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S-Adenosylmethionine (SAMe)

Nutrient Name: S-adenosylmethionine (SAMe).
Synonyms: S-adenosyl-L-methionine, S-adenosyl methionine, ademetionine; AdoMet.

Summary Table

Drug/Class Interaction Type	Mechanism and Significance	Management
Acetaminophen	SAMe reduces acetaminophen hepatotoxicity. Further research warranted to confirm efficacy and establish dosage and treatment guidelines.	May be effective with or in place of NAC as an antidote in treatment of acetaminophen toxicity.
Imipramine Tricyclic antidepressants (TCAs) / /	SAMe can accelerate onset of action of imipramine. Concomitant administration could be therapeutic with proper management. Additive or synergistic effect may theoretically result from concomitant use of SAMe and TCAs because of their potentially similar influences on CNS.	Coadministration may be beneficial. May need to modify drug dosage. Monitor and titrate.
Levodopa Antiparkinsonian medications / / /	SAMe tends to be low in Parkinson's disease and levodopa therapy depletes the body of SAMe. However, SAMe may contribute to Parkinson-like motor impairments and interfere with action of L-dopa by promoting methylation. Concomitant administration of L-dopa and SAMe might potentially amplify, distort, or harmonize endogenous L-dopa and SAMe equilibrium. Research lacking to provide conclusive advice.	Concomitant use could aggravate symptoms or interfere with drug action. If clinically appropriate, may need to modify drug dosage. Monitor closely and titrate.
Oral contraceptives (OCs)	By enhancing liver detoxification, glutathione production, and related metabolic processes, SAMe may protect against tendency of OCs to raise cholesterol saturation of bile by increasing biliary cholesterol secretion. Clinical trials warranted to follow and validate findings from supportive indirect research.	Coadministration may be beneficial in patients at risk of hepatobiliary dysfunction.
Ursodeoxycholic acid (UDCA) Chenodeoxycholic acid (CDCA)	Both UDCA and SAMe can be efficacious in treatment of conditions related to hepatobiliary dysfunction and disease, including pruritus and intrahepatic cholestasis of pregnancy (ICP). UDCA was more effective than SAMe in controlling some symptoms, but research indicates that coadministration can increase efficacy and reduce potential fetal toxicity of UDCA.	Coadministration may be beneficial in patients at risk of hepatobiliary dysfunction, particularly ICP.
Venlafaxine Selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor (SSRI and SNRI) Antidepressants	Coadministration of SAMe with SSRIs, including venlafaxine, may augment therapeutic effect, particularly in individuals with partial or resistant responses to standard antidepressant pharmacotherapy. Mechanisms of action not fully elucidated, but preliminary evidence suggests minimal adverse effects.	Coadministration may be beneficial. May need to modify drug dosage. Monitor and titrate.
NAC, N-acetylcysteine; CNS , central nervous system.

nutrient description

Chemistry and Forms

Sulfuradenosylmethionine, S-adenosyl-L-methionine; S-adenosylmethionine butanedisulfonate, S-adenosylmethionine tosylate.

Physiology and Function

S-Adenosylmethionine (SAMe) is a naturally occurring compound functioning in a multitude of biochemical reactions and biosynthetic processes throughout the central nervous system (CNS), liver, connective tissue, and detoxification systems and within cellular metabolic activities. Dietary methionine is primarily metabolized in the liver, where it is combined with adenosine triphosphate (ATP) to form SAMe in a reaction catalyzed by methionine adenosyltransferase I/III (MAT I/III), the product of the MAT1A gene, which is exclusively expressed in the liver. SAMe serves as a precursor molecule to three main metabolic pathways within all cells: methylation, transulfuration, and aminopropylation.

S-Adenosylmethionine is the body's main biological methyl donor. After donating a methyl group in the synthesis of nucleic acids (DNA and RNA), choline, creatine, carnitine, proteins, phospholipids, catecholamines, epinephrine, and various neurotransmitters, SAMe is converted to S-adenosylhomocysteine (SAH). Subsequent trans-sulfuration reactions enable and regulate formation of sulfur-containing amino acids such as cysteine, glutathione, and taurine. After donating sulfur in this way, SAH gives up adenosine and is rapidly metabolized to homocysteine. Through the pathway known as aminopropylation, SAMe is metabolized to decarboxylated SAMe and functions as a cofactor in the synthesis of polyamines, including spermidine, puescine, and spermine, which are essential for cellular growth and differentiation, gene expression, DNA repair, protein phosphorylation, and neuron myelination and regeneration. As a key facilitator of phosphatidylcholine synthesis, SAMe plays a role in promoting flexible and responsive cellular membranes and supports healthy bile production and flow. SAMe influences levels of 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite, and homovanillic acid, a dopamine metabolite, in the cerebrospinal fluid (CSF) and appears to cross the blood-brain barrier via carrier-mediated transport.

nutrient in clinical practice

Known or Potential Therapeutic Uses

Human clinical trials investigating SAMe have reported positive outcomes in the treatment of a range of conditions, reflecting the broad and diverse functions of this substance in human physiology. In particular, researchers have focused on depression, osteoarthritis, and liver disorders. Although a number of studies have shown clinical benefit, most have been limited by small numbers, brief duration, and preliminary or flawed design. Further, the research findings from human trials cannot be extrapolated readily to self-prescribed use or typical clinical practice, since oral dosages in European clinical trials have usually been significantly higher than those typically used by many individuals, and many studies have used intravenous (IV) or intramuscular (IM) modes of administration.

