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S-Adenosylmethionine (SAMe) - Effects on mental health

Dr. Philip Rouchotas
6 November 2014

S-Adenosylmethionine (SAMe) - Effects on mental health
by: Philip Rouchotas, MSc, ND

Bolton Naturopathic Clinic
64 King St W, Bolton, ON, L7E 1C7

S-Adenosylmethionine (SAMe) - Effects on mental health

What is SAMe?

S-Adenosylmethionine (SAMe) is a molecule that is distributed widely throughout the body and is crucial in a number of biochemical reactions. SAMe first garnered research attention in the 1970s, and has been used as an antidepressant in Europe since that time.[1] However it has not become available in North America until the last 15 years or so. Biochemically, SAMe functions as a methyl-group donor, and works in the same pathways as folic acid and vitamin B12. The most notable of these is the homocysteine cycle, which recycles homocysteine to methionine, using up folic acid, vitamin B12, and SAMe along the way. Homocysteine is a well-known marker for cardiovascular risk. Therefore, SAMe maybe crucial in reducing risk of heart disease and stroke. SAMe is also required in the synthesis of creatine, carnitine, as well as important neurotransmitters in the brain.[1] Although there is interest in SAMe for a variety of conditions including fibromyalgia, osteoarthritis, and liver disease, as well as mental health, we will focus primarily on its role in mental health and mood disorders.

There have been several possible mechanisms proposed to explain the effect of SAMe on mental health. First, SAMe is a required cofactor in the synthesis of certain neurotransmitters, signaling chemicals produced by the brain. These include norepinephrine, serotonin, and dopamine.[1] An increased supply of SAMe may increase the production of neurotransmitters thought to be deficient in patients with mood disorders. Secondly, SAMe is though to have a possible role in methylating the components of the cell membrane, called phospholipids, which may alter membrane fluidity and thereby affect cell-to-cell signaling, including in the brain.[1] Finally, SAMe is capable of methylating DNA, affecting the expression of genes involved in mood regulation.[1]

Depression Depression

Antidepressant medications belonging to the category Selective Serotonin Reuptake Inhibitors (SSRI) represent the most frequently prescribed type of antidepressant. SSRIs are also commonly used in the first-line treatment of depression, before stronger medications are prescribed. Unfortunately, SSRIs are subject to certain limitations. Frist, the response rate to SSRI medications is often suboptimal, with inadequate symptom relief achieved especially for patients with mild-to-moderate depression, and/ or a high rate of relapse. Secondly, side effects such as fatigue, worsening mood, insomnia, poor concentration, loss of libido, and weight gain are not uncommon. The discovery of natural agents that have the ability to increase the effectiveness and decrease the side effects of antidepressants would be a major advancement in this area.

A number of studies have examined the antidepressant effects of SAMe. One randomized, double blind, placebo controlled trial examined the ability of SAMe to augment the effectiveness of SSRI medications.[2] A total of 73 participants were enrolled who were deemed “nonresponders” to SSRI therapy. Participants continued with their SSRI medications and received in addition 800 mg SAMe twice daily, or placebo, for six weeks. Patients depression was monitored using the 17-item Hamilton Depression Rating Scale (HAM-D). At the end of six weeks, both the HAM-D response and remission rates were higher for patients treated with SAMe (36.1% and 25.8%, respectively) compared to placebo. In the SAMe group, over 36% of patients experienced a treatment response, compared to only 17% in the placebo group. A total of 25% of patients in the SAMe group had a remission, while only 11% in the placebo group did. The authors concluded that “SAMe can be an effective, well-tolerated, and safe adjunctive treatment strategy for SSRI nonresponders with major depressive disorder”.[2]

A secondary analysis was performed on these same patients, examining the effect of SAMe on the rate of cognitive-related impairments that are frequently associated with depression.[3] The results showed that there was a greater improvement in the ability to recall information, and a trend toward improved word-finding for patients who received adjunctive SAMe, compared to patients that received placebo. The authors concluded that “SAMe can improve memory-related cognitive symptoms in depressed patients”[3] and deserves further investigation.

An earlier study looked at the effect of SAMe in patients with resistant depression who were on the SSRI venlafaxine.[4] A total of 30 patients who were partial or non-responders to venlafaxine were given SAMe 800-1600mg per day for six weeks. After six weeks, the Hamilton Depression Rating Scale revealed a response rate of 50% and a remission rate of 43% following treatment with SAMe. This is an impressive outcome given that the subjects had been poor responders to pharmacologic therapy. Side effects included mild gastrointestinal symptoms and headache.

