of clinicians. So, in this case, the package insert for viloxazine not only includes being a norepinephrine reuptake inhibitor, but being a selective modulator of the partial agonists of serotonin 2C.  

That then takes me to a number of studies that have been done. And I think this mechanism helps us to understand some of the study results. One of my good friends, Dr Price, did a study where he said, "Listen, I'm going to take children and adults in my practice, children and adults who have tried a standard nonstimulant for ADHD, in this case, atomoxetine." And he said, "Let's try them on atomoxetine first. Let's give them a month or so on atomoxetine. And then, let's take all of those children and adults, and let's try them on viloxazine instead." So, it was a crossover study where every patient got to experience both molecules.  

And what he found was that viloxazine was significantly more effective for overall ADHD symptoms. Similar to what we saw in the phase III clinical trials, he also said that viloxazine had a faster onset of action. And when he asked patient preference, I think it was 92% of his patients preferred viloxazine over atomoxetine.  

A final important part of that message is that many of these patients were taking concurrent stimulants. They were coming from a stimulant. Perhaps they didn't want to be on it. They wanted to reduce the dose. But he was able to find that somewhere between 70% to 75% of his patients who came to viloxazine from a stimulant were able to either reduce the dose of that stimulant or discontinue with the stimulant altogether. So, viloxazine not only was effective for improving ADHD symptoms, but it had the ability to reduce stimulant use and doses of stimulants for many of the patients that that was a desired benefit.  

That leads us to one of the more recent findings, a study that was done by my good friend and colleague, Ann Childress, the past president of APSARD. Where we had said, "How about the combination of viloxazine plus a stimulant?" Sometimes, 1 plus 1 is more than 2. One plus 1, it's like peanut butter and jelly. It may be more preferred than either one by itself. In this case, they said for children who have had breakthrough symptoms on a stimulant, does it make sense to add viloxazine to help smooth out the edges, to help with symptom control where a stimulant by itself maybe wasn't getting the job done, to help with symptoms at the end and the beginning of the day, where a stimulant either hasn't started or hasn't lasted.  

So, in this case, we added viloxazine on top of a previously administered stimulant. We found significant reductions in ADHD symptoms by more than 50% for the average patient. And we started out with morning dosing. We then moved it to evening dosing to say, “Is viloxazine truly a 24-hour medicine that you can dose it in the morning, but if desired, you could dose it in the evening and not lose any effect?” And the answer was, we saw no difference—actually a little bit of improvement when dosed in the evening versus morning. So, that gets clinicians the flexibility and the option to dose this whenever they think is optimal for their patients.  

So, let me just wrap up the evolving nature of ADHD. ADHD is no longer a disorder of just children. It's no longer a disorder of just boys and men. We know that for 90% of our patients, it's going to persist into adulthood. And we know that in particular for women, most women will not get a diagnosis until they reach the adult years. So, the average age of diagnosis quite often is 25 to 35 for women—symptoms that started in childhood but were missed or overlooked. We know that untreated ADHD is like any other health condition. It becomes more complicated, more comorbid, and becomes more lethal.  

We know that we now have innovations that are coming to us that go beyond the stimulant molecule. And the focus of our topic today was new innovations with viloxazine XR and an exciting new update from the FDA, where they modified the pharmacodynamic section of the package insert to include not just norepinephrine modulation, but modulation of the serotonin 2C receptor. I think this helps us to understand the basic mechanisms of viloxazine, the potential benefits for the patients, potentially why we saw onset a little faster—within 1 week for children and 2 weeks for adults. Why we saw holistic symptom improvement, not just in ADHD symptoms, but improvement in executive function, improvement in quality of life.  

My final message with viloxazine is: to get the optimal results, you have to do the optimal dose. So, titrate that dose up to optimal outcomes for your patients. So, for children, try to get the dose up around 300 milligrams for any of them. For adolescents, 300 to 400 milligrams. For adults, try to push that dose up to around 400 milligrams, with a maximum dose of 600 milligrams available for our adult patients to optimize the outcomes for your patients. Let me thank you for joining me. This is Greg Mattingly, coming to you from the Psych Congress Network, bringing you important new updates on viloxazine and the field of ADHD. 

Greg Mattingly, MD, is a physician and principal investigator in clinical trials for Midwest Research Group. He is also a founding partner of St. Charles Psychiatric Associates where he treats children, adolescents, and adults. A St. Louis native, he earned his medical degree and received a Fulbright scholarship while attending Washington University. Dr. Mattingly is board certified in adult and adolescent psychiatry and is a Diplomat of the National Board of Medical Examiners. He is an Associate Clinical Professor at Washington University where he teaches psychopharmacology courses for the 3rd year medical students. Dr. Mattingly has been a principal investigator in over 400 clinical trials focusing on ADHD, anxiety disorders, major depression, bipolar disorder and schizophrenia.