Drugs, Genes and ADHD

The Effects Specific "ADHD Genes" Have on Dosing ADHD Medications:

Below is a list of five of the most common medications for ADHD. In order to break down or metabolize these drugs, however, a series of steps must take place for effective absorption, delivery and clearance of these drugs. This process, however, requires a series of enzymatic steps. Generally, when a physician prescribes these drugs, he or she considers factors such as the patient's age, gender, symptom severity and past medication history. However, lost in the shuffle is a lesser-known, but often equally critical factor: the particular genes of the individual. It is these genes which play a large role as to how well these enzymes function (alongside other factors such as the person's nutritional status, as most vitamins and minerals act as chemical "helpers" to these enzymes, and deficiencies can lead to lower enzyme function and sub-optimal metabolic efficiency).

Unfortunately for prescribing physicians, the landscape of enzyme capabilities among the general population is far from uniform. Some individuals naturally possess enzymes or enzyme systems (which are coded for and dependent on the genetic makeup of the particular individual)which are more efficient than others (often by multi fold differences). If these enzymes are essential to drug metabolism (including ADHD medications), then a potentially crucial piece of information may be missing from the physician's repertoire of assessment tools for medicating at the proper dosage.

Much to the dismay of many a frustrated parent of an ADHD child, this often begins the laborious process of adjusting medication dosages through a glorified "guess and check" process. However, due to the need for a relatively small window of effective dosing (especially for psychotropic drugs such as those prescribed for ADHD and related disorders) and unforgiving margins of error in the optimization process, bits of information, such as a child's genetically-dictated levels of drug-metabolizing enzymes could be extremely useful. With the increasing efficiency, lowering costs of and wider availability of genetic screening methods, we may soon be able to predict a child's enzyme levels by their genetic makeup and facilitate the dosing of (and eliminating much of the guess-work from) their medications for ADHD or other disorders, saving both time and money while on the medication circuit.

Given the powerful role of enzymes and enzyme systems (and the specific genes which encode for them) for the delivery, metabolism and clearance of these medications, we should take a look at some of the genetic variations of these enzymes and the implications they may having in assisting the diagnosing physician in the near future for more effectively dosing ADHD medications.

Here are 5 common ADHD drugs (including one which is not prescribed but often used as a "self-medication" tool among the ADHD population), and the genetically-dictated enzymes which can play a role in their metabolism and dosing patterns and levels.

ADHD Drug #1: Strattera (Atomoxetine)

Key enzymes involved and gene of interest: SLC6A2, CYP2D6

We have already investigated another gene believed to have an impact on dosing with Strattera, the SLC6A2 gene. However, in that earlier post, we alluded to another gene responsible for the metabolism of the non-stimulant ADHD drug Atomoxetine. This gene is called CYP2D6. The CYP2D6 gene codes for an important enzyme of the same name (which is an important enzyme produced in the liver). The gene is located on the 22nd human chromosome (the 22q13.1 genetic region to be more specific if you are familiar with genetic markers).

Approximately a dozen different genetic forms (or alleles) of this CYP2D6 gene are seen in individuals of European ancestry. These forms are often designated by a star followed by a number, such as *1 or *4. While these numbers are used for naming purposes, it is worth noting that most individuals of European descent appear to carry either the *1 (the most common), the *2 or the *4 form of this gene. Additionally, *3, *6, and *10 forms are each found in about 1-2 percent of the population.

Interestingly, the *10 form of this gene is found in higher levels in individuals of East-Asian descent. A Chinese study found that a higher frequency of this *10 form in the population (the *10 form shows up in over half of the Chinese population, about 10 times more frequently than in whites), resulted in slower rate of drug metabolism of the ADHD medication Strattera (Atomoxetine) by the CYP2D6 enzyme.

Relevance of the CYP2D6 gene to medicating ADHD with Strattera: The *10 form of the CYP2D6 produces less enzymatic activity than the most common *1 form. This can result in about a 50% increase in Atomoxetine concentration in the blood and duration before clearance, which was seen in the Chinese study. As a result, for individuals with the exclusive *10 form (such as seen in much of the East Asian population), slightly lower or less frequent dosing levels of atomoxetine might be needed to get the same therapeutic effects. This is in agreement with another study suggesting a 50 to 75% dosage reduction of Atomoxetine for those with hepatic impairment (liver dysfunction), as the CYP2D6 enzyme is produced in the liver.

Additionally, this population may be at a slightly greater risk of side effects with the drug due to a slower clearance and greater buildup of the drug. Of course other genes and additional factors in the Atomoxetine pathway certainly play a role, but these genetic variations can still play a significant role in medication dosing strategies.

ADHD drug #2: Adderall (Mixed amphetamine salts)

Genes of interest: Catechol O-Methyltransferase (COMT) gene, Dopamine Transporter Gene (DAT)

In previous posts, we have spoken extensively about a gene called COMT, short for Catechol O-Methyltransferase and its role on dosing for amphetamine-related ADHD medications such as Adderall and Vyvanse. This previous discsussion on COMT and ADHD medication dosing can be found here.

However, there are a few other genes worth noting here for their potential roles in dosing with amphetamine-based ADHD medications such as Adderall. One of these is the Dopamine Transporter gene (DAT), which is located on the 5th human chromosome. This gene also goes by other names such as DAT1 or SLC6A3. The DAT gene codes for an important protein called the Dopamine Transporter protein, which is responsible for shuttling the important brain chemical dopamine in and out of neuronal cells.

A number of stimulant drugs used to treat ADHD and related disorders work, at least in part, by interacting with this dopamine transporter (DAT) to correct a dopamine imbalance (in general, individuals with ADHD often have too little dopamine in the regions between brain cells or neurons in key regions of the brain. Many stimulant ADHD drugs remedy this by blocking the shuttling of dopamine back into the cells, keeping adequate amounts in these "gaps").

Interestingly, on a side note, the DAT gene has been implicated (in conjunction with another dopamine-related gene called DRD4) in IQ levels an behavior problems.

Like the genes mentioned above, DAT exists in a wide number of different forms across the human gene pool. Some forms appear to increase ones predisposition to ADHD and various neurophysiological or behavioral disorders and have earned the moniker "high risk alleles" (remember, an "allele" is simply a specific form of a gene which varies within the population).

A study on families of ADHD children found that a specific form of the DAT gene which included a 480 base pair repeat (simply a repeating section of DNA which is 480 DNA "letters" long) allele was associated with greater severity of ADHD symptoms, especially in the combined ADHD subtype (which includes high levels of both inattentive and hyperactive/impulsive symptoms as opposed to a predominance of one).

Potentially, individuals with ADHD who carry this "high-risk allele" of the DAT gene (which is a substantial portion of the general population) may require slightly higher levels of medication dosage with amphetamine-based stimulants than their "lower-risk" counterparts. These differences may be even more pronounced if the individual carries the "Val" form of the COMT gene, mentioned in a previous post (given the current body of research on the subject, the contributions of the COMT gene dwarf those of the DAT gene with regards to governing amphetamine dosage levels).

ADHD drug #3 Vyvanse (lisdexamfetamine dimesylate)

Gene of Interest: Trypsinogen

Due to its chemical proximity to amphetamines (Vyvanse is essentially an "inactivated" form of the drug Dexedrine, which is an isolation of one of the potent components of Adderall). A special chemical "tag" is linked to the active part of the drug, which must be chemically cleaved to release the active form of Vyvanse (think of it as essentially breaking a seal to free up the drug) into its functional amphetamine-based product. Naturally, the genes listed above (and the enzymes which they encode) which metabolize amphetamines are of substantial interest for potentially influencing the effectiveness of ADHD treatment with Vyvanse as well.

However, the actual cleaving process of releasing the active component of Vyvanse is equally as important. If the drug is not freed, then it cannot be effectively metabolized.

Several enzymes which are called upon to metabolize the other ADHD drugs in this post do NOT appear to have a significant effect on Vyvanse. These include CYP2A6, CYP2B6 (both for nicotine), and CYP2D6 (for Strattera). This is good news for those who are already taking medications, as Vyvanse's relative independence of these drug-metabolizing enzymes means fewer adverse drug-drug interactions.

