NAD+: Benefits, Supplements, and How to Restore It

NAD+ (nicotinamide adenine dinucleotide) is a molecule found in every cell of your body. It powers over 500 different cellular reactions — from converting food into energy, to repairing DNA, to regulating the proteins that control aging.

The problem: NAD+ levels drop by roughly 50% between your 20s and your 50s, according to tissue studies in humans and animal models (Covarrubias 2019). When this happens, the systems that depend on NAD+ start to fail — energy production slows, DNA damage accumulates, and the proteins that keep cells young go offline.

This guide explains what NAD+ does, why it declines, what the benefits of restoring it are, and how to choose between oral supplements (NMN vs NR) and IV/injection therapy.

What Is NAD+ and Why Does It Matter?

Think of NAD+ as cellular currency. Every time your cells need to do something that requires energy or involves repair, they spend NAD+.

NAD+ does three critical jobs:

1. Energy Production

NAD+ carries electrons into your mitochondria — the power plants inside your cells — to produce ATP (the energy molecule that powers everything). Without enough NAD+, your mitochondria can't generate energy efficiently.

When NAD+ runs low, two things happen:

• Energy output drops (you feel tired, recovery slows)
• Your mitochondria produce more "exhaust" — reactive oxygen species (ROS) that damage cells

2. DNA Repair

Your DNA gets damaged thousands of times per day from stress, sun exposure, and normal metabolism. Repair enzymes called PARPs fix this damage, but they consume massive amounts of NAD+ to do their job.

During chronic stress or inflammation, PARPs run constantly — like emergency generators that never shut off — draining your NAD+ reserves.

3. Longevity Proteins (Sirtuins)

Sirtuins are enzymes that control whether your cells invest in long-term repair or just survive day-to-day. They regulate:

• Mitochondrial function
• Inflammation control
• Circadian rhythms (your internal clock)
• Gene expression for healthy aging

But sirtuins need NAD+ as fuel. When NAD+ levels drop, sirtuins go offline — and your cells shift from "repair and regenerate" mode to "bare survival" mode.

NAD+ Benefits: What You Can Expect

If you're considering NAD+ supplementation or therapy, here's what the research and clinical experience show:

Energy and Fatigue

NAD+ is the foundation of cellular energy production. When levels are restored:

• ATP production increases
• Mitochondria work more efficiently
• The "brain fog" that comes from low cellular energy often lifts

This isn't a stimulant effect like caffeine. It's more like your baseline capacity returning to what it used to be.

Cognitive Function

Your brain is one of the most energy-demanding organs. Low NAD+ means neurons can't produce enough ATP, leading to:

• Poor concentration
• Mental fatigue
• Slower processing

NAD+ restoration supports neuronal energy production and may help with focus, mental clarity, and memory. Some research suggests it also promotes neuroplasticity — the brain's ability to form new connections.

Sleep and Circadian Rhythm

NAD+ levels naturally oscillate over a 24-hour cycle, rising during the day and falling at night. This rhythm helps set your internal clock.

When NAD+ levels are chronically low, this oscillation flattens — which disrupts sleep architecture and hormonal rhythms. Restoring NAD+ can help re-synchronize your circadian timing, leading to:

• More restorative sleep
• Better morning alertness
• More consistent daily energy

Recovery and Tissue Repair

Tissue repair is one of the most energy-intensive processes in your body. Healing requires:

• Massive ATP production
• Active DNA repair
• New cell growth

Without adequate NAD+, healing stalls — wounds close slowly, inflammation lingers, and recovery drags on. NAD+ restoration often helps when other recovery protocols aren't progressing.

Inflammation Control

Sirtuins (which need NAD+ to function) act as brakes on inflammation. When NAD+ is low:

• Sirtuins can't restrain inflammatory signaling
• NF-κB (a key inflammatory switch) stays active
• Chronic low-grade inflammation persists

Studies show that NAD+ supplementation can reduce inflammatory markers like IL-6 and TNF-α — which may explain improvements in joint pain, autoimmune symptoms, and general inflammation.

Timeline of Effects

Why NAD+ Declines With Age

NAD+ doesn't just decline randomly. There are specific mechanisms that drain it:

Age-Related Decline

By age 50, most people have about half the NAD+ they had at 20. This happens because:

• Production slows (the enzymes that make NAD+ become less active)
• Consumption increases (more damage to repair, more inflammation to manage)

Chronic Inflammation Drains NAD+

Three processes accelerate NAD+ depletion:

CD38 (The Drain)
CD38 is an enzyme that breaks down NAD+. During chronic inflammation, CD38 expression increases substantially — studies show 200-300% higher NADase activity in aged or inflamed tissues (Chini 2018, Camacho-Pereira 2016). Senescent cells accumulate with age and secrete inflammatory cytokines that upregulate CD38 on macrophages, creating a feed-forward loop: inflammation → more CD38 → faster NAD+ depletion → impaired sirtuin function → more inflammation.

