S-Adenosylmethionine supplement benefits and side effects, the right dosage, is it 100 mg, 200, or 400 a day? by Ray Sahelian, M.D.
September 16 2016

S-Adenosylmethionine is made from the amino acid methionine and ATP. It is is a methyl donor involved in the making of dozens of important compounds in the body. SAM-e has been available by prescription in Europe for many years as an antidepressant but has been available over the counter in the US only since about 1996. Dr. Ascanio Polimeni, a physician in Rome, Italy, says, "S-Adenosylmethionine is a wonderful supplement. Some doctors prescribe SAM-e in Europe for the therapy for many conditions, including depression, chronic fatigue syndrome, and fibromyalgia."

Unlike other methyl donors where the research is scarce, there have been a number of studies with S-Adenosylmethionine. These studies have shown that it influences brain chemicals by helping to convert norepinephrine to epinephrine and serotonin to melatonin, helping make creatine, an important energy reservoir in muscle tissue, and helping the preservation of glutathione, an important antioxidant. Furthermore, SAM-e is involved in the formation of myelin, the white sheath that surrounds nerve cells and it can improve brain cell membrane fluidity, thus potentially enhancing the function of receptors.

Benefits, which medical conditions is it useful for?

Depression and low mood
Because of its role in the making of neurotransmitters,
S-Adenosylmethionine has been tested in the therapy of depression. A number of studies have been published, mostly in Europe, evaluating this nutrient’s role in mood disorders. Back in 1994, Dr. Bressa, from the University Cattolica Sacro Cuore School of Medicine, in Rome, Italy conducted a meta-analysis of the studies on SAMe. A meta-analysis is a statistical pooling of already published research papers. Dr. Bressa concludes, "Its efficacy in treating depressive syndromes and disorders is superior to that of placebo and comparable to that of standard tricyclic antidepressants. Since it is a naturally occurring compound with relatively few side-effects, it is a potentially important treatment for depression."

The influence of S-Adenosylmethionine on depression has also been tested in the United States. Back in 1994, researchers at the University of California, Irvine Medical Center, did a double-blind randomized trial involving a total of twenty-six patients. They compared oral S-Adenosylmethionine with oral desipramine (a pharmaceutical antidepressant). At the end of the four-week trial, 62 percent of the patients treated with SAM-e and 50 percent of the patients treated with desipramine had significantly improved.

S-Adenosylmethionine has even been tested in depressed postmenopausal women. Researchers from the University of La Sapienza in Rome, Italy gave SAM-e for thirty days to eighty women between the ages of 45 and 59 with depression following either natural menopause or hysterectomy. There was a significantly greater improvement in depressive symptoms in the group treated with SAM-e compared to the placebo group. Side effects were mild and transient.

SAM-e has been found to improve mood in those with Parkinson's disease.

Researchers found that adding the supplement S-Adenosyl Methionine to a patients' antidepressant treatment helped more people with major depression improve their symptoms than those that took an inactive placebo on top of their normal medication. The supplement also had fewer side effects than medications that are approved by the FDA for people with depression who don't respond to antidepressants. Dr. George Papakostas is the study's lead author and a psychiatrist at Harvard Medical School and Massachusetts General Hospital, Boston. American Journal of Psychiatry, published online July 1, 2010.

Sam-e, 100 mg,  60 Enteric-Coated Tablets - Source Naturals

purchase S-Adenosyl Methionine
• Pharmaceutical Grade, Stabilized
These tablets are enteric coated and blister packed to prevent breakdown and inactivation of the ingredients. Dozens of clinical studies have demonstrated that SAMe supports joint comfort, function and mobility in the spine, hips and knees. It is important to the joints because of its critical role in cartilage formation. Studies also show that SAMe helps support a positive outlook. It is able to cross the blood-brain barrier where it affects the synthesis and activation of various proteins, such as neurotransmitters.
S-Adenosylmethionine is present in every living cell in the body. However, levels of SAMe tend to decline with age. SAM-e 100 is manufactured under low temperature and low humidity and is enteric-coated to ensure a biologically active product.

 Buy S-adenosyl-l-methionine pills
Supplement Facts
Serving Size: 1 Tablet
  Amount Per Serving %DV
SAMe (S-Adenosyl-L-Methionine) (from 200 mg of S-Adenosyl-L-Methionone Disulfate
100 mg *
* Daily Value not established.

