What does the evidence show about SAM-e (S-adenosylmethionine)'s effects?

Read Off Label rates the evidence for SAM-e (S-adenosylmethionine) as Moderate and the benefit magnitude as moderate, producing an overall grade of B- (6.3/10). Enteric coating and cool, dry storage address SAM-e's documented degradation and formulation stability.

What safety findings are reported for SAM-e (S-adenosylmethionine)?

SAM-e (S-adenosylmethionine) has a low-med risk profile in the database. Low-Med (GI upset; manic switching can occur in bipolar disorder; expensive; stability issues in storage) Legal status: Rx in EU; OTC in US.

Rankings / Mood, Anxiety & Stress

SAM-e (S-adenosylmethionine)

Mood, Anxiety & Stress · Methyl donor

Tier B-

Reviewed by Read Off Label · Last reviewed Jun 8, 2026 · How we grade

methylationprescriptionotc

6.3 / 10

Tier B-

Ev 6 Bn 5 Sf 7

Bottom line

Read Off Label grades SAM-e (S-adenosylmethionine) as B- (6.3/10) based on moderate evidence, moderate benefit magnitude, and a low-med-risk safety profile.

Enteric coating and cool, dry storage address SAM-e's documented degradation and formulation stability.

Studied, labeled, or reported-use context: 400-1600 mg/day PO divided, enteric-coated, empty stomach — Rx in EU; OTC in US; not individualized guidance.

What the evidence says

Enteric coating and cool, dry storage address SAM-e's documented degradation and formulation stability. Papakostas 2010 trial showed SSRI augmentation benefit in MDD nonresponders. Expensive relative to other antidepressant augmentation options. Clinical safety context includes bipolar-spectrum history because hypomania and mania appear in case reports.

Mechanism

Endogenous methyl donor; essential cofactor for methylation reactions including neurotransmitter synthesis and phospholipid production; influences homocysteine and folate cycle

Studied, labeled, or reported dose & route

400-1600 mg/day PO divided, enteric-coated, empty stomach

This records doses and routes described in studies, approved labeling, clinical practice, or documented use. It is not individualized guidance and does not establish safety; context changes with indication, formulation, health history, monitoring, and other medicines.

Citations

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Common questions

What does the evidence show about SAM-e (S-adenosylmethionine)'s effects?: Read Off Label rates the evidence for SAM-e (S-adenosylmethionine) as Moderate and the benefit magnitude as moderate, producing an overall grade of B- (6.3/10). Enteric coating and cool, dry storage address SAM-e's documented degradation and formulation stability.
What safety findings are reported for SAM-e (S-adenosylmethionine)?: SAM-e (S-adenosylmethionine) has a low-med risk profile in the database. Low-Med (GI upset; manic switching can occur in bipolar disorder; expensive; stability issues in storage) Legal status: Rx in EU; OTC in US.
What doses or routes are reported for SAM-e (S-adenosylmethionine)?: 400-1600 mg/day PO divided, enteric-coated, empty stomach This is context from studies, approved labeling, clinical practice, or documented use; it is not individualized guidance and does not establish safety.
How does SAM-e (S-adenosylmethionine) work?: Endogenous methyl donor; essential cofactor for methylation reactions including neurotransmitter synthesis and phospholipid production; influences homocysteine and folate cycle

This is an independent synthesis of published research by a non-clinician. Scores are opinions supported by citations, not prescriptions. See the full disclaimer and methodology for how this score was produced and what it does and doesn't mean.