Talk:Serotonin syndrome

Request

Would someone who knows what they're doing please add the chemical cause of seratonin syndrome to the summary instead of hiding it in an abstruse paragraph near the bottom of the page?

"The syndrome is caused by increased serotonin in the central nervous system.[4]" should be at the beginning. It's the seratonin itself, not the drugs, and this could be made more clear. — Preceding unsigned comment added by 71.161.77.83 (talk) 23:51, 18 August 2016 (UTC)

In the first paragraph; ondansetron should not be listed as a serotonergic agent. It is a 5-HT ANTAGONIST. — Preceding unsigned comment added by 140.193.190.124 (talk) 04:21, 22 October 2016 (UTC)

Changes made

I made several changes and added a footnotes section. Note I forgot to log in and made them as 70.157.54.56, but it was me. Joema 20:14, 31 March 2006 (UTC)

Ondansetron

I would like to challenge what is says in this article about ondansetron contributing to serotonin syndrome. As far as I know all this drugf does is selectivly antagonise the subtype 3 receptor, absolutly nothing to do ith serotonin syndrome. —Preceding unsigned comment added by 82.30.229.218 (talk) 00:29, 2 April 2010 (UTC)

Diphenhydramine?

I'm not a biochemist but the article on diphenhydramine (Benadryl, Unisom, Tylenol PM, etc.) says that it inhibits serotonin reuptake similar to an SSRI. Should it be on the list of medications that can cause serotonin syndrome? I take an SSRI so now that I know about serotonin syndrome I might stop taking my Tylenol PM at night, although I haven't had any problems so far. CBRQ 18:06, 8 June 2006 (UTC)

Don't change any medication you take without first discussing with your doctor. You're right the article on diphenhydramine says that, however I don't see any medical literature indicating serotonin syndrome resulting from diphenhydramine and SSRIs. Drugs affecting serotonin reuptake vary widely in their strength. It's possible diphenhydramine is a very weak reuptake inhibitor or somehow affects only specific serotonin receptors (there are many). The point you raise is logical based on the article wording, but I'd suggest discussing with your doctor. Joema 02:21, 9 June 2006 (UTC)

RE: Here's some medical literature indicating serotonin syndrome from Diphenhydramine as an SSRI with an MAOI: http://meeting.chestpubs.org/cgi/content/abstract/134/4/c4002 —Preceding unsigned comment added by Illuminateur21 (talk • contribs) 10:53, 30 March 2010 (UTC)

Okay, great. Thanks a lot for the answer, I appreciate it. I should be seeing a psychiatrist again in a month or so; when I do I'll try to get an answer about that. CBRQ 01:47, 13 June 2006 (UTC)

It's not biochemist, it's pharmacist, I believe. Either way :P, most over the counter medications will not raise serotonin levels in the brain to levels at which serotonin syndrome is even moderately acquireable. The syndrome simply means youve in a way 'overdosed' on serotonin. Your brain will typically be able to work with these things if you have the help of a psychiatrist, but OTC meds will rarely cause the syndrome if taken at the recommended dosages.--Neur0X ^.talk 19:52, 5 October 2006 (UTC)

I'm quite sure it's pharmacologist, not pharmacist, to which you are referring, Neur0X (I say this as someone with many friends and colleagues in the organic chemistry and pharmacology communities). As for the subject of whether or not diphenhydramine could be responsible for serotonin syndrome, I agree with you, Joema, that there is no extant research to draw upon for inclusion in this article. However, I do know that diphenhydramine was the chemical which inspired the original push to develop SSRIs, starting with fluoxetine (see the History section of the Prozac article for details). Therefore, it seems reasonable to assume that diphenhydramine (and probably other members of the ethanolamine class of antihistamines such as doxylamine) could indeed be causative agent of the syndrome. I'd also like to add that I, too, have been afflicted by severe serotonin syndrome after taking (admittedly larger than recommended) doses of diphenhydramine along with 5-HTP. Wowbobwow12 (talk) 21:40, 2 October 2008 (UTC)

