Eutropoflavin, otherwise known as 4’-DMA-7,8-DHF, is one of the more interesting nootropics to have hit the scene as of late, but data on it is very limited. In fact, there is no formal study that I could find written on it, only studies regarding it’s less effective sister compound 7'8-DHF, and no human studies, just animal trials. However, there are some pretty incredible results to have come out of these animal trials.
Increased BDNF Regaining lost memory function Increased spatial awareness Increased motor control Anti-depressant effects Obesity prevention Even promotes autophagy
… and that’s just to name a few.
So we’re going to explore the evidence that exists and piece together whether this is something worth taking or if it’s better to wait for further research (I’ve definitely not waited).
How Does it Work?: Eutropoflavin works as a TrkB agonist. TrkB is a high-affinity catalytic receptor which binds to BDNF and is responsible for neuronal survival, differentiation, and is crucial for synaptic plasticity. CRUCIAL. Reduced TrkB signaling is associated with increased risk of Alzheimer’s and Parkinson’s disease. A lot of the studies we are going to look at are going to focus on Alzheimer’s and Parkinson’s models in rats, but it should be noted that benefits were also found in other conditions such as healthy mice and chronically stressed mice.
We will also going to touch on why long-term TrkB agonism may not be a good idea (assuming it actually is agonizing TrkB) and a few workarounds to ensure we can get year-round neurogenesis.
Study 1: Found that 7,8-DHF prevented synaptic loss, restored long-term potentiation, and rescued spatial memory deficits in mice with Alzheimer’s disease through TrkB activation. The study looked at 10-14 female mice per group aged 2-6 months and treated them with 7,8-DHF for a duration of 4 months. They used a dose of 5mg/kg/day which is very high by human standards (a 90kg man would typically not take any more than 25mg/day). What they found: significantly increased TrkB levels in the dentate gyrus, and activated Akt and ERK/MAPK pathways. Prevented loss of dendritic spine density and synaptic density in the hippocampal CA1 region. Reversed decreases in presynaptic and postsynaptic markers. Restored long-term potentiation (LTP) in hippocampal slices. Improved spatial learning acquisition and memory recall in Morris water maze test. Reduced A-beta plaque deposition but did not change total A-beta-42 concentration. “7,8-DHF inhibited the loss of hippocampal synapses, restored synapse number and synaptic plasticity, and prevented memory deficits” https://pmc.ncbi.nlm.nih.gov/articles/PMC3895241/
Study 2: Found very high promise but found 7,8-DHF to have an abysmal 4.6% oral bioavailability. They paired it with a prodrug they called R7 which increases the bioavailability to 84.2% but is not currently commercially available. Study also found binding to the TrkB receptor, found that the compound induces receptor dimerization and autophosphorylation without causing degradation. Found effectiveness in crossing BBB. Found that the 4’-amino group enhances activity. Plasma half life is longer than 2 hours. Crazy part: anti-obesity activity via muscle TrkB activation and increased lipid oxidation. Found no toxicity in mice, even in high doses. https://pmc.ncbi.nlm.nih.gov/articles/PMC4702337/
Blows my mind that it straight up targets fat oxidation. A nootropic that makes you lose weight as well. Ridiculous.
Study 3:
Found antidepressant-like effects in rats exposed to chronic mild stress within 7 days and partial anxiolytic effects in chronically stresses rats by reducing corticosterone and increasing hippocampal BDNF. Sample size 28 rats. The study exposed the rats to chronic mild stress for 8 weeks and then introduced the compound for 4 weeks to observe changes. Used 5mg/kg and up to 20mg/kg via daily injection.
5mg group:
reduced despair behavior
saw increased hippocampal BDNF levels
20mg group:
reversed anhedonia within 7 days
increased locomotor activity
Both groups:
Reduced elevated serum corticosterone levels.
Compound acted via a dual mechanism by affecting HPA axis through corticosterone and neurotrophic pathways via BDNF.
https://pmc.ncbi.nlm.nih.gov/articles/PMC5067348/
Study 4: Found improved motor function in mice with Parkinson’s disease, found that it promoted autophagy through ERK1/2-LKB1-AMPK pathway activation. Did find that it bound to TrkB by antagonizing TrkB through ANA-12 and finding the benefits blocked, confirming the relationship. https://www.nature.com/articles/s41420-021-00643-5
Other Findings: One study failed to replicate the TrkB agonism. https://www.mdpi.com/1424-8247/14/8/704 Another in vitro study siggests that maybe it’s pathway is related to Vitamin B6 by inhibiting PDXP, thereby reducing B6 deficiencies. https://pmc.ncbi.nlm.nih.gov/articles/PMC11164532/ Another study: daily administration for 2 weeks on 22 month old rats improved spatial memory. Showed improvement in behavior associated with increased synapse formation and synaptic plasticity, as well as activation of proteins crucial for synaptic plasticity and memory. Modified density but not number of spines in hippocampus. Study concluded that it can counteract age-induced decline, but found more effective in younger rats with cognitive deficiency. https://pubmed.ncbi.nlm.nih.gov/22694088/
Conclusion: Every study except one found it to directly act on TrkB, crossing the blood brain barrier (which BDNF can’t efficiently do), found that it prevents obesity, is a powerful and fast antidepressant, prevents age-related cognitive decline, increases cognitive ability regardless of age, changes vitamin B6 metabolism, is valuable for Alzheimer’s and Parkinson’s patients, improved spatial memory, restores lost synapses, prevents memory deficits, reduces corticosterone, increases BDNF, even found that it promotes autophagy. As far as the 4’DMA group, only once study referenced that it may increase activity of the compound, so more research needs to be done. Bioavailability also needs to be improved, best routes are sublingual (taking the pill apart and pouring the powder under your tongue) and maybe even through injection. THERE ARE NO HUMAN TRIALS, however, toxicity was not found in rats across doses (from 5mg/kg to 50mg/kg).
Is it actually a TrkB agonist?
Probably. Every study we looked at except one observed and was able to reproduce this effect.
However, long term TrkB agonism could lead to a plateau in effects, not a decrease, just a plateau. This means that you wouldn’t notice any cognitive decline whatsoever, you’d only wonder why “good” became your new normal due to desensitization of the receptor. Luckily, TrkB agonism isn’t the only way to stimulate BDNF.
To ensure you don’t plateau it would be best to alternate for year-round neuroplasticity and BDNF activation: 1 month Eutropoflavin, one month Semax, assuming you have a strong year-round stack already (Alpha GPC, Thiamine TTFD, Lion’s Mane, Magnesium L-Threonate + racetam of your choice).
IMPORTANT: Long-term TrkB activation may be linked to certain types of lung cancer, if you are thinking about using this compound ensure you are not smoking or have a significant history of smoking. Also I am not a doctor.
I think this compound has incredible potential and it seriously needs to be a part of the conversation. I’ve found great effects from it myself. First time I took it I noted how I hit a flow state so deep I forgot I existed. That’s not to say there aren’t risks, there just isn’t enough data. Experiment at your own risk.