NMN with TMG: Benefits, Dosage and Risks

If you’ve been looking into nicotinamide mononucleotide (NMN) supplements, you’ve probably come across recommendations for taking it with trimethylglycine (TMG).

This idea comes from a theory that NMN might use up methyl groups—key biochemical components your body needs for many functions.

But do you really need to take both together? Does the research actually back this up?

In this article, we’ll break down the relationship between NMN and methylation, look at the potential pros and cons of combining these supplements, and give you practical advice on dosing.

NMN and TMG: What Are They?

NMN is a direct precursor to nicotinamide adenine dinucleotide (NAD+), a key coenzyme that drives hundreds of biological processes in your cells.

NAD+ helps with energy production, DNA repair, gene expression, and cellular communication—all functions that decline as we age when NAD+ levels naturally drop.

NMN works by entering cells and turning directly into NAD+ through an enzyme reaction that does not directly consume methyl groups. This efficient conversion makes NMN one of the most promising supplements for maintaining NAD+ levels and supporting cellular health as we get older.

TMG, also known as betaine, is a methyl-rich compound that helps support methylation—a key biochemical process that affects everything from gene expression to detoxification.

You can find TMG naturally in beets, spinach, and whole grains. Its main job is to help convert homocysteine back to methionine, which then produces S-adenosylmethionine (SAMe), the body’s universal methyl donor.

This recycling function makes TMG valuable for keeping methylation balanced, especially when your body’s metabolic demands go up or when you’re not getting enough methyl sources from your diet.

Why Some People Take NMN and TMG Together

The main reason for combining NMN with TMG is to keep methylation balanced during NAD+ metabolism.

While NMN doesn’t directly use up methyl groups when it turns into NAD+, the processes that follow might indirectly affect the body’s methylation capacity.

This is the basic process that some researchers and supplement users are concerned about:

1. NMN turns into NAD+ without using methyl groups
2. Enzymes like sirtuins and PARPs use up NAD+ during normal cell functions
3. This releases nicotinamide (NAM) as a byproduct
4. When there’s too much NAM to recycle back to NAD+, the body clears the excess through methylation
5. This clearing process uses S-adenosylmethionine (SAMe), which can drain methyl reserves

The NNMT enzyme helps with this clearing by moving a methyl group from SAMe to NAM, creating methylnicotinamide that the body can excrete. Some speculate that taking high doses of NMN could speed up this cycle, potentially putting strain on methyl donor reserves over time.

Benefits of NMN and TMG Supplementation

While experts still debate whether these supplements need to be taken together, there are several good reasons to pair TMG and NMN. The benefits go beyond just fixing theoretical methylation issues – they might work together to support health and longevity.

Supporting Healthy Methylation

As we’ve explored, NMN doesn’t directly use up methyl groups when it turns into NAD+, but the way NAD+ breaks down later might indirectly increase the need for methylation.

People with MTHFR gene variants (which can reduce methylation capacity by 30-70%) might also react differently to NMN supplements and could benefit more from TMG co-supplementation.

TMG works as a safety net by:

• Providing extra methyl groups to support this clearance process
• Helping recycle homocysteine back to methionine, which then creates SAMe
• Potentially preventing high homocysteine levels, a marker linked to poor methylation

Promoting Heart Health and Metabolism

Beyond methylation, both NMN and TMG offer heart and metabolic benefits that may complement each other when taken together.

NMN works by raising NAD+ levels, which are vital for metabolism, DNA repair, and stress responses. This NAD+ boost has been linked to improvements in obesity, diabetes, and heart failure.

NMN research shows it can improve cardiac function in aging hearts by fixing age-related heart problems and boosting mitochondrial health. ¹ It also helps restore heart function in cardiomyopathy models by activating SIRT3, a mitochondrial protein deacetylase. ²

TMG helps convert homocysteine to methionine, which can lower plasma homocysteine by up to 20% in one study. ³ This matters because high homocysteine is a risk factor for heart disease.

In animal studies, TMG increases bile acid secretion and normalizes lipid metabolism, which may help turn cholesterol into bile acids and reduce atherosclerosis. ⁴

Enhancing Physical Performance

The combination of TMG and NMN might work together to boost physical performance and help you recover faster—areas that can benefit both athletes and older adults.

Research with older adults shows NMN supplements can help increase muscle strength and improve aerobic capacity. In a six-week clinical trial, people taking moderate to high doses of NMN showed better oxygen uptake and improved power compared to those taking a placebo⁵.

Researchers think NMN helps aerobic capacity by improving how muscles use oxygen during activity.

Athletes have also used TMG (often labeled betaine in sports supplements) to boost power output and increase their training volume.

Studies show it can help build lean muscle and reduce body fat when combined with resistance training. ⁶ Its role in supporting methylation might also speed up recovery by helping cells repair themselves after exercise.

Improving Cognitive Function

The brain consumes about 20% of our energy while only making up 2% of our body weight. This high energy demand makes brain cells highly dependent on efficient NAD+ metabolism.

Studies in animals show NMN supplementation improves cognitive function in models of Alzheimer’s disease and age-related cognitive decline. ^{7 8} Human research is still limited, but early findings suggest NMN might support cognitive aspects like processing speed and executive function.

TMG (as betaine) shows potential to protect the brain through its antioxidant and anti-inflammatory effects, with promising research in Alzheimer’s models.

Studies show betaine prevents memory problems while lowering brain levels of malondialdehyde (MDA), an important marker of oxidative damage. ⁹ This suggests TMG might help shield brain cells from the oxidative stress that comes with aging and neurodegenerative conditions.

