THE PROBLEM with CAPSULES – DIGESTED IN STOMACH
More recently, this research published in 2018 confirms that most oral supplements of NMN and NR are digested to NAM in the GI tract or the liver.
Future pharmacological and nutraceutical efforts to boost NAD will need to take into account the minimal oral bioavailability of NR and NMN (R)
We also showed that intravenous, but not oral administration of NR or NMN delivered intact molecules to multiple tissues (R)
Unlike in cell culture where NR and NMN are readily incorporated into NAD, oral administration fails to deliver NR or NMN to tissues (R)
Interestingly, we found that neither compound was able to enter the circulation intact in substantial quantities when delivered orally (R)
The most recent studies showing tremendous health benefits with NMN were accomplished by feeding mice very large dosages of NMN in water (r). However the dosage of 300-400 mg per kg of bodyweight used in many of these studies would equate to approximately 2,000 Mg per day for a 70 kg human. A more effective delivery method is needed !
SUBLINGUAL VS CAPSULES
The absorption of the different molecules delivered through the sublingual route can be 3 to 10 times greater than oral route and is only surpassed by direct IV injection (r).
SUBLINGUAL CAN BE MORE BIOAVAILABLE THAN INJECTION !
With intraperitoneal injection, the primary route of absorption is via the mesenteric vessels, which drain into the portal vein and pass through the liver before reaching the bloodstream.
This means, IP avoids the GI tract, but is still sent directly to the Liver, where much of it is converted to NAD+. Elevated NAD+ in the liver is good, but its far better to reach the bloodstream with intact NMN.
Sublingual delivery is not filtered by the Liver and can reach systemic circulation intact, so can actually result in greater bioavailability that direct injection! Some examples are:
- A sublingual formulation of zol… exhibited a faster rate of absorption and higher drug exposure as compared to subcutaneous injection (r)
- sublingually administered epin… results in more rapid absorption and a higher peak plasma concentration compared to injected epin… .(r)
- 40mg of sublingually administered pir.. was found to be as effective as a 75 mg intramuscular injection of dicl… (r)
NMN PERFECT FOR SUBLINGUAL
Depending on the molecule, Sublingual delivery can substantially improve the speed and bioavailability. Smaller molecules that are hydrophilic such as NMN are well-suited.
a drug which has been formulated for sublingual should ideally have a molecular weight of less than 500 (r)
SHORT WINDOW FOR MAXIMUM AVAILABILITY
The chart at right is from the 2016 Mills study with mice given 300 mg/kg of bodyweight by oral gavage.
It clearly shows NMN is found in blood plasma within minutes, peaking at around 15 minutes. After that, NMN drops rapidly in blood, and appears as increased NAD+ in the liver.
Of course this is in Mice, and humans have a slower response, but we believe it is during the short time period when NMN is available in the bloodstream and can reach tissues throughout the body that the real benefits occur.
FREQUENCY – HOW OFTEN TO TAKE
Nearly all research on mice and humans using NR and NMN is focused on measuring NAD+ and the various metabolites in the Liver as it is the primary supplier of NAD+ throughout the body (r).
If elevating NAD+ in the liver is the goal, 1-2 larger dosages per day seem to be sufficient to achieve the maximum increase in liver NAD+ (r).
OUTSIDE THE LIVER
However, we believe supplying NMN directly to the bloodstream is more effective at increasing NAD+ not just in the Liver, but throughout the body.
Smaller, More Frequent dosages
Based on the short window that exogenous NMN is available in the bloodstream before being filtered out by the Liver, we believe smaller, more frequent dosages are likely more effective than 1-2 larger dosages.
Using this philosophy, many of our customers have been reporting more perceived benefit from more frequent intake, with many taking 6-12 times per day. We recommend taking 4-8 times per day, with at least 1 hour between dosages.
NOT EVERY DAY
We recommend taking 2-3 days off per week, ideally on days when you will be getting the least exercise. If you relax more on the weekend that is a good time to not take NMN.
CONCLUSION – WHAT WE RECOMMEND
Dr Sinclair takes 500 Mg of NMN CAPSULES per day and prescribes the same for his father, which is in line with dosages used in current and recently completed research on humans.
There is likely an upper limit on the effective dosage of NMN and NR capsules, which seems to be between 500 and 1,000 Mg per day.
We believe that sublingual delivery allows a much greater percentage of NMN to bypass the liver and reach other tissues.
When split between multiple smaller dosages, we believe 1,000-1,500 Mg a day can be taken before reaching the limit on maximum effectiveness.
We recommend taking 1 tablet, 4 to 8 times per day. Ideally, 1 upon waking, 1 immediately before and after exercise, and 1 before bed, with any others spread throughout the day.
