View source for Serotonin syndrome

{{Short description|Symptoms caused by an excess of serotonin in the central nervous system}}
{{Distinguish|SSRI discontinuation syndrome}}
{{Infobox medical condition
| name            = Serotonin syndrome
| image           = Serotonin-2D-skeletal.svg
| caption         = [[Serotonin]]
| field           = [[Critical care medicine]], [[psychiatry]]
| synonyms        = Serotonin toxicity, serotonin toxidrome, serotonin sickness, serotonin storm, serotonin poisoning, hyperserotonemia, serotonergic syndrome, serotonin shock
| symptoms        = [[hyperthermia|High body temperature]], agitation, [[hyperreflexia|increased reflexes]], [[tremor]], [[diaphoresis|sweating]], [[dilated pupils]], [[diarrhea]]<ref name=Fer2016/><ref name=Vol2013/>
| complications   =
| onset           = Within a day<ref name=Vol2013/>
| duration        =
| causes          = [[Selective serotonin reuptake inhibitor]] (SSRI), [[serotonin norepinephrine reuptake inhibitor]] (SNRI), [[monoamine oxidase inhibitor]] (MAOI), [[tricyclic antidepressants]] (TCAs), [[amphetamine]], [[methylene blue]], [[pethidine]] (meperidine), [[tramadol]], [[dextromethorphan]], [[ondansetron]], [[cocaine]]<ref name=Vol2013/>
| risks           =
| diagnosis       = Based on symptoms and medication use<ref name=Vol2013/>
| differential    = [[Neuroleptic malignant syndrome]], [[malignant hyperthermia]], [[anticholinergic toxicity]], [[heat stroke]], [[meningitis]]<ref name=Vol2013/>
| prevention      =
| treatment       = [[Active cooling]]<ref name=Fer2016/>
| medication      = [[Benzodiazepine]]s, [[cyproheptadine]]<ref name=Fer2016/>
| prognosis       =
| frequency       = Unknown<ref name=Dom2013/>
| deaths          =
}}
<!-- Definition and symptoms -->

'''Serotonin syndrome''' ('''SS''') consists of a group of symptoms that may occur with the use of certain [[Serotonin|serotonergic]] medications or [[Recreational drug use|drugs]].<ref name="Fer2016">{{cite book|last1=Ferri|first1=Fred F.|title=Ferri's Clinical Advisor 2017: 5 Books in 1|date=2016|publisher=Elsevier Health Sciences|isbn=978-0-323-44838-3|pages=1154–1155|url=https://books.google.com/books?id=rRhCDAAAQBAJ&pg=PA1154|language=en}}</ref> The symptoms can range from mild to severe, and are potentially fatal.<ref>{{Cite journal|last1=New|first1=Andrea M.|last2=Nelson|first2=Sarah|last3=Leung|first3=Jonathan G.|date=2015-10-01|editor-last=Alexander|editor-first=Earnest|editor2-last=Susla|editor2-first=Gregory M.|title=Psychiatric Emergencies in the Intensive Care Unit|url=https://aacnjournals.org/aacnacconline/article/26/4/285/15256/Psychiatric-Emergencies-in-the-Intensive-Care-Unit|journal=AACN Advanced Critical Care|language=en|volume=26|issue=4|pages=285–293|doi=10.4037/NCI.0000000000000104|pmid=26484986|issn=1559-7768|url-access=subscription}}</ref><ref>Boyer EW , Shannon M . The serotonin syndrome . N Engl J Med. 2005 ; 352 ( 11 ): 1112-1120</ref><ref name="Vol2013" /> Symptoms in mild cases include [[high blood pressure]] and a [[fast heart rate]], usually without a [[fever]].<ref name="Vol2013" /> Symptoms in moderate cases include [[hyperthermia|high body temperature]], agitation, [[hyperreflexia|increased reflexes]], [[tremor]], [[sweating]], [[dilated pupils]], and [[diarrhea]].<ref name="Fer2016" /><ref name="Vol2013">{{cite journal | vauthors = Volpi-Abadie J, Kaye AM, Kaye AD | title = Serotonin syndrome | journal = The Ochsner Journal | volume = 13 | issue = 4 | pages = 533–40 | date = 2013 | pmid = 24358002 | pmc = 3865832 }}</ref> In severe cases, [[body temperature]] can increase to greater than {{convert|41.1|C|F|1}}.<ref name="Vol2013" /> Complications may include [[seizure]]s and [[rhabdomyolysis|extensive muscle breakdown]].<ref name="Vol2013" />

<!-- Cause -->
Serotonin syndrome is typically caused by the use of two or more serotonergic medications or drugs.<ref name=Vol2013/> These may include [[selective serotonin reuptake inhibitor]]<nowiki/>s (SSRIs), [[serotonin norepinephrine reuptake inhibitor]]<nowiki/>s (SNRIs), [[monoamine oxidase inhibitor]]<nowiki/>s (MAOIs), [[tricyclic antidepressant]]s (TCAs), [[Substituted amphetamine|amphetamines]], [[pethidine]] (meperidine), [[tramadol]], [[dextromethorphan]], [[buspirone]], {{nowrap|[[L-tryptophan]]}}, {{nowrap|[[5-hydroxytryptophan]]}}, [[St.&nbsp;John's wort]], [[triptan]]s, [[MDMA]], [[metoclopramide]], or [[cocaine]].<ref name=Vol2013/> It occurs in about 15% of SSRI [[overdose]]s.<ref name=Dom2013/> It is a predictable consequence of excess [[serotonin]] on the [[central nervous system]].<ref name="BoyerShannon2005">{{cite journal | vauthors = Boyer EW, Shannon M | title = The serotonin syndrome | journal = The New England Journal of Medicine | volume = 352 | issue = 11 | pages = 1112–1120 | date = March 2005 | pmid = 15784664 | doi = 10.1056/NEJMra041867 | url = http://toxicology.ucsd.edu/art%203%20serotonin%20syndrome.pdf | archive-url = https://web.archive.org/web/20130618053344/http://toxicology.ucsd.edu/art%203%20serotonin%20syndrome.pdf | url-status = live | archive-date = 2013-06-18 | author-link2 = Michael Shannon (pediatrician) }}</ref> Onset of symptoms is typically within a day of the extra serotonin.<ref name=Vol2013/>

<!-- Diagnosis -->
Diagnosis is based on a person's symptoms and history of medication use.<ref name=Vol2013/> Other conditions that can produce similar symptoms such as [[neuroleptic malignant syndrome]], [[malignant hyperthermia]], [[anticholinergic toxicity]], [[heat stroke]], and [[meningitis]] should be ruled out.<ref name=Vol2013/> As of 2013, no laboratory tests exist that can confirm the diagnosis.<ref name=Vol2013/>

<!-- Treatment and epidemiology -->
Initial treatment consists of discontinuing medications which may be contributing.<ref name=Fer2016/> In those who are agitated, [[benzodiazepine]]s may be used.<ref name=Fer2016/> If this is not sufficient, a [[serotonin antagonist]] such as [[cyproheptadine]] may be used.<ref name=Fer2016/> In those with a high body temperature, [[active cooling]] measures may be needed.<ref name=Fer2016/> The number of cases of serotonin syndrome that occur each year is unclear.<ref name=Dom2013>{{cite book|last1=Domino|first1=Frank J.|last2=Baldor|first2=Robert A.|title=The 5-Minute Clinical Consult 2014|date=2013|publisher=Lippincott Williams & Wilkins|isbn=978-1-4511-8850-9|page=1124|url=https://books.google.com/books?id=2C2MAwAAQBAJ&pg=PA1124|language=en}}</ref> With appropriate medical intervention the risk of death is low, likely less than 1%.<ref name=Fri2015>{{cite book|last1=Friedman|first1=Joseph H.|title=Medication-Induced Movement Disorders|date=2015|publisher=Cambridge University Press|isbn=978-1-107-06600-7|page=51|url=https://books.google.com/books?id=BqymCQAAQBAJ&pg=PA51|language=en}}</ref> The high-profile [[Libby Zion Law|case of Libby Zion]], who is generally accepted to have died from serotonin syndrome, resulted in changes to graduate medical school education in [[New York State]].<ref name="BoyerShannon2005" /><ref name=Bre1998>{{cite journal | vauthors = Brensilver JM, Smith L, Lyttle CS | title = Impact of the Libby Zion case on graduate medical education in internal medicine | journal = The Mount Sinai Journal of Medicine, New York | volume = 65 | issue = 4 | pages = 296–300 | date = September 1998 | pmid = 9757752 }}</ref>

==Signs and symptoms==
[[File:ClonusfromSS (edited).webm|thumb|upright=1.5|[[Clonus]] seen in a person with serotonin syndrome]]

Symptom onset is usually relatively rapid, and serotonin syndrome encompasses a wide range of clinical findings. Mild symptoms may consist of [[increased heart rate]], shivering, [[diaphoresis|sweating]], [[dilated pupils]], and [[myoclonus]] (intermittent jerking or twitching), as well as [[hyperreflexia]] (overresponsive reflexes).<ref name="BoyerShannon2005" /> Many of these symptoms may be side effects of the drug or drug interaction causing excessive levels of serotonin rather than an effect of elevated serotonin itself.

