Warning, this stuff below is boring. Read only if you have insomnia.
I am trying to understand the effects of Dipyridamole and Adenosine in RLS. In reading all the papers, I have been taking notes. It's interesting to me that some of the things I have been reading about are quite common to read about in RLS groups and may be Adenosine related.
Below is a cut an paste of the good stuff I found in the papers.
“Dipyridamole is proposed to increase coronary blood flow (CBF) by inhibition of adenosine uptake into cells, resulting in an increase in interstitial fluid (ISF) adenosine and an adenosine-mediated vasodilation.”
Dipyridamole is also and ENT1 inhibitor.
“ENT1 inhibitors may increase adenosine tone in tissues. Adenosine is a molecule that plays several roles in brain function. In neurons, it regulates cell survival and neurotransmitter release. In glia cells, it controls cell differentiation, astrogliosis, proliferation, and neurotransmitter uptake. “
The goal it seems is to increase intercellular adenosine.
“Therefore, if BID is also associated with down regulation of spinal A1Rs, this could be an important mechanism that would contribute to the development of PLMS in RLS. The same mechanism could then explain the supraspinal and spinal hyperexcitability that leads to PLMS in RLS. The term BID should then be extended to central nervous system iron deficiency (CNSID), to also include the spinal cord. “ Whoa, this guy knows me!
So what increases Adenosine? 'Adenosine acts quickly and is rapidly broken down afterward. When administered intravenously, it has a half-life of around 10 seconds in human blood.' So clearly supplementing with Adenosine isn't going to do much.
Exercise: Whereas moderate exercise did not affect adenosine levels in the brains of rats, intense exercise increased adenosine as a result of ATP (energy) breakdown. (Have you read any exercise questions?)
Diet: "Following a high-fat low-carb (ketogenic) diet can increase adenosine levels. The ketogenic diet alters energy metabolism and increases both ATP and adenosine. " Where have I heard this before.
ADA Blockers: Since ADA is the enzyme that breaks adenosine down, substances that block ADA could theoretically increase adenosine levels. Some natural ADA blockers include:
• Berberine
• Curcumin
• Stinging nettle
• Naringenin, a bioactive compound found in citrus fruits
• Increasing nitric oxide, which will also boost your blood flow and brain circulation
Finally as a bonus
"Caffeine, the most widely used psychoactive compound, is an adenosine receptor antagonist. It promotes wakefulness by blocking adenosine A2A receptors (A2ARs) in the brain"
All in all it was a fun little rabbit hole and I learned quite a bit.
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WideBody
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Thank you for posting and working through this. Trying to keep this simple for me ..
Do you think RLS is made worse by more adenosine or less adenosine? Your point about BID causing downregulation of A1R (adenosine receptors) would suggest that the body is less receptive to adenosine and therefore a similar effect might be experienced if you have less adenosine? I.e. Less adenosine = worse symptoms.
However intense exercise seems to have the effect of worsening RLS but also generates more adenosine which goes against the previous relationship.
Well for me, I do long distance endurance type exercises. That does not seem to affect adenosine (as I understand it). It is the high intensity exercise that does. I lay around like a zombie when I do that stuff. But that is me.
Something else I picked up on was that this seems to be specifically caused by a BID (Brain Iron Deficiency). I know that my RLS was caused by prolonged iron deficiency (without anemia). I have heard from people that Dipyridamole did not help. I wonder if they respond to iron as well as I did.
I took iron everyday for a year and got my ferritin to 200. It did not help my RLS. The nurse suggested I stop taking iron and it took 18 months to fall to a ferritin of 30. An iron infusion woke me up so to speak. I now take iron every other day, sometimes more frequently depending on how I feel.
Thanks WideBody. You've picked out important parts from the readable papers. Some/the original by Ferre I found quite difficult to read, and mind you, I am a well-experienced researcher/scientist myself. Several later paper were far easier to follow. Anyway, thanks for doing the reading for us 🙏
In reply to Munroist, WideBody is mostly quoting from papers. And the finding by the scientists (Ferré and coworkers) is that people with RLS have reduced adenosine, due to fewer AdR(1) receptors. AdR stands for adenosine receptors. Ferré and co also write a lot about adenosine-dopamine receptor heteromers. These are kind of combined receptors for both dopamine and adenosine. Hence the link to RLS and the point of interest for Ferre and co.
RLS have reduced adenosine? I'm tired all the time during the day. I thought that was due to having elevated levels of adenosine (so I take caffeine pills every 5 hours to block them). If we increased our adenosine, wouldn't that make us even sleepier?
