Can Dextromethorphan be neuroprotective?
 

I recall reading that RLSmi has taken DXM since his dx and seems to have had a relatively slow progression. If he reads this and would elaborate on effect & dosage, I would be appreciative. Has anyone else had experience with DXM? Sounds promising enough for a clinical trial...

http://www.hindawi.com/journals/mi/2012/401264/
Volume 2012 (2012)

Oxidative Stress and Microglial Cells in Parkinson's Disease

Morphinan-Based Anti-Inflammatory TherapeuticsSeveral studies using PD animal models or in vitro cell cultures have shown that the morphinan compound dextromethorphan (DM) and its metabolites are neuroprotective due to their anti-inflammatory properties and inhibitory function towards microglia activation [59, 109, 110].

DM inhibits microglia activation and is neuroprotective when administered daily to mice that had been injected with MPTP [109].

Another metabolite of DM, 3-hydroxymorphinan (3-HM) was shown to have the greatest potency (of several tested methorphanins) for attenuating the loss of DA neurons in the SN, as well as restoring motor functions in the same MPTP-mouse model of PD

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255316/

The Neuroprotective Disease-Modifying Potential of Psychotropics in Parkinson's Disease

Results indicate that, from a PD pathobiology perspective, the safest drugs (i.e., drugs least likely to promote cellular neurodegenerative mechanisms balanced against their likelihood of promoting neuroprotective mechanisms) include pramipexole, valproate, lithium, desipramine, escitalopram, and dextromethorphan. Fluoxetine favorably affects transcription of multiple genes (e.g., MAPT, GBA, CCDC62, HIP1R), although it and desipramine reduced MPTP mouse survival. Haloperidol is best avoided.

In MPTP mice, dextromethorphan protected dopamine neurons [87, 88], dopamine concentrations [87], and locomotor activity [87] and reduced glutamatergic excitotoxicity on dopamine neurons [89]. A previous study had not demonstrated protection of dopamine concentrations in this model [89]. Dextromethorphan also protected dopamine concentrations in mice treated with both MPTP and diethyldithiocarbamate [89]. In the methamphetamine mouse model of PD, dextromethorphan protected dopamine neurons and prevented microglial activation [90]. Finally, in the mouse neuroinflammatory LPS model of PD, dextromethorphan protected dopamine neurons, dopamine concentrations, and locomotor activity [87].

Drugs with multiple actions that may confer disease-modifying neuroprotection include dextromethorphan, valproate, lithium, and pramipexole. These drugs have neuroprotective effects on αSyn, except that the HDACI dextromethorphan lacked direct data for this protein, and lithium had neuroprotective effects on both αSyn and tau protein. One potential therapeutic strategy that might be tested in animal models and humans is the combination of valproate with dextromethorphan in attempting to therapeutically modulate H3 HDAC, GSK-3, αSyn, ROS, apoptosis, and trophic factors.

Hi, Lemonlime!
I see that you are logged on to the forum tonight. I want to thank you for the two links to great recent reviews on possible approaches to neuro-protection for PD. Although i am familiar with many of the published studies that were included, especially those on suppression of neuroinflammation with morphinans by JS Hong and his research group, there are many other very interesting ones that I am looking forward to studying more closely.

My experience with dextromethorphan makes me an enthusiastic supporter of clinical trials of that very safe, inexpensive drug for neuroprotection in PD. Unfortunately, it is unlikely that such trials will ever occur without funding from non-commercial sources. There is simply no money in it!

Regarding your inquiries about my use of dextromethorphan, I actually began taking it regularly in 2005, 4 years after my dx in 2001. A year or so earlier I was exploring the possibility of using naltrexone, another morphinan, for neuroprotection. I had read about the use of that drug for neuroprotection at very low dosages by individuals with multiple sclerosis on Braintalk, an earlier incarnation of neurotalk. There was also anecdotal mention of benefit by the drug in Parkinson's.
When I read Hong's work in which both naltrexone and dextromethorphan at femtomolar concentrations inhibited inflammation in mixed neuron-microglial cell cultures, it occurred to me that I could avoid the complication of needing a prescription for naltrexone, as well as the hassle and expense of having to get a compounding pharmacy to prepare the tiny doses of the drug by simply substituting dexromethorphan in over-the-counter cough syrup. I arrived at what seemed like reasonable doses and timing of this very safe drug by matching those recommended for low-dose naltrexone; 4-5 mg every night at bedtime.

