The Problem with Capsules

THE PROBLEM with CAPSULES – DIGESTED IN STOMACH

It has also long been suspected that most NR is digested to NAM in the Gastro-Intestinal tract intact (r).

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

SUBLINGUAL VS CAPSULES

Sublingual (under the tongue) delivery can provide rapid absorption via the blood vessels under the tongue rather than via the digestive tract. (r,r)

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)

NMN is very hydrophilic, with a molecular weight of 324, making it a perfect fit for sublingual delivery.
Dosage and Frequency

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)

Customer Reviews

– Some Amazing Reviews from our customers on Amazon –

Testimonials

December 2017
Not bad for 57 year old (I thought)

June 2 2018
after 3 months taking Sublingual NMN

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.

Click here to read more

Research

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

Long-Term Administration of Nicotinamide Mononucleotide Mitigates Age-Associated Physiological Decline in Mice (mills, 2016)

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

Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (Gomes, Sinclair,2013)

DNA Repair

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.

A conserved NAD+ binding pocket that regulates protein-protein interactions during aging (Sinclair, 2017)

WEIGHT

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

Nicotinamide Mononucleotide, a Key NAD+ Intermediate, Treats the Pathophysiology of Diet- and Age-Induced Diabetes in Mice (Yoshino, 2011)

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

Head to Head Comparison of Short-Term Treatment with the NAD(+) Precursor Nicotinamide Mononucleotide (NMN) and 6 Weeks of Exercise in Obese Female Mice (Uddin, 2016)

NMN significantly increased the level of NAD+ in the heart

NMN protected the heart from I/R injury

Nicotinamide mononucleotide, an intermediate of NAD+ synthesis, protects the heart from ischemia and repercussion (Yamamoto, 2014)

NMN reduces vascular oxidative stress

NMN treatment normalizes aortic stiffness in old mice

NMN represents a novel strategy for combating arterial aging

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice (de Picciotto, 2016)

NMN can reduce myocardial inflammation NMN thus can cut off the initial inflammatory signal, leading to reduced myocardial inflammation

Short-term administration of Nicotinamide Mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure (Zhang, 2017)

ENERGY

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

Nicotinamide mononucleotide requires SIRT3 to improve cardiac function and bioenergetics in a Friedreich’s ataxia cardiomyopathy model

VISION

Exogenous NMN prevents photoreceptor degeneration and restores vision

NMN rescues retinal dysfunction in light-induced degeneration

 

NAMPT-mediated NAD+ biosynthesis is essential for vision in mice (lin, 2016)

Clinical Studies with NMN

Completed and pending publication

Beginning 2018

  • 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+

WHAT IS NAD+

NAD+ is a key co-enzyme that the mitochondria in every cell of our bodies depend on to fuel all basic functions. (3,4)

NAD+ play a key role in communicating between our cells nucleus and the Mitochondria that power all activity in our cells (5,6,7)

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

As we age, our bodies produce less NAD+ and the communication between the Mitochondria and cell nucleus is impaired. (5,8,10).

Over time,  decreasing NAD+ impairs the cell’s ability to make energy, which leads to aging and disease (8, 5) and perhaps even the key factor in why we age (5).

Read more about NAD+