Protocol·Detox·Intermediate·Reviewed June 9, 2026
Detox & Methylation Support.
This protocol pairs phase I and phase II liver detoxification support (Nrf2 activation, glutathione precursors, and conjugation cofactors) with one-carbon methylation cycle support so that bioactivated compounds are conjugated and cleared efficiently rather than left as reactive intermediates. The strategy emphasizes raising endogenous glutathione, supporting glycine and methyl group availability, and gently supporting estrogen metabolism, with several inputs treated as adjuncts given emerging or mixed human evidence.
The detox & methylation support in brief.
A quick summary. The full stack, with dose and timing for each supplement, is below.
The Detox & Methylation Support is an intermediate stack of 7 supplements aimed at detox: NAC, Glycine, Methylfolate, Methylcobalamin, Vitamin B6, Sulforaphane, and Milk Thistle. 4 are core and the rest are optional add-ons, at roughly $35-55/mo. Each supplement below lists its dose, timing, role, and the evidence behind it.
What is in the detox & methylation support.
Dose, timing, role, and evidence tier for each supplement. Core items carry the protocol; optional ones are situational. Open any name for the full profile.
| Supplement | Dose | Timing | Role | Evidence |
|---|---|---|---|---|
| NAC | 600-1200 mg daily, in 1 to 2 divided doses | With food, morning and/or early afternoon (separate from chelating minerals such as iron) | Core | Strong |
| Glycine | 3-5 g daily | Evening with or after dinner (may be taken before bed) | Core | Moderate |
| Methylfolate | 400-800 mcg daily | Morning with breakfast | Core | Moderate |
| Methylcobalamin | 500-1000 mcg daily | Morning with breakfast (alongside Methylfolate) | Core | Moderate |
| Vitamin B6 | 10-25 mg daily (as pyridoxal-5-phosphate) | Morning with breakfast | Optional | Moderate |
| Sulforaphane | 10-30 mg daily (standardized broccoli sprout extract, ideally with active myrosinase) | Morning with food, taken separately from very hot beverages | Optional | Emerging |
| Milk Thistle | 200-400 mg daily of silymarin (standardized to about 80 percent silymarin) | With meals, in 1 to 2 divided doses | Optional | Emerging |
NAC supplies cysteine, the rate-limiting amino acid for de novo glutathione synthesis, supporting phase II conjugation and antioxidant capacity in hepatocytes. It is an established precursor strategy used clinically to replenish hepatic glutathione.
Glycine is the third amino acid in the glutathione tripeptide and also serves as a phase II conjugation substrate, so adequate intake supports both glutathione synthesis and conjugation throughput. Supplementation alongside a cysteine precursor has been shown to raise glutathione concentrations in humans.
Methylfolate (5-MTHF) is an active folate form that supplies the methyl group used by methionine synthase to remethylate homocysteine to methionine, which is then converted to the methyl donor S-adenosylmethionine. Using a pre-reduced form does not require the MTHFR-dependent conversion step needed for folic acid.
Methylcobalamin is an active B12 cofactor for methionine synthase, the enzyme that uses methylfolate to remethylate homocysteine, so it is functionally paired with folate in the one-carbon cycle. Pairing the two helps avoid masking an underlying B12 deficiency when supplementing folate.
Vitamin B6 as pyridoxal-5-phosphate is the cofactor for the transsulfuration enzymes that route homocysteine toward cysteine, a glutathione precursor, linking the methylation cycle to detoxification capacity. The dose is kept modest because chronic high-dose B6 can cause sensory neuropathy.
Sulforaphane activates the Nrf2 transcription factor, which upregulates phase II detoxification and antioxidant enzymes, including those involved in glutathione conjugation. Human evidence for clinical detoxification endpoints is still emerging, so it is positioned as an adjunct.
Silymarin from Milk Thistle has antioxidant activity in the liver and may help support intracellular glutathione and hepatocyte membrane stability, complementing the other detoxification inputs. Human outcome data are mixed, so it is included as a supportive adjunct.
How the pieces combine.
The mechanistic rationale for stacking these together rather than taking them in isolation.
- NAC and Glycine together supply two of the three amino acids needed to build glutathione, so pairing them supports glutathione status more reliably than either alone.
- Methylfolate, Methylcobalamin, and Vitamin B6 work together on the one-carbon cycle: folate and B12 remethylate homocysteine while B6 routes homocysteine through transsulfuration toward cysteine and glutathione, linking methylation to detoxification.
- Sulforaphane activates Nrf2 to upregulate phase II enzymes, while NAC and Glycine supply glutathione substrate those pathways rely on, so enzyme induction and substrate availability reinforce each other.
- Take the methylation cofactors (Methylfolate, Methylcobalamin, Vitamin B6) together in the morning for consistent daily methyl group support, and shift Glycine to the evening to spread amino acid intake and support relaxation before sleep.
- Milk Thistle provides background hepatic antioxidant support that complements the glutathione-building core, but it is an adjunct and should not replace the NAC plus Glycine foundation.
- Safety: if you take prescription medication (for example anticoagulants, immunosuppressants, or hormonal therapy) or have liver or kidney disease, consult your clinician before starting, because NAC, Milk Thistle, and high-dose B vitamins can interact with some drugs and conditions.
Cost and commitment.
A rough monthly cost and how involved the protocol is to run.
The evidence behind it.
Overview citations for this protocol. Each supplement's own profile carries its full source list.
- Lu SC. Glutathione synthesis. Biochim Biophys Acta. 2013;1830(5):3143-53. PubMed
- Hodges RE et al. Modulation of Metabolic Detoxification Pathways Using Foods and Food-Derived Components: A Scientific Review with Clinical Application. J Nutr Metab. 2015;2015:760689. PubMed
- Selhub J et al. The pathogenesis of homocysteinemia: interruption of the coordinate regulation by S-adenosylmethionine of the remethylation and transsulfuration of homocysteine. Am J Clin Nutr. 1992;55(1):131-8. PubMed
Common questions.
Quick answers drawn from the stack above.
What is in the Detox & Methylation Support?
The Detox & Methylation Support combines 7 supplements for detox: NAC, Glycine, Methylfolate, Methylcobalamin, Vitamin B6, Sulforaphane, and Milk Thistle. 4 are core; the rest are optional.
How much does the Detox & Methylation Support cost?
NutriStack estimates the Detox & Methylation Support at about $35-55/mo, depending on the forms and brands you choose and whether you run the optional add-ons.
Is the Detox & Methylation Support backed by evidence?
Each supplement in the protocol carries its own evidence tier (1 rated strong here) and links to PubMed-cited sources. NutriStack does not rank or score brands and takes no manufacturer payments; this is an informational reference, not medical advice.
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