Fighting the winter blues with complementary and alternative therapies
This is the second in a series of posts on complementary and alternative (CAM) approaches to depressed mood. As I write I am thinking of many of my own patients who find themselves struggling more as the days grow shorter. This post is about S-adenosyl-methionine (SAMe), a widely used natural supplement with an established track record for treating depressed mood. Future posts will review the evidence for other natural supplements, mind-body approaches, exercise, and a variety of other complementary and alternative approaches you can use to fight the winter blues.
How SAMe works to improve depressed mood
SAMe is a naturally occurring molecule in bacteria, plants, and animals and plays many important roles at the level of genes, immune function, and amino acid metabolism. In humans, SAMe is an important methyl donor, an essential step in the synthesis of several neurotransmitters from amino acids in the diet. The antidepressant effects of SAMe are probably related to multiple mechanisms of action including increased brain levels of serotonin, dopamine, and norepinephrine. The synthesis of these neurotransmitters by SAMe requires vitamin B12 and folate. Many depressed individuals are deficient in B vitamins thus individuals taking SAMe for depressed mood will benefit from taking vitamin B12 and folate (especially in the form of l-methyl-folate) concurrently. In addition to the effects of SAMe on the above neurotransmitters, it has been suggested that antidepressant effects of SAMe are mediated by anti-inflammatory effects, changes in neuronal membrane fluidity, increased rate of serotonin turnover, inhibition of norepinephrine reuptake, and beneficial synergistic effects of SAMe on dopamine activity. Antidepressant effects of SAMe may also be mediated by anti-inflammatory effects and changes in neuronal cell membrane fluidity.
Research findings show efficacy comparable to antidepressants
SAMe has been widely used for decades to treat depressed mood and osteoarthritis in many European countries where it is available on a prescription basis in oral form, as an intramuscular injection, or for intravenous use. SAMe degrades rapidly when exposed to air and stable oral preparations posed manufacturing challenges for many years. Thus, many early studies investigated the antidepressant efficacy of SAMe administered intramuscularly or intravenously. Early studies reported that effective antidepressant doses of SAMe are significantly smaller when administered intravenously, and showed that few patients receiving SAMe intravenously had adverse effects.
In the U.S., SAMe is available in oral form only and can be purchased as an over-the-counter tablet in pharmacies and health food stores. Shelf-life can be prolonged by refrigeration and protecting SAMe from degradation in blister packs. e-counter supplement in pharmacies and health food stores. Oral SAMe is available in two different forms. Oral forms of SAMe are combined with other molecules to reduce the rate of oxidative degradation and extend shelf life. The butane-disulfonate is available as an enteric-coated tablet and may have significantly greater bioavailability and longer shelf life than the tosylate form.
The standard maintenance regimen of oral SAMe for depressed mood is between 800 and 1600 mg/day in two to four divided doses. A common dosing strategy is to start SAMe at a dose of 200mg twice daily, and gradually increase to 400mg twice daily, monitoring for side effects and therapeutic response. Absorption is improved when SAMe is taken on an empty stomach (i.e., before meals).
Advantages of SAMe compared to prescription antidepressants
Most currently available antidepressants have a delayed onset of action thus consistent improvement in mood may be noticeable only after four to six weeks of daily use. In contrast, SAMe has a relatively rapid onset of action, usually within one week of starting treatment. Another important advantage of SAMe is the absence of clinically significant interactions with prescription medications and relatively few side effects compared to antidepressants.
In addition to its mood enhancing effects, there is evidence that augmentation with SAMe 400mg twice daily in individuals who are not responding to antidepressant therapy, may improve memory and other cognitive problems that often accompany depressed mood (Levkovitz 2012)
SAMe enhances response to antidepressants
Meta-analyses of placebo-controlled studies support that SAMe when used as a monotherapy is as effective as many widely prescribed antidepressants (Hardy et al 2003; Sharma et al 2017). Studies published in peer-reviewed medical journals support that combining SAMe with an SSRI antidepressant or venlafaxine (a serotonin-norepinephrine reuptake inhibitor) improves overall response and may accelerate response rate equivalent to results achieved when augmenting an SSRI antidepressant with bupropion or venlafaxine. The mechanism of action by which SAMe augments the effects of widely used prescription antidepressants in cases where a patient has become non-responsive, may involve re-externalizing neurotransmitter receptors that have been internalized by the nerve cell membrane during prolonged exposure to an antidepressant.
Findings of a landmark study published in the American Journal of Psychiatry provided “preliminary evidence that SAMe can be an effective, relatively well-tolerated, and safe adjunctive treatment strategy for SSRI non-responders diagnosed with major depressive disorder (Papakostas 2010).” Individuals included in the study continued on recommended doses of commonly prescribed antidepressants including paroxetine, citalopram, duloxetine and other, while also taking SAMe. The authors noted that significantly more patients treated with adjunctive SAMe experienced clinical improvement and remission compared to matched patients receiving a placebo. The significance of findings was limited by small study size (73 total patients), the short duration of the study (6 weeks), failure to include a comparison group taking an antidepressant only.
Combining SAMe with an SSRI or other antidepressant is an integrative approach that improves outcomes while permitting a reduction in the dose of the conventional antidepressant by as much as 30% in some cases. The advantages of reducing the dose of a conventional antidepressant include fewer side effects and improved adherence to treatment. In addition to improving the efficacy of antidepressants, there is evidence that the adjunctive use of SAMe may reduce sexual side effects frequently caused by SSRIs and other antidepressants.
Safety issues
Although SAMe is well tolerated, transient anxiety, insomnia, gastrointestinal side effects, dry mouth, and dizziness have been reported. With continued treatment, most side effects resolve within days or a few weeks. Although many studies (including those reviewed above) show that SAMe may be safely used in conjunction with antidepressants, as SAMe affects serotonin synthesis, taking it together with another supplement or medication that increases CNS serotonin may cause serotonin syndrome, a potentially serious syndrome characterized by anxiety, agitation and insomnia. Please consult with your physician before taking SAMe together with an SSRI antidepressant or another medication that increases brain levels of serotonin. Rare cases of hypomania have been reported in patients diagnosed with Bipolar Disorder and it is advisable to avoid SAMe if you have been diagnosed with bipolar disorder.