Meta Information
ID:sam-e
Name:
Schema Version:2.4_uniform_evidence_2026_06_18
Created
2026-05-21T22:30:00Z
Model
phase-a-upgrade-claude-sonnet-4.6
Interactions
Target id:
/class/serotonergic-agents
Target name:
Serotonergic Medications (SSRIs, SNRIs, TCAs, Triptans)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
SAM-e can increase serotonin levels, and combining it with other serotonergic drugs creates a high risk of serotonin syndrome, a potentially life-threatening condition caused by excessive serotonin activity.
Actionable advice:
SAM-e should not be combined with these medications unless under the strict guidance of a prescribing physician.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The serotonin syndrome occurs following the use of serotomimetic agents (serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, tryptophan, 3,4-methylenedioxy-methamphetamine, dextromethorphan, meperidine, S-adenosylmethionine) alone or in combination with monoamine oxidase inhibitors.
Label source:
PubMed: Neurology (1995)
Source url:
Exact phrase from label:
our results suggest that the antidepressant-like effects induced by SAMe treatment are dependent on serotonin synthesis and 5-HT1A receptor activation.
Label source:
PubMed: Neurochemistry international (2023)
Source url:
Exact phrase from label:
Use of SAMe elicited no significant adverse effects beyond placebo, however it was implicated in one case of serotonin syndrome-like symptoms.
Label source:
PubMed: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology (2018)
Action type:
avoid
Target id:
/class/maois
Target name:
Monoamine Oxidase Inhibitors (MAOIs)
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The combination of SAM-e with MAOIs poses a very high risk of severe serotonin syndrome and/or hypertensive crisis due to a massive increase in available monoamines like serotonin and norepinephrine.
Actionable advice:
This combination is contraindicated; never take SAM-e with MAOIs.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
Evidence suggests dangerous interactions are likely to occur when taking SAMe and 5-HTP with MAO inhibitors, such as serotonin syndrome. These substances should not be combined.
Label source:
Primary literature: https://www.ebsco.com/research-starters/health-and-medicine/monoamine-oxidase-mao-inhibitors-drug-interactions
Action type:
avoid
Target id:
/condition/bipolar-disorder
Target name:
Bipolar Disorder
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
The antidepressant effects of SAM-e can trigger a switch from a depressive episode into a manic or hypomanic state in individuals with bipolar disorder.
Actionable advice:
SAM-e should not be used in bipolar disorder, except under the direct supervision of a psychiatrist.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
SAM is safe to use in most patients, but is contraindicated in those with bipolar disorder.
Label source:
PubMed: S-Adenosyl Methionine in the Therapy of Depression and Other Psychiatric Disorders. (PMID 27594595)
Action type:
avoid
Target id:
/dietary/meal
Target name:
Any Caloric Food or Meal
Severity:
major
Interaction type:
diminishing
Nature:
temporal
Temporal spacing:
Hours before target:
1
Hours after target:
2
Description:
Food, particularly protein, can significantly interfere with the absorption of SAM-e in the gut, reducing its bioavailability and effectiveness.
Actionable advice:
SAM-e should be taken on an empty stomach, at least 1 hour before or 2 hours after eating.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
There was a significant food effect for MSI-195 with a delayed time to maximum absorption Tmax, going from 4.5 h under fasted conditions to 13 h under fed conditions, and area under the curve with food reduced to 55% of that seen under fasting conditions.
Label source:
PubMed: BMC pharmacology & toxicology (2020)
Source url:
Exact phrase from label:
The impact of food on the drug was noticeable, with faster absorption in the fasting group (Tmax , 4.50 ± 1.07 and 7.50 ± 1.58 for the fasting and postprandial groups, respectively) but higher exposure in the postprandial group (AUC0-inf , 4021.02 ± 3377.13 and 5087.28 ± 3539.26 for the fasting and postprandial groups, respectively).
Label source:
PubMed: Journal of clinical pharmacy and therapeutics (2022)
Action type:
separate
Target id:
/intervention/folate
Target name:
Folate (Vitamin B9)
Severity:
major
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Folate is an essential cofactor for the metabolic pathway that recycles homocysteine, a potentially harmful byproduct of SAM-e's activity. Inadequate folate can lead to elevated homocysteine levels.
Actionable advice:
Adequate folate intake, ideally as L-methylfolate, should be maintained when supplementing with SAM-e.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
homocysteine can then be recycled back to methionine by the enzyme methionine synthase in a reaction that requires folate in the form of 5-methyltetrahydrofolate as the methyl donor and vitamin B12 in the form of methylcobalamin as a cofactor
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC10294675/
Action type:
informational_none
Target id:
/intervention/vitamin-b12
Target name:
Vitamin B12
Severity:
major
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin B12 is a critical cofactor for the enzyme methionine synthase, which is necessary for converting homocysteine back to methionine as part of the SAM-e cycle.
Actionable advice:
Adequate Vitamin B12 intake should be maintained when supplementing with SAM-e to support healthy homocysteine metabolism.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Methionine synthase catalyzes the methyl-Cbl dependent (re)methylation of homocysteine to methionine within the methionine cycle; a reaction required to produce this essential amino acid and generate S-adenosylmethionine, the most important cellular methyl-donor.