The Right TMG Dosage with NMN

The evidence shows a 1:1 ratio of TMG to NMN works well for most people. This ratio appears to strike the right balance between NAD+ synthesis and methyl group replenishment, based on available information. Most people who take NMN use between 250-1000 mg per day, with matching TMG doses in the same range.

When to Take TMG and NMN

Timing considerations can impact how well NMN and TMG supplements work:

• Morning with food: Take both NMN and TMG in the morning with breakfast. This works with your body’s natural rhythms and helps you absorb them better while supporting your energy levels all day.
• With meals: Some NAD+ precursors might work better on an empty stomach, but taking NMN and TMG with food can help prevent stomach discomfort and might actually improve absorption, especially for TMG.
• Daily routine: Taking these supplements at the same time each day helps maintain steady levels of both compounds in your system, which likely optimizes their effects on NAD+ levels and methylation balance.

Potential Risks and Side Effects

While both NMN and TMG have good safety profiles when used appropriately, there are some potential downsides to consider when combining them.

The most common side effects are digestive issues:

• NMN sometimes causes mild nausea or bloating, especially at higher doses
• TMG can cause temporary stomach discomfort
• Taking these with food often helps reduce these effects

Excessive methylation from high TMG doses can throw off your neurotransmitter balance, which might affect your mood and thinking. This risk is pretty small with standard doses (500-1000 mg of TMG daily) but could matter if you’re taking several methyl donors at once.

You should also be careful and consult with a healthcare provider if you have:

• Liver problems (TMG plays a role in liver metabolism)
• Existing methylation disorders
• A history of cancer

Medication interactions are possible with antifolate drugs like methotrexate, certain antidepressants, and medications metabolized through methylation pathways.

As with any supplements, it’s best to start with lower doses and check with your doctor about possible interactions to get the most benefit with the least risk.

Should You Take TMG with NMN?

The science suggests most people taking standard NMN doses (250-500mg daily) probably don’t need extra TMG.

You might want to add TMG if you:

• Take high doses of NMN (750-1000mg+ daily) for a long time
• Have genetic variations that affect methylation (like MTHFR variants)
• Have high homocysteine levels in your blood tests
• Feel unexplained fatigue or notice cognitive changes when taking NMN alone

If you don’t have these factors, NMN by itself is likely fine. Your body can usually maintain enough methylation capacity to handle standard NMN doses.

If you’re worried about methylation but want alternatives to TMG, you can:

• Make sure you’re getting enough B-vitamins (especially folate, B6, and B12)
• Eat foods that support methylation like leafy greens, legumes, and eggs
• Take moderate doses of methylfolate or methylcobalamin
• Regularly test your methylation markers to keep track of your status

Most people taking standard doses of NMN do well without TMG. The concerns about methyl depletion haven’t really been proven in typical supplementation at normal doses.

If you want a science-backed approach to boost NAD+, Jinfiniti’s Vitality ↑® NAD+ Booster Powder offers a balanced mix of NMN, D-ribose, niacinamide, and creatine monohydrate. These compounds work together to support cellular energy and NAD+ levels without needing extra methylation support.

If you’d rather take the guesswork out, you can pair Vitality ↑® with our Intracellular NAD® Test to measure your actual NAD levels and adjust your supplements based on real data instead of theoretical concerns.

Frequently Asked Questions

Do you need to take TMG with NMN?

No, most people don’t need TMG with standard NMN doses (250-500mg daily). TMG may be beneficial for those taking high NMN doses (750mg+), individuals with MTHFR gene variants, or those with elevated homocysteine levels. For the average person, NMN alone is typically sufficient.

How does TMG compare with other methyl donors?

TMG (trimethylglycine) is just one of several methyl donors. Compared to alternatives:

• SAM-e: More potent and direct as a methyl donor but significantly more expensive and less stable than TMG
• Folate: Works synergistically with B12 to support methylation through a different pathway than TMG
• Betaine: TMG is actually betaine anhydrous, so they’re essentially the same compound with identical effects

Each has different absorption profiles and mechanisms, but TMG offers a good balance of effectiveness, stability, and value for methylation support.

Can you take NMN and TMG with resveratrol?

NMN, TMG and resveratrol can be taken together safely. The NMN and resveratrol combo is popular among longevity enthusiasts because resveratrol helps activate sirtuins while NMN supplies the NAD+ that sirtuins need to work. These supplements don’t have any known negative interactions, and they might actually work well together to give you better results.

Does Dr. David Sinclair take TMG?

Dr. David Sinclair mentions in podcasts that he takes TMG with his NMN supplements. He includes TMG in his routine to play it safe about NMN possibly affecting the body’s methylation processes. This shows his careful approach, though scientists still debate whether it’s actually needed.

Referenced Sources:

1. https://onlinelibrary.wiley.com/doi/10.1111/acel.13213 ↩︎
2. https://pubmed.ncbi.nlm.nih.gov/28724806/ ↩︎
3. https://www.eurekaselect.com/article/5318 ↩︎
4. https://pubmed.ncbi.nlm.nih.gov/3620644/ ↩︎
5. https://pmc.ncbi.nlm.nih.gov/articles/PMC8265078/ ↩︎
6. https://www.sciencedirect.com/science/article/abs/pii/B9780128139226000606 ↩︎
7. https://www.sciencedirect.com/science/article/pii/S0753332224010837 ↩︎
8. https://pubmed.ncbi.nlm.nih.gov/31015147/ ↩︎
9. https://pmc.ncbi.nlm.nih.gov/articles/PMC10427792/ ↩︎