Hi. Good afternoon and welcome. My name is Vishal Madan. I'm the Chief of the Division of Education and Deputy Medical Director at the American Psychiatric Association. Apologies for starting a couple of minutes late. We ran into a little technological issue. I'm pleased that you're joining us today for today's emerging topic webinar series titled Non-Pharmacological Treatments for ADHD. And we are joined by L. Eugene Arnold, MD, M.Ed., Professor Emeritus of Psychiatry at Ohio State University. Next slide, please. Today's webinar is part of our Emerging Topics in Psychiatry webinar series. Stay up to date on important topics and trends impacting psychiatry by participating in this new Emerging Topics webinar series, which is presented by specialists across the field and looks into and explores a range of diverse pertinent topics and offers a chance to interact with peers and subject matter experts. Next slide, please. Today's activity webinar has been designated for one and a half CME credits. The credit for participating in today's webinar will be available for 90 days. As you can see on the slide, it talks about the Q&A. So please feel free to submit your questions throughout the presentation by typing them into the question and answer area, Q&A area at the bottom, found in the attendees control panel. We will reserve about 20 minutes or so for the Q&A after the presentation. And we'll be able to send over the slides after the presentation as well. Next slide, please. Now I'd like to introduce the faculty for today's webinar. We are joined today by Dr. Gene Arnold, MD, M.Ed. Dr. Arnold is Professor Emeritus of Psychiatry at Ohio State University, where he was formerly Director of the Division of Child and Adolescent Psychiatry, as well as the Vice Chair in Psychiatry. Dr. Arnold graduated from Ohio State University College of Medicine, summa cum laude, and turned at the University of Oregon, and then took residencies at Johns Hopkins, where he earned the M.Ed. and served in the U.S. Public Health Service. Dr. Arnold is a co-investigator in the OSU Research Unit on Pediatric Psychopharmacology. He has 53 years of experience in child pediatric research, including being on and serving on the multi-site NIMH MTA study or Multimodal Treatment of ADHD study, which was one of the earliest and largest studies we've ever had in ADHD. He served as an Executive Secretary and Chair of the Steering Committee on that. For his work on the MTA, Dr. Arnold received the NIH Director's Award. A particular interest of his is alternative and complementary treatments for ADHD, and a lot of knowledge that we have as a child psychiatrist about complementary and alternative treatments comes from his work. Dr. Arnold has published more than 70 chapters, 10 books, and more than 400 articles. Thank you, Dr. Arnold. Next slide, please. Okay, I need to…I mentioned disclosures, which includes, besides NIMH funding and Autism Speaks, also multiple drug companies. And it's important to note that although I'm focused on complementary and alternative treatments, that I'm not anti-drug, and they often work very well together with a complementary treatment, such as behavioral treatment, reducing the need for the dose of medication, reduces the optimal dose with better results. The treatments for ADHD are numerous, and no one person could be an expert on all of them. So, I'll mention as many as I can in this presentation, and I'll give you a few details on the ones that I'm most familiar with. The only established treatment recommended by professional societies for ADHD that is non-pharmacological is behavioral treatments, including things like cognitive behavioral therapy. There are many, many complementary and alternative treatments, sometimes called complementary and integrative medicine. Some of the major categories are listed here. This is not exhaustive, but gives a notion of the various kinds of things that we'll be talking about. First, we need to paint the big picture of ADHD to see how these various treatments fit in. We all know that it's diagnosed by operational criteria in DSM involving two symptom lists. Children have to have six and adults five out of each nine symptom list, and it's a quantitative disorder. It's like hypertension. We all have a blood pressure. Without it, we'd be dead, but some people have too much of a good thing, and if they have excessive blood pressure, it needs to be treated. It's then pathological. In the same way, we all have some of the symptoms of ADHD in moderation, and it's an evolutionary advantage to be distractible enough that you notice a saber-toothed tiger poised to pounce, and to be impulsive enough to throw your spear without thinking, and the same way with an oncoming car or other various dangers, and even in terms of creativity. For example, Leonardo da Vinci became an expert on anatomy, did some groundbreaking work on that because he was distracted in his painting with wondering how to paint the muscles under the skin, how to make, should make them show up, so he started dissecting cadavers and produced the groundbreaking work that we often see in pictures. It's only the impairing extreme that's a problem. If somebody is getting straight A's, has a lot of friends, and is doing their chores, and they may have the symptom count, but it's not impairing them, so you wouldn't make a diagnosis in that case, and the impairment may be dependent on the setting and the expectations of the situation, which brings us to the issue of mimics and things that aggravate or can actually cause ADHD symptoms. One of the chief ones is sleep deprivation. Others are endocrine disorders, nutritional deficiencies. Most mental disorders have the executive function that's the the essence of ADHD. Diagnosis requires a chronic pattern across settings. Of course, it's not, you know, if someone is fidgety and inattentive during a two-hour sermon, that doesn't count. And then the final issue, which is often neglected, is that the diagnosis can't be better explained, the symptoms can't be better explained by another disorder. It comes in, ADHD comes in three flavors. Hyperactive impulse presentation is the best known in the popular mind, and tends to be more likely in toddlers and early school-aged children, tending to become less frequent with age. The predominantly inattentive presentation is illustrated by Agnes, who tells her friend Trout, the next step on my quest to avoid being a complete failure is organizational skills. Her friend Trout says, what will that involve? Agnes says, well, I'm not sure. I had a brochure on it, but I can't find it anywhere. And Trout, who seems to subscribe to the bartender school of psychotherapy, advises her, you should be more organized. And Agnes says, good idea. I'll write that on my chart when I