Serotonin Syndrome: Mechanisms, Diagnosis, High-Risk Interactions, and Management

In a nutshell

Serotonin syndrome is a potentially life-threatening drug-induced toxidrome caused by excess serotonergic neurotransmission. The diagnosis is purely clinical, no lab test confirms it. Most practitioners know to avoid MAOI + SSRI combinations, but severe cases increasingly involve “hidden” serotonergic agents: the antibiotic linezolid and methylene blue (increasingly used for “biohacking” without disclosure).

• Key clinical recommendations:
  • Diagnosis requires exposure + exam findings: Hunter Criteria are gold standard. Look for spontaneous clonus (diagnostic alone) or inducible clonus with agitation/diaphoresis. Don’t wait for the full triad.
  • Examine lower extremities: Hyperreflexia and clonus are more pronounced in the legs. Always check ankle clonus.
  • Onset timing narrows the differential: Symptoms emerge within hours of dose increase or new agent, unlike NMS (days to weeks). Rapid improvement after stopping agents (24 hours) confirms the diagnosis retrospectively.
  • Treat with benzodiazepines, NOT antipyretics: Hyperthermia in serotonin syndrome is caused by muscular activity, not a hypothalamic set-point change. Antipyretics (acetaminophen/NSAIDs) are ineffective; benzodiazepines are the cornerstone of treatment to control agitation and muscle heat production.
• High-risk combinations to avoid:
  • MAOIs + SSRIs/SNRIs/TCAs: Accounts for the majority of severe and fatal cases.
  • MDMA (Ecstasy) + MAOIs: Dangerous synergy, may cause massive serotonin release while inhibiting its metabolism, leading to rapid, and severe.
  • Opioids: Tramadol, meperidine (pethidine), and dextromethorphan (OTC cough syrup) carry high serotonergic risk compared to morphine or oxycodone.
• Screen beyond psychiatric meds: Ask about OTC dextromethorphan, St. John’s Wort, tryptophan supplements, recreational drug use
  • Safer opioid alternatives: Choose morphine, hydromorphone, or oxycodone; avoid tramadol or meperidine with antidepressants
  • Respect washout periods: 2 weeks for most MAOIs, 5 weeks for fluoxetine (long half-life) before starting MAOI
  • Watch CYP interactions: Fluconazole + citalopram, paroxetine + tramadol, ciprofloxacin + venlafaxine can cause drug accumulation

Introduction

Definition

• Serotonin Syndrome (SS), also referred to as serotonin toxicity, is a potentially life-threatening drug-induced condition associated with increased serotonergic activity in both the central and peripheral nervous systems ^[1,2]
• The classical triad of clinical manifestations includes neuromuscular abnormalities, autonomic hyperactivity, and mental status changes ^[1,2]
• SS is characterized by a dose-dependent spectrum of clinical findings related to elevated levels of serotonin or excessive 5-HT receptor activation ^[1–3]
  • It can be caused by therapeutic dosing, by drug–drug interactions, or by overdose
  • The clinical presentation exists on a continuum, ranging from mild, often-missed symptoms to a rapidly progressing, fatal toxidrome
    • Mild presentations: tremor, diarrhea, mild anxiety
    • Severe presentations: hyperthermia and muscular rigidity ^[3,4]

Epidemiology

• Incidence in primary care SSRI treatment has been estimated around 0.5–0.9 cases per 1,000 patient-months on monotherapy ^[4,5]
• In serotonergic medication overdoses, incidence reaches up to ~15% ^[6]
• The true incidence of serotonin syndrome remains unknown and is likely significantly higher than reported ^[1,2,7]
  • Clinical manifestations vary widely, and symptoms can resemble those of several other medical conditions ^[1]
  • Mild cases are frequently overlooked or dismissed, making serotonin syndrome likely to be underdiagnosed in clinical practice ^[1]
• Serotonin syndrome occurs in all age groups, including neonates, due to maternal exposure ^[3,4]
• Increasing incidence parallels the widespread use of serotonergic medications, particularly SSRIs, which is the most commonly implicated outpatient drug class ^[1,2]