[[Tremor]] is a common side effect of [[MDMA]]'s action on [[dopamine]], whereas hyperreflexia is symptomatic of exposure to [[serotonin agonists]]. Moderate intoxication includes additional abnormalities such as hyperactive bowel sounds, [[high blood pressure]] and [[hyperthermia]]; a temperature as high as {{convert|40|°C|°F}}. The overactive reflexes and [[clonus]] in moderate cases may be greater in the lower limbs than in the [[upper limb]]s. Mental changes include [[hypervigilance]] or [[insomnia]] and [[Psychomotor agitation|agitation]].<ref name="BoyerShannon2005" /> Severe symptoms include severe increases in heart rate and blood pressure. Temperature may rise to above {{convert|41.1|°C|°F}} in life-threatening cases. Other abnormalities include [[metabolic acidosis]], [[rhabdomyolysis]], [[seizure]]s, [[kidney failure]], and [[disseminated intravascular coagulation]]; these effects usually arising as a consequence of hyperthermia.<ref name="BoyerShannon2005" /><ref name="IsbisterBuckleyWhyte2007">{{cite journal |vauthors=Isbister GK, Buckley NA, Whyte IM |title=Serotonin toxicity: a practical approach to diagnosis and treatment |journal=Med J Aust |volume=187 |issue=6 |pages=361–365 |date=September 2007 |pmid=17874986 |url=http://www.mja.com.au/public/issues/187_06_170907/isb10375_fm.html |url-status=live |archive-url=https://web.archive.org/web/20090412024747/http://www.mja.com.au/public/issues/187_06_170907/isb10375_fm.html |archive-date=2009-04-12 |doi=10.5694/j.1326-5377.2007.tb01282.x |s2cid=13108173 |url-access=subscription }}</ref>

The symptoms are often present as a clinical triad of abnormalities and can be used to assess the severity of serotonin syndrome:<ref name="BoyerShannon2005" /><ref name="Dunkley"/>
{| class="wikitable"
|+Serotonin syndrome severity assessment scale<ref name="BoyerShannon2005" /><ref name="Dunkley" />
!Severity
!Autonomic effects
!Neurological (somatic) signs
!Mental status
!Other symptoms
|-
!mild
|
* absent or low-grade fever
* tachycardia
* [[mydriasis]]
* excessive sweating
* shivering
|
* intermittent tremor
* akathisia
* myoclonus
* mild hyperreflexia
|
* restlessness
* anxiety
|
|-
!moderate
|
* increased tachycardia
* fever up to 41&nbsp;°C
* nausea
* diarrhea
* hyperactive bowel sounds
* excessive sweating
* vasoconstriction
|
* moderate hyperreflexia
* inducible clonus
* ocular clonus (slow continuous eye movements)
* myoclonus (muscle twitching)
|
* easily induced startle response
* confusion
* agitation
* hypervigilance
|
* rhabdomyolysis
* metabolic acidosis
* renal failure
* disseminated intravascular coagulopathy
|-
!severe
|
* temperature higher than 41&nbsp;°C (caused by increased muscle tone)
|
* increased muscle tone, which is more severe in lower limbs
* spontaneous clonus
* intense myoclonus
* severe hyperreflexia
|
* delirium
* coma
|as above
|}

==Causes==
Numerous medications and street drugs can cause serotonin syndrome when taken alone at high doses or in combination with other serotonergic agents. The table below lists some of these.

