Iron Levels, Sleep Disorders and ADHD

The aim of this post is to investigate the potential connection between ADHD and sleep disturbances, and how a deficiency in iron levels may in fact be a possible triggering factor for both disorders. We will be drawing heavily from a very recent article by Cortese and coworkers on Sleep Disturbances and Serum Ferritin Levels in children with ADHD. Iron typically does not exist in the body in its free form, but rather in the form of larger complex molecules such as hemoglobin or ferritin (think of iron being "encaged" in these larger complexes).

We have previously dabbled in the field of ADHD and sleep issues in earlier posts, such as a recent one entitled CREM gene, Melatonin and ADHD. I also plan on doing further posts on the connection between ADHD and Restless Legs Syndrome, which is also believed to be connected to low iron levels. It is interesting to note that there may also be an underlying genetic component to this association as well.

Some of the major findings of the Cortese article are listed below:

1. Children with iron-containing ferritin below a concentration of 45 micrograms per liter (don't worry about these numbers yet, we will be discussing them further down) had higher levels of ADHD symptoms as well as sleep disorders than those above this concentration. We must consider the fact that sleep disorders appear at higher levels in individuals with ADHD than in the general population. With regards to ADHD, these results are in agreement with another prominent study by Konofal on Iron Deficiency in Children with ADHD. According to the study, among the different sub-categories of sleep disorders, the only disorders associated with a deficiency of the iron-rich protein ferritin were Sleep Wake Transition Disorders (SWTD). These SWTD's are characterized by "abnormal movements in sleep", according to the Cortese article.
   
   Carrying this a bit further, we find that iron-related sleep disorders are also seen in children with autism, a disorder which shares a fair degree of overlap with ADHD on a genetic basis as well as structure and function of specific brain regions and an overlap of motor problems and other symptoms. It is also important to note that iron is a critical factor for the synthesis of the brain chemical dopamine (which is often at lower levels in the areas between nerve cells in specific brain regions of individuals with ADHD), and that dopamine related functions are connected to motor control behaviors.
   
   
2. While it may be tempting to assume that these problems may be fixed by iron supplements, we need to be careful, especially based on the content of the study. The Cortese article indicated that none of the children had anemia. Keep in mind that anemia comes in multiple forms, with the most common being iron deficiency anemia, which can be caused either by a lack of dietary iron (a possibility) or inflammatory conditions such as parasitic infections (which was not seen in any of the patients). It is interesting to note that serum ferritin is also a bio-marker of inflammatory processes, so the fact that no inflammatory conditions were present was a crucial control for the Cortese study.
   
   While none of the children in the study exhibited outward signs of nutritional deficiencies, diet-related anemia is the result of prolonged deficiency in iron and other supporting nutrients, so it is entirely possible that the children in the Cortese study were simply not far enough along in their iron deficiency situation for anemia detection. However, we must be careful before administering iron supplementation as a potential treatment option. While studies have shown that iron supplementation can effectively reduce the occurrence of periodic limb movements, we must watch out for the toxic effects of rampant iron supplementation (for a general upper limit for iron supplementation, please click here).
   


3. Nevertheless, the effects of an iron deficiency can be drawn out, and symptoms can be delayed. Ferritin, which, mentioned above, is a type of storage protein for holding iron in the body, typically exists at a concentration roughly between 30-45 millionths of a gram (micrograms) of ferritin protein per liter of serum (serum is the watery part of the blood which does not include blood cells) in children, but can be significantly higher in adults. While this number may not mean much on its own to most of us, we should be more cautious about the next number: 12 millionths of a gram per liter of serum. If the concentration of iron-containing ferritin protein falls below this critical level, then hemoglobin synthesis begins to be impaired.
   
   While the difference between the 45 micrograms/liter and 12 micrograms/liter indicates that there is some room to play with between low iron levels and a hemoglobin deficiency, the same study that found the 12 micrograms/liter cutoff point also found that much higher levels than 12 micrograms/liter must be reached before iron stores (and subsequent hemoglobin synthesis) resume to full levels. Therefore, the complex restoration of iron balance is not something that can be typically achieved overnight or even within a week.
   
   Furthermore, the Cortese paper suggested that the transfer of iron stores in the nervous system may also take sufficient time to build back up and may depend on significant iron storage levels. In other words, the effects of iron supplementation and treatment and restoration of iron-containing complexes may not be felt immediately, especially in the brain region and the central nervous system, which is bad news for those suffering from ADHD and related disorders. While no exact quantity was specified, the 30-45 micrograms/liter concentration range seems to be a good starting place for children.
   
   
4. While many comorbid disorders are predominantly connected to one of the three major subtypes of ADHD (inattentive ADHD, hyperactive/impulsive ADHD or combined subtype ADHD), the sleep disorders in the Cortese article showed no particular subtype affiliation.
   


5. Another recent article may shed some light on the subject as far as to why serum ferritin levels and sleep disturbances may occur. We have previously reported the possible connection between ADHD and Celiac Disease and that Celiac Disease can Cause ADHD Symptoms. Picchietti and coworkers reported that treating patients who had restless legs syndrome and low serum ferritin levels but not overtly low iron levels responded well to a gluten-free diet (the most common treatment for celiac disease). Similar associations were seen in other studies involving iron deficiency and celiac disease (as well as generalized intestinal absorption difficulties).
   
   In other words, celiac disease and other digestive issues may be the underlying factor in individuals who exhibit low serum ferritin levels, but not abnormally low overall iron levels, and may contribute to negative symptoms such as restless legs syndrome. Unfortunately, the while generalized gluten-free diets can single-handedly restore the body to pre-anemic conditions, the process can take time, up to 6-12 months.
   
   It would be interesting to see how many of the patients in the Cortese study who exhibited low serum ferritin levels without other forms of iron deficiency have undetected cases of celiac disease or other digestive problems as potential underlying causes to their ADHD and sleep disturbances. This could be a great follow-up study for the population in the Cortese study.
   


6. It is also important to note that a large number of the children with ADHD in the study also had at least one type of comorbid (co-occurring) disorder. Among the most common ones were Oppositional Defiant Disorder (ODD, seen in around half of the patients in the study) and Anxiety Disorders. At the moment, it is unclear as to what the confounding effects of these comorbid disorders may be with regards to iron-related sleep problems. We will be discussing the nature and effects of these comorbid disorders in a later post, but for now, we must keep in mind that these co-occurring disorders have pronounced direct and indirect effects on the symptoms and treatment strategies for ADHD.
   
   
7. Finally, the Cortese paper cited another study in which Methylphenidate (Ritalin, Concerta, Daytrana), and Dextroamphetamine (Dexedrine), both of which are ADHD stimulant medications, decreased the amount of nocturnal motor activity in patients. Cortese suggested that iron supplementation, which can boost free dopamine levels in a manner similar to most ADHD stimulant medications, may possibly accentuate these postive effects. While this is certainly a possibility (which remains to be seen), I also recommend extending this drug/mineral supplementation strategy to zinc, which has been shown to boost Ritalin's effectiveness as an ADHD treatment.

This article ties together well with our recent posts on the numerous ADHD comorbid disorders. We will be having several further discussions on ADHD and sleep disorders, including potential underlying causes, in the near future.