- Shelly Albaum
NAD Injections and IVs: The Worst Way to Replenish NAD?
Updated: Dec 22, 2022
NAD injections and IVs are a big business, but there are important questions about cost, effectiveness, safety, and benefits
Before spending hundreds of dollars to inject NAD into your veins, consider the costs and benefits of this method of NAD replenishment. Not only is it the most expensive way, it may now also be the least effective.
But it wasn't always so.
NAD IV therapy was discovered and popularized decades ago, long before the availability of modern NAD precursors like nicotinamide riboside. It was discovered that some people could recover better from drug and alcohol addictions if NAD were dripped into their veins:
For several decades, IV NAD+ has been used as a holistic ‘underground’ approach for the treatment of various forms of addiction. IV NAD+ showed complete withdrawal of addictive drugs without subjects experiencing ‘agony of withdrawal’ symptoms...The significance of NAD+ in addictive disorders stems from the work of Dr. Paul O’ Hollaren (1961) who claimed to have successfully utilised IV NAD+ for the prevention and treatment of over 104 cases of addiction to alcohol and other drugs of abuse, including heroin, opium extract, morphine, dihydromorphine, meperidine, codeine, cocaine, amphetamines, barbiturates and tranquilisers
Exactly how NAD infusions might treat substance abuse disorders is a topic we will save for another day. But there is reason to think that it might work. Here is a study from June 2022:
This pilot study provides significant evidence that NAD infusions are beneficial in the treatment of Substance Use Disorder.
-- Current Psychiatry Research and Review, June 21, 2022
The question for us is not whether NAD replenishment might help people -- I think it does! -- but what's the best way to do it? In the 20th century, delivering NAD intravenously might have been state of the art. But do newer methods of NAD replenishment make the NAD IV obsolete? I think so. I think it's old technology that costs too much, takes too long, and doesn't do as much as it could.
I used to think that NAD IV drips and injections must be the biggest scam in the NAD business, maybe even in the anti-aging business. But now that I realize they had a noble past, I think they are merely obsolete. If that's right, then their continued use is a mistake that is costing a lot of people a fortune, and making a fortune for others. This should change.
The problem isn't that NAD IVs are completely ineffective. On the contrary, they are likely to work okay, because some of the NAD in the IV will get broken down into smaller molecules that can enter cells and replenish NAD. So if your NAD levels are low, you might well feel a difference.
The problem is that it is a wildly expensive approach, with no safety studies that I am aware of. Moreover, there is good reason to believe that injecting NAD may provide fewer benefits than oral supplements, and at a greater cost. Specifically, at best you may end up directing the exact same NAD precursors to most of your cells, but by bypassing the digestive tract you could miss out on the benefits of replenishing NAD in the gut stem cells and through the gut microbiome.
That's the opposite of what some of the advertisements claim, so we'll have to get into the science to sort it out.
The Theory Behind NAD IVs and Injections
The theory behind NAD IVs and injections is that consuming oral NAD supplements won't increase intracellular NAD because the digestive system prevents bioavailability, whereas injecting NAD directly into your bloodstream ensures complete absorption. Neither of those things is true.
And it is a terribly confused way of thinking, because it misunderstands how NAD becomes bioavailable and how absorption works. Before you pay 5x or 1ox too much to replenish your NAD levels, make sure to get the facts straight.
First, NAD is a really big molecule. It's this big:
NAD's size and structure prevent it from entering your cells directly.
That means that if you inject NAD directly into your blood stream, it's going to just bounce off your cells, unless it gets broken down into something that can get through. Scientists know this:
NAD is considered impermeable to the plasma membrane, and NAD administration cannot efficiently increase NAD levels. Therefore, NAD precursors...are utilized to increase NAD levels in rodents and humans
-- Journal of Biomedical Science, May 11, 2019
Increasing evidence indicates that NAD+ cannot enter cells directly through the plasma membrane and that it must be converted into smaller, less charged molecules to enter cells.
-- Aging and Disease, December 1, 2021
NAD+ is highly polar and, like other nucleotides and dinucleotides, is not readily taken up by cells
-- Cell Metabolism, December 2, 2014
In general, cells are unable to take up NAD+...
