If not protected, NMN and NR supplements are almost entirely degraded to NAM (Nicotinamide) before reaching tissues beyond the liver.
While NAM is beneficial for many health conditions, excessive NAM levels can be detrimental to your health.
“high doses of NAM can cause genomic instability, reduce cellular methyl pools, and cause insulin resistance through methylated NAM” (r).
Too Much NAM
This can be a problem when users believe more is better and take excessive doses of standard NR or NMN capsules. Very little makes it intact through the digestive tract, liver, and bloodstream to reach the target tissue. The result is massive increases in NAM.
For example, this study gave 300 mg/kg of NR to mice and found NAM is increased 40x, while NR is not increased and exists only at trace levels
“The minute amount of dual-labeled NAD observed in muscle indicates that direct utilization of NR by the muscle does occur. However, oral NR dosing increased circulating NAM ~40-fold while NMN remained unchanged and NR was detected only at trace levels in the blood. Thus, the majority of the orally administered NR that reaches the muscle appears to enter in the form of liberated NAM or as NMN”
What happens if NAM levels are too high
High levels of NAM can have many negative effects such as inhibiting Sirtuins (r), which is the opposite of what you are trying to accomplish by taking NAD+ boosters.
The body does respond to try and bring NAM levels down, by attaching a Methyl group to the NAM to form MeNAM, which is then excreted (r).
This can result in other problems when there are insufficient methyl donors that are critical for other needs and promotes age related health problems (r).
TMG to restore Methyl groups depleted by excess NAM
As a result, it is common practice now for those taking NMN or NR to take TMG or other methyl donors (r).
That is thought to help with the problem of excessive NAM buildup from taking high dosage NMN or NR capsules, but excess TMG can also lead to problems (r).
Liposomes are a better solution
A far better solution is to take a form of NMN or NR that protects the active ingredient from digestion to NAM.
Sublingual delivery of NMN delivers up to 30% of NMN to the bloodstream, so much less is digested to NAM and depletion of methyl groups is much less of a problem
Liposomes are even better, as they can protect NAD+ metabolites from digestion and degradation in stomach, liver, and bloodstream.
Liposomal delivery prevents your expensive NAD+ precursors from being digested to NAM, which is a waste of money, and can actually be bad for your health.
Liposomes are the golden standard for drug delivery systems (r)
- Protect the payload from digestion in the stomach
- Increase circulating time (not filtered out by the liver)
- increases uptake by tissues throughout the body
- Prevents excessive buildup of NAM which can be harmful
“Small liposomes b 80 nm can escape from the liver sinusoids into the space of Disse through the fenestrae in the sinusoidal wall” (r).
“prolonging liposomal circulation by modifying the surface with polyethylene glycol (PEG)” (r).
“ability to circulate over longer periods leading to accumulation in tissues” (r).
Liposomes mimic the bodies own method of delivering nutrients such as NMN between tissues
“Adipose tissue actively secretes extracellular vesicles (EVs) that are enriched with NMN, and can circulate through the plasma. EVs are membrane-derived particles surrounded by a phospholipid bilayer that are released by cells in the human body.” (r)
DOSAGE – WHAT IS TOO MUCH NMN OR NR?
There are no conclusive studies showing NR or NMN have negative effects at dosages commonly used (up to 1,000 mg per day) , and it is unlikely the increased NAM which results from such dosages is a significant health risk.
On the other hand, there have been no studies showing dosages over 1,000 mg a day to have significant benefit over lower dosages.
It seems prudent to avoid dosages over 1,000 mg a day if taking oral capsules that result in huge increases in NAM and may cause methylation issues for some users.