From the Research
Methadone can cause serotonin syndrome at any dose, but the risk is significantly increased when combined with other serotonergic medications, and even low doses, such as 15 mg/day, can trigger the syndrome in susceptible individuals, as reported in a case study published in 2020 1. The risk of serotonin syndrome with methadone is not strictly dose-dependent, but rather is influenced by the presence of other serotonergic agents, such as SSRIs, SNRIs, MAOIs, or certain antibiotics like linezolid.
- Key factors that increase the risk of serotonin syndrome include:
- Combination with other serotonergic medications
- Presence of underlying medical conditions
- Individual susceptibility to serotonin syndrome
- Early symptoms of serotonin syndrome include:
- Agitation
- Tremor
- Diaphoresis
- Hyperthermia
- These symptoms can progress to more severe manifestations, including muscle rigidity, hyperthermia, and autonomic instability, as described in a study published in 2025 2. The mechanism of serotonin syndrome involves methadone's weak serotonin reuptake inhibition properties becoming problematic when combined with other medications that also affect serotonin levels, as discussed in a case report published in 2015 3. It is essential to monitor patients on methadone for symptoms of serotonin syndrome, especially when adding new medications, and to be aware of the potential for drug interactions, as highlighted in a study published in 2025 2.