Anup Sharma, MD, PhD,1 Patricia Gerbarg, MD,2 Teodoro Bottiglieri, PhD,3 Lila Massoumi, MD,4Linda L. Carpenter, MD,5 Helen Lavretsky, MD,6 Philip R. Muskin, MD,7 Richard P. Brown, MD,7 and David Mischoulon, MD, PhD8
Associated Data
Introduction
Complementary, alternative, and integrative medicine (CAIM) includes a wide range of biological, psychological and mind-body treatments being used to enhance standard medical practices and improve patient outcomes. Integrative Psychiatry (IP), a form of CAIM, “seeks to enrich mainstream mental health care with valuable treatments from global healing traditions as well as from modern laboratories in related fields.” (1,2). CAIM interventions include nutraceuticals, classified by the US Food and Drug Administration [FDA] as “dietary supplements,” defined as products intended for ingestion that contain ingredients such as vitamins, minerals, amino acids, herbs or other botanicals and nutrient concentrates, metabolites, or constituents. Many patients with mental health disorders utilize these modalities, often without physician supervision (3,4). Understanding the growing evidence supporting the efficacy of certain CAIM therapies will prepare clinicians to better advise patients when discussing integrative treatments.
S-adenosylmethionine (SAMe) was discovered in 1952 by the late Italian scientist and former National Institutes of Health biochemistry director, Giulio Cantoni (5,6). It is an endogenous, intracellular amino acid metabolite and enzyme co-substrate involved in multiple crucial biochemical pathways, including biosynthesis of hormones and neurotransmitters (7–9). SAMe concentrations have been measured in blood and cerebrospinal fluid (CSF) with ranges established in normal (10,11) and disease states. SAMe deficiency in CSF has been reported in patients with rare inherited defects in folate and methionine metabolism (12,13) as well as in more common diseases such as depressive disorders, Alzheimer’s Dementia, Parkinson’s Disease and HIV infection (14,15). Deficiencies of folate and vitamin B12, necessary co-factors in the synthesis of SAMe, may account for decreased SAMe levels, especially in patients with depression and dementia. Studies have shown that with either oral or parenteral treatment, SAMe crosses the blood-brain barrier and increases CSF levels, including in patients with neuropsychiatric conditions (14,15). As a CAIM therapy, SAMe has been utilized for treatment of psychiatric and medical conditions in Europe for over 30 years. In the United States, it became better known after 1999 as an over-the-counter dietary supplement under the Dietary Supplement Health and Education Act (DSHEA).
This review summarizes clinical trials of SAMe for treatment of neuropsychiatric disorders and co-morbid conditions encountered by psychiatrists in practice. To provide information that will assist clinicians considering treatment options in a broad range of complex clinical situations, we discuss literature encompassing samples of patients with a wide variety of neuropsychological symptoms for whom decisions about psychiatric treatments may take into account co-existing medical conditions and medication interactions. In addition to preclinical research, we include results from controlled trials, open studies and case reports on SAMe monotherapy and augmentation therapy. SAMe safety, contraindications, and medication interactions are addressed. This review also highlights limitations of the current literature and suggests future potential areas for research.
Results
Preclinical Studies
SAMe is the universal methyl donor in more than 100 methyltransferase reactions, which regulate essential metabolic pathways (see review, by 6,16). Methylation involves the transfer of a methyl group (CH3) to an acceptor molecule (Figure 2), including DNA bases, proteins, phospholipids, free amino acids and neurotransmitters. DNA methylation can turn gene transcription “on” or “off.” Similarly, methylation of proteins results in post-translational modifications that can regulate enzyme activity. Methylation of phospholipids is necessary for cell-membrane integrity and optimal function of receptors in the lipid membrane bilayer. Aberrant methylation has been implicated as a pathogenic mechanism in central nervous system (CNS) disorders, including depression and dementia (16,18). Methyl group donation is a target mechanism for disease prevention, to delay disease progression, and to enhance therapeutic outcomes (16,19).
Figure 2S-adenosylmethionine in the Methylation Cycle
DHF, dihydrofolate; THF, tetrahydrofolate; 5-MTHF, 5-methyltetrahydrofolate; SAMe, S-adenosylmethionine; SAH, S-adenosylhomocysteine; MTHFR, methylenetetrahydrofolate reductase; MTR, methionine synthase; MAT, methionine adenosyltransferase; SAHH, S-adenosylhomocysteine hydrolase.
Reproduced with permission from Psychiatric Clinics of North America17
SAMe has been studied in animal models of depression (20,21). In rodents, SAMe dose-dependently decreases immobility time in the forced swimming test (22) and increases concentrations of CNS monoamine neurotransmitters, serotonin and norepinephrine (23). Animal studies show that chronic SAMe administration increases dopaminergic tone in brain regions, including rat striatum (24), and increases CNS beta-adrenergic receptor density and activity (25,26). Thus, studies of central monoaminergic neurotransmitters support proposed mechanisms for SAMe antidepressant effects. SAMe may also have modulatory effects on cell signaling pathways in the CNS. In rats, chronic treatment with SAMe resulted in a marked increase in calcium/calmodulin dependent protein kinase II (CaMKII) in synaptic vesicles from the hippocampus, as well as a marked increase of synapsin I in the synaptic cytosol of the hippocampus and frontal cortex (27). Typical antidepressants have been shown to activate CaMKII and synapsin I, which suggests that SAMe may share a similar modulatory action on neurotransmitter release.
A growing literature linking relative hypomethylation to disease pathophysiology in dementia includes reports of decreased SAMe concentrations in CSF in patients with Alzheimer’s disease (28), hypomethylation of proteins that regulate levels of CNS phosphorylated-Tau, (29,30) and hypomethylation of genes that affect expression of beta-amyloid protein (31). SAMe affects site-specific methylation of DNA-promoter regions that regulate gene function, and carboxymethylation of proteins that can regulate b-amyloid and Tau proteins, neuropathological hallmarks of Alzheimer’s disease (18).
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