Hey everyone, welcome back to My Weird Prompts. We are coming to you from our usual spot in Jerusalem, and today we are diving into a topic that hits close to home for a lot of people, including our housemate Daniel. He actually sent us a voice note this morning about something he has been navigating lately, which is the really complex world of attention deficit hyperactivity disorder medications.
Herman Poppleberry here, and I am ready to get into the weeds on this one. Daniel’s prompt is fascinating because it touches on that very specific tension between what works for the brain and what the body can actually handle. He is dealing with that classic trade-off between the effectiveness of stimulants and the physical side effects, particularly when you have something like high blood pressure in the mix.
It is a tough spot to be in. He mentioned that he has tried non-stimulants like Strattera and found them lacking, but stimulants like Vyvanse or Adderall come with that cardiovascular baggage. And then there is the whole bureaucratic nightmare of actually getting those prescriptions filled because of how they are scheduled.
Right, and we have touched on some of these themes before. I think back to episode one hundred and two, where we talked about the bureaucracy of the medication maze, and episode three hundred and sixty-six, where we looked at the neuroscience of late diagnosis. But today, I want to really focus on the chemistry. Why do these drugs feel so different? Why does one give you focus while the other just makes you feel like you drank ten cups of coffee and then got stuck in traffic?
That is a great way to put it. Daniel specifically asked about the roles of dopamine and norepinephrine. So, Herman, let’s start there. In the context of ADHD, what are these two chemicals actually doing, and how do the different classes of medication play with them?
To understand this, we have to look at the catecholamine hypothesis of ADHD. Basically, the idea is that the ADHD brain has a bit of a supply-and-demand issue with two main neurotransmitters: dopamine and norepinephrine. Dopamine is often called the reward chemical, but in the prefrontal cortex, it is more about signal-to-noise ratio. It helps you focus on the important thing by making it more rewarding or salient.
So it is the "this matters" chemical.
Exactly. It helps you stay on task because it provides that internal thrum of engagement. Norepinephrine, on the other hand, is closely related to adrenaline. Its job is to reduce the background noise. It helps with alertness and arousal. If dopamine is the spotlight, norepinephrine is the guy turning off the other lights in the theater so you can see the stage.
Okay, that makes sense. So where do the medications come in?
Stimulants, like the methylphenidates—think Ritalin or Concerta—and the amphetamines—like Adderall or Vyvanse—are very effective because they hit both. They increase the levels of both dopamine and norepinephrine in the synaptic cleft. They do this by blocking the reuptake, meaning the brain doesn't vacuum them up as fast, and in the case of amphetamines, they actually prompt the brain to release more.
And that is why they feel so powerful. You are getting the spotlight and the darkened theater at the same time.
Precisely. But Daniel’s experience with Strattera, which is the brand name for atomoxetine, was very different. Strattera is what we call a selective norepinephrine reuptake inhibitor, or an SNRI. It specifically targets norepinephrine. It does not have a direct, significant effect on dopamine in the reward centers of the brain, although it does increase dopamine slightly in the prefrontal cortex as a side effect of how norepinephrine transporters work there.
So if it is mostly hitting norepinephrine, why did Daniel say it made him feel stressed without the focus?
That is the big complaint with Strattera. Because it is amping up norepinephrine everywhere, it can trigger the body’s fight-or-flight response. If you are increasing norepinephrine but not getting that hit of dopamine to provide the reward or the purpose for that alertness, you just feel... alert. You feel on, but you don't necessarily have a direction to point that energy. That is why people describe it as feeling like physical anxiety or stress. Your heart rate might go up, you might feel jittery, but your brain is still wandering around looking for something interesting to do.
It is like having a car with a high-revving engine but the transmission is stuck in neutral. You are making a lot of noise and burning fuel, but you aren't going anywhere.
That is a perfect analogy. And for some people, that extra norepinephrine eventually helps the brain regulate itself over several weeks, but for others, the side effects just drown out any potential benefit.