{| class="wikitable"
|-
!Class
!Drugs that can induce serotonin syndrome
|-
|[[Antidepressant]]s
|[[Monoamine oxidase inhibitor]]s (MAOIs),<ref name="BoyerShannon2005" /> [[tricyclic antidepressant]]s (TCAs),<ref name="BoyerShannon2005" /> [[Selective serotonin reuptake inhibitor|SSRI]]s,<ref name="BoyerShannon2005" /> [[Serotonin-norepinephrine reuptake inhibitor|SNRI]]s,<ref name="BoyerShannon2005" /> [[nefazodone]],<ref name="Ener">{{cite journal|vauthors=Ener RA, Meglathery SB, Van Decker WA, Gallagher RM |title=Serotonin syndrome and other serotonergic disorders |journal=Pain Medicine |volume=4 |issue=1 |pages=63–74 |date=March 2003 |pmid=12873279 |doi=10.1046/j.1526-4637.2003.03005.x |doi-access= free }}</ref> [[trazodone]]<ref name="Ener"/>
|-
|[[Opioid]]s
|[[Dextropropoxyphene]],<ref name = "National Prescribing Service"/> [[tramadol]],<ref name="BoyerShannon2005" /> [[Tapentadol#Adverse effects|tapentadol]], [[pethidine]] (meperidine),<ref name="BoyerShannon2005" /> [[fentanyl]],<ref name="BoyerShannon2005" /> [[pentazocine]],<ref name="BoyerShannon2005" /> [[buprenorphine]]<ref>{{cite journal|vauthors=Isenberg D, Wong SC, Curtis JA |title=Serotonin syndrome triggered by a single dose of suboxone |journal=American Journal of Emergency Medicine |volume=26 |issue=7 |pages=840.e3–5 |date=September 2008 |pmid=18774063 |doi=10.1016/j.ajem.2008.01.039 }}</ref> [[oxycodone]],<ref name="Gnanadesigan">{{cite journal|vauthors= Gnanadesigan N, Espinoza RT, Smith RL |title=The serotonin syndrome |journal=New England Journal of Medicine |volume=352 |issue=23 |pages=2454–2456 |date=June 2005 |pmid=15948273 |doi=10.1056/NEJM200506093522320}}</ref> [[hydrocodone]]<ref name="Gnanadesigan"/>
|-
|[[Stimulant]]s and [[entactogen]]s
|[[MDMA]],<ref name="BoyerShannon2005" /> [[3,4-Methylenedioxyamphetamine|MDA]],<ref name="BoyerShannon2005" /> [[α-methyltryptamine|AMT]],<ref name="WHO2014">{{Cite report |title=Alpha-methyltryptamine (AMT) – Critical Review Report |date=20 June 2014 |publisher=World Health Organisation – Expert Committee on Drug Dependence |publication-date=2014-06-20 |url=https://legal-high-inhaltsstoffe.de/sites/default/files/uploads/amt.pdf |access-date=2019-11-18}}</ref> [[caffeine]],<ref name="h020">{{cite web | last=Taylor | first=Marygrace | title=Does the Caffeine in Your Coffee, Tea, or Soft Drinks Interfere With Antidepressants? | website=HealthCentral | date=2009-05-12 | url=https://www.healthcentral.com/article/coffee-tea-not-good-maintaining-antidepressants-system | access-date=2024-06-30}}</ref> [[methamphetamine]],<ref name="Schep">{{cite journal|vauthors=Schep LJ, Slaughter RJ, Beasley DM |title=The clinical toxicology of metamfetamine |journal=Clinical Toxicology |volume=48 |issue=7 |pages=675–694 |date=August 2010 |pmid=20849327 |doi= 10.3109/15563650.2010.516752|s2cid=42588722 }}</ref> [[lisdexamfetamine]],<ref>{{Cite news| url= http://www.rxlist.com/vyvanse-drug/side-effects-interactions.htm |title=Vyvanse (Lisdexamfetamine Dimesylate) Drug Information: Side Effects and Drug Interactions – Prescribing Information |work= RxList.com |access-date=2017-03-22 |language=en| url-status=live |archive-url=https://web.archive.org/web/20170325051612/http://www.rxlist.com/vyvanse-drug/side-effects-interactions.htm|archive-date=2017-03-25}}</ref> [[amphetamine]],<ref>{{Cite news|url=http://www.rxlist.com/adderall-drug/side-effects-interactions.htm|title=Adderall (Amphetamine, Dextroamphetamine Mixed Salts) Drug Information: Side Effects and Drug Interactions – Prescribing Information |work=RxList|access-date=2017-03-22|language=en|url-status=live|archive-url=https://web.archive.org/web/20170323053309/http://www.rxlist.com/adderall-drug/side-effects-interactions.htm|archive-date=2017-03-23}}</ref> [[phentermine]],<ref name="National Prescribing Service">{{cite web |year=2005 |title=Prescribing Practice Review 32: Managing depression in primary care |publisher=National Prescribing Service Limited |url=http://www.nps.org.au/__data/assets/pdf_file/0006/16971/ppr32.pdf |access-date=16 July 2006 |archive-url= https://web.archive.org/web/20110727175404/http://www.nps.org.au/__data/assets/pdf_file/0006/16971/ppr32.pdf |archive-date=27 July 2011 }}</ref> [[amfepramone]] (diethylpropion),<ref name="National Prescribing Service"/> [[sibutramine]],<ref name= "BoyerShannon2005"/> [[methylphenidate]],<ref name= "National Prescribing Service"/> [[cocaine]]<ref name="National Prescribing Service"/>
|-
|[[5-HT receptor|5-HT<sub>1</sub>]] agonists
|[[Triptan]]s<ref name="BoyerShannon2005" /><ref name="National Prescribing Service"/>
|-
|[[Psychedelics]]
| [[NBOMe]]s (e.g., [[25I-NBOMe]])<ref name="Thomas2024">{{cite book | vauthors = Thomas K | title=Toxicology and Pharmacological Interactions of Classic Psychedelics | series=Current Topics in Behavioral Neurosciences | publisher=Springer Berlin Heidelberg | publication-place=Berlin, Heidelberg | date=2024 | doi=10.1007/7854_2024_508 | url=https://link.springer.com/10.1007/7854_2024_508 | access-date=14 May 2025 | page=| pmid=39042251 }}</ref>
|-
|[[Herbs]]
|[[St John's wort]],<ref name="BoyerShannon2005" /> [[Syrian rue]],<ref name= "BoyerShannon2005"/> [[Panax ginseng|''Panax'' ginseng]],<ref name="BoyerShannon2005" /> [[nutmeg]],<ref>{{cite journal |vauthors=Braun U, Kalbhen DA |title=Evidence for the Biogenic Formation of Amphetamine Derivatives from Components of Nutmeg |journal=Pharmacology |volume=9 |issue=5 |pages=312–316 |date=October 1973 |pmid=4737998 |doi=10.1159/000136402 }}</ref> [[yohimbe]]<ref>{{cite web |url= http://www.erowid.org/plants/yohimbe/yohimbe_info1.shtml |title=Erowid Yohimbe Vaults: Notes on Yohimbine by William White, 1994 |publisher= | website= Erowid.org |access-date=2013-01-28 |url-status=live |archive-url= https://web.archive.org/web/20130126141846/http://www.erowid.org/plants/yohimbe/yohimbe_info1.shtml |archive-date=2013-01-26 }}</ref>
|-
|Others
|[[Tryptophan]],<ref name="BoyerShannon2005" /> [[L-DOPA|{{small|L}}-DOPA]],<ref name="Birmes"/> [[valproate]],<ref name="BoyerShannon2005" /> [[buspirone]],<ref name="BoyerShannon2005" /> [[Lithium (medication)|lithium]],<ref name="BoyerShannon2005" /> [[linezolid]],<ref name="BoyerShannon2005" /><ref>{{cite journal|vauthors=Steinberg M, Morin AK |title= Mild serotonin syndrome associated with concurrent linezolid and fluoxetine |journal=American Journal of Health-System Pharmacy |volume=64 |issue=1 |pages= 59–62 |date=January 2007 |pmid=17189581 |doi=10.2146/ajhp060227}}</ref> [[dextromethorphan]],<ref name="BoyerShannon2005" /> {{nowrap|[[5-hydroxytryptophan]]}},<ref name="Ener"/> [[chlorpheniramine]],<ref name="National Prescribing Service"/> [[risperidone]],<ref name="pmid12639169">{{cite journal|vauthors=Karki SD, Masood GR |title=Combination risperidone and SSRI-induced serotonin syndrome |journal=Annals of Pharmacotherapy |volume=37 |issue=3 |pages=388–391 |year=2003 |pmid=12639169 |doi=10.1345/aph.1C228|s2cid=36677580 }}</ref> [[olanzapine]],<ref name="Verre">{{cite journal |vauthors=Verre M, Bossio F, Mammone A, etal |title=Serotonin syndrome caused by olanzapine and clomipramine |journal=Minerva Anestesiologica |volume=74 |issue=1–2 |pages=41–45 |year=2008 |pmid=18004234 |url= http://www.minervamedica.it/index2.t?show=R02Y2008N01A0041 |url-status= live |archive-url= https://web.archive.org/web/20090108231948/http://www.minervamedica.it/index2.t?show=R02Y2008N01A0041 |archive-date=2009-01-08 }}</ref> [[ondansetron]],<ref name="BoyerShannon2005" /> [[granisetron]],<ref name="BoyerShannon2005" /> [[metoclopramide]],<ref name="BoyerShannon2005" /> [[ritonavir]],<ref name="BoyerShannon2005" /> [[metaxalone]],<ref name="BoyerShannon2005" /> [[methylene blue]]<ref name="pmid 17721552">{{cite journal|vauthors= Ramsay RR, Dunford C, Gillman PK |title=Methylene blue and serotonin toxicity: inhibition of monoamine oxidase A (MAO A) confirms a theoretical prediction |journal= Br J Pharmacol |volume=152 |issue=6 |pages= 946–51 |year=2007 |pmid=17721552 |doi= 10.1038/sj.bjp.0707430 |pmc=2078225 }}</ref>
|}

Many cases of serotonin toxicity occur in people who have ingested drug combinations that synergistically increase synaptic serotonin.<ref name="Dunkley">{{cite journal|vauthors=Dunkley EJ, Isbister GK, Sibbritt D, Dawson AH, Whyte IM |title=The Hunter Serotonin Toxicity Criteria: simple and accurate diagnostic decision rules for serotonin toxicity |journal=QJM |volume=96 |issue=9 |pages=635–642 |date=September 2003 |pmid=12925718 |doi=10.1093/qjmed/hcg109 |doi-access=free }}</ref> It may also occur due to an overdose of a single serotonergic agent.<ref>{{cite journal |vauthors=Foong AL, Grindrod KA, Patel T, Kellar J |author2-link=Kelly Grindrod|title= Demystifying serotonin syndrome (or ''serotonin toxicity'') |journal= Canadian Family Physician |date=October 2018 |volume=64 |issue=10 |pages=720–727 |pmid=30315014|pmc=6184959 }}</ref> The combination of [[monoamine oxidase inhibitor]]s (MAOIs) with precursors such as {{nowrap|[[L-tryptophan]]}} or {{nowrap|[[5-hydroxytryptophan]]}} pose a particularly acute risk of life-threatening serotonin syndrome.<ref>{{cite journal|vauthors= Sun-Edelstein C, Tepper SJ, Shapiro RE |title=Drug-induced serotonin syndrome: a review |journal=Expert Opinion on Drug Safety |volume=7 |issue=5 |pages=587–596 |date=September 2008 |pmid=18759711 |doi= 10.1517/14740338.7.5.587 |s2cid=71657093 }}</ref> The case of combination of MAOIs with tryptamine agonists (commonly known as [[ayahuasca]]) can present similar dangers as their combination with precursors, but this phenomenon has been described in general terms as the [[cheese effect]]. Many MAOIs irreversibly inhibit [[monoamine oxidase]]. It can take at least four weeks for this enzyme to be replaced by the body in the instance of irreversible inhibitors.<ref name="Sternbach">{{cite journal|author= Sternbach H |title=The serotonin syndrome |journal=American Journal of Psychiatry |volume=148 |issue=6 |pages=705–713 |date=June 1991 |pmid=2035713 |doi= 10.1176/ajp.148.6.705|s2cid=29916415 }}</ref> With respect to [[tricyclic antidepressant]]s (TCAs), only [[clomipramine]] and [[imipramine]] have a risk of causing serotonin syndrome.<ref>{{Cite journal|last=Gillman|first=P. Ken|date= 2006-06-01|title=A Review of Serotonin Toxicity Data: Implications for the Mechanisms of Antidepressant Drug Action| url= https://www.biologicalpsychiatryjournal.com/article/S0006-3223(05)01441-1/abstract|journal=Biological Psychiatry|language=en|volume=59|issue=11|pages=1046–1051|doi=10.1016/j.biopsych.2005.11.016|pmid= 16460699 |s2cid=12179122|issn=0006-3223|url-access=subscription}}</ref>

