Life Extension Magazine January 2005
By Dale Kiefer
S-adenosyl-L-methionine, or SAMe, is a naturally occurring compound found in every cell in the human body. This ubiquitous substance is involved in many critical biochemical pathways. Although regulated as a prescription drug in Europe, SAMe is available in the US as a nutritional supplement. Extensive clinical research indicates that SAMe is a safe and effective remedy for depression, osteoarthritis, and liver disease, providing powerful relief without the side effects commonly associated with prescription medications.
SAMe and Depression
Depression affects 10-15 million Americans each year, with costs in treatment and lost wages estimated to be as much as $53 billion a year.1 While many prescription drugs are designed to treat depression, they are not always effective and often are associated with troublesome side effects. Fortunately, SAMe appears to offer significant relief from depression.
In 2002, the US government published a comprehensive report entitled “S-Adenosyl-L-Methionine for Treatment of Depression, Osteoarthritis, and Liver Disease.”1 The report represents a distillation of data gleaned from numerous published studies conducted around the world through 2000. In order to render its unbiased verdict, the federal Agency for Healthcare Research and Quality (a division of the US Department of Health and Human Services) evaluated data from 102 individual studies.
The agency carefully reviewed 47 relevant studies on SAMe and depression; 28 of these studies were included in a meta-analysis of the efficacy of SAMe in countering the symptoms of depression. The agency concluded, “Compared to treatment with conventional antidepressant pharmacology, treatment with SAMe was not associated with a statistically significant difference in outcomes…”1 In plain language, SAMe is just as effective as standard antidepressant drugs at treating depression. The report delivers similar endorsements for the efficacy of SAMe in the treatment of osteoarthritis and a form of liver disease.
This good news about SAMe’s efficacy in treating depression is especially important in light of recent news about antidepressants. The Food and Drug Administration (FDA) recently imposed stern warnings regarding the risks associated with the use of the newest class of antidepressant drugs, selective serotonin reuptake inhibitors, or SSRIs. A federal advisory panel responsible for scrutinizing the efficacy and safety of antidepressants for children announced its recommendation in September 2004, after debating the evidence for a year.
A “Black Eye” for Antidepressants
The news for antidepressant drug manufacturers was, in fact, depressing. The panel found that SSRIs not only increase the risk of suicide for some younger patients, but also are often ineffective. The panel urged the FDA to impose its strongest caution—known as a black box warning—regarding the use of this class of antidepressants in children and adolescents.2 In October 2004, the FDA followed the recommendation and mandated warnings for all SSRI drugs.
The panel’s investigation came on the heels of several highly publicized incidents in which children and adolescents on the drugs committed suicide, and it highlighted the downside of antidepressant drugs.3 Although only Prozac® is approved by the FDA for the treatment of depression in children and adolescents, other medications such as Zoloft®, Paxil®, and Celexa® are also commonly prescribed to these populations. All of these drugs belong to the SSRI class of antidepressants and are believed to work similarly.
The US debate was prompted last year when British officials banned the use of all SSRIs, except Prozac®, for use in children. Despite that action, most experts agree it is unlikely that Prozac® is inherently safer than other SSRIs for use in children and adolescents. Although the various SSRIs differ chemically, their mechanism of action in the body is essentially the same. All inhibit activity at structures known as uptake pumps, located on nerve endings. Most affect the reuptake of serotonin from the synapses, or spaces, between nerve endings. Some affect another messenger chemical, norepinephrine, in a similar manner. These drugs are known as serotonin norepinephrine reuptake inhibitors (SNRIs).
Serotonin and norepinephrine are neurotransmitters that regulate mood, sleep, appetite, and emotion, and are involved in a variety of physiological and behavioral functions. By preventing the immediate reuptake of serotonin (and/or norepinephrine), more of the precious brain chemicals remain available to do their intended work.4,5
Antidepressant Therapy’s High Cost
Unfortunately, even in adults, the depression relief afforded by SSRIs often comes at a steep price, and not just in monetary terms, though most SSRIs are far from inexpensive. The list of potential side effects includes headache, nausea, diarrhea, anxiety, sleep disturbances, weight gain, fatigue, and, most common of all, sexual dysfunction.6-8 The latter strikes up to 60% of patients taking SSRIs, and usually manifests as loss of libido, insufficient lubrication or arousal, or an inability to achieve orgasm.8,9 Among men who experience sexual side effects, erectile dysfunction occurs in up to 90% of cases.10 Understandably, many patients find this side effect particularly distressing.
