88: How ADHD Medications Affect Fat Burning, Insulin & Brain Health with Dr. Ben Bikman

Welcome to the Metabolic Classroom. I'm Professor Ben Bickman, biomedical scientist and professor of cell biology. Today we're exploring the metabolism of ADHD medications and even some of the metabolism of ADHD itself, because there's a pretty interesting intersection of neuroscience and metabolic health and metabolic biochemistry that intersect here. So in the mini lecture today, we'll discuss the prevalence of ADHD and then go through some of the comm medications that are used to treat it, but of course not exploring the actual efficacy of the drug in the context of adhd, but looking at the rather metabolic outcomes of it. So what are the side effects of these ADHD medications that start to touch on metabolic processes? And then I also, through the course of this discussion, want to highlight to you some of the evidence that points the finger at actually some metabolic origins to adhd. Now, if this topic is of interest to you and you'd like to get in some questions at the end and interact live after the recording is over, remember, go over to BenBickman.com and become an insider there. And with that you are able to submit some questions and we talk about them after the lecture has concluded. Okay, so first of all, how common is attention Deficit Hyperactivity disorder or adhd? Well, it is one of the most common neurodevelopmental conditions affecting about 5 to 10% of kids worldwide. But it's not just a problem of children where about half of that number is also as a percent reflected in adults who experience some of these same symptoms, such as inattention or impulse control issues or hyperactivity, mostly inattention. The search for effective treatments, of course, has gone up in recent years as the prevalence of this has gone up. But this is leading to some widespread use of stimulant and non stimulant medications. That's the two general categories for these ADHD medications and that's how I'm going to present them as we discuss and go through these. Now, at the end of the conversation, we'll discuss some of the like I'd mentioned the metabolic origins that could be relevant to ADHD and then some of the metabolic solutions. All right, let's go into the common medications. As I noted, they fall into two broad categories, stimulants and non stimulants. The stimulants are mostly amphetamine based drugs and they're the most commonly prescribed. But the non stimulant options are also available for people and children that don't tolerate the stimulant versions very well. So the most widely used, the Stimulant medications include both amphetamine based drugs and these are the kind of most famous like Adderall and Vyvanse, but also the methylphenidate based drugs like Ritalin and Concerta. These medications generally work by simply increasing the dopamine and norepinephrine in the brain and this helps regulate attention and focus. But the changes it's thought to help, you know, and of course varying degrees of efficacy depending on the person. But the changes in these neurotransmitter levels also can affect metabolic processes. One that I want to mention now before just briefly reviewing the non stimulant is the effect on appetite suppression. These stimulant drugs will reduce hunger signals by altering the hypothalamic activity. So the hypothalamus deep within the brain which generally just going to lead to the individual eating less. And this of course can result in some weight loss. It's important as we'll get to in a moment to consider that there are direct effects on the fat cells, not in an unexpected way. I will tease you with that information. But not surprisingly, if you're eating less, there's going to be changes in the direction of energy storage with regards to the fat cell. But there are consequences to prolonged appetite suppression that we're going to talk about in just a moment. But it might make depending on the age and development, the physical development state of the individual a little difficult for growth. Now one of the paradoxical effects of stimulants is their influence on food cravings, particularly for high sugar, high fat foods. Now just to clarify, there is no evidence that people are craving just fat, but what is craveable is going to be high sugar alone or high sugar and high fat. That's a particularly craveable mix. But these because the medications increase dopamine signaling, they can heighten the brain's reward response to certain foods, potentially leading to some binge eating episodes, particularly when the medication wears off. Case in point, there is in fact a compelling clinical case that's been shared where and you can get this for insiders. You can get this in the show notes this reference to read more detail but researchers reported on two young patients that had been diagnosed with both ADHD and and something that tends to go along with it which is avoidant restrictive food intake disorder, something just sometimes referred to as arfid. And that's a condition characterized by extreme food avoidance leading to a person just generally not eating enough. When the patients began the stimulant treatment for adhd, the Appetite suppressing effects of the medication actually exacerbated their restrictive eating patterns, leading to significant growth restrictions. So it was literally preventing these young people from growing as. As they had, as they ought to have been. Both of these instances required hospitalization, just to underscore the severity of the issue, but it illustrates how the stimulant induced appetite suppression can contribute to some further eating disorders. All right, now let's move on to the non stimulant. And then after giving an overview of those, we're going to focus on the direct effects of these medications on some specific metabolically relevant tissues like fat cells and liver cells in particular. Okay, so for the