Many medications may have been incorrectly thought to cause serotonin syndrome. For example, some case reports have implicated [[atypical antipsychotic]]s in serotonin syndrome, but it appears based on their pharmacology that they are unlikely to cause the syndrome.<ref name="IsbisterDownesWhyte2003">{{cite journal|vauthors=Isbister GK, Downes F, Whyte IM |title=Olanzapine and serotonin toxicity |journal=Psychiatry and Clinical Neurosciences |volume=57 |issue=2 |pages=241–42 |date=April 2003 |pmid=12667176 |doi=10.1046/j.1440-1819.2003.01110.x |s2cid=851495 }}</ref> It has also been suggested that [[mirtazapine]] has no significant serotonergic effects and is therefore not a dual action drug.<ref>{{cite journal |author= Gillman P |title=A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status |journal= Human Psychopharmacology |volume=21 |issue=2 |pages=117–125 |year=2006 |pmid=16342227 |doi=10.1002/hup.750|s2cid=23442056 }}</ref> Bupropion has also been suggested to cause serotonin syndrome,<ref name= "pmid15602102">{{cite journal|author=Munhoz RP |title=Serotonin syndrome induced by a combination of bupropion and SSRIs |journal=Clinical Neuropharmacology |volume=27 |issue=5 |pages=219–222 |year=2004 |pmid= 15602102 |doi=10.1097/01.wnf.0000142754.46045.8c}}</ref><ref name= "pmid20238197">{{cite journal|vauthors=Thorpe EL, Pizon AF, Lynch MJ, Boyer J |title=Bupropion induced serotonin syndrome: a case report |journal=Journal of Medical Toxicology |volume=6 |issue=2 |pages=168–171 |date=June 2010 |pmid=20238197 |doi=10.1007/s13181-010-0021-x|pmc=3550303}}</ref> although as there is no evidence that it has any significant serotonergic activity, it is thought unlikely to produce the syndrome.<ref name="pmid20440594">{{cite journal|author=Gillman PK |title=Bupropion, bayesian logic and serotonin toxicity |journal=Journal of Medical Toxicology |volume=6 |issue=2 |pages=276–77 |date=June 2010 |pmid=20440594 |doi=10.1007/s13181-010-0084-8|pmc=3550296}}</ref> In 2006 the US [[Food and Drug Administration (United States)|Food and Drug Administration]] (FDA) issued an alert suggesting that the combined use of either SSRIs or SNRIs with triptan medications or sibutramine could potentially lead to severe cases of serotonin syndrome.<ref name="Evans">{{cite journal |author= Evans RW |title=The FDA alert on serotonin syndrome with combined use of SSRIs or SNRIs and Triptans: an analysis of the 29 case reports |journal= MedGenMed |volume=9 |issue=3 |page=48 |year=2007 |pmid=18092054 |pmc=2100123 }}</ref> This has been disputed by other researchers, as none of the cases reported by the FDA met the Hunter criteria for serotonin syndrome.<ref name="Evans"/><ref>{{cite journal|vauthors= Wenzel RG, Tepper S, Korab WE, Freitag F |title=Serotonin syndrome risks when combining SSRI/SNRI drugs and triptans: is the FDA's alert warranted? |journal=Annals of Pharmacotherapy |volume=42 |issue=11 |pages=1692–1696 |date= November 2008 |pmid=18957623 |doi=10.1345/aph.1L260 |s2cid= 24942783 }}</ref> The condition has however occurred in surprising clinical situations, and because of phenotypic variations among individuals, it has been associated with unexpected drugs, including mirtazapine.<ref name="pmid11925312">{{cite journal |vauthors=Duggal HS, Fetchko J |title=Serotonin syndrome and atypical antipsychotics |journal=American Journal of Psychiatry |volume=159 |issue=4 |pages=672–73 |date=April 2002 |pmid=11925312 |doi=10.1176/appi.ajp.159.4.672-a |doi-access= }}</ref><ref name= "pmid15948272">Boyer and Shannon's reply to {{cite journal|author= Gillman PK |title=The serotonin syndrome |journal=[[New England Journal of Medicine]] |volume=352 |issue=23 |pages=2454–2456 |date=June 2005 |pmid=15948272 |doi=10.1056/NEJM200506093522320 }}</ref>

Despite acting as [[binding selectivity|non-selective]] [[serotonin receptor agonist]]s, major [[serotonergic psychedelic]]s like [[lysergic acid diethylamide]] (LSD) and [[psilocybin]] do not cause serotonin syndrome even in the context of extreme [[overdose]].<ref name="MalcolmThomas2022">{{cite journal | vauthors = Malcolm B, Thomas K | title = Serotonin toxicity of serotonergic psychedelics | journal = Psychopharmacology (Berl) | volume = 239 | issue = 6 | pages = 1881–1891 | date = June 2022 | pmid = 34251464 | doi = 10.1007/s00213-021-05876-x | url = }}</ref><ref name="Thomas2024" /><ref name="TapThomasPáleníček2025">{{cite journal | vauthors = Tap SC, Thomas K, Páleníček T, Stenbæk DS, Oliveira-Maia AJ, van Dalfsen J, Schoevers R | title = Concomitant use of antidepressants and classic psychedelics: A scoping review | journal = J Psychopharmacol | volume = 39| issue = 10| pages = 2698811251368360 | date = September 2025 | article-number = 02698811251368360 | pmid = 40937732 | doi = 10.1177/02698811251368360 | pmc = 12572353 | url = | quote = Importantly, the idea of increased risk for developing serotonin syndrome and/or serotonin toxicity, when [antidepressants (ADs)] are co-administered with high doses of psychedelics, has recently been challenged, in part because classic psychedelics are partial agonists of the 5-HT2A receptor and would also compete for serotonin binding (Malcolm and Thomas, 2022; Rickli et al., 2016; Sarparast et al., 2022). Based on this clinical rationale, the concomitant use of ADs and classic psychedelics may be preferred, or patients could temporarily reduce the dose of ADs around dosing days with psychedelics to have minimal interactions. Simultaneously, the competition for 5-HT2A receptors could impede the biological action of psychedelics during concomitant use of ADs and potentially limit efficacy (Halman et al., 2024), particularly as the 5-HT2A receptor induces neuroplasticity (Cameron et al., 2023; Ly et al., 2018; Vargas et al., 2023).}}</ref> This is thought to be due to the fact that they act as [[partial agonist]]s of [[serotonin receptor]]s like the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptor]], in contrast to serotonin itself which is a [[full agonist]].<ref name="MalcolmThomas2022" /><ref name="TapThomasPáleníček2025" /> Combination of psychedelics like LSD and psilocybin with antidepressants such as SSRIs is also not thought to pose a risk of serotonin syndrome.<ref name="TapThomasPáleníček2025" /> A 2018 retrospective analysis of 3,554 LSD-only exposures reported to [[poison control center]]s in the [[United States]] between 2000 and 2016 found that serious [[toxicity]] was infrequent.<ref name="Thomas2024" /><ref name="LeonardAndersonKlein-Schwartz2018">{{cite journal | vauthors = Leonard JB, Anderson B, Klein-Schwartz W | title = Does getting high hurt? Characterization of cases of LSD and psilocybin-containing mushroom exposures to national poison centers between 2000 and 2016 | journal = J Psychopharmacol | volume = 32 | issue = 12 | pages = 1286–1294 | date = December 2018 | pmid = 30182795 | doi = 10.1177/0269881118793086 | url = }}</ref> On the other hand, [[NBOMe]] psychedelics like [[25I-NBOMe]] are more [[intrinsic activity|efficacious]] at the serotonin 5-HT<sub>2A</sub> receptor and have been uniquely associated with serotonin syndrome-like toxicity.<ref name="Thomas2024" /> In addition, serotonergic psychedelics additionally acting as [[serotonin releasing agent]]s like [[methylenedioxyamphetamine]] (MDA) and [[α-methyltryptamine]] (AMT) or additionally acting as MAOIs like [[ayahuasca]] or AMT can cause serotonin syndrome.<ref name="IsbisterBuckley2005">{{cite journal | vauthors = Isbister GK, Buckley NA | title = The pathophysiology of serotonin toxicity in animals and humans: implications for diagnosis and treatment | journal = Clin Neuropharmacol | volume = 28 | issue = 5 | pages = 205–214 | date = 2005 | pmid = 16239759 | doi = 10.1097/01.wnf.0000177642.89888.85 | url = }}</ref><ref name="Thomas2024" /><ref name="WHO2014" /><ref name="BoyerShannon2005" /><ref name="SchifanoChiappiniMiuli2021">{{cite journal | vauthors = Schifano F, Chiappini S, Miuli A, Corkery JM, Scherbaum N, Napoletano F, Arillotta D, Zangani C, Catalani V, Vento A, Pettorruso M, Martinotti G, Massimo DG, Guirguis A | title = New psychoactive substances (NPS) and serotonin syndrome onset: A systematic review | journal = Exp Neurol | volume = 339 | issue = | article-number = 113638 | date = May 2021 | pmid = 33571533 | doi = 10.1016/j.expneurol.2021.113638 | url = }}</ref>

