Triacetyluridine

Triacetyluridine: Effects, Benefits, Dosage and More

Triacetyluridine (sometimes called Uridine Triacetate or simply TAU) is a relatively novel nootropic supplement. This compound has a history of use as a pharmaceutcial drug to reverse the effects of chemotherapy overdose. However, as a potent pro-drug for uridine, it is now being investigated for use as a brain supplement in its own right. As uridine is currently thought to have beneficial effects on mood, cognitive function and various neurodegenerative diseases (not to mention everything from cysitc fibrosis to schizophrenia), triacetyluridine could turn out to have tremendously utility as a nootropic.

In this article, I’ll examine triacetyluridine’s benefits, mechanisms of action, side effects, and more. At the end of the article, I’ll give you my recommendations for how to use uridine supplements and how to stack uridine with some of the best nootropics out there. As always, if you have questions, please post them in the comments section at the end and I’ll get right back to you.


What Is Triacetyluridine?

As I already mentioned above, triacetyluridine is a prodrug of uridine. To be exact, triacetyluridine is a tri-aceylated form of uridine. This means that there has been three acetyl funcitonal groups added to uridine. This is an extremely common process in drug manufacturing, as it makes compounds much more potent (for example, Heroin is diacetylmorphine, while Aspirin is acetylated Salicylic acid).

So in simple terms, triacetyluridine is uridine that has been acetylated to make it more bioavailable, just like with other common pharmaceutical drugs.

Triacetyluridine bioavailability comparison

You may hear triacetyluridine referred to as vistonuridine, or as some of its former brand names such as Xuriden or Vistoguard. These drugs were used to treat acute overdose from fluorouracil or capecitabine; two chemotherapy drugs. Vitoguard in particular appears to have been astoundingly successful for treating 5-FU or capecitabine toxicity, with up to 96% of patients surviving if treated within 96 hours of ending chemotherapy (compared to 16% survival rate before Vistoguard).


Triacetyluridine Benefits

Triacetyluridine is a much more bioavailable form of uridine. Therefore, when we are discussing the benefits of triactyluridine, we are really talking about the benefits of uridine itself; it is just that TAU gives us much more bang for our buck when supplementing that form of uridine.

So what are the benefits of using uridine? Is it a good nootropic? Does it promote brain health?

The existing clinical literature on triacetyluridine shows that supplementing may:

  1. Improve symptoms of depression and bipolar disorder[1][2]
  2. Have neuroprotective properties in the context of Huntington’s disease[3]
  3. Decrease neurodegeneration in patients with Alzheimer’s Disease, Huntington’s Disease, and dementia[4]
  4. Reduce neuroinflammation[4]

These are only the benefits found in clinical trials using triacetyluridine alone and not in conjunction with other nootropic agents, such as omega 3 fatty acids, a choline source, or any other supplements known to positively affect brain function.

Triacetyluridine benefits

But as I explained above, the benefits of triacetyluridine are really one and the same with the benefits of uridine. Thankfully, there is substantially more scientific evidence and detailed information on the benefits of uridine supplementation.

Proven benefits of uridine supplementation include: enhanced learning and memory function, reduced brain fog, greater mental energy, and ameliorated symptoms of cognitive decline including impairment caused by mild neurodegeneration. Uridine is a fairly potent nootropic with varied benefits in terms of brain health and performance. By extension, it seems that triacetyluridine is also a potent nootropic offering multifaceted brain benefits.

So how does it work?


Triacetyluridine Effects: How does it work?

The reason triacetyluridine is being investigated is because it appears to be so much more bioavailable than uridine.

But why is it so much more bioavailable than uridine?

The enhanced bioavailability of triacetyluridine comes down to the acetyl functional groups that have been attached to the molecule. Acetyl groups increases a compound’s lipophilicity, or its ability to dissolve in fats. Being more readily dissolved in fats makes a compound much easier to absorb in the intestine. In the case of TAU, the magnitude of the effect is immense; animal studies have found that “the relative bioavailability of plasma uridine from orally administered TAU was 7-fold greater than that achieved by an equimolar amount of oral uridine”[5].

