2 days ago

david 4.4k

@david_fe

One of our members asked about the combination of berberine and citicoline for neuroprotection. This post is a response to those specific questions.

Is berberine for liver or kidney protection? I can't remember which.

It’s for cardiovascular protection.

Here are more details for those who are interested. (If you don't care about these details, skip to my next response below.) That cardiovascular concern relates to things that increase TMAO, which include choline, citicoline, carnitine, ALCAR, phosphatidylcholine, lecithin, TMG (betaine), ergothioneine, meat, eggs and a few less common things. (Among all of those citicoline appears increase TMAO the least, while carnitine raises it the most.)

Berberine is highly effective for stopping this TMAO increase. Berberine also offers neuroprotection. Other studies suggest that may promote weight loss by reducing body fat and inhibiting the growth of fat cells, may contribute to improved heart health by lowering cholesterol and triglyceride levels, and shows strong potential for managing blood sugar levels.

You may have heard some people dispute that TMAO is a problem — but they are almost certainly wrong. The current medical consensus is that TMAO is indeed a cardiovascular risk predictor. Strong epidemiological evidence suggests TMAO elevation reflects cardiovascular risk. Research is ongoing, and we cannot say whether elevated TMAO is a biomarker or a causative agent, but in either case it is smart to avoid elevated TMAO, especially the type created by gut bacteria.

The key to this is modulating the TMA-producing gut bacterial species, and berberine is highly effective for this. Berberine is good for gut in general.

Combined citicoline and berberine supplementation offers complementary neuroprotective mechanisms that could theoretically enhance cognitive function through distinct but synergistic pathways. Both compounds have favorable safety profiles with high tolerability.

I can only tolerate 500 mg. of berberine

Overall, berberine has an outstanding safety profile. The main side effects are related to digestion, and there are some reports of diarrhea, constipation, and bloating. These potential side effects are dose dependent. Lower doses of berberine stimulated beneficial Lachnospiraceae bacteria without causing digestive side effects. It sounds like you found the right dose of berberine for yourself.

I won’t be able to take 2000mg of citicoline.

That’s fine. Not everyone needs to take a dose equal to the upper range used in the studies. For some people, 2000mg per day of citicoline is an optimal target, but for others that may be too much. Everyone is individual. However, citicoline has a great safety profile.

Or is citicoline that important?

Absolutely, citicoline is that important. (More details are given below.)

Is there some other supplement that I could use instead of the berberine?

Yes. While berberine is considered the most efficacious in this context, you can also try one or more of the following:

• PQQ (however, the effect is indirect)
• Green tea polyphenols
• Specific probiotic strains (e.g., Bifidobacterium and Lactobacillus species)
• Plant-based dietary patterns

There’s no reason a person couldn’t combine several or all these things. And if you cannot tolerate a higher dose of berberine, just use a dose that works best for your body. 

As I stated above, of all the supplements that may raise TMAO, citicoline appears to be the safest.

You do not have to take berberine or any of the other supplements mentioned above (PQQ, green tea, etc.). If you did not want to take any of the other things I suggested above, it appears that taking citicoline alone is very safe -- much safer and more efficacious than even lecithin, for example.

However, a strong reason for preferring the combination of berberine and citicoline is that combined citicoline and berberine supplementation offers complementary neuroprotective mechanisms that could theoretically enhance cognitive function and visual function through distinct but synergistic pathways. Citicoline primarily supports membrane synthesis and neurotransmitter production, while berberine provides anti-inflammatory, antioxidant, and metabolic modulation.

