Editing Serotonin syndrome (section)

==Causes==
Numerous medications and street drugs can cause SS 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=Boy2005/> [[tricyclic antidepressant]]s (TCAs),<ref name=Boy2005/> [[Selective serotonin reuptake inhibitor|SSRI]]s,<ref name=Boy2005/> [[Serotonin-norepinephrine reuptake inhibitor|SNRI]]s,<ref name=Boy2005/> [[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=Boy2005/> [[Tapentadol#Adverse effects|tapentadol]], [[pethidine]] (meperidine),<ref name=Boy2005/> [[fentanyl]],<ref name=Boy2005/> [[pentazocine]],<ref name=Boy2005/> [[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"/>
|-
|Central nervous system [[stimulant]]s
|[[MDMA]],<ref name=Boy2005/> [[3,4-Methylenedioxyamphetamine|MDA]],<ref name=Boy2005/> [[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 |url-status=dead |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"/> [[serotonin releasing agent]]s<ref name="Isbister Buckley"/> like [[hallucinogenic]] [[substituted amphetamine]]s,<ref name="National Prescribing Service"/> [[sibutramine]],<ref name= Boy2005/> [[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=Boy2005/><ref name="National Prescribing Service"/>
|-
|[[Psychedelics]]
|[[5-Methoxy-diisopropyltryptamine]],<ref name=Boy2005/> [[alpha-methyltryptamine]],<ref>{{Cite web |url= https://www.drugwise.org.uk/amt/ |title=AMT |date=2016-01-03 |website=DrugWise.org.uk |language=en-GB |access-date=2019-11-18}}</ref><ref>{{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> [[lysergic acid diethylamide|LSD]]<ref>{{cite journal|author=Bijl D |title=The serotonin syndrome |journal=Netherlands Journal of Medicine |volume=62 |issue=9 |pages=309–313 |date=October 2004 |pmid=15635814 |quote= Mechanisms of serotonergic drugs implicated in serotonin syndrome&nbsp;... Stimulation of serotonin receptors&nbsp;... LSD}}</ref>
|-
|[[Herbs]]
|[[St John's wort]],<ref name=Boy2005/> [[Syrian rue]],<ref name= Boy2005/> [[Panax ginseng|''Panax'' ginseng]],<ref name=Boy2005/> [[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=Boy2005/> [[L-DOPA|{{small|L}}-DOPA]],<ref name="Birmes"/> [[valproate]],<ref name=Boy2005/> [[buspirone]],<ref name=Boy2005/> [[Lithium (medication)|lithium]],<ref name=Boy2005/> [[linezolid]],<ref name=Boy2005/><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=Boy2005/> {{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=Boy2005/> [[granisetron]],<ref name=Boy2005/> [[metoclopramide]],<ref name=Boy2005/> [[ritonavir]],<ref name=Boy2005/> [[metaxalone]],<ref name=Boy2005/> [[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 antidepressants, only clomipramine and imipramine have a risk of causing SS.<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}}</ref>

Many medications may have been incorrectly thought to cause SS. For example, some case reports have implicated [[atypical antipsychotic]]s in SS, but it appears based on their pharmacology that they are unlikely to cause the syndrome.<ref>{{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 SS,<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 SS.<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 SS.<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>

The relative risk and severity of serotonergic side effects and serotonin toxicity, with individual drugs and combinations, is complex. SS 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= }}</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 SS 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="Isbister Buckley"/> 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=Boy2005/><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>

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 SS from certain opioids without the [[loss of consciousness]]. However, most cases of opioid-related SS 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 SS 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> SS 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.