Ademetionine (SAMe): Side Effects and Contraindications
Ademetionine, also known as S-adenosylmethionine or SAMe, is used in several European countries as a prescription medicine for liver conditions and is sold in the UK as a food supplement. Among people who train, it is often discussed as a "liver protector". The editorial team reviews its known side effects, who should not take it and which interactions deserve attention.
What ademetionine is
S-adenosylmethionine is a molecule the body makes from the amino acid methionine and ATP. It is the main donor of methyl groups in the body, involved in the synthesis and regulation of DNA, proteins, phospholipids and neurotransmitters. It is also a precursor of glutathione, one of the key antioxidants in the liver.
In liver disease, the body's ability to produce SAMe may be reduced, which is the basis for its therapeutic use. In countries such as Italy, Germany, Russia and others, ademetionine is licensed as a medicine for intrahepatic cholestasis (impaired bile flow within the liver), including in chronic liver disease and in pregnancy. It is also used for depression in some countries.
In the UK, ademetionine is not a licensed medicine. It is available as SAMe in supplement form, usually as enteric-coated tablets, since the molecule is unstable and degraded by stomach acid. Product quality varies, and stability is a known issue.
Research on its benefits is mixed. A Cochrane review on alcoholic liver disease found insufficient evidence to support or refute its use, while some trials in cholestasis and depression have reported positive results. This uncertainty makes a careful look at its risks all the more important.
Common side effects
In clinical trials, ademetionine has generally been well tolerated. The most frequent complaints involve the digestive system and usually arise at the beginning of treatment or with higher doses.
- Nausea, abdominal pain and indigestion
- Diarrhoea or constipation, flatulence
- Dry mouth
- Headache and dizziness
- Insomnia, restlessness or anxiety
- Sweating and skin itching
Because SAMe has activating effects on mood and energy, many prescribing documents in countries where it is licensed advise against taking it in the evening. Taking it in the morning or early afternoon reduces the likelihood of sleep disturbances.
Allergic reactions, including rash and, rarely, more serious hypersensitivity, have been reported, particularly with injectable forms used in hospitals abroad. Any swelling of the face, throat or difficulty breathing requires urgent medical help.
Overall, the side-effect profile is milder than that of many prescription antidepressants or liver drugs, which partly explains its popularity. However, "mild" does not mean "suitable for everyone".
Contraindications
Official product information for licensed ademetionine products in Europe lists several situations in which it should not be used or requires particular caution. These are summarised below.
| Condition | Reason | Recommendation |
|---|---|---|
| Bipolar disorder | Risk of switching to hypomania or mania | Contraindicated unless a psychiatrist advises otherwise |
| Genetic defects of the methionine cycle (e.g. cystathionine beta-synthase deficiency) | Risk of raised homocysteine | Contraindicated |
| Vitamin B12 or folate deficiency | Impaired metabolism of SAMe and raised homocysteine | Correct deficiency first; check levels |
| Hypersensitivity to the substance | Allergic reactions | Contraindicated |
| Pregnancy (first trimester) and breastfeeding | Limited data | Only under specialist supervision |
| Children | Safety not established | Not recommended |
The psychiatric caution is the most practically important. Case reports describe hypomania and mania in people with bipolar disorder taking SAMe, sometimes when used for depression without a proper diagnosis. Anyone with a personal or family history of bipolar disorder should not take it without psychiatric input.
The B12 and folate issue is also relevant to athletes on restrictive diets, vegans who do not supplement B12, and people with malabsorption. Low levels of these vitamins can be checked easily with a blood test before starting.
Interactions with medicines
Because SAMe influences serotonin metabolism, the main concern is with medicines that increase serotonin activity. Combining it with SSRIs, SNRIs, tricyclic antidepressants, MAO inhibitors, tramadol, triptans or St John's wort may theoretically increase the risk of serotonin syndrome, a potentially serious reaction with agitation, sweating, fever, tremor and rapid heartbeat.
SAMe may also interact with levodopa used in Parkinson's disease, possibly reducing its effectiveness over time through methylation processes. People taking levodopa should consult their neurologist before using SAMe.
There are also theoretical concerns about combining SAMe with other stimulating substances, including high doses of caffeine and some pre-workout products, as the combination may increase anxiety and insomnia. This is not a dangerous interaction for most people but can affect sleep and recovery.
As with any supplement, the safest approach is to show the pharmacist a full list of medicines and supplements before starting.
Ademetionine in sport and "liver protection"
Ademetionine is often recommended informally in sports circles for protecting the liver during use of oral anabolic steroids or other hepatotoxic substances. There is no clinical evidence that SAMe prevents liver damage from such substances, and relying on it can create a false sense of safety.
Liver injury from oral 17-alpha-alkylated steroids includes cholestasis, peliosis hepatis and liver tumours. These are serious conditions that require stopping the cause and seeing a doctor, not adding a supplement. Our editorial team does not support any approach that presents SAMe as a way to make hepatotoxic drug use acceptable.
Ademetionine is not on the WADA Prohibited List. Supplements, however, can be contaminated, so tested athletes should use batch-tested products if they take it at all.
If liver blood tests are abnormal, the priority is to find out why. Common causes in active people include recent intense exercise (which raises AST and ALT from muscle), alcohol, fatty liver, medications and viral hepatitis. A GP can arrange appropriate follow-up.
Conclusions of the editorial team
Ademetionine is generally well tolerated, with digestive upset, headache and sleep disturbances as the main side effects.
It should not be used in bipolar disorder, inherited methionine cycle defects or untreated B12 or folate deficiency, and caution is needed in pregnancy and in children.
The main interaction risk involves serotonergic medicines, with a theoretical risk of serotonin syndrome. SAMe is not a proven protection against liver damage from hepatotoxic substances.
For related reading, see our articles on blood tests during ademetionine use, on interpreting liver enzymes after exercise, and on TUDCA and other liver-support supplements.
References
- 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.
- Rambaldi A, Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev. 2006;(2):CD002235.
- Sharma A, Gerbarg P, Bottiglieri T, et al. S-Adenosylmethionine (SAMe) for neuropsychiatric disorders: a clinician-oriented review of research. J Clin Psychiatry. 2017;78(6):e656–e667.
- 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.
- Frezza M, Surrenti C, Manzillo G, et al. Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis: a double-blind, placebo-controlled study. Gastroenterology. 1990;99(1):211–215.
- Pope HG Jr, Wood RI, Rogol A, et al. Adverse health consequences of performance-enhancing drugs: an Endocrine Society scientific statement. Endocr Rev. 2014;35(3):341–375.
