Evaluation of Vyvanse for ADHD Treatment

A new drug called Vyvanse (Lisdexamfetamine) has entered the world of ADHD stimulant medications relatively recently. Vyvanse was originally marketed as an ADHD treatment for children, but has recently been approved by the FDA for adult and adolescent use this past April. A cousin of the popular ADHD medications Dexedrine and Adderall, Vyvanse includes some key modifications from these other meds. Some reports (unverified) suggest that Shire Pharmaceuticals, the makers of Vyvanse, are pushing this new drug aggressively over Adderall XR. While Adderall is a chemical mixture of amphetamine salts including enantiomers, Vyvanse only contains the one enantiomer thought to be more "active".

A quick side note on enantiomers: Entantiomers are essentially "mirror images" of the same chemical compound, like a person's left and right hand. The body, like most objects in nature, react differently to and often heavily prefer one "mirror image" over the other. Certain ADHD medications such as Focalin, have already employed this technique. Focalin is an isolation of only one of the two mirror images that make up Ritalin, another popular ADHD medication. In addition, the ADHD medication Dexedrine also employs this mirror-image selectivity regarding its composition.

The second major difference between Vyvanse and other amphetamines such as Adderall, is that Vyvanse is listed as a "pro-drug". A pro-drug is essentially an inactive form of a drug, which, when broken down or metabolized by the body, releases the active drug form. Vyvanse contains an amphetamine which is chemically linked to an amino acid (a building block component of proteins) called lysine. In the body, this chemical linkage is severed by special enzymes which separate Vyvanse into the amphetamine drug and leftover lysine fragment (which is easily disposed of, since lysine is a naturally occurring amino acid in its own right).

***Blogger's note: I will be citing a number of studies previously conducted on the drug lisdexamfetamine. Keep in mind that this is a relatively new drug, so it does not have the history of a drug such as methylphenidate. Nevertheless, I have tried to keep a good balance of sample studies on the drug to report on. The list of studies mentioned and referred to here, are by no means exclusive! While not all of the studies used the Vyvanse brand of the drug, I will be using the terms "Vyvanse" and lisdexamfetamine interchangeably throughout the post.

***Additionally, please do not take this information as official medical advice. I am simply trying to highlight some of the pluses and minuses of the drug and arm you with information so you can better consult with your physician on the merits of this drug.

This chemically-modified form carries several apparent advantages for Vyvanse:

• Since the lysine link must be cleaved to release the active form of the amphetamine drug, Vyvanse naturally lasts longer in the system than do straight amphetamines. While most other stimulant medications rely on the capsules encasing the drugs to slowly dissolve and thereby slow down the release of the drug, Vyvanse already has what is essentially a controlled release built in to the drug itself. As a result, a single dose taken early in the day can last up until the evening hours, which allows individuals to avoid the hassle or stigma of needing to take the medication during the work or school day.

• Most of amphetamines problems stem from their addiction potentials. Generally, the faster the amphetamine gets into the blood stream and gets into (as well as out of), the brain, the greater the "high", and the more addiction-forming the drug. Again, by its built-in slow release mechanism, Vyvanse enters the blood (as well as the nervous system) at a slower, more controlled pace, thereby reducing its addiction potential. Even when snorted or injected, lisdexamfetamine exhibits notably reduced addiction potentials, when compared to other amphetamine-based stimulants. For example, when injected via IV, subjects who took Vyvanse needed 1-3 hours to feel the drug effects while isolated d-amphetamine (analogous to Dexedrine) felt the effects in only 15 minutes.

• Due largely in part to the fact that Vyvanse's drug effect needs to be "activated" biochemically, it is poses less risk for tampering and related abuses (i.e., crushing and snorting) as well.

Additionally, Vyvanse also carries some other distinctive advantages:

• While many drugs effectiveness are often dependent on the level of acidity in the stomach and intestinal tract, Vyvanse appears to be only mildly affected. It dissolves quickly in the gastro-intestinal tract, and its solubility is minimally affected by digestive pH.

• The presence of food only results in a slight delay in Vyvanse's absorption. When taken alongside a fatty meal (fatty foods generally impede the absorption process, as they themselves are slow to clear the gastro-intestinal tract) the delay in amphetamine release from Vyvanse was only about an hour. This was in contrast to around a 2.5 hour delay when Adderall was taken with fatty foods. As a result, Vyvanse appears to be less affected by the presence of food than other well-known amphetamines, suggesting an increased versatility as an ADHD stimulant medication treatment.