find my Sharpies. Thus illustrating the feckless plight of inattentive presentation, ADHD. It's a very prevalent disorder, one of the most common, and tends to be higher in other disorders. For example, half of people with autism also have ADHD, and it also has, tends to have a lot of comorbidity, other diagnoses occurring with it. Mainly oppositional defiant disorder, but also very close second is anxiety. And then of course, mood disorders, both bipolar and depression. These comorbid co-occurring disorders tend to aggravate the ADHD symptoms. So if you treat those disorders, it helps the ADHD symptoms. It's another approach to a kind of coming in the back door to help the ADHD. I mentioned some of these sources and mimics of ADHD earlier. One thing I'd like to call your attention to is the possibility of endocrine dysfunction in various samples up to 5%, usually lower proportion, but up to 5% have been found to have a thyroid abnormality. And treating the thyroid dysfunction tends to alleviate the ADHD symptoms. Sleep deprivation is probably one of the most common problems in our society. Over the past 20 or 30 years, the amount of sleep at all ages has decreased by about an hour, probably partly due to the screens that are available to keep people up. The amount of sleep needed is for preschoolers should be about 12 hours, school-aged children, about 10 hours, a little over 10, teenagers, a little over nine, and adults, eight or more. We have a problem in that high schools tend to start later than elementary school, which has the situation reversed because normally in adolescence, the diurnal chronological clock advances a little bit. So, the natural sleep cycle is to stay up later and sleep later, but they have to actually have to get up earlier. Some school districts are addressing that by changing around the start times. And that is one non-pharmacological treatment that could, or maybe it might be better called accommodation that could be useful for adolescents. There are a lot of toxins in the environment. Over the past 50 years, or maybe I should say 70, following World War II, we've had a big influx of various chemicals in the environment, insecticides, herbicides, and consumer chemicals, plastics, plastic bottles that leach phthalates into the water that's in them, especially if allowed to be in the heat for a while. And of course, heavy metals, the classical one being lead, of course, but also more recently mercury. And of course, cadmium is the new kid on the block there. One heavy metal that is an essential mineral is iron. And this is the most common mineral deficiency in the world, particularly for preschoolers and adolescents who are in the process of outgrowing their iron stores. And particularly teenage girls who not only are outgrowing their iron stores, but they're often eating very iron deficient diets and menstruating and losing iron that way. Lack of exercise is another issue. Couch potatoes are particularly vulnerable to ADHD symptoms or aggravation of their ADHD. And of course, I mentioned various mental disorders can also mimic ADHD symptoms. And not mimic, they actually have the symptoms, but this is the reason for criterion five that the symptoms are not better explained by another disorder, which of course should be addressed. And note that good treatments for anxiety and ODD and conduct disorder and mood disorders are non-pharmacological. There are also pharmacological treatments, but you could take a non-pharmacological approach, but most studies have indicated that a combination, the multimodal approach, give us the best results and that a lower dose of medication. I want to mention a pitfall that comes from the widely known fact that ADHD is highly heritable. 70 to 80% is shown by most studies. And this includes a very thorough array of approaches, twin studies, family history studies, genome-wide associations, and various things like that. Actually, there's a risk score factor, genome genetic risk factor, polygenic risk factor that's been developed. However, we can't conclude from that, that it's only 20% environmental. And therefore, there's not a whole lot we can do about it. That's genetic determinism. Because let me give you an example with PKU, phenylketonuria. It's a well-known, well-established inborn error of metabolism, a lack of the enzyme that converts dietary phenylalanine to tyrosine, a necessary precursor of many neurotransmitters. And this backs up the phenylalanine into an alternate pathway that's toxic so that this is eventually fatal and very disabling in the meantime. But this gene is only expressed in an environment where phenylalanine is in the diet. So, if phenylalanine is removed from the diet of these babies, they can have a pretty normal life. That's why we do the diaper test, of course. So, the fact that ADHD is 80% heritable means that the environmental contribution is between 20% and 100%. And there's accumulating evidence that there are various toxins in the environment, especially insecticides in their residues, their metabolites, that might be contributing to the epidemic of ADHD that's developed in the past 50 years or so. These are from very reputable sources, National Institute of Environmental Health Sciences, and peer-reviewed journals. One of the chemicals that's in the food supply are the food dyes, artificial food colors, that are classified by the FDA as generally regarded as safe. That's grass, generally regarded as safe. The studies on which that conclusion was based did not consider behavioral effects and tended to focus more on cancer and use doses lower than what are consumed these days. You can see that the per capita consumption from the FDA data has increased from 1950 to 2010 and continues today as about five times, a five-fold increase in the consumption. A more modern study, this has been a controversial issue, and there have been consensus in all the conferences and FDA conferences to evaluate the situation. The thing is, the effect size is small if you look at a large sample, but a meta-analysis, in fact, two meta-analyses have shown a small but significant effect. And there is a biological basis for this, illustrated, I'll show you three examples of it. One is interactions with nutrients. Wesnes, back in the 90s, did a couple of studies that I think should have received more attention and more follow-up, further investigation. He did a small study first with 10 hyperactive children versus 10 controls, and then repeated that with a larger sample later on. In both studies, the children who were classified as hyperactive, the ADHD term had not yet come into vogue. In both cases, the children with hyperactivity showed lower serum urine, nail levels of zinc. And then with a tartrazine challenge, the serum and saliva zinc went down, and urine zinc