individuals who don't tolerate the stimulants too well, the non stimulant medications like atomoxetine and guanfacine are. And they have other brand names like Strattera or intuniv. Those can be prescribed as alternatives. And the medications do work differently. So let's look at amoxetine, one of the more common ones. This is a norepinephrine reuptake inhibitor, and that's the class of drug. It can modestly affect weight and appetite, but it is generally more modest than what you'd see in the stimulant. But there are effects that tend to go a little further. Some studies suggest that it can slightly increase resting energy expenditures, so just basal metabolic rate, possibly due to its effects on catecholamines, norepinephrine. Additionally, atomoxetine can influence glucose metabolism, with some evidence actually suggesting that it can be helpful in insulin sensitivity. And once again, this is probably a result of the effects on norepinephrine. But overall, these effects are going to be quite subtle and may not result in anything obvious. Now, guanfacine works by stimulating something called the alpha 2 adrenergic receptors. Now, that ends up depressing sympathetic nervous activity. So as I state this, I realize I'm getting a little deep, but the adrenergic receptors, you, you may hear in that term adrenergic, there is this evoking of the, this thought that comes up of the hormone adrenaline or what we would say in the US Epinephrine. Now I've said norepinephrine, and that falls into it as well, also known as noradrenaline. So the adrenergic receptors are receptors throughout the body, sprinkled across cells. And there are lots of different types of adrenergic receptors. The one I just mentioned is Alpha 2. And me noting that Guanfacine, a non stimulant activates Alpha 2. But there are a lot of these receptors that are built to respond to adrenaline, epinephrine and noradrenaline, norepinephrine. Now, with that little physiology teaching tangent, the inhibition of the alpha 2 adrenergic receptor actually can lower blood pressure. And so a person on the drug may notice that if they already have lower blood pressure, like let's say a very thin teenage girl whose blood pressure is always kind of bordering on low, it may take it too low and she finds that she's getting very light headed. But overall, by dampening the, by inhibiting the adrenergic receptor, the alpha 2 guanfacine can actually go the other way with regards to metabolic rate than what I'd mentioned with atomoxetine, depressing metabolic rate a little bit. And this could be manifested in a just a greater sense of lethargy, but also it can slow, it could theoretically slow fat breakdown a bit by inhibiting it. Now I'm getting a little ahead of myself because I actually want to devote an entire little section to fat, which we'll do right now. So with all of these drugs in mind, just as a reminder, we have the two categories, stimulant, which is going to have more noticeable effects on fat suppression and then, or rather appetite suppression, not fat suppression, appetite suppression. And then the non stimulant category, which may also, although it depends on the particular drug, have some appetite effect, but all of its effects are generally going to be a little more subtle. Okay, now let's actually get down to the level of the fat cell. So I've been talking about the general effects on appetite and whole body metabolism. These drugs do have effects on the fat cells that are worth highlighting, just out of interest. So stimulant medications like the amphetamine based drugs do significantly affect fat cells because of their activation of the sympathetic nervous system. Now that, that's something I've discussed before, but there are a lot of ways to define the nervous system within the body. And the sympathetic nervous system is colloquially referred to as the fight orf flight. This is when you're kind of feeling a little amped up where the body's ready to physically do something. These drugs will increase norepinephrine, which is a hormone that binds beta adrenergic receptors in fat cells. This will trigger particularly beta 3 adrenergic receptor. This will trigger lipolysis or the breakdown of triglycerides. So just as a reminder, fat, sometimes people say this is fat burning, but it's not fat burning. I try to be clear on this. With lipolysis, it's not fat burning at the cell, it's fat breakdown. I may accidentally use the word fat burning referring to what's happening at the fat cell, but that's not correct. Its fat breakdown, or more technically, it's lipolysis. So it's taking the triglyceride molecule with its glycerol backbone and its individual fatty acids and pulling those fatty acids off, putting them into the blood to then be moved to tissues where the burning will actually occur. So with this in mind, it's no surprise that you are going to increase lipolysis. So the stimulants will put fat cells into a temporary state of accelerated fat breakdown mode. Now, what about the atomoxetine, the not on the non stimulant side? It also will increase norepinephrine by slowing the amount, the degree to which it's cleared out of the blood. But it is more subtle. And so it's going to be a less obvious or intense effect. So there can be some lipolytic effect, but it's going to be less pronounced. Um, but throughout this, it's noteworthy that when the sympathetic nervous system is turned on too high for too long, it actually can promote a degree of insulin resistance. But with atomoxetine, some of the limited evidence suggests that it might actually improve insulin sensitivity. And that could be just because of that sympathetic effect being a little more modest. Now, what about another one like the guanfacine, for example? This, in this case the Alpha, that's the Alpha 2 Adrenergic Activator, it can have the opposite effect. So now we're not stimulating the beta adrenergic receptors which want, which want to