• This next statement is the blogger's opinion and is not supported by direct evidence. Nevertheless I believe this is a topic worthy of investigation: In a previous blog post, we discussed celiac disease and how it can ravage the digestive tract and result in ADHD-like symptoms. While these symptoms are likely the result of a different path than ADHD caused by genetic or environmental factors, it may be worth noting that Vyvanse may alleviate some of these inattentive symptoms better than other ADHD medications, due to the fact that it may absorb better in a digestive system damaged by celiac disease or the pH changes which often accompany it (poorly digested carbohydrates can alter the pH in the digestive system immensely). While this will not treat the underlying cause of celiac disease, it may mask the some of the ADHD-like symptoms better than other medications. This assertion is simply a personal hypothesis and is yet to be studied or verified.

• In addition to its resiliency regarding foods and digestive pH, it appears that Vyvanse may be less susceptible to negative drug-drug interactions than many other agents. Many medications target a key metabolic system referred to as Cytochrome P450. While to complex to discuss in detail in the limited scope of this post, the P450 system of proteins plays an integral role in drug metabolism, the body's antioxidant levels, and regulation of toxicities, it appears that the effects of the drug lisdexamfetamine on the P450 system are minimal. Since many drugs do operate via this system, Lisdexamfetamine should therefore pose less of a threat regarding negative drug-drug interactions.

• The drug apparently has a good track record as far as behavioral improvements and attention span are concerned. A study was done using a rating scale called SKAMP (which stands for the initials of its creators: Swanson, Kotkin, Agler, M-Flynn and Pelham), which is used to determine classroom behavior. According to the study using this particular rating scale, measurable improvements were seen in both attention span and classroom conduct for periods of up to 12 hours after taking their last dose of lisdexamfetamine. Prolonged behavioral changes are typically not seen to this degree, and the fact that the subjects were diagnosed and medicated previously suggest the potential effectiveness of Lisdexamfetamine even for "stubborn" ADHD cases.

• The same study also employed a mathematics-based test called PERMP (short for Permanent Product Measure of Performance). Notable improvements were seen in both both speed and accuracy on this test following a 5-week amphetamine treatment program. Lisdexamfetamine's positive effects on this cognitive task peaked around 4.5 hours after the last dose was administered and held relatively steady for the next 7-8 hours. The results of this study suggest that Lisdexamfetamine can improve the inattentive and behavioral symptoms of ADHD as well as enhance cognitive performance abilities for a prolonged period of time. This suggests great potential for use as a "school drug".

• A study on adult stimulant drug abusers by Jasinski and Krishnan presented at the 2006 US Psychiatric and Mental Health Congress found that the study's subjects found Lisdexamfetamine to be much less "likable" than other amphetamines, further suggesting a reduced addiction potential for an already-at-risk group.

• When taken around breakfast time (7:30-8:00 a.m.), Vyvanse showed remarkable "staying power" throughout the day, based on results from a behavioral rating scale taken in the mid-morning, afternoon and evening time (the last being around 6:00 p.m.). This is good news for teachers and parents, and suggests a more gradual tapering-off of effects, and a lesser "rebound effect", in which negative symptoms rapidly reappear, often within the hours of 4 and 6 p.m.

• Amphetamine levels delivered via the lisdexamfetamine system are thought to stabilize within about 5 days. This is good news, especially since many ADHD medications can take up to 3 weeks to normalize their effects.

• Lisdexamfetamine is apparently processed and broken down in an efficient manner, and is typically cleared from the body without system buildup.

• Lisdexamfetamine has also shown more consistency than many other drugs as far as less variation from patient to patient. While this is neither good or bad by itself, it does suggest a greater inherent stability in that it appears to be less susceptible to the effects of other bodily functions which are variable from person-to-person. As a result, I see this greater predictability will make it a preferable choice for many prescribing physicians. Of course, the flip side is that ADHD is an extremely complex and multi-faceted disorder, and clinicians may fall into the trap of seeing a "one-size-fits-all" solution and begin to treat Lisdexafetamine as a fall-back, default prescription.
  

This blog, of course, is not designed to sound like some sort of promotional "infomercial" touting all of the benefits of Vyvanse while leaving out potential risk factors. To keep things balanced, I have included some of the negative attributes of this particular stimulant medication as well:

• While the study by Jasinski and Krishnan on the reduced "likability" of Vyvanse was encouraging, it is not recommended for individuals with a history of drug abuse, as previous non-prescription drugs can interfere with its effectiveness.

