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.

read more...

The Manganese and Hyperactivity Connection

In a previous post, we examined whether lead exposure was responsible for worsening ADHD symptoms. We saw that there is a solid (although still somewhat hypothetical) connection between lead and hyperactive behavior. This lead to the blog's conclusion that high lead levels (the exact amount is still hotly debated, but a federal recommendations appear to be headed to a cutoff of around 10 micrograms lead/deciliter of blood. This converts roughly to half of a gram of lead total in the entire blood supply in the average adult male, or less than half a gram of lead total in a child's blood). This post can be found here.



A follow-up post suggested that adequate iron intake can help counteract some of lead's negative effects on ADHD and related symptoms through a variety of possible mechanisms. A link to this blog post can be found here.



Now it appears that another metal may be connected to hyperactivity. While the connection between manganese and hyperactivity appears to be more strained that that between lead and hyperactivity, it is at least worth mentioning. Additionally, manganese seems to be less tied to actual ADHD behavior (including inattention and impulse control problems alongside hyperactivity), and more towards generalized hyperactivity. Nevertheless, like the post on lead and hyperactivity mentioned previously, there at least remains that possibility that unhealthy buildup of manganese in the body may lead to hyperactive behavior. This could, at least hypothetically, "push" an individual with the predominantly inattentive form of ADHD to more of a mixed or combined subtype of ADHD, which includes hyperactive/impulsive behavior as well. A study of French Canadian children who lived in an area with naturally high levels of manganese found a significant tie-in between high manganese levels and hyperactive behavior. A summary of that study can be found here. Some key points of the article (along with some of my thoughts and comments) are listed below:

• Hair samples, while not a perfect method of evaluating manganese intake, is typically a good indicator of overall manganese exposure. This was the method used in the study of children in a region of Quebec, Canada with naturally high manganese levels in the drinking water. Children whose drinking water source came from a well with higher manganese levels showed consistently higher manganese levels in their hair samples.

• 46 children, ages 6-15 were examined in the study. Most were previously non-medicated and untreated for ADHD or related conditions before the study.

• A strong positive correlation was seen between high manganese levels in the hair and oppositional behavior scores in the children, as based on the teacher rating scale mentioned above. This was done using a form of the revised Connner's Teacher rating scales (a common method used for diagnosing ADD, ADHD and related symptoms and behaviors). For a brief synopsis of the different elements or categories of Conner's rating scales, please click here. Briefly, oppositional is characterized by "angry" or "annoyed" temperament as well as "rule-breaking" behavior.

• Additionally, an even stronger statistical correlation was seen between high manganese hair levels (above the study threshold level of 3 millionths of a gram of manganese per gram of hair sample, which was established based on detection methods and previous studies) and hyperactivity. Here, hyperactivity is characterized by restlessness and the inability to sit still, impulsive behavior and the inability to maintain adequate focus for a given task.

• Every single child who displayed the necessary score to be considered "hyperactive" or "oppositional" had manganese levels above the study cutoff amount of 3 millionths of a gram of manganese per gram of hair. Additionally, a large majority (11 of 13), who tested above the critical score for ADHD risk had manganese levels above the cutoff mark mentioned above.

• In contrast, cognitive problems (i.e. difficulty concentrating, slow learning, poor organizational skills) did not seem to be linked to manganese levels based on the study. Hypothetically, this suggests that high manganese exposure, should it be a factor in the onset and symptomology of ADHD, would likely be aligned or affiliated more with the hyperactive/impulsive subtype of ADHD and less towards the inattentive form of ADHD.

• Interestingly, the high degree of connection between high manganese levels and hyperactivity or oppositional behavior was not present in an analogous Conners Parent rating scale as it was for the teacher rating scale. While it may be simply due to differences in observational patterns and previous history with the children (i.e. parents may be more "accustomed" to specific behaviors based on long-terms relationships, or may be less objective in identifying problem behaviors in their children for a study), this should raise some questions to the replicability of this study and its findings. Additionally, it is possible that some of these observed behaviors are more relevant to an academic setting, and solutions such as trying to reduce manganese exposure at home, may provide more benefits in the classroom than at home. None of these should be ruled out as possibilities.