 Other products sold online
Doctor's Best, SAM-e 400, Double-Strength, 60 Enteric Coated Tablets

The retail price of SAMe is about 30 cents per 100 mg pill. The suggested dose of
S-Adenosylmethionine in the therapy of depression ranges from 100 to 400 mg a day, although many individuals do well with even less than 100 mg. Many over the counter products contain 200 mg, but I have found a product that has 100 mg per tablet.
   Many nutrients work is a similar fashion to
S-Adenosylmethionine, particularly other methyl donors such as DMAE, TMG, DMG. In fact, B12 and folate help the body produce SAM-e. Therefore, your dosage of SAM-e should be reduced if you are taking other methyl donors.

Q. Since i have read that the original Italian SAMe (Butanedisfunate) is more effective, i have purchased it online from Amazon. it is 400mgs and from VitaWorld, Germany and expensive. my question is, is Butanedisulfonate a more effective product., it seems not to be sold in the United States, only for Veterinarians. Why not this form in the United States?
   A. I have not seen comparisons between Butanedisfunate versus regular forms of SAM-e sold in the US, so I do not know if it offers any advantages. 400 mg is too high a dose, in my opinion.

How it works
The primary methyl group donor S-adenosylmethionine is important for a number of cellular pathways including methylation of nucleic acids, proteins, and the 5' cap structure of mRNAs, as well as biosynthesis of phospholipids and polyamines. In addition, because it is the cofactor for chromatin methylation, it is an important metabolite for the establishment and maintenance of epigenetic marks. Cells halt proliferation when levels become low.

S-Adenosylmethionine helps support the incorporation of sulfate groups into proteoglycans which help maintain cartilage and protect joints. Some studies have suggested that S-Adenosylmethionine possesses anti-inflammatory and tissue-healing properties that may help protect the health of joints, and perhaps may lessen pain. It is quite possible that SAM-e may be useful for people with osteoarthritis, although more research needs to be done in this area.

Randomized prospective comparative study of ursodeoxycholic acid and S-adenosyl-L-methionine in the treatment of intrahepatic cholestasis of pregnancy.
J Perinat Med. 2006. Binder T, Salaj P, Zima T. Department of Obstetrics and Gynecology, 2nd Medical School Charles University and Teaching Hospital Motol, Prague, Czech Republic.
To compare the efficacy of the ursodeoxycholic acid (UDCA) and S-adenosyl-L-methionine monotherapy with their combined effect on intrahepatic cholestasis of pregnancy (ICP). We studied singleton pregnancies at <36 weeks with a moderate or severe form of ICP between January 1999 and March 2004. Patients were randomized to either oral UDCA 3x250 mg daily or 500 mg S-adenosyl-L-methionine twice daily in slow running infusion for twelve days followed by oral administration of 500 mg twice daily until delivery. Intensive hematological, biochemical and fetal monitoring were carried out. Ursodeoxycholic acid is an effective drug in the treatment of ICP, and combined with S-adenosyl-L-methionine, has probably a synergistic effect on biochemical parameters. This mode of treatment seems more effective but the effect of the successful treatment on the fetus is unclear. Therefore, the ante- and intrapartum monitoring of the fetus should be part of the management of severe forms of ICP.
   Comments by Dr. Sahelian: The S-adenosyl-L-methionine dosage of 500 mg twice a day is very high. I would prefer using much lower amounts.

Effects of excessive alcohol ingestion
Alcohol Res. 2013. Alcohol, DNA methylation, and cancer. Cancer is one of the most significant diseases associated with chronic alcohol consumption, and chronic drinking is a strong risk factor for cancer, particularly of the upper aerodigestive tract, liver, colorectum, and breast. Several factors contribute to alcohol-induced cancer development (i.e., carcinogenesis), including the actions of acetaldehyde, the first and primary metabolite of ethanol, and oxidative stress. However, increasing evidence suggests that aberrant patterns of DNA methylation, an important epigenetic mechanism of transcriptional control, also could be part of the pathogenetic mechanisms that lead to alcohol-induced cancer development. The effects of alcohol on global and local DNA methylation patterns likely are mediated by its ability to interfere with the availability of the principal biological methyl donor, S-adenosylmethionine, as well as pathways related to it. Several mechanisms may mediate the effects of alcohol on DNA methylation, including reduced folate levels and inhibition of key enzymes in one-carbon metabolism that ultimately lead to lower SAMe levels, as well as inhibition of activity and expression of enzymes involved in DNA methylation (i.e., DNA methyltransferases). Finally, variations (i.e., polymorphisms) of several genes involved in one-carbon metabolism also modulate the risk of alcohol-associated carcinogenesis.

