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Pain after a few weeks of NR or NMN and resveratrol

nmn resveratrol

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#1 aloequasar

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Posted 23 March 2020 - 03:09 AM


Has anyone else experienced progressively worsening skeletal/muscular pain while being on NR or NMN and resveratrol (or anything similar)?  My experiences with NR or NMN and resveratrol worsen with time when I'm on them.  They start as skeletal/muscular pain about a month out and intensifies until I stop the NR or NMN and resveratrol.  Has anyone else had this experience?  If so, have you changed anything you are doing so you can still benefit from these compounds?  Is there any research to suggest what might be going on?
 
Two years ago, I tried NR.  Initially, there was no noticeable change whatsoever.  The most I could say was that there was no effect or side-effect period.  There was nothing positive or negative to note.   After about a month, I started to get some slight back pain -- a new experience for me.  I had no reason to suspect NR at the time.  Over a few weeks, the pain worsened.  I stopped the NR ... not because I thought there was a connection, but because of an abundance of caution due to the pain.  The pain cleared up in a week.  I didn't suspect the NR at the time.    
 
I tried the NR again a month later.  I saw no effect until a few weeks passed by.  This time I got a pain in a tendon on the chest -- also a new experience.  It worsened until I stopped the NR and then cleared up in about a week.
 
I tried the NR a third time with the same results. 
 
I haven't taken NR since and haven't run into any similar problems until I recently tried NMN and resveratrol.
 
I tried fasting in the morning while taking NMN and resveratrol.  Taking the NMN and resveratrol was different than the NR.  I felt good a few minutes after taking the NMN and resveratrol.  So much so that I looked forward to taking it each morning.  After about three weeks, I started to notice muscular/skeletal pain again.  It got worse over time.  I stopped the NMN and resveratrol but kept the fasting.  The pain began to subside after the second day and cleared up in a week.  I restarted the NMN and resveratrol, and the pain came back.  I tried just the NMN and the pain came back.  I'm trying just the resveratrol now.  Its too early to tell, but so far so good.
 
I couldn't find accounts of similar experiences or anything in the scientific literature that points to a similar experience.  I would describe the experience as pain or inflammation that won't turn off.  Has anyone else had a similar experience?  Did you do anything different so you could still enjoy the longevity benefits of these compounds?

Edited by aloequasar, 23 March 2020 - 03:18 AM.

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#2 Turnbuckle

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Posted 23 March 2020 - 04:43 PM

Search this site for resveratrol "joint pain" and you will find threads going back more than a decade.

 

Where does the pain come from? Resveratrol is known to activate the Sonic Hedgehog [Shh] gene, and activating the Shh gene is involved with Rheumatoid Arthritis [RA]. Thus taking resveratrol every day can produce symptoms of arthritis.

 

Taken together, these findings provide evidence that Sirt1 may mediate effects of resveratrol-activating the Shh signaling...

 https://www.karger.c...FullText/494593

 

 

Our results show that Shh, Ptch1, Smo, and Gli1 proteins were highly expressed in synovial tissue of patients with RA, especially in FLS, while expression in synovial tissue of patients with knee trauma was much lower. Based on these findings, we hypothesize that Shh signaling pathway activation may play an important role in excessive proliferation of FLS in RA synovium.

https://www.ncbi.nlm...les/PMC3987882/

 

 


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#3 Oakman

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Posted 23 March 2020 - 05:04 PM

Please give us your dosage for NMN, NR, and R and when you take them during the day/night.


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#4 aloequasar

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Posted 23 March 2020 - 05:44 PM

Oakman, 

 

NR - 250 mg every morning (for the periods indicated in the OP)

 

NMN - 1000 mg in the first two tries, 125 mg in the last try

resveratrol - 1000 mg

 

Turnbuckle,

I'll search resveratrol and join pain on the site.  I was more focused on NAD+ boosters.

 

I appreciate your citing sources.  I'll have a read.  



#5 Turnbuckle

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Posted 23 March 2020 - 06:41 PM

Oakman, 

 

NR - 250 mg every morning (for the periods indicated in the OP)

 

NMN - 1000 mg in the first two tries, 125 mg in the last try

resveratrol - 1000 mg

 

Turnbuckle,

I'll search resveratrol and join pain on the site.  I was more focused on NAD+ boosters.

 

I appreciate your citing sources.  I'll have a read.  

 

NR also activates Sirt1, and thus can potentially activate Shh. You might want to try nicotinamide alone, or nicotinamide + ribose instead, as nicotinamide does the opposite, at least in vitro. The effects in vivo are mixed, but I've never had any problem with it.

 

In any case, you don't want to use NAD+ supplements every day, as a high NAD+/NADH ratio drives mito fission. Fission is good for mito QC, but fusion is also necessary. The usual state in cells is mixed. 

