Update on the Safety and Efficacy of Nicotinamide for Skin Cancer Chemoprevention

Nicotinamide, also known as niacinamide, is a water-soluble vitamin B₃ derivative that has long been associated with beneficial impacts on skin cancer risk.^1,2 Nicotinamide functions by replenishing cellular nicotinamide adenine dinucleotide (NAD+), which aids DNA repair mechanisms following ultraviolet (UV)–induced DNA damage. Supportive data from the ONTRAC trial in 2015 led to more widespread clinical adoption, with one survey revealing that approximately 75% of Mohs surgeons recommended it to their patients.^3,4 Nicotinamide has also been included in National Comprehensive Cancer Network guidelines for both basal cell carcinoma and squamous cell carcinoma.^5,6 More recently, nicotinamide has come under scrutiny for potential risks of major adverse cardiovascular events (MACE), as well as for possible lack of efficacy among solid organ transplant recipients (SOTRs), for whom it is often recommended due to their high burden of skin cancers.^7,8 In this review, we discuss recent research on the safety and efficacy of this inexpensive over-the-counter vitamin. 

SAFETY CONCERNS

Some concerns have emerged recently regarding the safety profile of nicotinamide. In early 2024, a study from Stanley Hazen and colleagues suggested that metabolites of niacin and nicotinamide, N1-methyl-2-pyridone-5-carboxamide (2PY) and N1-methyl-4-pyridone-3-carboxamide (4PY), were associated with an increased risk of MACE, presenting molecular, genetic, and epidemiologic data to support this finding.⁷ Specifically, the authors described a “niacin/NAD pool,” grouping nicotinamide with niacin due to their shared metabolic pathway, in which metabolites may foster excess production of 2PY and 4PY, potentially leading to vascular inflammation and increased cardiovascular disease risk. However, the study did not directly measure nicotinamide; rather, its similar metabolism to niacin led to extrapolation of potential risk.

Shortly following this study, three large epidemiologic studies provided reassurance that real-world data do not support this increased risk. First, data from the National Health and Nutrition Examination Survey (NHANES) estimated daily niacin intake, again not directly measuring nicotinamide, and observed a weak but statistically significant inverse association with cardiovascular and all-cause mortality.⁹ Next, work from our group directly measured nicotinamide use in two cohorts and found no association with a composite outcome of MACE.¹⁰ Lastly, a study using data from TriNetX evaluated nine separate cardiovascular outcomes and observed decreased risk ratios for ST-elevation myocardial infarction, peripheral vascular disease, and cardiac arrest, with the remaining outcomes nonsignificant, several trending toward a protective direction.¹¹

None of these studies had the same molecular and genetic granularity as the original study by Hazen and colleagues, and ongoing collaborative work is investigating these relationships further.¹² In the near future, more precise recommendations may emerge regarding safe use of nicotinamide and identification of subgroups in whom risks may outweigh benefits. Until then, current population-level data are reassuring, with no demonstrated association between nicotinamide use and increased MACE or mortality. MACE are not the only safety concern linked with nicotinamide. Its prior investigation as a phosphate-lowering agent in patients with end-stage renal disease (ESRD) provided a sizable cohort for safety evaluation. Although nicotinamide was not ultimately effective in reducing phosphate levels, it was associated with increased rates of thrombocytopenia, approximately threefold higher, likely related to elevated 2PY levels.¹³

Another commonly discussed adverse effect is an increased risk of myopathy among patients taking statins. This risk has long been associated with niacin, with extended-release formulations demonstrating improved tolerability.^14,15 However, concerns regarding nicotinamide are extrapolated from niacin data, and no studies have directly evaluated nicotinamide in this context. Mechanistically, niacin-induced myopathy is thought to occur through inhibition of the mevalonate pathway and drug-drug interactions involving CYP3A4 and OATP1B1 hepatic transport proteins.¹⁴ In contrast, nicotinamide has not been shown to affect the mevalonate pathway, as evidenced by its lack of lipid-lowering effects. Additionally, pharmacologic studies suggest that nicotinamide does not undergo hepatic uptake via the same transporters as niacin and therefore would not be expected to interact with pathways involved in statin metabolism.¹⁶

