SAMe Explained

SAMe, pronounced “sammy” or “sam ee”, is short for S-adenosyl-L-methionine, a molecule that is essential for the function of virtually every cell in the body. Often referred to as the “universal methyl donor”, SAMe provides methyl groups for over 100 different enzymatic reactions and essential processes such as DNA metabolism and neurotransmitter synthesis [1].

There are three main pathways that SAMe uses to influence our physiology:

1. SAMe in the Methionine Cycle

SAMe is a by-product and intermediary in the metabolism of the amino acid, methionine. SAMe is formed when methionine and ATP react, and can be converted back into methionine as needed. However, when SAMe donates its methyl group to other processes, it is further converted into an amino acid called homocysteine.

Homocysteine can continue the cycle by being converted into methionine (with the help of vitamin B12 and folic acid), or it can be metabolised into other amino acids and antioxidants. Homocysteine is used throughout the body for cell signalling and inflammation regulation but when the methionine cycle becomes stuck, high levels of homocysteine can occur – a biomarker for chronic diseases such as heart disease and Alzheimer's disease (more on this in a moment!).

2. SAM-e in Epigenetics and Gene Alteration

SAMe can support DNA synthesis and expression by donating a methyl group to DNA molecules as they are formed, giving it a potential role in epigenetics – a science which explores the idea of altering genetic expression rather than targeting the gene or DNA / itself. Some genes require methylation to be “switched on”, while others require methylation to remain switched “off”.

A 2014 study showed that SAMe can affect DNA methylation and gene expression to decrease pro-inflammatory cells and increase anti-inflammatory cells  [4].

A 2013 study showed that SAMe could protect the anticancer activity of a lung cancer drug by modulating DNA methylation [3].

3. SAMe for Glutathione & Superoxide Dismutase

SAMe supplementation may help to boost antioxidant activity in the body, but this is actually due to the further metabolism of homocysteine that leads to high levels of the master antioxidant, glutathione. This process is called transulfuration, and it requires other nutrients like magnesium and vitamin B6 to run smoothly. Studies have found that supplementing with SAMe can increase glutathione concentrations in the liver due to this process [2].

SAMe has also been shown to boost the synthesis of antioxidant enzymes such as superoxide dismutase (SOD) by supporting RNA and DNA expression [2].

SAMe for Brain & Nervous System Support

Methyl groups from SAMe are essential for the synthesis and function of neurotransmitters – “brain chemicals” that are used for stimulating and sustaining mood, focus, memory, cognition and sleep. 

Major imbalances in neurotransmitters are associated with conditions including depression, schizophrenia and Alzheimer's disease.

Major Depressive Disorder is frequently treated with SSRI medications, and SAMe may be a beneficial co-treatment. A 2010 study found that SSRIs were more effective in patients who also took SAMe [5].

A smaller study in 2004 looked at the effects of taking SAMe for major depressive disorder in people with HIV/AIDS. The participants took SAMe for 8 weeks and the results showed a rapid improvement in symptoms with few side effects [6].

Hereditary disease, schizophrenia may be linked to DNA methylation issues. SAMe has researched as a co-therapy in the treatment of schizophrenia, and a key study has shown a reduction in aggressive behaviour after 8 weeks of a 800mg dose per day [7].

CAUTION: SAMe is NOT  therapy for any mental health conditions and must only be taken under supervision in schizophrenia. Speak to your doctor and psychiatrist before taking SAMe.

Studies have shown that SAMe levels are often low in patients with Alzheimer’s Disease. Supplementation has been seen to improve cognitive performance and decrease aggressive behaviour in clinical trials [8] [9].

CAUTION: SAMe use is cautioned in all mental health conditions unless prescribed by a qualified specialist. Extreme caution should be used when taking SAMe with bipolar disorder or Parkinson’s disease.

SAMe for Fibromyalgia Relief

Fibromyalgia pain and fatigue may be relieved with the use of SSRI medications in patients who also suffer from depression; although the why is still unknown, this shows that neurotransmitters play a huge role in fibromyalgia, and SAMe may also improve symptoms by balancing these nervous system chemicals.

Multiple double-blind trials have looked at the effects of SAMe on fibromyalgia and all demonstrated positive results – SAMe supplementation was shown to relieve pain and  fatigue, reduce the frequency of migraine onset and their severity, and improve morning mobility [10] [11] [12] [13].

SAMe in Cardiovascular Disease

High levels of homocysteine is a risk factor for cardiovascular disease. Hyperhomocysteinemia  – excessive levels of homocysteine in the blood – has been shown to cause damage to walls of blood vessels.

