NAC vs Silymarin: what is the difference

N-acetylcysteine (NAC) and silymarin are both associated with «antioxidant liver protection» and glutathione. But NAC is a recognised antidote with treatment protocols for poisoning, while silymarin is a plant extract with traditional use. The editorial team breaks down how these substances differ at the level of chemistry, mechanism and evidence.

Chemical nature and origin

NAC is an acetylated form of the amino acid cysteine. The acetyl group makes the molecule more stable than free cysteine, which oxidises easily. NAC is a synthetic substance with a single clear formula, used in medicine since the 1960s: first as a mucolytic to thin sputum, and later as an antidote.

Silymarin, as we have already written, is an extract of the seeds of milk thistle, a mixture of flavonolignans with silibinin as the main component. Its composition depends on the raw material and extraction technology, so «silymarin» from different manufacturers may differ.

This difference alone determines the approach to assessment. For NAC one can speak of a specific molecule with known pharmacokinetics and a dose-dependent effect. For silymarin one must each time specify exactly which extract, in which form and with what silibinin content was studied.

The «natural» role also differs. Cysteine is an ordinary component of dietary protein, and NAC effectively supplies the body with the amino acid that limits glutathione synthesis. Silymarin, on the other hand, is a xenobiotic of plant origin that has no physiological role in the human body.

Glutathione: the direct and indirect pathway

Glutathione is a tripeptide of glutamate, cysteine and glycine, the main intracellular antioxidant and a participant in neutralising toxic metabolites in the liver. The most limiting component for its synthesis is usually cysteine. After deacetylation NAC yields cysteine, and the cell can use it to replenish glutathione stores.

The review by Rushworth and Megson (2014) stresses an important detail: the antioxidant benefit of NAC is realised mainly when glutathione is depleted. In a person with normal stores, extra cysteine does not necessarily turn into «more glutathione», because synthesis is regulated by a feedback principle.

Silymarin affects glutathione indirectly. In cell and animal models it reduced glutathione depletion under toxic loads and acted as a free radical scavenger. In addition, membrane-stabilising and anti-inflammatory effects have been described that are not directly linked to glutathione.

Thus, NAC is the «raw material» for glutathione, while silymarin is more of a «protection» against its depletion and against membrane damage. Hence the different clinical logic: NAC is especially useful in acute glutathione depletion, silymarin is considered a long-term auxiliary agent.

The clinical evidence base

The strongest argument in favour of NAC is paracetamol poisoning. In a paracetamol overdose the toxic metabolite NAPQI depletes glutathione and destroys hepatocytes. Back in 1979 Prescott and co-authors showed the effectiveness of intravenous NAC, and today this is the standard of treatment, described in particular in the review by Heard (NEJM, 2008). Effectiveness is highest with early administration.

The second group of data is acute liver failure not related to paracetamol. In a randomised study by Lee and co-authors (Gastroenterology, 2009) intravenous NAC improved transplant-free survival in patients with early stages of coma. This is treatment in an intensive care unit, not self-administration.

As for silymarin, the Cochrane systematic review (Rambaldi et al., 2007) found no reliable effect on mortality in alcoholic and viral liver injury in high-quality studies. There is historical use of intravenous silibinin in death cap mushroom poisoning in some European countries, but the evidence base there is mainly observational.

Pharmacokinetics and forms

On oral intake NAC is rapidly absorbed, but its bioavailability in unchanged form is low because of active metabolism in the intestine and liver. For the liver this is not entirely a drawback: it is precisely here that the substance is converted to cysteine and used for glutathione synthesis. Oral forms exist (tablets, effervescent tablets, powders) and a solution for intravenous administration.

Silymarin has low solubility in water and low oral bioavailability. To increase it, complexes with phosphatidylcholine and other technological forms are created. A significant part of the absorbed silibinin is conjugated and excreted with bile, that is, to some extent it concentrates precisely in the hepatobiliary system.

A characteristic feature of NAC is a specific sulphurous smell and taste linked to the thiol group. This is not a sign of spoilage but a property of the molecule. When stored in a moist environment, NAC can oxidise, so it is important to follow the storage conditions stated by the manufacturer.

The regimens in studies also differ. For NAC as a mucolytic and supplement, doses of hundreds of milligrams one to three times a day were most often studied, while antidote protocols are an entirely different, intravenous regimen carried out only in hospital. For silymarin, standardised extracts in studies were split across several intakes a day.

Safety, interactions and status

Oral NAC is usually well tolerated. Nausea, vomiting, diarrhoea and an unpleasant taste are possible. Intravenous administration can cause anaphylactoid reactions, so it is carried out under supervision. People with bronchial asthma should be careful with inhaled forms because of the risk of bronchospasm.

In studies silymarin has a favourable profile: mild digestive upset, rarely allergic reactions, especially in people allergic to Asteraceae. A possible effect on drug-metabolising enzymes is discussed, so when taking drugs with a narrow therapeutic window it is worth consulting a doctor.

• NAC:a medicinal product (mucolytic, antidote), in the USA also sold as a supplement; not on the WADA Prohibited List.
• Silymarin:a plant medicinal product or supplement; not on the WADA Prohibited List.
• Both:not a way to «neutralise» the hepatotoxicity of oral steroids or regular alcohol consumption.

It is worth stressing separately: if paracetamol or other poisoning is suspected, self-administration of NAC at home does not replace emergency medical care. The effectiveness of the antidote depends on timing, dose and the correct protocol, and only a doctor can assess the risk from the drug level in the blood.

Editorial conclusions

NAC and silymarin differ fundamentally. NAC is a single molecule that directly supplies cysteine for glutathione synthesis and has an undeniable evidence base as an antidote in paracetamol poisoning. Silymarin is a plant extract with mainly experimental pharmacology and weak clinical evidence.

The only thing they have in common is that both are in one way or another linked to antioxidant liver protection. But the strength and specificity of that link, as well as the level of evidence, are entirely different.

The practical comparison - who should choose what and in which situations - we cover in the article «NAC vs Silymarin: what to choose and for whom». We also recommend the editorial pieces on UDCA and silymarin, on TUDCA and essential phospholipids and on glutathione in sports nutrition.

References

1. Prescott LF, Illingworth RN, Critchley JA, et al. Intravenous N-acetylcystine: the treatment of choice for paracetamol poisoning. Br Med J. 1979;2(6198):1097–1100.
2. Heard KJ. Acetylcysteine for acetaminophen poisoning. N Engl J Med. 2008;359(3):285–292.
3. Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology. 2009;137(3):856–864.
4. Rushworth GF, Megson IL. Existing and potential therapeutic uses for N-acetylcysteine: the need for conversion to intracellular glutathione for antioxidant benefits. Pharmacol Ther. 2014;141(2):150–159.
5. Rambaldi A, Jacobs BP, Gluud C. Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev. 2007;(4):CD003620.
6. Saller R, Meier R, Brignoli R. The use of silymarin in the treatment of liver diseases. Drugs. 2001;61(14):2035–2063.
7. World Anti-Doping Agency. The World Anti-Doping Code International Standard: Prohibited List. Montreal: WADA; оновлюється щорічно.