Increased adenosine especially around bedtime should make us sleepier. I believe that is part of the goal. Adenosine builds up during the day and is removed by sleep. One of the hallmarks of RLS is that we get very little sleep but are not as tired during the day. I know that is hard to understand, because we are exhausted. Caffeine is considered a no-no for some people with RLS. It is discussed frequently.
I do still drink coffee in the morning only. Generally I don't touch the stuff after lunch. Have you tried not having caffeine for a week or two? Mind you there are withdrawls from caffeine so please be careful.
Thanks LotteM. That is exactly what I did. I started with the earlier papers and read slowly and looked up everything. I did the cut and paste into my own notes to try and organize my thoughts. I intend to keep doing this until I have an inkling of understanding. But now I know who to ask when I have questions.
😉
Of course I am doing this because I respond so well to dipyridamole.
BTW, have you read anything about augmentation and dipyridamole? That is my biggest concern.
No, nothing about augmentation and dipyridamole. But, I think I said this earlier, it is early days still. Still very few people are probably taking dipyridamole for RLS. And IF augmentation may occur, lime with the dopamine agonists, it needs numbers and time to get it surfaced.
Did you experience augmentation? Even if not, I assume you will know the signs, so remain alert. Don't forget, though, that often a medicine taken long term needs dose adjustment i. The first year. Dr Winkelman and coworkers nicely showed this with the people in the opioid registry.
Thanks for this WideBody. Given your positive experience with dipyridamole, i'm going to ask my sleep specialist for a script at the end of the month. (He issued one several years back but it expired before i filled it).
I have the same questions for you. Have you done a morning fasted full iron panel? I am trying to understand who benefits from Dipyridamole and who doesn’t. Thanks.
I’d hypothesize that a hypoadenosinergic state would or, could, theoretically divert dopamine for conversion to adenosine resulting in a hypodopaminergic state and BID. I took 300mg Dipyridamole for 4 weeks with no improvements in PLMD or EDS.
I am sorry Dipyridamole didn’t help you. Have you checked your iron levels with a morning fasted full iron panel? Do you respond to iron supplements? I would like to determine why some people respond better than others. Thanks.
I replied below. And I was just reviewing my theory above and a study re: adenosine and RLS that contradicts it - stating that BID results in a hyperdopaminergic and hyperglutaminergic state, which is weird because many people get relief from dopamine agonists. Aug.
Here are my results from 11/21. Everything is within range though my Ferritin is on the low end. However, in 2017/2018 my Ferritin was 132 and 168 respectively and I was worse then than now. The difference may lie in the etiology and because I have PLMD rather than RLS, though the recent studies with Dipyridamole showed an improvement in PLMD as well. Also, the feeling I get about 10-15 seconds before a movement sounds a lot like what people with RLS feel. For me, it’s like electricity building up then, bang, I kick out my leg or knee myself in the mouth (only a few times). As far as etiology, the PLMD I have is from stopping Zoloft to quickly so is secondary to Antidepressant Withdrawal Syndrome (AWS) or Antidepressant Discontinuation Syndrome (ADDS) which likely involves different mechanisms that someone with idiopathic RLS - it seems with dopamine, glutamate and adenosine and all their various receptors and metabolites, there may be several ways to develop RLS and PLMD…. it’s a mess to figure out.
But, I’m glad you messaged as I think I will start taking heme iron supplements again and try to get to 200 or so and see if that makes a difference. I’m still jerking all over all night and sleeping 12-15 hours a day. It bites.
Thank you for this. I am not sure what to make of it. I do think the Dipyridamole works on my PLMA (Periodic Limb Movement while Awake). Please let us know if you do end up trying Dipyridamole
Oh, I forgot to even mention it. I did take 300mg for 4 weeks without a noticeable difference in my nighttime PLMS (video myself) or EDS. My PLMA has been well controlled for years with a combination of several medications but am now in the process of slowly tapering off of them as I believe I’ve built a tolerance to them and then try a rotational monotherapy or maybe 2 medications. Just one brief episode of breakthrough PLMA so far and hoping I can get through the process without too much of that, though expect it as has always happened in the past. Maybe if/when hat starts to happen, I’ll try Dipyridamole again. So, it;s likely I will try it again and will let you know how it goes.
If you don’t mind, I’m wondering what you mean when you say that you “think” it’s helping your PLMA? I’m curious as to what I might expect and also what dosage you take.