Label source:
PubMed: Vitamin B12 , folate, and the methionine remethylation cycle-biochemistry, pathways, and regulation. (PMID 30693532)
Action type:
informational_none
Target id:
/intervention/levodopa
Target name:
Levodopa
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
SAM-e is a methyl donor that can increase the peripheral breakdown of levodopa, potentially reducing its effectiveness for treating Parkinson's disease symptoms.
Actionable advice:
It is important to talk to a neurologist before combining SAM-e with levodopa.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Because SAM in higher dosages may also counteract the antiparkinsonian efficacy of levodopa according to animal trials, this SAM increase may hypothetically contribute to the onset of wearing-off phenomena and other clinical signs of limited efficacy of levodopa during long-term treatment with levodopa in PD patients.
Label source:
PubMed: Clinical neuropharmacology (2005)
Source url:
Exact phrase from label:
During the therapy of PD with L-dopa, it is well known that L-dopa reacts avidly with S-adenosyl-L-methionine (SAM), the biologic methyl donor, to produce 3-O-methyl-dopa.
Label source:
PubMed: Pharmacology, biochemistry, and behavior (1992)
Source url:
Exact phrase from label:
S-adenosylmethionine (SAM), which is synthesized from adenosine triphosphate and methionine (MET), serves as methyl donor for this O-metabolisation of levodopa with resulting conversion of SAM to total homocysteine (tHcy) via S-adenosylhomocysteine (SAH).
Label source:
PubMed: Neuroscience letters (2001)
Action type:
informational_none
Target id:
/class/antidiabetic-medications
Target name:
Diabetes Medications
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
SAM-e may have a mild glucose-lowering effect, which can be additive with diabetes medications, potentially increasing the risk of hypoglycemia (low blood sugar).
Actionable advice:
Blood glucose levels are best monitored closely if combining SAM-e with diabetes medications, and it is important to consult a doctor.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Metformin decreases liver uptake of lactate increasing lactate blood levels which may increase the risk of lactic acidosis, especially in patients at risk.
Label source:
Action type:
monitor
Target id:
/biomarker/homocysteine
Target name:
Homocysteine
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
SAM-e is metabolized into homocysteine; without sufficient B-vitamin cofactors (B6, B9, B12) for recycling, homocysteine levels can rise, which is a risk factor for cardiovascular disease.
Actionable advice:
Periodically monitor homocysteine levels and ensure adequate B-vitamin intake when using SAM-e.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
S-Adenosylhomocysteine, which is a product of these methyltransferases, gives rise to homocysteine. Homocysteine may be remethylated to methionine or converted to cysteine by the transsulfuration pathway.
Label source:
PubMed: The Journal of nutrition (2006)
Source url:
Exact phrase from label:
Homocysteine is a metabolic intermediate in methyl group metabolism that is dependent on a number of nutritional B-vitamin cofactors. An emerging aspect of homocysteine metabolism is its relation to health and disease. Perturbations of homocysteine metabolism, particularly intracellular and subsequently circulating accumulation of homocysteine (i.e., hyperhomocysteinemia), are associated with vascular disease risk, as well as other pathologies.
Label source:
PubMed: BioFactors (Oxford, England) (2010)
Source url:
Exact phrase from label:
Homocysteine can be re-methylated to methionine [precursor of S-adenosylmethionine (SAM)] via the re-methylation or 5-methyltetrahydrofolate pathway or undergoes transsulfuration to form cysteine by the action of metabolic enzymes and cofactors. Impaired metabolism due to genetic alteration in metabolic enzymes (methionine synthase, methyltetrahydrofolate reductase (MTHFR), cystathionine β-synthase (CβS), and cystathionine-γ-lyase (CγL) or deficiency in cofactors (vitamin B6 , B12 , folate) may lead to acquired metabolic anomaly known as hyperhomocysteinemia.
Label source:
PubMed: Fundamental & clinical pharmacology (2015)
Action type:
monitor
Target id:
/intervention/saint-johns-wort
Target name:
Saint John's Wort
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Both SAM-e and St. John's Wort increase serotonin levels, and their combined use significantly elevates the risk of developing potentially fatal serotonin syndrome.
Actionable advice:
SAM-e and St. John's Wort should not be taken together.
Validation status:
validated_via_pubmed
Evidence tier:
tier_b
Evidence basis:
pubmed_abstract_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
The serotonin syndrome occurs following the use of serotomimetic agents (serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, tryptophan, 3,4-methylenedioxy-methamphetamine, dextromethorphan, meperidine, S-adenosylmethionine) alone or in combination with monoamine oxidase inhibitors.
Label source:
PubMed: Neurology (1995)
Source url:
Exact phrase from label:
Use of SAMe elicited no significant adverse effects beyond placebo, however it was implicated in one case of serotonin syndrome-like symptoms.
Label source:
PubMed: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology (2018)
Source url:
Exact phrase from label:
St. John's wort acts as a weak selective serotonin reuptake inhibitor with fewer side effects.