I had been using this regimen, along with the standard carbidopa-levodopa and amantadine, prescribed at the time of my dx by my neurologist, when I was able to talk to Dr. Hong at the 2006 World Parkinson's congress. He essentially confirmed the dosage and timing of my dextromethorphan use. At that time he also pointed out that the cough syrup should not contain any other active ingredients such as antihistamines, decongestants or polystyril, a substace added to slow the release of dextromethorphan. You can search my earlier postings for other details of my experience with the drug.
Robert

What brand of cough syrup do you take. I also take 4.5mg of Naltrexone every night and find in a pain to get a Rx from a doctor I rarely visit. Do you think I can exchange it for dextromethorphan.?

Hello, John.
Welcome to Neurotalk!
I currently use Children's Robitussin Cough, Long Acting. The concetration of dextromethorphan hydrobromide in this preparation is 7.5mg /5ml (1tsp), as with all of the DXM pediatric syrups I have used over the years. I take approximately 1/2tsp at bedtime every night.
As to switching over to DXM from LDN, that would be entirely your decision. All I can tell you is that I have experienced apparently very gradual progression of my PD symptoms. I have, with my Movement Disorder Neurologist's approval, increased the dosage of carbi/levo (generic) to one each of both 50/200 mg CR and 25/100 mg regular every 3.5 hrs., or 4X each day. As I mentioned in a recent post, I am having some fairly mild dyskinesia, mostly in my legs.
I wish you well with our common adventure!
Robert

Gonna give it a try
 

RLS, do your symptoms improve with DXM? -and if so, which symptoms improve? Or is your experience with DXM more subtle--in other words, do you feel it is not necessarily improve a symptom, but does appear to be slowing your overall progression?

The literature I have read indicates DXM appears to help improve dyskinesia, but I am not seeing where it might help a tremor dominant PWP. In fact, I was reading where tremors can even be a side effect of DXM.

Even though my main problem is tremors, I am going to give DXM a trial and see where it gets me. But if in the meantime, you could answer my questions, I'd appreciate it!:winky:

Thanks!
 

Hi RLSmi

Thanks so much for your response! It seems, from your experience and everything that I have read, that low dosages work best. That seems to be a reoccurring theme with PD meds...moderation being most effective. It looks as if they have known about the potential of Dextromethorphan being neuroprotective for a long time. I've read research papers dating back to 1993, citing possible neuroprotection of neurons. It's unfortunate that no one has taken the initiative for a clinical trial due to funding. It sounds like it would be a perfect study for the lab rats or impatient patient. :)

We are at cross roads with my husband right now. He has been on Azilect since dx 8 years ago, but the time has come for additional meds. We are exploring all options and would like to add DXM, but there seems to be serious life-threatening contraindications with taking both!

We are currently trying to decide whether to drop Azilect, which could also be neuroprotective, add DXM and start Sinemet. Or, if possible, wait for a neurotrophic factor trial - GDNF & MANF both seem to be promising. We are meeting with the MDS soon to discuss options and are open to suggestions.

He is tremor dominant and has some slowness. Of course, our main goal is, first and foremost, keeping him comfortable and then working as long as he can. (we have 3 young kids) Our main fear is starting Sinemet, having dyskinesia and not being able to work. Now that some of you have reported having reduced dyskinesia is yet another reason to try DXM.

It's so remarkable that you are on such a low dose of Sinemet after all of this time....14 years? That's so great! Please keep us posted! I hope you are able to work out the mild dyskinesia that you are experiencing and glad to hear that it is a mild form. I hope you have continued success with your slow progression!
I have two more questions, if you don't mind.
From my research, the effects seem to peak around 2 to 4 hours. I was curious if you suggest taking the DXM at night or if that just works for you?
I was also wondering if you have experienced any side effects from taking it for such a long period?