Mechanisms

• Serotonin syndrome reflects excess serotonergic neurotransmission, primarily through overstimulation of postsynaptic 5-HT₂A and 5-HT₁A receptors in the brain and spinal cord ^[1–3]
• The risk of toxicity increases exponentially when drugs with different mechanisms are combined, as this creates a synergistic effect on the serotonin system
• 5-HT2A receptors: Mediate life-threatening effects (severe hypertonicity and hyperthermia); activated at higher serotonin concentrations ^[1–3]
• 5-HT1A receptors: Higher affinity for 5-HT; contribute to milder symptoms (anxiety, hyperactivity) at lower concentrations ^[2,8]

Inhibition of Serotonin Metabolism

• MAO inhibitors prevent the metabolism of serotonin, leading to increased presynaptic concentrations of 5-HT ^[2,7]
• Clinical significance: Episodes involving MAOIs may be more severe and more often lead to adverse outcomes, including death

Increased Serotonin Release

• Increased 5-HT release by drugs including amphetamines and their derivatives, cocaine, MDMA, and levodopa ^[2]

Inhibition of Serotonin Reuptake

• Increased synaptic levels of 5-HT due to inhibition of the SERT by reuptake inhibitors ^[2,7]

Direct Serotonin Receptor Agonism

• Direct or indirect activation of postsynaptic 5-HT receptors (predominantly 5-HT1A) ^[2]
• Multiple drug classes can directly activate serotonin receptors, including triptans (such as sumatriptan and rizatriptan), ergot derivatives (ergotamine, dihydroergotamine), certain opioids (fentanyl, meperidine), psychoactive drugs (LSD, buspirone), and other medications like mirtazapine, trazodone, and lithium ^[2]
• Clinical note:
  • Direct-acting serotonergic agents are associated with a lower risk of severe or typical serotonin toxicity compared to drug combinations or MAOIs that cause synaptic serotonin accumulation ^[9]

Increased Serotonin Synthesis

• Increased levels of L-tryptophan lead to increased levels of endogenous 5-HT through the catalytic action of tryptophan hydroxylase 2 (TPH2) ^[2]
• Agents: Dietary supplements containing tryptophan or oxitriptan ^[2]

Enhanced Receptor Sensitivity

• Some agents, such as lithium, may increase the sensitivity of postsynaptic serotonin receptors ^[10,11]
• This can potentiate the effects of other serotonergic agents without directly increasing serotonin levels

Additional Mechanism: Cytochrome P450 Inhibition

• Serotonin syndrome is a pharmacodynamic toxidrome, but it is often precipitated by a pharmacokinetic (PK) interaction ^[1,7]
• Core concept: CYP inhibition → substrate accumulation → ↑ serotonergic toxicity
  • E.g., SSRI inhibiting CYP2D6 leads to higher tramadol exposure, which in turn increases serotonergic effect from tramadol

Clinical Presentation and Diagnosis

• Serotonin syndrome is a clinical diagnosis requiring no confirmatory laboratory test ^[1,3,7]
• Diagnosis relies on identifying the characteristic triad of symptoms in the context of serotonergic agent exposure:
  • Altered mental status
  • Autonomic instability
  • Neuromuscular hyperreactivity

• Ankle clonus (adapted from ^[12])
  • Clonus is more pronounced in the lower extremities. Always check ankles
  • If you can elicit ankle clonus and the patient is diaphoretic + agitated on serotonergic meds, the diagnosis is made

• Ocular clonus in serotonin syndrome (adapted from ^[13])

• Increased tendon reflexes and myoclonus of the lower extremities in serotonin syndrome (adapted from ^[13])

Hunter Serotonin Toxicity Criteria

• Hunter Serotonin Toxicity Criteria are the most accurate diagnostic tool ^[1,2,7]
• Performance: ~84% sensitivity, 97% specificity vs toxicologist gold standard, and better than Sternbach’s original criteria especially for early/mild presentations ^[3,4,14]

Diagnostic Requirements

• Presence of a serotonergic agent (recent addition, dose increase, overdose, or interaction) PLUS one of the following:^[1,2,7,14]
  1. Spontaneous clonus
  2. Inducible clonus + agitation OR diaphoresis
  3. Ocular clonus + agitation OR diaphoresis
  4. Tremor + hyperreflexia
  5. Hypertonia + temperature >38°C (100.4°F) + ocular clonus OR inducible clonus
• Limitations: Hunter Criteria may miss mild cases, which can be difficult to distinguish from side effects or other medical conditions ^[1]