Historical/Ethnomedicine Precedent

S-Adenosylmethionine has not been used historically as an isolated nutrient.

Possible Uses

Alzheimer's disease, attention deficit–hyperactivity disorder (ADHD), cardiovascular disease, cirrhosis, dementia, depression, fibromyalgia, Gilbert's syndrome, infertility (male), insomnia, intrahepatic cholestasis of pregnancy, migraine, osteoarthritis, rheumatoid arthritis, Sjögren's syndrome, vacuolar myelopathy.

Dietary Sources

Methionine, from which SAMe is formed, can be obtained from a variety of dietary sources, but SAMe itself is not available through foods in any significant amounts. Dietary deficiencies in methionine, folate, or vitamin B12can reduce SAMe levels.

Nutrient Preparations Available

S-Adenosylmethionine butanedisulfonate, S-adenosylmethionine tosylate.

In Europe, pharmaceutical preparations of SAMe are available mainly as IV, IM, and oral forms. In the United States, SAMe is primarily available in an over-the-counter (OTC) nutraceutical oral form as a capsule or tablet. SAMe is extremely hygroscopic and highly unstable; enteric-coated tablets packaged in foil or foil blister packs are considered the most stable form to avoid degradation.

Dosage Forms Available

Enteric-coated tablets. Parenteral preparations are available in Europe.

Source Materials for Nutrient Preparations

Biofermentation or synthesis from adenosine and methionine, generally complexed with a stabilizing salt, such as tosylate, disulfate tosylate, disulfate ditosylate, or 1,4-butanedisulfonate.

Dosage Range

Adult

Dietary: Not applicable.

Estimated safe and adequate daily dietary intake: Not applicable.
Average U.S. daily intake: Not applicable.
Recommended dietary allowance (RDA): None established.

Supplemental/Maintenance: Not applicable.

Pharmacological/Therapeutic: 400 mg three or four times daily, based on clinical trials.

Oral: 200 to 1600 mg daily.

Adequate dose-escalation studies using the oral formulation of SAMe have yet to be performed to demonstrate the most effective oral dose of SAMe.

The most common dosage is 400 mg daily, even though this level is significantly below the efficacy threshold indicated by research and clinical experience. Its relatively high cost has often been considered a limiting factor in the effective use of SAMe as a nutraceutical, especially when self-prescribed.

Toxic: No dietary reference intake (DRI) has been set for S-adenosylmethionine.

Pediatric (<18 Years)

No guidelines have been established for therapeutic or toxic dosage levels of SAMe for infants or children. Use within such populations is not usually recommended as appropriate.

Laboratory Values

Plasma levels of SAMe. Levels ofL-methionine S-adenosyltransferase activity in erythrocytes, SAMe concentrations in CSF, and concentrations of SAMe and S-adenosylhomocysteine (SAH) in whole blood have also been used in clinical trials.

safety profile

Overview

In clinical trials and reported clinical use, SAMe has generally been well tolerated and considered safe.

Nutrient Adverse Effects

No toxic effects have been reported in research or clinical experience involving SAMe. Dry mouth, nausea, restlessness, and skin rashes are among the several minor adverse effects occasionally associated with SAMe intake and generally reported at higher doses. One case report of “serotonin syndrome” involving concomitant use of IM SAMe (100 mg/day) and clomipramine (75 mg/day) represents the most severe adverse event known. ^1-4

Adults

Mutagenicity: Research thus far indicates that SAMe is nonmutagenic in vitro and in vivo, even using high doses.

Adverse Effects Among Specific Populations

S-Adenosylmethionine use may trigger a manic episode in individuals with bipolar disorder. ^5-7

Pregnancy and Nursing

The safety of SAMe use in pregnant or breast-feeding women has not been established. However, several studies investigating SAMe in the treatment of intrahepatic cholestasis of pregnancy (ICP) have reported the agent as apparently safe during pregnancy.

Infants and Children

The safety of SAMe administration in infants and children has not been established.

Contraindications

Bipolar disorder, migraines, Parkinson's disease; individuals with active bleeding.

Precautions and Warnings

Given that SAMe is a precursor to homocysteine and that methionine may elevate homocysteine, it would be prudent to assess homocysteine levels before treating with SAMe in individuals with a significant family history of coronary heart disease.

interactions review

Strategic Considerations

S-Adenosylmethionine's central role in several critical metabolic pathways indicates that both excessive intake and drug-induced depletion are likely to produce significant consequences. Well-designed studies will be required to clarify and articulate the particulars of these patterns in a systematic manner. Likewise, further research is needed to determine therapeutic approaches to synergistic use of SAMe as part of integrative therapeutics employing the nutraceutical in conjunction with various conventional therapies for treatment of the conditions for which SAMe shows promise.