– Some Amazing Results with NMN –
“After 6 days of NMN, 22 month old mice had the muscle capacity, endurance and metabolism of 6 month old mice” (2013 Sinclair)
“NMN effectively mitigates age-associated physiological decline in mice ” (2016 Sinclair)
“NAD+ and SIRT1 levels were HIGHER in OLD Mice than in YOUNG Mice that did not receive NMN.” (2017 Hao)
“The old mice became as fit and strong as young mice”(2018 Sinclair)
At 57 years old, I felt I was in pretty good shape from running, swimming or lifting weights 5-6 days a week. Yes, knee, hip, back and shoulder pains limited to how much I could run or lift. I was slower and weaker than when I was young, but who isn’t?
At 58 years old, I am back to running a 6 minute mile, lifting the heavier weights and carrying around MORE muscle than I had in my 20’s. Most amazing is, the improvements came from less than 3 months of taking frequent doses of sublingual NMN (under the tongue).
My personal experience has been that taking NMN sublingually (under the tongue) improves the effectiveness such that I achieved even better and faster results than the mice in Dr Sinclairs’ experiments.
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NMN was able to mitigate most age-associated physiological declines in mice Treatment of old mice with NMN reversed all of these biochemical aspects of aging
Raising NAD+ levels in old mice restores mitochondrial function to that of a young mouse
Restore the mitochondrial homeostasis and key biochemical markers of muscle health in a 22-month-old mouse to levels similar to a 6-month-old mouse
This study showed supplementation with NMN was able to repair the DNA in cells damaged by radiation
The cells of old mice were indistinguishable from young mice after just one week of treatment.
NMN was immediately utilized and converted to NAD+ within 15 min, resulting in significant increases in NAD+ levels over 60 min
Administering NMN, a key NAD+ intermediate, can be an effective intervention to treat the pathophysiology of diet- and age-induced T2D
Surprisingly, just one dose of NMN normalized impaired glucose tolerance
NAD(+) levels were increased significantly both in muscle and liver by NMN
NMN-supplementation can induce similar reversal of the glucose intolerance
NMN intervention is likely to be increased catabolism of fats NMN-supplementation does mimic exercise
NMN treatment reduces brain cell death and oxidative stress These results further support the neuroprotection of NMN/NAD+
We now demonstrate that mitochondrial respiratory function was restored
NMN could restore cognition in AD model rats
NMN Treatment Rescues Cognitive impairments
NMN significantly increased the level of NAD+ in the heart
NMN protected the heart from I/R injury
NMN reduces vascular oxidative stress
NMN treatment normalizes aortic stiffness in old mice
NMN represents a novel strategy for combating arterial aging
NMN can reduce myocardial inflammation NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation
Remarkably, NMN administered to FXN-KO mice restores cardiac function to near-normal levels.
Restoration of cardiac function and energy metabolism upon NMN supplementation
Remarkable decrease in whole-body EE and cardiac energy wasting
Exogenous NMN prevents photoreceptor degeneration and restores vision
NMN rescues retinal dysfunction in light-induced degeneration
Completed and pending publication
- 2016 Keio University Study – UMIN000021309
- 2017 Keio University Study – UMIN000030609 Phase 2, 8 weeks, 30 subjects
- 2017 Hiroshima University Study – UMIN000025739 24 weeks, 20 subjects, 100 & 200mg
- 2017 University of Washington Study – 8 weeks, 50 subjects
- 2017 Sinclair Metrobio study – Phase 1
- 2018 Sinclair Metrobio study – Phase 2
The Phase 1 study by Dr Sinclair has been completed, and they are ready to go forward with the Phase 2 study, so we can conclude there were positive results, and no negative side effects, else they would have to publish those immediately.
In the University of Washington study, participants are 50 healthy women between 55 and 70 years of age with slightly high blood glucose,BMI and triglyceride levels.
Using a dose of 2 capsules of 125mg NMN per day over a period of 8 weeks, researchers are testing for:
- change in beta-cell function
- works to control blood sugar
- blood vessels dilate
- effects of NMN on blood lipids
- effects of NMN on body fat
- markers of cardiovascular and metabolic health
The active supplementation portion of this study has ended, but testing of metabolic parameters will continue for 2 years after supplementation has ended. So researchers know the immediate effects and preliminary results are expected to be announced in 2018, with final results expected in 2020.
WHAT IS NAD+
Scientists have now confirmed a direct link between falling NAD+ levels and aging in both animal and in human subjects.
Read more about NAD+
NAD+ DECLINES WITH AGE
Read more about NAD+