Severity Stratification

• Clinical presentation exists on a spectrum from mild to life-threatening, reflecting the degree of excess serotonergic activity and the specific 5-HT receptor subtypes activated ^[1,2]

Mild

• Symptoms: Anxiety, hypertension, tachycardia, hyperreflexia, diarrhea ^[1]
• Patients are typically normothermic with mild autonomic symptoms and neuromuscular signs ^[2]

Moderate

• Symptoms: Agitation, clonus, tremor, hyperthermia ^[1]
• Hyperthermia (>40°C) may be present ^[2]

Severe

• Life-threatening features: Hyperthermia (>41°C), confusion, marked hypertonicity or rigidity (especially truncal), respiratory failure, coma, death ^[1,2]
• Temperature >38.5°C and/or marked hypertonia indicates severe serotonin syndrome with risk of progression and respiratory compromise ^[2]
• Complications: Acute respiratory distress syndrome, respiratory failure, disseminated intravascular coagulation, multiorgan failure ^[7]
• Morbidity and mortality:
  • Early recognition and treatment are crucial to prevent significant morbidity and mortality ^[1]
  • Severe cases often present with hyperthermia >41°C and require urgent treatment in the intensive care unit ^[1]
  • With proper treatment, serotonin syndrome usually resolves within 24 hours without sequelae ^[1]
  • The prognosis is favorable if the patient is diagnosed and treated promptly ^[1]

Timing of Symptom Onset

• ~60% present within 6 hours (typically with rapid dose increases or overdose) ^[2]
• 25% present later than 24 hours (typically with gradual medication titration or cross-tapering) ^[2]
• Clinical pearl: Onset can be very rapid—symptoms may occur within minutes after medication changes or overdose ^[3]

Laboratory Evaluation

• No diagnostic laboratory test confirms serotonin syndrome ^[1,7]
• Serum serotonin concentrations do not correlate with clinical severity ^[7]
• Nonspecific laboratory abnormalities may be present (leukocytosis, low bicarbonate, elevated creatinine, elevated transaminases) ^[1,7]
• Laboratory testing purpose: Exclude other etiologies and monitor for complications in severe cases

Differential Diagnosis

• Serotonin syndrome and neuroleptic malignant syndrome (NMS) are the two most commonly confused hyperthermic syndromes in psychiatric practice ^[1]
• They can be distinguished by a careful history and physical exam

• Rapid differential mnemonic:
  • Hyperreflexia + clonus: Serotonin syndrome
  • Rigidity + bradyreflexia: NMS
• Also consider severe stimulant intoxication, sedative withdrawal, CNS infection, sepsis ^[3,4]

Comparing Serotonin Toxicity Risk Across Agents

• The risk of serotonin syndrome follows mechanistic principles rather than traditional drug classifications.
• Severe toxicity most often occurs when two or more drugs that increase serotonin in different ways are combined. The same drug can be low-risk as monotherapy but high-risk in combination. ^[15]
• Consider these three questions when evaluating any drug combination:
  1. Are multiple mechanisms being targeted? (MAO inhibition + reuptake inhibition = synergistic danger)
  2. What is the potency at the serotonergic target? (High-affinity SERT binding vs. weak affinity)
  3. Are pharmacokinetic factors amplifying exposure? (CYP inhibition causing accumulation)

Agents Organized by Mechanism and Risk

MAO Inhibitors

• MAOIs carry the highest individual agent risk for severe serotonin syndrome ^[1,3]
• Can precipitate syndrome as monotherapy at therapeutic doses ^[7]
• MAOI + SSRI/SNRI combinations account for the most severe and fatal cases ^[2,15]
• MAOI Risk Stratification:
  • Highest risk: Irreversible, nonselective MAOIs
    • Agents: Phenelzine, tranylcypromine, isocarboxazid
    • Greatest risk for severe serotonin syndrome
    • Symptoms can persist for several days after discontinuation due to irreversible enzyme inhibition ^[2]
    • Clinical consideration: Require longest washout periods before switching to other serotonergic agents
  • Lower risk: Reversible MAO-A inhibitors (RIMAs)
    • Agent: Moclobemide
    • Lower risk than irreversible MAOIs but still significant
    • Shorter washout period required (24 hours) due to reversible binding ^[2]
  • Lowest risk within class: MAO-B selective agents
    • Agents: Selegiline, rasagiline
    • Lower risk at low, selective doses
    • Risk increases at higher doses when selectivity is lost and MAO-A inhibition occurs ^[2]

