Uridine (uridine monophosphate)

What uridine is

Uridine is a nucleoside made of the base uracil and the sugar ribose. The body produces it itself; it is found in breast milk, according to the Danish food authority at 2.2 mg per kilogram, and in most foods mainly as a component of RNA. As a food supplement, uridine 5′-monophosphate, UMP for short, is usually sold, often as the disodium salt.

Uridine is also encountered indirectly: citicoline is split in the body into choline and cytidine, and the cytidine is converted into uridine in humans. In infant formula, uridine monophosphate is permitted as one of five authorized nucleotide additives.

How it works

To build phosphatidylcholine, the nerve cell needs three ingredients from the blood: choline, a pyrimidine source such as uridine, which becomes CTP via UTP, and a polyunsaturated fatty acid such as DHA. Wurtman’s group showed in gerbils, whose pyrimidine metabolism resembles that of humans, that more of these precursors allows more membrane to form: phosphatidylcholine in the brain rose by 13 to 22 percent with uridine and choline or with DHA alone, and by 45 percent with all three. The synaptic proteins synapsin-1 and PSD-95 increased by 41 and 38 percent. In addition, UTP activates so-called P2Y receptors.

This is the basis of the combination of uridine, choline and omega-3 fatty acids known in the scene as the synapse stack. Whether more synapses form in humans as a result has not been measured. What was measured were memory tests, EEG and brain volume, and only under the mixture Fortasyn Connect.

What the studies show

Souvenir I (Scheltens 2010) – mild Alzheimer’s disease, 12 weeks

225 patients without Alzheimer’s medication drank Souvenaid or a control drink daily. On delayed recall of a word list, one of the two primary endpoints, the Souvenaid group was ahead after 12 weeks (p = 0.021). The second primary endpoint, an Alzheimer’s cognition test, and all other measures such as daily functioning and quality of life remained unchanged.

Souvenir II (Scheltens 2012) – mild Alzheimer’s disease, 24 weeks

Confirmatory trial in untreated patients with mild Alzheimer’s disease. The memory score of a neuropsychological test battery rose more over 24 weeks than under control (p = 0.023; Cohen’s d = 0.21). The EEG showed differences in functional connectivity in favour of the active group; for the overall score of the test battery there was only a trend (p = 0.053).

S-Connect (Shah 2013) – moderate Alzheimer’s disease under medication

527 patients who were already taking Alzheimer’s medication received Souvenaid or a control drink for 24 weeks. Cognitive performance declined equally in both groups, a difference of 0.37 points on the cognition test (p = 0.513). Side effects and blood values did not differ. The trial describes the mixture: uridine monophosphate, choline, phospholipids, EPA, DHA, vitamins E, C, B12 and B6, folic acid and selenium.

LipiDiDiet (Soininen 2017 and 2021) – early Alzheimer’s disease, up to 36 months

311 people with prodromal Alzheimer’s disease, that is, memory impairment without dementia, were assigned to Fortasyn Connect or a control drink; the trial was publicly funded. After 24 months, the primary endpoint missed significance (difference 0.098; p = 0.166), because the control group also declined much more slowly than expected. After 36 months, decline in the test score was 60 percent lower (p = 0.014), and on the dementia severity measure CDR-SB 45 percent lower (p = 0.014); only 81 participants with 36-month data were still included in this analysis.

Cochrane 2020 – Souvenaid in Alzheimer’s disease

Three randomized trials with 1,097 participants, with low risk of bias, two of them funded by the manufacturer. In early Alzheimer’s disease, there were not fewer cases of dementia after 24 months (RR 1.09; 95 % CI 0.82 to 1.43). For cognitive performance there was probably little or no difference; for combined measures of thinking and daily functioning the results were contradictory. Side effects were rare; the data were not sufficient for a statement on long-term tolerability.

Kondo 2011 – uridine alone in depression

The only human study found with uridine as a single substance in the neuropsychiatric field: an open-label case series with seven depressed adolescents with bipolar disorder, six weeks. The depressive symptoms declined, and uridine was well tolerated. Without a control group, no effect can be inferred from this.

Where the data stop

The gap is fundamental: all controlled human studies tested a mixture of eleven nutrients. What share uridine has in the result has not been investigated, nor whether uridine with choline and omega-3 alone achieves the same. For healthy people who want to improve their memory or concentration, there is not a single study.

The Alzheimer’s data are not clear-cut either. Positive memory findings come from short trials in mild disease, the largest trial under medication was negative, and the favourable 36-month finding from LipiDiDiet rests on a greatly shrunken group. That more synaptic proteins form in animals is a surrogate, not proof of better brain performance.

Status, approval and legal

Uridine is not a medicine in Germany. Souvenaid is marketed as a medical food for people with early Alzheimer’s disease. In infant formula, uridine 5′-monophosphate is permitted up to 1.75 mg per 100 kcal (Commission Delegated Regulation (EU) 2016/127).

For food supplements, there is no official maximum amount and no authorized health claim. In 2020 the Danish food authority had uridine monophosphate assessed as a new nutrient for food supplements; the National Food Institute of the Technical University of Denmark could not rule out a health risk at 300 mg per day, because safety studies are lacking.

Safety

Harmful effects of uridine have not been described in the literature, but there are also hardly any data that would have looked for them. The Danish food institute found only a limited acute toxicity study in rodents; studies in animals with repeated dosing or in healthy people were not available. The Souvenaid trials with 625 mg of uridine monophosphate daily over up to 24 weeks showed no accumulation of side effects, but they were not designed to detect safety problems and were conducted in older patients, not in the general population.

Anyone who has depression or bipolar disorder or takes psychiatric medication should discuss uridine with a physician; the only data in this area come from a case series with seven adolescents. There are no studies on pregnancy and breastfeeding.

Sources

• Wurtman RJ et al., Brain Res 2006 – uridine, choline and DHA increase synaptic proteins in the gerbil brain (PMID 16631143)
• Scheltens P et al., Alzheimers Dement 2010 – Souvenir I, 225 patients with mild Alzheimer’s disease (PMID 20129316)
• Scheltens P et al., J Alzheimers Dis 2012 – Souvenir II, 24 weeks (PMID 22766770)
• Shah RC et al., Alzheimers Res Ther 2013 – S-Connect, 527 patients on Alzheimer’s medication (PMID 24280255)
• Soininen H et al., Lancet Neurol 2017 – LipiDiDiet, 24 months in prodromal Alzheimer’s disease (PMID 29097166)
• Soininen H et al., Alzheimers Dement 2021 – LipiDiDiet, 36 months (PMID 32920957)
• Burckhardt M et al., Cochrane Database Syst Rev 2020 – Souvenaid in Alzheimer’s disease (PMID 33320335)
• Kondo DG et al., J Child Adolesc Psychopharmacol 2011 – open-label case series with uridine in bipolar depression (PMID 21486171)
• DTU Fødevareinstituttet 2020 – Risikovurdering af uridin i kosttilskud (risk assessment of uridine in food supplements)
• Commission Delegated Regulation (EU) 2016/127 – permitted nucleotides in infant formula