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Very comprehensive risk/benefit analysis of all NAD restoration supplements

nad+ nmn

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#1 smithx

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Posted 30 September 2019 - 06:19 PM

The Forever Healthy Foundation in Germany has a very comprehensive, recently updated risk/benefit analysis of all NAD restoration supplements:

https://brain.foreve...oration Therapy


Here are excerpts on the main benefits and the risks. They suggest that NR has the most safety data and that doses above about 300mg are probably not advised.


NMN has some potential safety issues including axonal degradation.


Let's discuss.




Main benefits

Restoration of NAD+ levels has been shown to have beneficial effects on several organ systems and diseases (Table 4) with an excellent acute toxicity profile. The main benefits are in diseases or conditions that threaten the energetic status of the cell such as ischemic stroke, heart failure/infarction, and mitochondrial diseases. The highest level of evidence for NAD+ restoration therapy in humans is for skin diseases. There is a multitude of potential benefits for which the evidence level is still quite low because of the lack of clinical trials.

Main risks

The major risks are related to tumorigenesis, the buildup of metabolites with undesirable effects, and an increase in the proinflammatory SASP of senescent cells (Table 5). These have not appeared in clinical trials to date but have been identified during mammalian preclinical trials. More clinical trials are necessary to adequately assess the risk of long term NAD+ supplementation. Short and medium-term supplementation (up to twelve weeks) with NR elevates NAD+ levels safely and effectively but there is a lack of studies examining the potential adverse health effects of chronic, year-long NAD+ supplementation.


Risk Mitigation Strategies

  • Consult your physician before beginning therapy
  • Assess baseline NAD+ metabolome values with a comparison to reference values from clinical papers to determine the appropriateness of beginning therapy.
  • Repeat screening of the NAD+ metabolome at regular intervals to determine the effectiveness of the therapy, the appropriateness of the dose as well as to identify the accumulation of possible toxic levels of metabolites
  • Screen for cancer before beginning therapy
  • Avoid NAD+ restoration if cancer has been diagnosed or treated within the previous 5 years
  • Assess senescent cell burden and remove senescent cells when possible before beginning NAD+ therapy
  • Measure blood values, liver & kidney function and electrolyte values at regular intervals
  • Self-monitor for signs of decreased exercise performance or fatigue
  • Cease therapy if any identifiable adverse effects occur
  • Exercise caution when combining NAD+ with other treatments
  • Limit the duration of NAD+ restoration therapy as safety studies have only been performed up to 12 weeks in humans


Form & Dose

  • Clinical studies have shown that NAD+ levels are raised effectively by NR and NAM.
  • The effectiveness and safety of the direct use of NAD+ by i.v. and patches in humans is unknown and therefore, cannot be recommended at this time.
  • The same applies to NMN.
  • NAM has the best safety profile according to the current evidence base. However, its role as a SIRT-1 inhibitor makes it questionable for use as a rejuvenation treatment.
  • NADH has a good safety profile but there is a lack of data on its effectiveness in raising NAD+ levels.
  • NR is currently the method of choice for raising NAD+ levels due to its proven effectiveness and safety profile.
  • More isn't necessarily better. 
  • The dose recommendation for NR is 150-300 mg/day (3 mg/kg/day).
  • According to the latest evidence, 1000 mg/day has been established as the tolerable upper limit of NR for medium durations (up to 8 weeks).


(Major Risks Section)

Tumorigenesis, invasion, and motility

One major concern with increasing NAD+ levels is whether it leads to an increased risk of cancer and/or faster growth of tumors. To date, there is no data from clinical trials addressing this risk. However, in support of this view, NAD+ depletion has been explored as a means of controlling/decreasing tumor growth and these studies have shown positive results (Takao et al., 2018van Horssen et al., 2012Ginet et al., 2014) while restoration of NAD+ levels by supplementation has abolished the positive effects. 

An increase in NAD(H) pool size and NAD+: NADH ratio due to activation of the salvage pathway was identified in human tissue samples of colorectal cancer and mice (Hong et al., 2019). The increases in NAD(H) inhibit the accumulation of ROS, allowing the tumor to grow. In an in vitro study, pharmacological and genetic inhibition of NAMPT decreased NAD+ levels and glioblastoma-like stem cell self-renewal capacity, and NAMPT knockdown inhibited the in vivo tumorigenicity of GSCs (Gujar et al., 2016). A recent preclinical trial has shown that NAD metabolism clearly promotes the progression of pancreatic cancer through enhancement of the inflammatory environment (Nacarelli et al., 2019).