The “Hidden MAOIs”

• MAO-inhibiting properties are not exclusive to psychiatric medications. Failure to recognize non-psychiatric MAOIs is a major prescribing hazard.
• Screen all medications before prescribing serotonergic agents, not just psychiatric drugs
• Minimum washout: 2 weeks for most MAOIs; 5 weeks for fluoxetine before starting MAOI ^[4]
• Linezolid (Zyvox):
  • Reversible, nonselective MAOI with potent activity ^[16]
  • FDA safety communication specifically warns against co-administration with serotonergic agents ^[17]
  • SSRI + linezolid had the highest pharmacovigilance signal for serotonin syndrome ^[18]
  • Real-world case: Elderly patient on stable SSRI receives linezolid for MRSA pneumonia: classic high-risk situation
• Methylene blue:
  • Potent, reversible MAO-A inhibitor used as surgical dye and for methemoglobinemia ^[19]
  • Off-label “biohacking” use: Methylene blue has been increasingly promoted in wellness circles as a cognitive enhancer and anti-aging supplement ^[20]
    • Patients may be self-administering without disclosing to prescribers, explicitly ask about supplement use.
  • FDA warning for severe cases in post-operative patients on chronic SSRIs/SNRIs receiving IV methylene blue ^[21]
  • Real-world case: Patient on sertraline undergoes parathyroid surgery with methylene blue dye injection

MDMA (“Ecstasy”) and Illicit Serotonergic Agents

• Screen for recreational drug use in any suspected serotonin syndrome case
• MDMA is one of the most dangerous agents for serotonin syndrome
  • Consistently associated with severe serotonergic toxicity and fatalities ^[2]
  • Triple mechanism: 5-HT release + reuptake inhibition + direct 5-HT2B agonism ^[2]
  • Can cause severe syndrome as single agent at recreational doses ^[22]
  • Extremely dangerous when combined with prescription serotonergic medications ^[23,24]
• Real-world case: Young adult taking chronic SSRI attends music festival and uses MDMA
  • Hot environment: MDMA causes hyperthermia; 5-HT2A receptors sensitized ^[25]
  • Hot temperature + physical activity (typical rave/club environment ) creates perfect storm for severe or fatal outcomes ^[25]
• Novel psychoactive substances (cathinones, aminoindanes, piperazines, phenylethylamines):
  • High serotonin:dopamine transporter-inhibition ratio likely increases risk ^[2]
  • Often unknown composition; patients may not disclose use

Selective Serotonin Reuptake Inhibitors (SSRIs)

• SSRIs account for most reported cases in FDA Adverse Event Reporting System (FAERS), primarily due to prescription volume ^[18]
• Monotherapy risk
  • Therapeutic doses: Low risk ^[7]
  • In overdose or with co-medications risk increases significantly
• Fluvoxamine:
  • Highest odds ratio among SSRIs; potent CYP1A2/2C19 inhibitor amplifies pharmacokinetic risk ^[18]
• Fluoxetine:
  • Long half-life (7 days) and active metabolite norfluoxetine (2.5 weeks) can precipitate syndrome up to 6 weeks after discontinuation ^[2]
  • Requires longer washout period before starting MAOI (5 weeks vs. 2 weeks for other SSRIs)

Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

• Monotherapy risk
  • Similar to SSRIs at therapeutic doses
• Combination Risk Stratification:
  • High risk combinations^[2,7]
    • SNRIs + MAOIs: Contraindicated
    • SNRIs + TCAs
    • SNRIs + serotonergic opioids (tramadol, methadone, fentanyl)
    • Venlafaxine + mirtazapine ± tramadol: Well-documented high-risk triple combination ^[7]
  • Moderate risk combinations^[2,7]
    • Venlafaxine + lithium: Requires monitoring
    • Venlafaxine + calcineurin inhibitors (tacrolimus, cyclosporine): Moderate risk due to CYP3A4 interactions