went up in those with hyperactivity and not in controls, indicating that the tartrazine elicited some zinc wasting, excessive excretion of zinc. And this zinc wasting correlated with behavioral deterioration in both of those studies. The Southampton studies by Stephen's group in the UK is, I think, pretty well nailed that the food dyes and possibly sodium benzoate as a preservative. Do have a deleterious effect on behavior, very small. But significant. In samples of 100 or so. Over several 100 these, these were pretty large samples. They took all the school children and they didn't necessarily have a diagnosis of ADHD and that the diagnosis didn't make a big difference. On on whether they showed the effect. What I'm going to show you here is the genetic basis for this. As I mentioned, the genes are only expressed by interaction with the environment. So here's a gene that's expressed by interaction with the food dyes. On the left, you can see that this histamine gene. 939 T 939 C. For those that have the C allele present either homozygous or heterozygous. Don't show a response to the dye challenge. The red circle is mix a mix B is a larger dose of the. Dye, which is shown by the blue square and the green triangle in each case here is placebo. So, if you see a present, you don't get any any effect. But with the C allele absence, those who are homozygous T have the homozygous T alleles. You can see this separation of of placebo. The green triangle from the two doses of the dye. There was one other histamine gene that also showed an effect and one dopamine gene that showed an effect. This was the most dramatic difference here. The the prevalence of this having a C allele absence, that prevalence in the population was about 60%. So, this actually is a public health problem, not just an ADHD problem. There was some physiological evidence, brain electrical activity, mapping showing with the provoking food that had the dye in it, an increase in the frontal temporal beta one band, which could also be associated with anxiety. And the behavioral symptoms correlated with that. However, the this was the challenge was not blinded. So, there is that outside possibility. The parents could have influenced the child's EEG. So, the conclusions from this, there's a small deleterious effect regardless of diagnosis. And it was replicated twice. And there's a possible mechanism identified. The magnitude is reminiscent of subclinical lead poisoning. That is a lead level of under 10 micrograms per deciliter, which in Needleman's work had a correlation of an effect size of 0.17 after correcting for social factors. So, this and of course, lead was banned from gasoline based on that research. Trying to get a warning label on foods has been a monumental task. It's been done in Europe already, but we can't get it done in the US because of industry pressure. So, one thing to keep in mind is that this is not confined to ADHD diagnosis, but a possible small effect on many children in the classroom can have a big effect on the classroom climate. And of course, under stressful or chaotic conditions, kids with ADHD have a lot more problems. Stress makes blood pressure worse. It makes ADHD symptoms worse. Here's a provocative little thing that has not been pursued adequately that I'd like to share with you. On the left is a map showing the prevalence of ADHD diagnoses. The lightest color has about half the prevalence of the darkest color states. Difference of between 5 and 7 percent diagnosis versus 14 to 16 percent diagnosis in school age children. On the right is a map showing solar intensity. Red being the most solar intense and highest in the Southwest, not unexpectedly. So, what do you notice? Well, there is quite a congruence between high solar intensity and the low rate of ADHD. So, what could be causing that? Well, one thing to consider is altitude, because those same Southwestern states tend to have a higher altitude. And indeed, altitude correlates with the ADHD diagnostic rate. But if you co-vary the solar intensity, the significant altitude association disappears. It becomes non-significant. If you co-vary altitude, the significant solar intensity association with ADHD prevalence persists. It survives that. So, what else could be going on here? Well, one obvious thought is vitamin D, which, of course, is produced in the skin by solar radiation and is the main source for many people. Not many foods contain vitamin D. Milk is enriched with some vitamin D, but not everybody drinks milk. And some people have lactose intolerance and so forth. So, what else? Well, those more solar intense climates also tend to be not only hotter, but also drier. And with a drier climate, you get a difference in flora and fauna. So, it could be possibly a difference in intestinal microbes or things like fungus or infections. Perhaps the Lyme disease bacteria of eastern deer ticks from eastern deer ticks has a different behavioral effect than the rickettsial infection from Rocky Mountain spotted fever, also tick-borne. Or looking at the fungi, maybe Ohio Valley lung from histoplasmosis has different behavioral effects than San Joaquin Valley fever from a different fungus. So, this is a very provocative thing that may point to new treatments in the future. Okay. All right. Let's talk a little bit about how we evaluate the non-pharmacological treatments. Most of them are difficult to blind for randomized clinical trials, which is the gold standard for evaluating treatments. It takes a lot of ingenuity to try to accommodate the blinding. And this is a problem the behavioral treatments have along with other things. Some of the nutritional treatments, the supplement treatments, they can be blinded easily with placebos, but not the others. Therefore, the evidence varies widely in quality, and partly because there's so little investment in studying them. Many of them are not patentable, and so there's little interest in venture capital. Some of them are just common sense or good for health in general. So, we have this sex versus rude criterion, which states that a treatment is safe, easy, cheap, and sensible. Doesn't need as much evidence of efficacy to try it in an individual patient as one that's risky, unrealistic, difficult, or expensive. Notice the conjunctions, which are, you have to have all four to be sex. You have to have only one to be rude. Behavioral treatments are well-established. They're recommended by professional societies and are generally considered evidence-based, with some exceptions. Parent training is well-studied and very effective for the hyperactive, impulsive behavior and associated oppositional defiant behavior and conduct disorder. Classroom modification is pretty effective, not only for the child with ADHD, but for the whole class. And this needs to