• ***Blogger's note: The following 2 points was addressed briefly in the manganese article, are rather long and complex and stray slightly off-topic. They can be omitted if necessary. Nonetheless, I think there are some interesting affiliations between this post, which deals primarily with manganese and common symptoms seen in ADHD and related disorders, and previous posts, which have dealt with genes associated with ADHD.
• Signaling and proper communication in the nervous system is dependent on certain chemicals such as GABA (which is also important for proper muscle tone and function) as well as dopamine and their respective systems or "targets". These complex systems in the body have been shown to be effected by high manganese levels. The negative effects of high manganese exposure are thought to work through these very systems. A quick summary of a study done on this can be found here.
• Interestingly, the very systems associated with these two agents (GABA and dopamine) are also thought to be affiliated with hyperactivity. A summary and link to the full article on this can be found here. Note that this study investigated a genetic connection between these systems and the onset of ADHD. Some of the genes indicated in this paper have been investigated in previous posts on this blog. Among these are the DRD4 gene, the DRD5 gene, and the DAT gene.

• We have seen previously in recent blog posts that there is a possible correlation between lead and hyperactive behavior thought to be associated with ADHD. However, the likelihood of interference from other environmental toxins on the outcome of the study was thought to be minimal. The area was investigated, and found to have relatively low levels of toxic metals such as lead, mercury or arsenic.

• There appear to be slight but noticeable differences based on age and sex. Based on the teacher (but not parent) rating scales, older children appeared to have more severe symptoms of ADHD behavior, hyperactivity, cognitive impairment and oppositional behavior. While the effects were relatively small, there remains the possibility that cumulative exposure to elevated levels of manganese can lead to increased impairment over time. However, I am personally not comfortable in making this assertion based solely on the limited scope of this study.

• What I did find interesting was the fact that girls showed substantially higher manganese concentrations in their hair samples than did boys. I am intrigued by the possibility that there may be hormonal reasons behind this, especially given the context of a previous post which mentioned that magnesium has a tendency to be stored better in females due to the effects of estrogen, and iron levels are thought to be lower in females due to menstruation as well as other effects.

• Alluding to this same earlier post, we have seen that iron is thought to counteract some of the negative effects of lead on hyperactivity and related ADHD behaviors. Interestingly, iron absorption in the body has been found to be hampered by manganese, based on a 2003 study. While the amount of iron in the water was found to be high in the French Canadian study, it is entirely possible that the manganese levels were sufficient to counteract these effects. It is unfortunate that the study did not take blood samples to investigate possible iron deficiencies in the subjects.

While the study made several noteworthy observations, there are too many loose ends and questions left to be answered before determining whether manganese can pose similar risks to lead as far as inducing hyperactive behavior and ADHD-related symptoms. As of now, we are unsure whether the effects were do more to interference with iron absorption (given that numerous studies have shown that individuals with ADHD are typically iron deficient) or through a non-iron-based regulation of the GABA and dopamine pathways mentioned above. Further clouding this is the fact that iron itself plays a key role in dopamine synthesis and manufacturing.

As of now, my conclusion is that there is a possible correlation between high manganese and ADHD (especially the hyperactive form), but this connection is much weaker than that of lead (which is debatable in its own right at the moment). It certainly appears that manganese is more tolerable and overall more benign than lead, at least with regards to similar levels of exposure.

Unlike lead, manganese is actually a trace element micronutrient (i.e., it's good for the body at low levels). Manganese-rich foods include teas, beans, nuts and many types of whole grains. Additionally, excess manganese can be cleared more easily from the body than can lead. While common sources are food and drinking water (with water thought to be a more potent source of intake than food), inhalation is also a common mode of entry. This is especially true of specific occupations such as welders. Typical blood manganese levels hover around 1 microgram of manganese/deciliter of blood. This roughly translates into about .05 grams total manganese in the bloodstream.

It is easy and often tempting to try to assimilate anything and everything to a disorder such as ADHD. Many professionals and researchers often fall into this trap. However, I caution against this, since this clouds the picture as to what the real underlying causes of the disorder might be. That is why I urge restraint before passing judgment on this particular metal, at least in regards to its causative role with respect to ADHD and related disorders.