The issue of SAMe use by individuals diagnosed with bipolar disorder continues to be controversial; well-designed research is needed to assess its efficacy as a therapeutic agent, alone or in conjunction with conventional pharmacological treatments.

The scientific understanding of the physiology and pharmacology of SAMe is generally in a preliminary state, particularly with regard to genetic variability and its pharmacogenomic implications. In particular, the critical roles of SAMe in the areas of DNA methylation, neurotransmitter self-regulatory processes, and hepatic conjugation of pharmaceutical agents all deserve continued research and will undoubtedly reveal significant implications for SAMe's therapeutic application and interactions with other medications. Recent clinical trial data suggest that SAMe appears to augment the antidepressant effect of SSRI and SSRI/SNRI agents. Large, randomized, placebo-controlled trials addressing the difficult clinical problem of antidepressant-refractory depression are warranted.

nutrient-drug interactions

Acetaminophen

Acetaminophen (APAP, paracetamol; Tylenol); combination drugs: acetaminophen and codeine (Capital and Codeine; Phenaphen with Codeine; Tylenol with Codeine); acetaminophen and hydrocodone (Anexsia, Anodynos-DHC, Co-Gesic, Dolacet, DuoCet, Hydrocet, Hydrogesic, Hy-Phen, Lorcet 10/650, Lorcet-HD, Lorcet Plus, Lortab, Margesic H, Medipain 5, Norco, Stagesic, T-Gesic, Vicodin, Vicodin ES, Vicodin HP, Zydone); acetaminophen and oxycodone (Endocet, Percocet 2.5/325, Percocet 5/325, Percocet 7.5/500, Percocet 10/650, Roxicet 5/500, Roxilox, Tylox); acetaminophen and pentazocine (Talacen); acetaminophen and propoxyphene (Darvocet-N, Darvocet-N 100, Pronap-100, Propacet 100, Propoxacet-N, Wygesic), acetaminophen, butalbital, and caffeine (Fioricet).

Prevention or Reduction of Drug Adverse Effect

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

S-Adenosylmethionine reduces acetaminophen hepatotoxicity and lethality by metabolism of the active moiety to glutathione.

Research

In mouse models, SAMe (intraperitoneal administration, 1 g/kg or 2.5 mmol/kg) within 1 to 5 hours reduced depletion of plasma and liver glutathione, liver damage, and release of aspartate transaminase (AST) after acetaminophen administration. ^8,9 Other researchers concluded that SAMe presented a therapeutic alternative to N-acetylcysteine (NAC) as an antidote for poisoning with acetaminophen. ¹⁰

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Further research is indicated to confirm the efficacy and determine most effective dosage levels for use of SAMe, in place of or in conjunction with NAC, as an antidote in the treatment of acetaminophen poisoning.

Imipramine and Other Tricyclic Antidepressants

Evidence: Imipramine (Janimine, Tofranil). Extrapolated, based on similar properties: Clomipramine (Anafranil) Similar properties but evidence lacking for extrapolation: Amitriptyline (Elavil); combination drug: amitriptyline and perphenazine (Etrafon, Triavil, Triptazine); amoxapine (Asendin), desipramine (Norpramin, Pertofrane), doxepin (Adapin, Sinequan), nortriptyline (Aventyl, Pamelor), protriptyline (Vivactil), trimipramine (Surmontil).

	Beneficial or Supportive Interaction, with Professional Management
	Bimodal or Variable Interaction, with Professional Management
	Minimal to Mild Adverse Interaction—Vigilance Necessary

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

S-Adenosylmethionine accelerates the onset of action of imipramine. Experiments using rats demonstrated that SAMe prevents the 5-HT(1A) receptor upregulation induced by acute imipramine in the frontal cortex. ¹¹ SAMe and tricyclic antidepressants (TCAs) exert potentially similar influences on the CNS and together can generate an additive or synergistic effect.

Research

Numerous clinical trials have investigated the efficacy of SAMe in the treatment of various degrees of depression, often in comparison to TCAs, particularly imipramine. TCAs and SAMe have both been used successfully in treatment of depression; double-blind clinical studies show approximately equivalent efficacy, both superior to placebo, with TCAs associated with more frequent adverse events and SAMe being better tolerated. Pancheri et al. ¹² estimated IM 400 mg/day SAMe to be comparable to oral 150 mg/day imipramine in terms of antidepressive efficacy. Although many clinical trials of SAMe have involved IM, parenteral, or other modes of administering SAMe, oral administration of SAMe has demonstrated antidepressant activity, independent of its combination with imipramine or other antidepressants. ¹³

Preliminary research has focused on the concomitant administration of these two agents with promising implications. In a double-blind clinical trial with 40 subjects receiving oral imipramine (150 mg/day initially and then according to symptoms), half also received IM 200 mg/day SAMe, and the other half also received placebo. The patients receiving the SAMe-imipramine combination reported a more rapid decrease in depressive symptoms than did those in the placebo-imipramine group. ¹⁴

Report

In 1993, Iruela et al. ¹⁵ published a case report describing an episode of “serotonin syndrome” in a woman after combining IM 100 mg SAMe daily, with 75 mg/day clomipramine.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing imipramine or other TCAs may consider use of SAMe within an integrative strategy combining the two agents and using SAMe as a support during weaning from TCA therapy. However, the potential for therapeutic synergy also invokes the risk of excessive pharmacological response. A clear need exists for well-designed clinical studies with larger numbers of subjects and a variety of combination therapies to determine conclusively which patients will benefit from conventional antidepressants, SAMe, or some combination and to establish appropriate dosage levels and therapeutic protocols. Pending such evidence, individuals should be dissuaded from unsupervised concomitant use of SAMe and TCAs or other antidepressant medications.