be distinguished from classroom accommodations. Accommodations would be like giving somebody a crutch rather than physical therapy to improve their gait, adapting the environment to fit the pathology rather than trying to improve the pathology. But classroom modification, things like whole-class reinforcement for the behavior of each child. And if everybody stays in their seat, they can have whatever is rewarding to that class. Social skills training is good for those who notice that their inattention to social cues is resulting in a problem keeping friends. And cognitive behavioral therapy has now been shown in several studies to be effective, first for adults and then for adolescents. Coaching, to my knowledge, doesn't have any randomized clinical trials, but it's kind of a common-sense approach. I can illustrate it with an anecdote. We published the first report of adults with ADHD in 1972 in JAMA. And that patient came back to me after a couple of years, after graduating from college, and said that he was getting in trouble with his boss. And the reason was that he was getting out of his seat and wandering around the room. He had a job as an accountant, a poor choice of occupation for somebody with ADHD, as an accountant. And he was sitting at one desk and rows of desks in a huge office. And he would keep getting up and going to the water cooler and various things. So he had put himself back in a classroom and was getting in trouble with the teacher. So I did something that at that time no respectable psychiatrist would do. I don't claim to be respectable, but I told him to change jobs. And if I had reported that back in the 70s, there would be some gasps of exasperation about it. But it's now become pretty much accepted to provide some occupational advice to people with ADHD, to find a niche where they can do well. He came back two months later, said he quit the accounting job, got a job as an insurance salesman, and was doing very well. His energy and enthusiasm and nice personality was serving him well in that occupation. So coaching is very widely used now without a lot of supporting scientific research for it. But it's a common sense kind of thing. The coach kind of becomes a prosthetic ego for the patient with ADHD or a prosthetic executive function. And the ability to plan your work and work your plan, executive function. One behavioral treatment that I think has not been adequately utilized, although it's very effective in my experience, is the daily report card. It's important in development. And there are websites that can tell how this can be done, as well as books. The example here shows five different behaviors stated positively that are checked by the teacher three times a day. It could be four. You don't want more than five, but it could be four or even as few as three if there are three really important ones. And then the child takes this scorecard home each day, presents it to the parent to be rewarded by a menu, a reward menu that's been developed between the parent and child. And it's important to ask the child what's reinforcing, what will motivate you to behave this way in school, according to this report card. And this is like a Chinese menu where you can select one from list A and two from list B or whatever. List C would be the most rewarding. So I highly recommend that one. The dietary nutritional treatments are some of the most common and extremely varied and numerous. They come in three types. One is an altered diet. There's some presumptive evidence, I'd call it, for Mediterranean diet or whole foods diet. It hasn't really been put to a good randomized clinical trial test, to my knowledge, but it's presumptive. And the nice thing about it is it's good for general health. You know, what's to not like about it? Okay. Then the other two types are either taking things away or adding things. So the restrictions include dyes and other additives. We've already talked about those. Sugar. And then an extreme of this is the oligoantigenic diet. I'll show you in a minute. And then supplementation of various nutrients and herbs are often included in this. I'm not going to talk about herbs because they're actually crude drugs. So it's not a non-pharmacological treatment. Also, the quality control is not consistent. So you may get contaminants. You may get varied potencies of the different lots or batches, and certainly between brands. So it's a class that I don't recommend, and it's actually pharmacological. The oligoantigenic diet is sometimes a few food diet because it's easier to list what you're allowed to have than what you're not allowed. And this should only be, oh, Brassica, by the way, is things like Brussels sprouts, kale, broccoli, cabbage. All the goodies that kids savor so enthusiastically if they don't have anything else to eat. This diet is also deficient in calcium and maybe some other things. So you have to add the vitamin minerals to it and should not be used for more than two weeks as is. If there's no improvement in two weeks, you give up the whole thing. If there is, then you start adding things back one each day and record whether there's a bad reaction or not. So you develop two lists, the foods that are okay and the foods that are not okay. Sugar restriction has had a bad press despite the well-known health dangers of sugar. Due to some studies that were done back in the 80s in which aspartame was used as a control condition, at that time it was not known that aspartame could adversely affect behavior and other health issues. This is becoming increasingly known now about aspartame. It's a bad thing to use and it's in a lot of diet drinks. This study was done by Wesness in the 90s and I think deserved more attention and more pursuit, more follow-up studies exploring it further. Very interesting results because he took a normal classroom, a regular classroom, which probably had one or two kids with ADHD in it, but most of them were essentially normal kids, and he tried out different breakfasts. The red line represents what happens to inattention that rises over the course of the morning till noon with no breakfast. And then if you give the kids a whole grain cereal breakfast with milk, you get the green and blue lines, which show a blunting of that increase of inattention over the course of the morning. You are going to get some increase of inattention because that's well known. That's why they have arithmetic and reading the first few things in the morning while the kids are paying better attention. But obviously, the breakfast had an effect on it. So, the school breakfast programs are a very good thing for learning as well as for children's health if the right food is provided. If you substitute a glucose drink with the same number of calories as the whole grain breakfast, you get