10 Ways Carnitine can help treat ADHD

Carnitine: The missing link to omega-3 supplementation for ADHD

Carnitine is one of the new "trendy" supplements out there today, due in part to the number of heart-healthy benefits that can be derived from it's usage (often alongside other new popular supplements such as Coenzyme Q10). I am not here to discourage these supplements, I definitely see a number of positives from taking them, but for this post I would like to address the topic on Carnitine and ADHD: Can Carnitine, with all of it's heart-healthy benefits, actually be useful in treating ADHD? Here are 10 possible reasons why carnitine may be a powerful new treatment option for ADHD and related disorders:

As a quick aside: Carnitine, like many other nutrients, can exist in different forms, one of which is acetylcarnitine. This form, actually has a number of metabolic roles, but for the sake of simplicity, I will not go into too much detail about the different forms of carnitine unless absolutely necessary.

1. Potential for boosting the effectiveness of omega-3 fatty acid supplementation: We have already discussed the theory and applications of omega-3's and their possible benefits as alternative non-pharmaceutical treatment options for ADHD. Nonetheless, despite the recent surge in population of omega-3's (including the ever-popular fish oil supplements), only marginal amounts of improvements as far as behavior and symptom reductions are often seen. A big possibility for this limited effectiveness may actually stem from missing pieces of the puzzle with regards to omega-3 metabolism. This may include a deficiency in carnitine. There is even some speculation that abnormalities in fatty acid metabolism may play a role in autism, and that carnitine levels may play a role in this. Given the degree of inter-relationship between autism and ADHD, this possible connection may be at least worth mentioning. In particular, carnitine plays an important role in the synthesis of the docosahexaenoic acid (DHA), and a carnitine deficiency can result in a reduction of this key nutrient. Like several other important fatty acids, DHA deficency is often seen in ADHD individuals.
   


2. Carnitine may be beneficial for "refractory" ADHD (unresponsive to conventional pharmaceutical treatment): This one is somewhat surprising. Typically supplementation and "natural" measures can be tried, but if they fail, the more "heavy-hitting" pharmaceutical treatment options for ADHD are often employed. However, a Dutch study done by Van Oudheusden and Scholte which investigated the efficacy of carnitine in treating children with ADHD mentioned that carnitine was found to be effective in treating ADHD in children who were previously unresponsive to methylphenidate, clonidine or behavioral therapy treatments.
   
   What's interesting is that this group found a strong connection between plasma carnitine levels and a reduction in behavior problems (i.e., those children who were able to build up higher levels of carnitine in the blood were more likely to show direct benefit with regards to ADHD symptoms, while those with lower blood levels exhibited more severe ADHD-like behavior). This strongly suggests the carnitine/ADHD connection and also highlights the fact that there is a relatively wide degree of variation among individuals as far as carnitine storage and metabolism is concerned. Even more interesting, this same group found that when carnitine treatment was discontinued, the negative ADHD symptoms re-appeared relatively soon (within 3-4 weeks), but upon re-administration of the previous carnitine doses, the behavioral problems quickly subsided again.
   


3. Potential for use for both inattentive and hyperactive/impulsive ADHD: The same study on carnitine treatment for ADHD noted that a decrease in aggression and conduct problems (which are often comorbid to or co-occur with the more hyperactive/impulsive side of ADHD) upon treatment with carnitine. Not to be outdone, another study found that carnitine was more useful in treating the inattentive subtype of ADHD. Interestingly, the inattentive ADHD study found that individuals with the combined subtype ADHD subtype (which includes high levels of both the inattentive and hyperactive/impulsive behaviors) actually showed a worsening of symptoms upon treatment with carnitine.
   
   It's important to note that the Dutch study did see some improvement in inattentive symptoms as well, so it appears (at least for now), that carnitine may be more of benefit towards treating the inattentive aspects of ADHD. This may actually be in line with other studies which link carnitine treatment to increased energy (individuals with the inattentive form of ADHD are often more likely associated to be more lethargic as opposed to the bouncing-off-the-walls behavior typically exhibited by the hyperactive/impulsive or combined ADHD subtypes).