Certainly, manganese toxicity is a problem, with the deleterious effects of manganism (sometimes referred to as "manganese poisoning" and is characterized by loss of balance and coordination and impaired reaction timing) going back hundreds of years and still seen in certain metal-related occupations such as welding. Nevertheless, the relative ease of excretion of manganese (at least when compared to other heavy metals such as lead) and somewhat higher limits of tolerability make it a possible foe in the ADHD symptom world, but not a powerful one, at least for the time being.

In the next post, we will be shifting gears a bit and looking into the connection between celiac disease and ADHD and its degree of association with specific symptoms of the disorder.

read more...

Using Iron to Combat the Effects of Lead in ADHD

In the previous post, we were discussing the potential connection between lead exposure early in life and the subsequent onset of ADHD symptoms. We saw that higher lead levels are more likely to be associated with the hyperactive or impulsive symptoms of ADHD than the inattentive symptoms. At the moment, the amount of lead necessary to precipitate these negative symptoms is debatable, especially when individual variations are taken into account. However, a rough estimate of upper level lead limits can be found here. At the end of the post, I alluded to the fact that iron supplementation either via diet or pills may be effective as a possible treatment option. I will go into some of the details here:

Iron supplementation has been found to be useful in multiple cases regarding ADHD. Numerous studies have indicated that a large percentage of individuals with ADHD are iron deficient. Iron is responsible, among other things, for the synthesis and regulation of levels of the key brain chemical dopamine. Dopamine deficiencies are often seen in multiple brain regions (especially in the area behind the forehead, called the prefrontal cortex) in individuals with ADHD. Additionally, iron is a key component of hemoglobin, which is responsible for carrying oxygen in the blood to other organs and tissues in the body. Not surprisingly, many ADHD individuals have lower than average oxygen levels delivered to their brains.

Finally, other co-existing or comorbid disorders of ADHD also have been associated with iron deficiencies. One of the most notable is Restless Leg Syndrome (RLS), which is characterized by unwanted leg movements during rest, and is thought to be a major contributing factor to many types of sleep disorders and impairments. Individuals with ADHD have been shown to suffer from Restless Leg Syndrome at disproportionately high frequencies, when compared to the general population and iron deficiency may be a key contributing factor to Restless Leg Syndrome seen alongside ADHD.

However, one of the unexpected benefits of iron, especially with regards to ADHD, is its potentially protective role in reducing the negative effects of early lead exposure. In a couple of correspondences in the August 2007 edition of the journal Environmental Health Perspectives, some key findings were summarized involving the protective role of iron to lead-induced damage. One of them (based on previous literature) reported on how lead can negatively impact levels of free dopamine (which is often correlated with ADHD, as many of the positive effects derived from most stimulant medications is due to their abilities to boost levels of dopamine in between neuron cells).

Additionally, lead is also thought to inhibit the interactions of dopamine and its targets as lead can alter the presence of these targets or dopamine receptors. Both of these reduce proper dopamine function, and it is thought that adequate levels iron can offset some of these negative effects (on the flip side, iron deficiencies are thought to exacerbate several of these negative occurrences). Finally, iron is also thought to restore a balance in the blood-brain barrier, which serves as a sort of controlled gateway, regulating the passage of nutrients and necessary neuro-signaling chemicals into (as well as keeping toxic substances out of) the brain. The role of iron is thought to restore and offset some of the negative and damaging effects of lead on the blood-brain barrier, which is especially sensitive to toxins during the early stages of life and childhood.


There is some dispute and controversy over some of these findings, however. Another study (which is frequently cited in numerous journals on toxins/heavy metals and ADHD or cognitive disorders) was done on the protective effects of iron and zinc on Mexican schoolchildren exposed to lead showed no statistically significant results as far as improving cognitive function.

While I do not advocate excessive iron supplementation, (watch for upper limits which are described here), I do strongly suggest that pregnant and nursing mothers, as well as children and adults with ADHD do ensure that their iron intake is adequate. It is interesting to note that magnesium deficiency is also affiliated with increased ADHD symptoms. Due to the role of estrogen in improving magnesium retention, women require less daily magnesium than do men (a table of recommended daily magnesium intake can be found here). However, in iron, the opposite is true. Several factors, including less efficient iron binding and loss of iron due to menstruation and pregnancy result in higher iron requirements in pre-menopausal women. A summary of recommended iron levels for men women and children can be found here.