promote a fat breakdown. Now we're stimulating the alpha 2 receptor in particular, which actually has an opposite effect. So instead of stimulating fat breakdown, these drugs are going to reduce sympathetic nervous system activity, which is going to slow lipolysis. And by dampening this response, it could overall facilitate greater fat storage. This would be certainly more obvious in people who have a greater tendency to store fat, like just a family history of struggling with excess body weight or insulin resistance and type 2 diabetes. And there is a little bit of evidence to suggest that it can result in some negative effects on insulin sensitivity overall. So that is a kind of brief primer of the effects on the fat cell. But before moving on to the metabolic origins, I wanted to highlight the effects on the liver, because when you start playing around with the sympathetic nervous system, and its signaling. Yes, you're going to have effects on the fat cells, but you're also really going to have some demonstrable movement or some action at the liver. Let's talk about it. And the liver matters in, in this context of metabolism and insulin resistance, et cetera, all the things I usually talk about. Because the liver is at the nexus of all nutrient metabolism, most especially glucose, the liver plays a critical role in maintaining normal glucose levels. And so once again, what's going to happen at the liver is generally going to be a result of how these medications are playing around with the adrenergic signaling or the sympathetic nervous system. Okay, so the stimulants like the amphetamines will increase this sympathetic activity, which will have a direct effect at the liver, specifically activating glycogenolysis, meaning that the liver is taking all of its stored glycogen and now snipping off individual pieces. It's like a string of pearls where each pearl is a molecule of glucose. Now, with the activation of sympathetic activity, it's like we have a little enzymatic pair of scissors coming in and clipping them off. So there's a molecule of glucose, there's another one, there's another one. And so it starts releasing that stored glucose into the blood. This happens because the stimulant medications are activating the beta adrenergic receptors. So you're, you may be getting a theme here where I just have described that beta adrenergic activity at the fat cell is stimulating breakdown of the nutrients. Activity or activation of the beta adrenergic receptors at the liver is once again stimulating the breakdown. So that is a class of receptor or an effect, all in the context of the ADHD medications where you are mobilizing energy at the same time it's promoting glycogenolysis or the breakdown of stored glycogen into glucose. It's also stimulating gluconeogenesis. That's where the liver is going to be producing new glucose from non carbohydrate sources, most especially lactate. That's something I've discussed before. People always want to clamor and claim that it's mostly coming from protein and amino acids. That's relatively modest contributor, but the net effect is that the overall amount of glucose in the blood can go up. Now, what about another popular one at amoxetine? This also affects glucose metabolism, but it's different from the stimulant. It's, it's once again the one that's a little more gradual because it just changes the way the body clears the norepinephrine. So the norepinephrine increase will be a little more subtle, but it would have some same degree of effect, potentially increasing liver glucose production. Now the unlike the stimulants and amoxetine, the non stimulant alpha 2 adrenergic agonists or activators like guanfacine will have an opposite effect. These medications tend to reduce sympathetic activity, so it's going to lead to less glycogen breakdown and less gluconeogenesis, thereby leading to less glucose coming from the liver. Now again, that's generally going to be a modest effect, but this may be an individual who on the drug notice this is that their blood sugar levels may tend to be a little lower, perhaps in a fasted state. All right, now before we finish up, I want to take a moment to explore the intersection, like I mentioned earlier, between the neurological condition ADHD and brain metabolism. There is evidence that suggests that it may be a condition of impaired brain energy use, meaning that the brain just isn't able to use fuel as efficient as efficiently as it should. The first major study that linked ADHD to metabolism that I'm aware of came from Zemetkin et Al in 1990 that was using a technique called positron emission tomography, or PET scan. PET scans. This research showed that adults with ADHD had lower glucose metabolism in the prefrontal cortex. That's the brain region responsible for attention, impulse control, and decision making. All things that tend to be a little compromised or sketchy with adhd. So this means that the neurons in these areas were not using energy as efficiently, potentially making it harder for them to work well enough to help the individual stay focused and to moderate behavior. Some more recent studies have found that in individuals with adhd, also the dorsolateral prefrontal cortex and striatum, two key areas involved in cognitive flexibility and reward processing, also have reduced metabolic activity. And this could certainly explain why many of the classic ADHD symptoms, such as difficulty concentrating, impulsivity, manifest, as well as some struggles with needing some constant stimulation. Now, when we talk about metabolism, we often think about insulin and blood glucose. But also insulin is relevant and active in the brain. Insulin helps neurons take in glucose. So there are some neurons that do have an insulin dependency for at least a portion of their glucose uptake. And some studies suggest that ADHD can involve impaired brain insulin sensitivity. If the neurons can't efficiently take