There may be no need for expensive liposomal formulations.
https://pubmed.ncbi.nlm.nih.gov/31673018/
Despite the fact that numerous studies showed efficacy following oral dosing of cordycepin, we found that intact cordycepin was not absorbed following oral administration to rats. However, 3’-deoxyinosine, a metabolite of cordycepin previously considered to be inactive, was absorbed into the systemic blood circulation. Further investigation was performed to study the conversion of 3’-deoxyinosine to cordycepin 5’-triphosphate in vitro using macrophage-like RAW264.7 cells. It demonstrated that cordycepin 5’-triphosphate, the active metabolite of cordycepin, can be formed not only from cordycepin, but also from 3’-deoxyinosine.
And a full summary by @RapAdmin
Cordycepin’s Disappearing Act: The “Inactive” Metabolite That Does the Real Work
Cordycepin, the celebrated bioactive molecule from the caterpillar fungus Cordyceps militaris, has a problem that this paper exposes bluntly: when swallowed, essentially none of it reaches the bloodstream intact. In rats given oral cordycepin at doses up to 80 mg/kg, the drug was undetectable in plasma. Yet decades of studies report real effects from oral dosing. The Nottingham led team resolves the paradox by showing that a breakdown product long dismissed as inert, 3’-deoxyinosine, is actually absorbed efficiently and can be converted back inside cells into cordycepin triphosphate, the active form. The proposed “nucleoside rescue” pathway rewrites how we should think about dosing cordycepin and other adenosine analogues by mouth.
For years, cordycepin has been sold and studied as if the molecule that goes into your mouth is the molecule that acts in your tissues. This study says that assumption is wrong. Working in rats and in cell culture, researchers at the University of Nottingham tracked what actually happens to cordycepin after oral dosing, and the headline result is stark. Intact cordycepin never showed up in the blood, not at 8 mg/kg, not even at 80 mg/kg, despite a detection method sensitive down to 2 nanograms per millilitre.
The reason is a pile-up of biological obstacles. Cordycepin crosses the gut lining poorly. It is chewed up by an enzyme called adenosine deaminase both in the gut wall and in the liver, which strips it apart on first pass before it can enter the general circulation. In the laboratory, cordycepin only survived long enough to be measured when the team added pentostatin, a deaminase blocker.
Here is the twist that makes the paper interesting. That deaminase reaction does not destroy cordycepin so much as convert it into 3’-deoxyinosine, a metabolite the field had written off as inactive. When the researchers looked for this compound, they found it flooding into the bloodstream, with an oral bioavailability of roughly 37 percent. They then showed in mouse macrophage cells that 3’-deoxyinosine can be phosphorylated back up to cordycepin triphosphate, the molecule that actually interferes with RNA synthesis and inflammation. In other words, the “waste product” is a Trojan horse that smuggles cordycepin’s activity into the body by a back route.
The bigger idea reaches past this one fungal compound. Adenosine analogues as a drug class have been hobbled by exactly this kind of rapid deamination. If an “inactive” metabolite can quietly reload the active drug inside cells, then medicinal chemists have been optimising for the wrong thing. Designing future analogues around this rescue pathway, rather than fighting to keep the parent molecule intact, could be a smarter route to oral drugs. The work is preliminary and confined to rats and cultured cells, but it reframes a long standing puzzle.
Actionable Insights
The honest take home is a caution, not a supplement recommendation. This study measured absorption chemistry, not health outcomes.
First, swallowing pure cordycepin is inefficient. In rats, oral bioavailability of the intact molecule was effectively zero, because gut and liver enzymes convert it before it reaches circulation. If any benefit occurs after oral dosing, it appears to be carried by the metabolite 3’-deoxyinosine, which reached about 37 percent bioavailability. To put that number in perspective, for every 100 units of cordycepin you swallow, none arrives as cordycepin, but a meaningful fraction arrives as the metabolite that cells can reactivate.
Second, the effect sizes that exist here are biochemical, not clinical. In cultured immune cells, cordycepin sharply suppressed inflammatory genes such as Il1b and Tnf, cutting some LPS driven signals by well over 90 percent, a very large effect in a dish. But a dish is not a person, the cell studies were tiny, and none of this demonstrates that a capsule improves human health. Treat cordycepin marketing claims about oral potency with skepticism, and understand that formulation, not just dose, likely governs whether anything reaches your cells.
Context and Source
Full title: A novel nucleoside rescue metabolic pathway may be responsible for therapeutic effect of orally administered cordycepin.