The Potential Risks of Spermidine

Are there any downsides to trying to restore youthful spermidine levels? The lack of reported side effects is not surprising given that our own body makes so much of it and the fact that it’s found naturally in the diet and, in fact, concentrated in some of the very foods associated with health and longevity. But is it safe for everyone?

Up until 2018, there was said to be a “darker side to spermidine” given its apparent toxicity to human cells in vitro. Culture cells with spermidine in a petri dish and the spermidine undergoes enzymatic oxidation to produce free radical-generating breakdown products like hydrogen peroxide that damage the cells. But, it turns out that’s only because the researchers were bathing the cells in fetal calf serum, a slaughterhouse byproduct of the dairy industry commonly used as a cheap culture medium. Enzymes present in cow serum (and goat and horse serum) oxidize spermidine into toxic byproducts in the presence of human cells, but the enzymes in human serum did not. So, spermidine shouldn’t be a problem, as long as you don’t get a blood transfusion from Mr. Ed.

There is at least a theoretical concern that spermidine could play a double-edged sword role in cancer patients. The quality control role of autophagy would be expected to prevent cancer, but once you already have it, the nutrient replenishment action could help sustain tumor viability. For this reason, patients with cancer are sometimes advised to avoid spermidine-rich foods. In fact, clinical trials are underway to evaluate the addition of autophagy inhibitors to chemo cocktails to fight cancer like chloroquine and hydroxychloroquine—remember those from COVID lore? Some have even speculated that the decline in spermidine levels as we age may be one way our body protects itself from cancer. OK, so that’s all in theory. What do the data say?

As I described before, epidemiologically spermidine intake is associated with a lower risk of all major causes of death, including death from cancer. One study suggested spermidine intake may be linked to the development of colon polyps, but a follow-up study by the same group of researchers found, if anything, spermidine intake was associated with a lower risk of colorectal cancer. A commentary in the journal Autophagy summarizing the data was entitled “Spermidine Reduces Cancer-Related Mortality in Humans.” This may not wholly be an autophagy effect, however, as spermidine may also boost anti-cancer immunity. What if you already have cancer, though?

A preliminarily trial published in 2010 followed a group of prostate cancer patients that failed to respond to hormone therapy (chemical castration). They were asked to clear their friendly flora with antibiotics and then go on a low spermidine diet (along with reducing the intake of other polyamines, putrescine and spermine). The survival of those who complied was compared to those who refused (or simply couldn’t, for example, those institutionalized in a setting that didn’t allow special diets). Cancer survival in the polyamine-restricted group was twice that of the others (36 months compared to 17 months on average), and those who started the diet earlier (within nine months of treatment failure) died from their cancer later than those who waited (44 months compared to 34 months). Because this was not a randomized trial, no concrete conclusions can be made. (Those who couldn’t or wouldn’t comply may have just had worse cancers.) Unfortunately, no further such studies have been published. Until we know more, cancer patients perhaps shouldn’t go out of their way to increase their spermidine intake, but at the same time may not want to shy away from foods like soy and broccoli that have specifically been associated with improved survival after a cancer diagnosis.

The other group I would advise caution for are those with kidney failure. They have elevated levels of the enzyme activity implicated in the calf serum toxicity and, consequently, higher accumulation of toxic spermidine byproducts like acrolein in their bloodstream.

The only other potential adverse effect I could find was in that remarkable dementia treatment study. Compared to the control group, those in the spermidine group experienced a drop in vitamin B12 levels in their blood. If this is confirmed, B12 levels may have to be monitored and/or supplemented.