in glucose, that leads to unstable energy levels in the brain, which can explain the fluctuations in attention and impulse control. In fact, children with ADHD have been found to have higher variability in blood sugar levels, suggesting that their brains may be dealing with more unstable energy regulations. And some researchers have hypothesized that this could contribute to hyperactivity and some difficulty with sustained focus. Now, with all of that in mind, one of the more controversial questions in ADHD research is whether diet, specifically sugar intake, plays a role in the development or severity of complications. A very interesting study was published in Postgraduate Medication or Medicine by Johnson et Al in 2011 and it re examined the idea arguing that chronic sugar consumption could contribute to ADHD through its effects on dopamine signaling and brain metabolism. What they highlight in this interesting study is that there are similarities between ADHD and other things like addiction and even obesity, both of which involve reduced dopamine receptor activity in the brain's reward centers. So when someone consumes sugar, it triggers a surge in dopamine, creating a short term boost in motivation and focus and just overall sense of feeling good. But with chronic sugar consumption, the dopamine receptors do become a little desensitized, meaning that the brain requires more and more stimulation to get the same effect. This pattern of dopamine dysregulation is also seen in individuals with adhd, leading researchers in this particular study to question whether the excessive sugar intake might worsen attention and impulse control issues over time. But in this same study, I I I, I need to also share that they actually went a little further than just dopamine, where the study also points a finger to metabolic factors, particularly the way fructose metabolism, which is a component of sugar, leads to ATP depletion and increased uric acid production, both of which can impair brain function. So the authors propose that ADHD may not just be a neurodevelopmental condition, but also metabolic one, where the dietary factors, particularly excessive sugar consumption, could contribute to some brain energy issues. Now, before I'm done discussing brain metabolism, let's include one final character in the story. Since ADHD could involve impaired glucose metabolism, some researchers have begun exploring whether alternative energy sources could help. One area of interest is the ketogenic diet, which shifts brain metabolism of course, away from glucose and towards ketones. One of the benefits of ketones is that when a person is adhering to the diet, you are completely wiping out the variability in the energy source. To say that all another way, if the brain is reliant mostly on glucose as its fuel, then it is subject to the highs and lows of glucose because glucose is capable of changing more rapidly and to such a larger degree than any other fuel in the blood. Yes, ketones can change, of course fat levels can change, but it's going to be much more subtle and slower, so not as dramatic swings and a slower shift. Having said all of that, the idea is that if you can help the brain have access to a more stable fuel supply, it could result in improved function. A fascinating report was published by a site called Psychiatry Redefined and it explored the effects of a ketogenic diet on a 13 year old girl diagnosed with a type of ADHD. Before the dietary intervention, she struggled with focus, impulsivity and emotional regulation despite conventional treatments being in place. And the healthcare team implemented a ketogenic diet nutrition plan emphasizing low carb, higher fat, adequate protein, just to help stabilize brain energy access over time. They reported that she experienced marked improvements in attention, behavior and overall cognitive function, suggesting that by allowing the brain to have access to the ketones that a more stable fuel source that it was able to optimize or balance out any of the previous imbalances in brain metabolism. So, some final thoughts. While ADHD is certainly, and I would say even correctly considered a neurodevelopmental condition, there's obviously a metabolic relevance here. Not only is the metabolic relevance reflected in the effects of some of these common medications, where the medications are eliciting metabolic changes, some of which may facilitate the the efficacy of the medication. Like for example, if you have someone who is on a medication that is both burning more fat and making them eat less, it's not surprising that they're going to perhaps be making more ketones. So that might be playing into that. But also as well, just the overall neurodevelopmental condition of ADHD could itself be some manifestation of altered glucose metabolism, particularly in like the prefrontal cortex, like I'd mentioned from that earlier study, the one published in 1990. So these findings all collectively do kind of play into this idea that ADHD may involve, at least in part, some underlying energy regulation issues. But it does raise, as I wrap up, an important question. Could targeting brain metabolism improve ADHD symptoms? Some of the early evidence suggests that it indeed could. And what is particularly exciting for me is to think about how some of these, some of the research into treatments for neurological conditions may benefit from the same overall ultimate therapies. Like for example, more evidence is suggesting that Alzheimer's disease is a metabolic issue. Well, what if there was a drug used to improve brain metabolism that is therapeutic for Alzheimer's but at the same time it's helping address this particular quirk of adhd depending on the person. So there is, I believe, reason to be excited as this area of research is gaining steam. Thanks for tuning in. I hope you've learned something valuable today. Until next time, more knowledge, better health.