DXM'm manufacturer's insert alerts about the dangers of taking it while on SSRIs. 201.95.194.203 (talk) 00:53, 10 July 2011 (UTC)

Symptoms and mechanisms

I like this article, but I suspect it would be difficult for a layman to distinguish between Serotonin syndrome and simple medication side effects. Maybe one should set out that section more clearly. The reasons why the diffeent drug combinations affect 5-HT should be interesting, I have such a list somewhere and will post when I've found it. That would be a mechanism-based table as opposed to a drug-class table. The mechanism lay-out was easier for me to understand when I first came across this entity. --Seejyb 00:07, 14 August 2006 (UTC)

You are spot on there. Much of the discussion is confusing side effects with serotonin syndrome. The term serotonin syndrome is being used rather loosely in many medical reports, which are often by doctors who are not very familiar with this complex topic. This is why Professor Ian M Whyte (who has done the lions share of original research in this field), and I, advocate the term toxicity. This is meant to emphasise severity: i.e. toxicity = poisoning. That is essentially different to side effects, no matter how distressing those may be to individuals. The term toxidrome is being used increasingly (search the NLM data base) because it describes the picture of intoxication. For some drugs that effect the central nervous system (CNS) the picture is so unique that it is useful to describe it as precisely as possible to aid recognition when it presents. Serotonin toxicity is such a condition and only results from drug over-dose of single drugs, e.g. monoamine oxidase inhibitors like tranylcypromine, or combinations of monoamine oxidase inhibitors with serotonin reuptake inhibitors. I have written a series of explanatory pieces about this that may be seen on my website www.psychotropical.com under the section serotonin syndrome. Signature for aboveKen Gillman 00:11, 21 September 2006 (UTC)

Re serotonin syndrome being hard to confuse with other other conditions: As a thyroid patient, I would like to point out that the named symptoms are also characteristic of hyperthyroidism. Newtonium 12:28, 13 January 2007 (UTC)

Regarding the distinction between Serotonin Syndrome (SS) and Neruoleptic malignant syndrome (NMS): Fever is listed under the symptoms for SS and is also listed under symptoms which are exclusive to NMS. The paper sited (Birmes P, Coppin D, Schmitt L, Lauque D (2003). "Serotonin syndrome: a brief review.". CMAJ 168 (11): 1439-42) has a table listing some key differences between the two and fever is listed there as exclusive to NMS. However, elsewhere in the paper, it does list fever as a symptom of SS. The same paper does provide diagnostic criteria which may be worth including in the wiki, it lists the triad of autonomic, cognitive and somatic signs and symptoms and provides an inclusion criterion of addition of a serotonergic agent and an exclusion criterion of introduction or change of a neruoleptic treatment. --Dr. Doof 18:49, 10 June 2007 (UTC)

Removed from page

The following paragraph was in the actual page, I have removed it here in case anyone would like this information, it was added by 58.87.7.43 which appears to be an IP used by Dr P Ken Gillman.

This table would benefit from being updated, and made more relevant to primary verifiable references, but I cannot see who produced the original table. However, I would comment that almost all the references are secondary or tertiary, rather than primary, this is not ideal for a verifiable account. Perhaps if they would like to contact me I could assist with sources that would increase its direct science base and topicality. by user 58.87.7.43 08:22, 22 September 2006 (UTC)

Mr Bungle 07:37, 17 November 2006 (UTC)

Above is correct assumption, it was I. Ken Gillman 08:35, 26 November 2006 (UTC)

Much of the above is personal experience and has no direct relevance to improving the article. I suggest it would be helpful if such items were removed to avoid clutter and confusion. Can that be done? If so, who might do it? Ken Gillman 08:44, 26 November 2006 (UTC)

Confusing sentence

This very informative article is marred by a confusing sentence:

For example, it suggests mirtazapine, which has no serotonergic toxicity, has no significant serotonergic effects at all, and is not in fact a dual action drug.[12] (Where does the "which" clause end?)