A study in 2014 also found a connection between elevated serum homocysteine and central arterial stiffness in an elderly population – a big risk factor for atherosclerosis [14]. As covered above, SAM-e is converted into homocysteine through the methionine cycle and methylation pathway – so wouldn't high levels of SAMe lead to elevated homocysteine levels?

As it turns out, no! Rather than causing a boost to homocysteine levels in the body, SAMe has been shown to actually lower homocysteine levels by up-regulating its complete conversion into cysteine and the antioxidant glutathione [15].

A 2009 study demonstrated that healthy subjects who took SAMe supplements did not have increased plasma homocysteine levels. Instead, the SAMe supplementations was linked to an increase of co-factors in homocysteine metabolism, therefore having the potential to reduce total homocysteine levels [16].

SAMe for Liver Disease 

Most SAMe is produced in the liver , and this may be because SAMe has a huge role to play in protecting the liver against damage and disease.

A meta-analysis of SAMe supplementation in liver disease concluded that SAMe can reduce some liver enzymes that are characteristically elevated in liver disease. However, the results also suggested that SAMe was NOT more effective than common medications for liver disease. It may play a role as a co-therapy but should not be used in place of conventional treatment [17]. 

A study in 2011 showed that SAMe could improve the effects of medical treatment for viral hepatitis C in patients who were previously not responding to treatment  [18].

On the flipside, SAMe doesn't appear to be an effective treatment for alcohol liver disease. A 24 week double-blinded, randomised, placebo-controlled trial showed that SAMe supplementation was no more effective than taking placebo for the treatment of alcoholic liver disease [19]. Abstinence was shown to be the most effective treatment.

How to Take SAMe Supplements

SAMe has poor bioavailability. When taking an oral SAMe supplement, it must be metabolised through first-pass liver detoxification – and this is where a lot of it is destroyed before it can move into the general circulation. Of course supplement companies account for this. However, the amount of SAMe that makes it into the blood stream will always differ between individuals. 

SAMe dosage

Always start with a low dose. Starting with a dose of 200mg per day and working up to 400mg – 600mg per day is generally considered to be safe and effective for most people. Speak to your practitioner for personalised dosage advice.

Take SAMe on an empty stomach – but be aware that this may cause nausea! Take with food to limit tummy upsets.

SAMe Side effects

• Agitation, anxiety, irritation and restlessness. SAMe can trigger bipolar episodes.
• Bloating, gas and flatulence can occur and SAMe can exacerbate gastrointestinal conditions.

Do NOT take SAM-e if pregnant or breastfeeding.

Speak to an integrative doctor, nutritionist or naturopath before beginning SAMe supplementation to ensure it is safe and appropriate for your condition.