The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. Serotonin syndrome has been reported in patients of all ages, including the elderly, children, and even newborn infants due to [[Uterus|in utero]] exposure.<ref>{{cite journal| vauthors=Laine K, Heikkinen T, Ekblad U, Kero P |title=Effects of exposure to selective serotonin reuptake inhibitors during pregnancy on serotonergic symptoms in newborns and cord blood monoamine and prolactin concentrations |journal= Archives of General Psychiatry |volume=60 |issue=7 |pages=720–726 |date=July 2003 |pmid=12860776 |doi=10.1001/archpsyc.60.7.720 |doi-access=free }}</ref><ref name="Mackay1999"/><ref>{{cite journal|vauthors=Isbister GK, Dawson A, Whyte IM, Prior FH, Clancy C, Smith AJ |title=Neonatal paroxetine withdrawal syndrome or actually serotonin syndrome? |journal= Archives of Disease in Childhood. Fetal and Neonatal Edition |volume=85 |issue=2 |pages= F147–48 |date= September 2001 |pmid=11561552 |doi=10.1136/fn.85.2.F145g |pmc= 1721292}}</ref><ref>{{cite journal|vauthors=Gill M, LoVecchio F, Selden B |title=Serotonin syndrome in a child after a single dose of fluvoxamine |journal=Annals of Emergency Medicine |volume=33 |issue=4 |pages=457–459 |date=April 1999 |pmid=10092727 |doi=10.1016/S0196-0644(99)70313-6}}</ref> The serotonergic toxicity of SSRIs increases with dose, but even in overdose, it is insufficient to cause fatalities from serotonin syndrome in healthy adults.<ref name= "Isbister-JToxClinTox"/><ref>{{cite journal|vauthors=Whyte IM, Dawson AH |title=Redefining the serotonin syndrome [abstract] |journal=Journal of Toxicology: Clinical Toxicology |volume=40 |issue=5 |pages=668–69 |year=2002 |doi=10.1081/CLT-120016866 |s2cid=218865517 }}</ref> Elevations of [[central nervous system]] (CNS) serotonin will typically only reach potentially fatal levels when drugs with different [[Mechanism of action|mechanisms of action]] are mixed together.<ref name="IsbisterBuckleyWhyte2007" /> Various drugs, other than SSRIs, also have clinically significant potency as serotonin reuptake inhibitors, (such as [[tramadol]], [[amphetamine]], and MDMA) and are associated with severe cases of the syndrome.<ref name="BoyerShannon2005" /><ref>{{cite journal|vauthors=Vuori E, Henry J, Ojanperä I, Nieminen R, Savolainen T, Wahlsten P, Jäntti M |title=Death following ingestion of MDMA (ecstasy) and moclobemide |journal=Addiction |volume=98 |issue=3 |pages=365–368 |year=2003 |pmid=12603236 |doi=10.1046/j.1360-0443.2003.00292.x}}</ref> Severe and life-threatening serotonin syndrome has been said to almost exclusively be due to a combination of [[antidepressant]]s, for instance an MAOI with an SSRI.<ref name="IsbisterBuckley2005" /> However, combination of an MAOI and a [[serotonin releasing agent]] (SRA) like [[MDMA]] can also consistently result in severe and life-threatening serotonin syndrome.<ref name="MalcolmThomas2022" />

Although the most significant health risk associated with [[opioid overdose]]s is [[respiratory depression]],<ref name="respdepress">{{cite journal|vauthors=Boyer EW|date=July 2012|title=Management of opioid analgesic overdose|journal=The New England Journal of Medicine|volume= 367|issue=2|pages=146–155|doi=10.1056/NEJMra1202561|pmc=3739053|pmid= 22784117}}</ref> it is still possible for an individual to develop serotonin syndrome from certain opioids without the [[loss of consciousness]]. However, most cases of opioid-related serotonin syndrome involve the concurrent use of a [[Serotonin|serotergenic drug]] such as [[antidepressant]]s.<ref>{{Cite journal |last1=Rickli |first1=Anna |last2= Liakoni |first2=Evangelia |display-authors=1 |date=2018 |title= Opioid-induced Inhibition of the Human 5-HT and Noradrenaline Transporters in Vitro: Link to Clinical Reports of Serotonin Syndrome |journal=[[British Journal of Pharmacology]] |volume=175 |issue=3 |pages=532–543 |doi=10.1111/bph.14105 |pmid=29210063 |pmc=5773950 }}</ref> Nonetheless, it is not uncommon for individuals taking opioids to also be taking antidepressants due to the comorbidity of pain and depression.<ref name="depressionpain">{{cite journal|vauthors=Bair MJ, Robinson RL, Katon W, Kroenke K |date=November 2003 |title=Depression and pain comorbidity: a literature review |journal=Archives of Internal Medicine|volume=163|issue=20|pages=2433–2445|doi=10.1001/archinte.163.20.2433 |doi-access=free |pmc=3739053|pmid=14609780}}</ref> Cases where opioids alone are the cause of serotonin syndrome are typically seen with tramadol, because of its dual mechanism as a [[serotonin-norepinephrine reuptake inhibitor]].<ref name= tramadol>{{cite web|title=Tramadol Hydrochloride | website= drugs.com|url= https://www.drugs.com/monograph/tramadol-hydrochloride.html |publisher= The American Society of Health-System Pharmacists|access-date=12 December 2020}}</ref><ref name=tramadolss>{{cite journal|vauthors= Takeshita J, Litzinger MH|date=2009|title=Serotonin Syndrome Associated With Tramadol|journal=Primary Care Companion to the Journal of Clinical Psychiatry|volume=11|issue= 5|page=273|doi=10.4088/PCC.08l00690|pmc=2781045 |pmid=19956471}}</ref> Serotonin syndrome caused by tramadol can be particularly problematic if an individual taking the drug is unaware of the risks associated with it and attempts to self-medicate symptoms such as headache, agitation, and tremors with more opioids, further exacerbating the condition.

==Pathophysiology==
[[Serotonin]] is a [[neurotransmitter]] involved in multiple complex biological processes including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting.<ref name="Dunkley"/> In humans the effects of excess serotonin were first noted in 1960 in patients receiving an MAOI and [[tryptophan]].<ref>{{cite journal|vauthors=Oates JA, Sjoerdsma A |title=Neurologic effects of tryptophan in patients receiving a monoamine oxidase inhibitor |journal=Neurology |volume=10 |issue=12 |pages=1076–8 |date=December 1960 |pmid=13730138 |doi=10.1212/WNL.10.12.1076 |s2cid=40439836 }}</ref> The syndrome is caused by increased serotonin in the CNS.<ref name="BoyerShannon2005" /> It was originally suspected that [[Agonist|agonism]] of serotonin [[5-HT receptor|5-HT<sub>1A</sub> receptors]] in [[central grey]] nuclei and the [[medulla oblongata]] was responsible for the development of the syndrome.<ref name="Whyte"/> Further study has determined that overstimulation of primarily the serotonin [[5-HT2A receptor|5-HT<sub>2A</sub> receptors]] appears to contribute substantially to the condition, while the serotonin 5-HT<sub>1A</sub> receptor seems to play little role.<ref name="IsbisterBuckley2005" /><ref name="Whyte">{{cite book|last=Whyte |first=Ian M. |chapter=Serotonin Toxicity/Syndrome |title=Medical Toxicology |publisher=Williams & Wilkins |location=Philadelphia |year=2004 |pages=103–6 |isbn=978-0-7817-2845-4}}</ref> However, the serotonin 5-HT<sub>1A</sub> receptor may still contribute through a [[pharmacodynamic]] interaction in which increased synaptic concentrations of a serotonin agonist saturate all receptor subtypes.<ref name="BoyerShannon2005" /> Additionally, noradrenergic CNS hyperactivity may play a role as CNS [[norepinephrine]] concentrations are increased in serotonin syndrome and levels appear to correlate with the clinical outcome. Other neurotransmitters may also play a role; [[NMDA receptor]] antagonists and [[γ-aminobutyric acid]] have been suggested as affecting the development of the syndrome.<ref name="BoyerShannon2005" /> Serotonin toxicity is more pronounced following supra-therapeutic doses and [[overdose]]s, and they merge in a continuum with the toxic effects of overdose.<ref name="Isbister-JToxClinTox">{{cite journal|vauthors=Isbister G, Bowe S, Dawson A, Whyte I |title=Relative toxicity of selective serotonin reuptake inhibitors (SSRIs) in overdose |journal=J Toxicol Clin Toxicol |volume=42 |issue=3 |pages=277–85 |year=2004 |pmid=15362595 |doi=10.1081/CLT-120037428|s2cid=43121327 }}</ref><ref>{{cite journal|vauthors=Whyte I, Dawson A, Buckley N |title=Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants |journal=QJM |volume=96 |issue=5 |pages=369–74 |year=2003 |pmid=12702786 |doi=10.1093/qjmed/hcg062|doi-access= }}</ref>