On a side note....I just wanted to say Thanks! Everyone here has been so nice! My husband is my soulmate of 25 years and I just want to help him and everyone else in any way that I can! I am committed to contributing, advocating, praying, researching and even participating in "lab rat" trials...through reports from my husband or even being a variable, if it helps. I am an Interior Designer who now also studies the design of the brain. :confused: I have a lot to learn and I am so grateful for this forum!!!! So, please feel free to correct me if I get something wrong. :)

Thanks!
Cynthia

Reverett - I saw your post regarding the liver enzyme and rate of processing DXM. I just found this and it sounds encouraging...if I am reading it correctly.

http://phoenix.corporate-ir.net/phoe...190&highlight=

Avanir Pharmaceuticals and Concert Pharmaceuticals Announce License Agreement to Develop and Commercialize Deuterium-modified Dextromethorphan for Disorders of the Nervous System
ALISO VIEJO, Calif. and LEXINGTON, Mass., Feb. 29, 2012

"Concert's DCE Platform (Deuterated Chemical Entity Platform) has produced several deuterium-modified dextromethorphan compounds that we believe may provide therapeutically effective levels of dextromethorphan, potentially without the need for an enzyme inhibitor such as quinidine,"

The incorporation of deuterium into specific molecular positions of dextromethorphan, resulting in d-DM, maintained the pharmacology of dextromethorphan and provided significantly enhanced resistance to CYP2D6 metabolism and improved plasma exposure in preclinical testing. As a result, d-DM has the potential to be effective as a treatment for neurological and psychiatric disorders for which dextromethorphan has shown pharmacological activity.

lemonline, please don't think DXM improves symptoms
 

RSLIMI is taking 400mg 25/100 and 800mg 50/200CR sinemet + amantadine plus other pharmaceuticals based on his previous posts.

if you assume 60% bioavailability of the CR sinemet, thats 400mg + 480mg = 880mg l-dopa daily.

so the DXM certainly hasn't halted pd. might have slowed down the progression

also keep in mind that thousands of pd'ers are doing fine on l-dopa and other pd drugs after many years and don't post here. so you aren't getting a normal distribution of experiences here imho.

DXM isn't going to do anything for the day to day quality of your husband's life imho. i've tried it and low dose naltrexone, didn't notice a thing. the naltrexone was years ago and it gave me such vivid dreams i had to stop. i tried the DXM this year, why i stopped i can't remember. certainly not being critical of taking DXM.

carbidopa/levodopa could make a big difference for your husband. he can try it for a short time and taper off it i assume with no consequences. i noticed a big improvement after the 2nd day, you need to have the carbidopa build up a little before the l-dopa has it's maximum affect.

if exercise proves to be neuro-protective, then you want your husband able to do it.

my philosophy is meds are a trade off between quality of life and the chance of side affects down the road as doseages go up but don't limit yourself to the point where you have no life. everyone worries about dyskinesias, i for one was diagnosed in 2001, take only about 800mg of sinemet, have no dyskinesias, don't feel great at times, feel ok most of the time, when "on" can drive, jog/walk, ride a bike, pretty much do whatever i want if not slower at times. mentally about 70% of when i was about 5 years ago, my pd progression has sped up. when off, i'm like a 90 year old man.

i hope you join a support group and talk to other pd'ers and get opinions other from this board.

Yes, it can be used in symptom management as well
 

I don't think this thread has been brought back to life. If I missed it, my apologies.

http://neurotalk.psychcentral.com/sh...xtromethorphan

As you read through this you will notice that there is a bit of self discpline involved. Once you notice positive results the "more is better" mindset really kicks in. You have to fight that or loose the benefits.

