24 replies to this topic

[AOIministrator]

So as you know a lot of preliminary research has been done on NAC, as it has on piracetam. But what is the downside?

 

In short: no one really knows.

 

I have been abusing stimulants in the past and I also suffer from being a part time alcoholic (Iike many people probably).

 

This has lead me to notice vascular issues more intensely than maybe the average person would. And my system has also grown weak spots. I also suffer from PVCs, that is double as intense heartbeats every 4th beat or so, or in other words high pulse pressures.

 

On my road to recovery, I have done a lot of exercise: bicycling dozens of miles, strength training 3x a week mostly.

 

As you can see, this puts stress on the cardiovascular system beyond what people usually experience who take part in studies.

 

In this time, I have taken NAC on and off for weeks and month because it helps, or supposedly helps with some of the issues.

 

And although NAC is good for most things short term, what is most concerning to me is long-term side effects.

 

Those are mainly noticable to me in the form of strange pressure headaches and weird, yet very alarming sensations in my brain. As if vessel strength has been impaired.

 

I began to research this and it turns out that NAC is a potent inhibitor of the Van Willebrand Factor. A coagulation factor that is responsible for blood vessel repair that also happens to be the the primary indicator of alarming aneuryrism activity.

 

Or in other words: The Van Willebrand factor makes sure that damaged vessels receive adequate reinforcement if they are weakened and compromised.

 

Now if you read the studies, it is all about ishemic attacks and fucked up clogged up brains that seemingly see improvements on the short run.

 

But you have to ask yourself: what's on the long run for healthy people? If NAC knowingly impairs vessel repairs, how do you know it might not grow aneuyrisms as a side effect and pop them over the course of 5 or 10 or 20 years?

 

This is exactly the same issue as you face with acidic drain cleaners: Yes, maybe it unclogs your sink. But then if you pour this stuff down the drain 20 and 200 times, it will probably burn holes in your pipes and fuck them up beyond repair.

 

Be cautious, peace.

[pamojja]

 

Those are mainly noticable to me in the form of strange pressure headaches and weird, yet very alarming sensations in my brain. As if vessel strength has been impaired.

 

Never had such or any side-effects, used NAC regularly at in average 700 mg/d for 11 years. Initially started comprehensive supplementation because of a walking-disabilty from PAD with an 80% blocked non-aneuyristic stenosis at my abdominal aorta. Meanwhile in remission.

 

Addtional remissions from COPD I and ME/CFS symptoms. An old stroke in my cerebelium was also found, where I don't even remember its occurance. Must have been as a toddler.

 

 

I began to research this and it turns out that NAC is a potent inhibitor of the Van Willebrand Factor.

 

Does it also do that in vivo with all water- and fat-soluble vitamins, essential mineral, amino-acids and phytonutrients provided plenty? Or only in-vitro, without the whole web of interdependencies, also with internal enzym-systems?

[Oakman]

I've taken NAC for lengthy periods (months and months over years) without any negative side effects (that I can notice), and certainly those that you mention. And looking at WebMD's listing for NAC (certainly one of the most conservative health websites) shows a long, long list of probable and possible positive effects. Negatives listed are: if you are allergic to NAC, have asthma, or bleeding disorder, take nitroglycerin, or are about to go into surgery...an almost negligible list compared to most supplements.

 

For a relatively healthy person, there appears to be almost no downside to NAC supplementation. Just saying.

[awarren]

Every time I took NAC, I had chest pains related to breathing for 2-3 days

[AOIministrator]

Never had such or any side-effects, used NAC regularly at in average 700 mg/d for 11 years. Initially started comprehensive supplementation because of a walking-disabilty from PAD with an 80% blocked non-aneuyristic stenosis at my abdominal aorta. Meanwhile in remission.

 

Well for one, this is extremely anecdotal. 

 

But you also have to understand, that the Von Willebrand Factor is responsible for repairing vessels that undergo high shear stress and rapid fast blood flow. 

 

Or in other words: very small vessels such as found in the brain. In the brain, even aneurysms less than a millimeter big are fatal. In other organs, something of this size probably wouldn't even matter if it popped.

 

The Von Willebrand Factor isn't really much involved in repairing huge aneurysms, such as aortic aneurysms. This is a whole other issue.