Special Populations Special Populations

Finally, SAMe has also been studied in specific patient populations suffering from depression. These include patients living with HIV/ AIDS and patients with Parkinson’s disease. A total of 20 patients who were HIV positive were treated with SAMe for eight weeks.[5] At the end of this time period, there was a significant and rapid improvement in depression. The onset of effect was as early as one week, with added improvement progressively over the course of the eight weeks.

A pilot study examined thirteen patients with Parkinson’s disease (PD) who had previously been treated with antidepressants, with either lack of benefit or intolerable side effects.[6] Patients were administered 800-3600mg SAMe per day for ten weeks. Of eleven patients that completed the study, ten had improvements of 50% or more on the 17-point Hamilton Depression Scale (HDS). Two patients prematurely terminated participation in the study because of increased anxiety, however it is unclear if this was due to SAMe treatment or not.

Schizophrenia Schizophrenia

One study examined the effects of SAMe supplementation in patients with schizophrenia. Since SAMe has been shown to increase the activity of the enzyme catechol-O-methyltransferase (COMT), this study included patients known to have low activity of this enzyme.[7] A total of 18 patients with chronic schizophrenia were randomized to receive 800mg SAMe or placebo daily for 8 weeks. The results indicated a mild reduction in aggressive behavior and improved ratings for quality of life following SAMe administration. Two patients receiving SAMe experienced some exacerbation of irritability. However, researchers were cautiously optimistic that SAMe may have the potential to improve certain aspects of schizophrenia and improve patients’ quality of life.

Cognitive decline Cognitive decline

Various natural agents that act as methyl donors have been investigated for use in the treatment of cognitive decline, including methylcobalamin, betaine, and choline. In a study of patients with Alzheimer’s found that compared to healthy controls, Alzheimer’s patients had lower levels of SAMe present in the cerebrospinal fluid, the fluid surrounding the brain.[8]

In patients with Alzheimer’s disease, supplementation with a combinational formula of nutritional agents including folic acid, B12, vitamin E, N-acetyl cysteine, Acetyl-L-carnitine, and SAMe resulted in improved symptoms.[9] A total of 14 patients with Alzheimer’s were given the formula for the duration of one year. There were improved in the Dementia Rating Scale as well as Clock-drawing tests (Clox 1 and 2). Family also reported improvement in areas of the Neuropsychiatric Inventory (NPI) and maintained ability to perform the activities of daily living. Performance on the Neuropsychiatric Inventory at three months was equivalent to results obtained through treatment with the Alzheimer’s medication donepezil.

A year later, the same research group published results of a randomized, controlled trial. This study examined the effects of the same formula in patients with moderate-stage or later-stage Alzheimer’s, compared with placebo.[10] In this study, participants receiving the nutritional formula had a clinically significant delay in decline in the Dementia Rating Scale and clock-drawing test, compared to patients on placebo. Caregivers reported an approximate 30% improvement in the Neuropyschiatric Inventory, along with maintained ability to perform activities of daily living for more than nine months, an impressive outcome.

In animal studies, supplementation with SAMe alone has been shown to reduce age-related mental decline.[11] A total of 36 dogs eight years of age or older who displayed signs of impaired cognitive function for at least one month were given oral SAMe or placebo for two months. Dogs treated with SAMe showed greater improvements in activity and awareness compared to those treated with placebo. In the SAMe treated group, there was a 57% improvement in activity, compared to only 9% in the placebo group. For mental awareness, there was a 59% improvement in the SAMe group, compared to just 21% in the placebo group. Overall, the aggregate mental impairment score was reduced by more than 50% in 41.2% of dogs treated with SAMe after two months. Authors concluded that SAMe was both safe and effective in improving signs of mental decline related to age in dogs.


SAMe is an important cofactor for many biochemical reactions in the body, including the production of neurotransmitters, cell membrane fluidity and signaling, as well as regulation of gene expression. SAMe levels may be lowered in patients with age-related cognitive decline. A number of studies have demonstrated effectiveness of SAMe as an adjunctive treatment for major depression. SAMe has also been shown to have promise in the treatment of certain aspects of schizophrenia, as well as age-related cognitive decline. SAMe may help maintain function in patients with early as well as moderate to late stage Alzheimers.