Thursday, February 18, 2010

Do Tyrosine Supplements for ADHD Actually Work? (part 7)

Homocysteine Buildup: The (Potential) Dark Side of Tyrosine and L-DOPA Supplementation for ADHD

Throughout the last six posts on this blog, all of which were concerned with tyrosine supplementation strategies for ADHD, we alluded to the fact that introducing high levels of tyrosine into the body can precipitate a number of other biochemical processes besides the conversion to dopamine and norepinephrine in the brain of the ADHD patient. For reference, I have included the diagram we've been following for the past six blog posts on ADHD and supplementing with tyrosine (you can click on the diagram below and get a larger picture in most browsers):

As we can see, there are a number of enzymes, processes and intermediate steps involved in just this one pathway of tyrosine. Please note that other nutrients, such as ascorbic acid (a.k.a. vitamin C, which has a number of connections to ADHD) and S-Adenosyl methionine (also known as SAM or SAMe, which has also been discussed in greater detail in relation to ADHD elsewhere) are required in this process.

Also, a number of enzymes are required to make this process go.

Here is a quick summary of some of the enzymes used and some of the key vitamins and minerals required (either directly or indirectly) to optimize this enzyme's function:

Tyrosine Hydroxylase: (iron, vitamin C, magnesium, zinc, copper, folic acid or folate, niacin). This is perhaps the most important step of the process, in that it is the slowest or "rate-limiting" step. Because of this, we want to make sure all necessary nutrient "co-factors" (helpers) are in place to help move along this "slow" step as fast as possible)

Dopa Decarboxylase: (vitamin B6, zinc. Also note that excessive levels of some other amino acids, such as leucine, isoleucine, valine, and, especially, tryptophan can compromise this step of tyrosine metabolism. Furthermore, buildup of one of the products of tryptophan metabolism, serotonin, can inhibit or begin to shut down the activity of this Dopa Decarboxylase enzyme and compromise our tyrosine-to-dopamine conversion pathway. This spells bad news if we want to attempt to regulate these dopamine levels in an ADHD brain)

Dopamine Beta Hydroxylase: (vitamin C, but also requires additional antioxidants to "recycle" the used vitamin C)

Phenylethanolamine N-methyltransferase: (S-Adenosyl-methionine or SAMe)

Keep in mind that this list is not extensive. However, the vitamins and minerals are some of the key players in the conversion processes of tyrosine metabolism.

Other Pathways of Tyrosine Metabolism and the Generation of Homocysteine

This is extremely important. A lot of times we get lulled into believing that just because we're using a natural or dietary-based treatment strategy instead of potentially harmful medications, we are immune to negative and/or dangerous side effects typically associated with drugs. However, as a blogger, I urge everyone to reject this idea as quickly as possible. While the side effects as a whole may be a bit more benign or have more room for error for nutrient-based ADHD treatments, going overboard can be just as harmful.

Minerals such as iron, copper and chromium all can be extremely toxic at high levels, and overdosing on certain vitamins (especially the fat soluble ones such as vitamins A and E, which are more difficult to flush out of the system than the water soluble ones), can also be harmful (or even fatal). Even the water-soluble B vitamins can cause problems if overdone (there is a high degree of interaction among most of these, and there is a relatively delicate balance between their levels. Over-supplementing on one, therefore, can greatly compromise the others).

Amino acid supplementation can also be tricky. We mentioned in an earlier posting that chemically similar amino acids often "compete" with each other in areas such as entry into the brain and competition for the same enzymes. As a result, if we go overboard with supplementing on one type of amino acid (such as tyrosine, in the case of ADHD treatment), we need to examine some of the possible repercussions of disturbing the balance of the other amino acids and the products of their metabolism.

Additionally, we need to be aware of other biochemical pathways in the body in which tyrosine is involved. While it may be true that supplementing with tyrosine can boost levels of dopamine and norepinephrine (although the extent of this is debatable, and will be discussed in our final "wrap-up" post), boosting tyrosine intake can result in higher levels some potentially harmful agents such as the compound homocysteine. For this, we will begin by examining the last step of the tyrosine metabolic process (this was covered in the last post in more detail):

Here we see that tyrosine-derived norepinephrine can be converted to epinephrine (adrenaline) in a process which utilizes the enzyme (phenylethanolamine N-methyltransferasePNMT). Even without a chemistry background, we can still see the chemical transformation process above. A methyl (CH3) group was added to the Nitrogen (N) on the right side of the norepinephrine molecule to form norepinephrine. But where does this methyl group come from?