Dxm
 

Thank you Soccertese! It sounds like you have had a slow progression, on a low dosage of Sinemet. Do you attribute the low dose of Sinemet to not having dyskinesia? I really appreciate all of your advice and the gentle reminder about the advantages of Sinemet. I will take it all into careful consideration. I just have been impressed by all of the positive research on DXM and it's symptom relieving properties. Apparently, it is proving to have benefits for many diseases. ie. In ALS, it is beneficial in speech, swallowing, incontinence, anxiety...
Not to mention, it's potential to have neuro protection and reduction of
Dyskinesia in PD.
I think RLSmi's slow progression is a testament to DXM. 14 years since dx, DXM taken for 10 of those years and he only has slight dyskinesia...imo, that says encouraging, as well.

http://www.ncbi.nlm.nih.gov/pubmed/9674803
Dextromethorphan improves levodopa-induced dyskinesias in Parkinson's disease.
With DM, average and maximum dyskinesia scores improved by >50%

This is a more recent paper with free PMC article:
http://www.ncbi.nlm.nih.gov/pubmed/21052935
Neuropsychopharmacological understanding for therapeutic application of morphinans.
(Dextromethorphan is a morphinan derivitave)
This review will demonstrate novel neuroprotective effects of several morphinans such as, dextromethorphan,

The fact that DXM is already an FDA approved drug with proven safety and efficacy...taken in recommended doses, over the counter & inexpensive is very appealing.
We are definitely going to wait and talk to our MDS before doing anything. Btw, our MDS is Stewart Factor at Emory University.... He is an amazing doctor if anyone ever needs an MDS in Atlanta, GA. You recently posted a link to his video presentation in reference to PD Research Trends. He told us the same exact thing that you said about meds being a trade off between quality of life and potential side effects. We feel very fortunate that we found him early in diagnosis and that he didn't push Sinemet right away. Before we knew to see an MDS, we saw a regular Neurologist, who prescribed Requip the very same day as dx. By that night, my husband "literally" thought he was dying. We almost ended up in the emergency room - it was awful! Please don't take that as my saying Requip is bad. I know it helps a lot if peolple! Apparently, some people have an adverse effect to agonist and he is one of them. The point is, that his only symptom at the time, was slight hand tremor and reduced arm swing....he really did not need to be medicated. For the record, I agree with yours & Dr. Factor's philosophy implicitly. I can see what a difference Sinemet has made in so many lives and hope my husband tolerates it, as well. We just want to make sure we have exhausted all other possibilities before making the plunge. One reason is due to the statistics of age at PD onset & dyskinesia. He was 40 when diagnosed and statistics show that dyskinesia is 70% more likely after 5 years of Levodopa treatment, when age of PD onset is 40 - 49.

http://www.ncbi.nlm.nih.gov/pubmed/20310028?log$=activity
Age of Parkinson's disease onset as a predictor for the development of dyskinesia.

I am happy to hear that MJFF is delving into dyskinesia. It's just unfortunate that a med that can help so many can have such debilitating side affects. I pray they can find an answer! I am thankful that we have Sinemet as an alternative. I also have high hopes for DXM and other meds, in the neuroprotective & dyskinesia arena.

This looks like it is going to be a great paper. Unfortunately, it is " in process" at PubMed, but it has an intriguing abstract.
http://www.ncbi.nlm.nih.gov/pubmed/23172094#
[Levodopa in the treatment of Parkinson's disease: myths and realties].

Take Care!
Cynthia

lemon,
i tried DXM and got no symptom relief. i don't have tremor, maybe it will help your husband, maybe it won't. not sure why you feel compelled to post the papers supporting the possibility it might help, you don't have to convince me and its over the counter, it's a very low dose, just try it.

i have no idea why i don't have dyskinesias. i can't say that means i'm a slow progressor because when i'm "off" i just want to sit in a chair or lay down, i just happen to respond well to sinemet. when on, the avg. person wouldn't know i had pd. That's why i suggest you visit a pd support group and meet some advanced pd'ers rather than try to become an expert from browsing the internet.

i do know dyskinesias asre a result of having pd, not sinemet. dyskinesias are greatly reduced when the level of l-dopa is kept constant via a duodopa intestinal pump delivery and they actually increase the amount of l-dopa delivered with the pump. in fact, when oral l-dopa is administered after duodopa is stopped, it takes awhile for dyskinesias to start again, implying a physical change in neurons. dyskinesias can be created in advanced pd'ers from short lived agonists. so since most of us will need sinemet, your're delaying dyskinesias, not preventing them. and there are improved controlled release l-dopa formulations coming to market which will greatly reduce dyskinesias by themselves. so my layman's advice is not be so scared of sinemet. impax labs is hopefully going to get approval for such a drug shortly, hopefully insurance will pay for it.