Tricyclic Antidepressants (TCAs)

• Rarely cause syndrome as monotherapy ^[7]
• Risk stratification by SERT potency:
  • Higher risk: Clomipramine, imipramine (potent serotonin reuptake inhibitors)—especially with MAOIs ^[26]
  • Lower risk: Amitriptyline, desipramine (weaker SERT affinity) ^[15]
• Reported high-risk combinations:
  • Imipramine + tranylcypromine (MAOI)
  • Clomipramine + methylene blue

Opioids

• Not all opioid analgesic drugs carry equal serotonergic risk ^[27,28]
• A recent study found higher risk of serotonin syndrome only when SSRIs were combined with high-risk opioids, while the combination with low-risk opioids showed no safety signal ^[18]
• The highest risk of serotonin toxicity by far is with irreversible Monoamine Oxidase Inhibitors (MAOIs) combined with high-risk opioids, such as pethidine, tramadol, or dextromethorphan ^[29]

Other Antidepressants

• Mirtazapine:
  • Mechanistic controversy: Does not increase synaptic serotonin (blocks α2-autoreceptors, antagonizes 5-HT2A/2C/3)
  • Some experts argue cases represent misclassification rather than true serotonin toxicity ^[30,31]
  • Documented cases with SSRIs and in combination with venlafaxine + tramadol
  • Rare monotherapy reports exist ^[32]
  • Clinical tip: Treat as low-moderate risk in combinations; high vigilance with polypharmacy
• Trazodone:
  • Activates 5-HT1 receptors; moderate risk in combinations ^[2]
• Buspirone:
  • 5-HT1A partial agonist; moderate risk with SSRIs ^[2,7]
• Bupropion:
  • Safer alternative when serotonin syndrome risk is a concern
  • Minimal serotonergic activity—primary mechanism is norepinephrine-dopamine reuptake inhibition ^[7]

Over-the-Counter and Herbal Products

• Often overlooked—patients may not report OTC agents during medication history.
• Explicitly ask about cough medicines, supplements, and herbal products during medication reconciliation.
• Dextromethorphan (cough suppressant):
  • Uncompetitive NMDA-receptor antagonist and high-affinity σ-1 receptor agonist
  • Multiple reports with SSRIs, TCAs, MAOIs ^[2,7,33,34]
• St. John’s Wort (Hypericum perforatum):
  • Moderate risk with SSRIs/MAOIs; Inhibits serotonin reuptake and metabolism ^[2]
• L-tryptophan (supplement):
  • Serotonin precursor; can contribute to syndrome with other serotonergic agents ^[7]
• Ginseng (Panax ginseng):
  • Reported cases with MAOIs ^[3]

Antiemetics and Migraine Medications Controversies

• Triptans (5-HT1B/1D agonists):
  • FDA warning (2006) highlighted risk with concurrent SSRI/SNRI use ^[35]
  • Actual risk appears low: Large cohort study found only 2.3 possible/definite cases per 10,000 person-years ^[36]
• 5-HT3 antagonists (ondansetron, granisetron):
  • Regulatory warnings: FDA and Health Canada issued warnings about serotonin syndrome risk ^[37]
  • Expert consensus: “Highly doubtful” these agents contribute to syndrome ^[37]
• Metoclopramide:
  • Activates serotonin receptors; should be used with caution in combination with other serotonergic agents ^[1,4]

Second-Generation Antipsychotics

• Reported combinations  ^[2,7]
  • Olanzapine + citalopram + lithium: Moderate risk
  • Risperidone + fluoxetine or paroxetine: Moderate risk
  • Quetiapine + venlafaxine + tramadol + trazodone: High-risk polypharmacy

Management

• Management of serotonin syndrome is based on severity-dependent treatment escalation and centers on three core interventions ^[1,2,7]
  1. Discontinuation of all serotonergic agents
  2. Supportive care aimed at normalizing vital signs
  3. Sedation with benzodiazepines