As far as genetics go, the genes coding for the breakage of de-activating chemical tag placed on Vyvanse may be of most importance, especially since this breakage (or "hydrolysis") is believed to be the slowest (or rate-determining) step in metabolizing Vyvanse for ADHD. The de-activating "tag" attached to Vyvanse is none other than the amino acid lysine. While the exact mechanism of cleaving this link is not fully known, one enzyme in particular may be extremely relevant to this process.

Trypsin is an extremely common digestive enzyme produced predominantly in the pancreas. It is responsible for breaking up chemical linkages much like that of the one used to de-activate Vyvanse. Thus, a genetically-governed deficiency of the trypsin enzyme could lead to a severely hampered absorption (and subsequent metabolism and clearance of the ADHD drug Vyvanse).

Trypsin is actually coded for by a series of enzymes, often referred to as Trypsinogen, which located on the 7th human chromosome (in the "q35" region of the chromosome to be more exact). Individuals with pancreatic deficiencies, including pancreatitis have been tied down to having mutations in this trypsinogen gene.

Therefore, while this genetic region on the 7th chromosome hasn't been sufficiently studied with regards to Vyvanse (at least to the best of this blogger's current knowledge), this blogger personally believes that aberrations in the region of the Trypsinogen gene on this 7th human chromosome may be a worthwhile place to look for genetic response-based differences to the ADHD medication Vyvanse.

ADHD drug #4: Concerta/Ritalin/Daytrana/Biphentin (methylphenidate)

Genes of Interest: Carboxylesterase 1 (also referred to as "CES1"), DAT (refer to ADHD drug #2: Adderall section for DAT's genetic location)

Carboxylesterase 1: Although the affected form of this enzyme, which is coded for by a gene on the 16th chromosome, is relatively rare, some key studies have indicated that deficiencies in the CES1 enzyme can be coded from specific forms of this gene. These rare, low-functioning gene-mutation forms of Carboxylesterase 1 result in extremely poor methylphenidate metabolism, resulting in a buildup of abnormally high levels of the drug in individuals with this enzymatically-deficient form.

In addition to their effects on amphetamines such as Adderall or Dexedrine, variations (often referred to in the literature as "polymorphisms") in the DAT gene also play a role in the response to methylphenidate. A Korean study found that a specific allele (the 10-repeat allele, which is the same form as the "high-risk" 480 base-pair allele mentioned earlier in the amphetamines section) predicted a poor response to methylphenidate.

Interestingly, however, several Irish studies suggest the exact opposite: the "high-risk" 10-repeat 480 base pair form of the DAT gene may produce larger amounts of the DAT protein (which shuttles essential dopamine out of the gaps between the cells, the opposite effect of what one wants if they suffer from ADHD), so the higher levels of expression of this transporter may make it a better candidate for methylphenidate.

Another Irish study may help resolve some of this discrepancy. It found that individuals with the so-called "high-risk" form of the DAT gene mentioned above exhibit a more positive response to treatment with methylphenidate with regards to treating their attentional symptoms based on the left side of the brain. Left sided inattention can be a reflection of brain damage or brain asymmetry, the latter being a common trait in the ADHD population. It should be worth noting that methylphenidate has been an effective treatment method for improving cognitive processes for those suffering from traumatic brain injuries.

Given the fact that in the amphetamine section we mentioned that the DAT gene was more connected to the Combined ADHD subtype (the original article specifically stated that the association did not hold for the strictly inattentive ADHD subtype). If this holds true, then we may have discovered a potentially significant gene/medication/ADHD subtype association.

It is this blogger's current hypothesis that the "high-risk"/480 base pair/10-repeat allele form of the DAT gene might predispose one to a MORE FAVORABLE response to methylphenidate treatment if inattention is the most persistent ADHD symptom (as in the predominantly inattentive ADHD subtype). Conversely, if the hyperactive/impulsive behavior either predominates or is largely present in an individual (such as in the hyperactive/impulsive or combined ADHD subtypes, respectively), then the "high-risk" label holds for this particular gene type, and the methylphenidate response potential goes down.

In other words, if large amounts of hyperactivity are present (which is the case in most ADHD children, as the combined subtype is by far the most common form), then this "high-risk" form of the DAT gene hampers methylphenidate's effectiveness, whereas if hyperactivity is largely absent, then the response to methylphenidate is actually more favorable. If this hypothesis were to hold true, then we could screen youngsters for this form of the gene and keep them far away from methylphenidate if they were bouncing off the walls, whereas if the exhibited more of an inattentive "space cadet" type of behavior then methylphenidate might be a good first choice of pharmaceutical treatment. Of course this theory could be completely off-base, but given this blogger's current knowledge and exposure to the current literature, this may be a plausible explanation.

Another possible explanation for this discrepancy between Irish and Korean studies: We have already seen that specific forms of certain genes can be found at considerably higher levels such as the *10 form of the CYP2D6 gene mentioned above with regards to the East Asian population. Keep in mind that this gene form was associated with the metabolism of Strattera (which exhibits a significantly different mode of operation than do stimulants such as methylphenidate or mixed amphetamine salts). However, there are a number of so-called ADHD genes which have been implicated with the disorder. The current thought here is that some genes exhibit a more powerful influence on physical or behavioral traits than do others. In other words, some genes simply act more "powerfully" than others. This is known as epistasis ("Epistasis" roughly means "standing upon").

***As a side note, please don't confuse "epistasis" with the whole dominant/recessive "big A/little a" (Aa) gene thing you probably learned about in middle school biology. Dominant/recessive refers to different forms of the SAME gene, whereas epistasis refers to DIFFERENT genes. For example, let's say, hypothetically that there was a rare gene for green hair located on the 20th human chromosome. However, a more "powerful" gene, say on the 14th chromosome codes for brown hair. This brown hair gene in this case would be epistatic, meaning that it would overpower the effects of the green hair gene altogether. This phenomena is quite common in genetics.

Getting back to our discussion, this blogger hypothesizes that there may be one or more other unidentified genes in either the Korean or Irish population which are epistatic to the DAT gene with regards to the methylphenidate response. If this was true, then it's quite possible that the effects of these hypothetical yet-to-be-identified genes might "mask" or override the effects of the DAT gene, and that the association with the "high-risk allele" may be largely coincidental rather than causative. Given the state of the current research on current "heavyweight" genes such as the COMT gene mentioned earlier, it is entirely possible that the overall level of contribution among specific "high-risk" DAT alleles might be less significant than many of these studies seem to indicate.

Of course the discrepancy could just as easily be attributed to small sampling sizes, slight differences in experimental methods or uncontrolled variables in the experiment (or a complete lack of true association between methylphenidate and the DAT gene at all, although given the current body of literature, this last assertion seems highly unlikely).

ADHD drug #5: Nicotine:

Genes of interest: CYP2A6, CYP2B6

I have included this drug due to the high rates of smoking among those with ADHD. As with alcohol, nicotine is often widely used as a form of self-medication for those with ADHD. Some research even suggests that individuals with ADHD exhibit a different response to nicotine and that nicotine withdrawal may produce different patterns in certain critical brain regions between ADHD'ers and the general population. Interestingly, there are some genetic regions which may tie into this behavior.

With regards to nicotine metabolism, 2 genes appear to stand out in particular: CYP2A6 and CYP2B6 (note the similarity in nomenclature between these and the gene/enzyme mentioned above for Strattera metabolism CYP2D6. This is not an accident, as all three of these belong to the same "superfamily" of enzymes and carry many similar chemical and functional similarities). Out of these, the CYP2A6 (hereafter abbreviated as "2A6") enzyme is responsible for the lion's share of nicotine metabolism. It is coded for by by a gene of the same name, located in the "q13.2" region on the 19th human chromosome.

Like the 2D6 gene for Strattera, the 2A6 gene can exist in multiple different forms. Some 2A6 gene forms produce higher levels of the 2A6 enzyme than others. Other forms of 2A6 are less efficient, which results in a slower breakdown and clearance of nicotine. As a result, the nicotine stays in the body longer, and less of it is typically required. As a result individuals with these less efficient forms (called "slow metabolizers") of the 2A6 genes are less likely to develop nicotine addictions.