 

As expected, NR treatment significantly upregulated Sirt1 gene expression.

https://www.ncbi.nlm...les/PMC6369115/

 

 

Since the finding that NAM exerts feedback inhibition to the sirtuin reactions, NAM has been widely used as an inhibitor in the studies where SIRT1, a key member of sirtuins, may have a role in certain cell physiology. However, once administered to cells, NAM is rapidly converted to NAD+ and, therefore, the cellular concentration of NAM decreases rapidly while that of NAD+ increases. The result would be an inhibition of SIRT1 for a limited duration, followed by an increase in the activity. 

https://www.ncbi.nlm...pubmed/28417163

 


Edited by Turnbuckle, 23 March 2020 - 06:57 PM.

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#6 Phoebus

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Posted 23 March 2020 - 09:05 PM

Instead of NAD precursors you might want to try actual NAD+

 

I am using the NAD lyposomal sublingual product from ABN and so far its been great 



#7 Oakman

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Posted 24 March 2020 - 01:47 AM

Oakman, 

 

NR - 250 mg every morning (for the periods indicated in the OP)

 

NMN - 1000 mg in the first two tries, 125 mg in the last try

resveratrol - 1000 mg

 

Turnbuckle,

I'll search resveratrol and join pain on the site.  I was more focused on NAD+ boosters.

 

I appreciate your citing sources.  I'll have a read.  

 

I don't have much for you. That's a lot on NMN and also a lot of R. 300 mg NR in the AM is what I take wo/problems. Larger amts of NMN I only take exercising and occasionally 150 mg at night, with no problems. So it is an off & on thing, not daily, more like couple days on, a day or two off.

 

At the same time, a couple months ago, daily, I started taking 600 mgs R in the day, with 600 mg curcumin and some EMIQ. I developed joint pain and changed to 300/300 mgs plus EMIQ at evening meal, and the soreness disappeared. Perhaps too much of a good thing is bad. Plus R in the day is a pro-oxidant, but it changes to an anti-oxidant in the PM.  One might think the pro-oxidant that could effect joints.


Edited by Oakman, 24 March 2020 - 01:49 AM.


#8 aloequasar

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Posted 26 March 2020 - 02:48 AM

Thanks for the posts, the feedback, and the reading.  Who comes up with names like Sonic Hedgehog? :) There must be a Sega fan in there somewhere.

 

I should clarify that when I was taking the NR, I was taking it alone.  When I was taking the NMN and resveratrol, on the last try, I took only 125 mg of NMN and the symptoms came back.

 

I've been taking the resveratrol only for a week and the pain is gone.  I'm thinking of switching over to NMN only at 125 mg to see what I can learn.  Will the pain come back?  Two things are stopping me at the moment.  

 

1. NMN degrades to Nicotinamide, so there's a question now if the NMN is still NMN.

2. I read an account in an NIH paper of a person with a Vitamin B deficiency.  It seems we share the same symptoms.  Are there any findings that supplementing with NMN causes you to loose any of your Vitamin B stores? Does that ring a bell with anyone? If so, can you point me in the right direction?  My google search results are diluted by the fact that Vitamin B is related to the NMN process.

 

 


Edited by aloequasar, 26 March 2020 - 02:57 AM.


#9 Keizo

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Posted 30 March 2020 - 03:32 PM

It's also somewhat plausible Resveratrol could have some significant effect on estrogenic activity for some people taking very large doses. Arimidex (extremely potent aromatase inhibitor) has a lot of side effects like joint pain etc.

Although I think a lot of people on this forum have discounted this, but I personally don't due to anecdotal experience of testicular growth (from ~15ml to ~30ml each during the course of a few months) years ago. I was using something like 500mg 98% trans-resveratrol (maybe less). I.e. I'm not excluding the possibility Resv might've kickstarted my testicular function as my body attempted to restore normal estradiol function/levels by ramping up testosterone production.

 

I did some rough calculations back then (2014 or so) and I think I ended up at something like 1.5 - 4.5 grams in humans being enough to see noticeable effects on sex hormones or aromatase (forgot if it even was aromatase inhibition, SERM effect, or overall boost seen in some study on testosterone), converted from animal studies. And yes I tried taking into account the difference humans have in metabolism, compared to say rats.

 

There's an old thread or two on this forum about Resveratrol and hormones, and a bunch of anecdotes spread around (mostly about the joint/tendon ache). My case is however extremely confounded by things like 1. starting to take 2000 or more IU vitamin D3 at the same time, 2. increased dietary nutrition, 3. previous benzodiazepine withdrawal some years prior and (which might've messed with hormonal regulation) 4. I might've simply been late in develoopment of male sex characteristics, and/or had some weird genetics whereby I got  a late growth spurt at around 23 (not height). 