I suggest reformulating it as follows (if this is what is actually intended):

For example, it suggests that mirtazapine (which has no serotonergic toxicity) has no significant serotonergic effects at all and is not in fact a dual action drug.[12] Jedwards05 04:16, 9 March 2007 (UTC)

Carcinoid tumors

It might be interesting to add a rare, but interesting cause of serotonin syndrome secondary to secretion by carcinoid tumors with liver mets. Not sure if its relevant enough for this article, as it is a rare complication. Secretions from carcinoid tumors only become problematic in a small portion of cases. Thanks. EmilioVolz 19:16, 30 May 2007 (UTC)

Drugs which may contribute - revamp needed

This table is incomplete, the categories are vague or even incorrect and some of the drugs are misclassified. Additionally, as part of a new list/table, should we distinguish between those drugs which can trigger SS on their own and those that only cause SS in interactions with other drugs? I'm swamped for time right now, but I'm planning on working to make it an informative and logical table. If anyone else would like to take a swing at it, I'd certainly appreciate it. My suggestion would be to start with eliminating the elicit drug category altogether, as a drug's legal status is not the same thing as it's class and mode of action. Dreadloco (talk) 08:01, 24 January 2008 (UTC)

This is probably the wrong place to report it, but I've experienced serotonin syndrome after taking SAMe, and also after taking a combination of Ginkgo Biloba and Genseng. The second time that I had problems with Gingko Biloba and Genseng it was in a 'healthy' fruit drink I purchased at a local bodega. I couldn't figure out why I had the problem until I went over everything that I'd recently eaten and drunk, and then looked at the fine print of the fruit drink bottle. I've also experienced serotonin syndrome with Wellbrutrin (Bupropion). 4.232.105.24 (talk) 01:56, 13 July 2008 (UTC)

What were the symptoms you experienced? I'm not very familiar with most of the OTC herbals/food supplements, but bupropion is not documented as ever having been associated with serotonin syndrome and does not have significant serotonergic activity, to the best of my knowledge. Mia229 (talk) 15:03, 3 January 2013 (UTC)

Hunter criteria

Hunter's criteria are apparently quite good in assessing for likelihood of serotonin syndrome. Described here. JFW | T@lk 10:39, 5 February 2008 (UTC)

Older systems include Sternbach's 1991 JFW | T@lk 10:40, 5 February 2008 (UTC)

Ooh look, an NEJM review: 2005 JFW | T@lk 10:43, 5 February 2008 (UTC)

The conclusion of this section as it stands today - "Then the diagnosis is serotonin syndrome. If these are not met then it is not serotonin syndrome." - seems to be in the voice of the Hunter group. Typographically it can easily read as if it is the voice of Wikipedia. Is there a convention to fix this? Thanks! 23:37, 20 August 2008 (UTC) —Preceding unsigned comment added by Douglas Michael Massing (talk • contribs)

Strong statement removed

I've removed the following statement because it appears a rather strong claim to make from a single letter to a journal editor: "The most frequent, and perhaps the only, combination of therapeutic drugs likely to elevate serotonin to that degree is the combination of monoamine oxidase inhibitors with serotonin reuptake inhibitors." Xasodfuih (talk) 15:13, 15 February 2009 (UTC)

Access to PMID 18759711 review

I see it mentioned once in the article, but only with the fact from the abstract. Since it's published in one of "lesser" Expert Opinion journals, I don't have access to it. Anyone reading this having better luck please email me the pdf at my username at gmail. It probably says nothing really new compared to the other recent (and open access) review. Thanks, Xasodfuih (talk) 21:01, 15 February 2009 (UTC)

Mirtazapine

There is sentence about mirtazapine not causing ST based on a review by Gillman, but this is somewhat disputed by Boyer and Shannon. I'm not even convinced that such a detail belongs to this article instead of the article on the drug. Xasodfuih (talk) 22:21, 15 February 2009 (UTC)