On the other hand, increasing NAD+ levels locally, in the skin, has been shown to markedly reduce the progression of precancerous skin lesions to squamous cell carcinomas (Jacobson et al., 2007) likely via increased DNA repair activity, driven by the increased NAD+ that is available for use by reparative enzymes. NAD+ precursor supplementation has also been shown to prevent and reduce the size of established hepatic tumors (Tummala et al., 2014), decrease the survival of tumor cells (Petin et al., 2019) by increasing oxidative stress (Zhao et al., 2011) and increasing autophagy (Han et al., 2011).

In summary, increasing NAD+ levels may be tumorigenic or accelerate the growth of existing lesions under stressed conditions such as in premalignant senescent lesions.


Buildup of metabolites

Only a few studies have measured the effects of increasing NAD+ levels on the complete NAD metabolome (Trammell et al., 2016, Elhassan et al., 2019). Most metabolites are elevated in response to precursor treatment (Trammell et al., 2016) and a better understanding of the potential consequences of increased levels of the various metabolites is necessary.

For example, NR is a direct precursor of NAAD and has been shown to generate high levels of NAAD in the murine liver and heart (45-fold higher levels following a single dose compared to an NAD+ rise of 2.3 fold) (Trammell et al., 2016). In humans, NAAD levels in muscle and blood rose 2-fold and 4.5 fold respectively with NR supplementation while NAD+ levels were unchanged in muscle and rose 2 fold in the blood (Elhassan et al., 2019). NAAD normally circulates at very low levels. Its physiological role other than being an NAD+ precursor is unclear though once phosphorylated to NAADP it is involved in Ca signaling.

Some preclinical studies suggest that high levels of NAM, NMN, and MeNAM may also cause adverse effects (Liu et al., 2018Parsons et al., 2003Naia et al.,2017Mori et al., 2012). One dose of NR also resulted in an 8.4-fold higher plasma level of 2PY, the methylated metabolite of NAM (Trammell et al., 2016). Clinical trials of NR at doses of 1000 mg/day also showed increases between 5 and 10 fold in MeNAM and 2-PY concentrations (Conze et al., 2019; Elhassan et al., 2019).

It has been suggested that at high levels, NAM can act as a uremic toxin contributing to thrombocytopenia (Rutkowski et al., 2003Lenglet et al., 2016). This is supported by reports of thrombocytopenia and increased bruising in some clinical trials (Airhart et al., 2017Martens et al., 2018). Trials on NAM supplementation in kidney disease reported extremely high levels of 2-PY with resultant thrombocytopenia as well as increased MeNAM and NMN levels (Mehr et al., 2018). It has been proposed that this results from a NAM-induced drop in the serum level of thyroxin-binding globulin or one of its derivatives (Lenglet et al., 2016). 

In vitro, mouse neuronal cell survival rate dropped when the cells were cultured with MeNAM or NAM (Mori et al., 2012). NAM and MeNAM are able to cross the blood-brain barrier and at high concentrations can have a toxic effect on neurons, as shown in Parkinson’s and Huntington’s disease models (Parsons et al., 2003Naia et al.,2017Mori et al., 2012; Harrison et al., 2018).

Epidemiological surveys suggest that niacin may play a role in Parkinson’s disease, in that niacin deficiency appears to protect against it. The average NAM intake in western populations is around 35 mg a day while the recommended daily allowance is 15 mg a day. Assuming a 20 mg/day overdose, that equates to 350 g over 50 years. Even over an extended period, that is a large number of toxin equivalents reaching neurons.

It has been suggested that superoxides formed by MeNAM via complex I destroy complex I subunits either directly or indirectly via mitochondrial DNA damage (Fukushima, 2005). NAM exacerbated dopaminergic degeneration, behavioral deficits and structural brain changes in rats (Harrison et al., 2018). High concentrations of NAM also blocked mitochondrial-related transcription in an in vitro Huntington's disease model, worsening the motor phenotype (Naia et al., 2017).

Exposure to MeNAM also markedly reduced liver NAD content and NAD/NADH ratio, while increasing H202 production and insulin resistance, leading to the hypothesis that NAM overdose may play a role in the development of diabetes. In human diabetics, MeNAM levels were significantly higher after an oral dose of NAM than in controls (Zhou et al., 2009). On the other hand, MeNAM supplementation has been shown to extend the lifespan of worms (Schmeisser et al., 2013). 

