SAMe and medications.
SAMe is not in the Distil recommendation database. We surface it here deliberately, because why a compound is left out is as useful as what we recommend.
SAMe has genuine antidepressant evidence, better than most supplements marketed for mood. The reason it sits outside the Distil database is the same one that keeps 5-HTP out: it raises serotonin activity. Taken alongside an SSRI or SNRI it adds to the serotonin load, and a 2018 trial that added SAMe to antidepressants recorded a serotonin-syndrome-like reaction. With an MAOI the stakes are high enough that we treat it as do-not-combine.
Most people who reach for SAMe are doing so for mood or joints, and many of them are also on a serotonergic medicine, often without thinking of it as one. Because the pipeline cannot safely carry a serotonergic supplement across those cases, SAMe stays out rather than going in with a caution. The documented pairs below are the ones to check first. If mood is the goal, the options below carry none of that serotonin risk.
What to consider instead. Every option below is in the Distil database, so you can check each against your own medications:
- Saffron Extract: has antidepressant trial evidence and no serotonin-syndrome signal at normal doses
- Omega-3 EPA: EPA-dominant omega-3 has the better mood evidence of the two fatty acids
- Vitamin D3: worth checking and correcting a low level first
We still hold the documented interactions for SAMe, which is why it stays in the interactions checker even though we do not recommend it. Below are the 26 documented pairs we have explicitly assessed: 7 red and 19 amber. Every call is cited to a clinical reference (PMID) or the British National Formulary.
Documented interactions
Last reviewed 30 June 2026. Each interaction below is assessed against PubMed-indexed evidence.
Additive serotonergic activity
Red Does interact with Isocarboxazid?
SAMe raises serotonin-related activity, and isocarboxazid is an MAOI that blocks serotonin breakdown. Stacking the two could push serotonin too high, risking serotonin syndrome. We treat this as a do-not-combine pair without specialist sign-off.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Red Does interact with Linezolid?
SAM-e has antidepressant, serotonin-raising activity, and linezolid is an antibiotic that also acts as an MAOI, blocking serotonin breakdown. Stacking the two could push serotonin too high, risking serotonin syndrome. We treat this as a do-not-combine pair without specialist sign-off.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Red Does interact with Moclobemide?
SAM-e has antidepressant, serotonin-raising activity, and moclobemide is an MAOI (the reversible kind) that blocks serotonin breakdown. Stacking the two could push serotonin too high, risking serotonin syndrome. We treat this as a do-not-combine pair without specialist sign-off.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Red Does interact with Phenelzine?
SAMe raises serotonin-related activity, and phenelzine is an MAOI that blocks serotonin breakdown. Stacking the two could push serotonin too high, risking serotonin syndrome. We treat this as a do-not-combine pair without specialist sign-off.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Red Does interact with Rasagiline?
Taking SAMe with rasagiline (an MAO-B inhibitor used for Parkinson's) can push serotonin to dangerous levels, because SAMe has its own serotonin-related activity and there is less MAO available to break it down, so we treat this as a do-not-combine pair without specialist sign-off.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Red Does interact with Selegiline?
Taking SAMe with selegiline (an MAO-B inhibitor used for Parkinson's) can push serotonin to dangerous levels, because SAMe has its own serotonin-related activity and there is less MAO available to break it down, so we treat this as a do-not-combine pair without specialist sign-off.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Red Does interact with Tranylcypromine?
SAMe raises serotonin-related activity, and tranylcypromine is an MAOI that blocks serotonin breakdown. Stacking the two could push serotonin too high, risking serotonin syndrome. We treat this as a do-not-combine pair without specialist sign-off.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Amitriptyline?
SAMe has its own antidepressant, serotonin-related activity, which may add to amitriptyline's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your amitriptyline dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Citalopram?
SAMe has its own antidepressant, serotonin-related activity, which may add to citalopram's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your citalopram dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Clomipramine?
SAMe has its own antidepressant, serotonin-related activity, which may add to clomipramine's. Clomipramine is the most strongly serotonin-acting of the tricyclics, so the effects are the most likely to add up. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your clomipramine dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Dosulepin?