Significant potential exists for safe and effective therapy using coadministration within the context of integrative care, providing close supervision and regular monitoring by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics. Clinical trials investigating the use of SAMe for treatment of depression suggests that an effective dose could be anywhere in the range of 800 to 1600 mg daily. Any concomitant use of SAMe and a TCA such as imipramine would need to be determined on the basis of the relative dose of the antidepressant and the particular needs of the individual being treated.

Levodopa (L-dopa; Dopar, Larodopa); combination drugs: levodopa and benserazide (co-beneldopa; Madopar); levodopa and carbidopa (Atamet, Parcopa, Sinemet, Sinemet CR); levodopa, carbidopa and entacapone (Stalevo). Related antiparkinsonian medications: Carbidopa (Lodosyn), selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak).

	Potential or Theoretical Adverse Interaction of Uncertain Severity
	Drug-Induced Effect on Nutrient Function, Supplementation Contraindicated, Professional Management Appropriate
	Bimodal or Variable Interaction, with Professional Management
	Potential or Theoretical Beneficial or Supportive Interaction with Professional Management

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

S-Adenosylmethionine levels tend to be low in individuals with Parkinson's disease, and levodopa therapy depletes the body of SAMe. However, SAMe may contribute to Parkinson-like motor impairments and interfere with the action of L-dopa. Thus, the dynamic equilibrium between endogenous L-dopa and SAMe can potentially be amplified, distorted, or harmonized by the introduction of exogenous L-dopa and SAMe.

SAMe promotes methylation and, as suggested by both rodent and human studies, excessive methylation can cause depletion of dopamine, is associated with Parkinson's disease, and can interfere with the effects of L-dopa. SAMe is the rate-limiting endogenous methyl donor, and its biochemical roles include the metabolism of dopamine and the synthesis of acetylcholine. Thus, SAMe may produce effects that resemble the changes that occur in Parkinson's disease, such as hypokinesia, tremor, rigidity, and abnormal posture. Therefore, SAMe may play a role in Parkinson-like motor impairments, particularly under conditions of excessive SAMe-dependent methylation. ^16-18

Levodopa is administered with dopa decarboxylase inhibitors (DDIs) to prevent its peripheral degradation. This increases conversion of levodopa to 3- O-methyldopa (3-OMD) by catechol- O-methyltransferase (COMT). SAMe serves as methyl donor for this O-metabolization of levodopa, with resulting conversion of SAMe to total homocysteine (tHcy) via S-adenosylhomocysteine (SAH). ¹⁹

Research

Studies of the interaction between L-dopa and SAMe, both endogenous and exogenous, reveal several significant trends, but no conclusive patterns of substantive evidence have confirmed a safe and effective approach to clinical management. Whereas some evidence suggests that individuals with Parkinson's disease may benefit from SAMe therapy, other research indicates that SAMe may deplete dopamine, aggravate motor symptoms, and possibly block the intended therapeutic action of L-dopa.

In two early studies, Charlton et al. ¹⁶ and Crowell et al. ²⁰ found that exogenous SAMe intake was associated with Parkinson-like symptoms in rats, specifically decreases in motor activity. Subsequent research with human subjects undergoing treatment of Parkinson's disease with L-dopa showed that L-dopa reacts avidly with SAMe to produce 3-OMD. ²¹

Levodopa has been shown to deplete the concentration of SAMe in the brain and increase tHcy levels. ^19,22 This depletion pattern may contribute to the depression often experienced by individuals with Parkinson's disease and may constitute a significant factor in the adverse effects associated with levodopa therapy. ^22,23 General evidence regarding the function of SAMe and preliminary research both suggest that SAMe administration could benefit individuals with Parkinson's disease through positive effects on the depression and impaired cognitive function typically associated with the condition. ²³ A double-blind, crossover study published by Carrieri et al. ²⁴ in 1990 demonstrated beneficial effects of SAMe (400 mg orally, twice daily, plus 200 mg daily intramuscularly), versus placebo, against depression in 21 patients with Parkinson's disease. Parkinsonian symptoms appeared to be unchanged, adverse effects were moderate and of brief duration, and there was no indication that the effectiveness of levodopa had been reduced. Likewise, in a more recent (2000) open-label pilot study involving 13 subjects with Parkinson's disease and comorbid depression, Di Rocco et al. ^24a found that 10 of the 11 patients who completed the clinical trial demonstrated at least a 50% improvement on the 17-point Hamilton Depression Scale (HDS) after 800 to 3600 mg SAMe daily for 10 weeks.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