4. Carnitine as a memory booster: I am personally hesitant to suggest supplementation with generalized memory boosters for ADHD (multiple ADHD websites love to do this), due to the distinct nature of the disorder. Nevertheless, individuals with ADHD do typically exhibit deficiencies in working memory, and some studies on carnitine on memory improvement are of interest. There is evidence that memory improvement from carnitine treatment may be seen in certain sub-populations. For example, carnitine treatment improved visual memory and attention in Down Syndrome patients, but the same effects were not seen in non-Down Syndrome individuals. Additionally, carnitine has also been shown to be useful in Alzheimer's dementia. The possibility that unique subsections of the population may be particularly receptive is intriguing, to say the least.


5. Carnitine may play a role in reducing toxicity of other psychiatric medications: We have previously addressed the possible association of ADHD and epilepsy. Valproic acid, an anti-epileptic medication (which is also used in treating bipolar disorders, which often has a fair amount of overlap with ADHD itself) has risks of toxicity. However, carnitine treatment of Valproic acid toxicity has been shown in a recent study. In general, carnitine can also help the body clear toxic carboxylic acids from its cells.
   
   
6. Carnitine's lack of addiction potential compared to stimulant ADHD medications: One of the classic problems with many medications (including ADHD stimulant medications) is the potential for addiction. In general, addiction potential is increased by rapid uptake into and rapid clearance by the brain. Although much more rare than prescription medications, herbs and supplements may also be addiction forming. However, there is a relatively slow uptake of carnitine into the brain, which reduces its addiction potential to virtually zero. While not entirely significant (addictions of similar types of nutrients are almost non-existent), it is worth mentioning, if for no other reason than to inform those who are looking for non-prescription alternatives to ADHD some of the benefits to nutrient supplementation.
   
   
7. Acetyl-carnitine may offer the brain an alternative energy source during glucose shortages: Multiple studies have found glucose deficiencies in key specific brain regions in ADHD patients. A study found that glucose can actually inhibit the uptake of acetyl-carnitine into the brain, indicating a similar metabolic pathway. This conclusion of acetyl-carnitine as an alternative energy source was reached by the authors, however, it has been backed up by a body of research from numerous other studies. This seems to indicate that carnitine and its various forms may offer a viable means of alternative energy for glucose-starved ADHD brains.
   
   
8. Carnitine plays a role in acetylcholine (and possibly dopamine) synthesis: Acetylcholine is an important neuro-transmitter in the brain. While it often takes a back seat to more well-known ADHD-related neuro-signaling agents such as dopamine and norepinephrine, several stimulant drugs which alleviate ADHD symptoms may target acetylcholine-dependent pathways (interestingly, nicotine appears to have a high degree of interaction with the acetylcholine receptors, and is often a popular drug of choice in ADHD individuals, often as a means to "self-medicate").
   
   It appears that carnitine can help offset acetylcholine deficiencies in the brain, especially with regards to neuro-degenerative diseases. These effects can be even more pronounced if carnitine is co-administered with other key nutrients such as S-Adenosylmethionine (SAMe) and N-Acetylcysteine (NAc). To do these other two nutrients justice with regards to their effects on ADHD and related disorders or illness, they will need to be covered in their own separate posts. Finally, it appears that carnitine also affects dopamine-related pathways as well, which has numerous potential implications for ADHD, given that dopamine shortages and metabolic differences in key brain regions are often associated with the disorder.
   
   
9. Improved circulation via administration of carnitine (and vitamin E?): There is a mounting body of evidence that supports the assertion that individuals with ADHD have reduced bloodflow to key regions of the brain necessary for maintaining focus, eliminating distractions and maintaining attention to specific tasks. Certain ADHD medications, such as methylphenidate (Ritalin, Concerta, Metadate, Daytrana), can actually alter patterns of cerebral bloodflow in ADHD patients. It appears that carnitine can also improve blood flow to brain tissue (the study refers to the term "ischemia", which is simply a reduction of blood supply via blood vessels). These effects may possibly be increased even further, when combined with vitamin E, as highlighted in the same study. Carnitine can also help reduce ischemia to the spinal cord.
   
