S-Adenosyl-L-Methionine: Effects on Brain Bioenergetic Status and Transverse Relaxation Time in Healthy Subjects Marisa M. Silveri, Aimee M. Parow, Rosemond A. Villafuerte, Karen E. Damico, Jessica Goren, Andrew L. Stoll, Bruce M. Cohen, and Perry F. Renshaw Background: S-adenosyl-L-methionine is an effective treatment for clinical depression, although the neural mechanism is unclear. Presently, in vivo phosphorus magnetic resonance spectroscopy ( 31 P MRS) and brain transverse relaxometry were employed to test if S-adeno- syl-L-methionine alters brain bioenergetics and/or trans- verse relaxation time (T2RT) in a nondepressed cohort. If these magnetic resonance techniques are sensitive to S-adenosyl-L-methionine induced alterations in neuro- chemistry, these methods may be used in cases of clinical depression to elucidate the mechanism underlying the antidepressant effect of S-adenosyl-L-methionine. Methods: Twelve subjects self-administered 1600 mg of oral S-adenosyl-L-methionine daily. Phosphorus spectra and T2RT were acquired at baseline and after treatment using a 1.5 Tesla scanner. Results: Phosphocreatine levels were significantly higher after treatment, whereas  nucleoside triphosphate levels, predominantly adenosine triphosphate in brain, were sig- nificantly lower. A surprising gender difference in T2RT time emerged after supplementation, with women exhibit- ing significantly lower T2RT than men. Conclusions: Alterations in phosphocreatine and  nucle- oside triphosphate are consistent with the report that S- adenosyl-L-methionine is involved in the production of cre- atine, which in turn is phosphorylated to phosphocreatine using adenosine triphosphate. These findings suggest that S-adenosyl-L-methionine alters parameters associated with cerebral bioenergetic status and that some effects of S- adenosyl-L-methionine (T2RT) occur in a gender-specific manner. Biol Psychiatry 2003;54:833– 839 © 2003 Society of Biological Psychiatry Key Words: Depression, SAMe, cerebral metabolic func- tion, 31 P MRS, T2RT, MRI Introduction T here is a growing body of evidence that patients diagnosed with depression exhibit compromised cere- bral bioenergetic status (e.g., blood flow and metabolism). For instance, positron emission computed tomography (PET) and single photon emission tomography (SPECT) studies have shown that rates of cerebral glucose metab- olism in depressed patients are reduced when compared to healthy controls (Buchsbaum et al 1986; Drevets 1998; Dunn et al 2002; Kimbrell et al 2002; Mayberg 1994). Noninvasive phosphorus magnetic resonance spectros- copy ( 31 P MRS) studies also have demonstrated that patients with major depression exhibit significantly re- duced levels of  nucleoside triphosphate (-NTP) (pre- dominantly adenosine triphosphate [ATP] in brain) when compared to nondepressed individuals (Moore et al 1997; Renshaw et al 2001; Volz et al 1998). S-adenosyl-L-methionine (SAMe) has been implicated as an effective means of treating clinical depression (Bressa 1994; Kagan et al 1990; Sherer et al 1986), especially when patients are unresponsive to standard tricyclic treatment such as clomipramine or imipramine (Bell et al 1994; Rosenbaum et al 1990). Interestingly, when compared to healthy individuals, patients with major depression exhibit low levels of SAMe in cerebral spinal fluid (Bottiglieri et al 1990), as well as reduced activity of methionine adenosyltransferase (MAT), an enzyme involved in the synthesis of SAMe from methio- nine (Alarcon et al 1985; Bottiglieri et al 1994). Although, to date, the neural mechanism underlying SAMe’s antidepressant effect is unclear, it is well docu- mented that SAMe serves as a principal biological methyl donor and thus participates in several cellular processes (Baldessarini 1987; Lu 2000; Stramentinoli 1987). For example, SAMe (with N-guanidinoacetate methyltrans- From the Department of Psychiatry (MMS, ALS, BMC, PFR), Harvard Medical School, Boston; Brain Imaging Center (MMS, AMP, RAV, ALS, BMC, PFR) and Psychopharmacology Research Laboratory (KED, JG, ALS, BMC), McLean Hospital, Belmont; and Pharmacy Practice (JG), Northeastern Univer- sity, Boston, Massachusetts. Address reprint requests to Marisa M. Silveri, Ph.D., Brain Imaging Center, McLean Hospital, Belmont, MA 02478. Received September 20, 2002; revised December 17, 2002; accepted December 20, 2002. © 2003 Society of Biological Psychiatry 0006-3223/03/$30.00 doi:10.1016/S0006-3223(03)00064-7