References

1. Moore, L. D., Le, T., & Fan, G. (2013). DNA Methylation and Its Basic Function.Neuropsychopharmacology, 38(1), 23–38. http://doi.org/10.1038/npp.2012.112
2. Lozano-Sepulveda, S. A., et al. (2016) S-adenosyl-L-methionine modifies antioxidant-enzymes, glutathione -biosynthesis and methionine adenosyltransferases-1/2 in hepatitis C virus-expressing cells. World J Gastroenterology, 22:14, 3746- 3757. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4814737/
3. Ham, M.S., Lee, J.K., & Kim, K.-C. (2013). S-adenosyl methionine specifically protects the anticancer effect of 5-FU via DNMTs expression in human A549 lung cancer cells. Molecular and Clinical Oncology, 1(2), 373–378. http://doi.org/10.3892/mco.2012.53
4. Pfalzer, A. C., Sang-Woon, C., Tammen, S. A., Park, L. K., Bottiglieri, T., Parnell, L. D., & Lamon-Fava, S. (2014). S-adenosylmethionine mediates inhibition of inflammatory response and changes in DNA methylation in human macrophages. Physiological Genomics, 46(17), 617-623. https://www.ncbi.nlm.nih.gov/pubmed/25180283
5. Papakostas, GI., Mischoulon, D., Shyu, I, Alpert, J.E. & Fava, M, (2010). S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. American Journal of Psychiatry, 167(8), pp: 942-8. DOI: http://doi.org/10.1176/appi.ajp.2009.09081198 
6. Shippy, R. A., Mendez, D., Jones, K., Cergnul, I., & Karpiak, S. E. (2004). S-adenosylmethionine (SAM-e) for the treatment of depression in people living with HIV/AIDS. BMC Psychiatry, 4, p. 38. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC535560/ 
7. Strous, R.D., Ritsner, M.S., Adler, S., Ratner, Y., Maayan, R., Kotler, M., Lachman, H. & Weizman, A. (2009). Improvement of aggressive behaviour and quality of life impairment following S-Adenosyl-Methionine (SAM-e) augmentation in schizophrenia. European Neuropsychopharmacology, 19(1), pp: 14-22. DOI: https://doi-org.ezproxy.endeavour.edu.au/10.1016/j.euroneuro.2008.08.004
8. Rudolph, M. L., Rabinoff, M., & Kagan, B. L. (2011). A prospective, open-label, 12 week trial of S-adenosylmethionine in the symptomatic treatment of Alzheimer's disease. Neuroscience & Medicine, (3), 222.   https://www.researchgate.net/publication/276488559_A_Prospective_Open-Label_12_Week_Trial_of_S-adenosylmethionine_in_the_Symptomatic_Treatment_of_Alzheimer's_Disease
9. Shea, T. B., & Chan, A. (2008). S-Adenosyl Methionine: A Natural Therapeutic Agent Effective Against Multiple Hallmarks and Risk Factors Associated with Alzheimer's Disease. Journal Of Alzheimer's Disease, 13(1), 67-70. https://www.ncbi.nlm.nih.gov/pubmed/18334758
10. Jacobsen, S., et al. (1991) Oral S-adenosylmethionine in primary fibromyalgia. Double-blind clinical evaluation. Scand J Rheumatol 20:4, 294–302.  https://www.ncbi.nlm.nih.gov/pubmed/1925418
11. O’Malley, P. G., et al. (2000) Treatment of fibromyalgia with antidepressants: a meta-analysis. J Gen Intern Med, 15:9 , 659–666. https://www.ncbi.nlm.nih.gov/pubmed/11029681
12. Volkmann, H., et al. (1997) Double-blind, placebo-controlled cross-over study of intravenous S-adenosyl-l-methionine in patients with fibromyalgia. Scand J Rheumatol., 26:3, 206–211.  https://www.ncbi.nlm.nih.gov/pubmed/9225876
13. Sarac, A. J. & Gur, A. (2006) Complementary and alternative medical therapies in fibromyalgia. Curr Pharm Des, 12:1, 47–57. https://www.ncbi.nlm.nih.gov/pubmed/16454724
14. Zhang, S., Bai, Y.-Y., Luo, L.-M., Xiao, W.-K., Wu, H.-M., & Ye, P. (2014). Association between serum homocysteine and arterial stiffness in elderly: a community-based study. Journal of Geriatric Cardiology : JGC, 11(1), 32–38. http://doi.org/10.3969/j.issn.1671-5411.2014.01.007
15. Obeid, R. (2013). The Metabolic Burden of Methyl Donor Deficiency with Focus on the Betaine Homocysteine Methyltransferase Pathway. Nutrients, 5(9), 3481–3495. http://doi.org/10.3390/nu5093481
16. Thompson, M. A., Bauer, B. A., Loehrer, L. L., Cha, S. S., Mandrekar, J. N., Sood, A., & Wahner-Roedler, D. L. (2009). Dietary Supplement S-Adenosyl-l-Methionine (AdoMet) Effects on Plasma Homocysteine Levels in Healthy Human Subjects: A Double-Blind, Placebo-Controlled, Randomized Clinical Trial. Journal of Alternative and Complementary Medicine, 15(5), 523–529. http://doi.org/10.1089/acm.2008.0402
17. Guo, T., Chang, L., Xiao, Y., & Liu, Q. (2015). S-Adenosyl-L-Methionine for the Treatment of Chronic Liver Disease: A Systematic Review and Meta-Analysis. Plos ONE, 10(3), 1-17. http://doi.org/10.1371/journal.pone.0122124
18. Feld, J. J., Modi, A. A., El-Diwany, R., Rotman, Y., Thomas, E., Koh, C., … Liang, T. J. (2011). S-adenosyl methionine improves early viral responses and interferon-stimulated gene induction in hepatitis C nonresponders. Gastroenterology, 140(3), 830–839.e3. http://doi.org/10.1053/j.gastro.2010.09.010.
19. Medici, V., et al. (2011). S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial. Alcoholism, Clinical And Experimental Research, 35(11), 1960-1965. https://www.ncbi.nlm.nih.gov/pubmed/22044287