The relevance of these 2A6 genes on ADHD: The stimulating effects of nicotine are believed to be a major contributing factor to the higher prevalence of smoking among the ADHD population. If this is true, then slow metabolizers of nicotine may not derive the full effect of nicotine self-medication for attentional deficits, at least not as immediately as the fast metabolizers. On the flipside, they have lower cravings (like with virtually all stimulant drugs, the speed and rate of uptake and clearance of nicotine is a major factor in its addiction potential) and are exposed to less tobacco and often find it easier to quit smoking.

At least two alleles or forms of the 2A6 gene (using the "star/number" nomencalture us used in 2D6 for Strattera earlier in this blog), have been shown to coincide with slower rates of nicotine metabolism. They are 2A6*2 and 2A6*4 (these two forms are actually referred to as "null alleles" meaning that the 2A6 enzyme they code for has no activity).

Additionally, there are noticeable differences in the frequencies of these forms across different ethnicities among the global population. For example, these "slow metabolizing" gene/enzyme forms of are found in higher percentages in individuals of Asian ancestry (around 20%) compared to those of European descent (around 8%).

With regards to ADHD behavior, it is likely that people possessing these *2 or *4 forms of the CYP2A6 gene, may be less likely to use nicotine as a self-medication tool for their ADHD, or at least use the drug in lower doses, due to its lesser effects. On the flipside, however, there is another allele of the 2A6 gene, referred to as CYP2A6*1B. This version of the 2A6 nicotine metabolism gene actually promotes greater activity of the nicotine metabolizing enzyme, and speeds up the processing and clearance of the drug. As a result, individuals who possess this relatively rare CYP2A6 form may be more prone to more frequent use and abuse of nicotine, and individuals with ADHD who attempt to self-medicate with this drug may cycle through their nicotine more rapidly if they carry this *1B form of the gene.

Interestingly, another drug, bupropion (Wellbutrin), which is an anti-depressant often used off-label to treat more "depressive" forms of ADHD is a relatively common anti-smoking drug. Given the fact that a number of ADHD'ers who typically do not respond well to stimulants, but do respond to Wellbutrin may fall in this smoking category, it is possible that the fast metabolizers (i.e. the *1B individuals), may be good candidates for Wellbutrin, not only to stop smoking, but possibly also to treat unwanted ADHD symptoms.

Alleles of the CYP2B6 gene and enzyme with regards to nicotine and ADHD:

Shifting gears for a minute, we see that the CYP2B6 gene (as well as the enzyme which it encodes) also may also play a unique role in ADHD. The CYP2B6 gene is located on the 19th human chromosome (in the 13.2 region of the 19th, to be more specific). For individuals who lack CYP2A6 enzyme activity because of the reduced-activity or even "null" alleles, the enzyme CYP2B6 can metabolize nicotine in its place (it turns out that CYP2D6, the enzyme responsible for Strattera metabolism can also do the trick). For those who need to metabolize nicotine, but lack an effective CYP2A6 enzyme system, this is good news (however, this "B6" enzyme only functions at about 10% of the level of the "A6" enzyme, so B6 is not a very efficient "backup" for A6).

Beyond its role as a "backup" for the CYP2A6 enzyme, CYP2B6 may also be of clinical significance with regards to ADHD and similar disorders. In contrast to "A6", whose enzymes are predominantly generated in the liver, the CYP2B6 generated enzymes are expressed in brain tissue. With regards to the differences in neurochemistry and neurological functioning of the ADHD brain, the role of CYP2B6 is therefore potentially noteworthy.

Additionally, as we have discussed in earlier posts regarding ADHD and alcoholism, the 2B6 enzyme apparently also plays a role in alcoholism, and individuals who express higher levels of this genetically-encoded CYP2B6 enzyme in their brains may be more sensitive to alcohol, nicotine and other centrally acting drugs. The study even suggests that individuals with high levels of this gene-coded enzyme may be more prone to damages induced from these common chemical agents, including possible higher susceptibility to cancer.

For reference (using the "star" notation again), genetic forms of CYP2B6 which typically yield higher levels of this enzyme in the brain include the CYP2B6*4 (which shows up in about a third of the European popluation) form and the CYP2B6*9 (which is present in about a quarter of those of European descent) form. Again, don't worry too much about the specifics of these "starred" variants, just know that if you were to get a genetic screen and had one of these two enzymatic forms, you may be more sensitive to nicotine as a self-treatment ADHD "medication".

What this means is that ADHD individuals who harbor the higher-expressing "*4" and "*9" forms of the CYP2B6 enzyme in their brains may be more sensitive to chemical agents such as nicotine, and these same individuals may be more likely to suffer the toxic effects of this popular form of ADHD "self-medication".

In conclusion, we should note that some of these genes (such as DAT) have been well-studied and have repeatedly shown to be associated factor in proper dosing of ADHD medications. Others, however, such as the trypsinogen gene for Vyvanse are more at the theoretical level at the moment. However, this blogger believes that in the next couple of decades, (due in part to our expanding knowledge of the human genetic code and functional genomics), genetic screens will become foutinely more commonplace as a necessary tool for both prescribing and dosing medications. With regards to this general trend, psychotropic medications for disorders such as ADHD should be no exception.

Methylphenidate, Anxiety and ADHD: How do they fit together?

Effects of Comorbid Anxiety on Methylphenidate Treatment in the ADHD Child:

Medication with stimulants such as methylphenidate has consistently proven to be a popular and relatively effective mode of treatment for the ADHD child. However, questions arise regarding its side effects. In particular, the effectiveness of methylphenidate (Ritalin, Concerta, Daytrana, Metadate) can be jeopardized if the child with ADHD also has some type of comorbid disorder (such as depression, obsessive compulsive behaviors, Tourette's and a host of other common associate disorders) which may be negatively impacted by the ADHD treatment. Anxiety-related disorders are seen in up to 35% of ADHD individuals, according to some studies.

Typically, treatment is met with some type of adjunctive medication to treat the comorbid disorder (which can be quite tricky, as it introduces the problem of potential drug-drug interactions, as well as a possible impairment in the effectiveness of the ADHD treatment medication), a non-stimulant method of treatment such as Strattera (atomoxetine), or non-drug alternatives (behavior therapy, EEG, nutrition and dietary strategies, etc.). While isolated behavioral therapy has limitations for treating ADHD (especially in cases of "refractory" ADHD), it has proven to be a beneficial mode of treatment for childhood anxiety disorders.

In the case of anxiety disorders alongside ADHD, treatment with stimulant medications such as methylphenidate can also be tricky. However, recent findings seem to indicate that methylphenidate is a safe mode of treatment for ADHD with comorbid anxiety. However, a new publication notes that there may be a significant distinction between the effects of anxiety on methylphenidate's effectiveness from a behavioral standpoint vs. a cognitive standpoint. Let me explain further.

When attempting to determine whether a child should be diagnosed and treated as having ADHD, the supervising physician often gives out rating forms to both parents and teachers of the child in question. Numerical rating scales with regards to classic ADHD symptoms (i.e. impulsivity, hyperactivity, inattentiveness, etc.) comprise the majority of the rating forms, and these results are tabulated and typically used in the diagnostic process. Additionally, these rating forms are often administered after a specific period of time following treatment (with medication, nutritional therapies, counseling or ADHD coaching programs, etc.) to assess the effectiveness of these treatments.

While the level of agreement between parent and teacher rating forms is generally high, significant differences may often be seen. In other words, how a child's perceived behavior in the home may be notably different than his or her behavior in the classroom. While there are an array of possible factors and explanations for this, the presence of comorbid anxiety may be an important but often overlooked reason for this discrepancy.

In the study titled: Predicting Response of ADHD Symptoms to Methylphenidate Treatment Based on Comorbid Anxiety, the researchers found that the behavioral improvements in children with ADHD were similar regardless of whether the child also had an accompanying anxiety disorder. In other words, a notable decrease in symptoms of hyperactivity, impulsiveness and behavioral annoyances was frequently seen. Since these symptoms are often more of the obvious tell-tale signs of the disorder, it would be easy to conclude (especially from a parent's standpoint) that all is well again.