Supportive Care

• Agitation & Myoclonus: Benzodiazepines (e.g., diazepam, lorazepam) are the first-line treatment ^[2,4]
  • They reduce agitation and myoclonus. By controlling muscular hyperactivity, they also help lower core body temperature.
  • Dosing: Lorazepam 1-2 mg IV per dose or diazepam in standard doses   ^[2]
  • Titrate to clinical effect—goals are:
    • Adequate patient sedation (not somnolence)
    • Elimination of agitation and neuromuscular abnormalities (tremor, clonus)
    • Normalization of vital signs (heart rate, blood pressure)
  • Clinical pearl: Diazepam has been studied most extensively and has demonstrated ability to blunt hyperadrenergic symptoms ^[7]
• Hyperthermia:
  • Aggressive external cooling measures are essential for any patient with a temperature > 38°C. This includes cooling blankets, ice packs to the axillae and groin, and mist and fan techniques ^[2]
  • Avoid antipyretics:
    • The hyperthermia in SS is caused by excessive muscular activity (rigidity, clonus), not by an inflammatory-mediated change in the hypothalamic temperature set-point. Antipyretics are ineffective ^[4]
    • Do not use acetaminophen or NSAIDs. 

Antidotal Therapy: Cyproheptadine

• Indication: Benzodiazepines and supportive care fail to improve agitation and correct vital signs ^[2,7]
• Mechanism: Histamine-1 receptor antagonist with nonspecific 5-HT1A and 5-HT2A antagonistic properties ^[1]
• Evidence Base: Used off-label
  • Supportive data from case reports in mild to moderate serotonin syndrome ^[2,38,39]
  • Limitations: Efficacy in severe cases unproven; does not shorten time course of syndrome ^[7]
• Dosing  ^[2,3,7]
  • Initial dose: 12 mg orally (or via nasogastric/orogastric tube)
  • Additional dosing: 2 mg every 2 hours until clinical response is seen
  • Maintenance: 8 mg every 6 hours once response achieved
  • Total in 24 hours: May require 12-32 mg
• Formulation:
  • Available only in oral form (4 mg tablets or 2 mg/5 mL syrup).
  • Tablets may be crushed and administered via tube

Management Algorithm Summary

References

1. Mikkelsen, N., Damkier, P., & Pedersen, S. A. (2023). Serotonin syndrome—A focused review. Basic & Clinical Pharmacology & Toxicology, 133(2), 124–129. https://doi.org/10.1111/bcpt.13912

2. Scotton, W. J., Hill, L. J., Williams, A. C., & Barnes, N. M. (2019). Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions. International Journal of Tryptophan Research, 12, 1178646919873925. https://doi.org/10.1177/1178646919873925

3. Boyer, E. W., & Shannon, M. (2005). The Serotonin Syndrome. New England Journal of Medicine, 352(11), 1112–1120. https://doi.org/10.1056/NEJMra041867

4. Wang, R. Z., Vashistha, V., Kaur, S., & Houchens, N. W. (2016). Serotonin syndrome: Preventing, recognizing, and treating it. Cleveland Clinic Journal of Medicine, 83(11), 810–816. https://doi.org/10.3949/ccjm.83a.15129

5. Isbister, G. K., Buckley, N. A., & Whyte, I. M. (2007). Serotonin toxicity: A practical approach to diagnosis and treatment. The Medical Journal of Australia, 187(6), 361–365. https://doi.org/10.5694/j.1326-5377.2007.tb01282.x

6. Ellahi, R. (2015). Serotonin syndrome: A spectrum of toxicity. BJPsych Advances, 21(5), 324–332. https://doi.org/10.1192/apt.bp.114.013037

7. Volpi-Abadie, J., Kaye, A. M., & Kaye, A. D. (n.d.). Serotonin Syndrome.

8. Mignon, L., & Wolf, W. A. (2002). Postsynaptic 5-HT(1A) receptors mediate an increase in locomotor activity in the monoamine-depleted rat. Psychopharmacology, 163(1), 85–94. https://doi.org/10.1007/s00213-002-1121-3

9. Chiew, A. L., & Buckley, N. A. (2022). The serotonin toxidrome: Shortfalls of current diagnostic criteria for related syndromes. Clinical Toxicology (Philadelphia, Pa.), 60(2), 143–158. https://doi.org/10.1080/15563650.2021.1993242

10. Francescangeli, J., Karamchandani, K., Powell, M., & Bonavia, A. (2019). The Serotonin Syndrome: From Molecular Mechanisms to Clinical Practice. International Journal of Molecular Sciences, 20(9), 2288. https://doi.org/10.3390/ijms20092288