The emerging pattern of evidence reflects the delicate interplay and dynamic equilibrium between L-dopa and SAMe. On the one hand, individuals with Parkinson's disease tend to be deficient in SAMe, inclined to depression, and subject to the depleting effects of levodopa therapy. On the other hand, SAMe could in theory contribute to excessive methylation, which appears to exacerbate motor impairments similar to parkinsonism, and concomitant SAMe may interfere with the therapeutic action of levodopa. Furthermore, the significant adverse effects associated with L-dopa (or carbidopa/levodopa) therapy cannot be easily overlooked, whereas SAMe is generally considered to produce minor adverse effects. Well-designed clinical trials with substantial numbers of human subjects will be required to clarify the diverse and paradoxical findings of the available preliminary research.

The possibility of enhanced synergistic benefits from combined therapy needs to be considered in light of the reasonable risk of serious exacerbation of symptoms. Given the weight of the evidence and the significant risk probability, it would be prudent to consider unsupervised and unmonitored use of SAMe during levodopa therapy as contraindicated. SAMe may benefit the person with Parkinson's disease as a whole while aggravating the pathophysiology.

The question of SAMe administration, particularly in conjunction with levodopa therapy, may be a matter of determining the individual (and dynamic) balance of SAMe depletion and excessive methylation effects or attendant risk. At this time, the balance of the evidence available warrants a cautionary avoidance of SAMe intake by individuals with Parkinson's disease, pending more conclusive research confirming safety and efficacy. In cases where SAMe administration is indicated by determination of a deficiency or depletion pattern and the broader clinical picture, any such use should only be undertaken within the context of close supervision and regular monitoring by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics. In some of these individuals, levodopa dosage might need to be increased to compensate for any potential interference caused by SAMe coadministration. Given the lack of a comprehensive understanding of the pathophysiological processes involved and the complete implications of either of the therapeutic interventions, no dosage ranges for SAMe (or concomitant levodopa) can reasonably be suggested without reference to the particular individual being treated, his or her peculiar characteristics and needs, and clinical response. An integrative approach to personalized care will generally emphasize respecting and enabling, rather than imposing on or obstructing, the normal feedback cycles and self-regulatory processes involved in these neurotransmitters, their complex interrelationships, and pervasive influences.

Oral Contraceptives: Monophasic, Biphasic, and Triphasic Estrogen Preparations (Synthetic Estrogen and Progesterone Analogs)

Ethinyl estradiol and desogestrel (Desogen, Ortho-TriCyclen). Ethinyl estradiol and ethynodiol (Demulen 1/35, Demulen 1/50, Nelulen 1/25, Nelulen 1/50, Zovia). Ethinyl estradiol and levonorgestrel (Alesse, Levlen, Levlite, Levora 0.15/30, Nordette, Tri-Levlen, Triphasil. Trivora). Ethinyl estradiol and norethindrone/norethisterone (Brevicon, Estrostep, Genora 1/35, GenCep. 1/35, Jenest-28, Loestrin 1.5/30, Loestrin1/20, Modicon, Necon 1/25, Necon 10/11, Necon 0.5/30, Necon 1/50, Nelova 1/35, Nelova 10/11, Norinyl 1/35, Norlestin 1/50, Ortho Novum 1/35, Ortho Novum 10/11, Ortho Novum 7/7/7, Ovcon-35, Ovcon-50, Tri-Norinyl, Trinovum). Ethinyl estradiol and norgestrel (Lo/Ovral, Ovral). Mestranol and norethindrone (Genora 1/50, Nelova 1/50, Norethin 1/50, Ortho-Novum 1/50). Related, internal application: Etonogestrel/ethinyl estradiol vaginal ring (Nuvaring).

Prevention or Reduction of Drug Adverse Effect

Probability: 4. Plausible
Evidence Base:

Preliminary

Effect and Mechanism of Action

Oral contraceptives (OCs) raise the cholesterol saturation of bile by increasing biliary cholesterol secretion. ²⁵ SAMe enables liver detoxification and related metabolic processes, including glutathione production.