So let’s talk about the blood pressure issue. Daniel mentioned he has to be careful with stimulants because his blood pressure is already a bit high. This seems like a really common catch-twenty-two. You need the meds to function, but the meds might be a risk for your heart. How do doctors actually navigate that?
It is a major clinical challenge. Hypertension, or high blood pressure, is incredibly common, and so is ADHD. When you combine them, you are essentially trying to treat a brain that needs more stimulation while protecting a vascular system that needs less. The first thing a good psychiatrist or cardiologist will do is try to get the blood pressure under control independently. Often, they will use something like a beta-blocker or an ACE inhibitor.
But wait, don't some ADHD medications actually help with blood pressure? I remember reading about certain non-stimulants that were originally blood pressure meds.
You are thinking of the alpha-two agonists! This is where the sweet spot starts to appear, or at least a different way of thinking. Drugs like Guanfacine—brand name Intuniv—and Clonidine—brand name Kapvay—were originally developed to treat high blood pressure. They work by stimulating alpha-two adrenergic receptors in the brain, which actually has a calming effect on the sympathetic nervous system.
So they lower blood pressure and help with ADHD? That sounds like a win-win for someone like Daniel.
It can be! They aren't usually as punchy as stimulants for pure focus, but they are excellent for the emotional regulation, impulsivity, and hyperactivity sides of ADHD. In a patient with hypertension, a doctor might prescribe a stimulant but buffer it with Guanfacine. The Guanfacine helps keep the blood pressure and heart rate lower while also providing some cognitive benefits, allowing a lower dose of the stimulant to be more effective.
That is fascinating. So it is a cocktail approach rather than a single silver bullet. But I imagine that adds even more complexity to the bureaucratic hurdles Daniel mentioned. If you are juggling three different scripts just to get your brain to work, the room for error or pharmacy drama goes way up.
Oh, the bureaucracy is the silent killer of ADHD treatment. Because stimulants are Schedule Two controlled substances in the United States, and similarly restricted in many other countries, you have these rigid rules. You can't get refills; you need a new prescription every thirty days. You can't pick it up early. And even now, in February twenty twenty-six, we are still feeling the tail end of those massive shortages that started years ago.
I saw some news about that recently. Didn't the DEA just increase the production quotas for this year?
They did! Just last month, the DEA raised the production ceiling for Adderall-related ingredients by about fourteen percent and Vyvanse by twenty-two percent. It is a win for advocacy groups, but on the ground, patients are still stuck calling twenty different pharmacies like they are looking for a rare collectible.
It is a man-made crisis, like we said in episode one hundred and two. It is wild that we treat people who have a disorder characterized by executive dysfunction and forgetfulness by giving them the most bureaucratically demanding task imaginable every single month.
It is cruel, honestly. And that is why the appeal of non-stimulants is so high. Strattera or Qelbree are not scheduled. You can get a ninety-day supply mailed to your house. No one treats you like a criminal at the pharmacy counter. For many patients, the effectiveness of a drug isn't just about the neurochemistry; it is about the access-to-benefit ratio. If a drug is eighty percent as effective as Adderall but one hundred percent easier to actually get, that might be the better choice for your life.
But for Daniel, it sounds like the effectiveness just wasn't there. If the non-stimulant doesn't work, the ease of access doesn't matter. So, let’s look at the future. Daniel asked if we will ever find that sweet spot—something as effective as Vyvanse but as easy to handle as a non-stimulant. What is in the pipeline?
There is some really exciting stuff happening right now. The biggest news is a drug called centanafadine. It is currently under priority review by the FDA with a target decision date of July twenty-fourth, twenty twenty-six. It is what we call a triple reuptake inhibitor, or an NDSRI. It hits norepinephrine, dopamine, and serotonin all at once.
A triple threat! How is that different from what we have now?