However, on the opposite side of the coin, the side dealing with the cognitive deficits of ADHD (which, not surprisingly have immense academic implications), may tell a different story. The study found that for the ADHD children without an accompanying anxiety disorder, methylphenidate treatment often contributed to vast improvements in their cognitive function (and subsequent academic achievement potential). However, if the ADHD child did have an accompanying anxiety disorder, the methylphenidate treatment was significantly less effective (and possibly even counter-effective). This may serve as a possible explanation for at least some of the variability between parent and teacher evaluations of the same ADHD child.

This leads to the question: does comorbid anxiety affect the cognitive ability-enhancing effects in all academic areas or just in some of the sub-fields of academic-related cognitive functioning?

The study investigated this by administering a Weschler Intelligence Test (WISC III) to the children and examined the effects of comorbid anxiety and methylphenidate medication on three subcomponents of the test: Coding, Arithmetic and Symbol Search. An explanation of the results in these three subcategories with regards to what they measure, possible implications of these subcategories, and the effects of anxiety and methylphenidate treatment are summarized below:

• Arithmetic: This is a timed test in which arithmetic questions are orally presented to the children and the responses are measured, assessing both speed and accuracy. Methylphenidate treatment produced a slight improvement in the ADHD children without comorbid anxiety. However, for the children with comorbid anxiety, the use of methylphenidate was ineffective (in fact, a slight decrease in performance was seen, but this was exceedingly small. It should be concluded that methylphenidate treatment had no reasonable positive effect for the ADHD children with comorbid anxiety for this particular subcategory).
  
  This should lead to an array of questions, including ones such as "does anxiety hamper one's performance in math, if one is ADHD (or even if one is not ADHD)?". Intuitively, we would expect the answer to be "yes", as evidenced by the huge number of children (and adults) who have self-reported "mathphobia". However, some well-reputed studies seem to indicate that methylphenidate treatment can actually help with mathematical abilities. Is there something else going on here?
  
  One potential explanation (not mentioned in the study) may reside in the possible presence of a third comorbid factor, such as an underlying comorbid auditory processing disorder. Auditory processing disorders are relatively common in individuals with ADHD, however, since the two disorders often exhibit symptomal overlap, comorbid auditory processing disorders are often missed in ADHD children.
  
  Interestingly, some recent evidence has come out that there may be a connection between auditory processing issues and anxiety disorders. This possible link between anxiety and auditory processing disorders has been addressed previously in another section of this blog. Note that the arithmetic subsection is administered orally in the WISC III test.
  
  If the theory that auditory processing difficulties are seen alongside anxiety disorders, it is entirely possible that the discrepancies in the ADHD with comorbid anxiety performances me be largely due to the nature of how the arithmetic portion of the test is administered. It would be interesting to see if any improvements were seen in the arithmetic scores were improved in the anxiety subgroup if the questions were presented in a written, non-auditory format.

• Coding: This section of the WISC III test measures skills involving visual-spatial coordination, speed and concentration. The individual (for those over 8 years old) is instructed to copy a line of code substituting a number for a symbol (this would involve something along the lines of writing, say, a "1" where a star is presented, "2" for a "circle", "3" for a smiley face, etc.). A high performance in this section has implications for advanced academic tasks that involve utilizing tables and formulas (think of solving chemistry problems using data from a periodic table at the top of the page, etc.).
  
  In addition, a strong visual-spatial aptitude may have implications for things such as note taking skills and the like. As a result, a strength in this area may be particularly useful in upper-level courses involving the sciences, foreign languages and anything that requires an individual to "decode" and translate new information quickly. With regards to the anxiety vs. non-anxiety ADHD groups, both showed some degree of improvement with methylphenidate treatment for this subsection.
  
  However, the non-anxiety group showed a significantly greater positive response (around twice as big of an increase in scores for this subsection following methylphenidate treatment as the comorbid anxiety group) to the methylphenidate treatment, suggesting that comorbid anxiety was a relative impediment to methylphenidate-mediated improvements in this area as well.

• Symbol search: This subsection involves picking out or identifying whether a particular symbol is present in a row of symbols. It has direct implications on one's ability to pay attention to detail as well as the ability to quickly scan through information to find what is relevant. Both the anxiety and non-anxiety groups showed slight improvements following methylphenidate treatment, however, once again, the improvements in post-methylphenidate scores were about twice as large for the non-anxiety group of ADHD children.

Of the 3 subtests, methylphenidate treatment helped the most in the coding section, had minimal effects in the symbol search section and little (for the non-anxiety group) to no or negative (for the anxiety group) effects for the arithmetic section.

Other studies have also investigated the effects of comorbid anxiety on cognitive task performance in ADHD children. By and large, it appears that memory-based tasks are the hardest hit by an accompanying anxiety disorder when methylphenidate is administered as an ADHD treatment. Other studies have confirmed this finding on anxiety disorders impeding memory enhancement via methylphenidate treatment. This seems to agree with the data on the coding section, which involves a type of working memory for the symbol deciphering process.

Based on what we have covered here, it would be reasonable to scrutinize significant differences between parent and teacher ratings and behavioral and attentive improvements for the possibility of an accompanying anxiety disorder to go along with an ADHD diagnosis in a child. While anti-anxiety medications can be useful, and co-administered with ADHD stimulant drugs under the watchful eye of a carefully trained physician, there is also evidence that

These findings suggest that comorbid anxiety can be a serious handicap to achieving cognitive and academic-related improvements in response to stimulants such as methylphenidate. However, please note that, based on the main study of our discussion on ADHD, anxiety and methylphenidate, notable behavioral improvements were seen from methylphenidate treatment in both the ADHD + anxiety and the ADHD minus anxiety groups.

The implications of this discrepancy can be noteworthy. To the parent who is only marginally involved with their child's academic progress, and is simply concerned with getting more manageable behavior out of their ADHD child, the sharp reduction of negative behavioral symptoms may lull the parent into a false sense of security that all is well on the home front. This stratified response to the methylphenidate medication may be lost to the unassuming parent.

However, it may be possible that an accompanying anxiety disorder (and maybe even an auditory processing disorder) may be lying there dormant to the oblivious parent. For the teacher, however, an improvement in classroom behavior due to medication, but a lack of improvement in academic work (especially in memory-related tasks) may be a tip-off that an undiagnosed accompanying anxiety disorder may be in place in this ADHD child. Thus this discrepancy in medication-derived improvements may actually serve as a potentially powerful diagnostic tool for detecting an accompanying anxiety disorder in a child being treated for ADHD.

ADHD, Methylphenidate and Blood Sugar Levels

ADHD medications may interfere with blood sugar levels and glucose metabolism:

When we think of common side effects of ADHD medications (especially of the stimulant variety), we often consider things such as cardiovascular risks (increased heart rates and blood pressure), appetite suppression (which may subsequently result in temporary growth impairment), interference with sleep, dampening of creativity and emotions (i.e. taking on a zombie-like state), irritability, moodiness, and the like.

However, it appears that another equally important, but often less-considered side effect of many ADHD medications is a change in blood sugar and glucose metabolism. The first part of this post will investigate some of the research out there on the effects of common ADHD medications on brain glucose metabolism. The second half will zero in on some of the general metabolic differences between the ADHD brain and the non-ADHD brain, and will also investigate possible effects of age, gender and co-existing disorders:

1. A drop in blood sugar following methylphenidate treatment: A case study involving a diabetic woman who underwent a surgical operation for a brain tumor. While we cannot make any logical conclusions about the population based on one individual of unique needs, the fact that a pronounced drop in blood glucose (over 25%) following methylphenidate treatment is at least worth noting. It is unclear as to whether the effects were due merely to the methylphenidate (common forms of this drug include Ritalin, Metadate and Concerta), or rather to a drug-drug interaction.
   
   
2. Methylphenidate reduces required brain glucose amounts to perform cognitive tasks: A study done at the National Institute of Drug abuse found that the administration of methylphenidate reduces the amount of glucose (the brain's desired energy source) needed to perform a thinking task. It is believed that this lower energy requirement is mainly due to less "wasted" energy from a constantly wandering and side-tracked mind, such as one seen in individuals with ADHD.
   