actually a worsening of the inattention rise. It happens faster and reaches the same peak as no breakfast. So a high sugar breakfast is worse than no breakfast at all. Okay, let's talk a little bit about adding things. We talked about restrictions, taking things away from the diet. How about adding them? 20% of dry brain weight is omega-3. And most of this is DHA, there's some EPA. DHA, of course, docosahexaenoic acid. The 22 carbon, six unsaturated fat, bonds acid, and EPA, icosapentaenoic acid, the 20 carbon with five unsaturated bonds, and some omega-6. Now, ideally, the omega-3 would be in that proportion, up to 21%. But if that is not available, mammalian metabolism cannot make these, they have to be ingested. If that's not available, omega-6 polyunsaturated fatty acids will be substituted. It's like putting high-performance, low-octane gas in a high-performance engine. It will run, but not as efficiently. These fatty acids are necessary for normal brain function in several ways, membrane fluidity, Nespr receptors, and the 20 carbon acids provide, they are precursors for the prostaglandins, leukotrienes, thromboxanes, and other icosanoids that regulate cell communication and immune regulation in particular. And we know that there is some immune irregularity in ADHD, and shown by several studies. This shows what happens. At the top, we have the little lake acid, which is the omega-6, you might say, beginning molecule, and the alpha-linolenic acid, the omega-3 beginning molecule, which then with intact metabolism, no deficiency of enzymes, normal metabolism genetically, delta-60 saturates, then adds unsaturated bond to these, and they compete, the two series, omega-3 and omega-6 compete for the access to this enzyme. And then an elongase enzyme, not shown here, adds two more carbons to them, resulting in gamma-linolenic acid, and on this side, an analogous acid in the omega-3 series. This acid is important because, over here on the left, because it is the precursor for the series one icosanoids, prostaglandins and so forth, which are both inflammatory and anti-inflammatory. Then another desaturation, another unsaturated bond is added by delta-5 desaturase, and this results in arachidonic acid in the omega-6 series, which produces pro-inflammatory icosanoids, which can be a problem if not balanced by the anti-inflammatory icosanoids from EPA over here on the right. Then elongase adds a couple more carbons, and you can get DHA, docosahexaenoic acid, on the right. This is the one that's the ideal building block for neuronal membranes, up to 20%. There have been three meta-analyses that show a small but significant effect of omega-3 fatty acids for ADHD symptoms, and that's usually an effect size of 0.2 to 0.4. Up to 0.5 is small, 0.5 or more is a medium effect, and 0.8 or more is a large effect. In one sample, they were given also daily moly vitamins and minerals, and this was 72 children selected for mood disorder, but most of them also had ADHD, and they were in a two-by-two randomized clinical trial with psychoeducational psychotherapy versus no intervention for the other treatment, omega-3 versus placebo for the treatment part we're interested in. The omega-3 helped executive function significantly more than the aggregated placebo, and this was with approaching a large effect size, certainly more than moderate, and those with ADHD showed even better gains than those without ADHD. Although this was in the children selected, not selected for ADHD, selected for mood disorder, it's important because executive function is the common denominator here. As I mentioned before, executive function is the basic essence of ADHD, difficulty planning your work and working your plan, and this was a measure of that, and if you can help that, you go a long way towards helping the individual with ADHD. There was also a genetic finding in that. On the left is the fatty acid desaturation enzyme two, I'm sorry, one, this is one, and this shows that at baseline on the left, the placebo group and omega-3 group had about the same level of the EPA and DHA, but once they were supplemented, those who got the supplement, the green bars, increased their level of EPA and DHA, placebo did not, of course, as expected, but the thing is that the homozygous GG allele here had a bigger response than the, either the homozygous CC or the heterozygous CG. That situation was reversed with the FADS2 enzyme, fatty acid desaturase two, in which the homozygous GG enzyme had the least improvement in blood levels of the omega-3s we were interested in. The AA homozygote had the best response there. So the clinical application, we can say that omega-3 fatty acids pass the sex criterion, and EPA may be the most important because it's the precursor of the prostaglandins and other eicosanoids, but it's best to stay with a mix of EPA and DHA because some people may not be able to increase EPA, add the unsaturated bond and the extra two carbons to get DHA. It's a fairly cheap supplement. You can get fish oil for about $20 for a six month supply. Make sure the label says mercury-free or USP. USP means US pharmacopeia, which means it's drug grade quality, it's pure. The dose should be about a gram a day of EPA or DHA. Some people recommend more, but there's a hint in the study that I showed you results from a little while ago. There was a hint that those who were larger and older had a better result from it, which means that maybe the dose was a little bit too high for the younger, smaller kids. You have to be patient with it. It takes three months to the results and it's not dramatic like a stimulant drug. And you have to pay attention to other fat intake. The ratio of omega-3 to omega-6 is important. And the trans fats are deleterious, of course. They compete for the enzymes and make sure that they're getting vitamins and minerals. And I'll talk more about that in a minute. Micronutrients have, in the broad spectrum, there are over 30 vitamins and essential minerals known. There may be others unknown because the most recent ones were just discovered less than a hundred years ago. There've been a lot of research, but most of them have not been randomized clinical trials. But fortunately, we have three randomized clinical trials for ADHD, one adult and two child, showing pretty much the same results, which makes it technically an evidence-based treatment. In the most recent one, the North American study with 126 kids aged six to 12, the micronutrients showed a 54% reduction or showed a 54% response rate on the CGI, the clinical global impression of improvement of one or two, which is much or very much improved, which is three times the rate found in the placebo group. And this was very highly significant. Now, there was another primary outcome in the same study that did not