No published human trials yet; mechanism predicts ≥ NAC effect (see below)
*Human PK for NACET has not been formally published but rat & primate data plus in-vitro human tissue studies show 5- to 15-fold higher effective exposure.
Why NACET should, in theory, beat NAC for homocysteine (Hcy)
**More cysteine inside the cell → faster trans-sulfuration.**Hcy + serine → cystathionine → cysteine. When intracellular cysteine rises, cystathionine-β-synthase (CBS) activity is pulled forward, draining Hcy. NACET delivers cysteine far more efficiently than NAC.
**Steeper glutathione (GSH) gradient.**Raised GSH pushes the redox couple toward a more reduced state, freeing vitamin B12 and 5-MTHF from oxidation traps that otherwise stall re-methylation pathways.
**Thiol-exchange in plasma.**Like NAC, NACET’s free –SH can break the albumin-Hcy disulfide, liberating Hcy so it can be renally cleared. Because NACET is ~10× more reactive toward Ellman’s reagent than NAC , it should perform this swap faster.
**Lower oxidative stress.**Oxidative stress raises SAH and inhibits methionine synthase. NACET’s stronger antioxidant action (shown in retinal cells and endothelial models) indirectly relieves that bottleneck.
Bottom line: mechanistically NACET ought to match or exceed the ≈10–15 % Hcy drop seen with high-dose NAC, but we have to extrapolate from surrogate endpoints until a formal trial is run.
Practical “experimental” protocol
Timing
Dose
Rationale
Breakfast
NACET 250 mg (caps come 200-300 mg)
Start low; observe for GI warmth / mild headaches (sign of rapid cysteine rise)
Glycine and taurine both enhance trans-sulfuration; riboflavin stabilises MTHFR 677TT
Cycle
6-week block → re-check plasma Hcy, cysteine, GSH
Expect effect within 2–3 weeks; plateau by week 6
If you’re already using NAC 600 mg BID, swap gram-for-gram:250 mg NACET ≈ 600 mg NACfor thiol delivery.
Safety & caveats
Data gap: no large human safety series, but animal LD₅₀ is similar to NAC and small human use-cases report no adverse liver or cardiac signals.
Thiol “dip”: Very high intracellular cysteine can transiently lower SAMe/SAH ratio. If mood dips or you notice “brain fog,” reduce dose and add a little methyl-B12 (e.g., 500 µg).
Sulfur smell & flatulence are stronger than with NAC — another reason to titrate slowly.
Renal function: Like NAC, NACET relies on kidneys to clear mixed disulfides. Check eGFR if you have CKD.
Regulatory status: Not FDA-approved; sold as a “research chemical” in the US. Quality varies — look for COA with <0.5 % residual solvents and verified optical rotation (should be L-isomer).
If NACET alone doesn’t move the needle
Add GlyNAC: NACET 250 mg + glycine 3 g in one dose mimics the 2022 GlyNAC human trial (aged cohort) and may amplify GSH/Hcy effects.
Micro-methionine restriction: 20–30 % cut in meat & egg intake often shaves another 1–2 µmol/L off stubborn Hcy.
Check hidden drivers: thyroid (TSH), cystatin-C eGFR, unfiltered coffee load, estrogen (even in men), certain meds (niacin, PPIs, anti-epileptics).
Consider low-dose SAMe (200 mg) or phosphatidylcholine: If SAH is elevated, these can restore the SAMe/SAH ratio and kick CBS forward.
Take-aways
NACET is the “hot-rod” version of NAC—~10× better cell penetration, brain-accessible, and a stronger antioxidant.
Direct clinical data on homocysteine are still missing, but every mechanistic step points toward equal or greater Hcy-lowering than high-dose NAC.
A 250 mg BID experiment, layered onto your existing B-vitamins/TMG/creatine stack, is a low-risk way to test the hypothesis.
Re-test Hcy at week 6. If it hasn’t budged, audit oxidative stress and kidney clearance rather than piling on more methyl donors.
Let me know if you’d like a more detailed lab-tracking sheet or meal templates to combine NACET with mild methionine restriction.
It depends on price. Let’s say the bioavailability is 60 to 10, 250mg X 6 = 1500 mg, still less than my current daily dosage. ( I take 2g to 3g of NAC daily with glycine )
I have used NACET. You get more dose per pill, but the cost is about 2X for a comparable amount of NAC. I’m concerned more about the price than the number of pills I take, so I stick with regular NAC.
Yes I know there isn’t a ton of data but there is enough to convince me that it seems obvious that NACET is the better choice.
My biggest concern, however, is the risk of knee osteoarthritis (for both of them). I have been taking one or the other for more than a decade and have significant shoulder arthritis. I’m a bodybuilder so I would assume that’s the primary cause but is it possible that NAC added fuel to the fire? I have no idea.
I am honestly not sure why this 2020 study doesn’t get much attention. It seems like only Reddit likes to talk about it. Siim Land also once mentioned it in a video.
I think the health benefit potential is huge, especially combined with glycine, but that large observation study lives in my head rent free. If NAC really is causing knee osteoarthritis, I would imagine NACET would make it worse, given that it is much more bioavailable. I still take NACET but I keep flipping back and forth on whether I should stop or not.