Citicoline's primary mechanisms include enhancing phosphatidylcholine synthesis for neuronal membrane repair, increasing acetylcholine availability, stabilizing cellular membranes to reduce glutamate excitotoxicity, and elevating SIRT1 levels to reduce neuroinflammation.[[1]][[2]] Clinical evidence demonstrates citicoline's efficacy in preventing dementia progression, improving post-stroke prognosis, and enhancing cognitive functions in both healthy individuals and those with mild cognitive impairment.[[3]][[4]]

Berberine's neuroprotective actions operate through multiple complementary pathways: attenuation of oxidative stress via upregulation of antioxidant enzymes, mitigation of neuroinflammation, modulation of signaling pathways, bidirectional regulation of autophagy, and promotion of angiogenesis.[[5]][[6]][[7]] Berberine also increases choline levels in the brain, which could theoretically enhance citicoline's acetylcholine-boosting effects.[[8]] Animal studies demonstrate berberine's ability to preserve hippocampal structure, reduce blood-brain barrier permeability, and improve both short- and long-term memory following ischemic injury.[[9]]

Potential synergies include:

- Overlapping SIRT1 activation: Both compounds upregulate SIRT1, potentially providing additive anti-inflammatory and neuroprotective effects[[1]][[10]]
- Complementary antioxidant mechanisms: Citicoline reduces free radical production while berberine enhances endogenous antioxidant enzyme activity[[1]][[9]]
- Dual cholinergic support: Citicoline directly provides substrate for acetylcholine synthesis while berberine increases brain choline availability[[8]]
- Shared PI3K/Akt pathway modulation: Both compounds activate this pro-survival pathway through different upstream mechanisms[[6]][[10]]
- Combined membrane and metabolic protection: Citicoline stabilizes membranes while berberine addresses mitochondrial dysfunction and metabolic dysregulation[[1]][[5]]

References

1. Unveiling Citicoline's Mechanisms and Clinical Relevance in the Treatment of Neuroinflammatory Disorders. Cavalu S, Saber S, Ramadan A, et al. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2024;38(17):e70030. doi:10.1096/fj.202400823R.
2. The Role of Neuro-Supportive Substances of Natural Origin in Neurological Conditions-a Literature-Based Formulators' Perspective. van Brummelen R, van Brummelen AC. Frontiers in Neurology. 2025;16:1647092. doi:10.3389/fneur.2025.1647092.
3. Application of Citicoline in Neurological Disorders: A Systematic Review. Jasielski P, Piędel F, Piwek M, et al. Nutrients. 2020;12(10):E3113. doi:10.3390/nu12103113.
4. Is Citicoline Effective in Preventing and Slowing Down Dementia?-a Systematic Review and a Meta-Analysis. Bonvicini M, Travaglini S, Lelli D, Antonelli Incalzi R, Pedone C. Nutrients. 2023;15(2):386. doi:10.3390/nu15020386.
5. Neuroprotective Properties of Berberine: Molecular Mechanisms and Clinical Implications. Tian E, Sharma G, Dai C. Antioxidants (Basel, Switzerland). 2023;12(10):1883. doi:10.3390/antiox12101883.
6. Berberine: Pathways to Protect Neurons. Lin X, Zhang N. Phytotherapy Research : PTR. 2018;32(8):1501-1510. doi:10.1002/ptr.6107.
7. Neuroprotective Effect and Preparation Methods of Berberine. Sunhe YX, Zhang YH, Fu RJ, Xu DQ, Tang YP. Frontiers in Pharmacology. 2024;15:1429050. doi:10.3389/fphar.2024.1429050.
8. Anti-Neurodegenerative Treatment In Alzheimer's Disease: Multifaceted Mechanisms of Action of Berberine. Song D, Zhang C. International Journal of Clinical Pharmacology and Therapeutics. 2025;:192119. doi:10.5414/CP204725.
9. Effect of Berberine on the Hippocampal Structure, Biochemical Factors, Memory, and Blood-Brain Barrier in Rat Model of Transient Global Cerebral Ischemia. Mehboodi D, Shahedi A, Namavar MR, Yadegari M, Vakili M. Phytotherapy Research : PTR. 2024;38(8):4230-4239. doi:10.1002/ptr.8234.
10. The Efficacy and Mechanism of Berberine in Improving Aging-Related Cognitive Dysfunction: A Study Based on Network Pharmacology. Yao J, Wei W, Wen J, Cao Y, Li H. Frontiers in Neuroscience. 2023;17:1093180. doi:10.3389/fnins.2023.1093180.