Drug interactions with antidepressants are also a concern. Alcohol, the most common drug of all, may be especially risky. It causes potentially perilous sedation when mixed with antidepressants. Because of these side effects, many patients discontinue their medication at the risk of sinking back into depression. Not all patients respond to SSRIs, even when they do follow the dosage recommendations of the prescribing physician. Treatment failures range from 40% to 60%, and relapse rates are similarly discouraging. According to a recent report from Duke University Medical Center, an analysis of more than a decade of research on the subject shows that recurrence and relapse rates for drug-treated depression range as high as 80%.11 The same report noted that up to 44% of patients starting drug therapy discontinue taking the drug within three months. Many patients (28%) discontinue drug therapy due to intolerable side effects, often within the first month, before the drug takes effect.11
Although they are not perfect, the SSRIs are a vast improvement over previously available drugs and therapies for depression. In the first half of the twentieth century, physicians could offer little more than talk therapy or electroconvulsive therapy (ECT) as treatment for their patients with major depression. Although the former was often ineffectual, the latter works very well. However, ECT is time consuming, requires multiple treatments, and often produces some memory loss, as the brain is literally zapped with electrical current. Understandably, a certain amount of stigma is associated with the use of ECT. According to a survey of thousands of Consumer Reports subscribers who had recently undergone treatment for depression, talk therapy, while often useful, may require at least 13 sessions to achieve relief comparable to that available through drug therapy.12
Thus, when the first true antidepressant drug, a monoamine oxidase inhibitor (MAOI), was introduced in the 1950s, doctors hailed the dawn of a hopeful new era in the treatment of depression. But all was not rosy. MAOIs are particularly risky drugs; their side effects are numerous and often severe, and drug interactions are potentially fatal. The advent of tricyclic antidepressants in the 1960s marked a further advance in treatment. But even tricyclics, such as imipramine and amitryptyline, come with unpleasant side effects. Dosages must be carefully monitored, as therapeutic ranges are narrow and toxic overdoses are potentially fatal. Side effects tend to manifest quickly, but onset of action can take so long (from four to six weeks) that many patients discontinue the drug long before experiencing mood elevation.11,13
A Safer Alternative
Fortunately, a safer alternative to antidepressant drugs exists. For more than 30 years, SAMe, a natural substance that occurs in abundance in every living cell of every organism,14,15 has been prescribed in Europe for the treatment of depression. It finally became available in the US in the 1990s, where it is used improve mood, alleviate osteo-arthritis, and promote liver health.
SAMe is believed to banish depression by increasing the synthesis of neurotransmitters that are crucial to normal mood, behavior, and emotion.16,17 Although normally abundant, SAMe levels decline with age and drop dramatically during bouts of depression. A noticeable drop in SAMe levels is also associated with neurological disorders such as Alzheimer’s disease, Parkinson’s disease, and dementia due to HIV complications.18-20
In the body, SAMe is assembled from two building blocks: methionine, a simple amino acid, and adenosine triphosphate (ATP), a molecule that provides energy to cells. SAMe is a sort of biological jack-of-all-trades. It assists in transforming other molecules into more useful entities through a variety of chemical reactions. As a methyl donor, it enables the brain to manufacture vital neurotransmitters, including dopamine, serotonin, and norepinephrine from substrate molecules. Methyl groups are chemical entities—one carbon atom and three hydrogen atoms—that are added to or subtracted from other molecules to change their properties, in essence switching the molecules on or off, and prompting them either to fulfill their potential or to remain dormant. By donating a methyl group to DNA, SAMe acts to regulate production of important proteins involved in everything from immune function to cellular growth and repair.19
One of the components needed to synthesize SAMe in the body is methionine. Without adequate supplies of methionine, SAMe production falters. It is interesting to note that maintaining healthy levels of methionine depends on adequate levels of folic acid and vitamin B12. Depression has been associated with a deficiency in either of these vitamins.21,22 The implication of this is that deficiencies of vitamin B12 and folic acid lead to deficiencies of SAMe, and thus to deficiencies in crucial neurotransmitters such as dopamine, serotonin, and norepinephrine—all of which require the help of SAMe for synthesis.
Comparable Yet Better Results
Remarkably, in clinical trials, SAMe has proven to be just as effective an oral antidepressant therapy as the tricyclics.14,23,24 The tricyclics are, in turn, about as effective at relieving depression as the newer SSRIs,25 but SAMe has not yet been compared directly to any SSRIs. In clinical trials of SAMe versus a tricyclic and/or placebo, both SAMe and the tricyclic drug were judged equally effective at relieving depression, and both were significantly more effective than placebo.14,23,24,26,27
In fact, in numerous trials, the only significant difference noted between SAMe and a standard tricyclic favors the use of SAMe over the tricyclic: SAMe takes effect faster and has virtually no side effects. In a recent multi-center study conducted in Italy, for instance, researchers found that 1600 mg of SAMe taken orally each day provides the same antidepressant benefit as 150 mg per day
of the prescription tricyclic antidepressant imipramine. “However, significantly fewer adverse events were observed in the patients treated with SAMe,” wrote the researchers, in an article published in the American Journal of Clinical Nutrition.14 By contrast, the side effects of imipramine and other tricyclics are so many, and some are so serious, that a vast majority of physicians now prescribes SSRIs rather than tricyclics.28