S-Adenosyl l-methionine, or SAM-e, is a chemical produced naturally within the body for use in a number of different metabolic pathways. Supplements containing SAM-e have been used for decades in the treatment of a number of seemingly unrelated conditions. SAM-e has garnered a B rating from the Mayo Clinic for its demonstrable efficacy in the treatment of pain and inflammation, and C ratings for depression and intrahepatic cholestasis, requiring more studies for a strong endorsement as of 2011. In Europe, SAM-e is available by prescription only as the drug Ademetionine. Despite its established efficacy and long history of use, SAM-e's mechanism of action is not clearly understood. However, SAM-e is known to increase the levels of dopamine, serotonin and epinephrine in the brain, as do several newly developed anti-depressant medications. According to the Yale Prevention Research Center, SAM-e may may address some of the symptoms of depression not addressed by serotonin specific medications by increasing both dopamine levels and serotonin levels.
Discovered in 1952, SAM-e was quickly determined to play a central role in cellular biochemical pathways. SAM-e is an essential precursor in the transsulfuration, aminopropylation and methylation pathways. In transsulfuration, SAM-e directly rejuvenates homocysteine to produce glutathione, the body's most powerful antioxidant. It also facilitates pain relief and the reduction of inflammation through the synthesis of the pain-killing polyamines spermidine and spermine. This, as well as the recycling of the amino acid methionine, are accomplished through aminopropylation. In cellular methylation reactions, SAM-e acts as a methyl donor. Through this process, proteins, phospholipids and nucleic acids are manufactured. The monoamine neurotransmitters serotonin, norepinephrine and dopamine are also made in part through methylation.
The first generation of anti-depressant medications was the monoamine oxidase inhibitor class. Discovered accidentally, these drugs increased synaptic levels of not only serotonin, but also dopamine and norepinephrine. Although they were remarkably effective in treating depression, they fell into disuse because of their potentially lethal side effects. Although second and third generation antidepressants focused almost exclusively on increasing serotonin levels, new anti-depressant drugs in 2011 are once again focusing on increasing synaptic dopamine and norepinephrine. Increasing norepinephrine levels in the brain is thought to produce a feeling of increased energy, excitement and potentially stress. Increased dopamine levels, however, promote feelings of self-assurance, well-being, and satisfaction.
Although reduced levels of dopamine, serotonin and norepinephrine are associated with clinical depression, these chemicals cannot be taken as oral supplements. They are quickly destroyed by the enzyme monoamine oxidase. Regardless, they are structurally unable to cross from the bloodstream into the brain. SAM-e, however, is capable of crossing the blood-brain barrier, and may work by enabling the body to make more of these neurotransmitters directly within the brain.
Effects on Depression
As of 2011, serotonin specific anti-depressant drugs such as Prozac have been overtaken by drugs which also affect norepinephrine or dopamine levels. According to Pharmacy Times, the dopamine agonist medication Abilify has become the sixth most prescribed medicine in the country since it was approved as an add-on medication for depression. This trend is likely due to the inability of serotonin specific anti-depressants to adequately treat a pattern of symptoms accompanying depression that includes apathy, loss of pleasure, fatigue, excessive sleep, loss of interest and decreased motivation. These are all believed to be moderated not through the serotonergic system, but the dopaminergic system. SAM-e, with its dopamine and serotonin elevating properties, could potentially exert its antidepressant effects through this mechanism, as well.
- "American Journal of Clinical Nutrition"; Role of S-Adenosyl-L-Methionine in the Treatment of Depression: A Review of the Evidence; David Mischoulon and Maurizio Fava; November 2002
- "Clinical and Investigative Medicine"; S-Adenosylmethionine (SAMe) as Treatment for Depression: A Systematic Review; Yale Prevention Research Center; January 2005
- "Expert Opinion of Investigational Drugs"; Ademetionine (S-Adenosylmethionine) Neuropharmacology: Implications for Drug Therapies in Psychiatric and Neurological Disorders; Teodoro Bottiglieri; April 1997
- "Acta Psychiatrica Scandinavica"; The Antidepressant Potential of Oral S-Adenosyl-L-Methionine; J.F. Rosenbaum, et al.; August 2007