Well, it is being positioned as a non-stimulant with low abuse potential, but because it hits all three pathways, the Phase Three trials are showing it might be much more effective for core focus than the older non-stimulants like Strattera. It is aiming for that holy grail Daniel mentioned—stimulant-level efficacy without the Schedule Two restrictions or the massive cardiovascular load.
That would be a game changer. What about things that aren't drugs at all? We talk a lot about tech on this show. Are there digital therapeutics that are actually showing promise?
There are! We’ve talked about EndeavorRx for kids, but now there is EndeavorOTC specifically for adults. It is an FDA-cleared video game treatment that uses specific sensory stimuli to target the neural systems involved in attentional control. It is not going to replace Vyvanse for an adult with a high-pressure job, but as a supplementary treatment, it might allow someone to use a much lower dose of medication, which solves that blood pressure concern.
I think about the sweet spot not just as a new molecule, but as a more personalized way of using what we already have. We are getting better at pharmacogenomics—testing your DNA to see how you metabolize these drugs. Some people are fast metabolizers of stimulants, so they get a huge spike and then a crash. Others are slow, so the drug builds up in their system and ruins their sleep.
Exactly. If Daniel knew exactly how his liver was processing these meds, his doctor could tailor the dose much more precisely. We are moving away from the try this for a month and see if you feel like a zombie phase of psychiatry and moving toward something more data-driven.
You know, it is interesting that Daniel mentioned the stress of Strattera. I wonder if there is a psychological component to that sweet spot too. When you take a stimulant, there is often a euphoric or motivational kick in the beginning. Some people argue that is a side effect, but for someone who has spent years feeling lazy or unmotivated, that feeling of I can do this is a huge part of the therapeutic benefit.
That is a controversial point in the field! Some clinicians want to eliminate that kick because they see it as a sign of potential abuse. But for the patient, that shift in internal monologue is often what allows them to start building the habits they need. Non-stimulants don't give you that. They are more like a background process. You just notice, three weeks later, that you didn't lose your keys as often. It is less rewarding, even if it is technically working.
It is the difference between a coach giving you a pep talk and just having better sneakers. Both help you run, but the pep talk changes how you feel about the race.
I love that. And for someone with high blood pressure, the pep talk of a stimulant might be making their heart race too much. So maybe the future is a combination of a very low-dose, smooth stimulant for that salience and a non-stimulant like Guanfacine to handle the background noise and protect the heart.
It feels like we are in this transition period where the science is there, but the medical system is still catching up. We have all these tools—alpha agonists, prodrugs, genomic testing—but most people are still just getting a standard prescription and a good luck.
And that is why being an informed patient is so important. Daniel is doing exactly what he should be doing—tracking his reactions, understanding the difference between norepinephrine and dopamine, and asking about comorbidities like hypertension. If you can go to your doctor and say, I think I need to look at an alpha-two agonist to buffer the cardiovascular effects of a stimulant, you are going to get much better care than if you just say, the meds make me feel weird.
It is about becoming the architect of your own treatment plan. Which, again, is hard when your executive function is struggling! But it is why having a support system, or even just a podcast like this to help frame the ideas, can be a lifeline.
Speaking of framing ideas, I think we should talk about the non-medical sweet spot for a second. We’ve been talking about pills, but for a lot of people, the environment is the biggest non-stimulant factor. If you can change your environment to require less focus, you don't need as much medication.
The pills don't teach skills mantra.
Exactly. But it goes deeper. It is about scaffolding. If I use a digital assistant to handle all my norepinephrine tasks—the alerting and reminding—then my brain only has to handle the dopamine tasks—the actual creative work. That reduces the total cognitive load, which in turn reduces the amount of medication I might need to stay afloat.
I wonder if Daniel has explored that. He is a busy guy, and sometimes the pressure we put on ourselves to perform like neurotypicals is what drives us to seek higher and higher doses of stimulants, which then triggers the blood pressure issues. It is a feedback loop.