i too was given a rx for requip when first diagnosed and told it was up to me if i wanted to use it. i didn't feel any pressure to fill the rx but was happy i had it so i wouldn't have to make another trip to the doctor. i waited 4-5 years before really taking meds full time, played around with mirapex which i couldn't tolerate so have seen on sinemet 5-6 years.

i suggest you get a used copy on ebay or amazon of "THE PARKINSON' DISEASE TREATMENT BOOK" by AHLSKOG, it's from a neuro that has a lot of pd experience.

l-dopa is a simple, natural occurring amino acid, it was a godsend when it was finally formulated with carbidopa to relieve pd, it is unfortunate that we have pd and we continue to progress but thank god we have sinemet. every central nervous system treatment, from autism to epilepsy to depression has side affects, the brain is a lot more complex than any other organ.

keep in mind that it's likely everyone active on this board has gone thru the same anxiety, literature searches, worries about drugs that you have posted. yet were're mostly all taking pharmaceutical drugs. even after years of trying everything mentioned on the internet, every supplement, every off label drug, were're taking sinemet and/or agonists, amantadine, azilect, COMT inhibitors, etc. so your're not the first person getting excited about DXM because they found some articles on the internet or read someone's anecdotes.

i apologize if i seem rude, but you seem to be lecturing me about sinemet and how your're sure DXM will relieve your husband's symptoms when he's tried neither. i don't get it.

I'm sorry!
 

Soccertese - I am so sorry you feel that way! I would never try to lecture you or anyone. I truly apologize if I came cross that way! I really appreciated the help you offered me and took it to heart. I definitely do not feel as if I am an expert! I only posted those papers because they were from my research and posted it for anyone to read that may be interested. I apologize again if you felt it was directed to you. I can see how you would have taken it that way. I already had those links from previous research and just threw them in where applicable. I should have posted my thank you to you and then posted my links. I'm sorry if I came across overly excited!

Thank you for the information that dyskinesia is not always from Sinemet, but can be from PD. I did not know that! I thought it was a side effect of the meds and was merely pointing out that it was a fear. I too, am happy that we have Sinemet and see how it has helped so many people. I am not discounting Sinemet and know that it is in our near future. I am happy that we have that option. It's just that its new territory and we're scared! Thank you for easing the fear!

We were not given the option of whether to take Requip. The Neurologist basically said, take this, titrate up the dosage and I'll see you in 6 months. My point was that some doctors don't think about the patient or the long term and prescribe away. Yes, we always have a choice, but on diagnosis day, we were like putty in the hand. He didn't really need to take any meds, at the time, except maybe anxiety medicine. I wasn't discounting the med or anyone taking it. Sorry if it came across that way.

Please don't think I was trying to be anything but a newbie posting info that I thought was exciting research. I am truly sorry and will refrain from posting such info.
I appreciate your insight and hope you will accept my apology! :(

just trying to put things in perspective. i'd get that book, i learned a lot and it provided a a platform for better evaluating what i find on the internet and read on message boards which can sometimes be misleading. you did all that internet searching and imho came away with an incomplete understanding of dyskinesias which spending $10 on a general book about pd would have clearly explained.
as far as your statements about sinemet sometimes causing dyskinesias, be aware that if you give sinemet to someone without pd, they don't get dyskinesias. my point is get what works the best for your husband and not worry so much about dyskinesias. from your description of your husband's experience with requip, sounds like sinemet might be his only choice. if he gets them, then you deal with it. from my understanding , sinemet doesn't change the brain and ultimately cause dyskinesias, it temporarily causes them and when it wears off it stops. I assume when michael j fox wakes up in the morning he doesn't have dyskinesias until he takes his sinemet. so taking sinemet doesn't prevent a future drug from working better without causing dyskinesias.

i'd spend more time researching what's going on in research, here's a podcast posted today on the MJFF
https://www.michaeljfox.org/files/mp3/mjf_todd_mark.mp3

I found a product today called Koffex. It is purely dextromethorphan. Has anyone tried it?