===Spectrum concept===
A postulated "spectrum concept" of serotonin toxicity emphasises the role that progressively increasing serotonin levels play in mediating the clinical picture as side effects merge into toxicity. The [[dose-response relationship]] is the effect of progressive elevation of serotonin, either by raising the dose of one drug, or combining it with another serotonergic drug which may produce large elevations in serotonin levels.<ref>{{cite journal|author=Gillman PK |title=The spectrum concept of serotonin toxicity |journal=Pain Med |volume=5 |issue=2 |pages=231–2 |date=June 2004 |pmid=15209988 |doi=10.1111/j.1526-4637.2004.04033.x|doi-access= }}</ref><ref name="Gillman PK-2006" /> Some experts prefer the terms serotonin toxicity or serotonin toxidrome, to more accurately reflect that it is a form of [[poisoning]].<ref name="IsbisterBuckleyWhyte2007" /><ref name="Gillman PK-2006">{{cite journal|author=Gillman PK |title=A review of serotonin toxicity data: implications for the mechanisms of antidepressant drug action |journal=Biol Psychiatry |volume=59 |issue=11 |pages=1046–51 |date=June 2006 |pmid=16460699 |doi=10.1016/j.biopsych.2005.11.016 |s2cid=12179122 }}</ref>

==Diagnosis==
There is no specific test for serotonin syndrome. Diagnosis is by symptom observation and investigation of the person's history.<ref name="BoyerShannon2005" /> Several criteria have been proposed. The first evaluated criteria were introduced in 1991 by Harvey Sternbach.<ref name="BoyerShannon2005" /><ref name="Sternbach"/><ref name="pmid9684919">{{cite journal |vauthors=Hegerl U, Bottlender R, Gallinat J, Kuss HJ, Ackenheil M, Möller HJ |title=The serotonin syndrome scale: first results on validity |journal=Eur Arch Psychiatry Clin Neurosci |volume=248 |issue=2 |pages=96–103 |year=1998 |pmid=9684919 |doi=10.1007/s004060050024 |s2cid=37993326 |url=http://link.springer.de/link/service/journals/00406/bibs/8248002/82480096.htm |archive-url=https://web.archive.org/web/19991011013705/http://link.springer.de/link/service/journals/00406/bibs/8248002/82480096.htm |archive-date=1999-10-11 |url-access=subscription }}</ref> Researchers later developed the Hunter Toxicity Criteria Decision Rules, which have better [[sensitivity and specificity]], 84% and 97%, respectively, when compared with the gold standard of diagnosis by a medical toxicologist.<ref name="BoyerShannon2005" /><ref name="Dunkley"/> As of 2007, Sternbach's criteria were still the most commonly used.<ref name="IsbisterBuckleyWhyte2007" />

The most important symptoms for diagnosing serotonin syndrome are tremor, extreme aggressiveness, [[akathisia]], or clonus (spontaneous, inducible and ocular).<ref name="Dunkley"/> [[Physical examination]] of the patient should include assessment of [[deep tendon reflex]]es and muscle rigidity, the dryness of the [[Mucous membrane|mucosa of the mouth]], the size and reactivity of the pupils, the intensity of bowel sounds, skin color, and the presence or absence of sweating.<ref name="BoyerShannon2005" /> The patient's history also plays an important role in diagnosis, investigations should include inquiries about the use of prescription and [[over-the-counter drug]]s, illicit substances, and [[dietary supplement]]s, as all these agents have been implicated in the development of serotonin syndrome.<ref name="BoyerShannon2005" /> To fulfill the Hunter Criteria, a patient must have taken a [[serotonergic agent]] and meet one of the following conditions:<ref name="Dunkley"/>
* Spontaneous clonus, or
* Inducible clonus plus agitation or [[Perspiration|diaphoresis]], or
* Ocular clonus plus agitation or diaphoresis, or
* [[Tremor]] plus [[hyperreflexia]], or
* Hypertonism plus temperature > {{convert|38|°C|°F}} plus ocular clonus or inducible clonus

===Differential diagnosis===

Serotonin toxicity has a characteristic picture which is generally hard to confuse with other [[medical conditions]], but in some situations it may go unrecognized because it may be mistaken for a [[viral illness]], [[anxiety disorder]]s, [[neurological disorder]], [[anticholinergic]] poisoning, [[sympathomimetic]] toxicity, or worsening psychiatric condition.<ref name="BoyerShannon2005" /><ref name="IsbisterBuckleyWhyte2007" /><ref>{{cite journal|vauthors=Fennell J, Hussain M |title=Serotonin syndrome: case report and current concepts |journal=Ir Med J |volume=98 |issue=5 |pages=143–4 |year=2005 |pmid=16010782}}</ref> The condition most often confused with serotonin syndrome is [[neuroleptic malignant syndrome]] (NMS).<ref>{{cite book|vauthors=Nisijima K, Shioda K, Iwamura T |title=Neurobiology of Hyperthermia |chapter=Neuroleptic malignant syndrome and serotonin syndrome |journal=Prog Brain Res |volume=162 |pages=81–104 |year=2007 |pmid=17645916 |doi=10.1016/S0079-6123(06)62006-2 |series=Progress in Brain Research |isbn=978-0-444-51926-9}}</ref><ref name="Tormoehlen">{{cite book |last1=Tormoehlen |first1=LM |last2=Rusyniak |first2=DE |title=Thermoregulation: From Basic Neuroscience to Clinical Neurology, Part II |chapter=Neuroleptic malignant syndrome and serotonin syndrome |series=Handbook of Clinical Neurology |date=2018 |volume=157 |pages=663–675 |doi=10.1016/B978-0-444-64074-1.00039-2 |pmid=30459031|isbn=978-0-444-64074-1 }}</ref> The clinical features of neuroleptic malignant syndrome and serotonin syndrome share some features which can make differentiating them difficult.<ref>{{cite journal|vauthors=Christensen V, Glenthøj B |title=[Malignant neuroleptic syndrome or serotonergic syndrome] |journal=Ugeskrift for Læger |volume=163 |issue=3 |pages=301–2 |year=2001 |pmid=11219110}}</ref> In both conditions, [[Autonomic nervous system|autonomic]] dysfunction and altered [[mental status]] develop.<ref name="Whyte"/> However, they are actually very different conditions with different underlying dysfunction (serotonin excess vs dopamine blockade). Both the time course and the clinical features of NMS differ significantly from those of serotonin toxicity.<ref name="Dunkley"/> Serotonin toxicity has a rapid onset after the administration of a serotonergic drug and responds to serotonin blockade such as drugs like [[chlorpromazine]] and [[cyproheptadine]]. [[Dopamine receptor]] blockade (NMS) has a slow onset, typically evolves over several days after administration of a [[neuroleptic]] drug, and responds to dopamine agonists such as [[bromocriptine]].<ref name="BoyerShannon2005" /><ref name="Whyte"/>

[[Differential diagnosis]] may become difficult in patients recently exposed to both serotonergic and neuroleptic drugs. [[Bradykinesia]] and [[extrapyramidal symptoms|extrapyramidal]] "lead pipe" rigidity are classically present in NMS, whereas serotonin syndrome causes [[hyperkinesia]] and clonus; these distinct symptoms can aid in differentiation.<ref name="Birmes">{{cite journal|vauthors=Birmes P, Coppin D, Schmitt L, Lauque D |title=Serotonin syndrome: a brief review |journal=CMAJ |volume=168 |issue=11 |pages=1439–42 |date=May 2003 |pmid=12771076 |pmc=155963 |url=http://www.cmaj.ca/cgi/pmidlookup?view=long&pmid=12771076}}</ref><ref>{{cite journal|vauthors=Isbister GK, Dawson A, Whyte IM |title=Citalopram overdose, serotonin toxicity, or neuroleptic malignant syndrome? |journal=Can J Psychiatry |volume=46 |issue=7 |pages=657–9 |date=September 2001 |pmid=11582830 |doi= 10.1177/070674370104600718|doi-access=free }}</ref>