• Additionally, Vyvanse reduces the presence of a key enzyme in the body which is targeted by anti-depressants called monoamine oxidase. A number of anti-depressants called monoamine oxidase inhibitors (MAOI's) also target this enzyme and reduce its presence. Due to the potentially harmful combination of amphetamines and MAOI's, these MAOI drugs should not be taken alongside Vyvanse. Please note that certain substances, such as cigarettes, and even turmeric or curry (in large doses) can also have potentially negative effects with Vyvanse.

• Slight elevations in heart rate and blood pressure (mainly the diastolic pressure, which is the smaller of the two numbers and represents the blood pressure at the "resting" phase of the heart) and slight changes in heart rhythms were seen with Vyvanse, especially in the upper dose (70 mg) levels. However, this is a relatively common occurrence within the family of stimulant medications. For further information, please see the earlier post Are ADHD Stimulant Drugs Bad for your Heart?

• Like most stimulant medications used to treat ADHD, appetite suppression was also a common side effect (this is due, in part, to increased levels of free dopamine, an important signaling agent in the nervous system, which, also plays a role in the feeling of "fullness" in an individual. By artificially boosting free levels of this neuro-chemical, a reduction of hunger symptoms are often seen), even at the lower 30 mg doses. However, actual weight loss did not become a huge symptom until the upper levels (around 70 mg doses) were approached.

• Insomnia can also be a problem with Vyvanse, even at lower doses. As a result, it is advised to give this medication as early in the day as possible.

• The "classic" side effects (that almost all medications now somehow seem to evoke!) such as headache, nausea, vomiting, etc. all remained relatively low until the 70 mg level was approached.

• Keep in mind that this drug still functions as a stimulant, and is therefore inherently better-suited for the more inattentive or impulsive forms of ADHD. Given the negative interactions with the MAOI class of antidepressants and the fact that stimulant drugs in general can worsen depressive symptoms, I recommend that extreme caution be used when prescribing this medication for individuals with comorbid ("comorbid" means "occurring alongside of") depressive symptoms alongside their attention deficit disorder.

Medication Doses Available:

30 mg, 50 mg and 70 mg were the original strengths available, but recently 20 mg, 40 mg and 60 mg doses have been added. The amount of amphetamine delivered in Vyvanse compared to Dexedrine approximately a 5:2 ratio. For example, 50 mg of Vyvanse corresponds roughly to 20 mg Dexedrine, 25 mg Vyvanse to 10 mg Dexedrine, etc. 30 mg is often a starting point for children, but doses can be carefully ramped up under the guidance of a physician. In general, it appears that many of the negative side effects can be kept at bay by staying under the 70 mg amount.

A quick side note: For another good source of information on medication dosages, I recommend the blog of Dr. Charles Parker. His blog can be found here. Additionally, he talks about a paradox called the therapeutic window. This is interesting to note, because sometimes ADHD medications which are prescribed at too high of a dosage actually result in ADHD symptoms to re-emerge and give the false impression of underdosage. You can check out this blog article here.

With regards to upper limits and safety measures, based on the studies mentioned above, negative side effects tend to increase around the 70 mg mark. Nevertheless, studies have been done at levels up to 130-150 mg. It is interesting to note that once this high range was reached, the amphetamine concentration in the blood began to taper off. This is good news with regards to the potential for overdose and buildup of toxic levels (note the relatively efficient rate of clearance of Vyvanse mentioned earlier in this post).

As a final word of caution: Remember that Vyvanse is essentially a new delivery method of amphetamines. I have highlighted some of the positives such as lower addiction potential and prolonged modes of action. However, keep in mind that there is often a strong "publication" bias, in that studies which find a drug to be ineffective or even counter-effective are often not reported or published. I therefore urge you to take some of these "glowing" reports on the drug with a grain of salt. Nevertheless, I remain at least cautiously optimistic with regards to the potential merits of lisdexamfetamine for treating ADHD and related disorders. We will be investigating other ADHD medication options shortly in future blog posts.