EFFICACY FOR SKIN CANCER PREVENTION

Efficacy of oral nicotinamide for skin cancer prevention has been demonstrated in clinical trial data, most notably in the ONTRAC trial.³ In this phase 3, double-blind randomized controlled trial, 386 patients with at least two nonmelanoma skin cancers (NMSCs) within the previous 5 years were randomized in a 1:1 ratio to receive oral nicotinamide 500 mg twice daily or placebo for 12 months. Patients were evaluated at 3-month intervals for a total of 18 months. During the 12-month intervention period, there was a 23% reduction in the number of NMSCs in the nicotinamide group compared with placebo. This chemopreventive effect did not persist after treatment cessation, suggesting that continuous therapy is required to maintain benefit.³ More recently, our group published the largest study to date evaluating nicotinamide for skin cancer prevention, including more than 33,000 US veterans with at least one prior skin cancer, of whom 12,000 had received nicotinamide for at least 30 days.¹⁷ In this study, there was an overall 14% reduction in the rate of new skin cancer development among patients receiving nicotinamide compared with unexposed patients. Because of the large sample size, stratified analyses were performed based on the number of prior skin cancers. It is well established that the risk of developing subsequent skin cancers increases with each additional lesion, both in the general population and among SOTRs.¹⁹

Earlier initiation of nicotinamide was associated with greater reductions in new skin cancer rates, with more than 50% reduction observed when therapy was started after the first one or two skin cancers. This benefit declined in a near-linear fashion, such that initiation after eight or more skin cancers was no longer associated with reduction in new cancer development. These findings suggest that earlier initiation of systemic chemoprevention may be beneficial. Although limited by retrospective design, these results support calls for prospective randomized trials.¹⁸

Despite these findings, not all patients with skin cancer will benefit from nicotinamide. Approximately 40% to 45% of patients diagnosed with a first skin cancer will develop a second within 5 to 10 years.¹⁹ Ongoing efforts aim to identify clinical and molecular biomarkers to better guide chemopreventive strategies. At present, initiation after two to three skin cancers may represent a reasonable threshold for consideration.

SOLID ORGAN TRANSPLANT RECIPIENTS

The ONTRANS trial did not demonstrate efficacy of nicotinamide in SOTRs, though several limitations have been discussed.⁸ These include limited statistical power, potential sampling bias, and a high baseline burden of disease, with a mean of more than seven prior skin cancers. Notably, the point estimate for cutaneous squamous cell carcinoma (cSCC) reduction was similar to that observed in ONTRAC (0.73 vs 0.70).

Additional studies suggest that timing of initiation may again be critical. A single-center study evaluating the number of skin cancers before and after nicotinamide initiation demonstrated a reduction in overall skin cancer incidence, with many patients experiencing benefit.²⁰ Similarly, subgroup analyses from larger datasets suggest that SOTRs who initiate nicotinamide earlier in their disease course may derive greater benefit, although sample sizes remain limited.¹⁷

CONCLUSIONS

Nicotinamide is a well-tolerated, low-cost over-the-counter supplement that has demonstrated efficacy in preventing keratinocyte carcinoma in at-risk patients, with evidence suggesting greater benefit when initiated earlier in the disease course. Recent concerns regarding potential cardiovascular risk have not been supported by current observational data.

Additional safety considerations highlight the importance of distinguishing nicotinamide from niacin. In patients with ESRD, thrombocytopenia has been observed, whereas concerns regarding statin-associated myopathy are largely extrapolated and not supported by mechanistic evidence. Overall, current data support the safety of nicotinamide in the general population, with appropriate clinical monitoring.

Future studies integrating mechanistic and clinical data will be essential to identify subpopulations that may experience differential risk or benefit. Ongoing randomized controlled trials are expected to provide more definitive guidance regarding optimal timing, duration, and patient selection. 

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11. Salem Y, Liaqat M, Gonna N, et al. Decreased risk of cardiovascular disease in dermatology patients taking niacinamide: a TriNetX cohort study. J Am Acad Dermatol. 2026;94(3):828-834. 

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16. Mathialagan S, Bi YA, Costales C, et al. Nicotinic acid transport into human liver involves organic anion transporter 2 (SLC22A7). Biochem Pharmacol. 2020;174:113829. 

17. Breglio KF, Knox KM, Hwang J, et al. Nicotinamide for skin cancer chemoprevention. JAMA Dermatol. Published online 2025. doi:10.1001/jamadermatol.2025.3238 

18. Tan E, Williams HC. Nicotinamide for skin cancer chemoprevention: the jury was out and still is. Am J Clin Dermatol. 2026;27(2):209-215. 

19. Wheless L, Liao KP, Zheng S, et al. Frequency and timing of multiple skin cancer development in five cohorts. J Am Acad Dermatol. Published online February 2025. doi:10.1016/j.jaad.2024.12.047

20. Hwang JC, Savage KT, Pugliano-Mauro M. Nicotinamide for secondary keratinocyte carcinoma prevention in solid organ transplant recipients. Arch Dermatol Res. 2025;317(1):807.

Sami Jelousi, MD

• PGY-3 Dermatology Resident
• Vanderbilt University Medical Center

Nashville, TN

Lee Wheless, MD, PhD

• Assistant Professor, Department of Dermatology
• Vanderbilt University Medical Center
• Staff Physician, Tennessee Valley Health System VA Hospital

   Nashville, TN