In a review of published studies on S-adenosyl methionine (SAMe), the American Agency for Healthcare Research and Quality (AHRQ) concluded that SAMe was effective at treating depression, arthritis and liver disease, particularly in cases where no other treatment had proved successful.
SAMe was first discovered in Italy in 1952 but it was another 24 years before a stable form that could be studied became available. The first significant study on depression was published in 1976 and SAMe was made available in Italy in 1980.
SAMe is produced in the body naturally but probably at insufficient levels (especially by the time we reach our forties). It is crucial for the liver in particular, and also for the adrenal glands and the brain.
SAMe is created in the body from methionine and ATP. Though to some extent, it acts like a B vitamin, it does much more besides. Some experts even claim it is the body’s most important molecule after ATP. It appears to participate in numerous reactions, the three principal ones being:
- Methylation: during methylation, SAMe donates a methyl group which contributes to a number of vitally important reactions including the formation of DNA, proteins, phospholipids and neurotransmitters such as catecholamines and serotonin.
- Trans-sulphuration: in donating a sulphur group, SAMe encourages the formation of cartilage. This process stimulates the incorporation of sulphate into the cartilage matrix, hence SAMe’s role in arthritis. Trans-sulphuration also induces production of acetyl cysteine, taurine and our most important endogenous antioxidant, glutathione.
- Polyamine formation: in donating an aminopropyl group, SAMe helps form spermine and spermidine which control cell growth and differentiation and which have analgesic and anti-inflammatory properties.
SAMe also helps improve membrane fluidity through the incorporation of phosphatidylcholine. It affects beta-adrenergic, cholinergic and GABA receptors and possibly other receptors too. SAMe also plays an important role in the formation of growth hormone, prolactin, adrenalin and melatonin as well as in the healthy function of insulin receptors.
A potent antioxidant
SAMe’s antioxidant potential was demonstrated in a study on rats which highlighted its ability to prevent lipid peroxidation and support constant production of glutathione, the body’s most important endogenous antioxidant 1
Treatment with SAMe (10mg/kg a day), for one, six and 22 months resulted in significant reductions in the accumulation of oxidative stress markers in the brain, compared with a control group given a placebo.
A number of psychiatric, neurological and metabolic problems are associated with lower levels of SAMe in cerebrospinal fluid. They include in particular, depression, Parkinson’s disease, Alzheimer’s disease and HIV-related neurological complications. Researchers suggest these diseases are problems of methylation.
SAMe has been shown to be effective at relieving all forms of depression except bi-polar disease. It is particularly beneficial in cases of depression for which there is no apparent cause.
SAMe is thought to exert its antidepressant effect by increasing production of the neurotransmitters that play a crucial role in mood, behaviour and emotions.
The first research into SAMe’s antidepressant effect dates back to 1973 when scientists in Italy examining its effect on patients with schizophrenia noted that a significant proportion of them became less depressed. This prompted a number of clinical trials aimed at confirming and understanding these unexpected findings 2
Years of research followed, with a considerable number of studies concluding that SAMe was at least as effective at treating depression as its pharmaceutical counterparts and sometimes more effective. In addition, these studies suggested that SAMe had few side-effects, worked within a few days and was well-tolerated by elderly patients3
These results were confirmed by an open clinical trial of 20 patients with severe depression who had failed to respond to standard anti-depressant drugs. All the patients who received oral doses of SAMe showed a significant improvement with seven of them experiencing full anti-depressant response 4
In 2002, the US government published a detailed report, entitled ‘S-Adenosyl-L-methionine for depression, osteoarthritis and liver disease’, which distilled data from numerous published studies from around the world up to the year 2000. The Agency for Healthcare Research and Quality (a division of the US Health and Human Services Department) evaluated data from 102 different studies in order to reach an unbiased conclusion 5
The Agency carefully reviewed 47 relevant studies on SAMe and depression, 28 of which were included in a meta-analysis of SAMe’s efficacy in countering the symptoms of depression. It concluded that “Compared with conventional antidepressant medication, treatment with SAMe was not associated with a significant difference in outcomes”. In other words, SAMe was judged to be just as effective as standard antidepressant drugs at treating depression. Various studies have reported that patients often felt better around the 7th or 10th day of supplementation. The majority of these studies used oral formulations at doses of 1600mg a day.