Edited by AOIministrator, 13 July 2020 - 07:53 PM.

[pamojja]

Or in other words: very small vessels such as found in the brain. In the brain, even aneurysms less than a millimeter big are fatal. In other organs, something of this size probably wouldn't even matter if it popped

 

An MRI even found an old stroke in my left cerebellium (1,5-2.5cm), only that I didn't noticed anything. Guess must have been happing as a toddler. Also with my remission of PAD, my maximal carotid intima thickness reduced from 1.9 down to 1mm (normal <0.9mm).

Edited by pamojja, 13 July 2020 - 10:22 PM.

[Mr Serendipity]

Well NAC is the only thing which pretty much cures my ocd and helps with anhedonia. However I wouldn’t take it without selenium now as I believe it exacerbated a selenium deficiency in me, as selenium is required to create the enzyme to convert NAC, glycine, and glutamine to glutathione.

Edited by Jesus is King, 09 August 2020 - 11:25 PM.

[Daniel Cooper]

Well NAC is the only thing which pretty much cures my ocd and helps with anhedonia. However I wouldn’t take it without selenium now as I believe it exacerbated a selenium deficiency in me, as selenium is required to create the enzyme to convert NAC, glycine, and glutamine to glutathione.

 

That's interesting. Do you have a reference for that?

[pamojja]

Glutathion peroxidase is selenium dependent. In fact, I lab-tested GSH-Px for monitoring my selenium status, because its a cheaper test than selenium itself.

[Gal220]

Some discussion in this  thread  in reference to Derek Lowe's article, "N-Acetyl Cysteine: A Warning Shot"

Edited by Gal220, 18 August 2020 - 04:49 PM.

[Daniel Cooper]

NAC can induce pulmonary hypertension in mice:
 
One Type Of Antioxidant May Not Be As Safe As Once Thought

 

Is this a problem for humans?  My recollection is that the equivalent dose was in the range of 2400mg/day in a human.  I personally won't take over 1200mg/day.

[Oakman]

NAC can induce pulmonary hypertension in mice:
 
One Type Of Antioxidant May Not Be As Safe As Once Thought

 

Is this a problem for humans?  My recollection is that the equivalent dose was in the range of 2400mg/day in a human.  I personally won't take over 1200mg/day.

 

I take NAC daily so I was intrigued by this seeming negative effect. The apparent key in the linked study is given as, "Mice missing an enzyme known as endothelial nitric oxide synthase did not convert NAC to SNOAC (note: the nitrosothiol that causes the problem) and were protected from the adverse effects of NAC..."

 

So endothelial nitric oxide synthase (eNOS) seems the bad guy here. Perhaps limiting it's production would be helpful when taking NAC? A more nuanced approach may be better.

 

A bit more looking at eNOS shows it to be essential and perhaps should not be limited but rather kept "coupled". 

 

 

Endothelial nitric oxide synthase uncoupling

 

Recently, it was revealed that under certain pathological circumstances, eNOS becomes dysfunctional and produces superoxide rather than NO [3]. The pathophysiological role of dysfunctional eNOS has attracted attention in vascular disorders, including atherosclerosis, hypertension, and diabetes mellitus [4–6].

Among a number of molecular mechanisms proposed for eNOS uncoupling, evidence indicates that BH₄ may be a key molecule in the control of NO and superoxide generation, and consequently the formation of hydrogen peroxide and peroxynitrite by eNOS [7]. 

 

This study, Endothelial Nitric Oxide Synthase in Vascular Disease, indicates that it is the uncoupling of the eNOS system and subsequent simultaneous up-regulation of NADPH production that is the culprit for some bad cardio effects, and esp. as that allows for ONOO- production, which inhibits necessary BH₄ through increased oxidative stress and therefore eNOS. It's certainly does get convoluted. 

 

In the end, sufficient Vit C and Folic Acid may be key to helping out in re-coupling eNOS and limiting any negative NAC effects when these problems arise? Of course that's my lay person understanding of something far out of my wheelhouse. Certainly dose must play into this too, but I have no idea other than the "600 mg serving one to three times a day" on the bottle I have. I use the lowest dose.