 

One of the reasons I've been avoiding resveratrol for recent years is I notice it rather easily, maybe just a few hundred mg's is enough to give me some very mild aches. 



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#10 DaveX

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Posted 16 April 2020 - 12:52 AM

I'm experiencing pain in my wrist after taking Pterostilbene (more bioavailabe Resveratrol analogue). Can one do anything about it? Is that Shh gene activation harmful or can it be actually good (like being the pain of healing of minor unnoticed damage)?
I've had ca. 4 different days of taking Pterostilbene, and the (minor) pain appeared pretty much the morning after the first dose, and I never had anything like it. When pausing it for one or two days, I didn't notice any pain anymore, but when I was taking Pterostilbene again, the pain reappeared (still relatively minor).
It also seems to have negative effects on my stamina, although I noticed some mental benefits, which however aren't perfect either and very specific.

Edited by DaveX, 16 April 2020 - 01:11 AM.


#11 Keizo

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Posted 16 April 2020 - 01:15 AM

I'm experiencing pain in my wrist after taking Pterostilbene (more bioavailabe Resveratrol analgoue). Can one do anything about it? Is that Shh gene activation harmful or can it be actually good (like being the pain of healing of minor unnoticed damage)?

I've had ca. 4 different days of taking Pterostilbene, and the (minor) pain appeared pretty much the morning after the first dose, and I never had anything like it. When pausing it for one or two days, I didn't notice any pain anymore, but when I was taking Pterostilbene again, the pain reappeared (still relatively minor).

It also seems to have negative effects on my stamina, although I noticed some mental benefits, which however aren't perfect either and very specific.

Someone mentioned vitamin D3 helping for their resv. related aches (and for arimidex side effects according to study).

 

Me: Been taking 1gram resv. every morning for 7 days (with some olive oil etc). Have barely noticed aches this time around, less than I remember anyway, same supplier and etc. I've also been taking some fulvic acid (which might act as a mild painkiller). Don't remember what dose of D3 I was taking back then when I noticed the mild ache but it was probably about the same as now (5k iu /d). If aches etc really is related to estrogen in some way then perhaps my now higher body fat percentage is preventing those effects to get out of hand, (I used to be way skinnier), or for that matter perhaps my hormones are simply more plentiful now (more testosterone - > more estrogen, sometimes) whereas those years ago I might have had significantly lower sex hormone levels (if testicular size and well-being is any indication).

 

The only possible immediate benefit I get right now from Resveratrol is some sort of energy boost, like inability to sleep (which I hope is very limited in time after dosage), getting a little bit agitated in some peculiar way. But not sure if that's a benefit really. I'm just taking it for health purposes long-term, like cardio-vascular.


Edited by Keizo, 16 April 2020 - 01:20 AM.


#12 DaveX

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Posted 16 April 2020 - 02:02 PM

I tend to take relatively high levels of Vitamin D, but never the cofactor Vitamin K, and rarely Calcium, and I also find some results for that associated with joint pain and arthritis.

Energy boost is interesting, since I think I notice the opposite, shortness of breath and the body feeling depleted in energy more quickly. Maybe there are other factors involved.

 

I was taking it as an alternative to Bacopa Monnieri, which I was using repeatedly, as it's also a HDAC inhibitor (and I notice longterm positive effects of HDAC inhibitors compared to things which are Histone Acetytransferase Inhibitors, the opposite, or SIRT-activators and  P300-activators compared to deactivators) and upregulates AMPA-receptors, though I found out it also inhibits them. (Bacopa and also Resveratrol seems to cause upregulation by another mechanism than inhibition.) I was choosing Perostilbene, since all indicators were that it's practically the same as Resveratrol but more bioavailable. I still don't doubt that it's true.



#13 Hip

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Posted 17 April 2020 - 03:26 AM

It may be the resveratrol. It can be a toxic supplement: the Sirtris Pharmaceuticals clinical trial of resveratrol led to some people getting kidney failure:

 

The study was terminated noting five patients developed renal failure

 

Source: here



#14 Keizo

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Posted 17 April 2020 - 10:02 AM

I tend to take relatively high levels of Vitamin D, but never the cofactor Vitamin K, and rarely Calcium, and I also find some results for that associated with joint pain and arthritis.

Energy boost is interesting, since I think I notice the opposite, shortness of breath and the body feeling depleted in energy more quickly. Maybe there are other factors involved.

 

I was taking it as an alternative to Bacopa Monnieri, which I was using repeatedly, as it's also a HDAC inhibitor (and I notice longterm positive effects of HDAC inhibitors compared to things which are Histone Acetytransferase Inhibitors, the opposite, or SIRT-activators and  P300-activators compared to deactivators) and upregulates AMPA-receptors, though I found out it also inhibits them. (Bacopa and also Resveratrol seems to cause upregulation by another mechanism than inhibition.) I was choosing Perostilbene, since all indicators were that it's practically the same as Resveratrol but more bioavailable. I still don't doubt that it's true.