A different study by the same authors found that triacetyluridine increased uridine plasma concentrations by 250-fold[6]. The researchers co-administered TAU with uridine phosphorylase, which is the enzyme responsible for uridine catabolism. They found that TAU was impervious to uridine phosphorylase, and that co-amdinistration led to a further 1.7 – 3.9 fold rise in plasma uridine concentrations.

The clinical literature therefore makes it quite clear that triacetyluridine is an exceptional uridine prodrug; far more powerful and efficient than uridine itself!

I’ve explained how triacetyluridine works; it is essentially just a more powerful, highly-bioavailable form of uridine. As such, it appears to offer all of the same benefits associated with uridine, just with a faster, more efficient delivery mechanism.

But how does uridine actually work?

How Uridine Works

Uridine is a ribonucleotide which your body uses to construct RNA. Along with adenosine, thymidine, cytidine and guanosine, uridine is one of the five standard nucleosides which make up nucleic acids.

As the primary messenger used to decode information in DNA, RNA is a vital component in the growth of new cells and the proper functioning of existing cells. By increasing uridine availability, you can increase RNA availability and optimize the growth, proliferation and function of your existing cells.

Studies have found that supplementing with uridine stimulates the growth of specific structures in the central nervous system. In one study conducted on rodents, researchers found that supplementation with uridine increased neurite outgrowth by a significant degree[7]. Increases in neurite outgrowth were accompanied by increases in neurite branching; that is, the number of branches connecting one neuron to another increased.

It is thought that this effect is caused by several different observed effects of uridine: an increase in phosphatidylcholine synthesis, an increase in intracellular levels of cytidine triphosphate, the accumulation of inositol phosphates, and its acting as a P2Y receptor agonist[7]. The idea that uridine works by accelerating the synthesis of synaptic proteins and phosphatides is supported by studies looking at uridine and DHA (docosahexaenoic acid) stacks[8].


Triacetyluridine Dosage

How much triacetyluridine should you be using?

Triacetyluridine dosage

The correct triacetyluridine dosage for the vast majority of people is going to be under 50mg per day. Most users take 25mg 1-2 times daily depending on their goals and how much they are affected.

This is considerably less than the dosage recommended for uridine monophosphate (100-250mg per day). This is because uridine monophosphate is nowhere near as bioavailable as uridine triacetate.

The half-life of triacetyluridine is roughly 2 hours. Peak plasma concentration of uridine occurs 2-3 hours after oral administration of triacetyluridine. Exact half-life depends on the health of your liver and its ability to process uridine. No differences in elimination half-life have been observed between fed and fasted states[9].


Triacetyluridine Side Effects

Triacetyluridine is generally well tolerated by the vast majority of users. Uridine is a naturally occurring compound; it is found in beer, tomatoes, sugarcane, and even human breast milk. It is present in the cells of all living organisms. As such, it is unlikely to cause adverse effects when consumed at sensible doses. There are no long-term health risks associated with uridine supplementation. All of this applies to tiacetyluridine, as the acetyl groups merely increase lipophilicity and do not substantially change the action of uridine in the body.

A very small number of users have experienced acute nausea, vomiting and diarrhea from triacetyluridine. However, these are dose-dependent side effects; they normally occur when an individual is given a very large dose to counteract fluorouracil or capecitabine overdose/toxicity. For regular nootropics users taking the recommended doses, side effects are highly unlikely.


How To Stack Triacetyluridine and Nootropics

Triacetyluridine is a very general nootropic in terms of its effects and benefits. It promotes neurite outgrowth and prevents neurodegeneration. Obviously, such effects are going to promote overall cognitive performance and good brain health over the long-term. That means triacetyluridine users can expect improved memory function, sharper focus, and attenuated cognitive impairment.

While Citicoline is partly composed of uridine, the low bioavailability of the standard form of the molecule means citicoline is unlikely to raise uridine levels by a substantial margin. As such, if you really want to maximize neurite outgrowth and branching, triacetyluridine is your best bet.

