High-Dose Spermidine Supplements Don’t Raise Blood or Saliva Levels

Spermidine is a naturally occurring polyamine essential for cell growth, metabolism, and autophagy, and its decline with age has been linked to various age-related diseases. In the study High-Dose Spermidine Supplementation Does Not Increase Spermidine Levels in Blood Plasma and Saliva of Healthy Adults: A Randomized Placebo-Controlled Pharmacokinetic and Metabolomic Study, Senekowitsch et al. investigated whether oral spermidine supplementation effectively raises its levels in blood and saliva. Given previous claims about spermidine’s potential anti-aging and immune-boosting effects, this study aimed to fill gaps in pharmacokinetic data. Using a randomized, placebo-controlled crossover trial, the researchers analyzed how the body processes spermidine and whether it influences metabolic markers. Their findings challenge common assumptions about spermidine supplementation, suggesting that its health effects may be mediated through its conversion into spermine rather than direct absorption.

Spermidine is a natural compound found in the body that helps with cell growth, metabolism, and a process called autophagy, which is vital for maintaining healthy cells. As people age, their spermidine levels drop, and scientists believe this may contribute to aging and diseases like Alzheimer’s. Because of this, some researchers suggest that taking spermidine supplements might help slow down aging and improve overall health. However, there is not much data on how the body absorbs and processes spermidine when taken as a supplement.

This study set out to answer a key question: Does taking high-dose spermidine actually increase its levels in the bloodstream and saliva? The researchers focused on how spermidine moves through the body, whether it gets absorbed, and whether it affects other related compounds. Since some past studies have suggested spermidine could help fight age-related diseases or even protect against infections like COVID-19, this research is crucial for understanding whether supplementation really works as expected.

To test how the body processes spermidine, the researchers designed a randomized, placebo-controlled, triple-blinded, two-armed crossover trial—a fancy way of saying they made sure the experiment was fair, accurate, and thorough.

Twelve healthy adults took part in the study. They received 15 mg of spermidine per day for five days in one phase and a placebo (a fake supplement) for another five days after a nine-day break in between. The study was designed so that neither the participants nor the researchers knew who was taking the real supplement and who was taking the placebo.

Throughout the experiment, participants gave blood and saliva samples to check their levels of spermidine and related compounds. These samples were analyzed using liquid chromatography–mass spectrometry (LC–MS/MS), a high-tech method for measuring small molecules in the body. The researchers also used nuclear magnetic resonance (NMR) metabolomics to see if spermidine affected overall metabolism.

One of the most surprising findings was that spermidine levels in blood and saliva did not increase, even though participants were taking 15 mg per day. This suggests that spermidine is not directly absorbed into the bloodstream in measurable amounts.

Previous research has shown that the human body regulates polyamine levels tightly, which could explain why extra spermidine from supplements doesn’t appear in circulation. The researchers stated:

"It is rather unlikely that spermidine supplements with doses <15 mg/d exert any short-term effects."

Instead of increasing spermidine levels, the study found that blood plasma spermine levels rose significantly. This suggests that the body quickly converts spermidine into spermine before it reaches the bloodstream.

The researchers explained:

"Our data strongly suggest that dietary spermidine is presystemically converted into spermine, which then occurs in the systemic circulation."

This means that spermine, not spermidine, might be responsible for the health benefits linked to spermidine supplementation.

Putrescine, another related polyamine, showed no significant changes in blood or saliva levels. This suggests that putrescine metabolism remains unaffected by spermidine supplementation, at least in the short term.

Some researchers have proposed that spermidine might help prevent infections like COVID-19 by increasing its concentration in saliva, where it could act against viruses. However, this study found no evidence to support that idea.

Even at the highest recorded levels, spermidine in saliva was more than 10 times lower than the concentration needed to show antiviral effects in lab studies. The researchers wrote:

"Even the highest individual salivary spermidine concentration [...] is smaller by more than a factor of 10 than the aforementioned effective in vitro concentration."

This means that taking spermidine supplements is unlikely to provide direct protection against viruses in the mouth and throat.

Because spermidine has been described as a calorie restriction mimetic (CRM)—a compound that mimics the effects of fasting—the researchers checked whether it altered metabolism.

They used NMR metabolomics to measure metabolic markers like glucose and acetone, which usually change when fasting-mimicking substances are consumed. However, no major metabolic shifts were found, suggesting that spermidine does not act as a calorie restriction mimetic in the short term.

This study raises important questions about whether spermidine supplements work the way people think they do.

First, it shows that spermidine supplements may not increase spermidine levels in the blood. Instead, the body seems to turn it into spermine before it enters circulation. This suggests that spermine, not spermidine, might be responsible for the health benefits linked to spermidine.

Second, many commercial spermidine supplements contain doses far lower than 15 mg/day. Since even a high dose of 15 mg/day had only minor effects, lower-dose supplements may not provide noticeable benefits. This could change how people think about spermidine as an anti-aging supplement.

Third, the study found no impact on saliva levels, meaning that spermidine is unlikely to help prevent infections in the mouth and throat, including COVID-19. If future studies want to test spermidine for this purpose, they may need to explore different delivery methods, such as sprays or mouth rinses.

Lastly, the results challenge epidemiological studies that link spermidine-rich diets with health benefits. Many of these studies assume that eating spermidine-rich foods leads to higher spermidine levels in the body, but this study suggests that the body processes spermidine in unexpected ways. Future research may need to focus on spermine instead of spermidine.

This study provides the first controlled data on how spermidine is processed in the body, challenging common beliefs about its supplements. Despite taking high doses, participants did not see an increase in blood or saliva spermidine levels, suggesting the body quickly converts it into spermine.

For those considering spermidine supplements for anti-aging or immune health, this research highlights the need for higher doses, longer studies, and a shift in focus to spermine as the potential key compound.

Low-dose spermidine supplements may not be effective, and taking spermidine won’t increase saliva levels enough to prevent infections. Future research should explore whether direct spermine supplementation offers greater benefits.