==Management==

Management is based primarily on stopping the usage of the precipitating drugs, the administration of [[serotonin antagonist]]s such as [[cyproheptadine]] (with a regimen of 12&nbsp;mg for the initial dose followed by 2&nbsp;mg every 2 hours until clinical, while some claim that a higher initial dose up to 32&nbsp;mg has more benefit<ref name="n860">{{cite journal | last1=Prakash | first1=Sanjay | last2=Shah | first2=Chetsi S. | last3=Prakash | first3=Anurag | title=Serotonin syndrome controversies: A need for consensus | journal=World Journal of Critical Care Medicine | volume=13 | issue=2 | date=2024-06-09 | issn=2220-3141 | pmid=38855279 | pmc=11155509 | doi=10.5492/wjccm.v13.i2.94707 | doi-access=free | article-number=94707}}</ref>),<ref name="Scotton Hill Williams Barnes 2019 p=117864691987392">{{cite journal | last1=Scotton | first1=William J | last2=Hill | first2=Lisa J | last3=Williams | first3=Adrian C | last4=Barnes | first4=Nicholas M | title=Serotonin Syndrome: Pathophysiology, Clinical Features, Management, and Potential Future Directions | journal=International Journal of Tryptophan Research | publisher=SAGE Publications | volume=12 | year=2019 | issn=1178-6469 | doi=10.1177/1178646919873925 | page=117864691987392| article-number=1178646919873925 | pmid=31523132 | pmc=6734608 }}</ref> and supportive care including the control of agitation, the control of autonomic instability, and the control of hyperthermia.<ref name="BoyerShannon2005" /><ref>{{cite journal|author=Sporer K |title=The serotonin syndrome. Implicated drugs, pathophysiology and management |journal=Drug Saf |volume=13 |issue=2 |pages=94–104 |year=1995 |pmid=7576268 |doi=10.2165/00002018-199513020-00004|s2cid=19809259 }}</ref><ref>{{cite journal | title=Recognition and treatment of serotonin syndrome | author=Frank, Christopher | pmc=2464814 | pmid=18625822 | volume=54 | issue=7 | year=2008 | journal=Can Fam Physician | pages=988–92}}</ref> Additionally, those who ingest large doses of serotonergic agents may benefit from gastrointestinal decontamination with [[activated charcoal]] if it can be administered within an hour of overdose.<ref name="IsbisterBuckleyWhyte2007" /> The intensity of therapy depends on the severity of symptoms. If the symptoms are mild, treatment may only consist of discontinuation of the offending medication or medications, offering supportive measures, giving [[benzodiazepine]]s for myoclonus, and waiting for the symptoms to resolve. Moderate cases should have all thermal and cardiorespiratory abnormalities corrected and can benefit from serotonin antagonists. The serotonin antagonist cyproheptadine is the recommended initial therapy, although there have been no [[controlled trials]] demonstrating its efficacy for serotonin syndrome.<ref name="IsbisterBuckleyWhyte2007" /><ref name="Graudins"/><ref>{{cite journal|author=Gillman PK |title=The serotonin syndrome and its treatment |journal=J Psychopharmacol (Oxford) |volume=13 |issue=1 |pages=100–9 |year=1999 |pmid=10221364 |doi=10.1177/026988119901300111|s2cid=17640246 |url=https://zenodo.org/record/844143 }}</ref> Despite the absence of controlled trials, there are a number of case reports detailing apparent improvement after people have been administered cyproheptadine.<ref name="IsbisterBuckleyWhyte2007" /> Animal experiments also suggest a benefit from serotonin antagonists.<ref>{{cite journal|vauthors=Nisijima K, Yoshino T, Yui K, Katoh S |title=Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome |journal=Brain Res. |volume=890 |issue=1 |pages=23–31 |date=January 2001 |pmid=11164765 |doi=10.1016/S0006-8993(00)03020-1|s2cid=29995925 }}</ref> Cyproheptadine is only available as tablets and therefore can only be administered orally or via a [[nasogastric tube]]; it is unlikely to be effective in people administered activated charcoal and has limited use in severe cases.<ref name="IsbisterBuckleyWhyte2007" /> Cyproheptadine can be stopped when the person is no longer experiencing symptoms and the half life of serotonergic medications already passed.<ref name="Vol2013"/>

Additional pharmacological treatment for severe case includes administering atypical antipsychotic drugs with serotonin antagonist activity such as [[olanzapine]] or [[asenapine]].<ref name="BoyerShannon2005" /> Critically ill people should receive the above therapies as well as sedation or neuromuscular paralysis.<ref name="BoyerShannon2005" /> People who have autonomic instability such as low [[blood pressure]] require treatment with direct-acting sympathomimetics such as [[epinephrine]], norepinephrine, or [[phenylephrine]].<ref name="BoyerShannon2005" /> Conversely, hypertension or tachycardia can be treated with short-acting [[antihypertensive]] drugs such as [[nitroprusside]] or [[esmolol]]; longer acting drugs such as [[propranolol]] should be avoided as they may lead to hypotension and shock.<ref name="BoyerShannon2005" /> The cause of serotonin toxicity or accumulation is an important factor in determining the course of treatment. Serotonin is catabolized by [[monoamine oxidase&nbsp;A]] in the presence of [[oxygen]], so if care is taken to prevent an unsafe spike in body temperature or metabolic acidosis, oxygenation will assist in dispatching the excess serotonin. The same principle applies to alcohol intoxication. In cases of serotonin syndrome caused by MAOIs, oxygenation will not help to dispatch serotonin. In such instances, hydration is the main concern until the enzyme is regenerated.

===Agitation===
Specific treatment for some symptoms may be required. One of the most important treatments is the control of agitation due to the extreme possibility of injury to the person themselves or caregivers, benzodiazepines should be administered at first sign of this.<ref name="BoyerShannon2005" /> [[Medical restraint|Physical restraints]] are not recommended for agitation or delirium as they may contribute to mortality by enforcing isometric [[muscle contraction]]s that are associated with severe [[lactic acidosis]] and hyperthermia. If physical restraints are necessary for severe agitation they must be rapidly replaced with pharmacological [[sedation]].<ref name="BoyerShannon2005" /> The agitation can cause a large amount of muscle breakdown. This breakdown can cause severe damage to the kidneys through a condition called [[rhabdomyolysis]].<ref>{{cite web |url=https://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004531/ |title=Serotonin syndrome – PubMed Health |date=8 July 2012 |publisher=Ncbi.nlm.nih.gov |access-date=2013-01-28 |archive-url=https://web.archive.org/web/20130201070649/http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0004531/ |archive-date=2013-02-01 }}</ref>

===Hyperthermia===
Treatment for hyperthermia includes reducing muscle overactivity via sedation with a benzodiazepine. More severe cases may require muscular paralysis with [[vecuronium]], [[intubation]], and artificial ventilation.<ref name="BoyerShannon2005" /><ref name="IsbisterBuckleyWhyte2007" /> [[Suxamethonium]] is not recommended for muscular paralysis as it may increase the risk of cardiac dysrhythmia from hyperkalemia associated with rhabdomyolysis.<ref name="BoyerShannon2005" /> [[Antipyretic]] agents are not recommended as the increase in [[body temperature]] is due to muscular activity, not a [[hypothalamic]] temperature set point abnormality.<ref name="BoyerShannon2005" />

==Prognosis==
Upon the discontinuation of serotonergic drugs, most cases of serotonin syndrome resolve within 24 hours,<ref name="BoyerShannon2005" /><ref name="IsbisterBuckleyWhyte2007" /><ref>{{cite journal|author=Prator B |title=Serotonin syndrome |journal=J Neurosci Nurs |volume=38 |issue=2 |pages=102–5 |year=2006 |pmid=16681290 |doi=10.1097/01376517-200604000-00005}}</ref><ref>{{cite journal|vauthors=Jaunay E, Gaillac V, Guelfi J |title=[Serotonin syndrome. Which treatment and when?] |journal=Presse Med |volume=30 |issue=34 |pages=1695–700 |year=2001 |pmid=11760601}}</ref> although in some cases [[delirium]] may persist for a number of days.<ref name="Sternbach"/> Symptoms typically persist for a longer time frame in patients taking drugs which have a long elimination [[half-life]], active metabolites, or a protracted duration of action.<ref name="BoyerShannon2005" />