Research

Some women experience adverse reactions to the synthetic estrogens in OCs, including dysfunctional liver bile production, especially bile cholesterol supersaturation. ²⁶ In particular, women with past histories of intrahepatic cholestasis of pregnancy (ICP), a relatively rare condition, exhibit an exaggerated genetic sensitivity to estrogens, which may express as abnormal hepatic reactivity to OC intake and increased risk of developing gallbladder disease. Studies have provided findings supporting the efficacy of SAMe in the treatment of ICP. ^27,28 In a 1984 preliminary report of a controlled randomized trial, Di Padova ²⁹ and a group of Italian researchers found that SAMe antagonizes OC-induced bile cholesterol supersaturation in healthy women. In a related small study published in 1988, Frezza et al. ³⁰ found that oral SAMe (800 mg daily for 2 weeks) protects women with previous ICP from ethinyl estradiol–induced liver toxicity and normalizes bile cholesterol saturation index (CSI) in women who secrete lithogenic bile. These researchers concluded that SAMe acts as a physiological antidote against estrogen hepatobiliary toxicity caused by OCs in susceptible women.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Weight gain in women using OCs has been debated for decades, and concern remains over estrogen's role in contributing to liver dysfunction and increased susceptibility to weight gain and gallbladder disease among women entering their fourth decade. Although ICP is a relatively uncommon condition, the research into its pathophysiology suggests that SAMe administration might counter the adverse effects on hepatobiliary function and fat metabolism experienced by some women in relation to estrogen metabolism, particularly under the potential stress of OCs. In this situation the emerging tools of pharmacogenomics may provide effective means for assessing relative risk among women in relation to estrogen stress and exogenous hormones in particular. Further, the trend toward decreasing the estrogen dosage in OCs has undoubtedly reduced the frequency and degree of bile cholesterol supersaturation and other, more subtle manifestations of hepatobiliary dysfunction among susceptible women.

Clinicians might consider concomitant SAMe as a supportive adjunctive therapy, with minimal attendant risk, for female patients prescribed OCs (or in other cases involving potential liver and/or gallbladder reactivity to estrogen, including hormone replacement therapy) who have a history of or now exhibit changes in bile function, fat metabolism, or other indication of estrogenic distress. A dosage in the range of 200 to 400 mg per day, in divided doses, would be a reasonable starting point, subject to individual patient characteristics and needs and tailored to clinical response.

Ursodeoxycholic Acid and Chenodeoxycholic Acid

Evidence: Ursodeoxycholic acid (UDCA, ursodiol; Actigall, Destolit, Urdox, Urso, Ursofalk, Ursogal). Extrapolated, based on similar properties: Chenodeoxycholic acid (CDCA, chenodiol; Chenix).

Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Emerging

Effect and Mechanism of Action

Ursodeoxycholic acid (UDCA) is used in the treatment of several hepatobiliary conditions to reduce pruritus, treat cholelithiasis, and improve biochemical parameters, particularly bile constituents. The medical use of bear gallbladder (Xiongdan)in Chinese medicine was first recorded in the Yao Xing Lun(“Treatise on the Nature of Medicinal Herbs”), a now-lost text from the Song Dynasty that originated in the early Tang Dynasty (ca. 600 CE). Currently, the material is produced synthetically or extracted from byproducts of slaughterhouses. In many respects, UDCA inhabits the intermediary zone where traditional “herbal” medicine and pharmaceuticals overlap. Within conventional practice, UDCA is considered the only therapeutic modality whose effectiveness in the treatment of ICP is supported by evidence from controlled trials. ^28,31 Similarly, UDCA is used for symptomatic relief of itching in the treatment of primary sclerosing cholangitis. UDCA is also used in the treatment of primary biliary cirrhosis to improve liver biochemistry, increase survival, and delay liver transplantation. Recent research on the use of UDCA in the treatment of Huntington's disease is considered promising.

S-Adenosylmethionine exerts numerous metabolic effects within the liver that can assist detoxification functions and alter bile formation in ways that may provide an additive effect with, or alternative to, UDCA as a therapeutic agent.

Research

In a randomized clinical trial published in 1996 involving 20 women with ICP in the last trimester of pregnancy, Floreani et al. ³² compared the effects of SAMe (1000 mg/day intramuscularly) and UDCA (450 mg/day). The treatment was continued until delivery, at least 15 days, in all women. They found that UDCA was more effective than SAMe in controlling pruritus and total bile acids. Subsequently Nicastri et al. ²⁷ conducted a randomized placebo-controlled study involving 32 women exhibiting ICP who were divided into four groups. These researchers determined that, after treatment for 20 days, a “combination of ursodeoxycholic acid and S-adenosylmethionine is more effective than placebo and than either drug alone.” Roncaglia et al. ³³ conducted a randomized controlled trial of oral UDCA (300 mg twice daily) and oral S-adenosyl- L-methionine (500 mg twice daily) in the treatment of severe gestational cholestasis. They found that women receiving UDCA demonstrated a significantly greater improvement in tests of liver function (i.e., concentration of serum bile acids, aspartate transaminase [AST], alanine transaminase [ALT], and bilirubin) compared with those receiving SAMe. Duration of therapy was significantly greater in women receiving UDCA compared with SAMe.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

A relatively rare disorder, ICP appears to be related to an exaggerated genetic sensitivity to estrogens and manifests during pregnancy with pruritus and icterus as the chief complaints. Although ICP is generally considered as carrying minimal medical risk to the mother, it is regarded as presenting significant risk of perinatal mortality to the fetus, preterm delivery, fetal distress, and meconium staining. Elevated alkaline phosphatase and serum bilirubin levels are characteristic, as are other increased values of parameters indicating altered liver function and bile composition. The trend in clinical trials reveals a pattern of research focusing on the relative efficacy of UDCA and SAMe in the treatment of ICP. There is general agreement that UDCA represents a therapeutic agent supported by both clinical experience and research evidence. The available studies, although all small in size, suggest that a combination therapy provides synergistic, or at least additive, therapeutic efficacy. Given the consensus and evidence that both substances are safe during pregnancy, for both mother and fetus, such approaches deserve further research and empirical investigation. The utility of SAMe in the treatment of other conditions for which UDCA has shown efficacy has yet to be investigated in well-designed clinical trials of adequate size.