Depression and mood studies
J Affect Disord. 2014. S-adenosyl methionine (SAMe) versus escitalopram and placebo in major depression RCT: efficacy and effects of histamine and carnitine as moderators of response. To assess the antidepressant efficacy of S-adenosyl methionine (SAMe), a naturally occurring methyl donor, versus the selective serotonin reuptake inhibitor (SSRI) escitalopram and a placebo control; and to determine whether serum histamine or carnitine levels modified treatment response. Eligible subjects were randomized to SAMe (1600-3200mg/daily), escitalopram (10-20mg/daily), or matching placebo for 12 weeks of double-blind treatment (titration at week 6 in non-response). On the primary outcome of the Hamilton Depression Rating Scale (HAMD-17), a significant difference in improvement was observed between groups from baseline to week 12. These preliminary results provide encouraging evidence for the use of SAMe in the treatment of MDD.

Caution and side effects, risk and danger
High doses can lead to anxiety and restlessness, and even insomnia. Long term side effects are currently not known. The effects seem to be additive over several days of use, hence dosage may need to be reduced with time. Some do well on even 50 or 100 mg (one quarter or one half of a 200 mg pill) per day.
   S-Adenosylmethionine may induce a manic swing in those with bipolar disorder.You mentioned that Sam-e may cause anxiety in some. Does this mean that if you have anxiety you should not take it? Will the anxiety subside once the body adjusts to the supplement or are there any natural pills that help lower tension?
   Anxiety is dose dependent, 50 or 100 mg should not cause such symptoms. It is difficult to predict in each individual how they will respond to supplementation and whether worry and fear will develop or not.
Kava is a plant that can reduce tension, but it should be used only occasionally.

Testimonial side effects, email
I took a 400mg tablet (Jarrow) at mid-day and I experienced - so I believe the onset of a classic anxiety attack - tachycardia, panic, moist palms.

Q. I have been reading your writings for quite some time. I have a question that I cannot seem to find an answer for. I have been taking Sam-e for about 5 years now. I take the highest dose of 1600 mg every morning on an empty stomach. I have not experienced side effects but wondering if it is safe.
   A. I do not feel comfortable taking this high dose for so long. Long terms studies are not available. I would suggest using the lowest dose that works.

Summary and review
S-Adenosylmethionine is a useful therapeutic agent for depression and perhaps arthritis and perhaps other disorders. Long-term studies are needed before making widespread recommendations for its use. However, short-term human studies thus far have found it to be effective.
   Dr. Bottiglieri and colleagues, from Baylor Research Institute, in Dallas, Texas, published a review article on
S-Adenosylmethionine and other methyl donors. They summarize, "SAM-e is required in numerous methylation reactions involving nucleic acids, proteins, phospholipids, amines and other neurotransmitters. The synthesis of SAM-e is intimately linked with folate and vitamin B12 metabolism, and deficiencies of both these vitamins have been found to reduce central nervous system SAM-e concentrations. Both folate and vitamin B12 deficiency may cause similar neurological and psychiatric disturbances including depression, dementia, and peripheral neuropathy. Studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders."

S-adenosylmethionine (SAM-e or AdoMet) is the major biological methyl donor in reactions catalyzed by methyltransferases. It is also used as a source of methylene groups (in the synthesis of cyclopropyl fatty acids), amino groups (in the synthesis of 7,8-diaminoperlagonic acid, a precursor of biotin), ribosyl groups (in the synthesis of epoxyqueuosine, a modified nucleoside in tRNAs) and aminopropyl groups (in the synthesis of ethylene and polyamines).

Research studies
Brain Dev. 2013. Treatment of Lesch-Nyhan disease with S-adenosylmethionine: Experience with five young Malaysians, including a girl. This first report of a trial therapy in Lesch-Nyhan disease children showed remarkably encouraging results that warrant larger studies.