Dunkley et al. [1] list some more case studies which associated mirtazapine with ST, but if I'm grokking that paper they seem to say that mirtazapine could not have been the cause for ST in those case reports?! Xasodfuih (talk) 22:34, 15 February 2009 (UTC)

Mirtazapine has a link to an article in which Mirtazapine is used to treat ST

I re-added this drug back to the table. The official reason is that its WP:SYN to remove the drug based on a few sources saying it may not have a significant serotonergic activity, however all major secondary and tertiary source still have it listed. My personal experience is, since mirtazapine has been out I've taken it around 1/2 of the time (off and on). I have recently (this year) with my MD approval taken an MOAI Parnate with 15mg of Mirt. with no problems. Then I quit Parnate and started 25mcg Duragesic patch, and started having serious insomnia and serotonin activation. When my mirt. was increased to 30mg (doubled), signs of SS were evident. I was full manic, very little sleep, arm and hand tremor, diarrhea, feeling hot and sweating at temps I was normally comfortable with, etc. I quit (discontinued or DC'd) Mirtazapine 11 days ago, and since then almost all of those symptoms have gone away and my sleep is starting to come back to normal. My dr said that I am prone to SS (which I've had before) because I have an imbalance of neurotransmitters, particularly dopamine and GABA. Since mirtazapine increases the other monoamine, noradrenaline this may explain why it is a treatment for SS, or perhaps because people coming down from SS can experience profound depression and withdrawal symptoms from SSRI, so taking a low-activating antidepressant could help. - Stillwaterising (talk) 07:58, 27 September 2012 (UTC)

• Here's something to add to the article -- Hernández, José L; Ramos, Francisco J; Infante, Jon; Rebollo, Mariano; González-Macías, Jesús (2002). "Severe Serotonin Syndrome Induced by Mirtazapine Monotherapy". The Annals of Pharmacotherapy. 36: 641–643. doi:10.1345/aph.1A302. ISSN 1060-0280. - Stillwaterising (talk) 08:29, 27 September 2012 (UTC)

This may have been a reaction to the fentanyl. Some people experience "paradoxical stimulation" from opioids. Feeling very hot can be a side effect of opioids as well. I'd have to look it up, but there might also be a pharmacokinetic interaction between the two drugs, and if so, it could have contributed to your reaction. Fentanyl is not among the opioids that are known or believed ever to have been associated with serotonin syndrome (pethidine/meperidine and tramadol are the main ones I can think of offhand) and is often used as an analgesic for post-surgical pain in patients who are taking an irreversible MAOI (or have taken one within the preceding two weeks).

I recommend that you take the "neurotransmitter imbalance" thing with a grain of salt. I'm not a doctor myself, but I have a background in neuropharmacology, and it seems to me your doctor has, intentionally or not, led you to believe what is really just a rather vague form of the "neurotransmitter hypothesis." Physicians often seem to use imprecise, not-very-meaningful phrases like this one in order to avoid giving patients long and complicated explanations and/or admitting that we don't really know the biochemical cause of a condition. It's certainly not a diagnosis, and even if something that could generally fit this description had been proven to cause mood disorders, individual patients still would not be tested for it; among other things, the testing required would be very expensive and might only be possible to perform postmortem. Mia229 (talk) 20:19, 4 January 2013 (UTC)

A few changes and suggestions for a FA-level article

I was going to suggest these during the GA-review, but it closed before I had a chance to do so, so I've made the changes myself:

• "no lab tests" in the lede
• say that it's not idiopathic (unlike say neuroleptic malign. syn.)
• say more clearly in there are multiple diagnostic criteria proposed
• give specif. numbers
• Risk: rm Gillman statement (see two sections above)
• newborns: explain
• Gillman's mirtazapine opnion (disputed? see section above)
• 85% of phys. not aware of ST (NEJM)

FA suggestions:

• diff dx: fast/slow onset, give times
• diff between "normal" SSRI side-effects and ST
• survey dx criteria alternatives (mentioned in NEJM but not detailed), especially Sterbach's which still the most commonly used.
• perhaps a diagram of the Hunter "algorithm" fig. 4 here
• severity should be discussed in the dx section according to the 3 Hunter levels
• diff dx to other similar conditions (not just neuroleptic malignant syndrome) (see NEJM)
• list some drug combinations (NEJM doesn't have them)
• the spat about triptan SSRI interaction (FDA letter etc.) see PMID 18957623
• animal models! PMID 17935833 has a review
• neo-natal syndrome: withdrawal vs ST; see JAMA review PMID 15900008

All the best, Xasodfuih (talk) 23:11, 15 February 2009 (UTC)

5HTP and psychological effects

5HTP is a food supplement, a form of serotonin that can traverse the blood-brain barrier. Though not a drug, it can induce the syndrome in high enough quantities. Coincidental with the usual features of the syndrome, psychosis induced by 5HTP may bear a mystical tone. In fact, this frame of consciousness induced by 5HTP and coincidental with serotonin syndrome can become so extreme so as to shut out everything that is not itself. Hence, the sufferer may be self-aware but very estranged from his or her surroundings. 74.195.28.79 (talk) 16:08, 19 March 2009 (UTC)

5-HTP is a drug silly. 71.175.243.53 (talk) 23:58, 11 June 2009 (UTC)

5-HTP is sold without any restriction as a food supplement, at least in Canada (and probably in the US). 70.83.220.148 (talk) 21:05, 9 July 2009 (UTC)

in a very technical sense, this is not serotonin syndrome specificaally because there's a bunch of rate limiting steps which keep serotonin from accumilating on it's own in the brain (no matter how much 5-htp you take) in toxic quantities. The first one would be the AAAAD enzyme which also serves other functions. It is actually very likely that you would develop acute, temporary b vitamin deficiency from a large enough singular dose of 5-htp. This would suppress the conversion of other amines to neurotransmitter, and really what you describe sounds like some kind of nmda antagonistic effect.RotogenRay (talk) 05:39, 25 August 2014 (UTC)

PMID 2035713??

In section 2.1 the article says: "Many MAOIs inhibit monoamine oxidase irreversibly, so that the enzyme cannot function until it has been replaced by the body, which can take at least four weeks.[23]" Ref 23 points to PMID 2035713, which doesn't seem to have any reference to MAO taking 4 weeks to regenerate. I don't wish to change the article, but rather want to learn more about regeneration of MAO, which is very hard to come across as everything I can find is about surpressing MAO. So can the author tell us where he got that info, or make the reference available? A URL here would be fine as well. Thanks, blucat, David. —Preceding unsigned comment added by 198.142.19.124 (talk) 18:25, 21 May 2009 (UTC)

Permanent Nerve Damage

I never would have even heard the term Serotonin Syndrome had it not been for a drug interaction warning from my pharmacist about Tramadol and Axert (migraine med) So I looked it up and sure enough the Tramadol also interacts with my Benadryl, after reading the symptoms I realized that those are the very symptoms that perplexed my neurologists until I finally gave up and quit seeing them. One good thing did come of it. I was placed on Topamax because they suspected absence seizures early on and it did stop the muscle jerks. So that's my question(s) I know I overused the Benadryl as a sleep aid for years, could it have caused permanent nerve damage (all of the symptoms were there they just didn't connect the dots) and will Topamax mask these symptoms? EyorPG

It's unlikely to cause permanant damage. TBH you sound a bit of a worrier. (GimpyFauxHippy (talk) 22:13, 5 December 2009 (UTC))

Mini review

1. Having some difficulties getting much out of the management section. How effective is cyproheptadine? Do we have any evidence and if not this needs to be stated.
2. Treatment section needs some order to it based on either treatment used or disease aspect being addressed.
3. Uptodate refers to cyproheptadine as an antidote. Therefore it needs to be referenced that no antidote exists.[2]

Doc James (talk · contribs · email) 19:51, 23 December 2009 (UTC)

I am not a Dr. but one who has Carcinoid Tumors. Carcinoid tumors that start from the abdominal region produce several hormones including serotonin. Once the tumor metastasized to the liver the serotonin is released to the blood stream and remains until the lungs of liver remove it. These tumors do not release harmones at a steady rate. As the hormones build up within the tumor they are released when the pressure is great enough to break through the cell walls. Heavy lifting, straining, or just a sneeze can cause a release with the following reaction. The reaction depends on how much and what combination of hormones are released.