Venlafaxine and Related Selective Serotonin Reuptake Inhibitor and Serotonin-Norepinephrine Reuptake Inhibitor (SSRI and SNRI) Antidepressants

Evidence: Venlafaxine (Effexor). Extrapolated, based on similar properties: SSRI:Citalopram (Celexa), duloxetine (Cymbalta), escitalopram (S-citalopram; Lexapro), fluoxetine (Prozac, Sarafem), fluvoxamine (Faurin, Luvox), paroxetine (Aropax, Deroxat, Paxil, Seroxat), sertraline (Zoloft). SSRI/SNRI:Duloxetine (Cymbalta).

Beneficial or Supportive Interaction, with Professional Management

Probability: 2. Probable
Evidence Base:

Preliminary

Effect and Mechanism of Action

S-Adenosylmethionine and selective serotonin reuptake inhibitors (SSRIs) are both known to benefit individuals with depression. However, research data are as yet inadequate to elucidate fully the mechanisms of action involved and whether the effect is additive or synergistic.

Research

Alpert et al. ³⁴ conducted an open clinical trial to evaluate the safety, tolerability, and efficacy of oral SAMe as an antidepressant adjunct among partial responders and nonresponders to serotonin reuptake inhibitors or venlafaxine, a dual selective serotonin reuptake inhibitor and serotonin-norepinephrine reuptake inhibitor (SSRI/SNRI). They administered S-adenosyl- L-methionine tosylate (800-1600 mg) to 30 antidepressant-treated adult outpatients with persisting major depressive disorder. At the end of the 6-week treatment period, these researchers observed a response rate of 50% and a remission rate of 43% after augmentation of SSRI or venlafaxine with SAMe and reported minor gastrointestinal distress and headaches as the primary adverse effects. ³⁴ These findings indicate that further research in the form of a well-designed, adequately powered placebo-controlled clinical trial is warranted to further determine the efficacy, assess safety parameters, and refine clinical management guidelines for the integrative treatment of depression using SAMe and venlafaxine or SSRI antidepressants.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

A review of clinical practice and preliminary evidence suggests an emerging, but not yet coherent or articulate, proposition suggesting that SAMe, in graduated dosages in the range of 400 to 800 mg twice daily, can be used adjunctively with SSRI medications to enhance the clinical effectiveness of treatment for depression and other appropriate conditions. The variable mechanisms of action among different SSRIs, along with individual pharmacogenomic variability, life stage, and gender factors and other metabolic influences, may account for differing therapeutic responses and occurrences of adverse effects.

Such an integrative therapeutic strategy warrants close supervision and regular monitoring within the context of coordinated care by health care providers trained and experienced in both clinical nutrition and conventional pharmacology. The concomitant use of SAMe and SSRI medications and/or SSRI/SNRI agents such as venlafaxine should not be used outside of such context of active clinical management. Even though preliminary findings indicate a minimal level of adverse effects, unsupervised coadministration of SSRI drugs with SAMe must still be treated as a potential risk for higher incidence of serotonin-associated unintended effects and adverse events, pending more conclusive evidence. A rapid onset of symptoms indicating an adverse response, particularly CNS toxicity, is highly probable in the unlikely event that a serotonin syndrome or other adverse event does develop.

theoretical, speculative, and preliminary interactions research, including overstated interactions claims

Anticoagulant and Antiplatelet Medications

Limited in vitro studies of SAMe's effect on platelet activation, particularly platelet thromboxane and vascular prostacyclin, suggest that use by individuals with active bleeding disorders or undergoing anticoagulant therapy may be contraindicated, at a level of risk perhaps comparable to aspirin. The range of cautions and contraindications will be extensive in the event that such concerns are confirmed by high-quality clinical trials or a consistent pattern of well-documented case reports. Toward clarifying such potentially significant issues, physicians treating susceptible individuals or prescribing potentially interacting medications are advised to be cognizant of the plausibility of such concerns and document and report suspicious events in a thorough and systematic manner. ^35,36

Monoamine Oxidase (MAO) Inhibitors

MAO-A inhibitors:Isocarboxazid (Marplan), moclobemide (Aurorix, Manerix), phenelzine (Nardil), procarbazine (Matulane), tranylcypromine (Parnate).

MAO-B inhibitors:Selegiline (deprenyl, L-deprenil, L-deprenyl; Atapryl, Carbex, Eldepryl, Jumex, Movergan, Selpak); pargyline (Eutonyl); rasagiline (Azilect).

Concerns have been raised that unmanaged exogenous SAMe could produce an undesirable additive effect if taken in conjunction with MAO inhibitors or SSRI antidepressants. Although such interactions might be plausible, no readily available published evidence from animal studies or human trials supports the hypothesis that such an interaction actually occurs or describes its character and implications in human subjects. In the event that such a pattern of interaction should come to light, the example of TCAs suggests that synergistic coadministration might be efficacious within the context of integrative case management and personalized therapeutic adaptations. Although classic MAO inhibitors are no longer widely used, the potentially catastrophic nature of their interactions would dictate extreme caution in combining a neurotransmitter modulator such as SAMe with MAO inhibitors in the absence of any clinical trial or published anecdotal experience with the combination.