show significance, tended the right direction, the same direction. And that was the ratings on the child and adolescent symptom inventory by parents. However, there was another measure based on parental observations, a secondary measure that did show some interesting results. And the red crosses here, the red cross lines here show the means for the micronutrient group on the left, the placebo group on the right, and the red dash horizontal line represents no change on the ratings. These were behavioral observations of target symptoms selected by the parents that were quantified at baseline mid-treatment and end of treatment by frequency, duration, intensity, and consequences. And then rated by a panel of three blinded child psychiatrists with five being the no change and one being completely cured, the symptom completely gone. So the four is minimal improvement and the three is definite improvement and much improved down here for the two. And these dots represent the average of the three-shot psychiatrist ratings for individual children. So looking at this in a little more fine-grained way, we have 19 in the placebo group out of 55 who showed no change or actual worsening compared to only 16 for the micronutrient group out of 16 out of 69. And in contrast, only 14 of the placebo group showed definite improvement or better compared to 26, almost twice as many in the micronutrient group. We then subcategorized these parent-selected symptoms. Oh, this just shows the same thing in a visual form. Notice that the improvement due to micronutrients occurred in the second month. The first month, this is just placebo effect, but you get the micronutrient response in the second month and there may be further improvement on after that. In fact, our follow-up study did suggest that. But I wanna show you the categories which show some interesting things that might guide choice of who to try this treatment for. The 91 of the parent-selected and inattentive symptom as the basis. And here, this green diamond represents micronutrient and the circle, I think it's a blue circle, represents placebo for each of the categories. Among these 91 with inattentive selected symptom, there was a highly significant response with an effect size of medium. And then for those with anxiety and depression, remember the comorbid problems that they have, there was a very large effect there, 0.8, and a significant response for anxiety and depression, the internalizing comorbidity. These others were not significant, but showed tendencies in the same direction. This was a borderline finding here for aggression and autistic symptoms. Some of the parents selected, although none of the children had an autism diagnosis in the study, there are a lot of autistic symptoms in an ADHD sample. And those were selected by some of the parents, 37 of them, and they tended to show a response, but because of the small number, it wasn't significant. Here is a contrast with hyperactivity impulsivity. I wanted to show you in contrast to the inattentiveness, which showed a highly significant response. The hyperactivity and impulsivity was only a negligible response, not significant at all. Now, this multinutrient, broad spectrum multinutrient approach has been shown in some other studies of related problems to also show an effect. This was a randomized clinical trial in young offenders and showed significantly fewer rule infractions and violent acts, which is shown graphically here. Before supplementation, both the active blue and the placebo group showed the same amount of problems and they decreased significantly more during supplementation in that group. This was replicated in a Dutch sample, a different sample, pretty much the same kind of results. And a cognitive function in the study in people, adults that were thought to be vulnerable to cognitive deterioration. The centrum silver showed a significant improvement in cognition, memory, and executive function. And it's important to notice how many different things. These results were obtained with a broad spectrum nutrient. They work together. One single one doesn't do the job. This centrum silver is not quite as good as the more expensive formula used in the MADI study as the results show with the categories, but it's enough to do the job for many people. Okay, so to summarize, the omega-3 fatty acids have a small significant effect. A broad spectrum micronutrient showed effect in three randomized clinical trials. And in the most recent trial, the baseline measure of symptom, ADHD symptoms, correlated negatively with vegetable intake and the best response to the supplementation was in children who were eating more vegetables. Apparently there was something in the vegetables that worked well together with the supplementation, possibly fiber, I don't know, or maybe other vitamins that haven't been discovered. Okay, the Mediterranean diet has some encouraging results, sugar restriction as reasonable, and artificial diet was sort of reasonable. Lifestyle treatments, exercise, particularly sports. Sports have some advantage over other forms of exercise because they are training cerebellar vestibular function, which has been shown in some studies to be deficient in ADHD. And they're also exercising the mental capacity to plan. For instance, in baseball, if you're on base, you have to think about what to do next. If a pop fly is hit, or if a base hit is made, or if an out is coming, whether to try to steal a base, what you're gonna do on various contingencies. So you're working your mind as well as your body. And there's some suggestion that that helps to be using both at the same time. Sleep hygiene. We've talked about the hours of sleep needed, and it's important to avoid blue light emitting screens the last hour before bedtime because that mimics sunlight and sunlight inhibits the release of melatonin by the pituitary, which is the signal to go to sleep. There's a long sleep latency if you go straight to bed from looking at a blue light emitting screen. Meditation and yoga show some promising results. Again, a little bit difficult to blind that. What do you use for controls? The open green spaces is something that I forgot to mention as a possibility for the... When I showed you the map of the solar intensity correlating with other things, it was a possibility that in the sunnier climes, people get out more into open green spaces, and maybe they're picking up soil bacteria there, which could be important. There's one study that recently came out just in July showing a beneficial result from fecal microbial transplant, poop in a pill, and it doesn't sound very attractive, but it may be a treatment of the future, still in the developmental stage. Psychobiotics, which are prebiotics that have an effect on mental function, also are a