 

+=-+=-+=-

Cardiovascular Risk Factors Cause Endothelial Dysfunction: Potential Mechanisms Involved

 

In the presence of cardiovascular risk factors, endothelial dysfunction frequently is encountered. Several molecular defects could account for reductions in endothelium-dependent vascular relaxation.

 

Endothelial dysfunction could be due to decreased eNOS expression. However, several studies have shown that cardiovascular risk factors are associated with an increase rather than a decrease in eNOS expression.6 The increased expression of eNOS in vascular disease is likely to be a consequence of an excess production of H2O2. H2O2, the dismutation product of O2·−, can increase eNOS expression through transcriptional and posttranscriptional mechanisms.7

 

On the other hand, an accelerated degradation of NO· (by its reaction with O2·−) is likely to occur in vascular disease. NO· and O2·− react avidly to form ONOO−, which in turn leads to eNOS uncoupling and enzyme dysfunction (see below and Figures 2C, 2D, and 3).

Potential Clinical Interventions to Restore Normal eNOS Function

On the basis of the pathophysiology mentioned above, there are several possible approaches to restore eNOS functionality (ie, recouple eNOS) in the clinical situation. These include the intra-arterial infusion of the eNOS cofactor BH4 as demonstrated by studies in chronic smokers,30 diabetics,28 hypercholesterolemic patients,27 and hypertensive individuals.29

 

Folic acid increases intracellular BH4 levels and has been used successfully to restore endothelial function in patients with hypercholesterolemia,60 diabetes mellitus,61 or hyperhomocysteinemia.62 Folic acid also prevented or reversed eNOS dysfunction in nitroglycerin-treated patients31 and in healthy volunteers with postprandial endothelial dysfunction.65

 

In addition, infusions of high doses of vitamin C have been found to improve endothelial function acutely.57–59 The exact mechanism of action of ascorbic acid is unknown, but as detailed above, vitamin C also is likely to recouple eNOS (Figure 2A).

[Kalliste]

NAC can protect cancer-cells from oxidative bursts in mouse models. 

 

Once lung cancer is established, it promotes it.

Before the cancer is established, it can prevent it. I love those results    

Run this through google translate

 

https://akademiliv.se/2015/10/28712/

 

[Keizo]

NAC can protect cancer-cells from oxidative bursts in mouse models. 

 

Once lung cancer is established, it promotes it.

Before the cancer is established, it can prevent it. I love those results  

Run this through google translate

 

https://akademiliv.se/2015/10/28712/

"Det har gjorts ett stort antal när det gäller flera olika typer av naturliga och syntetiska antioxidanter och när man går igenom dessa så ser man att det inte finns något tydligt budskap. I enstaka fall har det skyddande effekt, i de flesta fall ingen effekt, och i flera fall en ökad risk för cancer. Faktum är att när det gäller de största studierna som gjorts så fick studierna avbrytas – för att de personer som fick antioxidanter fick en cancerdiagnos, i betydligt större grad än kontrollgruppen."

There has been a large number [of large randomized placebo controlled clinical studied] when it comes to several types of natural and synthetic antioxidants and when we look thru these we see that there is no clear message. In a few cases they have a protective effect, in most cases they have no effect, and in many cases there is a increased risk of cancer. The fact of the matter is when it comes to the largest studies that have been done the studies had to be aborted - because the people that received antioxidants got a cancer diagnosis, in significantly larger extent than the control group.

 

"Sammantaget finns alltså inget stöd för att antioxidanttillskott skyddar mot cancer, utan snarare att det kan öka risken för cancer. Alla dessa studier gjordes innan vi kom in i fältet."

On the whole there is no support that antioxidant supplements can protect against cancer, rather they can increase the risk of cancer. All of these studies were done before we came into the field.

 

"Varför gick ingen ut och varnade för kosttillskott med antioxidanter redan efter de studierna?"

Why did no one come out and warn about supplements with antioxidants right after these studies? 

 

"[...]-Men när det gäller just antioxidanter har det uteblivit och resultaten från alla dessa kliniska studier har lämnats vid vägkanten. En tänkbar förklaring till detta är att tron på antioxidanters cancer-hämmande effekter är djupt rotad i samhället och mycket väl marknadsförd av kosttillskottsföretag."