   Interestingly, this same study also found that during non-cognitive tasks, the differences in brain energy requirements did not change with or without the drug. This may at least call into question the merits of ADHD stimulant medication usage if higher order cognitive tasks are not required. Furthermore, if the brain is already focused, the utilization of methylphenidate may even be overkill. The authors concluded that this may be a primary reason why adverse effects in concentration and focus can be seen when methylphenidate is administered to "normal" functioning brains.
   
   
3. Methylphenidate's influence on brain metabolism may be regio-specific: Another study done by the same author as in study #2 found that the effects of methylphenidate on brain glucose metabolism may depend on individual subregions of the brain. For example, this study found that for the basal ganglia region of the brain (this brain region essentially governs how fast a particular individual's brain "idles"), the relative activity of this brain region was typically reduced following methylphenidate treatment, compared to activities in other brain areas. This may be a bit counter-intuitive, since basal ganglia activity is typically lower in individuals with ADHD and higher in individuals with obsessive compulsive or anxiety-ridden behaviors.
   
   However, other brain regions such as the frontal and temporal regions of the brain (which are responsible for filtering out unimportant external stimuli and inhibiting impulsive behaviors, and, perhaps not surprisingly, often show lower levels of activity in the ADHD brain), experienced a boost in metabolic activity following methylphenidate treatment. It is believed that these responses are modulated through categories of receptors for the brain chemical dopamine (called Dopamine D2 receptors, which help control levels of this important neuro-signaling agent, which is often deficient in key regions of the ADHD brain).
   
   In this blogger's opinion, this dual action of inhibiting impulsivity (which can potentially dampen creativity) and shutting down some of the basal ganglia activity may actually be a reason why "zombie-like" behaviors are sometimes seen in children medicated or overmedicated with stimulants for ADHD.
   
   
4. The "Energy Deficient" Hypothesis of ADHD: While still in the hypothetical stage, there is a fair amount of evidence suggesting that ADHD may be due, in a large part, to a lack of energy to specific neurons in key brain regions such as the prefrontal cortex (part of the "frontal" regions of the brain discussed in the past point). This ADHD as an energy-deficiency hypothesis carries that astrocytes (star-shaped cells that provide energy and nutrition for growth and repair of neuronal cells) may be starved of some of their important nutritional needs for glucose and related nutrients. As a result, they are unable to effectively "feed" the neurons in these key brain regions associated with governing attentional and impulsive behaviors in the brain. Should this hypothesis hold true, it would stand to reason that regulating and improving glucose levels either via either medication-manipulated, or alternative dietary methods may help offset some of the energy deficient imbalance in ADHD. Some natural supplemental options to boost glucose levels in the ADHD brain may include ginseng and carnitine.
   
   
5. Reduced brain metabolism in teenagers with ADHD: The results of this study on metabolic differences in teenage ADHD brains agree with many of the findings discussed in point #3 above. This study investigated the effects of an auditory-based attentional task on rates of brain glucose metabolism in adolescents with ADHD. It found that there was minimal differences between glucose metabolic patterns in the brains as a whole when comparing the ADHD and non-ADHD individuals.
   
   However, it is also worth mentioning that in other related studies on brain metabolism in teens with ADHD, it was found that metabolic deficits were seen at significantly lower levels throughout the brain as a whole. Interestingly, according to the second study mentioned, these differences in brain metabolism were only seen in the girls with ADHD and not the boys, which suggests possible gender-specific differences in the etiology of the disorder.
   
   However, upon investigating for the more hyperactive forms of the disorder in the first study (remember that ADHD behaves as a spectrum, in which some individuals have the predominantly inattentive symptoms, while others exhibit the hyperactive and impulsive symptoms more readily, these different predominant features are typically grouped together as unique subtypes of ADHD), it was found that the hyperactive component of ADHD corresponded to a significantly reduced level of glucose metabolism in the whole brain. This brings up the question as to whether these metabolic differences exhibit any sort of subtype-dependent effects with regards to ADHD.
   
   Also, as in point number 3 above, metabolic deficits were apparent in more specific brain regions such as the left frontal lobe regions of the brain. Even more remarkably, there appeared to be somewhat of a sliding scale with regards to the relationship between reduced glucose metabolism and increased symptom severity in this particular "hot spot" (the left frontal lobe) region of the ADHD brain.
   
   The following sidenote is a personal comment by the blogger regarding some of the methods of the previous study. As mentioned above, the test for this adolescent ADHD study involved an auditory based attention task. However, as discussed in earlier posts on this blog, we have seen that auditory processing disorders sometimes accompany ADHD.
   
   Furthermore, due to a high degree of symptom overlap, a comorbid auditory processing disorder can often be missed in an ADHD child or adolescent. Because of this, we should not rule out the possibility that comorbid auditory processing issues may interfere with the results of studies such as this one.
   
   We can see that auditory processing takes place in multiple regions throughout the brain, many of which do not have significant overlap with the "ADHD brain regions". One would expect the brain of an individual with an auditory processing disorder to work harder to achieve the same results as that of a non-auditory disordered individual. Thus, a confounding processing disorder could, in theory result in an increased demand for energy utilization to the portions of the brain responsible for stimulatory processing, which could leave less available energy for the frontal lobe regions of the brain responsible for modulating hyperactive and impulsive ADHD behavior. These assertions remain hypothetical at the moment, but this blogger feels that the presence of undetected comorbid disorders can easily skew the results of these metabolic studies on the ADHD brain.
   
   
6. Age-Dependent Decline in Brain Glucose Metabolism in Adults with ADHD: Apparently, metabolic differences in ADHD brains are not limited just to children, adolescents, and young adults with the disorder. Some of the findings of this following study may seem inherently counterintuitive at first. While ADHD symptoms often decline as an individual with the disorder ages, we would expect that an accompanying level of improvement in glucose metabolism in ADHD-specific brain regions would hold true. However, according to this study on brain glucose metabolism in older ADHD adults, it appears that the opposite is actually the case.
   
   The authors hold that the decrease in glucose metabolism may actually be markers of a more efficient process of brain metabolism (i.e. these older ADHD brains may somehow conform to an efficient energy-conservation state allowing them to function more optimally, thereby decreasing the prevalence of ADHD symptoms), although this finding is somewhat suspect in this blogger's personal opinion.
   
   As an interesting side note, the decrease in brain glucose metabolism in adults is apparently gender-specific, according to the study. This parallels the findings from some of the adolescent ADHD brain metabolic studies. The notable metabolic decreases were observed in women with the disorder to a much larger degree in men. The authors of the study suggested this may be due to hormonal influences, such as changes in post-menopausal women.
   
   Given the anecdotal evidence supporting the association between ADHD and higher onsets of neurodegenerative diseases later in life, this blogger finds the results of this study to be of particular interest. There may even be some claims that genetics may be partly to blame for the overlap between ADHD and neuro-degenerative diseases. For example, a gene referred to as DAT1 (short for dopamine transporter gene 1, located on the 5th human chromosome) may be connected to both ADHD and parkinsonism (a secondary or alternate form of Parkinson's disease). DAT1 also helps regulate dopamine function, (although via a different method than the dopamine receptors mentioned in point #3), by coding for an enzyme that helps transport or shuttle dopamine into and out of neuronal cells. We have discussed these dopamine transporter genes in earlier posts.

We have covered a number of works on the metabolic differences of glucose in the ADHD brain, and how they differ from the brains of non-ADHD individuals. There is the distinct possibility that stimulant medications used to treat ADHD, such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana) can significantly alter brain glucose requirements. It appears that significant differences in brain glucose utilization patterns and efficiency may affect the entire brain, but certain ADHD "hot spot" regions of the brain may be particularly hard-hit. It is unclear whether this is due to preferential metabolic differences of the ADHD brain (compared to the "normal" brain), or whether it is due to an all-out brain energy shortage.

It is also worth noting that significant gender-specific factors may also affect this process, with ADHD girls in particular showing the greatest metabolic deficits. It also appears that these effects are also being observed across the lifespan of the ADHD individual. Finally, there is at least a hypothetical possibility that sensory processing difficulties or other comorbid disorders commonly seen alongside ADHD may also play a role in these metabolic differences of ADHD brains.