As mentioned in the last post on ADHD and tyrosine, the compound S-Adenosyl Methionine or SAMe, is a very important nutrient in a number of biochemical processes, in that it is able to "donate" (give-up) a CH3 methyl group. This is a relatively rare property among nutrients, and we are just beginning to scratch the surface with regards to the role of this nutrient in treating neurological and psychological disorders such as depression, ADHD and the like.

However, when SAMe does donate it's CH3 methyl group, as in the case above, we are left with homocysteine (please note that there are a few additional steps to go from SAMe to homocysteine, it is not a 1-step conversion process. For simplicity, however, we will not go into these in any further detail. Nevertheless, homocysteine is a major end product of SAMe-related CH3 donor reactions, such as the one given above).

In other words, higher tyrosine (or L-DOPA) levels can make their way to this step of the metabolic process and begin to deplete SAMe levels and lead to high levels of homocysteine. High levels of homocysteine are known as hyperhomocysteinemia, is commonly seen in Parkinson's patients, who often take large amounts of L-DOPA (the second step of tyrosine metabolism in our first diagram in this blog post). Numerous studies have shown that long-term treatment with L-DOPA leads to elevated homocysteine levels in the blood of Parkinson's patients.

Elevated homocysteine levels have been linked from everything from cancer to diabetes to autoimmune disorders to stroke (however, please note that these results are far from unanimous, there are a number of studies showing the contrary for each of the diseases listed. Furthermore, there is still some debate as to whether the high levels of homocysteine are a causal factor for these disorders or just another side effect or symptom of these disorders. Nevertheless, the near-ubiquitous presence of high homocysteine levels in so many diseases across the board should at least suggest that homocysteine-lowering efforts are of great potential benefit, at least in this blogger's opinion).

With regards to ADHD, the actual role of homocysteine is, admittedly, much more murky. While the mechanisms and overall physiology of an ADHD brain vs. a Parkinson's brain show acute differences (In ADHD, chemical imbalances between the "inside" and "outside" regions of a neuron exist, which can be chemically modified via medications which target the proteins which shuttle this neuro-transmitting agents in and out of the cells. In Parkinson's, however, the imbalances are caused by cell death and neuronal degeneration, requiring overall higher levels of neurotransmitters like dopamine need to be supplied via chemical precursor agents like L-DOPA), the fact that the two disorders both share similar treatment methods should (in this blogger's opinion) at least sound a warning bell that some of the negative effects for one might also be prevalent in the other.

Surprisingly, there are very few studies (at least to the best of this blogger's knowledge) on homocysteine levels in the ADHD population, so it is difficult to get a good read on the subject. Nevertheless, given some of the points made earlier on tyrosine or L-DOPA supplementation or treatment and homocysteine buildup, we should at least examine some of the ways to reduce high homocysteine levels. Fortunately (at least in most cases), homocysteine-lowering efforts often respond very well to vitamin and mineral based treatments via supplementation or food fortification. At the center of this are the some of the well-known B vitamins.

B vitamin-based nutritional "weapons" which can combat potentially high homocysteine levels arising from tyrosine or L-DOPA supplementation:

  • Vitamin B6 (whose "active" form is known as pyridoxal phosphate. For simplicity, we will just be referring to this compound by its common vitamin name, vitamin B6)
  • Cobalamin (a version of vitamin B12)
  • Folate (a derivative of Folic Acid or Vitamin B9. For simplicity, as in the diagram below, we will just refer to this modified form of folate as "folic acid", but please note that there is a modest chemical difference here)


While the above diagram may look extremely complicated and "busy", please try not to get distracted. The first four "steps" at the top (the arrows simply refer to a metabolic pathway by showing the gradual transformation of one tyrosine-based compound to the next. We have discussed each of these steps in great detail in the previous postings) have already been covered extensively.

The last step, the conversion of norepinephrine to epinephrine was discussed in the last posting on ADHD and tyrosine. The curved arrow simply refers to the fact that the norepinephrine to epinephrine conversion requires another nutrient-based compound SAMe. The norepinephrine essentially "steals" a methyl (CH3) group from SAMe, leaving SAMe to transform into another compound S-Adenosylhomocysteine (which then proceeds to our "dreaded" homocysteine). To put it another way, in order to make the norepinephrine to epinephrine conversion, the valuable nutrient SAMe must be "sacrificed" to a more potentially harmful compound homocysteine.

