The History of the Drug Ademetionine

Ademetionine is a medicine that is at the same time a natural molecule of every cell. From its discovery by Giulio Cantoni in the 1950s to the stable dosage forms created in Italy, its path ran through complex chemical challenges and contradictory clinical studies. Our editorial team tells this story.

The discovery by Giulio Cantoni

Ademetionine is the drug name for S-adenosyl-L-methionine (SAMe), a molecule produced by every cell of our body. Its history begins in 1952, when the Italian-American biochemist Giulio Cantoni, working in the United States, discovered that methionine, before taking part in methylation reactions, is activated using ATP.

In 1953, Cantoni published an article in the Journal of Biological Chemistry describing a new compound formed enzymatically from L-methionine and adenosine triphosphate. This «active form of methionine» was later named S-adenosylmethionine.

The discovery was of fundamental importance. It turned out that SAMe is the main donor of methyl groups in the body: it participates in the methylation of DNA, proteins, phospholipids and neurotransmitters. In the number of reactions in which it is used as a cofactor, SAMe is second only to ATP.

Besides methylation, SAMe is the starting substance for two more important metabolic pathways: transsulfuration, which leads to the formation of cysteine and glutathione, the main intracellular antioxidant, and aminopropylation, which provides the synthesis of polyamines.

It was precisely the central place of SAMe in the metabolism of the liver, which synthesizes and uses it the most, that later became the theoretical basis for attempts to use it as a medicine.

The stability problem and the Italian breakthrough

For more than two decades after its discovery, SAMe remained a laboratory substance. The main obstacle was instability: the molecule quickly decomposes at room temperature and in aqueous solutions, which made it impossible to produce tablets or ampoules with an acceptable shelf life.

The solution was found in Italy in the 1970s. Researchers at the company BioResearch developed stable SAMe salts with strong acids, in particular with para-toluenesulfonic acid and later 1,4-butanedisulfonate. These salts made it possible to create industrial dosage forms.

The next task was the oral form. SAMe is sensitive to the acidic environment of the stomach, so tablets are released in an enteric coating. Even so, oral bioavailability remains low, which affects the discrepancy in study results with different forms and doses.

The drug, known in many countries under the trade name Heptral, entered the market in Italy and other European countries and later spread in Eastern Europe, where it became one of the best-known «hepatoprotectors».

One drug, different statuses

An interesting feature of the history of ademetionine is its different regulatory status in different countries. In Italy, Germany, Ukraine and a number of other states it is registered as a prescription or over-the-counter medicine with indications related to intrahepatic cholestasis and, in some countries, depression.

In the United States the situation is different: since 1999, SAMe has been sold as a dietary supplement in accordance with the DSHEA law. This means that the manufacturer is not required to prove effectiveness before the product reaches the market, and the quality and active-substance content of different products may differ substantially.

This contrast explains why information about SAMe in English-language and Ukrainian-language sources often differs substantially: some describe it as a supplement «for mood», others as a drug for treating cholestasis.

For the consumer, the practical conclusion is simple: even one and the same molecule may be represented by products of very different quality, so it is important to pay attention to the registration status and the manufacturer.

What clinical studies have shown

Ademetionine has been studied in several directions, and each has its own history. In hepatology, the best-known study is the multicenter randomized placebo-controlled trial by Mato and colleagues (1999) in patients with alcoholic liver cirrhosis. In the subgroup with less severe cirrhosis, a reduction in the combined endpoint of mortality and transplantation was reported, but in the overall sample the difference was not statistically significant.

A Cochrane systematic review (Rambaldi and Gluud) on alcoholic liver damage concluded that there is no convincing evidence of benefit or harm from SAMe and that additional high-quality studies are needed.

Regarding intrahepatic cholestasis, in particular cholestasis of pregnancy, study results are inconsistent; guidelines usually give preference to ursodeoxycholic acid. The review by Anstee and Day (2012) in the Journal of Hepatology summed up: the biological rationale is convincing, but the clinical evidence base for most indications is limited.

A separate direction is psychiatry. SAMe has been studied in depression, including as an add-on to antidepressants. Some studies showed positive results, but reviews noted the small number of participants and methodological limitations. Studies were also conducted in osteoarthritis, where the effect was compared with nonsteroidal anti-inflammatory drugs.

The overall picture is this: ademetionine is a biologically important molecule with a wide range of hypothetical applications, but for none of them has evidence at the level of large randomized studies with an unambiguous result been obtained.

Safety and nuances of use

Ademetionine is usually well tolerated. Among the side effects described are gastrointestinal symptoms, headache, insomnia and sometimes anxiety. Because of its effect on neurotransmitter metabolism, cases of a switch into a manic phase have been described in people with bipolar disorder, so such patients need particular caution.

Important practical points:

• possible interaction with antidepressants, in particular the risk of serotonin syndrome when combined;
• enteric-coated tablets should not be chewed or split, since this destroys the protective coating;
• the drug does not replace diagnosing the cause of elevated liver values;
• for SAMe dietary supplements, independent checks have repeatedly recorded a discrepancy between the content and the label claim.

In the sports community, ademetionine, like silymarin, is often perceived as «liver protection» against the background of taking hepatotoxic substances. There are no data confirming that it prevents such damage. Monitoring of liver condition should be based on laboratory values and a doctor's consultation.

Ademetionine is not on the WADA Prohibited List.

Editorial conclusions

The history of ademetionine, from Cantoni's discovery in 1952 to the stable salts developed in Italy, shows how a fundamental biochemical discovery turns into a medicine.

The molecule is of exceptional importance for metabolism, but clinical studies have given mostly modest or ambiguous results. The different regulatory status in Europe and the USA further complicates the evaluation of information.

For people who train, ademetionine is not a way to «neutralize» hepatotoxic substances; the decision about its use should be made by a doctor.

Our editorial team also recommends reviewing our materials on the history of silymarin, on interpreting liver values, and on ursodeoxycholic acid.

References

1. Cantoni GL. S-Adenosylmethionine; a new intermediate formed enzymatically from L-methionine and adenosinetriphosphate. J Biol Chem. 1953;204(1):403–416.
2. Mato JM, Cámara J, Fernández de Paz J, et al. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999;30(6):1081–1089.
3. Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev. 2006;(2):CD002235.
4. Anstee QM, Day CP. S-adenosylmethionine (SAMe) therapy in liver disease: a review of current evidence and clinical utility. J Hepatol. 2012;57(5):1097–1109.
5. Bottiglieri T. S-Adenosyl-L-methionine (SAMe): from the bench to the bedside — molecular basis of a pleiotrophic molecule. Am J Clin Nutr. 2002;76(5):1151S–1157S.
6. European Association for the Study of the Liver. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol. 2009;51(2):237–267.