Depression & SAMe

Written by KYRIAZIS, M.D., Marios

Over 17 million Americans are affected by depression and yet many of these cases are never diagnosed or treated properly. Depression is characterized by persistent symptoms lasting for over two weeks. Symptoms include feelings of sadness and pessimism, loss of motivation or initiative, changes in sleep patterns and in appetite, bouts of crying and thoughts of suicide.

There are many factors which can trigger depression but it is increasingly recognized that depression is a result of certain biochemical changes in specific areas of the brain. Drugs aimed at treating depression are effective at modifying the levels of neurotransmitters in the brain, with resulting clinical improvement of the symptoms.

Many synthetic drugs (although often helpful in the treatment of depression) can cause side effects which can sometimes be severe. For this reason there has been a renewed interest in natural substances which are used to lessen the symptoms of depression without causing significant side effects. Examples of these natural substances are kava kava, St John’s Wort and SAMe.


SAMe (pronounced ‘sa-me’ as in the name ‘Samy’) has been hailed as the safest and most effective natural antidepressant ever used. The full name is S-adenosyl-methionine (or adenmethionine) and it is a molecule derived from the union of the aminoacid methionine to a factor responsible for energy production, called adenosine triphosphate (ATP). The production of SAMe from these two molecules is under the control of the enzyme MAT (methionine adenosyl transferase) (1), see figure 1.

SAMe and methylation

SAMe is the most important methylating agent in the brain. It is a methyl donor meaning that it provides methyl groups (essential factors needed for optimal health) to proteins, DNA and other molecules (2).
Methyl group deficiency has been blamed for causing depression and other brain or neuron diseases. Methylation is an essential process needed for maintaining active neurotransmitters, hormones and phospholipids which help the brain remain in sharp condition.

Specifically, SAMe increases the action of several neurotransmitters (dopamine, serotonin and norepinephrine for example) by facilitating the binding of these to cell receptors (3). It also increases the function of the cell membrane by boosting the production of an essential constituent, phosphatidyl choline. It stimulates polyamine synthesis which, in turn, enhance phosphorylation of proteins within the neurons, a therapeutic mechanism of many classic antidepressants. SAMe helps maintain mitochondrial function at peak levels, thus increasing energy production in the brain. In addition, SAMe has antioxidant properties, protecting brain tissues against damage from lipid peroxidation. Importantly, it also increases the production of the body’s own glutathione which is a strong antioxidant involved in many brain processes (4).

SAMe, one of the best

The value of SAMe in treating depression has been well recognized (5) but it is not generally appreciated that SAMe is also one of the best all-round antiaging supplements available. In my book The Anti-Aging Plan (Element, 2000) I praise SAMe as one of the six key ingredients of the modern equivalent of the ‘elixir of youth’ (the others being DHEA, co-enzyme Q10, ginkgo biloba, carnosine and isoflavones).

SAMe has a host of antiaging benefits with virtually no serious side effects. It improves liver function, enhances cognition and protects the brain, reduces the symptoms of arthritis, may have a role to play in preventing heart disease and affects some basic mechanisms of the aging process. It is widely used in Europe (mainly Italy and Germany) to treat depression and arthritis, and it remains very valuable in treating not only many other age-related conditions, but also depression resulting from these conditions (see below). It is considered to be the day-time equivalent of melatonin. SAMe concentrations are high during the day (it is involved in daytime alertness by increasing serotonin). One the other hand, melatonin is low during the day and high during the night so it promotes sleep. SAMe works in unison with melatonin to co-ordinate day-night natural rhythms in the body. Also, SAMe is important in the synthesis of melatonin.

The levels of SAMe are low in people suffering from depression (6). The enzyme MAT which is necessary for the production of SAMe was also found to be low in the red blood cells of patients suffering from depression. Increasing age, dementia and alcohol abuse are all related to low concentrations of SAMe (7). Lack of folic acid or of vitamins B6 and B12 may also cause low SAMe concentrations in the brain. These vitamins play an essential part in the metabolism of SAMe.

SAMe – Supplementation

Supplementation with SAMe was shown to reverse many symptoms associated with depression, such as low mood, tiredness (5), and anxiety or stress (8). When depressed patients are treated with SAMe, they exhibit an increase of the levels of SAMe in their blood and cerebro-spinal fluid (9).

Depressed patients frequently turn to alcohol for relief of their problems but this actually worsens their condition. Too much alcohol interferes with the production of SAMe. Without SAMe protection, the liver becomes more susceptible to toxic damage. Also, the resulting reduction of SAMe worsens depression, creating a catch-22 situation. Thus, SAMe supplements not only protects the liver against alcohol-related damage, but also reduces alcohol-related depression (10).

Patients suffering from fibromyalgia or Parkinson’s disease frequently also have depression which is amenable to treatment with SAMe. In a double blind, cross-over study examining the effects of SAMe on depression associated with Parkinson’s disease, 72% of patients reported an improvement with SAMe as compared to placebo (11). SAMe has a positive effect on dopamine, a neurotransmitter which is low in Parkinson’s disease. Other studies in patients suffering from fibromyalgia, also showed improvement after using SAMe treatment. SAMe is known to positively affect the levels of serotonin and this neurotransmitter improves pain and depression, both very common symptoms in fibromyalgia patients.

