SAMe (S-Adenosyl L-Methionine) With Methadone Interaction

In our latest question and answer, the pharmacist discusses the potential interaction between methadone and SAMe (S-Adenosyl L-Methionine).

SAMe (S-Adenosyl L-Methionine) With Methadone Interaction
May 20, 2019

jack asked

Can I take S-Adenosyl L-Methionine and 5 mg methadone together?

At a glance

  • Both SAMe (S-Adenosyl L-Methionine) and methadone can increase serotonin concentrations, increasing the risk of a rare, but serious condition known serotonin syndrome. The risk of this is likely to be low, but you should speak with your doctor first before combining methadone and SAMe.


Methadone bottle with text - taking with SAMe

S-Adenosyl L-Methionine, more commonly known as SAMe, is popular over the counter supplement used for a variety of purposes, including:[1]

  • Depression
  • Anxiety
  • Arthritis pain
  • Liver protection
  • Sexual dysfunction
  • Liver disease

Drug interactions with SAMe have been investigated in a number of studies, but more are needed for conclusive evidence on whether or not any potential interaction is clinically significant.

Two types of drugs have the most evidence for impact when taken with SAMe. They are:[2][3]

  • Drugs that have serotonergic properties (i.e. affect serotonin concentrations)
  • L-dopa (a dopamine precursor used for the treatment of Parkinson's Disease)

As it concerns methadone, no interactions with it have been reported.

However, methadone is thought to be a (very) weak inhibitor of serotonin reuptake, which increases overall concentrations in the brain. It has been linked to causing a rare, but serious condition known as serotonin syndrome when used in conjunction with other serotonergic drugs.[4][5]

Since SAMe and methadone may both have serotonergic properties, there may be an increased risk of additive side effects and/or serotonin syndrome if used together.

There haven't been any published studies reporting on an interaction between these two drugs, but based on the known mechanism for them, it is theoretically possible. Caution is advised if using them together and you should certainly discuss the use of SAMe and methadone with your doctor first before combining them.

How Does SAMe Work?

SAMe (S-adenosyl-L-methionine) is a naturally occurring molecule in the human body and is involved in a number of chemical reactions responsible for the synthesis, activation or metabolism of a variety of compounds, including from hormones and neurotransmitters.[6]

The mechanism of action by which SAMe works for the treatment of many of the conditions listed above (e.g. pain, depression, Parkinson's Disease, etc) is wide-ranging.

For example, for depression and Parkinson's Disease, it has been shown to be involved in the production of several neurotransmitters, including serotonin, norepinephrine, and dopamine.[7]

As another example, for liver disease, SAMe supplementation may help to increase levels of glutathione, a powerful antioxidant.[8]

When it comes to drug interactions, since SAMe has so many different effects, they can be difficult to predict.

Most reported ones concern the ability of SAMe to influence neurotransmitter concentrations (like serotonin).

How Does Methadone Work?

Methadone is an opioid medication, working mainly by stimulating u (mu) opiate receptors in the body.

It is also thought to be a weak reuptake inhibitor of serotonin.[9]

Although methadone works in the same manner as other opioids, it is most commonly used as replacement therapy for opioid dependence for a variety of reasons:[10]

  • It has a relatively slow onset of action and doesn't generally cause a 'high' when appropriate doses are used
  • It has a long half-life, which reduces the risk of withdrawal
  • It lacks active metabolites
  • It is inexpensive

SAMe - Methadone Interaction

There haven't been published cases of interactions between SAMe and methadone, but that doesn't necessarily mean none exist.

SAMe is known to increase serotonin levels and methadone has been shown to be a weak serotonin reuptake inhibitor.

In fact, opioid medications, like methadone, are being more associated with increasing the risk of serotonin syndrome when used with other serotonergic drugs.

The FDA even released a warning about the risk of serotonin syndrome with opioid drugs.

The risk of serotonin syndrome doesn't appear to be all that high with the combined use of methadone and SAMe, but it important to be aware of regardless.

What is Serotonin Syndrome?

Serotonin syndrome, although uncommon, is a serious condition brought on by an excess of serotonin in the brain.

Symptoms include:[11]

  • Agitation
  • Hallucinations
  • Increased heart rate
  • Fever
  • Sweating
  • Shivering
  • Shaking
  • Muscle twitching
  • Incoordination
  • Nausea
  • Coma

Symptoms, should they occur, generally start quickly, within hours to days of taking an opioid with another serotonergic agent (like SAMe).

Just how risky combining methadone with SAMe is in regard to causing serotonin syndrome isn't known.

It is important to be aware of the symptoms however and seek medical attention if any occur when taking the combination.

  1. ^ S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial. PubMed
  2. ^ Parkinson's disease-like effects of S-adenosyl-L-methionine: effects of L-dopa. PubMed
  3. ^ Toxic interaction of S-adenosylmethionine and clomipramine. PubMed
  4. ^ A case of serotonin syndrome and mutism associated with methadone. PubMed
  5. ^ A case of serotonin syndrome associated with methadone overdose. PubMed
  6. ^ S-adenosyl-L-methionine. A review of its pharmacological properties and therapeutic potential in liver dysfunction and affective disorders in relation to its physiological role in cell metabolism. PubMed
  7. ^ S-adenosyl methionine (SAMe) for depression in adults. PubMed
  8. ^ Importance of a deficiency in S-adenosyl-L-methionine synthesis in the pathogenesis of liver injury. PubMed
  9. ^ Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. PubMed
  10. ^ Methadone maintenance treatment. PubMed
  11. ^ Recognition and treatment of serotonin syndrome. PubMed

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