But when it is about antioxidants in particular it [it: warnings] has not happened and the results from all these clinical studies has been left by the way-side. A possible explanation for this is the belief in antioxidants cancer-suppressing effect that is deeply rooted in the society and very well-marketed by supplement companies.

 

"-Slutsatsen från kliniska, genomiska och experimentella studier är att fria radikaler är skadliga för både friska celler och cancerceller. Forskning på möss från vår och andra forskargrupper har visat att om man ger antioxidanter till en ung frisk mus som är benägen att utveckla cancer senare i livet, så minskar tumörutvecklingen. Men den sammantagna forskningen visar också att så fort en tumör bildats så hjälper antioxidanterna även tumörcellerna att antingen växa snabbare (lungcancer) eller sprida sig fortare (melanom)."

The conclusion from clinical, genomic and experimental studies is that free radical are harmful to both healthy cells and cancer-cells. Research on mice from our and other research-teams have shown that if you give antioxidants to a young healthy mouse that's prone to develop cancer in late life, the growth of cancer is ameliorated. But the whole research taken as a whole also show that as soon as a tumor is present the anti-oxidants also help the tumors to either grow faster (lungcancer) or spread quicker (melanoma).

 

"-Sammanfattningsvis visar alltså vår och andras studier att antioxidanter skyddar friska celler mot fria radikaler men de skyddar även cancerceller mot fria radikaler. Fria radikaler är skadliga och det spelar ingen roll om det är en frisk cell eller en cancercell. Men det innebär att konsekvensen för en tumör-fri person och en cancerpatient som tar extra tillskott av antioxidanter kan bli den motsatta.

Men då kan väl friska personer fortsätta att äta kosttillskott med antioxidanter?

– Det stora problemet är att man inte generellt kan rekommendera alla som är friska att ta extra kosttillskott med antioxidanter eftersom det är omöjligt att upptäcka små, odiagnosticerade tumörer."

 

In summary our study and others show that antioxidants protect healthy cells against free-radicals but they also protect cancer-cells against free-radicals. Free radical are harmful and it does not matter if it is a healthy cell or a cancer cell. But it means that the consequences for a tumor-free person and a cancer-patient that supplements extra anti-oxidants could be the opposite. But then can healthy people continue eat supplements with anti-oxidants? -The big problem is that we can't generally recommend all healthy individuals to consume extra supplements with anti-oxidants because it is impossible to discover small, un-diagnosed tumors.

 

------------------------------------------

 

If any of these anti-oxidation promoters actually have any sort of indication that they actually extend life then I'm up for taking it. As far as I know there isn't much on that. To me it seems like NAC might be more specific use. I've heard that it can indeed boost glutathione, at least for short-moderate periods of time. (Here in Sweden acetylcysteine recently (5 years ago or so) became a prescription only drug for clearing mucous (taken as an effervescent tablet in water). I was caught unaware and customs took a bottle of NAC.) At this point in time I'm personally more convinced by David Sinclair's hypotheses and ideas about how aging works. That free radicals and their effects isn't the biggest thing in most situations, it's rather a lot of the surrounding systems that might be more important and could need a boost to deal with that and all sorts of stresses we are put thru as these system age since birth. Then it's not like he has great answers concretely for what to take, what he takes is somewhat speculative at this point (NMN, metformin, resveratrol).

 

As far as possible side effects of NAC, I've heard something about it might mess with the permeability of the blood brain barrier (same person who said it might boost glutathione temporarily: Steve Fowkes) or something like that, best I recall.

Edited by Keizo, 21 August 2020 - 10:18 PM.

[albedo]

This is NOT good ! OK, I am not a mice but how can I check for my JunD status?

 

The antioxidant N-acetylcysteine protects from lung emphysema but induces lung adenocarcinoma in mice

Marielle Breau, … , Fatima Mechta-Grigoriou, Serge Adnot

Published October 3, 2019

Citation Information: JCI Insight. 2019;4(19):e127647. https://doi.org/10.1....insight.127647.

 

see also other threads in this Forum, e.g.:

https://www.longecit...-for-daily-use/

https://www.longecit...organize-again/

 

 

[8bitmore]

On a purely personal note: I now get brown skin spots or moles quite consistently even after 2-3 daily consecutive dosages of sub-1g NAC. Was never a heavy user but only experienced this consistent side-effect (could not believe it after the this first popped so tried a 3-4 additional times with resulting extra moles..!) after on/off usage for about 5 years. Would advice caution to anyone using this in a supplementary fashion.