11. Foong, A.-L., Grindrod, K. A., Patel, T., & Kellar, J. (2018). Demystifying serotonin syndrome (or serotonin toxicity). Canadian Family Physician, 64(10), 720–727. https://pmc.ncbi.nlm.nih.gov/articles/PMC6184959/

12. Multimedia en medicina #1: clonus – INTERCONSULTA ON-LINE. (2019, February 1). https://interconsulta.online/multimedia-en-medicina-1-clonus/

13. Yoshidome, A., Yamasato, K., Harada, T., Ozawa, H., Inoue, T., & Nakai, M. (2023). Ocular clonus. Journal of the American College of Emergency Physicians Open, 4(5), e13055. https://doi.org/10.1002/emp2.13055

14. Dunkley, E. J. C., Isbister, G. K., Sibbritt, D., Dawson, A. H., & Whyte, I. M. (2003). The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for serotonin toxicity. QJM: Monthly Journal of the Association of Physicians, 96(9), 635–642. https://doi.org/10.1093/qjmed/hcg109

15. Foong, A.-L., Patel, T., Kellar, J., & Grindrod, K. A. (2018). The scoop on serotonin syndrome. Canadian Pharmacists Journal : CPJ, 151(4), 233–239. https://doi.org/10.1177/1715163518779096

16. Wali, H. A. (2025). Linezolid and serotonin syndrome. The Journal of International Medical Research, 53(2), 03000605251315355. https://doi.org/10.1177/03000605251315355

17. Research, C. for D. E. and. (Fri, 06/28/2019 – 09:02). FDA Drug Safety Communication: Serious CNS reactions possible when methylene blue is given to patients taking certain psychiatric medications. FDA. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-serious-cns-reactions-possible-when-methylene-blue-given-patients

18. Novella, A., Elli, C., & Pasina, L. (2025). Selective Serotonin Reuptake Inhibitors and Risk of Serotonin Syndrome as Consequence of Drug-Drug Interactions: Analysis of the FDA Adverse Event Reporting System. Medical Principles and Practice, 34(5), 456–463. https://doi.org/10.1159/000546109

19. Hazekamp, C., Schmitz, Z., & Scoccimarro, A. (2024). Methylene Blue–Induced Serotonin Toxicity: Case Files of the Medical Toxicology Fellowship at the New York City Poison Control Center. Journal of Medical Toxicology, 20(1), 54–58. https://doi.org/10.1007/s13181-023-00972-0

20. Mahdawi, A. (2025, February 11). Did RFK Jr really drink fish medicine? He definitely has weird ideas about ’making America healthy again’. The Guardian: Opinion. https://www.theguardian.com/commentisfree/2025/feb/11/did-rfk-jr-really-drink-fish-medicine-definitely-has-weird-ideas-making-america-healthy-again

21. Research, C. for D. E. and. (Fri, 06/28/2019 – 09:02). FDA Drug Safety Communication: Updated information about the drug interaction between linezolid (Zyvox) and serotonergic psychiatric medications. FDA. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-updated-information-about-drug-interaction-between-linezolid-zyvox-and

22. Makunts, T., Jerome, L., Abagyan, R., & de Boer, A. (2022). Reported Cases of Serotonin Syndrome in MDMA Users in FAERS Database. Frontiers in Psychiatry, 12, 824288. https://doi.org/10.3389/fpsyt.2021.824288

23. Dobry, Y., Rice, T., & Sher, L. (2013). Ecstasy use and serotonin syndrome: A neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors. International Journal of Adolescent Medicine and Health, 25(3), 193–199. https://doi.org/10.1515/ijamh-2013-0052

24. Mueller, P. D., & Korey, W. S. (1998). Death by “Ecstasy”: The Serotonin Syndrome? Annals of Emergency Medicine, 32(3), 377–380. https://doi.org/10.1016/S0196-0644(98)70018-6

25. Tao, R., Shokry, I. M., & Callanan, J. J. (2017). Environment Influencing Serotonin Syndrome Induced by Ecstasy Abuse. Annals of Forensic Research and Analysis, 4(1), 1039. https://pmc.ncbi.nlm.nih.gov/articles/PMC5931730/