Treatment with SAMe is also effective in depression associated with Alzheimer’s disease where the levels of SAMe were found to be virtually non-existent (12, 13). Preliminary studies suggest that SAMe may help improve not only depression but also other symptoms of Alzheimer’s dementia in some patients (14).

It is clear from many experiments that SAMe is effective in depression and this effectiveness is superior to placebo. Compared to conventional antidepressants, SAMe also does well. Several trials show that SAMe is as effective or superior to imipramine and other tricyclic antidepressants (such as amitriptyline, desipramine and clomipramine) (15). Patients who do not respond to treatment with other antidepressants or those who cannot tolerate tricyclic/SSRI antidepressants, may find SAMe particularly useful (11). SAMe is so efficient that it may also be used to protect the brain and moderate behavior during extended space flights in the future (for example, to Mars). In an experiment, it was shown that SAMe protects against irradiation by cosmic rays which cause accelerated brain aging and depression (16).

In total there are dozens of placebo-controlled trials showing the effectiveness of SAMe in depression, both as compared to placebo and as compared to other antidepressants (15, 17).

SAMe Dosage

Over 150,000 Americans and many thousands of Europeans use SAMe supplements regularly. In some European countries SAMe is used more frequently than the antidepressant Prozac ®.
The starting dose could be 200mg or even lower, but most users take anything between 400mg to 2000mg a day. This agrees with published studies using doses of SAMe in accordance to body weight. It can also be given intravenously for more pronounced effects (18). The use of SAMe, either in tablet or in injection form, is expensive but many people who can afford its use report significant and worthwhile benefits.

Advice on using SAMe

  • Use only pharmaceutical grade products.
  • Take it on an empty stomach.
  • The benefits are usually felt within a few days but it can take a few weeks for the full effects to become apparent. This is a characteristic common to many other antidepressants.
  • Choose enteric coated tablets (these facilitate absorption, reduce the likelihood of side effects and maintain high concentrations of the active product).
  • Don’t break, crush or chew the tablet.
  • Keep the tablets out of light, somewhere cool, preferably in the refrigerator.
  • Use under medical supervision.

For best results it is recommended to also take TMG (trimethylglycine) 500mg-2000mg twice a day (which increases the metabolism of SAMe), and also other co-factors such as folic acid (up to 1mg a day), vitamin B6 up to 100mg a day, and vitamin B12 1mg a day. These will prevent SAMe from being metabolized into harmful homocysteine and will help re-methylate homocysteine back to SAMe, so they may be useful in those who want to reduce the dose of SAMe and still get the full benefits.


The manufacturing of SAMe is a difficult process involving substantial costs. Also many SAMe preparations on the market may not provide as much active ingredients as advertised on the box (Ed.- This is why IAS carries the original Italian SAMe called Donamet, because it is pharmaceutical and the original clinical results were based upon results obtained with it). This is because it is difficult to test and substantiate any claims regarding the strength of the preparation, and also because the molecule is very unstable (particularly if exposed to light for some time), so by the time it reaches the patient there is little active ingredient left. Do not use it to treat manic depression or severe depression. All depressed patients should seek advice from their physician before using any drugs or supplements. Side effects are rare and mild. These may include gastric upset with nausea and vomiting. Adverse reactions are more severe if SAMe is used together with other antidepressants (this should only be done under strict medical supervision). If used at high concentrations it may also cause dry mouth, restlessness and, rarely, anxiety. Reducing the dose usually helps avoid these side effects. The main contraindication for its use is mania, because on rare occasions it can worsen the condition (19).

Summary of the mechanisms of SAMe action in depression

  • SAMe increases the action of dopamine, serotonin and other neurotransmitters in the brain, thus elevates mood and reduces depression (this is basically the same mode of action of other antidepressants).
  • SAMe protects the brain cells from damage (20) – it’s an antioxidant.
  • SAMe methylates molecules within neurons and keeps these in active condition.

SAMe is a natural substance found in every living cell, unlike other prescription antidepressants, and even unlike St Johns Wort or other “natural” remedies. It is a valuable agent in treating depression and other age-related diseases. It deserves more widespread use and evaluation of its benefits.


NB. The abbreviation ‘SAMe’ is used instead of ‘S-adenosyl-methionine’

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14. Effects of SAMe on cognitive and vigilance functions in the elderly. Curr Ther Res Clin Exp 1994, 55:6.

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16 . Joseph JA et al. Magnesium activation of GTP hydrolysis or incubation in SAMe reverses iron-56 particle-induced decrements in oxotremorine enhancement of K+evoked striatal release of dopamine. Radiat Res 1999, 152(6):637-41.

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20. SAMe protects against neurotoxicity, European J Pharmacol 1993, 241(1):1-6.