I should have worded it more carefully. I mean energy in a very narrow sense, like the part of caffeine that makes you spaced out and makes it hard to sleep (even then I'm not sure) --- not necessarily anything positive or anything that makes me have better endurance. Overall from me using a few 100 grams some years ago and now starting to take it again I think the subjective effects are near zero. (again with exception of half-way plausible testicular boost etc way back, and some hard to specify feelings, and the mild ache that might be present at times) 

 

Resveratrol can do a lot of things, from time to time I think I've noticed nausea (which might be due PDE4 inhibition), but very mild. Perostilbene is something I'd consider if it was more widely available and cheap. 



#15 Keizo

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Posted 17 April 2020 - 10:08 AM

It may be the resveratrol. It can be a toxic supplement: the Sirtris Pharmaceuticals clinical trial of resveratrol led to some people getting kidney failure:

 

 

 

 

Source: here

At what dosages? and how close to death were these people beforehand? I can't access the study.



#16 Turnbuckle

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Posted 17 April 2020 - 10:45 AM

At what dosages? and how close to death were these people beforehand? I can't access the study.

 

 

The study report can be found here -- https://sci-hub.si/10.1111/bjh.12154

 

Twenty four patients (median age 66.5 years) were enrolled into this phase 2 clinical trial of SRT501 with or without bortezomib in MM patients who had relapsed or were refractory to at least one prior therapy.... Patients received 5.0 g of SRT501 (Sirtris Pharmaceuticals Inc., Cambridge, MA, USA) following breakfast for 20 d in a 21-d cycle up to 12 cycles....The predominant study finding was unexpected renal toxicity, with five SAEs of renal failure leading to early study termination (Table II).


 

 

This is a case of dose makes the poison, as 5 grams is much higher than most people take. But as some have seen, including myself, 100-200 mg taken on a daily basis can cause joint damage. In my case it took a year or perhaps longer, as I didn't pin it on resveratrol until it had gotten pretty bad.


Edited by Turnbuckle, 17 April 2020 - 11:03 AM.


#17 DaveX

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Posted 17 April 2020 - 02:20 PM

I think Astragalus extract can help with joint aches. (Edit: I would say almost ridiclously fast, at least in the subjective sensory department.) I wonder if it might be a good adjunct.

By the way, what you said about testicular boost or something like that, Keizo, might be true. I have issues like that anyway, or more precisely sensitivity and other things being wrecked by neuroleptics (like others seem to be by Ampakines), and it's part of why I try different things.
I bet part of the effect is by PPAR alpha agonism, but not all of it, since Palmitoylethanolamide (PEA) is likely more effective at that, but is different. There is more to it.

Something about energy may be right. But I read Pterostilbene or Resveratrol lowers 5HT2C receptors (good) and Dopamine D1 receptors (not good, except from the perspective of "toxicity" in that study, which however encompasses almost any activity). I think the latter, downregulated Dopamine D1 receptors, might be responsible for some haziness over time. (And the lower 5HT2c might be part of improving sexual problems.)
Study: https://www.research...ic_side_effects
It is a mixed bag, and a little tricky. But I still find it worth trying for now... With some pauses.

Regarding price of Pterostilbene: the one from Focus Supplements (e.g. on Amazon) was just as cheap as any decent Resveratrol alternative.

Edited by DaveX, 17 April 2020 - 02:43 PM.


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#18 BrentS

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Posted 31 May 2020 - 10:17 PM

Thanks for the posts, the feedback, and the reading.  Who comes up with names like Sonic Hedgehog? :) There must be a Sega fan in there somewhere.

 

I should clarify that when I was taking the NR, I was taking it alone.  When I was taking the NMN and resveratrol, on the last try, I took only 125 mg of NMN and the symptoms came back.

 

I've been taking the resveratrol only for a week and the pain is gone.  I'm thinking of switching over to NMN only at 125 mg to see what I can learn.  Will the pain come back?  Two things are stopping me at the moment.  

 

1. NMN degrades to Nicotinamide, so there's a question now if the NMN is still NMN.

2. I read an account in an NIH paper of a person with a Vitamin B deficiency.  It seems we share the same symptoms.  Are there any findings that supplementing with NMN causes you to loose any of your Vitamin B stores? Does that ring a bell with anyone? If so, can you point me in the right direction?  My google search results are diluted by the fact that Vitamin B is related to the NMN process.

 

imho if you think the problem might be a vit B deficiencey, do a blood test.  I did one with Spectracell a year ago, here are the vit B part of the results (note I modified my vit B intake (increased a lot) after I got the results:

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