It really is. And the stress of the bureaucracy adds to that. Think about the physical toll of being on your last two pills, calling the pharmacy, being told they are out of stock, and knowing your work performance is going to tank in forty-eight hours. That stress alone will spike your blood pressure more than a five milligram Adderall would!
That is such a good point. The system itself is a health risk for people with ADHD.
It really is. I want to go back to Daniel’s question about where pharmacotherapy is headed. There is a drug that has become a big player recently called Qelbree, or viloxazine. It is another non-stimulant, but it works slightly differently than Strattera. It is a selective norepinephrine reuptake inhibitor, but it also has some activity on certain serotonin receptors that might help with that stress feeling Daniel described.
Is it showing better results for focus than Strattera?
The data is promising, especially for people who didn't respond to atomoxetine. It seems to have a slightly faster onset of action—maybe a week or two instead of a month. It still has the cardiovascular warnings, but for some, it seems to be a cleaner feel. It is not the sweet spot yet, but it is another arrow in the quiver.
It feels like we are slowly chipping away at the problem. We are moving from one size fits all to we have five different sizes and eventually we will get to custom-tailored.
I hope so. And I think the recognition of ADHD in adults is driving this. For a long time, this was seen as a childhood disorder. But when you are treating a forty-year-old with a career, a mortgage, and a history of hypertension, you can't just throw Ritalin at them and hope for the best. The stakes are higher, and the physiology is more complex.
So, if we were to give Daniel some takeaways from this deep dive—not medical advice, obviously, because we are just two brothers in Jerusalem with a lot of books and a microphone—but what are the themes he should be thinking about?
First, I would say: don't give up on non-stimulants just because Strattera was a bust. The alpha-two agonists like Guanfacine are a completely different mechanism and might be the missing link for someone with high blood pressure. Second, look into the combination therapy approach. It is not an either-or. Sometimes a very small amount of a stimulant with a buffer medication is the safest and most effective route.
And third, don't underestimate the impact of the bureaucracy on your health. If the monthly struggle for a Schedule Two drug is causing massive stress, that is a legitimate medical factor to discuss with a doctor. Maybe there are longer-acting formulations or different delivery methods that can bridge the gap.
And finally, keep an eye on the sweet spot research. We are moving toward a world where we might be able to target the focus parts of the brain without hitting the heart rate parts of the body. It is a matter of precision.
It is a lot to take in, but it is also hopeful. The fact that we even know enough about dopamine and norepinephrine to have this conversation is a huge leap from where we were twenty years ago.
Oh, absolutely. Back in the day, it was basically here is some speed, hope it works. Now we are talking about receptor affinities and synaptic reuptake ratios. We are getting there.
Well, I think we’ve covered a lot of ground today. Daniel, thanks for sending that in. It is a topic that affects so many people, and your specific experience with the stress of non-stimulants is something I think a lot of listeners will relate to.
Definitely. It is a journey of trial and error, which is frustrating, but every failed trial is actually just more data to help you find what eventually works.
Before we wrap up, I want to say a quick thank you to everyone who has been listening. We’ve been doing this for four hundred and eighty-five episodes now, and the community that has grown around My Weird Prompts is just incredible. If you are enjoying these deep dives, we would really appreciate it if you could leave us a review on Spotify or whatever podcast app you use. It genuinely helps other people find the show.
It really does. And if you want to see our back catalog or send us your own prompt, head over to myweirdprompts.com. We have everything archived there, including our previous episodes on ADHD like episode three hundred and forty-four, which goes into the practical side of navigating life after a diagnosis.
Yeah, there is a wealth of stuff in the archives. You can also find our RSS feed there if you want to subscribe directly.
Alright, I think that is it for today. Corn, any final thoughts?
Just that the sweet spot might not be a single pill, but the balance we find between the chemistry, our environment, and how we treat ourselves. It is a work in progress for all of us.
Well said. This has been My Weird Prompts. I am Herman Poppleberry.
And I am Corn. Thanks for listening, and we will talk to you next time.
See ya.