Vidarabine

Evidence: Vidarabine (Ara-A, arabinoside; Vira-A).

Potential: Ribaviran (Copegus, Rebetol, Ribasphere, Vilona, Virazole).

The most common use of vidarabine is as an ophthalmic preparation for the treatment of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) in acute keratoconjunctivitis and recurrent superficial keratitis. The therapeutic action of vidarabine is achieved by interfering with viral DNA synthesis, specifically inhibition of S-adenosylhomocysteine hydrolase (SAH), methionine synthesis, and SAMe-dependent DNA methylation. Vidarabine cannot be given orally because it is metabolized in the gut, so it is usually administered intravenously or topically. ^37-39

The action of vidarabine indicates a potential risk for interfering with methionine function in humans and potentially inducing a depletion of methionine with extended use. Any such depleting effect on methionine status is likely to be gradual and cumulative, but evidence from human trials is lacking. Concomitant administration of SAMe (or methionine) could theoretically interfere with the therapeutic activity of vidarabine or related antiviral medications.

Although the mechanism of interaction between vidarabine and SAMe is obvious and incontrovertible, the recognition of this interaction and its potential adverse effects has not been acknowledged or addressed in published scientific research. Human studies are lacking to determine whether vidarabine might induce clinically significant methionine depletion and whether methionine administration might interfere with the medication's antiviral activity. Further research is warranted.

Physicians prescribing vidarabine for an extended period may want to present a patient with options for countering the potential adverse effects of this drug. Some nutritionally oriented health care professionals have found value in monitoring serum methionine in their patients taking vidarabine. Coadministration of methionine could be used to counter this adverse effect of vidarabine. Concomitant use of SAMe has not been studied in this regard but may be appropriate. However, due consideration is appropriate, and future research could help clarify whether any such SAMe intake might be contraindicated as interfering with the intended therapeutic action of the medication.

nutrient-nutrient interactions

5-Hydroxytryptophan (5-HTP)

The concomitant administration of SAMe with 5-HTP or other supplements or herbs thought to exert an antidepressant effect should be approached with caution and subject to close supervision and regular monitoring. Such therapeutic synergies are common in clinical practice and have a presumed history of empirical efficacy. However, the safety and effectiveness of such prescribing practices have yet to be studied in any well-designed and systematic clinical trials and must always be considered within the context of an evolving and personalized therapeutic plan managed by health care professionals trained and experienced in both conventional pharmacology and the appropriate herbal or nutritional disciplines.

Selenium

The toxicity of selenium at high dosages, especially in its inorganic forms, is largely attributable to its depletion of SAMe reserves. SAMe is the body's principal methyl donor, and the metabolism of inorganic selenium requires both extra methyl donors and higher levels of antioxidants on its way to becoming methylselenol.

Citations and Reference Literature

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The information presented in InteractionsGuide™ is provided for healthcare professionals and members of the general public seeking information on healthcare options for educational and reference purposes only. The data is based on published scientific studies, clinical experience, and established usage, with selected sources cited as available for each topic. In considering the information provided healthcare professionals are advised to apply their educational training, clinical experience, and a reasonable standard of care.

InteractionsGuide™ is not intended to provide users with information on the treatment of specific medical conditions outside of the context of the relationship with their healthcare provider. The therapeutic options contained in InteractionsGuide™ will not be appropriate for all individuals nor will the therapeutic outcomes suggested necessarily occur in all individuals. Further, different individuals with the same symptoms or diagnosis often require differing treatments.

Users of InteractionsGuide™ who are not health care professionals are advised to consult their physician, appropriately-trained healthcare practitioner, and/or pharmacist before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using any supplements, herbs, remedies, dietary changes or other forms of self-care. Complete information about the effects of specific nutrients, herbs, dietary supplements and possible interactions between such substances and a prescription or over-the-counter medication should be confirmed with the prescribing physician, a pharmacist, or both. Health Resources Unlimited, Inc. does not recommend specific substances, therapies or practitioners.

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InteractionsGuide Index Page

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Health Resources Unlimited, Inc.

Chemistry and Forms

Physiology and Function

Known or Potential Therapeutic Uses

Historical/Ethnomedicine Precedent

Possible Uses

Dietary Sources

Nutrient Preparations Available

Dosage Forms Available

Source Materials for Nutrient Preparations

Dosage Range

Adult

Pediatric (<18 Years)

Laboratory Values

Overview

Nutrient Adverse Effects

Adults

Adverse Effects Among Specific Populations

Pregnancy and Nursing

Infants and Children

Contraindications

Precautions and Warnings

Strategic Considerations

Effect and Mechanism of Action

Research

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Report

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Effect and Mechanism of Action

Research

Nutritional Therapeutics, Clinical Concerns, and Adaptations