 This needs to be confirmed by a Dr. who has training and experience with Carcinoid Tumors.

 For those working in EMS and ER rooms follow procedure, look at the blood lab work for metabolic acidosis. This is listed as standard procedure but it is often overlooked. I know from first hand experience.

10/13/2010 Luther Browning BillWilliam (talk) 16:32, 13 October 2010 (UTC)

recent review article

[3] Doc James (talk · contribs · email) 22:55, 12 August 2011 (UTC)

Post-MAOI "washout" time

Hello. In the "Cause" section of the article, right below the table that lists the most common culprits in serotonin syndrome, this sentence can be found: "Many MAOIs inhibit monoamine oxidase irreversibly, so that the enzyme cannot function until it has been replaced by the body, which can take at least four weeks." First of all, the combination of "can take" and "at least" sounds strange to me. It should be either "can take up to" or "takes at least". More importantly though, I don't think four weeks is an accurate timeframe for the reestablishment of full MAO enzyme activity. The source is 20 years old. Basically all sources I know, including package inserts of tranylcypromine and phenelzine, say that MAOI diet has to followed until 14 days after stopping MAOI treatment. This seems to be more or less a consensus. I don't want to edit anything yet, but I was going to ask whether anyone insists on keeping the mention of four weeks. C.d.rose (talk) 20:42, 26 November 2011 (UTC)

Broken citation links

Citation 12 is broken, leads to 404 page. — Preceding unsigned comment added by 97.83.174.167 (talk) 01:41, 23 July 2012 (UTC)

Fixed now. Mr Bungle | talk 05:11, 23 July 2012 (UTC)

Clarify on the clarify

In the section entitled "Pathophysiology":

Serotonin is a neurotransmitter involved in multiple states including aggression, pain, sleep, appetite, anxiety, depression, migraine, and vomiting.

Can anybody be more specific? Are we wanting a summary of what serotonin does, or major points it influences? Are we relating certain symptoms to the neurotransmitter? Is this the backbone of the leading theories for serotonin syndrome?

Aggression, anxiety, depression, sleep, and appetite I can all trace back to serotonin (or explain how serotonin is involved), but the others are dubious.

Just because a substance increases serotonin does not mean one can state that it's involved with pain, vomiting, or migraines; this sounds like improper synthesis to me (counterargument: what about acetaminophen for pain, gag reflex for vomiting, and caffeine for a migraine? none directly impact serotonin or vice versa, to the best of my knowledge). It's much better to just state "Serotonin is a neurotransmitter with roles in aggression, mood, and appetite (among others)." and then perhaps "when the levels are raised, upsets to these systems are observed, resulting in symptoms X, Y, and Z."

A hatnote link to "Serotonin" (in this section) would be good.

This template might be useful for this sort of scenario: template:clarify-span Although it is much more obvious to the reader, it's easier for editors to use, allowing you to place words in it that need clarification in long sentences, etc. meteor_sandwich_yum (talk) 00:52, 29 November 2013 (UTC)

Confusion of cause

A lot of confusion exists on the nature of serotonin syndrome and what can cause it. Life-threatening serotonin syndrome is only likely to manifest with the use of monoamine oxidase inhibitors. The use of monoamine oxidase inhibitors alone is as likely to cause any metabolic syndrome akin to the cheese effect. The example of the death of Libby Zion in 1984 may be attributable to symptoms of serotonin syndrome, but the underlying drug interaction is poorly understood even today. Pethidine is supposed to have affinity for the dopamine transporters, not serotonin transporters; both substances implicated may have metabolites which could have some unknown interaction. The only thing which is definitely known is that the interaction between Pethidine and nonselective monoamine oxidase inhibitors has a potentially fatal interaction which can cause serotonin-mediated temperature dysregulation and other symptoms of serotonin syndrome.