If this SAMe to homocysteine conversion process is not kept in check, we run the potential risk of homocysteine buildup. However, based on the diagram above (look at the far right side of the diagram for this part), there are 2 different ways to "dump off" high levels of homocysteine by converting it to other more benign compounds. However, each of these two "paths" requires at least one type of B vitamin.

Path #1: conversion of homocysteine to the amino acid cysteine: This is actually a multi-step process, but for the sake of brevity and simplicity, I have left out some of the middle steps. The two major points of note here as follows:

  1. This process requires a specific enzyme called cystathione beta-synthase (don't worry about remembering this enzyme, just remember that this enzyme requires a form of vitamin B6 as a cofactor or "helper to function). Thus, to optimize this vitamin B6-based conversion process, we want to make sure that we don't have any deficiencies of this vitamin. Please note that we already mentioned the need for vitamin B6 in another step of the tyrosine supplementation process for ADHD, the conversion of L-DOPA to dopamine. Thus, it is doubly important that we don't come up short on this vitamin.

    A rough summary of recommended dosage levels for B6 will be given at the end of this post (Blogger's note: not to go into too much detail here, but this homocysteine to cysteine conversion process is also dependent on another amino acid called serine. I have not included serine as an essential nutrient because serine deficiencies are rare. However, there are some genetic disorders in which serine synthesis is compromised. Seizures and related symptoms are common among those with this genetic defect on serine metabolism).

  2. The conversion of homocysteine to cysteine is (largely) irreversible. This is good news if we want to "dump off" homocysteine levels and not have to worry about the process chemically finding its way back to homocysteine (at least not through this pathway).

Path #2: the conversion of homocysteine to the amino acid methionine: While path #1 is dependent on one type of B vitamin (B6), this pathway is dependent on 2 different B's: a form of vitamin B12 and a derivative of folic acid (vitamin B9). Without going into too much detail, this process requires a methyl (CH3) "donor" (which, in this case, is the modified form of folic acid here. This is very similar to like way the nutrient SAMe acts in helping the conversion from norepinephrine to epinephrine as mentioned earlier).

Please note that, unlike the last case, this process is chemically reversible (which means that the process can go backwards and regenerate homocysteine to a certain extent). This process also requires a special enzyme called homocysteine methyltransferase. Again, don't worry too much about this enzyme, just note that it requires a form of vitamin B12 to function.

To summarize: if we want to keep the "cycle" going to avoid homocysteine buildup by converting homocysteine to methionine, we need 2 different B vitamins: The folic acid as the chemical modifier, and vitamin B12 to help the enzyme involved in the process to function properly.

Perhaps not surprisingly, taking B12 (also known as cobalamin) and a form of folic acid (folate) together has shown to be advantageous in a number of cases. Combinations of folate and cobalamin have also shown to be useful in reducing homocysteine levels in those treated with L-DOPA.

A quick summary on using B vitamins to reduce potential homocysteine buildup from tyrosine (or L-DOPA) supplementation:

  • Homocysteine can be an inflammatory compound that is produced indirectly as a result of tyrosine metabolism. High levels of this compound have been linked to a wide number of diseases and health risks.

  • Vitamin B6 can be used to help "shunt" homocysteine to a common (and typically less-harmful) amino acid known as cysteine. This process is (essentially) irreversible. B6 is also a requirement for an earlier step of the tyrosine or L-DOPA metabolic process, the conversion of L-DOPA to dopamine.

  • Vitamin B12 and folic acid can both assist in the conversion of homocysteine to another amino acid, methionine. Unlike the cysteine conversion process above, this process is reversible, meaning that it is possible to "work" backwards towards homocysteine in a bi-directional pathway.

  • Because of the importance of these 3 B vitamin-derived factors in the prevention of homocysteine buildup, it is imperative that we try to avoid shortages of these agents at all costs (but be careful about over-supplementing, B vitamins work best in specific ratios, and overdosing on one can compromise the functions of the other, as we have noted in previous posts on ADHD and nutrient deficiencies).

  • Here are some good sites which list the suggested daily amounts for folic acid (folate), vitamin B6 and vitamin B12. Going slightly higher is often fine (as these agents have relatively high "ceilings" between recommended amounts and toxicity levels), but try to keep the ratio of these different B vitamins as close to the same as in the recommended amounts as possible. Again, please make sure your physician is in the know if you choose to supplement with anything significantly above the recommened levels.