   
10. Carnitine helps maintain cell membrane integrity: Numerous diseases and disorders are the result of damages to (or "leaky") cell membranes. These membranes are comprised mainly of fats, with several different proteins interspersed among the fatty acids. Ample omega-3 fatty acids play a critical role in maintaining a structure to the cell membranes, which is one of the reasons why adequate carnitine levels are so beneficial. However, fatty acids are prone to oxidation (think of a damage similar to rusting or corrosion, but within the body), so adequate antioxidant levels are needed to maintain these key components of cell structure and overall health.
    
    In addition to its numerous other roles, carnitine is considered to be an antioxidant. Dietary deficiencies, as well as environmental stresses can leave these membranes prone to damage, resulting in a whole slew of potential diseases and disorders, such as increased risks of viral infections, allergies, buildup of cellular toxins, impairment of blood flow (this is actually related to our previous point on carnitine and ischemia) etc. In addition, cells contain inner membranes, whose structure and function can also be dependent on carnitine.

How much carnitine should we be taking, especially for ADHD?
This is a good question, which, unfortunately, does not carry a straight answer. There is no official "RDA" for carnitine at the moment. One group studying carnitine metabolism suggested a recommended daily dose of carnitine to be 200 mg/day. The Dutch study used a dose that was proportional to the patient's body weight, 100 mg of carnitine/kg body weight to be precise. This corresponded to a maximum of 4 grams of carnitine (note that this study was done in children) for the study. Dosage at this level corresponded to about a doubling in plasma carnitine concentration. With regards to side effects, there were relatively few, although one individual discontinued the study due to onset of a strange odor emanating from his skin. It was believed that this may be due to a buildup of a compound known as trimethylamine, which has a characteristic fishy, ammonia-like smell.

However, some of the effects in other studies were seen at only a fraction of these doses, such as some reporting effects such as significant improvements in attention at only 25 mg carnitine/kg body weight. 50 mg/kilogram body weight was the dosage used in a study that found carnitine to be effective in combating hyperactivity. These studies are simply rough estimates for amounts needed to suppress inattentive and hyperactive/impulsive behaviors associated with ADHD. As far as safety and toxicity issues are concerned, there are few published reports about dangerously high levels of carnitine. For a one-year study on the effects of carnitine for ADHD boys, a daily dose of 1 gram per day was found to be safe. This study recommended 20-50 mg carnitine per kg of body weight, which is roughly one fifth to one half of the levels used in the Dutch study.

Regional/Geographic effects on carnitine supplementation for ADHD: A mult-site study on the effects of carnitine on ADHD by Arnold and co-workers made an interesting observation. They studied the effects of carnitine on ADHD symptoms in children in 10 different sites across the United States, and found that significantly more pronounced effects were seen in 3 sites in Ohio and northern Kentucky. All of these sites were about 150 miles northwest of the Allegheny Mountains. The other parameters (age range, demographics, ethnicity, ADHD symptom scores, doses of carnitine, etc.) were similar to the other sites, and the researchers in the study offered no explanation for the findings and suggested the difference to be merely coincidental. While this is obviously a possibility, this blogger offers a possible explanation: the potential effects of interaction between carnitine and minerals or heavy metals.

One possibility may have to do with magnesium deficiency in this particular region. Some studies note that the soil in the Allegheny region is deficient in magnesium due to erosion or poor soil management. It is possible that this magnesium depletion in the soil may result in a higher prevalance to dietary magnesium deficiency in these geographic regions. We have demonstrated the effects of magnesium deficiency in ADHD in several previous posts, such as one on Magnesium Deficiency and Childhood ADHD. However, we have also seen that magnesium can often work in conjunction with other vitamins, minerals and antioxidants in treating ADHD as well. These highlights can be found in an earlier post on magnesium combination treatments and ADHD.

Some research has found that magnesium can boost the activity of the enzyme Acetyl-CoA carboxylase, which plays a significant role in fatty acid biosynethesis. A fatty derivative of carnitine can also push this same enzyme along. It is possible, therefore, that carnitine supplementation may take over some of the roles of the depleted magnesium, thereby freeing up magnesium for some of the other ADHD-fighting fuctions as previously noted. Of course this is just a personal hypothesis, but this blogger earnestly believes that there are a number of carnitine-mineral interactions that have not been studied extensively that warrant further investigation.