[albedo]

On a purely personal note: I now get brown skin spots or moles quite consistently even after 2-3 daily consecutive dosages of sub-1g NAC. Was never a heavy user but only experienced this consistent side-effect (could not believe it after the this first popped so tried a 3-4 additional times with resulting extra moles..!) after on/off usage for about 5 years. Would advice caution to anyone using this in a supplementary fashion.

 

Agree on caution...

 

Le Gal K, Ibrahim MX, Wiel C, Sayin VI, Akula MK, Karlsson C, Dalin MG, Akyürek LM, Lindahl P, Nilsson J, Bergo MO. Antioxidants can increase melanoma metastasis in mice. Sci Transl Med. 2015 Oct 7;7(308):308re8. doi: 10.1126/scitranslmed.aad3740. PMID: 26446958.

https://pubmed.ncbi....h.gov/26446958/

"....NAC administration increased the number of lymph node metastases
and the proportion of tumor cells in each metastasis but had no impact
on the number and size of primary tumors. A potential explanation for
this result is that tumor cells that have left the primary tumor experience
oxidative stress that limits their ability to migrate, invade, and form
metastases, and NAC helps them overcome this limitation. This reason
is supported by three findings. First, the amounts of GSH and GSH/
GSSG ratios tended to be lower in metastases than in primary tumors of
untreated mice. Second, NAC increased these values in metastases but
not in primary tumors. Third, NAC increased migration and invasive
abilities of cultured human melanoma cells. Moreover, a previous study
showed that the amounts of GSH in the B16 mouse melanoma cell line
were higher in a clone with high metastatic potential than in a clone
with low metastatic potential (23)...."

[albedo]

Agree on caution ... again!

 

Increased risk of knee osteoarthritis in patients using oral N-acetylcysteine: a nationwide cohort study

 

"Our study sample comprised 12,928 people who used NAC and 51,715 NAC nonusers. NAC users had a significantly higher incidence of osteoarthritis (adjusted hazard ratio: 1.42, P < .001) than did NAC nonusers. Also, in analyses stratified by age group and sex, all subgroups exhibited a significantly higher incidence of knee osteoarthritis (P < .0001) among NAC users than among NAC nonusers. The use of oral NAC was associated with nearly four-fold increased the risk of knee OA in the young age group."

 

https://www.ncbi.nlm...les/PMC7418329/

 

[Harkijn]

Thank you Albedo, this certainly is a warning signal. However, it is only an association and the distinctions between the various subgroups seem rather arbitrary.

[Harkijn]

Yesterday in the NEWS section Michael posted about the role of low TOM70 in mitochondrial aging. In another forum a poster pointed to a review suggesting that supplementing NAC may perhaps  counter low TOM70 levels.

https://www.mdpi.com.../21/19/7262/htm

[albedo]

Thank you Harkijn.

"...These findings are in line with a report on a TOM70 deficiency causing mitochondrial damage and ROS overload and thereby aggravated injury after myocardial infarction (post-MI) in mice hearts [177,201]. The authors found that administration of antioxidant N-acetylcysteine (NAC) or melatonin reversed the effects of a TOM70 knockdown. The latter correlated with an upregulation of TOM70 expression, again confirming an involvement of TOM70 in the regulation of mitochondrial ROS production..."

Can you possibly also point to the other forum post?

[Harkijn]

It is very brief indeed:

 

https://www.fightagi...aging/#comments

[albedo]