This is our second-to-last post on ADHD and tyrosine. The last one on tyrosine supplementation strategies for ADHD will give a recap of all the key enzymes, nutrients, and chemical intermediates we've covered throughout the past seven postings. It will also provide a summary of what the main studies on exactly how effective tyrosine supplements really are based on clinical studies. Finally, we will briefly mention how tyrosine may be able to augment the effects of common ADHD stimulant medications.

41 comments:

  1. This post is very useful to know about the importance of supplement in our body. Thanks.

    ReplyDelete
  2. Thanks for sharing that info. I haven't tried that supplement but I hope it really works.

    ReplyDelete
  3. Vitamin B has many well-known benefits. It's an excellent supplement. I too haven't tried this but I do believe it can work.

    ReplyDelete
  4. It can't truly work, I think this way.

    ReplyDelete
  5. I like the way your write articles.Very organized and straight to the point.Your blog is very informative.

    ReplyDelete
  6. There are many parents these days that take their children for chiropractic treatment and care. It has been observed that children can take advantage of this treatment method starting from birth till throughout the childhood. Handling a child with ADHD in your house can be a problematic work but it has been observed that chiropractic treatment can help a lot with the symptoms of ADHD.

    Children suffering from the problem of ADHD or attention deficit/hyperactivity disorder can act out in various ways. They may control themselves, not obey commands and bully other children. These children might get violent and may have rough behavior like throwing things around.

    According to a survey by American Chiropractic Association in 1991, the number of chiropractic patients of sixteen years of age and younger has increased to 8.5%. Chiropractic services is the most common alternative method of treatment performed on children and it is completely safe.

    A study conducted in 1975 compared the effect of chiropractic treatment and drugs in children suffering from ADHD. The study showed that chiropractic services was twenty four percent more effective than normal drug prescription. It worked over the wide range of symptoms which are common in neurological dysfunction syndrome. So, chiropractic treatment works good with children having ADHD.

    It has been observed that children who suffer from the problem of ADHD have successful results with chiropractic treatment. It has also been noticed that children who have vertebral subluxation and do not show any symptoms of ADHD should still have chiropractic services. The best method of treatment in case of ADHD is chiropractic services. It is completely natural and so it does not have any side effects. This makes it very safe for your child. With proper treatment and care, the symptoms of this condition can be helped to a great degree.


    The effects of chiropractic services on children with learning and behavioral problems was investigated with 24 elementary and secondary level students, 12 receiving regular chiropractic treatment and 12 receiving medication. Results indicated that chiropractic treatment was more effective for the wide range symptoms common in the neurological dysfunction syndrome in which the following symptom areas were identified: attention span, hyperactivity, listening comprehension, reading comprehension, verbal output performance, writing output performance, following instructions, hand-eye coordination, overall coordination, effort, emotional maturity, behavior, and self-confidence.

    The hands-on nature of the chiropractic services requires patients to visit the chiropractor a number of times. To be treated by the best chiropractor, a patient needs to go into the office. A chiropractor may provide acute, chronic, and/or preventive care thus making a certain number of visits sometimes necessary. Your doctor of chiropractic should tell you the extent of treatment recommended and how long you can expect it to last.

    ReplyDelete
  7. I must say that overall I am really impressed with this blog.It is easy to see that you are impassioned about your writing. I wish I had got your ability to write. I look forward to more updates and will be returning.

    ReplyDelete
  8. Post is Nice!! I would like to say that the Supplements should have balance vitamins and other solutions, however they biotic or antibiotic.

    modalert

    ReplyDelete
  9. Great post! That was interesting.I like your quality that you put into your post.Please do continue with more like this.

    ReplyDelete
  10. Many thanks for such a write-up. I undoubtedly cherished reading it and talk about this it to my friends.

    ReplyDelete
  11. Excellent post! thanks a lot for the sharing, that greatly helped me to resolve the problem.now I am glad to share the latest fashionable news about the cheap jordan shoes with everyone.

    ReplyDelete
  12. Many thanks for such a write-up. I undoubtedly cherished reading it and talk about this it to my friends.

    ReplyDelete
  13. Hey, there is a great deal of effective info above!

    ReplyDelete
  14. Very this is a good post. This post give truly quality information.I’m definitely going to look into it.Really very useful tips are provided here.thank you so much.Keep up the good works.definition essay writer

    ReplyDelete
  15. Excellent post and wonderful blog, I really like this type of interesting articles keep it u. I am really loving the theme/design of your web site.logodesignmaestro.com

    ReplyDelete
  16. What could be better than having some extra cash when traveling? A payday loan site comes in handy for instant no credit approval and for a loan of upto $1500.