10 Ways Zinc can Combat ADHD

Here are 10 reasons why zinc may be an effective treatment method for ADHD and related disorders:

1. Protection against oxidative damage of omega-3 fatty acids: We've previously discussed the role of omega-3's and their use as a treatment option for ADHD. However, the downside to this is that these fats (along with many others) are prone to oxidation. As a result, dietary antioxidants are needed to preserve these effects. According to a work by Villet and coworkers, zinc may be beneficial in retarding this omega-3 fatty acid oxidation process. As a result, zinc may be a good supplement to go alongside omega-3 treatment for ADHD.
   
   
2. Conversion of Vitamin B6 to its active form: We have mentioned the role of vitamin B6 and its role in the treatment of ADHD, including how B6 can work alongside another key nutrient, magnesium. Zinc is needed to convert the inactive form of the vitamin B6, pyridoxine, to the active form pyridoxal phosphate. Thus, zinc is needed in vitamin B6 metabolism.
   
   
3. Production of melatonin: Melatonin is a hormone we have also discussed earlier with regards to its effects on ADHD in an earlier post titled CREM gene, melatonin and ADHD. It appears that melatonin deficiencies may be attributed to a shortage of zinc. In short, melatonin plays a role in regulating the important neuro-chemical signaling agent dopamine, which is a key neurotransmitter involved in the symptoms and treatment strategies for ADHD.
   
   
4. Zinc can modulate or affect thyroid function, especially when melatonin is a factor: We have also discussed how thyroid dysfunction may closely mimic ADHD symptoms, and highlighted the importance of iodine to combat this . Now it appears that imbalanced melatonin levels may disrupt the thyroid. However, zinc may combat the negative effects of excessive melatonin on thyroid function. Combining this point with the previous one, we now see that zinc may be needed not only for the production of melatonin, but can actually be used to reel in this hormone when excessive melatonin levels lead to unwanted side effects such as thyroid dysfunction. Thus, it appears that zinc may play a role of double duty with regards to regulating melatonin production and curbing the negative effects of its excess.
   
   
5. Production of serotonin: This piggy-backs on the vitamin B6 role highlighted in point number 2 above. ADHD is often considered a disorder associated with the neurochemicals dopamine and norepinephrine. However, serotonin may also play a role in this disorder. For individuals who exhibit anxiety and depressive symptoms alongside their ADHD (which is surprisingly common), a serotonin deficiency is often partly to blame. Serotonin is synthesized in the body from the amino acid tryptophan. However, for this conversion process to go through, sufficient and functional vitamin B6 is required for serotonin to be formed by the tryptophan conversion process via a special type of enzyme known as aromatic amino acid decarboxylase. As previously mentioned, zinc is needed for functional vitamin B6, and therefore plays an indirect role in the synthesis of serotonin. Thus, zinc may be extremely important in individuals with ADHD and comorbid (co-occurring) depression or depressive-like symptoms.
   
   
6. Reduction of hyperactivty, impulsivity and antisocial behavioral symptoms: For direct treatment of ADHD, it appears that zinc may be more effective in treating the hyperactive/impulsive aspects of the disorder than the inattentive portion of the disorder. This study also noted the effectiveness of zinc for older children and children with a higher body mass index, which at least suggests that the effectiveness of zinc as a treatment for children with ADHD may increase as the child ages and grows.
   
   
7. Zinc may also play a role in the process of brain waves associated with ADHD as well as other disorders: We have already investigated differences and discrepancies in the brain wave patterns of ADHD children, including how these may actually be tied to an individual's genes. Information processing, which is often impaired in ADHD individuals, is believed to be tied to a brain pattern known as N2 (which is short for second negative wave, no need to concern ourselves with the exact details of this process here). Some research suggests that N2 mediated information processing may be negatively affected by zinc deficiency. This relates to unwanted attentional shifting (i.e. distraction) to irrelevant stimuli. In other words, N2 is related to the "novelty effect" of a specific stimulus or change in stimuli. As an interesting aside, N2 brain patterns are thought to be affected by serotonin, which, as mentioned in point #5, is indirectly tied to zinc levels. Based on this, it is at least plausible that zinc may play an integral role in this mechanism of distraction.
   
   
8. Boosting the effectiveness of ADHD medications: While we have reported on this in an earlier post on zinc and Ritalin, I believe it is worth repeating here. Multiple studies suggest that zinc can boost the effectiveness of methylphenidate for treating ADHD and related disorders. This may be of importance with regards to reducing some of the negative side effects associated with the drug. Many of these negative side effects often don't set in at the lower doses of the various forms of the drug, but instead, begin to appear with greater frequencies at higher doses. Taking this into account, it seems reasonable (at least in this blogger's opinion) that concurrent treatment with zinc may be enough to hold some of these methylphenidate dosages below the threshold of some of these negative symptoms, thereby increasing the tolerability of this common ADHD drug.
   
   
9. Zinc Inhibition of the Dopamine Transporter Protein: This may offer a further explanation as to why zinc is effective in boosting the effectiveness of methylphenidate. We have spoken extensively about the dopamine transporter (DAT) protein and its effects on dopamine levels and ADHD. Several ADHD medications, especially of the stimulant variety (such as methylphenidate), work by inhibiting or blocking DAT. It appears zinc may also act as a natural DAT inhibitor, thereby mimicking the effects of some of the more commonly used drugs.
   
   In my previous post on zinc and its amplification of Ritalin's effectiveness, I wondered aloud as to whether zinc could be used as an outright substitute for the medication methylphenidate. While still a personal hypothesis, I still believe that for low level doses, zinc may be an ample natural alternative, but, this hypothesis obviously needs to be tested at a clinical level. Nevertheless, I personally believe it to be worthy of investigation.
   
   
10. Zinc as a possible treatment option for juvenile growth impairments: It is suggested that children with ADHD exhibit a delay in the overall growth process. We actually discussed this very topic in an earlier post titled: Do ADHD stimulant drugs stunt growth? Now it appears that zinc may possibly play a role in this. Using a primate model of zinc deficiency, Golub and coworkers found that zinc deficient monkeys showed a slowing of the growth process during what would normally be a period of growth spurt. If this translates into humans, then it is possible that underlying growth and attentional impairments, as well as abnormalities in activity levels (which is sometimes evident in children with ADHD, often more alongside those with the inattentive subtype of the disorder), may actually be due to zinc deficiencies.
    
    Perhaps on an even more interesting note, the study found that "attention performance was also impaired before the onset of growth retardation". In other words, an attentional deficit may serve as a proverbial canary in the coal mine that a child may suffer from a subsequent delinquency in growth in the upcoming years. As a result, this blogger personally believes that some of these "attentional deficits" may not simply indicate an isolated case of ADHD, but rather serve as a warning of a much larger underlying problem that may be tied to a nutritional deficiency. Furthermore, it is at least possible that the underlying problem of attentional deficits and growth impairments in children with ADHD may be remedied by an intervention strategy that involves adequate dietary zinc or treatment via zinc supplementation.
    

This list of zinc levels and the direct or indirect relationships to ADHD is by no means extensive. Further connections, such as the relationship between zinc deficiencies and digestive disorders such as Crohn's disease, should also be noted. On an interesting note, a very recent publication came out evaluating the effectiveness of various nutrition supplementation strategies for treatment of ADHD listed zinc as the nutrient of most promise.

Given that zinc deficiencies are common in both Western countries such as the U.K., as well as developing countries such as China it seems evident that ADHD symptoms may be part of a larger picture, a proverbial cry for help due to a widespread nutritional deficiency. In addition to ADHD, other disorders dealing with cognitive development may be susceptible to zinc deficiencies. Of course, a great deal of further study is needed to back up this assertion, but it leads us to wonder exactly how often a case of ADHD is actually due to something as simple as a deficiency in zinc or another common nutrient. We will have further discussions regarding this important mineral in future posts.

Ritalin and Cocaine: Similarities and Differences

We have previously investigated some of the similarities between the chemistry and modes of action of Ritalin and cocaine. In this past post, however, we looked more at the rates of uptake and metabolism of the two drugs and investigated a side-by-side structural comparison.