S-Adenosylmethionine versus celecoxib for the treatment of osteoarthritis symptoms: A double-blind cross-over trial. 
BMC Musculoskelet Disorders. 2004
Studies evaluating S-Adenosylmethionine in the management of OA have been limited to Non Steroidal Anti-inflammatory Drugs (NSAIDs) for comparison. The present study compares the effectiveness of S-Adenosylmethionine to a cyclooxygenase-2 (COX-2) inhibitor (celecoxib) for pain control, functional improvement and to decrease side effects in people with osteoarthritis of the knee. A randomized double-blind cross-over study, comparing S-Adenosylmethionine (1200 mg) with celecoxib (Celebrex 200 mg) for 16 weeks to reduce pain associated with OA of the knee. Sixty-one adults diagnosed with OA of the knee were enrolled and 56 completed the study. Subjects were tested for pain, functional health, mood status, isometric joint function tests, and side effects. On the first month of Phase 1, celecoxib showed significantly more reduction in pain than S-Adenosylmethionine. By the second month of Phase 1, there was no significant difference between both groups. The duration of treatment and the interaction of duration with type of treatment were statistically significant. On most functional health measures both groups showed a notable improvement from baseline, however no significant difference between S-Adenosylmethionine and celecoxib was observed. Isometric joint function tests appeared to be steadily improving over the entire study period regardless of treatment. S-Adenosylmethionine has a slower onset of action but is as effective as celecoxib in the management of symptoms of knee osteoarthritis. Longer studies are needed to evaluate the long-term effectiveness of SAM-e and the optimal dose to be used.

S-Adenosylmethionine improves depression in patients with Parkinson's disease
Researchers at Beth Israel Medical Center in New York report a study in 13 depressed patients with Parkinson's disease. All patients had been previously treated with other antidepressant agents and had no significant benefit or had intolerable side effects. The nutraceutical was administered in doses of 800 mg per day for a period of 10 weeks. Eleven patients completed the study, and 10 had at least a 50% improvement on the Hamilton Depression Scale. One patient did not improve. Two patients prematurely terminated participation in the study because of increased anxiety. One patient experienced mild nausea, and another two patients developed mild diarrhea, which resolved spontaneously. Although uncontrolled and preliminary, this study suggests that S-Adenosylmethionine is well tolerated and may be an alternative to the antidepressant agents currently used in patients with Parkinson's disease.
   Dr. Sahelian says:
S-Adenosylmethionine is a available over the counter in a dose of 200 mg. It is widely used in Europe to treat depression and has also been somewhat helpful in treating alcoholic liver cirrhosis and osteoarthritis. I often start my patients with 100 mg in the morning and build up to a maximum of 200 mg three times a day. High doses can lead to anxiety and restlessness. Prolonged use of SAM-e should only be done under medical supervision.

Emails and comments
Q. I had heart by pass surgery. For my low mood, my Doctor suggested I try Lexapro. Before doing that I did some research on natural products I had heard about. I read your extensive report on 5-HTP and less extensive one on SAM-e. I want to try SAM-e as it appears least side effects. However I have the following question: 1. I have bought 200mg tabs made in Italy. I want to start with may be 50mg. You have mentioned that one can bite off the pill. SAM-e is enteric coated as it is supposed to act in the intestines. If one bites off a pill, will the exposed portion have any negative effect? I am very impressed with you. Very many prominent Doctors make reference about your books and works.
As to the question of biting a piece of the tablet, as long as the same S-Adenosylmethionine piece is used within a few days it should not be a problem. For extra care, that bitten off piece could even be wrapped with a small amount of clear plastic wrap.