Researchers at Harvard Medical School studied 30 subjects who were still suffering from depression after more than a month’s treatment with an anti-depressant drug, venlafaxine.
Over the six weeks of the study, participants continued to take their medication alongside an initial 400mg dose of SAMe twice a day. After two weeks, the SAMe dose was increased to 800mg twice a day. After consulting their doctor, subjects were then given the choice of reverting to the 400mg dose or continuing with 800mg. The researchers used various measures to analyse participants’ symptoms and reported that, by the end of the study, 50% had seen a significant improvement in their symptoms and 43% a complete remission in their depression 6
Patients with fibromyalgia or Parkinson’s disease often suffer from depression which responds to treatment with SAMe. In a double-blind crossover study looking at the effect of SAMe on depression in Parkinson’s patients, 72% of subjects reported an improvement following treatment with SAMe 7
. It has a beneficial effect on the neurotransmitter dopamine, levels of which are low in Parkinson’s disease.
Other studies on patients with fibromyalgia have also demonstrated improvements following SAMe treatment. SAMe is known to increase levels of serotonin, a neurotransmitter which relieves pain and depression - two very common symptoms of fibromyalgia.
SAMe treatment is also effective for Alzheimer’s-related depression in which SAMe levels are practically non-existent. Preliminary studies suggest that SAMe may improve not only depression but also other disease symptoms in some individuals8
. Four Alzheimer’s patients who took 200-400mg a day for two weeks were observed for cognitive changes. While researchers in this study found no changes in cognitive function based on the doses taken and the small sample size9
, another study using orally-administered SAMe (1200mg a day for 3-6 months) showed significant improvements in cognitive function, mood and speed of mental processing10
Regenerates the liver
SAMe’s most significant benefits are to be found in the liver where it is at its most concentrated – indeed, it can, on its own, stimulate regeneration of the liver and repair or reverse cirrhosis-induced liver damage. It is thus a key metabolite in the biochemistry of the liver where it carries out two essential functions: methylation, and formation of the most essential substance – the amino acid glutathione which is both an antioxidant and detoxifier.
The liver is the body’s chief chemical filter. It detoxifies every chemical the body encounters, including drugs and toxins, by converting them into non-toxic metabolites. The liver also produces bile and other substances such as lipoproteins. While liver tissue can be destroyed by chemicals, pollutants and drugs, it is fortunately able to regenerate itself – up to 80% of the liver can be surgically removed and it will regain its normal size within three months.
Glutathione is one weapon used by the liver to eliminate toxins. When glutathione encounters a toxin such as a pesticide or drug, it immediately binds to it and makes it more water-soluble. In this form, the toxin can be eliminated via urine without causing more damage. Lesions occur when the liver is so overwhelmed by toxins that it can no longer produce sufficient glutathione.
And SAMe is essential for its production. Oral SAMe supplementation has been shown to increase glutathione levels.
In one study, 24 subjects were given daily oral supplements of 1200mg of SAMe for six months. Researchers observed an increase in liver concentrations of SAMe in patients suffering from alcoholic or non-alcoholic liver disease11
The liver is not invincible however, and toxins can create sufficient damage and structural blockages to cause increasing levels of liver impairment. Cirrhosis is a fibrotic process which leads to the slow death of the liver. It begins with fatty infiltration and progresses until the liver is replaced by scar tissue and can no longer function properly.
Clinical studies show that increasing levels of SAMe produces benefits in many situations. It has been used to treat various liver diseases including hepatitis, cirrhosis, cholestasis and obstructive jaundice.
Cirrhosis patients often have difficulty converting methionine into SAMe. Human studies show that when such patients are given SAMe, bile function is restored and bile salts increase. Other studies show that SAMe increases glutathione levels and restores detoxification processes in patients with liver damage.