26. Edinoff, A. N., Swinford, C. R., Odisho, A. S., Burroughs, C. R., Stark, C. W., Raslan, W. A., Cornett, E. M., Kaye, A. M., & Kaye, A. D. (n.d.). Clinically Relevant Drug Interactions with Monoamine Oxidase Inhibitors. Health Psychology Research, 10(4), 39576. https://doi.org/10.52965/001c.39576

27. Baldo, B. A. (2018). Opioid analgesic drugs and serotonin toxicity (syndrome): Mechanisms, animal models, and links to clinical effects. Archives of Toxicology, 92(8), 2457–2473. https://doi.org/10.1007/s00204-018-2244-6

28. Baldo, B. A., & Rose, M. A. (2020). The anaesthetist, opioid analgesic drugs, and serotonin toxicity: A mechanistic and clinical review. British Journal of Anaesthesia, 124(1), 44–62. https://doi.org/10.1016/j.bja.2019.08.010

29. Perananthan, V., & Buckley, N. A. (n.d.). Opioids and antidepressants: Which combinations to avoid. https://doi.org/10.18773/austprescr.2021.004

30. Berling, I., & Isbister, G. K. (2014). Mirtazapine overdose is unlikely to cause major toxicity. Clinical Toxicology (Philadelphia, Pa.), 52(1), 20–24. https://doi.org/10.3109/15563650.2013.859264

31. Gillman, P. K. (2003). Mirtazapine: Unable to Induce Serotonin Toxicity? Clinical Neuropharmacology, 26(6), 288. https://journals.lww.com/clinicalneuropharm/citation/2003/11000/mirtazapine__unable_to_induce_serotonin_toxicity_.3.aspx

32. Ubogu, E. E., & Katirji, B. (2003). Mirtazapine-induced serotonin syndrome. Clinical Neuropharmacology, 26(2), 54–57. https://doi.org/10.1097/00002826-200303000-00002

33. Schwartz, A. R., Pizon, A. F., & Brooks, D. E. (2008). Dextromethorphan-induced serotonin syndrome. Clinical Toxicology (Philadelphia, Pa.), 46(8), 771–773. https://doi.org/10.1080/15563650701668625

34. Okamoto, K., Hashimoto, N., Ishizeki, K., Nishimura, T., Makino, S., Takashima, A., Miyakawa, H., Ueda, Y., & Hayashi, T. (2025). Dextromethorphan-induced serotonin syndrome leading to rhabdomyolysis and dialysis-requiring acute kidney injury: A case report and review. Renal Replacement Therapy, 11(1), 23. https://doi.org/10.1186/s41100-025-00616-9

35. Research, C. for D. E. and. (n.d.). Drug Safety Information for Heathcare Professionals – Information for Healthcare Professionals: Selective Serotonin Reuptake Inhibitors (SSRIs), Selective Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs), 5-Hydroxytryptamine Receptor Agonists (Triptans) [WebContent]. Center for Drug Evaluation and Research. Retrieved November 9, 2025, from https://wayback.archive-it.org/7993/20170406044818/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm085845.htm

36. Orlova, Y., Rizzoli, P., & Loder, E. (2018). Association of Coprescription of Triptan Antimigraine Drugs and Selective Serotonin Reuptake Inhibitor or Selective Norepinephrine Reuptake Inhibitor Antidepressants With Serotonin Syndrome. JAMA Neurology, 75(5), 566–572. https://doi.org/10.1001/jamaneurol.2017.5144

37. Rojas-Fernandez, C. H. (2014). Can 5-HT3 Antagonists Really Contribute to Serotonin Toxicity? A Call for Clarity and Pharmacological Law and Order. Drugs – Real World Outcomes, 1(1), 3–5. https://doi.org/10.1007/s40801-014-0004-3

38. Graudins, A., Stearman, A., & Chan, B. (1998). Treatment of the serotonin syndrome with cyproheptadine. The Journal of Emergency Medicine, 16(4), 615–619. https://doi.org/10.1016/s0736-4679(98)00057-2

39. Baigel, G. D. (2003). Cyproheptadine and the treatment of an unconscious patient with the serotonin syndrome. European Journal of Anaesthesiology, 20(7), 586–588. https://doi.org/10.1017/s0265021503270927