Celiac Disease causes ADHD Symptoms

One of the biggest challenges in diagnosing and treating ADHD is trying to separate it out from other disorders that often present similar-looking symptoms. One such disorder is known as celiac disease. When gluten (a type of plant protein found in corn and wheat) is ingested in individuals with celiac disease, an inflammatory response in the upper portion of the small intestine occurs. When repeatedly challenged by gluten exposure, damage can occur to this portion of the digestive system, which leads to painful symptoms and impaired digestive and absorptive function.

The latter is of particular interest, since we have seen in other posts that nutrient deficiencies can lead to or exacerbate the onset of certain ADHD symptoms. For example, iron has been shown to be a useful supplement in treating certain underlying factors in ADHD, as seen in previous posts. It is thought that a celiac disease-damaged system can contribute to iron deficiency, likely through impaired iron absorption, thus presenting a challenge to the ADHD patient.

Interestingly, celiac disease has also been linked to other neurological disorders such as depression and depressive-like symptoms. This may be due to poor absorption of the amino acid tryptophan (which is found in high concentrations in turkey, and is a big reason why turkey can make a person sleepy). Tryptophan is converted to another important agent in the body called serotonin, which is often found to be reduced in patients with depression and other related symptoms (sugar and milk can also give a temporary rise in serotonin levels, which is why ice cream and chocolate are often "comfort foods").

In addition to depressive behaviors, possible connections have been identified between celiac disease and other metabolic disorders such as diabetes and thyroid problems. We have explored the possible connection between ADHD and thyroid dysfunction in a previous post. Additionally, there is a possible connection between celiac disease and other symptoms or common ADHD comorbid disorders such as epilepsy, dyslexia (which is thought to be a possible result of impaired gluten breakdown), anxiety disorders and social phobias and impaired sensory functions.

The good news to all this is that a gluten-free diet (which, unfortunately, can be very difficult to administer due to the prevalence of wheat in the Western diet) has been shown to ameliorate most of these negative symptoms. A study done on celiac disease patients and ADHD symptoms found that after treating patients with a gluten-free diet for 6 months, a number of ADHD-like symptoms subsided. The study used a method called Hypescheme, which is a type of computerized checklist used to quantify and analyze data involving ADHD and related disorders in a statistically significant fashion.

Statistically-significant improvements were seen in the following areas: attention to detail, duration of attention span, ability to complete tasks, distractibility, fidgety behavior, leaving a seat (when expected to remain seated), noisy disruptions and answering questions prematurely.

However, statistically significant improvements were not seen in other categories characteristic of ADHD. These include: losing/forgetting materials as well as restless and interruptive behaviors.

In previous posts, we have seen that certain treatments may be favorable for either inattentive ADHD type behaviors, hyperactive-impulsive ADHD behavior, or a combination of the two, called the ADHD Combined Subtype. It is interesting to note that the gluten-free diet results in improvements in characteristics that may be considered either "inattentive" (task completion, attention to detail, distractibility) or "hyperactive-impulsive" (fidgeting, noisy behavior and blurting out answers prematurely). While many studies on the possible connection between food additives and ADHD (see last paragraph of this post for more on this) seem to highlight the hyperactive side of the disorder, this celiac disease study seems to indicate a more mixed improvement across the whole spectrum of the disorder when a gluten-free diet is introduced.

Given the fact that many individuals who have celiac disease lack many of the outward signs of digestive symptoms of the disorder, and the fact that there are so many potential overlapping factors between the symptoms of ADHD and celiac disease, it is quite possible that you or your child's ADHD may be a misdiagnosis of an underlying cause of celiac disease or a related disorder. I therefore strongly recommend individuals who are diagnosed with the disorder of ADHD (especially those who have had poor or adverse responses to previous treatments) to consider testing for celiac disease. This of course, is not meant to knock the competence of most physicians and other professionals, but rather a plea to eliminate a potentially common misdiagnosis through a relatively simple procedure. Several antibody-based tests can be used to detect celiac disease or related disorders with relative ease.

In general, there has been a lengthy debate over the connection between ADD and ADHD and food allergies. While previous studies had certainly performed, a landmark study was done in the mid 1970's by Dr. Benjamin Feingold which sought to link the relationship between food additives and food coloring and hyperactivity. Numerous studies have since followed on this topic, many of which have supported Feingold's hypothesis and many which have refuted it. As a result, a number of physicians began to recommend elimination diets in an attempt to control attention deficits and hyperactive behavior. We will be investigating the original Feingold article and summarize the effectiveness of these elimination diets in treating ADHD symptoms in the near future.

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.

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.

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.