possibility. There are three ways the gut communicates with the brain, through the vagus nerve, through immune function, and through metabolites that are made by the gut bacteria. A new wave is electronically assisted device-based treatments. Trigeneral nerve stimulation looks encouraging, but not yet prime time. Neurofeedback is very complicated and controversial. The theta-beta ratio does not seem to show much, but slow cortical potential may have a possibility, or sensory motor rhythm. Transcranial magnetic stimulation and direct current stimulation are still experimental. Theta-beta ratio biofeedback is essentially non-specific effects. There's a big improvement found if you have a good sham, a good placebo, you can get a huge effect size, 1.5, which is due to non-specific things, not the actual neurofeedback itself. And one thing it does do, though, there was, in the secondary outcome, there was a significant benefit in lowering the need for medication. In the follow-up, in the 13-month follow-up, about 10 months after the end of treatment, the groups that got neurofeedback, the blue dashed line, needed significantly less medication than those who got the placebo-controlled treatment. Trigeminal nerve stimulation looked pretty good in a pilot trial. This dotted blue line represents the placebo, lower is better here, and the gold orange line represents those who got the nerve stimulation. Interesting thing, this is only a four-week treatment, and with this kind of results, and the follow-up looked like, that I had a peek at, looked like it was going to maintain that improvement. Okay, to summarize, ADH is a quantitative diagnosis, so anything that lowers the severity helps. It's often aggravated by comorbidities, so treating those disorders helps. Many treatments, only two established, meds and behavioral therapy, and others have varying degrees of evidence. We use the sex versus root criterion to try to decide whether something is worth trying with an individual patient, and these treatments, in my estimation, pass the sex criterion. Behavioral treatments, of course, by default, they're established treatments. Reasonable sugar and diet restriction, doesn't have to be spartan, but reasonable restriction. Omega-3 supplementation, or eating wild ocean fish three times a week, either way. Broad spectrum, multivitamins, minerals, sports, and other exercise, the sleep hygiene, and limiting the screen time before bedtime, so that the time in bed is actually spent asleep. Meditation and yoga, progressive relaxation, have some encouraging results. Very difficult to blind, so we don't have compelling evidence on them, but they're good for general health. Vegetables, Graham always right, eat your veggies. Whole foods and prebiotics, and probiotics, not necessarily expensive ones, but yogurt and other fermented foods. There are other promising ones to come online, and I would predict that in five or 10 years, we will probably have some treatments based on microbes and on devices, electronic devices, and probably more personalized, be able to pick people by genetic profile for which treatment they're likely to respond to. Sorry, I went over time, but this is a very complex topic and very exciting. Thank you. Thank you so much, Dr. Arnold, for a fantastic webinar, for fantastic, a lot of learning opportunities for the audience. A quick reminder to our audience to submit your questions in the Q&A area at the bottom. I do have a few questions, Dr. Arnold, if you're ready. Yes, sure. Okay, so the first one we have here is, it says, I'm curious to know if you have seen any improvement in ADHD symptoms with an increase in protein intake, which could either be to meet the daily protein requirements or otherwise? Would you repeat that? I didn't catch what it was. Oh, it was asking if you've seen any improvement in symptoms of ADHD with an increase in protein intake. Increase in? Proteins. Oh, in protein, yes. Okay. That's very, I'm glad you asked that question because we did some work with amino acids back in the 70s and found some trends, but they weren't significant. And one amino acid that somebody did find a significant effect from was SAMe. The tryptophan and tyrosine showed a little bit of a tendency of improvement, but the SAMe showed a significant effect. However, in a pilot study. However, this was never replicated in a compelling way, and there are risks to it because the toxic breakdown, it's essentially supply-side economics of neurotransmitters. You supply more than neurotransmitters by providing more substrate, but then they get broken down, and you have these toxic products in the cells. So there actually is a risk to the amino acid approach. Now, proteins, getting a high protein diet is a little safer because the digestive system and the liver will help to process that in a more natural way. And in the ICAN neurofeedback study that I showed you the results from, one of the things we had all the kids do, we gave them a brochure called Eat Smart. And one of the things recommended in that was a high protein breakfast. And we did find in some secondary analyses there that those who ate more protein had a tendency to do better on the primary outcome, the parent-teacher rated ADHD symptoms. And it wasn't highly significant, but it was sort of a hint. And it occurred the same regardless of whether they were in the placebo group or the neurofeedback group. So we think that may be one of the things contributing to the, one of many things contributing to that good outcome. I would say it's important for, to get at least the recommended daily amount, daily requirement of protein, but I wouldn't go for an all-protein diet or extreme input of anything, including proteins. Thank you. Thank you so much. On somewhat similar note, you know, there's the question about excluding or restricting food diets, right, that you mentioned. And sometimes, you know, clinically you come across parents who would go to really significant lengths to have their child consume a diet-free diet, sometimes to the point where the pursuit leads on to much more anxiety, both on the parents and the children. And is it wise to suggest sticking with a balanced diet instead in such cases clinically? Well, you need a balanced diet, but you should be able to get that without the food diets. Food diets were invented in the last hundred years. So for centuries and centuries, humans did fine getting a balanced diet without the dyes. And you can get those, you can buy them, places like Whole Foods, for example. But if you just read the labels, and more and more companies are putting out a choice between the dyed and the undyed things. So it makes sense to read the label. And also remember, there's a dose effect here. So you don't have to, you know, if a few dyes slip through, it's