PARP Overactivation (The Emergency Crew)
When DNA damage is constant (from stress, poor sleep, environmental toxins), PARP repair enzymes run 24/7, consuming NAD+ faster than you can make it.

Immune Cell Burn Rate
Activated immune cells burn through NAD+ at extremely high rates. When immune activation becomes chronic, this constant drain compounds the other losses.

The Vicious Cycle

Here's why NAD+ depletion tends to get worse over time:

1. Low NAD+ → Sirtuins can't restrain inflammation
2. More inflammation → More CD38 activity → Faster NAD+ breakdown
3. Lower NAD+ → Mitochondria produce less energy and more ROS
4. More ROS → More DNA damage → More PARP activation → Even faster NAD+ consumption

Each turn of this cycle makes the problem worse. This is why you can feel stuck — and why actively restoring NAD+ often breaks the cycle.

How to Restore NAD+: Your Options

There are three main approaches to raising NAD+ levels:

Oral Supplements: NMN vs NR

Both NMN (nicotinamide mononucleotide) and NR (nicotinamide riboside) are NAD+ precursors — molecules your body converts into NAD+ through natural pathways.

Note: Both require enzymatic conversion. The "fewer steps" argument for NMN is somewhat simplified — absorption and cellular uptake also matter, and NR has more human trial data.

What to expect from oral supplements:

• Gradual NAD+ elevation (not immediate)
• Peak effects at 600mg NMN or 1000mg NR — higher doses don't seem to help more
• Well-tolerated with minor GI side effects at high doses
• Effects plateau at 30-60 days (suggesting tissue saturation)

IV/IM NAD+ Therapy

Injectable NAD+ bypasses digestion and delivers the molecule directly into your bloodstream. This creates much higher peak levels than oral supplements can achieve.

IV NAD+:

• 500-1000 mg per session, infused over 2-4 hours
• Often done as a loading series (4-5 sessions over 2 weeks)
• Can produce noticeable effects within days
• Must be administered in a clinical setting
• Infusion can cause temporary discomfort (nausea, chest tightness) if done too fast

IM NAD+:

• 50-200 mg per injection
• Can be done 1-3 times per week
• Slower release than IV, fewer side effects
• Good for maintenance after IV loading
• Some people self-administer after initial supervision
• Use bacteriostatic water with sodium chloride (isotonic) to reduce injection site sting and prevent welts

Which Route Is Right for You?

Combined approach (most effective for severe depletion):

1. Weeks 1-4: IV loading (4-5 sessions)
2. During loading: Start oral NMN/NR at 300mg
3. Weeks 4-8: IM twice weekly + increase oral to 600mg
4. Week 8+: IM weekly or as needed + oral daily maintenance

Does NAD+ Actually Work? The Evidence

What Clinical Studies Show

Metabolic health:

• Oral NR (1000mg/day) reduced blood pressure by 5-10 mmHg in older adults
• NMN (250mg/day) improved insulin sensitivity in prediabetic women
• Multiple trials show improved muscle function and exercise capacity

Inflammation:

• NR supplementation reduced IL-6 and TNF-α within 6 weeks
• Reduced inflammatory markers correlate with improvements in joint pain and autoimmune symptoms

Post-viral fatigue:

• 52% responder rate in a small long COVID pilot trial (n=36) using NAD+ patches + low-dose naltrexone — promising but needs larger replication
• Improvements in energy, function, and quality of life scores reported

Neurodegenerative conditions:

• Early studies show promise for Parkinson's (improved alertness, reduced symptoms)
• Brain perfusion and cognitive trends improved in some trials
• NAD+ IV protocols are used in addiction recovery with reported benefits

Who Responds Best

People most likely to benefit from NAD+ restoration:

• Those with chronic fatigue or post-viral illness
• People over 40 with declining energy
• Those with high inflammation or autoimmune conditions
• People who've hit plateaus with other protocols
• Those recovering from injury or illness

People less likely to notice dramatic effects:

• Young, healthy individuals with good NAD+ levels already
• Those whose issues aren't related to cellular energy or inflammation

Realistic Expectations

NAD+ is not a magic bullet. It's a foundational intervention that:

• Restores the cellular environment needed for other processes to work
• Takes weeks to months for full effects
• Works best combined with sleep, exercise, and other basics
• May need to be maintained long-term

Think of it as restoring power to a building rather than installing new appliances. The power restoration doesn't do the work directly — it enables everything else to function.

NAD+ Side Effects and Safety

Oral NAD+ Supplements (NMN/NR)

NMN and NR have excellent safety profiles in studies up to 1-2 grams per day:

• Most common: mild GI upset at high doses
• No serious adverse events in clinical trials
• No liver toxicity or organ damage observed

IV NAD+

Side effects are rate-dependent (happen if infused too fast):

• Nausea
• Abdominal cramping
• Chest tightness or pressure
• Lightheadedness

These resolve by slowing the infusion. Thousands of IV NAD+ treatments have been administered with no serious adverse events reported in medical literature.