Acetaminophen (tylenol) is highly toxic to the liver. In a study on mice, imminent death from elevated doses of acetaminophen was completely halted when SAMe was administered within one hour.
Individuals with liver damage whether from alcohol, toxins or diseases like hepatitis are at greater risk of developing liver cancer. SAMe has been shown to reduce this risk, and correspondingly, low levels of SAMe create a toxic environment which increases the risk.
Beneficial for joint health
Studies have shown that SAMe has an analgesic effect though the mechanism responsible is not yet fully understood. Since this analgesic effect does not involve prostaglandins, SAMe does not produce the side-effects associated with them. Some trials have suggested that SAMe may significantly increase plasma concentrations of corticosteroids, which may contribute to its observed anti-inflammatory effect in animals and humans.
In 1975, a study published in Italy was the first to investigate SAMe’s effect on osteoarthritis, one of the most common forms of arthritis. The open study, involving 90 patients with severe degenerative joint disease, found that intravenous administration of 30mg of SAMe twice a day for two weeks produced considerable anti-inflammatory benefits with no side-effects. In another study, the effects of SAMe were compared with those of intramuscular injections of the analgesic indomethacin. The response to the two treatments was exactly the same but the SAMe treatment had none of the side-effects of indomethacin. 12
In test-tube experiments, SAMe increased numbers of chondrocytes (cartilage cells) and proteoglycans (structural proteins). This suggests that SAMe treatment could reverse the process of osteoarthritis by stimulating cartilage growth13
A two-year study conducted at the König Institute of General Medicine in Germany tested the efficacy of SAMe on 106 patients with osteoarthritis of the knee, hip or spine. Patients received 600mg of SAMe a day for the first two weeks, after which the dose was lowered to 400mg a day for the rest of the study. According to researchers, improvements in clinical symptoms were reported after just two weeks of treatment and continued until the end of the study. Minor, non-specific side-effects such as nausea affected 20 patients but in most cases disappeared over the course of the study 14
. The SAMe treatment was also found to improve depressive feelings among patients, a common problem in those suffering from osteoarthritis.
According to the report of the US Department of Health Services, SAMe was 80% more effective than placebo at relieving the pain of osteoarthritis and at least as effective as non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are recognised as having serious side-effects which is not the case with SAMe.
Scientists at the University of Maryland published a meta-analysis of randomised controlled trials on the efficacy of SAMe versus placebo or NSAIDs such as aspirin or ibuprofen at treating osteoarthritis. They concluded that “SAMe appears to reduce pain as effectively as NSAIDs and improve functional limitation in osteoarthritis patients, without the side-effects often associated with NSAIDs”15
In a randomised, double-blind, placebo-controlled study, scientists in Argentina compared SAMe’s efficacy with that of an anti-inflammatory drug, piroxicam. A small group of patients were given either SAMe at a dose of 1200mg/day, or 20mg of piroxicam, and evaluated after 84 days’ treatment. According to the researchers, “No difference was observed between the two treatments in terms of efficacy and tolerance”. However, they added that:
“The clinical improvements obtained by the end of the study were maintained longer in the SAMe-treated patients than in those who had received the piroxicam 16
A larger, double-blind study involving 734 subjects with arthritis of the knee, hip or spine was conducted across 33 clinics in Italy. Researchers compared the effects of SAMe to those of a placebo or naproxen, an NSAID. Both SAMe and naproxen, at a daily dose of 1200mg and 750mg respectively, were judged to be equally effective at relieving arthritic pain, significantly more so than placebo.
However, SAMe was judged to have far better tolerability by both patients and doctors.
Another randomised study compared SAMe with placebo for its efficacy in treating osteoarthritis of the knee. The study took place at two sites in the US state of Indiana, with patients at one site experiencing more severe symptoms than those at the other. All subjects were given 400mg of SAMe intravenously for five days, and then the same dose orally for a further 23 days. A control group received a similar-dose placebo. Those patients who at the start of the study had the mildest symptoms showed a much greater reduction in pain with the SAMe than with the placebo whereas with the more severely-affected patients, the results were not statistically significant. 18
In September 2000, 61 patients with arthritis of the knee were similarly investigated in a two-year, randomised, double-blind study. Thirty-one of them received 600mg of SAMe twice a day for eight weeks and after one week of no treatment, they were then given 100mg of a drug for a further eight weeks. The order of treatment was reversed for the other thirty participants. Fifty-six patients completed the study.
