Bioavailability and Lack of Toxicity of S-Adenosyl-L-Methionine (SAMe) in Humans

Jessica L. Gören, Pharm.D.; Andrew L. Stoll, M.D.; Karen E. Damico, B.A.; Ingrid A. Sarmiento, B.A.; Bruce M. Cohen, M.D., Ph.D.


Pharmacotherapy. 2004;24(11) 

In This Article

Abstract and Introduction

Study Objective: To determine if S-adenosyl-L-methionine (SAMe), a widely used dietary supplement with antidepressant properties, is significantly bioavailable, and whether toxic methylated compounds are produced with oral SAMe administration in humans. Serum homocysteine levels were also measured since alterations in these levels have been theorized in association with SAMe.
Design: Unblinded pharmacokinetic trial.
Subjects: Fifteen healthy volunteers.
Setting: Clinical research unit in a psychiatric hospital.
Intervention: Subjects received oral SAMe for 4 weeks; the dosage was titrated over 5 days to 1600 mg/day. Serum levels of SAMe, toxic methylated compounds (methanol, formaldehyde, and formic acid), and homocysteine were measured at baseline and at weeks 2 and 4. At baseline, a structured clinical interview for axis I disorders (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) was completed to assess for any undiagnosed psychiatric disorders. Mood was rated at baseline and at weeks 2 and 4 using the Zung Depression Rating Scale, Young Mania Rating Scale, Montgomery-Asberg Depression Rating Scale, Clinical Global Impression Scale, and the Global Assessment of Function Scale.
Measurements and Main Results: After oral administration, SAMe levels were significantly elevated. Slight, likely insignificant, elevations in serum formaldehyde levels were detected in three subjects. No subject exhibited elevated homocysteine levels during SAMe treatment. One subject developed a transient mixed manic state with suicidal ideation within 2 weeks of starting SAMe; she recovered fully within 3 days of discontinuing the compound.
Conclusion: Oral dosages of 1600 mg/day of SAMe appear to be significantly bioavailable and nontoxic, at least regarding toxic methylated metabolites and homocysteine. However, the risk of mania in vulnerable individuals remains a serious concern.

S-adenosyl-L-methionine (SAMe) is an endogenous compound that functions as a methyl donor in many cellular processes.[1,2,3,4,5,6,7] It is not an essential dietary supplement, as humans can synthesize it from methionine and adenosine triphosphate (ATP).[2] Since SAMe synthesis is dependent on vitamin B12 and folate metabolism, deficiencies in these vitamins may lead to decreased SAMe levels.[3]

S-adenosyl-L-methionine is commercially available as a dietary supplement and is being used for the treatment of many medical disorders, including depression. Reports on the antidepressant activity of SAMe date back more than 20 years. A critical review of the literature indicates that intravenous SAMe is almost certainly a mood-elevating substance[1,3,4,5,6,7,8,9,10]; however, debate continues as to whether definitive data exist regarding the antidepressant effects of oral SAMe. The compound crosses the blood-brain barrier. Potential explanations for its role as an antidepressant likely include decreased serotonin and norepinephrine uptake, dopamine turnover, and enhanced signal transduction through improved receptor-effector coupling by way of increased membrane fluidity.[5,6,7]

Exogenous SAMe has a low bioavailability due to first-pass effects, rapid metabolism, chemical instability of the molecule, and past problems with tablet dissolution in some commercial preparations.[5,8,11] An enteric-coated formulation is in widespread use, which reaches a peak plasma level within 5 hours and has a half-life of 1-2 hours.

Since SAMe is metabolized to S-adenosylhomocysteine and ultimately to homocysteine, it is theoretically possible that SAMe administration could lead to hyperhomocysteinemia.[12,13,14] Elevated homocysteine levels are an established risk factor for cardiovascular and renal disease.[12,13] In contrast, due to SAMe-associated elevations in 5-methyltetrahydrofolate, a cofactor of homocysteine metabolism, SAMe has been postulated to be effective in treating elevated homocysteine levels.[12]

A 1972 report indicated that rats produced substantial amounts of methanol after administration of SAMe.[14] Thus, a theoretical but particularly hazardous consequence of SAMe use is the formation of toxic methylated compounds in vivo (Figure 1). These small methylated molecules may be formed by enzymatic action on SAMe and water. Very high levels of methanol, and related molecules, such as formaldehyde and formic acid, are systemically toxic and may cause death. Lower levels may lead to blindness through destruction of the optic nerve.[2,14]

The metabolic pathway of methanol shows the formation of toxic methylated compounds in vivo.

It is not known if humans form methanol or other toxic methylated compounds in response to SAMe administration. Rats differ somewhat from humans in the relative activities of the various enzymes used in methylation reactions and in the degradation of small methylated compounds, such as methanol. Although it is unlikely that SAMe supplementation in humans is associated with the formation of acutely toxic concentrations of methanol, formaldehyde, or formic acid, small or moderate amounts of these toxic methylated molecules may be formed. Whether the subacute or chronic presence of low or moderate levels of such methylated compounds is toxic is also not known.

As it is a dietary supplement, SAMe has never undergone the rigorous safety testing required for prescription drugs, and although short-term trials have suggested that SAMe is safe, no long-term data exist. Enthusiastic media reports of SAMe have ignored documented hazards and adverse effects, particularly mania induction in patients with a bipolar diathesis.[5,10,15] Other potential adverse effects include flatulence, diarrhea, headache, and nausea.[4,5,10]

The widespread use of SAMe and the unanswered questions regarding toxicity led us to study the bioavailability and safety of oral SAMe by measuring serum levels of SAMe, homocysteine, methanol, formic acid, and formaldehyde.


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