Ircam2112 . My PLMA is/was sudden jerks and twitches at random times. Just standing, talking, sitting and even driving the car. Dozen of times a day. Those have 95% stopped. Remember, I have no control over them (wish I did).
BTW, I take 300mg a night. The average effective dose in the study was 217mg (IIRC).
Yes, mine were at least similar. Any time during the day but only when at rest, either lying or sitting down watching TV, reading, trying to nap, etc.. I don’t recall them happening very often while driving but definitely when a passenger. And then worse right before bed and all through the night. Do you recall if you were taking any medications at the time or had just discontinued?
Also completely involuntary. Every 15 - 60 seconds until I got up. If I got up to walk around then sat back down, they’d take a few minutes to kick-in again. Used to be all in my feet and legs but are now also in my torso, shoulders, wrists, arms and neck (during the night). Mine have 100% stopped during the day and even before sleep but I take several medications. As I discontinue the medications, having them during the day will be my metric as to whether I’m tapering too fast or if that medication is essential.
My neurologist just agreed to provide me with a dipyridamole prescription. It should arrive in two days and I am eager to try it. She recommends starting with 50mg twice a day for a week, then increasing to 100mg twice a day. I have both the creepy crawly electrical feeling RLS and the sudden jerking/twitching when trying to fall asleep. Should I take it on an empty stomach or does it matter? How soon will I know if it has an effect?
That’s great! I hope it works well for you. Here is the primary study that I’m aware of, and another is attached above in my earlier comments. I don’t recall reading anything about food making a difference in my research on drugsdotcom and other websites It is a blood thinner that has a long history of safe use but make sure you inform all your doctors as it would be very important to know if you had any injuries or surgeries. Looks like you could expect results in 2-3 weeks with your titration plan. Also, in both studies the average dose was around 250mg so, like me, you may want to go as high as 300 - 400mg before quitting if it doesn’t seem to be working. I took 300mg for 4 weeks without a noticeable difference (or any side effects) but I have primary PLMD/A, no RLS. In hindsight, I wish I would have tried 400mg before calling it quits - years ago I took gabapentin to 900mg for 6 weeks without a difference but a big difference as soon as I tried 1200mg. So, there may be a threshold or ceiling effect with it. I really hope it works for you and would really appreciate it if you’d let me/us know how it goes for you.
From drugsdotcom. It sounds like high-fat meals reduce peak plasma and absorption but then goes on to say “not clinically relevant”. A bit confusing. May want to ask doctor to clarify this. And wow, at up to a 66% reduction in absorption rate (with or without food). I think I’ll definitely try this again up to 400mg/day as maybe I don’t absorb it as well as others. I’m going to look to see if there’s a blood or urine test to find out the absorption rate.
That is regarding the extended release form of dipyridamole with aspirin. The immediate release probably has a different absorption rate. Were you taking the immediate release or the extended release?
immediate release for me. The package says to take on an empty stomach. I did have two "difficult" evenings. I think it may have been caused by taking it to close to dinner time.
Here’s some info re: absorbtion rate. It looks like in a more alkaline environment (either naturally or when taking antacids and/or PPI’s) the bioavailability and peak plasma concentrations are lowered by 53% and 57% when taking the immediate release formulation compared to the extended release formulation, even if you take the immediate release and aspirin at the same time. From another study, in normally more acidic environments (i.e. when you aren’t taking antacids or PPI’s), the absorption rate is the same for both formulations - 70%.
Fatniss, I would love to hear the out come. My doctor did the same thing 50mg twice a day for a week. Within 1 week I was up to 200mg. (better) by 1 month I was at 300mg. (4 * 75mg) I take it about 90 minutes before bed. Yes, I do think it helps to take on an empty stomach.
So far I have had to "bad" nights. I think it was because I took the dipyridamole to close to dinner.
Good luck and please let us know how it works for you.
Do you think it was the build up that relieved your symptoms (i.e. like how gabapentin has to be taken for a few weeks before it starts to work)? Or do you think it was just finally reaching the proper dose that made it start to work (i.e. it would have treated symptoms on day 1 if you had started off at the 300 mg)?
Dipyridamole at 300mg for a month didnt seem to help me but there may be threshold or ceiling effect such that you don’t have any improvement at 250mg but then have a huge improvement at 300mg. That happened to me with gabapentin where I had no improvement at 900mg but then a big difference at 1200mg.
I was originally prescribed 100mg a night. I felt something and quickly went to 200mg in a week. After a month I jumped to 300mg. I am staying there for now.
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