SAMe has its own antidepressant, serotonin-related activity, which may add to dosulepin's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your dosulepin dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Doxepin?
SAMe has its own antidepressant, serotonin-related activity, which may add to doxepin's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your doxepin dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Duloxetine hydrochloride?
SAMe has its own antidepressant, serotonin-related activity, which may add to duloxetine's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your duloxetine dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Escitalopram?
SAMe has its own antidepressant, serotonin-related activity, which may add to escitalopram's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your escitalopram dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Fluoxetine hydrochloride?
SAMe has its own antidepressant, serotonin-related activity, which may add to fluoxetine's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your fluoxetine dose has recently changed. Fluoxetine also stays in your system for weeks after stopping, so the caution applies for a while after a dose change.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Fluvoxamine?
SAMe has its own antidepressant, serotonin-related activity, which may add to fluvoxamine's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your fluvoxamine dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Imipramine?
SAMe has its own antidepressant, serotonin-related activity, which may add to imipramine's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your imipramine dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Lithium carbonate?
SAMe has its own antidepressant, serotonin-related activity, and lithium is often used alongside antidepressants in a way that can raise serotonin signalling. Adding SAMe may add to that effect. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP or psychiatrist before stacking them, especially if your lithium dose or levels have recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Paroxetine hydrochloride?
SAMe has its own antidepressant, serotonin-related activity, which may add to paroxetine's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your paroxetine dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Sertraline?
SAMe has its own antidepressant, serotonin-related activity, which may add to sertraline's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your sertraline dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Sumatriptan succinate?
SAMe has its own antidepressant, serotonin-related activity, and sumatriptan is a serotonin-receptor drug used for migraine. In theory they could add to each other's serotonin effect. Most people tolerate the combination and the real-world risk looks low, but it is worth telling your GP, and seek help if you notice agitation, sweating, shivering, tremor, or a racing heart, especially if you also take an antidepressant.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Tramadol hydrochloride?
SAMe has its own antidepressant, serotonin-related activity, and tramadol raises serotonin as part of how it works. Taking them together may increase the risk of serotonin syndrome. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your prescriber before stacking them, especially if your tramadol dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Trazodone hydrochloride?
SAMe has its own antidepressant, serotonin-related activity, and trazodone is a serotonergic antidepressant too. Taking them together may add to that serotonin effect. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your trazodone dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Venlafaxine?
SAMe has its own antidepressant, serotonin-related activity, which may add to venlafaxine's. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your venlafaxine dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Vortioxetine?
SAMe has its own antidepressant, serotonin-related activity, and vortioxetine works on serotonin too. Taking them together may add to that serotonin effect. Most people tolerate the combination, but watch for restlessness, sweating, tremor, shivering, or a racing heart, and tell your GP before stacking them, especially if your vortioxetine dose has recently changed.
Evidence: Limited human data, based on case reports and a known mechanism.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
Amber Does interact with Zolmitriptan?
SAMe has its own antidepressant, serotonin-related activity, and zolmitriptan is a serotonin-receptor drug used for migraine. In theory they could add to each other's serotonin effect. Most people tolerate the combination and the real-world risk looks low, but it is worth telling your GP, and seek help if you notice agitation, sweating, shivering, tremor, or a racing heart, especially if you also take an antidepressant.
Evidence: Based on an established mechanism, with no direct study of this exact combination yet.
Reviewer-flagged: awaiting clinical-reviewer sign-off.
What this page does not say. Leaving a compound out of our recommendations is not a verdict that it is useless for everyone. It is a statement about safety, evidence, or interaction load in the context Distil screens for. Discuss any supplement decision with whoever manages your prescriptions.
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How we grade severity, choose what's in scope, and what we exclude.
Every call on this page is reasoned. We publish the full rubric for severity tiers, the medication inclusion logic, the evidence grades we accept, and what we deliberately leave out. About three thousand words. Worth reading once if you use this tool more than occasionally.
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- the same graded, cited interaction check across your whole stack, not just the pairs you thought to type in
- where your current routine may be leaving you short of your goals
- the evidence-graded compounds worth adding, and the ones worth dropping
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