Although there have only been few human clinical trials, there is evidence that NAD+ precursors are safe for people to take at doses that may translate beneficial effects seen in animals(Selcuk1 | iStock)
NAD+, a compound essential for enzymes to participate in a great deal of biochemical reactions, has been found to be the key that activates enzymes that drive hundreds of diverse biological processes. In mammalian cells, NAD+ is one of the most abundant molecules, second only to water.
Given the vitality of NAD+, there has been a growing interest and market around methods to increase NAD+ levels primarily consisting of chemical precursors. So, what do we know about how much of these NAD+ boosters we can take to generate NAD+ and exert beneficial (or toxic) effects?
NAM was one of the first metabolic compounds used to elevate NAD+ levels. Since NAM is readily available and can pass into cells through their membranes, this precursor was the most logical candidate to use for treatment of conditions of brain tissue NAD+ deficiency (Hwang and Song, 2020). NAM’s ability to pass through cellular membranes explains its rapid penetration of the blood-brain barrier (BBB) — the roadblock for compounds trying to enter the nervous system from circulation. But this also suggests that NAM can be readily removed from tissue by blood flow.
Also, though, it is well established that as a by-product of NAD+ consumption, NAM also serves as a natural feedback inhibitor for enzymes dependent on NAD+. For example, enzymes that depend on NAD+ are inhibited as NAM concentrations increase, and this has been postulated to drive antidiabetic effects of NAM in humans.
Tolerance for NAM, even during long-term administration, has been demonstrated in many studies (Gale et al., 2004; Takahasi et al., 2004; Libri et al., 2014; Phelan et al., 2017). These studies assure safety in the current widespread practice of long-term dietary intake of 500-1500 mg per day. Adverse effects have been reported for humans in doses higher than 3 grams limited to several organs, namely liver, kidney, cells in plasma, and pancreatic β-cells.
Since NMN is a direct precursor to NAD+, it theoretically can more efficiently facilitate NAD+ synthesis by bypassing the rate-limiting steps; NMN will directly feed into the one-step enzymatic generation of NAD+ (Poddar et al., 2019; Hong et al., 2020; Khaidizar et al., 2021). There are several reports showing that intraperitoneal administration of NMN can significantly increase brain tissue NAD+ levels within 15 minutes post-injection (Klimova and Kristian 2019). This, with the identification of an NMN-specific transporter, supports the concept that there is an active transport of NMN into cells for conversion to NAD+ (Wu and Sinclair, 2019).
In humans, a clinical trial study showed the safety of single administration of NMN in ten healthy men and has confirmed that it can be safely administered and that it is effectively metabolized in the body (Irie et al., 2020). Although there are not many human studies, the doses that have been used to study NMN in people range from 100-1200 mg (Liao et al., 2021, Yoshino et al., 2021). There are no reports of significant adverse effects of NMN on physiological parameters like temperature, blood pressure, cerebral blood flow, or other forms of toxicity.
Another option for improving NAD+ levels is by supplementing NR (Mehmel et al., 2020). But NR is very unstable in the blood, which makes it difficult to measure and detect. Due to its instability, the doses often used to produce beneficial effects are often high.
NR has also been tested several six clinical trials, where NR was established as safe for short (8 days) and long-term (6 weeks) use along with confirmed oral availability (Trammel et al., 2016; Dellinger et al., 2018; Martens et al., 2018; Elhassan et al., 2019). Furthermore, a randomized 8-week placebo-controlled trial with three different doses (up to 1000 mg) of NR, tested in overweight and healthy adults, reported that NR chloride is safe and orally available. The instability of NR in blood samples has been observed across several studies.
NMN and NR oral administration dose and duration in human clinical trials
|NMN||600, 1200||6 weeks||Liao et al. 2021|
|NMN||250||10 weeks||Yoshino et al. 2021|
|NR||250, 500||8 weeks||Dellinger et al. 2017|
|NR||500||6 weeks||Martens et al. 2018|
|NR||1000||3 weeks||Elhassan et al. 2019|
Niacin is a B vitamin that’s made and used by your body to turn food into energy, working to help keep the nervous system, digestive system, and skin healthy. Niacin (vitamin B-3) is often part of a daily multivitamin, but most people get enough niacin from the food they eat. Niacin was shown to boost NAD+ levels in participants 750-1,000 mg/day for 10 months (Pirinen et al., 2020). Serious side effects are reported when taken between 2,000 to 6,000 mg of niacin a day.
NA represents the acid form of niacin (Ban, 1975; Hageman et al., 1998). It is commonly prescribed clinically for the treatment of hyperlipidemia. It has been reported that daily intake of 1,000 to 3,000 mg reduces blood triglyceride levels and low-density lipoproteins (LDLs), while increasing the level of high-density lipoprotein (HDL), thus favorably regulating the LDL:HDL ratio.
However, NA therapy can induce significant skin flushing in a majority of individuals, thus limiting its clinical uses. A mild skin flush has been reported in patients exposed to 50 mg oral NA, and the upper tolerable limit for NA has been set to 35 mg per day for adults in the United States and Canada. NA is preferentially removed from circulation at high levels with a half-life of 1 hour, compared with a half-life of 4 hours for NAM.
It has been postulated that pharmacological responses to long-term supplementation with NAD+ precursors may change over time. This also raises the important question of whether higher NAD+ levels have the potential to induce a deleterious impact on cellular function, thus stimulating an adaptive response. Nevertheless, the strategy for each person to take NAD+ boosters will change depending on the outcome sought because these precursors affect cells differently.