I was originally planning on continuing with posts on Daytrana, which is very similar to the more common ADHD medications Ritalin and Concerta (it is actually comprised of the same chemical agent, methylphenidate. However, I recently saw an interesting article on the topic of methylphenidate, cocaine and nicotine, and the mechanism of interaction between these different stimulants. As a result, in lieu of the Daytrana postings, I would like to discuss these findings in the next couple of posts.

Here are seven key points to be aware of regarding the similarities and differences between methylphenidate and cocaine:

1. SIMILARITY: Uptake patterns into the brain: Both methylphenidate and cocaine enter the brain at similar rates and target similar specific regions of the brain. When injected, around 7.5% of the injected compound makes it into the brain tissue for each compound at similar rates (peak uptake only takes around 2 to 8 minutes for cocaine and 4 to 10 minutes for methylphenidate in the injected form, oral administration, which will be discussed later, is significantly longer, especially for methylphenidate). The most favored target region of the brain is the striatum for both cocaine and methylphenidate (see brain diagram below). In fact, several studies have indicated that the two drugs share a number of target binding sites within the brain, to the point where the ADHD medication methylphenidate has actually been used as a treatment option for cocaine abuse.
   
   
2. Brain Regions Targeted by each drug: In addition to similar uptake patterns in the brain between the two drugs, there is a relatively large degree of overlap for particular brain regions targeted. However, there is at least one notable exception, which bears relevance to our discussion. On an interesting note, the method of delivery not only affects the speed of uptake of a drug (injected is almost always faster than snorted, which is almost always faster than ingested), but also the actual brain regions targeted by the drug. For example, another brain region, called the Nucleus Accumbens (see image below for approximate location) is targeted by cocaine and injected methylphenidate. However, when methylphenidate, such as Ritalin, Concerta or Metadate is taken orally, this nucleus accumbens region is not targeted (at least not anywhere near the level of injection).
   
   The nucleus accumbens is believed to play an important role in the addiction potential of a number of drugs, including many stimulant medications. Thus, proper use of the methylphenidate medication actually bypasses a key brain region believed to be critically involved in the "high" or addiction process of a stimulant drug. This highlights a major difference in the pharmacology between Ritalin and cocaine.
   
3. Key Difference between methylphenidate and cocaine: Rate of clearance from the striatum region of the brain: As mentioned in an earlier post, the addiction potential of a drug is typically correlated to the rate of exit or clearance from the brain. In other words, drugs that linger in the brain's receptors for extended periods of time are often much less addicting than ones which exhibit a short and rapid spike in their brain levels and then a quick drop-off in their concentration in the brain. In the striatum, the rate of clearance takes about 90 minutes for methylphenidate, and only 20 minutes for cocaine. If we go by peak concentration duration (i.e. the amount of time the highest concentration typically lasts in the brain before going back down), we see that methylphenidate's peak lasts around 15 to 20 minutes, while cocaine's is a fleeting 2 to 4 minutes. In both cases, the higher dissipation of the drug from high levels in the brain is much more pronounced in cocaine, giving this drug a much more addiction-worthy effect over methylphenidate (even when methylphenidate is abuses and either snorted or injected, it still cannot match the rates of clearance of cocaine).
   
   
4. Potency of the two drugs: The following may seem surprising at first. With regards to specific brain targets, methylphenidate is almost twice as potent as cocaine. We have discussed at length the role of the dopamine transporter protein (DAT), and its role in ADHD and related disorders. Essentially, this DAT protein is responsible for retaining a proper balance of the important brain chemical dopamine in and out of nerve cells. For individuals with ADHD, this balance is often skewed, typically with too much dopamine being taken up into the neuron cells and not enough in the gaps between the cells. Many stimulant medications remedy this problem by essentially binding to and plugging up the dopamine transporter proteins in the nervous system, which inhibits their abilities to shuttle dopamine into the cells. As a result of this medication-effected correction, dopamine balance can be somewhat restored. As a frame of reference, based on some of the current literature, it takes often takes at least a 60% saturation of these dopamine transporters with a drug to elicit the "high" (of course, there is a significant degree of variation between individuals).
   
   With regards to potency, we see that both cocaine and methylphenidate love to bind to these dopamine transporter proteins. To shut down the function of these dopamine transporter proteins to 50% of their original function (a common way of measuring the potency of a drug in pharmaceutical and laboratory testing), a 640 nanomolar concentration was needed for cocaine, while only a 390 nanomolar concentration was needed for methylphenidate to do the trick. If you're not familiar with these units of concentration, don't worry. These numbers work out to very small amounts (around the neighborhood of only 0.001 grams of drug per liter of fluid). I just put the numbers out there to show that only about half the amount of methylphenidate was needed to share the same effects with cocaine (i.e. the methylphenidate is approximately twice as potent for this particular process).
   
   
5. Difference between Ritalin and Cocaine: DAT saturation levels and perceived high: The relative saturation of these dopamine transporters are also believed to play a role in the "high" of stimulant drugs such as methylphenidate and cocaine. However, research by Volkow and coworkers found that while the level of saturation of the dopamine transporters with cocaine correlated with the "high" associated with this drug, the methylphenidate drug tells a different story. As mentioned previously, the reinforcing effects of a drug including the "high" typically correlate with the rate of clearance from the brain.
   
   We have also seen that methylphenidate clears much more slowly than cocaine. However, in the case of methylphenidate, the diminished effects of the the high occurred long before the drug had fully cleared from the dopamine transporter. In other words, there appears to be a relatively strong connection between the binding of cocaine to the dopamine transporter proteins and the perceived "high" but the effects are much less pronounced with methylphenidate. This highlights a major difference between methylphenidate and cocaine and at least suggests the possibility of a difference in mechanisms between the two stimulants.
   
   
6. Divergence in metabolic patterns between methylphenidate and cocaine: Furthering this issue a bit more, there is some evidence that the pathway of the two drugs is almost identical for the first part of the journey into the system, but their modes of action split off at some point when it comes to dopamine transporter occupancy and the corresponding reinforcement effects (see sketch below).
   
   
   
7. Difference between methylphenidate and cocaine: Drug lingering and tolerance: The persistence of methylphenidate on the dopamine transporter proteins may result in more than its reduction of abuse potential. It also appears that this "lingering" of the drug on these dopamine transporter proteins may also play a significant role in the phenomena of tolerance to methylphenidate.
   
   Acute tolerance to methylphenidate is nothing new. Newer formulations of the drug (Concerta, Metadate) were designed in part to address the problem of the reappearance of ADHD symptoms by ramping up and releasing increased levels of the drug throughout the day. This is important, because, the effects of methylphenidate appear to be best felt when its levels are climbing or building up, and not stabilizing (i.e. you do not want a constant level of methylphenidate throughout the day, but rather a constantly increasing one to maintain the same effects). Essentially, this is "micro-tolerance" to methylphenidate and is seen on a daily level. The ideal dosing strategy for methylphenidate typically entails a morning dosage which is approximately 50% of an evening dosage, i.e. a "ramping" effect of the drug throughout the day is often needed to maintain the desired results.
   
   It is suggested that this tolerance to methylphenidate may be due, at least in part to its continued presence and relatively slow clearance in specific areas, such as on the dopamine transporter proteins. Other faster-clearing drugs, such as cocaine, do not exhibit this property. However, given the fact that cocaine tolerance is also common, it is unlikely that the whole "dopamine transporter saturation" theory can fully address the issue of tolerance for stimulant drugs. Volkow and coworkers explored this role of blocking dopamine transporters with methylphenidate and the perceived high in greater detail. Nevertheless, at least in this blogger's personal opinion, the lingering effect of methylphenidate still plays some degree of significance to the process of tolerance to the drug, and the need for ramping its dosage to treat disorders such as ADHD.

Daytrana Absorption and Metabolism Patterns Compared to Ritalin and Concerta

In the previous post, we introduced the relatively new ADHD medication Daytrana. Composed of the same chemical compound as Ritalin and Concerta (methylphenidate), Daytrana offers the distinct advantage of existing in the patch form, which is typically worn on the hip. At the present moment, this medication is used exclusively for children with ADHD and related disorders, although it can also be used off-label for adults with the disorder.