Cell Metabolism, March 6, 2018
NAD+ cannot be taken up directly by the cell, but its precursors can...
Trends in Immunology, April 1, 2022
That also means that if the NAD you ate got broken down in the gut into smaller pieces -- precursors -- that could pass through the cell wall, and then get reassembled into NAD inside the cell, then absorption and bioavailability might be BETTER with oral NAD supplements, and WORSE when pumping NAD directly into your bloodstream, the opposite of what the ads suggest.
But there is another confusion, too. Getting NAD into your body isn't actually the problem we are trying to solve. There's already plenty of NAD in your diet. NAD is present in every cell of every living thing, so your salad and your steak contain NAD, and you're already eating it. The problem is getting the NAD into your cells, where it can be used by the mitochondria to power the cells' various operations.
Oral supplementation with NAD+ and NADH has not shown any significant elevation in plasma or tissue levels of NAD+, potentially due to inefficient metabolism of NAD+ through the gut, thus leading to poor bioavailability
Antioxidants & Redox Signaling, January 10, 2019
Because NAD is too big to get into the cells, NAD is not bioavailable in the way it needs to be, whether you eat it or inject it. It has to be broken down somehow first, and broken down the right way. In the study above, the gut didn't break down the NAD enough or the right way. Injecting it doesn't fully solve that problem.
The oral supplement industry knows this, which is why they mostly don't try to sell you NAD itself, but instead offer NAD precursors, like Niacin (NA), Niacinamide (NAM), and Nicotinamide Riboside (NR). These precursor molecules are all small enough to enter cells, and they can all be used to build intracellular NAD through different metabolic pathways.
So what happens when you inject NAD directly into your veins? It can't enter cells, so it should just get excreted out, and some of it does. But some of the intravenous NAD actually does get broken down into smaller pieces, and those smaller pieces actually do enter your cells and can help replenish NAD, because there are circulating enzymes that do that. So injecting NAD partly works.
I've only seen one study of human NAD IVs, and it said that the NAD largely got excreted but a fair amount got metabolized to NAM and could have been absorbed by cells and increased intracellular NAD through the NAM (salvage) pathway. Here's the study:
"The continuous IV infusion of NAD+ at a rate of 3 μmoles/min resulted in a significant (538%) increase in the urine NAD+ excretion rate…The urine excretion rate of the NAM metabolite meNAM was significantly increased (403%) at the 6 h time point..."
-- Frontiers in Aging Science, September 12, 2019
They are saying that some of the NAD got excreted, some got turned into NAM, and the NAM got used, which is why the NAM metabolite got excreted, and not the NAM.
So that means that the NAD injections will in fact raise NAD, but only because some of the NAD gets broken down into smaller pieces.
It's great that it works, but then you have to ask why not just take the smaller pieces directly by oral supplement and pay $1-2 per day instead of hundreds of dollars per injection?
NAD advocates hope that the NAD will get broken down into its proper precursors and get absorbed just as well as if you had taken NR. But there is experimental evidence that shows otherwise. In this study of neurodegeneration, the researchers compared NAD injections with NR injections and found that NR protected against axon degeneration "much more strongly than extracellular NAD+":
Recent description of extracellular conversion of NAD+ to NR prompted us to probe the effects of NAD+ and NR in protection against excitotoxicity. Here, we show that intracortical administration of NR but not NAD+ reduces brain damage induced by NMDA injection. Using cortical neurons, we found that provision of extracellular NR delays NMDA-induced axonal degeneration (AxD) much more strongly than extracellular NAD+.
-- FASEB Journal, August 21, 2017
The bioavailability question with NAD is how to get it broken down into the right precursors that get absorbed by cells. The bioavailability question with NR is how much gets through intact as NR, and how much needs to get through to achieve the desired effect.
Neither of those questions counsels in favor of injecting NAD. Instead, if you were worried that your NAD precursor of choice were not making it through the digestive tract in adequate quantities, you would be tempted to inject or drip the precursor itself (NR), so that the precursor could get to your cells through the bloodstream intact, avoiding at least one site of potential degradation.
