Key Takeaway:
- If you want to boost NAD+ levels, taking a supplement containing NAD+ precursors is likely your best bet. There is little or no evidence to support the efficacy of IV NAD+ infusions or NAD+ injections / shots.
Related Products:
- Basis: contains the highly efficient NAD+ precursor NR and is clinically proven to boost NAD+ levels by 40%. Basis combines NR with pterostilbene to target cellular aging and support DNA maintenance.
- Signal: contains the novel NAD+ precursor NMN which is also clinically proven to boost NAD+ levels by 40%. Signal combines NMN with a SIRT3 Activation Complex to target metabolic aging and support mitochondrial health.
With its rising popularity, NAD+ is being offered in an ever-increasing variety of forms, including intravenous (IV), subcutaneous (SC), and intramuscular (IM) injections and oral supplements. IV NAD+ is now widely available at IV “drip” bars with many—including celebrities Hailey and Justin Bieber, Jennifer Aniston, and Joe Rogan—spending $500 to $2000 per drip to get its touted benefits of mental clarity, energy, and improved athletic performance and recovery. But do they work? Before we dig into the purported benefits of these NAD+ therapies, we first need to understand what NAD+ is and how our body makes this molecule naturally.
What is NAD+?
NAD+, or nicotinamide adenine dinucleotide, is a critical coenzyme found in every cell in your body, and it’s involved in hundreds of metabolic processes. NAD+ and its reduced form, NADH, play a central role in creating ATP, the energy currency of cells. ATP is used by the cell to fuel a broad range of essential functions like muscle contraction, the conduction of nerve signals (the brain is the highest consumer of ATP in the body), and the synthesis of DNA and RNA. Mitochondrial function, maintenance of healthy DNA, sirtuin function—all of these need NAD+, too. It’s a molecule that is essential to our health and survival and a human study published in Nature Aging demonstrates that increased levels of NAD+ correlate with healthier aging and suggests that “a clear association exists between NAD+ and health status in human aging.” By middle age, however, we have about half the amount we had in our youth, so it makes sense that people are interested in strategies for increasing NAD+ levels and supporting the chemistry that keeps us up and running.
Our body makes NAD+ from “precursors”
NAD+ is made inside cells, from smaller, precursor molecules like nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN). A major source of NAD+ precursors is NAD+ itself. Once it’s used by NAD+ consuming enzymes inside the cell, NAD+ is broken down to its smaller components, which can be recycled to form new NAD+. This process of recycling NAD+ is called the “salvage pathway,” and it becomes less efficient with age, contributing to lower NAD+ levels. Another source for NAD+ precursors is our diet. Certain foods like milk, broccoli, and edamame contain small amounts of NAD+ precursors. Ingested NR and NMN are taken up by cells through dedicated “cellular transporters” (gates in the cellular membrane that allow molecules to move in and out of cells). Once inside cells, they are used by the cell to create new NAD+. And indeed, oral supplementation with NR and NMN has been validated in dozens of human clinical studies to significantly raise NAD+ levels in blood safely and sustainably. In a double-blind, randomized, placebo-controlled clinical trial published in the peer-reviewed journal Nature Partner Journals: Aging and Mechanisms of Disease, Elysium demonstrated that daily oral supplementation with Basis, which contains NR, safely and sustainably increases NAD+ levels by an average of 40%. Because the amount of NR and NMN in our diet is not enough to compensate for the age-related loss of NAD+, oral supplementation is a highly effective (and proven) way to counter this age-related decline.
Unlike precursors, NAD+ itself cannot enter cells
Unlike NAD+ precursors like NR and NMN, there is no credible evidence to suggest that externally supplied NAD+ (ingested or injected) gets inside cells, where they are needed. There is no known cellular transporter for NAD+ and orally ingested NAD+ is also unable to undergo direct intestinal absorption. For injected or orally supplied NAD+ to work, the molecule would first need to be broken down to a precursor form that can enter cells. While some of the injected NAD+ may break down into its precursors, a pilot clinical study on IV NAD+ demonstrated a 538% increase in urine NAD+ excretion rate at the end of a 6 hr IV NAD+ infusion session, suggesting that the majority of the NAD+ from IV infusion is rapidly excreted in the urine. Another human study in preprint, showed a significant delay (7 to 14 days) in the increase in blood NAD+ levels.
Aside from the metabolic inefficiency associated with direct administration of NAD+ (via IV, IM, SC, or oral routes) due to the requirement for NAD+ to be broken down to its precursors prior to cellular entry, increasing extracellular NAD+ levels (levels of NAD+ outside of cells) may provoke maladaptive effects. While NAD+ concentrations inside cells are in the millimolar range, concentrations of extracellular NAD+ are much lower, usually submicromolar in serum (resulting from injured or damaged cells, which release NAD+ into the extracellular environment). Preclinical studies suggest that increasing extracellular NAD+ concentrations beyond normal ranges may even result in pro-inflammatory signaling and potentially suppress immune responses (study 1, study 2), highlighting the need for caution with direct administration of NAD+.
There is little to no evidence that IV NAD+ infusions and NAD+ injections work
There is an alarming lack of human studies investigating the safety and tolerability of IV NAD+ despite its widespread use. Anecdotal reports from clinicians and patients include nausea, diarrhea, muscle cramping, chest pains, and dizziness, necessitating an extremely slow rate of administration (up to six hours).
While evidence is extremely limited for IV NAD+ infusion, human clinical studies are nonexistent for NAD+ shots, raising concerns not only regarding efficacy but their safety.
Injections and infusions do not provide sustained, elevated level of NAD+
While IV NAD+ typically provide 500 mg of NAD+, infused over a period of one to six hours depending on tolerability, IM or SC injections contain much lower doses of NAD+, around 20 mg per shot. Therefore the efficacy of IM or SC injections is even more questionable than IV NAD+, given the mediocre effects of infusing 500 mg of NAD+ directly into the bloodstream. With SC routes, a needle is inserted into fatty tissue just beneath the skin. The injected NAD+ would need to move into blood or lymphatic vessels to reach the bloodstream for systemic circulation. Intramuscular injections require longer needles in order to reach the muscles that lie below the skin and fatty tissue. How quickly the injected NAD+ is absorbed into the bloodstream will depend, in part, on the blood supply to the muscle. The sparser the blood supply, the longer it will take.
Even if an increase in NAD+ were achieved with IV, IM, or SC injections, the benefit will disappear rapidly without regular repeated infusions or injections. “In very plain words, intramuscular and IV NAD+ intake is silly,” says Charalampos Tzoulis, M.D., professor of neurology and neurogenetics at the University of Bergen and Haukeland University Hospital in Norway in an interview in VOGUE.
In contrast to NAD+ infusions and injections, there are dozens of rigorous, placebo-controlled studies, including those from Elysium Health, demonstrating the safety and efficacy of oral supplementation with NAD+ precursors like NR (in Basis) and NMN (in Signal). Taking Basis daily is proven to safely and sustainably raise NAD+ levels by 40% without any of the side effects of injections or infusions (at a fraction of the cost).