As someone with chronomalacia in my knees for over 30 years, I had to google…
I saw this and imagine you’ve seen it too.
I started taking NACET last summer.
In general, my knees keep improving, so if it is having a negative effect, I can’t tell. Could they be better without it, I don’t know?
I owe most of my improvement to intense training sessions with my PT, and perhaps a million other things I’m taking, but maybe NACET even helps. I’m following this!
PS
(Living rent free in your head is such a good expression!)
I have indeed seen that Beth and I’m glad you brought it up, since it’s important to know that also exists. We are getting mixed signals with all these studies here. Especially in mice, NAC seems to improve osteoarthritis. In the study I quoted above, the effect was worse for younger people in the 25-39 age group, mysteriously.
This kind of reminds me of glucosamine where one large observation study showed much lower all cause mortality but another (also out of China) showed increased.
I don’t know what to think, but NAC/NACET seems to have some good potential so I have a hard time making myself come off of it.
Using single-pass intestinal perfusion (SPIP) platform, we establish the microbiota-based permeability screening framework involving germ-free (GF) and specific-pathogen-free (SPF) rats to compare in-situ P eff-values and metabolomic profiles of 32 orally administered drugs with disputable classifications of permeability, prior to the verifications of bioorthogonal chemistry and LC-MS/MS. In contrast with SPF controls, N-Acetylcysteine (NAC) exhibits significantly increased permeability in GF rats, which is inversely related to reduced cysteine-3-ketosphinganine by Bacteroides .
Here is what Chat GPT had to say about comparing the studies
When comparing the two studies, here’s a clearer breakdown:
⸻
2024 MAG Online Library Study (Systematic Review & Meta-analysis of NAC in RA)
• Focus: Investigates the effects of NAC as an adjuvant therapy in rheumatoid arthritis (RA).
• Design: Systematic review and meta-analysis of clinical trials.
• Findings: It suggests potential benefits in RA (anti‑inflammatory effects), but does not examine osteoarthritis at all .
• Scope: Highly relevant for RA patients—generalizes to inflammation control, not OA risk or joint degeneration.
⸻
2020 Taiwan Cohort Study (Yeh et al., BMC 2020)
• Focus: Looks at knee osteoarthritis (OA) risk in people using oral NAC.
• Design: Large-scale, retrospective cohort study using Taiwan’s National Health Insurance data (2000–2013). Over 12,900 NAC users matched with >51,700 non‑users ().
• Key Result: NAC use was associated with a 42% higher adjusted risk of developing knee OA (adjusted HR = 1.42, p < 0.001). Among younger users, the risk almost quadrupled ().
• Importance: Directly relevant to OA, uses robust epidemiological methods and a large, real‑world population.
⸻
What Should You Pay More Attention To?
If you’re concerned about osteoarthritis, the Taiwan study is much more directly applicable:
• It specifically examines OA risk in humans.
• It’s large, population-based, and statistically strong.
• This is much more pertinent than the 2024 RA-focused meta-analysis, which doesn’t address OA.
By contrast, the NAC‑in‑RA meta-analysis is valuable only if you’re treating rheumatoid arthritis. It tells you nothing about OA.
Not related to osteoporosis or osteoarthritis, but here’s another interesting finding about NAC that I saw a while back (maybe it’s mentioned here):
It’s an associational study about a group of people in Taiwan with COPD.
Patients with pre-existing cancer before the index date were excluded from the analysis. The case group consisted solely of COPD patients who received a minimum of 28 cDDDs of NAC annually, while the control group comprised individuals who did not receive NAC therapy but were prescribed at least one type of non-NAC antimucolytic agent throughout the entire follow-up period. This threshold of 28 cDDDs annually was chosen based on established pharmacoepidemiological practices.
They found that:
The crude incidence of cancer significantly differed between the NAC group and the never NAC use group (P<0.001; Table 2). The incidences of all cancers were 13.18% and 9.44% in the Non-NAC antimucolytic agents group and the NAC Use group, respectively. For the Non-NAC antimucolytic agents group compared to the NAC Use group, the incidences of specific cancers were as follows: pancreatic cancer, 0.32% versus 0.24% (P<0.0001); hepatocellular carcinoma, 2.13% versus 1.31% (P<0.0001); esophageal cancer, 0.29% versus 0.19% (P = 0.0023); head and neck cancers, 0.88% versus 0.65% (P<0.0001); gastric cancer, 0.67% versus 0.49% (P = 0.0004); lung cancer, 2.29% versus 2.28% (P = 0.8944); colorectal cancer, 2.49% versus 1.63% (P<0.0001); gynecological cancer, 0.18% versus 0.11% (P = 0.0050); breast cancer, 0.81% versus 0.45% (P<0.0001); prostate cancer, 1.24% versus 0.76% (P<0.0001); and other cancers, 4.60% versus 2.98% (P<0.0001), respectively.
I should have probably said that: if this is what you’d see if you did a clinical trial with NAC in the general population, then that would be phenomenal. It would mean NAC is powerfully protective against cancer!
2024 MAG Online Library Study (Systematic Review & Meta-analysis of NAC in RA)
2020 Taiwan Cohort Study (Yeh et al., BMC 2020)