In addition to the potential role of iron in protecting against lead damage, will be discussing how boosting iron intake can offset the effects of ADHD and other related comorbid disorders in future posts.

read more...

Does Lead Exposure Cause ADHD?

Many of these findings were based off of an original journal article regarding prenatal tobacco and lead exposure and the onset of ADHD by Braun and coworkers in the December 2006 issue of the journal Environmental Health Perspectives. For a quick synopsis of this article on lead and ADHD, please click here. Interestingly, this same group also published more recent papers on the effects of lead on conduct disorders, which are often comorbid to ADHD cases. This should be especially relevant for pregnant or nursing mothers. For more information on ADHD and pregnancy, please check out the collection of posts on this blog addressing the topic, which can be found here.

While the relevance of several studies regarding the effects of lead on ADHD and cognitive dysfunction is called into question, often because the lead-levels reflect a much higher exposure than what is often faced by the general population, a relatively large study done recently indicates that even moderately high blood lead levels show a strong correlation with ADHD. This suggests either one of two things:

• Other unknown or "hidden" factors were present in the lead-based studies which were the major contributors to impaired mental function and disorders such as ADHD. Even with lower lead levels, these under riding factors were still present, and therefore the major contributing causes to the disorder were still present.

OR

• The sensitivity to lead exposure in children is even higher than previously thought.

An important question we should be asking ourselves is "Does lead exposure beyond a certain point trigger specific ADHD symptoms, or is there an increase in ADHD behavior across the board?".

ADHD is often defined by two major components, the hyperactive/impulsive component and the inattentive component. Based on a recent publication by Nigg and coworkers in the February 2008 Journal of Biological Psychiatry, it appears that the hyperactive/impulsive component of ADHD predominates based on exposure to lead.

Interestingly, the children investigated in the study above were of the inattentive subtype or the combined subtype (both inattentive and hyperactive/impulsive) of ADHD. Based on these results, it is my personal opinion that a child who, under other circumstances may otherwise be of the ADHD inattentive subtype, could instead fall into the ADHD Combined Subtype if he/she is exposed to a specific quantity of lead during the prenatal or early childhood stages of development. Furthermore, I propose that, had the individuals in the study have been of the predominantly Hyperactive/Impulsive Subtype of ADHD, the results would have shown that lead exposure beyond a critical thresh hold would have exacerbated the already-negative hyperactive behaviors for this particular subtype.

In addition to the negative effects surrounding the hyperactive elements of ADHD, the study also found a correlation between low-level lead exposure and child IQ's. This, of course, has been a hotly debated topic for years. While other factors may clearly be at work (lead exposure is often higher in areas with lower socioeconomic status, which is also a factor often correlated with lower IQ scores), the results of numerous studies, many of them recent, still support a strong possible connection.

Theoretically, then, by significantly reducing the prenatal or early-developmental exposure to lead, a child may be at least partially shielded from negative symptoms such as a lower IQ and hyperactive behavior. However, for individuals with the predominantly inattentive form of ADHD, these lead-restrictive measures would be less effective in addressing their inattentive behaviors. Therefore, it is my opinion that reducing lead exposure due to prenatal intervention, iron therapy, or, even possibly chelation methods (both of which will be discussed in future posts), would be most effective for treating the Hyperactive/Impulsive and Combined subtypes of ADHD and less effective for the Predominantly Inattentive ADHD Subtype.

While we should be careful not to overplay or overhype the lead/ADHD connection (especially given the fact that overall lead exposure risks have gone down throughout most of the world in recent years due to the uses of unleaded gasoline and lead-based paint, among other things), it is important to recognize that there is still a statistically significant connection between the two, at least according to a number of recent studies. The Nigg paper, mentioned above, found a strong correlation with hyperactive ADHD-like behavior at much lower lead levels (much closer to the average levels found in much of the United States) than those in most previous studies. This information is particularly important to pregnant mothers, since it has been demonstrated that the negative effects of lead, and other heavy metals and toxins are more harmful on developing brains and nervous systems than to mature ones. The protective effects of reducing lead exposure to mitigate the negative symptoms of ADHD, should not, in this blogger's opinion, be overlooked.

In the next post, we will be discussing how treatment or supplementation with iron may be able to offset some of these harmful effects of early lead exposure on ADHD, should they occur.

read more...