I took Sam-e several months ago for about a month or so and found it to be amazing stuff!  I had to quit because of gastro intestinal problems, mainly gas and loose stools.  However, after reading your info. on it, I may try it again in a lower dose.  I was taking 400 mgs SAM-e a day.  All in the morning 30 minutes before breakfast.  I even tried splitting it up in two doses, morning and before lunch, as recommended by it's manufacturer, to no avail.  I was having phenomenal results for my depression with it, but was experiencing what might be classified as anxiety later in the day.  No sleep problems, however.  I saw it as more hyperactivity, though.  The package warns that people with bi-polar disorder not use it, because of mania that could be experienced with it.  I have to say that may be what I was experiencing, even though I had only been diagnosed with major depression.  Recently, however, I was diagnosed with ADHD, which I think has been a major contributor and cause of the depression for all these years.  I do believe it helped me focus much better and my concentration was better over all.  I can't say it cured me of all of my ADD symptoms, but I felt better while taking Sam-e than I have in years!!  Simply amazing stuff and I think I am going to try the lower doses, as you recommend, to see what happens.  I was put on Ritilan last week, but had to stop it after two days due to severe anxiety from it.  I go back to my ADHD specialist tomorrow and I am going to see what he says about trying Sam-e.  A well known specialist in the field actually recommends Sam-e in one of his books for one of his six types of ADHD, which I happen to fall under.  Must explain why it worked so well for me.  Now, if I can only quell those bad gassy effects!

Q. I've been doing some research on SAM-e. What surprises me is the dosage you suggest. Other websites, studies and merchants uniformly recommend that therapeutic levels for depression are 800 to 1600 mg/day. I even found one site that said that dosages of 400mg to 800mg SAM-e recommended by some manufacturers are NOT usually therapeutic and not to get discouraged if you don't notice results using label recommendations.  Have you had patients who only responded to higher doses?
   A. It is possible that severely depressed patients may need up to 800 mg a day, however, most patients with mild to moderate depression respond on 100 to 200 mg a day, and the effects of
S-Adenosylmethionine are enhanced over several days of use. If too much is taken side effects, including insomnia, occur, which is counterproductive to mood enhancement. Many studies are done short term and use high doses to elicit a response, but this does not mean that high doses should be taken forever.

Can Sam-e cause high blood pressure in individuals?
   One small study did not indicate that it increases blood pressure. However, it is possible that some individuals respond with a higher bp after Adenosyl methionine intake.

Q. It was suggested for me to take 25mg of Zoloff for a week then increase to 50mg for mild depression.  I preferred to take a natural substance and I did some research on Sam_e and purchased 20 200mg of Sam-e.  I took two 200mg this morning now this afternoon I'm experiencing anxiety.
   A. Anxiety is a very common side effect of
S-Adenosylmethionine in doses greater than 100 or 200 mg.

Q. Quick question: I want to take 100mg of same but I can't find anyone that sells it. The minimum dose seems to be 200. Can you give me any leads?
   A. Unfortunately, I don’t know any company that sells the 100 mg. I recommend patients bite off half a pill.

Q. I am now 77 years old and have had fibromyalgia for more years than I would like to remember. Am in my third year of taking guaifensin under Dr. St. Amand's care with what I feel, think, and know are excellent results. Since Dr. St. Amand's office said sam-e would not block guai I tried it on 2/18/03. Without having done too much research I had taken 2 (200 mg) pills in the AM on an empty stomach. I was very surprised and almost frightened with an anxiety reaction the first day. However, my pain was relieved and my sense of well being was very good for a change, altho I am on Zoloft 200 mgm daily. I then cut the pill in half and have taken a half for three days. Very little anxiety if any, and pain is diminished. Have read of this side effect on maybe only one other internet article. Thank you for pointing out this reaction.

Q. I was interested in what  you had to say about SAM-e. I appreciate your caution and emphasis on the fact that little is known. I had a very bad reaction on 800 mg. a day. Had 5 months of severe gastro-intestinal disturbance, and severely high blood pressure (which rapidly abated when I discontinued the SAM-e). I was also taking B-complex daily but
homocystiene apparently built up anyway. Also, had bad withdrawal when I quit the stuff. About 4 or 5 days of high anxiety, mustle twitching, and depression. In my opinion, SAM-e is bad stuff.
   A. Actually a nutrient or herb can be beneficial or a poison depending on dosage. For many people, daily doses greater than 100 or 200 mg of
S-Adenosylmethionine can cause side effects in the long run.