    PAYDAY LOAN

    ReplyDelete
  17. taking moresupplements would just degrade your help much then improving .... so its useless better take a proper diet but taking a proper diet would help much more then taking any supplements .....

    ReplyDelete
  18. If only I had used www.essayservice.info. No doubt I've got a great mark.

    ReplyDelete
  19. wow, great news. Thank you so much for your information.
    ----
    i like play game jogos click online free and apply baixar facebook gratis online free and apply mobogenie baixar online free

    ReplyDelete
  20. I came across through your blog. I found valuable information. Thanks for sharing.
    Ayurvedic Treatment for Brain Stroke

    ReplyDelete
  21. I came across through your blog. I really found the valuable information about ADHD Treatment. Thanks for sharing.
    Ayurvedic Treatment in Kerala

    ReplyDelete
  22. I am happy to find so many useful information here in the post, thanks for sharing.

    ReplyDelete
  23. There are lots of people suffering from the problem of ADHD or attention-deficit disorder can act out in various ways and they need to treat it as soon as possible.
    regards,
    Buy online abortion pills USA

    ReplyDelete
  24. Amazing blog it is. I loved the post. Thanks for sharing.
    Buy Mifepristone and Misoprostol kit to discontine unplanned pregnancy.

    ReplyDelete
  25. This comment has been removed by the author.

    ReplyDelete
  26. GREAT POST, Thanks a lot for sharing nice information.
    Buy Provigil Online USA

    ReplyDelete
  27. In the event that you need to go further and utilize a mod, you can change the climate in case you're a Seasons player, and even adjust whether a Sim is pregnant.
    Download the sims 4 age up cheats 2019

    ReplyDelete


  28. Great post thanks for sharing.....

    our company provides the bestSEO Services at the best pocket-friendly cost.

    ReplyDelete
  29. Nice post. Thanks for sharing....!!!!

    Buy Valtrex online at Genuine Generic Online Pharmacy.

    ReplyDelete
  30. Thanks for sharing.....

    our company provides the best Digital Marketing Services at a pocket-friendly cost.

    ReplyDelete
  31. Informative post and it is very useful and knowledgeable. I really enjoyed reading this post, thank you!
    People who are facing hypotrichosis of the eyelashes issues can buy online careprost for treating the same.

    ReplyDelete
  32. I liked the informational item. Thanks for sharing.
    To end unintended pregnancy Buy Abortion Pills Online at an affordable cost.

    ReplyDelete
  33. The Collection Marts is platform where you can view latest designs about home décor and bedding. We have large range in different categories with finest fabric in cotton and silk. You can view not only present trends but also view huge collection with reasonable price. The Collection Marts can provide fast service about delivery as well as customer support too. Our products are not only self-made but also, well connected with markets to ensure for possibility of available designs if client want to purchase. The Collection Marts customer support open 24/7 to guide their customers about material or product stuff. crushed velvet sofa covers , velvet plush fitted bed sheet

    ReplyDelete
  34. You have written an amazing post with authentic content! Good job!!!

    Just visit https://getabortionpills.com and order abortion pills, MTP kit or mifegest kit MTP Kit Or Mifegest Kit or Misoprostol or Mifepristone at the comfort of your home

    Regards,

    States Pharmacy
    Mike Ross
    +1-256-515-6667

    ReplyDelete
  35. Great share. Buy MTP pill kit online for effective unwanted pregnancy From Safeabortionrx

    ReplyDelete
  36. I found you thanks to your blog. I discovered useful knowledge. I appreciate you sharing.
    buy mtp kit online with credit card


    ReplyDelete
  37. Thank you for sharing this blog. The article provides valuable information on the effectiveness of tyrosine supplements for managing ADHD symptoms. It highlights the benefits of tyrosine in improving focus and attention in individuals with ADHD. The author also provides cautionary advice on the potential side effects and recommends seeking medical advice before taking any supplements. Overall, an informative and useful read for anyone interested in alternative ADHD treatments. I remember about ADHD Treatment in Chennai who provides better treatment for ADHD students and Adults. Thank you.




    ReplyDelete
  38. This is one of the most significant information for me. And I m glad reading your article. Thank for sharing! Create a next-level online presence for your business with the Best Website Development Company in Bangladesh. At GaryWeb, our web design and development experts create responsive, modern, and user-friendly websites that will attract your customers to your website!

    ReplyDelete