In vitro administration of NR and NMN showed no effect on ATP levels and increased NAM 9-fold and 1.8-fold respectively (Oakey et al., 2018). NAM, as a SIRT inhibitor, has been shown to negatively affect lifespan in yeast (Bitterman et al., 2002). NAM treated rats also had higher hepatic and renal markers of DNA damage, and impaired glucose sensitivity and glucose tolerance (Li et al., 2009). NAM supplementation can lead to decreased methylation stores (Li et al., 2009) and has been shown to disturb monoamine transmitter metabolism (Tian et. al., 2013).

In humans, a 100 mg dose of NAM induced an increase in MeNAM, norepinephrine, and homocysteine and a decrease in metanephrine and betaine leading the authors to conclude that high NAM intake may be involved in cardiovascular disease (Sun et al., 2012). In contrast, a recent study found that homocysteine levels are not increased by NR supplementation (Conze et al., 2019) suggesting it is a precursor specific effect. 

Cumulative doses of NA also increase MeNAM and H202 levels and are associated with a decrease in liver and skeletal muscle glycogen levels. This increase may lead to oxidative stress, methyl group depletion, and insulin resistance, increasing the risk of diabetes (Li et al., 2012). 

Accumulation of NMN promotes axonal degeneration in cases of physical injury as well as in chemotherapeutic-induced mouse models of peripheral neuropathy (Di Stefano et al., 2015Di Stefano et al., 2017). In one experiment, NMN levels rose 2.5 fold (≈ 4 nmol/g) after axonal injury (Di Stefano et al., 2015). Although the rise is due to the inability of the required enzyme to reach its place of action, exogenous delivery of NMN also promoted axonal degeneration. Additionally, NR is converted to NMN so if the enzyme (NNMAT) is overwhelmed or not functioning well, it could lead to an accumulation of NMN and axonal toxicity. Bypassing NMN production has been shown to protect neurons from chemotherapy-induced degeneration (Liu et al., 2018).

Therefore, it is important to consider that creating a state of NAD+ excess and increased levels of metabolites could have unintended effects in the CNS or elsewhere. This underscores the importance of monitoring metabolite levels during NAD+ therapy. 


Detrimental effects on exercise performance

A preclinical study (Kourtzidis et al., 2016) found that exercise performance in young rats decreased by 35% after acute administration of NR. The rats were 4 months old, corresponding to a human age of 20 years and were given a high dose (300 mg/kg body weight = 48.6 mg/kg HED). Possible mechanisms for this decrease were explored in a follow-up study (Kourtzidis et al., 2018) and it was found that NR supplementation exerted several effects on redox-related markers (increased NADPH and glycogen in the liver, increased F2‐isoprostanes in plasma, decreased glutathione peroxidase, glutathione reductase, and
catalase in erythrocytes, and decreased glucose and maximal lactate accumulation in plasma). These findings support the hypothesis that exogenously administered redox agents in healthy populations might lead to adverse effects.

A follow-up study was performed in humans (Dolopikou et al., 2019) that compared the effects of acute NR administration on redox status and exercise performance in young (22.9 years old) and old (71.5 years old) age groups. It was found that although NR raised NAD(P)H levels in both groups, redox homeostasis, and exercise performance were improved only in the older group. This is in line with other studies that show a trend towards increased effectiveness of NAD supplementation in groups with the highest level of baseline dysfunction (Martens et al., 2018). These results emphasize the importance of developing a set of age-related reference NAD values to aid in decision making about the appropriate time to commence NAD+ treatment. 


Inflammatory arthritis

Increasing NAD+ levels may also have negative effects on inflammatory conditions such as rheumatoid arthritis due to increased NAMPT activity and NAD+ use by immune cells (Busso et al., 2008). A murine study showed upregulation and worsening of arthritis in response to increased NAD+ and decreased arthritic severity and cytokine release when NAMPT was blocked and NAD+ levels were lower (Busso et al., 2008). There is no data in humans on this topic.


Negative effects on senescent cells

Senescent cells exhibit both protective (inhibition of tumorigenesis) and deleterious (accelerated aging, increased tumorigenesis) effects through a complicated sequence of activities that are beneficial at first but become proinflammatory later (Nacarelli et al., 2019). Senescent cell phenotypes vary according to cell type and the way in which senescence is induced (Mendelsohn and Larrick., 2019).