Cases have reported persisting chronic symptoms,<ref>{{cite journal|author=Chechani V |title=Serotonin syndrome presenting as hypotonic coma and apnea: potentially fatal complications of selective serotonin receptor inhibitor therapy |journal=Crit Care Med |volume=30 |issue=2 |pages=473–6 |date=February 2002 |pmid=11889332 |doi=10.1097/00003246-200202000-00033 |s2cid=28908329 }}</ref> and [[SSRI discontinuation syndrome|antidepressant discontinuation]] may contribute to ongoing features.<ref>{{cite journal|author=Haddad PM |title=Antidepressant discontinuation syndromes |journal=Drug Saf |volume=24 |issue=3 |pages=183–97 |year=2001 |pmid=11347722 |doi=10.2165/00002018-200124030-00003 |s2cid=26897797 }}</ref> Following appropriate medical management, serotonin syndrome is generally associated with a favorable prognosis.<ref>{{cite journal|vauthors=Mason PJ, Morris VA, Balcezak TJ |title=Serotonin syndrome. Presentation of 2 cases and review of the literature |journal=Medicine (Baltimore) |volume=79 |issue=4 |pages=201–9 |date=July 2000 |pmid=10941349 |doi=10.1097/00005792-200007000-00001 |s2cid=41036864 |doi-access=free }}</ref>

== Epidemiology ==
Epidemiological studies of serotonin syndrome are difficult as many physicians are unaware of the diagnosis or they may miss the syndrome due to its variable manifestations.<ref name="BoyerShannon2005" /><ref>{{cite journal|vauthors=Sampson E, Warner JP |title=Serotonin syndrome: potentially fatal but difficult to recognize |journal=Br J Gen Pract |volume=49 |issue=448 |pages=867–8 |date=November 1999 |pmid=10818648 |pmc=1313553 }}</ref> In 1998 a survey conducted in England found that 85% of the [[general practitioner]]s that had prescribed the antidepressant [[nefazodone]] were unaware of serotonin syndrome.<ref name="Mackay1999">{{cite journal |vauthors=Mackay FJ, Dunn NR, Mann RD |title=Antidepressants and the serotonin syndrome in general practice |journal=Br J Gen Pract |volume=49 |issue=448 |pages=871–4 |date=November 1999 |pmid=10818650 |pmc=1313555 }}</ref> The incidence may be increasing as a larger number of pro-serotonergic drugs (drugs which increase serotonin levels) are now being used in clinical practice.<ref name="Graudins">{{cite journal|vauthors=Graudins A, Stearman A, Chan B |title=Treatment of the serotonin syndrome with cyproheptadine |journal=J Emerg Med |volume=16 |issue=4 |pages=615–9 |year=1998 |pmid=9696181 |doi=10.1016/S0736-4679(98)00057-2 }}</ref> One [[postmarketing surveillance]] study identified an incidence of 0.4 cases per 1000 patient-months for patients who were taking nefazodone.<ref name="Mackay1999"/> Additionally, around 14 to 16% of persons who overdose on SSRIs are thought to develop serotonin syndrome.<ref name="Isbister-JToxClinTox"/>

==History==
Serotonin syndrome, or serotonin toxicity, was first reported in humans in 1982.<ref name="IsbisterBuckley2005" /><ref name="InselRoyCohen1982">{{cite journal | vauthors = Insel TR, Roy BF, Cohen RM, Murphy DL | title = Possible development of the serotonin syndrome in man | journal = Am J Psychiatry | volume = 139 | issue = 7 | pages = 954–955 | date = July 1982 | pmid = 7091416 | doi = 10.1176/ajp.139.7.954 | url = }}</ref> It had previously been observed in animals.<ref name="IsbisterBuckley2005" /><ref name="InselRoyCohen1982" /><ref name="Jacobs1976">{{cite journal | vauthors = Jacobs BL | title = An animal behavior model for studying central serotonergic synapses | journal = Life Sci | volume = 19 | issue = 6 | pages = 777–785 | date = September 1976 | pmid = 823389 | doi = 10.1016/0024-3205(76)90303-9 | url = }}</ref> However, serotonin syndrome-like toxicity had previously been reported as early as the 1960s, but these cases were not recognized as serotonin toxicity.<ref name="IsbisterBuckley2005" /> Serotonin syndrome was first defined as a distinct clinical entity and formally given the name "serotonin syndrome" in 1991.<ref name="IsbisterBuckley2005" /><ref name="Sternbach1991">{{cite journal | vauthors = Sternbach H | title = The serotonin syndrome | journal = Am J Psychiatry | volume = 148 | issue = 6 | pages = 705–713 | date = June 1991 | pmid = 2035713 | doi = 10.1176/ajp.148.6.705 | url = }}</ref>

==Notable cases==
[[File:Phenelzine.svg|thumb|[[Phenelzine]] is an [[MAOI]] which contributed to serotonin syndrome in the [[Libby Zion]] case.]]

The most widely recognized example of serotonin syndrome was the death of [[Libby Zion]] in 1984.<ref>{{cite news |first=Jane |last=Brody |author-link=Jane Brody |title=A Mix of Medicines That Can Be Lethal |url=https://www.nytimes.com/2007/02/27/health/27brody.html?n=Top/News/Health/Diseases,%20Conditions,%20and%20Health%20Topics/Antidepressants |work=[[New York Times]] |date=February 27, 2007 |access-date=2009-02-13 |url-status=live |archive-url=https://web.archive.org/web/20131113094550/http://www.nytimes.com/2007/02/27/health/27brody.html?n=Top%2FNews%2FHealth%2FDiseases%2C%20Conditions%2C%20and%20Health%20Topics%2FAntidepressants |archive-date=November 13, 2013 }}</ref> Zion was a freshman at [[Bennington College]] at her death on March 5, 1984, at age 18. She died within 8 hours of her emergency admission to the [[New York-Presbyterian Hospital|New York Hospital Cornell Medical Center]]. She had an ongoing history of depression, and came to the Manhattan hospital on the evening of March 4, 1984, with a fever, agitation and "strange jerking motions" of her body. She also seemed [[disoriented]] at times. The emergency room physicians were unable to diagnose her condition definitively but admitted her for [[Management of dehydration#Medical uses|hydration]] and observation. Her death was caused by a combination of [[pethidine]] and [[phenelzine]].<ref>{{cite journal|vauthors=Asch DA, Parker RM |title=The Libby Zion case. One step forward or two steps backward? |journal=N Engl J Med |volume=318 |issue=12 |pages=771–5 |date=March 1988 |pmid=3347226 |doi=10.1056/NEJM198803243181209}}</ref> A medical intern prescribed the pethidine.<ref>{{cite news |url=https://query.nytimes.com/gst/fullpage.html?sec=health&res=990CE4DC1230F932A35752C0A963958260 |title=Doctors' Accounts Vary In Death of Libby Zion |author=Jan Hoffman |newspaper=The New York Times |date=January 1, 1995 |access-date=2008-12-08 |url-status=live |archive-url=https://web.archive.org/web/20090816081427/http://query.nytimes.com/gst/fullpage.html?sec=health |archive-date=August 16, 2009 }}</ref> The case influenced graduate medical education and residency work hours. Limits were set on [[Medical resident work hours|working hours for medical postgraduates]], commonly referred to as interns or residents, in hospital training programs, and they also now require closer senior physician supervision.<ref name=Bre1998/>

==See also==
* [[Carcinoid syndrome]]

==References==
{{Reflist}}

==External links==
* [http://www.nejm.org/action/showImage?doi=10.1056%2FNEJMra041867&iid=f02 Image demonstrating findings in moderately severe serotonin syndrome] {{Webarchive|url=https://web.archive.org/web/20210829054104/https://www.nejm.org/action/showImage?doi=10.1056%2FNEJMra041867&iid=f02 |date=2021-08-29 }} from {{cite journal|vauthors=Boyer EW, Shannon M |title=The serotonin syndrome |journal=N Engl J Med |volume=352 |issue=11 |pages=1112–20 |year=2005 |pmid=15784664 |doi=10.1056/NEJMra041867|s2cid=37959124 }}

{{Medical condition classification and resources
 | DiseasesDB      = 30044
 | ICD11           = {{ICD11|8D85}}
 | ICD10           =
 | ICD9            = {{ICD9|333.99}}
 | ICDO            =
 | OMIM            =
 | MedlinePlus     = 007272
 | eMedicineSubj   = ped
 | eMedicineTopic  = 2786
 | MeshName        = Serotonin+Syndrome
 | MeshNumber      = C21.613.276.720
}}
{{CNS diseases of the nervous system}}
{{Poisoning and toxicity}}

{{Good article}}

{{DEFAULTSORT:Serotonin Syndrome}}

[[Category:Neuropharmacology]]
[[Category:Clinical pharmacology]]
[[Category:Rare syndromes]]
[[Category:Adverse effects of psychoactive drugs]]
[[Category:Wikipedia medicine articles ready to translate]]
[[Category:Wikipedia neurology articles ready to translate]]