Given the entirely different delivery system of the patch form of Daytrana vs. the conventional pill form of Ritalin and Concerta, the question arises on how the rates and patterns of drug delivery compare between the two forms of the medication. A copy of a table from the previous post, titled Daytrana Dosing Equivalents to Ritalin and Concerta is given below:

Patch size refers to the size of the Daytrana patch worn by the individual. The total content of drug per Daytrana patch (in milligrams methylphenidate) and rate of delivery (per hour) of the different patch sizes are also listed above. The standard wear-time for the patch is 9 hours, so a comparison in total drug dosage for a 9-hour period is also listed. Finally, equivalents to Ritalin (Immediate release, abbreviated "MPH-IR", the dosage listed is given 3 times per day, in milligrams), as well as Concerta (given once per day, also in milligrams) are also listed.

As far as total methylphenidate content delivered, the three methods of comparison are all similar. However there are some differences in rates of delivery, drug absorption patterns, and drug metabolism between the three different methods. A comparison, based on a report from Pierce and coworkers on the pharmacokinetics of the methylphenidate transdermal system (a technical term for Daytrana) is highlighted below. Please note that some of the data are supplemented from other similar studies on children with ADHD, so don't take these numbers as absolute. There is still a large amount of variation between the different studies. Nevertheless, these values are, to the best of this blogger's knowledge and current research, a good representation of values typically found in the literature (sometimes numerical ranges are given in lieu of exact numbers to reflect this). In other words, look at the numbers for comparative purposes instead of absolute values. The important thing to note below are some of the trends and comparative differences between the different forms of methylphenidate.

About the table above:

The columns going across include Immediate Release methylphenidate ("MPH-IR", similar to short-acting Ritalin and the like), Osmotically released methylphenidate (MPH-OROS, which is the drug form used by Concerta) and the four different patch sizes of Daytrana currently available ("DT" 10, 15, 20 and 30, which reflect the amount of methylphenidate delivered in milligrams to the body over the standard 9 hour patch-wear time of the 4 different patch sizes, listed in our first table).

For the first column, Max Concentration reflects the highest concentrations of the drug methylphenidate which are typically seen (again, don't scrutinize the exact numbers too closely, just look for trends across the chart). The next entry, Time to Reach Cmax, reflects the approximate amount of time after first taking the methylphenidate capsule or putting on the Daytrana patch for this maximal concentration to occur (in hours, again, an approximation).

Effectiveness is a more relative term, but it is based on how long the desired effects typically last (in hours) of each drug formulation. Again, experts and studies disagree, so just use these as relative guidelines. Finally, the term half-life is used as a measuring tool for how fast the drug is eliminated or cleared from the body. For example, a drug with a half life of 3 hours means that every three hours, the amount of drug remaining in the system is cut in half (used in a similar matter to how radioactive decay is measured).

4 important trends to note from the table:

For convenience, the same table is listed again below.

1. Higher drug concentrations from the patch form: Note that much higher plasma concentrations are typically seen with the Daytrana patch form of the drug than the other delivery system. This is likely due to the route of administration which bypasses several enzymes and other metabolic factors in the digestive system reserved for oral delivery routes. As a result, higher plasma concentrations can more easily occur. This is especially apparent in the two largest Daytrana patch sizes, where maximum plasma concentrations are close to double the levels attained via the traditional oral delivery methylphenidate medications for ADHD.
   


2. Greater time to reach high concentrations: The time to reach these high concentrations is greater as well. This is often an advantage, given the fact that stimulant medications which exhibit the greatest abuse potential typically enter the bloodstream (and, subsequently the brain), extremely quickly (often in 15 minutes or less), and then leave the brain and body quickly. As a result, while this more drawn out process (relatively similar to that of Concerta, but slightly longer), is good news for lower abuse potentials. However, the relatively long time to reach maximum concentration can be difficult for seeing the desired effects shortly after medication. However, given the higher apparent "ceiling" for these patch-style delivery systems, adequate drug concentrations are typically seen within 2 hours (data not shown). In other words, medication effects can be felt long before these high maximal concentrations occur.
   


3. Longer duration of effectiveness: The pharmacokinetics study of the methylphenidate patch for ADHD noted that detectable levels of the drug, when given in the patch form, were still seen in the blood the next day, up to 15 hours after the patch was removed (although only around 5% of the maximum concentration). Nevertheless, this 9-hour patch delivery method may prove useful in maintaining a constant presence of the medication throughout the day, and may extend the drug's effectiveness beyond even some of the longest-lasting oral methylphenidate forms. This may prove useful for individuals who still need to control for lack of focus and hyperactivity, such as a child with a big homework project. Of course, the flipside to this could be a greater potential for long term side effects, due to the constant persistence of the drug (keep in mind that this Daytrana system is only 2-3 years old, so long-term evaluations are still not available to any sufficient extent).
   


4. Similar rates of clearance: Perhaps the most consistent parameter across the board, it appears that the clearance rates of the patch and oral systems of methylphenidate all seem to hover around the three hour mark. This suggests that once the drug is actually delivered (albeit by a different delivery system), the rest of the metabolic processes are pretty much the same for the different forms of methylphenidate.
   
   
   

The enantiomer effect of Daytrana:
Before going, I just wanted to mention another peculiarity of the transdermal (patch-based) form of the methylphenidate delivery system:

Most methylphenidate medications are actually a mixture of two compounds of the same formula that exist as mirror images of each other. These mirror images are called enantiomers. While they have the same chemical formula and structure, the two different mirror image forms of the drug can behave entirely differently. In some extreme cases, getting the wrong enantiomer or mirror image of a drug can even produce disastrous side effects. For example, for the drug thalidominde, which was prescribed for morning sickness in pregnant mothers was actually found to have one safe enantiomer, but the other enantiomer, or mirror image resulted in severe birth defects. As we can see, this one minor change in drug shape can have huge repercussions if we're not careful.

In the case of methylphenidate, however, the effects of the differnt mirror images of the drug are much less pronounced. However, one of the two enantiomers (called the "d form") of the drug is much more potent or active than the other form. As a result, new formulations containing only the more "active" form of the drug began to develop. The drug Focalin (dexmethylphenidate) is an example of this. It has been demonstrated that Focalin can produce similar effects to regular methylphenidate at half of the methylphenidate dosage. We will save further discussion on this topic for later posts.

The reason I mention this enantiomer effect is that the two mirror images of the methylphenidate are metabolized and cleared at different rates. What is interesting is that the actual form of delivery for the drug (i.e. the patch for Daytrana, or the oral form for Ritalin or Concerta) actually affects the ratio or balance of the two mirror images of the drug after short periods of time.

To illustrate, consider the following:

• For Methylphenidate Immediate Release (Ritalin-IR), the "L" form (the less active form) is almost non-existent shortly after dosage is administered. That is, the "D" form (the more active form, or the mirror image which exists exclusively for Focalin), is the overwhelmingly predominant form of the drug remaining within a period of 1-2 hours.

• For Concerta (a slower releasing form of the drug compared to the immediate release Ritalin form of methylphenidate), the ratio is still skewed shortly after administration of the drug, with the "D" form: "L" form exhibiting a ratio of around 40:1 (after a few hours). Once again, the more potent form of the drug predominates shortly after the drug is given, and the less active form is more quickly cleared.

• However, with Daytrana, the "D" to "L" mirror image ratio of the drug is still in favor, but not by nearly the amount of the two oral delivery forms (Ritalin and Concerta). In the case of Daytrana, the "L" form stays around longer, sitting at about 55-60% of the more active "D" form of the drug. It is still unclear at the moment as to why this is, but some possibilities include the difference in enzymes and enzyme systems used to break down the drug between the skin and the digestive forms of delivery. Nevertheless, this blogger would not be surprised to see another patch form of delivery comprised exclusively of the more potent "D" form of the drug (as in a patch form of Focalin) on the horizon as an even more effective treatment for ADHD.

To summarize, Daytrana appears to be an effective alternative form of delivering methylphenidate for children with ADHD. Given the fact that the individual can now control two variables (patch size and wear time), it appears that this form of the medication may be easier to tailor to the individual than the oral form of methylphenidate.


We will continue our discussion about some of the other pluses and minuses of the Daytrana form of methylphenidate and how they relate to strategies of ADHD treatment in the next few posts.