The NAD+/NADH ratio and NAD+ levels are significantly increased in oncogene-induced senescent (OIS) cells (Nacarelli et al., 2019) whereas the mitochondria dysfunction-associated senescence (MiDAS) secretory phenotype is linked to a lower NAD+/NADH ratio. A low proinflammatory SASP also accompanies replicative senescence (RS) (Nacarelli et al., 2019). 

It has recently been shown that exogenous NMN supplementation increases the strength of the proinflammatory SASP in OIS cells and converts a low proinflammatory SASP during RS into a high proinflammatory SASP (Nacarelli et al., 2019). Senescent cells with a high proinflammatory SASP have also been shown to induce senescence in neighboring cells (Mendelsohn and Larrick., 2019). NAD+ supplementation may result in an increased number of senescent cells with the detrimental high proinflammatory SASP. 


Feedback suppression

Interestingly, NAD+ levels appear to be downregulated chronically, though the level at which this occurs is unknown. This effect was observed in a clinical trial of NRPT in which a 40% elevation of NAD+ levels was sustained but a 90% elevation was not, despite continued treatment (Dellinger et al., 2017). Interestingly, the high dose treatment arm didn't experience as many beneficial effects as the moderate dose treatment arm. This downregulation raises the question of whether higher NAD+ levels eventually cause negative impacts on cell function, leading to an adaptive response. One theory is that the NAD+/NADH ratio is not controlled by the compounds but rather enzymatically, through NQ01 (anti-agingfirewalls.com). In support of this hypothesis, oral supplementation of NR has been shown to downregulate gene sets related to energy metabolism (Elhassan et al., 2019). 



One human study of NRPT has shown a slight increase in LDL (Dellinger et al., 2017). However, another study on NR in overweight adults showed no significant difference, suggesting the elevation was related to pterostilbene and not NR.

One study also reported significant decreases in potassium levels, hematocrit, hemoglobin, and platelet count although none of these had any clinical significance. 

In rats, NAM administration at a dose of 500 mg/kg/day was found to increase lipid peroxidation in the liver (Melo et al., 2000). Several studies have found no change in blood levels of glucose, insulin, TG or HDL (Bushehri et al., 1998Dollerup et al., 2018Conze et al., 2019). NMN has been shown to slightly impair glucose tolerance in mice (Ramsey et al., 2008). 


Immune cells

It has been demonstrated that extracellular NAD+ induces apoptosis in naive T-cells (Liu et al., 2001) and that injection of NAD+ in mice can lead to concentrations capable of inducing sequestration and apoptosis of T cells in the liver (Liu et al., 2001). The steady-state concentration of NAD+ in the serum is 0.1 uM and the NAD+ that is released from lysed cells, exceeding this base level during inflammation, could limit the destructive action of autoreactive T cells (Liu et al., 2001). However, in the case of NAD+ supplementation, this could lead to a depression of the T-cell count.

Edited by smithx, 30 September 2019 - 06:20 PM.

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#2 MikeDC

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Posted 02 October 2019 - 09:12 PM

NAD+ is very high in younger people. So higher NAD+ level should not results in side effects. NAD+ itself may not have negative feed back loop. But there is a limit on how high you can increase NAD+. The NAM mice study showed there is a negative feed back loop related to NAM and NAMPT.
The mice study that shows NMN increased SASP can not be trusted because the mice model have senescent cells and cancer at young age by design. It is genetically modified. So far old people are getting great responses on NR. Either the senescent cells can be renewed or killed or senescent cells are not a deciding factor in humans.
The effect of NMN on damages axons apply to all NAM and NR as well since NMN does not get into cells directly so NMN and NR and NAM are similar in this case. NA and NAR is better because they don’t convert to NMN.
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#3 Smith

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Posted 10 November 2019 - 05:29 PM

Very informative indeed!  What is interesting is that Niacinamide (NAM) was clinically shown to boost NAD+ about as well as NR, and has the best safety profile.


Is the only reason people are more interested in NMN and NR, versus the much cheaper NAM, because there's some evidence NAM downregulates SIRT1?  There has been recent evidence that shows that NAM may actually upregulate SIRT1 instead of downregulating it.


What does everyone think about this?  Could NAM be as (or more) effective than NR and NMN?  It certainly is about 10x cheaper.

Edited by Smith, 10 November 2019 - 05:30 PM.

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