Who Should Be Cautious

Active cancer: NAD+ supports cell growth and DNA repair, which could theoretically benefit tumor cells. Consult your oncologist first.

Pregnancy/breastfeeding: Insufficient safety data.

Very high chronic doses: Some animal studies suggest extremely high nicotinamide could affect liver metabolism. Stick to studied dose ranges.

Frequently Asked Questions

How long does it take to feel NAD+ working?

With IV therapy, many people notice something within the first week. With oral supplements, effects typically build over 2-4 weeks and plateau around 6-8 weeks.

Is NMN or NR better?

Both work. NMN is one step closer to NAD+ chemically; NR has more published clinical trials. Most people do well with either. Try one and see how you respond.

Can I take NAD+ supplements with other medications?

Generally yes, but discuss with your healthcare provider, especially if you're on immunosuppressants, cancer treatment, or drugs affecting metabolism.

How much does NAD+ therapy cost?

Oral supplements: $30-100/month depending on brand and dose
IV therapy: $250-1000+ per session depending on location and dose
IM injections: $50-150 per injection

Do I need to take NAD+ forever?

Not necessarily. Some people use it for a period (3-6 months) to restore levels, then maintain with lifestyle factors. Others benefit from ongoing supplementation, especially if dealing with chronic conditions or aging.

Can lifestyle changes raise NAD+ naturally?

Yes. Exercise, fasting, and caloric restriction all increase NAD+ through natural pathways. However, these may not be enough if you're severely depleted or have high inflammation. Supplements and therapy can provide a bigger boost, then lifestyle maintains it.

What's the difference between NAD+ IV and IM injections?

IV delivers NAD+ directly into your bloodstream over 2–4 hours, creating high peak levels quickly—500–1000mg per session. IM injects NAD+ into muscle tissue (50–200mg per injection), where it absorbs more slowly over hours. IV is more intense (may cause temporary nausea if too fast) and requires a clinical setting. IM is gentler, can be self-administered after training, and works well for maintenance after an IV loading phase.

How do I know if I have low NAD+?

There's no routine clinical test, but signs suggesting depletion include: persistent fatigue despite adequate sleep, slow recovery from exercise or illness, brain fog, poor stress tolerance, and accelerated signs of aging. People over 40, those with chronic inflammation, post-viral illness, or high stress are statistically likely to be depleted. If you've tried optimizing sleep, diet, and exercise without improvement, NAD+ depletion is worth investigating.

Can I test my NAD+ levels?

Some specialty labs offer NAD+ testing (blood or intracellular), but it's not routine and interpretation is limited—we don't have established "normal ranges" across populations. Most practitioners use clinical response rather than testing: start supplementation, track symptoms over 4–8 weeks, and assess improvement. Testing can be useful for research or tracking response over time, but it's not required to start supplementation.

What supplements help preserve NAD+?

Beyond NMN and NR (which provide raw material for NAD+ synthesis), several compounds help preserve existing NAD+ by blocking its breakdown. Apigenin and quercetin inhibit CD38, the enzyme that degrades NAD+. Resveratrol activates sirtuins, making better use of available NAD+. Reducing chronic inflammation (with omega-3s, curcumin, or lifestyle changes) slows the inflammatory CD38 upregulation that drains NAD+. These work best alongside precursors, not as replacements.

Related Topics

• MITT-Stack White Paper — scientific deep-dive on SS-31, MOTS-c, and NAD+ mitochondrial peptide synergy
• Semax vs Selank: Cognitive Peptides — nootropic peptides that complement NAD+ for brain function
• GLOW Protocol Guide — skin peptides that pair with NAD+ for anti-aging
• Retatrutide Guide — GLP-1 agonist that works better with adequate NAD+ levels
• Complete GLP-1 Comparison — metabolic interventions that pair with NAD+

References

• Covarrubias AJ, et al. NAD+ metabolism and its roles in cellular processes during ageing. Nature Reviews Molecular Cell Biology (2019).
• Yoshino J, et al. NAD+ intermediates: The biology and therapeutic potential of NMN and NR. Nature Aging (2021).
• Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Nature Reviews Molecular Cell Biology (2020).
• Elhassan YS, et al. Nicotinamide riboside augments the aged human skeletal muscle NAD+ metabolome. Cell Reports (2019).
• Yoshino M, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science (2021).
• Rajman L, et al. Therapeutic potential of NAD-boosting molecules. Circulation (2021).
• Mills EL, et al. Mitochondrial dysfunction and inflammation in chronic disease. Nature Reviews Immunology (2018).
• Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Physiological Reviews (2021).

This content is for educational purposes only. NAD+ supplements are available over the counter; IV/IM NAD+ therapy requires medical supervision and is used off-label. Consult a qualified healthcare provider before starting any NAD+ protocol.