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Q. Thank you for your great website and for the extensive information you provide. I have taken S adenosylmethionine supplement over the past few weeks. At first, dosage at 200 mg (1 AM, 1 PM) made a decent difference in my depression. However, after 4-5 days, I started getting horrible headaches within 30 minutes of taking it. I also have developed symptoms of increased joint pain, and have problems with my eyes not wanting to focus and hurting. Have you ever heard of these symptoms coming from S-Adenosylmethionine supplement?
   A. Yes, headaches and blurred vision are common with very high doses
. Many people do better with this supplement when they take 50 mg or 100 mg.
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S-Adenosylmethionine is the major biological methyl donor. S-Adenosylmethionine's methyl group arises both from the diet (eg, methionine, choline, and betaine) and from de novo synthesis. At least 50 Adenosylmethionine -dependent methylation reactions have been identified in mammals, and genomic analyses suggest that the final number will be much higher. Such methylation reactions play major roles in biosynthesis, regulation, and detoxification. Creatine synthesis is thought to account for the use of >70% of S-Adenosylmethionine -derived methyl groups in humans. This is not consistent with recent studies in mice, in which the phosphatidylethanolamine methyltransferase gene was deleted (PEMT–/–). Loss of this hepatic enzyme resulted in a 50% decrease in plasma homocysteine, which suggests that it accounts for a major component of whole-body AdoMet utilization. A reexamination of human creatine metabolism showed that dietary creatine can account for as much as 50% of daily creatine requirements in nonvegetarians and, therefore, that estimates of creatine synthesis need to be reduced. We suggest that creatine synthesis is responsible for a smaller proportion of AdoMet-derived methyl groups than has been suggested and that phosphatidylcholine synthesis via phosphatidylethanolamine methyltransferase is a major consumer of these methyl groups.

I am an engineer and I really appreciate the well-documented and well-attributed information on your website. I especially value the attribution of pieces of information as either general explanation of the effects of the product, study-based information (along with the occasional helpful evaluation by Dr. Sahelian), anecdotal information from users, or Dr. Sahelian's own experience. The more general information concerning how to select, experiment with, and choose supplement plans is also very helpful. I really appreciate fact-based sales approaches, as opposed to the usual propaganda. I am currently breaking 200mg S-Adenosylmethionine tablets in half and taking one a day. I concerned that since I break the enteric coating of the tablet, the S-Adenosylmethionine will be dissolved and destroyed by the stomach, thus reducing the bioavailability of the S-Adenosylmethionine and also preventing me from accurately judging the dosage that I am taking. Your site says nothing of an enteric coating being necessary, only that the half of the tablet that is not taken immediately should be plastic wrapped to avoid exposure to air (oxidation?). Is the "enteric coating" advertised for some S-Adenosylmethionine tablets actually useful as an enteric coating, or is it just to keep the S-Adenosylmethionine from being exposed to air? If the enteric coating is required to get the S-Adenosylmethionine past the gastric juices in the stomach, please ask your staff to help me find an enteric coating that can be applied at home. I found many commercial enteric coatings, but for various reasons, I cannot use these products at home.
   For practical purposes we have found that it is not necessary to have an enteric coating when using a S-Adenosylmethionine supplement. The wrapping of the half tablet is to prevent oxidation, and this probably is not necessary either if the half tablet will be taken the next day. S-Adenosylmethionine is best taken with breakfast and the benefits seem to occur whether it is enteric coated or not. The important factor is that each tablet be individually sealed in a foil pack when you buy it as a supplement. The effects of S-Adenosylmethionine add up over several days of use and you may find you need a lower dosage over time otherwise side effects of insomnia, anxiety, and restlessness could occur.

I have been seeing a doctor over the past four years for depression. I have tried every perscription given to me, and nothing, i mean nothing works, i have given all these perscriptions time to work, at least 8 weeks. and it is like taking a sugar pill, nothing ! I have been reading a lot about Sam-e, and want to give it a try. I understand i should start out with 100mg, once a day? before breakfast? I really hope this works, for i have lost interest in everything, including my grandsons, which i hate that feeling. Something has to bring my mood up! Just one question please, is it safe to take S-adenosylmethionine with blood pressure meds? as i take three different kinds at present, I have stopped taking antidepressant meds four weeks ago. But still must take blood pressure meds every day. Your web site is so very helpful, I am glad i found it.
   It is difficult to predict the blood pressure response to
S-adenosylmethionine when mixed with several prescription blood pressure medications. The best way is to take low dosages of S-adenosylmethionine and monitor the blood pressure response.