After the first month, pain levels in those taking the drug had decreased significantly, while those on SAMe reported only a slight reduction in pain. However, after two months, there was no difference between the two sets of patients, with both reporting similar, significant decreases in pain. Quality of life had also improved in the SAMe-treated group19
1- Dela Cruz J.P. et al., Effect of chronic administration of SAMe on brain oxidative stress in rats, Naunyn-Schmd Arch Pharmacol, 2000; 361: 47-52.
2- Elkins R., SAMe: the remarkable substance that promote detoxification, relieve arthritis and fight depression, Pleasant Grove, UT; Woodland Publishing, 1999, 10.
3- De Vanna M. et al., Oral SAMe in depression, Current Therapeutic Research, 1992; 52: 478-485.
4- Rosenbaum J.F. et al., The antidepressant potential of SAMe, Acta Psychiatr. Scand., 1990 May; 81(5): 432-6.
5- SAMe for treatment of depression, osteoarthritis and liver disease. Summary, Evidence report/technology assessment: Number 64. AHRQ publication N° 02-E033. Agency for healthcare research and quality. Rockville MD.
6- Alpert J.E. et al., SAMe as an adjunct for resistant major depression disorder: an open trial following partial or non response to selctive serotonin reuptake inhibitor or ventalafaxine, J. Clin. Psychopharmacol., 2004 Dec; 24(6): 661-4
7- Kegan B. et al., Oral SAMe in depression: a randomized, double-blind, placebo controlled trial, Am. J. Psychiatr., 1990, 147: 591-595.
8- Morrison L. et al., Brain SAMe levels are secerely decreased in Alzheimer disease, J. Neurochem., 1996, 67: 1328-1331.
9- Cohen B.M. et al., SAMe in the treatment of Alzheimer dementia, J. Clin. Psychoparmacol., 1987; 8: 43-7.
10- Battaglieri T. et al., Cerebrospinal fluid SAMe in depression and dementia: effect of treatment with parenteral or oral SAMe, J. Neurol. Neurosur. Psych., 1990; 53: 1096-8.
11- Vendemilae G. et al., Effect of oral S-adenosyl-L-methionine on hepatic glutathione in patients with liver disease, Scand. J. Gastroenterol., 1986; 24: 407-15.
12- Poli E. et al., Pharmacological and clinical aspects of SAMe in primary degenerative arthropathy (osteoarthrosis), Minerva Med., 1975 Dec 5; 66(83): 4443-59.
13- Di Padova C., SAMe in the treatment of osteoarthritis. Review of the clinical studies, AM J. Med., 1987 Nov 20; 83(5A):60-5.
14- Konig B., A long term (two years) clinical trial with SAMe for the treatment of osteoarthritis, AM J. Med., 1987 Nov 20; 83(5A):89-94.
15- Lazzaroni M. et al.
16- Maccagno A. et al., Double-blind controlled clinical trial of oral SAMe versus piroxicam in knee osteoarthritis, AM J. Med., 1987 Nov 20; 83(5A): 66-71.
17- Caruso I. et al., Italian double-blind multicenter study comparing SAMe, naproxen and placebo in treatment of degenerative joint disease, AM J. Med., 1987 Nov 20;83(5A): 66-71.
18- Bradley J.D. et al., A randomized double-blind placebo controlled trial of intraveinous loading with SAMe followed by oral SAMe therapy in patients with knee osteoarthritis, J. Rheumatol., 1994 May; 21(5): 905-11.
19- Najm W.I. et al., SAMe versus celecoxib for treatment of osteoarthritis symptoms: a
double blind cross-over trial, BMC Musculoskelet Disord., 2004 Feb 26; 5(1): 6