Glycine and cysteine are non-essential amino acids that are required to generate glutathione, an intracellular tripeptide that neutralizes reactive oxygen species and prevents tissue damage. During aging glutathione demand is thought to increase, but whether additional dietary intake of glycine and cysteine contributes towards the generation of glutathione in healthy older adults is not well understood. We investigated supplementation with glycine and n-acetylcysteine (GlyNAC) at three different daily doses for 2 weeks (low dose: 2.4 g, medium dose: 4.8 g, or high dose: 7.2 g/day, 1:1 ratio) in a randomized, controlled clinical trial in 114 healthy volunteers. Despite representing a cohort of healthy older adults (age mean = 65 years), we found significantly higher baseline levels of markers of oxidative stress, including that of malondialdehyde (MDA, 0.158 vs. 0.136 µmol/L, p < 0.0001), total cysteine (Cysteine-T, 314.8 vs. 276 µM, p < 0.0001), oxidized glutathione (GSSG, 174.5 vs. 132.3 µmol/L, p < 0.0001), and a lower ratio of reduced to oxidized glutathione (GSH-F:GSSG) (11.78 vs. 15.26, p = 0.0018) compared to a young reference group (age mean = 31.7 years, n = 20). GlyNAC supplementation was safe and well tolerated by the subjects, but did not increase levels of GSH-F:GSSG (end of study, placebo = 12.49 vs. 7.2 g = 12.65, p-value = 0.739) or that of total glutathione (GSH-T) (end of study, placebo = 903.5 vs. 7.2 g = 959.6 mg/L, p-value = 0.278), the primary endpoint of the study. Post-hoc analyses revealed that a subset of subjects characterized by high oxidative stress (above the median for MDA) and low baseline GSH-T status (below the median), who received the medium and high doses of GlyNAC, presented increased glutathione generation (end of study, placebo = 819.7 vs. 4.8g/7.2 g = 905.4 mg/L, p-value = 0.016). In summary GlyNAC supplementation is safe, well tolerated, and may increase glutathione levels in older adults with high glutathione demand.

 

Lizzo G, Migliavacca E, Lamers D, et al. A randomized controlled clinical trial in healthy older adults to determine efficacy of glycine and n-acetylcysteine supplementation on glutathione redox status and oxidative damage. Front Aging. 2022;3:852569.

https://www.frontier...022.852569/full

 

[fishfarm]

GlyNAC supplementation reverses aging hallmarks in aging humans

 

A randomized, double blind human clinical trial conducted by researchers at Baylor College of Medicine reveals that supplementation with GlyNAC—a combination of glycine and N-acetylcysteine—improves many age-associated defects in older humans and powerfully promotes healthy aging.

 

Published in The Journals of Gerontology: Series A, the study shows that older humans taking GlyNAC for 16-weeks improved many characteristic defects of aging. This includes oxidative stress, glutathione deficiency and multiple aging hallmarks affecting mitochondrial dysfunction, mitophagy, inflammation, insulin resistance, endothelial dysfunction, genomic damage, stem cell fatigue and cellular senescence. These were associated with improvements in muscle strength, gait speed, exercise capacity, waist circumference and blood pressure.

 

"This is the first randomized clinical trial of GlyNAC supplementation in older humans, and it found that a wide variety of age-associated abnormalities improved in older adults supplemented with GlyNAC, while no improvements were seen in those receiving placebo," said corresponding author Dr. Rajagopal Sekhar, professor of medicine—endocrinology, diabetes and metabolism at Baylor.

 

https://medicalxpres...-hallmarks.html

Edited by fishfarm, 20 August 2022 - 10:01 PM.

[Learner056]

I want to echo the comment on Pulmonary hypertension.  While my heart according to Echo/stress tests is excellent per Cardiologist, and my BP stays low (with diastolic occasionally over 80), however I do frequently get heart pains.  I am not sure how to read Echo report, but my left heart seems bit smaller than normal, while right heart is like 70% percentile, which to me points to that while I do not have Pulmonary hypertension but that my pulmonary system may not be ideal.  Long story short, I have started interpreting the pains as signals that my genes send to me as 'angry' when something is not optimal    When I take NAC (which I take occasionally) higher than 800mg I get too much pain in heart.  I recently started taking low dose Stearic acid on certain days with lots of Cocoa butter, and that suddenly has increased my NAC tolerance as now I do not feel that pain on taking higher NAC - so far tried 1200mg.  I feel a similar pain when I take 300mg or greater NMN too.  The one supplement that the higher dose I take the more my heart feels happier is Resveratrol (ironically one that everyone cautions to not take higher) and others being: Stearic acid, Ginsenosides, Cistanche.  

 

I think this has to do with mito Fission / Fusion balance.  I am impressed by Turnbuckle theory. 

Edited by Learner056, 26 August 2022 - 01:05 AM.