probably not going to be the end of the world. The thing is to cut down on the dose of them, avoid the highly colored things. You can get M&Ms that are not colored, for example. You can get, you can buy yogurts that aren't colored. You can buy various things. Of course, raw vegetables are not colored and undyed. And the vegetables are one of the things I'd recommended earlier, remember. And meat is generally not dyed unless it's processed. Things like weenies, wieners are dyed. Some sausages are dyed. And you have to read the label. Interestingly, citrus fruits are dyed. So be sure to peel them and don't eat the peelings. So you can just, by reading labels and being a little bit thoughtful, you can avoid the dyes. Okay. Yeah. Very interesting. Now on the topic of omega-3 fatty acids, you know, you talked about the EPA and DHA. Now, one of the challenges, you know, when you are looking for a combination is, you know, what's available out in the pharmacies and otherwise they're not regulated, right? So what happens is a particular brand may create, you know, a different bioavailability versus something else. Is there some... That applies to herbs, but the fish oil, it's a food. And it comes from the fish. And you just read the label. Did they add anything else to it? Well, they might've added vitamin E, which is a good idea because it's antioxidant. And you don't want the fish oil to, or krill oil, any marine oil. You don't want it to oxidize because these polyunsaturated fatty acids are used by varnish and paint makers as so-called drying oils. They'll oxidize into a film and you don't want that happening to the stuff you're ingesting. So first thing, most desirable would be to eat wild ocean, oily wild ocean fish, like cod, sardines, mackerels, and salmon three times a week. But a cheaper way of doing it would be to get the fish oil, make sure it's refined to eliminate mercury and, or USP, and check to make sure they didn't put anything else in it other than the selenium to prevent the, vitamin E rather, to prevent the oxidation. Thank you. And then the other question is about the dosing. I know you refer to one gram dosing. Is there any difference for children versus adolescents versus adults? We need research on dosing and on ratio of EPA to DHA. The studies I've seen get results with a gram a day. I think less than a gram a day is probably not useful. Some of the children's capsules have a half gram, so they should take two of them. But most of the adult capsules that I've seen are 1.2 grams, which is fine. And some people recommend two or three or four grams a day. Some studies are done with four grams a day. I have not seen compelling evidence that you need that. I haven't seen compelling evidence what the ideal dose is. This just based on my clinical instincts, on the data I've seen, I recommend a gram a day. Thank you. Now, you know, talking about the minerals and the micronutrients. So, I think used to be zinc showed up as something that stood out in the past in some of the studies with ADHD. You talked about the MADI study with, you know, and where you mentioned a mix of micronutrients, right. That would be helpful. Yeah, broad spectrum. You want something, you want to make sure it has at least 20 different vitamins and minerals in it. Ideally 30. And there are two commercially available ones available on websites that have all 30 vitamins and minerals. But things like Centrum Silver or Centrum Junior have 20 some in them, which is acceptable. And there are store brands that would mimic that, would be the same thing. It doesn't have to be particularly that brand. Just read the label and make sure that there's 20 or more listed. Understood. Now, another thing that you talked about was the psychobiotics and, you know, you refer to them at the very end. I think there was another study more on the autism spectrum area where there was conversations about low fecal chymotrypsin levels because they were not able to convert into neurotransmitters because of that. You know, could that be useful in autism? Are there any such studies in ADHD that you're aware of? I shared one that was in both ADHD and autism that came out in July. There hasn't been much done with ADHD on this. I can't really cite another study. We need to look at it more. And we also need a study that I can't get funded to look at what the the stimulant drugs do to the gut microbes. A lot of different chemicals alter the gut microbiota. And it's possible the stimulants also do that, but nobody's ever looked at it to my knowledge. And also what they do to nutrients. Do they affect absorption of nutrients or metabolism of nutrients? We know that the tartrazine, as an example, affects the metabolism of zinc. And the dyes and drugs are somewhat related. They come from, yeah, a lot of the same ones come from coal tar. So. So we. Interesting. And then I have one last question here is about video gaming for individuals with ADHD. You know, there's a commercially available video game that talks about improvement in ADHD. Is that something? There are even there are even ones that have been approved by the FDA. But remember that the FDA has a different standard, a different hoop for drugs and anything ingestible than it does for devices. And essentially, devices just have to be shown to be safe. And there I won't name brand names, but there are some that have been approved on the basis that they changed some cognitive lab test that was related to what was being trained on the video game, but didn't show a difference by parent and teacher ratings. And so you have to be a little wary of that. If they're real cheap and easy to do, OK, you might as well do that as some other video game, you know, you consider recreation. And if it helps on top of that, that's gravy. That's fine. But I wouldn't pay a lot for it. Pay a lot for the current state of knowledge. Thank you so much for for those answers and for your wisdom and the years of experience in the field and truly appreciate the audience for being with us. And if you could switch over to the next slide for me, credit. So this is the next one. So we just wanted to mention also that there will be a follow up email that you'll receive within an hour or two of the webinar concluding, which will have information and instruction on how to access your credit and certificate. And if you have other questions or other suggestions, please send those to this email address educme at psych.org. Again, thank you so much, Dr. Arnold, and thank you everyone for joining us this afternoon. Take care. OK, thanks.

ADHD

non-pharmacological treatments

parent training

cognitive behavioral therapy

lifestyle treatments

exercise

adequate sleep

healthy diet

omega-3 fatty acids

broad-spectrum micronutrients

research

personalized approach