Carnitine does not act in isolation:
If you get nothing else out of this post or any of the other posts in this blog dealing with nutrition strategies for ADHD, please remember this: nutrient therapies often do not work because not all the pieces are in place. In other words, the different nutrients are highly interdependent, and a missing piece or two can sabotage the whole system. I personally believe that this is why a number of ADHD supplementation strategies do not work to their full potentials, because they are often missing key ingredients. Instead, for ADHD combination treatments to be effective, it is vital that we begin to understand all of the individual steps of nutrient metabolism and their affiliation with the disorder.

Just from this post alone, we have seen that carnitine has potential interactions with:

Omega-3 fatty acids
Vitamin E and other antioxidants
S-Adenosylmethionine (SAMe)
N-Acetylcysteine (NAc)
Magnesium
Glucose
Coenzyme Q10
Valproic acid (and other medications often used to ADHD or disorders which often show up alongside of it)

The point is, is that the various ADHD medications and treatment alternatives do not exist in a vacuum. One of the goals of this blog is to further elucidate the many interactions and factors at work in the different treatment strategies for ADHD. We need to consider all possible food-food, drug-drug, food-drug, food-supplement, drug-supplement and supplement-supplement interactions in order to tailor an effective treatment method for any individual. It is my belief that only then will we be truly able to see consistently effective individual treatments for ADHD and related disorders.

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.

Daytrana Dosing Equivalents to Ritalin and Concerta

Methylphenidate remains one of the most popular choices of medications for individuals with ADHD. However, the combination of dosing difficulties and negative side effects connected with oral administration left room for an alternate form of delivery: the methylphenidate transdermal delivery system, more commonly known as Daytrana. Currently, this medication is prescribed for children with ADHD and not adults, although it is sometimes prescribed off-label for adults with ADHD and related disorders.

If you are not familiar with Daytrana as a method of treatment for ADHD, you are not alone. It is a relatively new medication, introduced in 2006. It consists of the drug methylphenidate, the same chemical compound used in the more common ADHD medications Ritalin and Concerta. It is currently the only ADHD medication available in the patch form.

We will begin a series of posts exploring this new player in the world of ADHD, but I would like to start off with just providing a table of approximate dosing equivalents between Daytrana and the more common forms of methylphenidate, Ritalin and Concerta. A rough comparison, obtained from an article by Arnold and coworkers in the journal Pediatrics titled Treating Attention-Deficit/Hyperactivity Disorder with a Stimulant Transdermal Patch: The Clinical Art.

Please note that there are four different patch sizes of Daytrana currently available, which, based on the pharmacokinetics of a 6-12 year old child, correspond to four different doses of both the immediate release methylphenidate (note this 2nd-to last column corresponds to a Ritalin immediate release dose that given 3 times/day) and an osmotic-based release form of methylphenidate (Concerta). The patch is typically placed on the relatively inconspicuous location of the child's hip, and should be administered to the same site on a daily basis for consistency (different locations can actually affect the releasing dosage patterns of the patch)

Typical wear is for 9 hours, which is why the 9-hour dosing equivalents are given. However, the theoretical maximum dose per patch (which is the delivery rate times a 24-hour period) is also given. However, anything beyond a 9-hour dose is typically considered "off-label" use for Daytrana. These delivery rates of dosing for the different patch sizes are slower than the other forms of methylphenidate, as we will see in future posts. Nevertheless, I have included them to illustrate the patch size/dosing rate relationship for Daytrana. Note that the patch area and delivery rate follow a linear relationship, which is indicative of a uniform distribution of the drug across the surface of the patch which provides approximately 2.2 mg of methylphenidate content per square centimeter of patch area (over a 24 hour period).

We will be going into much more detail about the modes of action and functional differences of the Daytrana form of the drug methylphenidate (especially the differences between this patch form and the conventional "pill" form) as well as highlight some of the advantages and disadvantages of this new form of treatment for ADHD in the next few posts. Topics addressing the difficulties of an oral delivery system (we have hinted at some of the problems of food or drug metabolism and the ensuing consequences due to digestive issues such as celiac disease and ADHD symptoms) will also be discussed in the very-near future. In the meantime, a good overview of Daytrana, as evaluated by the FDA can be found here.