Therefore, although injecting or IV dripping NAD doesn't make sense, injecting or IV dripping NR potentially could make sense. I wouldn't do it, though, because (1) the safety isn't adequately shown, (2) NR actually provides direct benefits to your digestive tract that you would be missing, and (3) I don't think it's necessary to inject NR for NR to work.
But you certainly wouldn't inject NAD directly into your blood because you actually need it to get broken down, and the blood system is not a controlled place for that to occur. It's more like a crapshoot. And if the NAD either doesn't break down at all in the bloodstream, or breaks down into NAM, then you lost the bet, because NAM is an inexpensive precursor that makes it through the digestive tract just fine. Injecting NAD to get NAM is your worst-case scenario: the most expensive way to do the least expensive thing.
I mentioned that ingesting NR as an oral supplement actually helps your digestive tract. Specifically, it supports stem cells in the gut, and it improves the gut microbiome. Here are the studies that say that:
These results indicate that the microbiota from NR-treated mice is sufficient to reduce HFD-induced weight gain by 6.52%...NR-conditioned fecal material transfer remodels the gut microbiome similarly to NR supplementation...NR-treated mice burn more calories than control mice, thus gaining less weight...
Our findings suggest that NR changes gut microbiota composition in a manner that may improve health...our evidence emphasizes that a supplementation time longer than 3 months is required to detect the impact of NR on muscle mitochondrial biogenesis in healthy individuals with overweight and obesity.
The treatment with the NAD(+) precursor nicotinamide riboside (NR) rejuvenates Intestinal Stem Cells (ISCs) from aged mice and reverses an impaired ability to repair gut damage.
Could There Be Dedicated NAD Transporters?
Even if NAD can't directly cross the cell wall, might not there be dedicated NAD transporters that could shepherd circulating NAD molecules into cells? Actually, there could be.
This study here says that there is one, and it's called Cx43, and there might be more.
Dedicated NAD+ transporters are thought to exist. One way of importing NAD+ is via connexin 43 (Cx43) channels, which are permeable to NAD+ and are highly expressed on cardiomyocytes. Indeed, exogenous NAD+ was shown to block cardiac hypertrophy, and this effect was abolished in the presence of the Cx43 blocker carbenoxolone. However, despite considerable evidence that exogenous NAD+ (without prior hydrolysis) can be taken up into different types of mammalian cells, besides Cx43 the transporters responsible for this are still to be discovered.
-- Antioxidants & Redox Signaling, September 20, 2019
The problem with Cx43 is that it is well-expressed in cardiomyocytes, which are the cells responsible for generating contractile force in the intact heart. That's not a bad place to replenish NAD, but there are a hundred other places, too like your brain, kidney, liver, pancreas, spleen, muscle, lungs, and your big toe. It's a sucker's game trying to find hundreds of transporters for hundreds of cell types. Better to use a form that is universally bioavailable.
And that is the main problem with Cx43 as a dedicated NAD transporter: You don't need a dedicated NAD transporter to replenish NAD. Circulating NAD is aggressively degraded to NMN, and NMN to NR, by many different enzymes, such as CD38, CD73, and CD 157. Here is the same study:
CD73 has also been shown to catalyze the conversion of NAD+ to NR via NMN
-- Antioxidants & Redox Signaling, September 20, 2019
And once it gets to NR, it is able to enter the cell. Which is why taking NR directly is so much better of an idea.
So trying to get NAD directly into your cells with dedicated transporters is essentially creating a problem so that you can solve it. That, at least, is what your body seems to think, because it has solved the NAD transport problem a different way.
Putting NAD directly into your blood stream will likely a positive effect to the extent that (1) it gets broken down into NAM and your salvage pathway is not down-regulated, or (2) it gets broken down into NR and is absorbed as NR.
But it is way, way less expensive and more convenient to just take the NR directly as an oral supplement. Concerns about bioavailability of NR are likely overstated, because (1) some NR gets through to cells as NR, and at the high doses recommended for NR supplementation that may be enough to make the difference we are looking for, and (2) NR has direct positive effects in the gut even if it is broken down there. That means oral supplements have unique benefits that NAD injections cannot offer, and may offer as good or better results at a much lower price.