Label source:
PubMed: American family physician (2000)
Action type:
avoid
Target id:
/intervention/dextromethorphan
Target name:
Dextromethorphan (Cough Suppressant)
Severity:
moderate
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Dextromethorphan has serotonergic properties and, when combined with SAM-e, can contribute to an increased risk of serotonin syndrome.
Actionable advice:
Dextromethorphan-containing cough and cold remedies are best avoided while taking SAM-e.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Dextromethorphan may cause serotonin syndrome, and this risk is increased by
overdose, particularly if taken with other serotonergic agents, SSRIs or tricyclic antidepressants.
Label source:
Action type:
avoid
Target id:
/intervention/tramadol
Target name:
Tramadol
Severity:
major
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Tramadol is an opioid analgesic with strong serotonergic activity. Combining it with SAM-e creates a high risk of serotonin syndrome.
Actionable advice:
SAM-e and tramadol should not be taken together.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
5.9 Serotonin Syndrome Risk Cases of serotonin syndrome, a potentially life-threatening condition, have been reported with the use of tramadol, particularly during concomitant use with serotonergic drugs.
Label source:
Action type:
avoid
Target id:
/intervention/vitamin-b6
Target name:
Vitamin B6
Severity:
moderate
Interaction type:
requirement
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Vitamin B6 is a required cofactor for the enzyme that converts homocysteine to cysteine, providing an alternative pathway for its clearance and preventing its accumulation.
Actionable advice:
It is a good idea to maintain adequate Vitamin B6 intake when supplementing with SAM-e.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
We saw similar inverse associations between homocysteine and intakes of folate and vitamin B6, but not vitamin B12.
Label source:
PubMed: Relationship between plasma homocysteine and vitamin status in the Framingham study population. Impact of folic acid fortification. (PMID 11411265)
Action type:
informational_none
Target id:
/class/anticoagulants-antiplatelets
Target name:
Anticoagulants and Antiplatelets
Severity:
minor
Interaction type:
adverse
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
There is a theoretical concern that SAM-e could affect platelet function, potentially increasing the risk of bleeding when combined with blood-thinning medications, although clinical evidence is limited.
Actionable advice:
This is best used with caution, and it is worth letting a doctor know when taking blood-thinning medications.
Validation status:
validated_via_fda_label
Evidence tier:
tier_a
Evidence basis:
fda_label_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Bleeding rates varied by patient population and clinical care center in pediatric observational studies and patient registries.
Label source:
Action type:
informational_none
Target id:
/circadian/sleep
Target name:
Going to Sleep
Severity:
minor
Interaction type:
adverse
Nature:
temporal
Temporal spacing:
Hours before target:
6
Hours after target:
null
Description:
SAM-e can have a mild stimulating or energizing effect in some individuals, which may cause anxiety or interfere with sleep if taken too close to bedtime.
Actionable advice:
SAM-e doses are generally best taken in the morning or early afternoon to avoid potential sleep disturbances.
Validation status:
validated_via_clinical_guidance
Evidence tier:
tier_b
Evidence basis:
clinical_guidance_verbatim
Evidence anchors:
Exact phrase from label:
the dose of SAM-e is raised gradually over a few weeks. This can help lessen side effects such as restlessness or anxiety.
Label source:
Clinical guidance: WebMD — SAM-e supplement guide
Action type:
avoid
Target id:
/intervention/creatine
Target name:
Creatine
Severity:
minor
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
A large portion of the body's SAM-e is used to synthesize creatine. Supplementing with creatine can reduce this metabolic demand, potentially 'sparing' SAM-e for other essential methylation reactions.
Actionable advice:
Consider taking creatine to reduce the metabolic burden on the body's SAM-e supply.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Source url:
Exact phrase from label:
Creatine biosynthesis consumes 40% of methyl groups produced as S-adenosylmethionine, and creatine uptake is controlled by AMP activated protein kinase, a ubiquitous sensor of energy depletion.
Label source:
PubMed: Creatine biosynthesis and transport in health and disease. (PMID 26542286)
Action type:
informational_none
Target id:
/intervention/betaine
Target name:
Betaine (TMG)
Severity:
minor
Interaction type:
synergistic
Nature:
absolute
Temporal spacing:
Hours before target:
0
Hours after target:
0
Description:
Betaine (TMG) supports an alternative metabolic pathway for recycling homocysteine back to methionine, complementing the folate/B12-dependent pathway and further protecting against homocysteine buildup.
Actionable advice:
Consider taking Betaine (TMG) alongside SAM-e to provide comprehensive support for homocysteine metabolism.
Validation status:
validated_via_primary_literature
Evidence tier:
tier_b
Evidence basis:
primary_literature_verbatim
Evidence anchors:
Exact phrase from label:
An alternative folate- and vitamin B12-independent reaction utilizes betaine (a metabolite of choline) as the methyl donor to convert homocysteine to methionine.
Label source:
Primary literature: https://pmc.ncbi.nlm.nih.gov/articles/PMC10294675/
Action type:
informational_none