How to stack uridine nootropics

If neurite outgrowth and dendrite branching is your goal, then you are obviously concerned primarily with neuroplasticity; the brain’s ability to adapt to higher cognitive demands by revamping physical brain architecture (synapses, neurons, dendrites, etc.). For maximizing neuroplasticity, I strongly recommend stacking triacetyluridine with other nootropics which promote brain adaptations and development along different pathways.

A great stack for neuroplasticity would be Bacopa monnieri, Lion’s Mane Mushroom, Citicoline, DHA, and Triacetyluridine. This would increase nerve growth factor (NGF), encourage dendrite branching, reduce neuroinflammation, protect brain cells from trauma, and support healthy brain cell development over the long-term.

It would also enhance cognitive function in the short to medium term, helping to counter symptoms of ADHD/ADD, promoting motivation through dopamine potentiation, and enhancing learning via multiple pathways.


References

[1] Kondo DG, Sung YH, Hellem TL, et al. Open-label uridine for treatment of depressed adolescents with bipolar disorder. J Child Adolesc Psychopharmacol. 2011;21(2):171-175. doi:10.1089/cap.2010.0054

[2] Jensen JE, Daniels M, Haws C, Bolo NR, Lyoo IK, Yoon SJ, Cohen BM, Stoll AL, Rusche JR, Renshaw PF. Triacetyluridine (TAU) decreases depressive symptoms and increases brain pH in bipolar patients. Exp Clin Psychopharmacol. 2008 Jun;16(3):199-206. doi: 10.1037/1064-1297.16.3.199. PMID: 18540779.

[3] Saydoff JA, Garcia RA, Browne SE, Liu L, Sheng J, Brenneman D, Hu Z, Cardin S, Gonzalez A, von Borstel RW, Gregorio J, Burr H, Beal MF. Oral uridine pro-drug PN401 is neuroprotective in the R6/2 and N171-82Q mouse models of Huntington’s disease. Neurobiol Dis. 2006 Dec;24(3):455-65. doi: 10.1016/j.nbd.2006.08.011. Epub 2006 Sep 29. PMID: 17011205.

[4] Saydoff J, Sheng JG, Hu Z, et al. [P-188]: PN401 decreases neurodegeneration in models of Alzheimer’s, Huntington’s and Parkinson’s disease, neuroinflammation, excitotoxicity and has antiepileptic activity. Alzheimer’s & Dementia. July 2005:S68-S68. doi:10.1016/j.jalz.2005.06.247

[5] Ashour OM, Naguib FN, el Kouni MH. 5-(m-Benzyloxybenzyl)barbituric acid acyclonucleoside, a uridine phosphorylase inhibitor, and 2′,3′,5′-tri-O-acetyluridine, a prodrug of uridine, as modulators of plasma uridine concentration. Implications for chemotherapy. Biochem Pharmacol. 1996 Jun 28;51(12):1601-11.

[6] Ashour OM, Naguib FN, Goudgaon NM, Schinazi RF, el Kouni MH. Effect of 5-(phenylselenenyl)acyclouridine, an inhibitor of uridine phosphorylase, on plasma concentration of uridine released from 2′,3′,5′-tri-O-acetyluridine, a prodrug of uridine: relevance to uridine rescue in chemotherapy. Cancer Chemother Pharmacol. 2000;46(3):235-40.

[7] Pooler AM, Guez DH, Benedictus R, Wurtman RJ. Uridine enhances neurite outgrowth in nerve growth factor-differentiated PC12 [corrected]. Neuroscience. 2005;134(1):207-14. doi: 10.1016/j.neuroscience.2005.03.050. Erratum in: Neuroscience. 2005;135(2):657. PMID: 15939540.

[8] Wurtman RJ, Cansev M, Ulus IH. Synapse formation is enhanced by oral administration of uridine and DHA, the circulating precursors of brain phosphatides. J Nutr Health Aging. 2009 Mar;13(3):189-97. doi: 10.1007/s12603-009-0056-3. PMID: 19262950.

[9] Cada DJ, Mbogu U, Bindler RJ, Baker DE. Uridine Triacetate. Hospital Pharmacy. June 2016:484-488.

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