Clinical studies performed as early as 1973 indicated that SAMe had antidepressant effects (38). Over the next two decades, the efficacy and therapeutic benefits of SAMe in depressive disorders was confirmed in over forty clinical trials. Several review articles that summarize these studies were published in 1988 (4), 1989 (5), 1994 (6), and 2000 (12).
In a meta-analysis, conducted by Bressa (6) where twenty-five controlled trials including a total of 791 patients where reviewed. The statistical outcome of this analysis showed that SAMe had a significantly greater response rate than the placebo and was comparable to tricyclic antidepressants. Brown et al (12) summarized the literature on the use of SAMe in depressive disorders up to the time of publication in 2000; they reported that SAMe had been studied in sixteen open, uncontrolled trials (660 patients); thirteen randomized, double-blind, placebo-controlled trials (537 patients); and nineteen controlled trials comparing SAMe with other antidepressants (1134 patients). Significant antidepressant effects were observed in all sixteen open trials. In eighteen controlled trials, SAMe was as effective as was impramine, chlorimipramine, nomifensine, and minaprine. An important observation from these studies is that SAMe had far fewer side effects than other remedies.
The antidepressant effect of SAMe is of particular interest because of the close metabolic relation between folate and SAMe and the association of a high incidence of folate deficiency with depression (39, 40). Experimental animal studies showed that folate deficiency can reduce brain SAMe concentrations (41), and folate-deficient patients were shown to have significantly lower concentrations of SAMe and metabolites of dopamine and serotonin in CSF (42). The restoration of CSF SAMe concentrations after parenteral or oral SAMe dosing, and by inference the replenishment of CNS tissue methyl groups, may in some way be related to the therapeutic effect.
The exact mechanism of the antidepressant effect of SAMe is not clear, although preclinical studies indicated that SAMe has stimulatory effects on monoamine metabolism, monoamine turnover, or both. In agreement with this, SAMe dosing reportedly increased rat brain concentrations of norepinephrine (43, 44) and serotonin (45, 46). In humans, SAMe dosing increased the concentrations of 5-hydroxyindole acetic acid (47), a marker for serotonergic activity. It has been theorized that the stimulatory effect of SAMe on central monoaminergic neurotransmitters is the mechanism underlying its antidepressant effect. Alternative mechanisms may exist in which increased or restored membrane phospholipid methylation plays a role in the antidepressant effect. SAMe, by virtue of its ability to act as a methyl donor, may increase the fluidity of cell membranes by stimulating phospholipid methylation. An increase in cell membrane fluidity was linked to an increase in β receptor density (48) and muscarinic (M1) receptor density (49). The effect of SAMe on receptor systems is of particular interest because evidence suggests that age changes in the membrane environment, especially those resulting in increased viscosity, may be responsible for G protein–receptor coupling-uncoupling dysfunction (50). The therapeutic beneficial effects of SAMe dosing suggest a possible strategy for various systems that exhibit G protein–receptor coupling-uncoupling dysfunction.
In summary, some research suggests that SAMe is more effective than placebo in supporting mild-to-moderate depression without the associated side effects (headaches, sleeplessness, and sexual dysfunction) with other therapeutic alternatives. In addition, other alternatives tend to take 6 – 8 weeks, while SAMe seems to begin more quickly.