The interesting thing about the example is the fatal fever. Levels of serotonin do not correlate directly to body temperature unless the serotonin being released is catabolized. In the instance of monoamine oxidase inhibitor use, catabolism is defeated. Elevated body temperature is only likely to occur as a significant amount of serotonin is catabolized.

Serotonin syndrome may exist with or without elevated body temperature, though a return to homeostasis will increase body temperature (i.e. regeneration of monoamine oxidase dispatches extra serotonin). Another compound oft implicated in serotonin syndrome is 5htp. Its conversion to serotonin is, however, highly rate limited. Concurrent use of 5htp and SSRIs is observed to produce hot flashes/spikes in body temperature; however dangerous this is rarely a fatal interaction on its own.

The combinatory danger of releasing agents such as MDMA and reuptake inhibitors is equally misunderstood. Cocaine and MDMA do not posess a fatal interaction, however many SSRIs inhibit or compete for the same enzymes (as mdma) for degradation. The potential for inability to clear mdma exists, this is the case in fatal intoxication mediated by concurrent use of MDMA and moclobemide (which is also a substrate of CYP2C19 and an inhibitor of CYP2C19, CYP2D6 and CYP1A2; at least some of these degrade mdma). Deaths from serotonin syndrome caused my MDMA alone or in combination with 5htp are exceedingly rare if they occur.

My last point before I offer suggestions, there is no logical way that something which affects the receptor (agonist) could cause serotonin syndrome in leiu of some other metabotropic property (i.e. mdma is also a weak agonist). LSD shouldn't be on the list of things with the potential to cause serotonin syndrome. LSD, or any agonist, would indeed worsen symptoms of serotonin syndrome as it would increase the receptor's sensitivity to the presence of the ligand. This would not affect body temperature at all if it were not for the fact that some of the receptors are in the control path for muscles, which can and do generate heat in response to activity. The agonist decreases the percieved effort it takes to do something by increasing the responsiveness to the control signal (in this instance, serotonin) which can manifest exterally as hyperflexia and has an equal chance of leading to dehydration in this regard.

So really, we can categorize several causal types of serotonin syndrome. There's the classic "can't get rid of serotonin" syndrome caused by MAO-A inhibitors; then theres "can't get rid of the catabolic shunt/inhibitor" which is drug a inhibits enzyme that digests drug b which is affecting the release or blocks the reuptake (or degradation of) of serotonin. This would manifest completely differently from the first example unless drug b was a monoamine oxidase inhibitor.

I would postulate another example of serotonin syndrome which is populated by 5ht agonists which would describe the effects only produced at the receptor without interfereing with serotonin metabolism and call it 'serotonin hypersensitivity' or perhaps the tryptamine effect or the ayahuasca effect (i.e. metabolic serotonin-system anomalies produced through non metabolic means) or 'non-metabolic serotonin syndrome". It is however inaccurate to characterize hallucinations as symptomatic of metabolic serotonin syndrome, or otherwise to list the side effects of drugs that may cause serotonin syndrome as symptoms of serotonin syndrome. Tremor is a side effect of MDMA, shaking may present with other agonists but this is a side effect of something besides serotonin. Hyperflexia is attributable to agonists. Hyperactivity or hypermotility might be accurate substituited for hyperreflexia for metabolic serotonin syndrome. Vasoconstriction is the appropriate reference for hypertension as excessive serotonin is not known to cause hypertensive crisis.

All examples of serotonin syndrome would be one or some combination of these examples. See something I've missed or have I uttered blaspheme? Please tell me if i'm completely wrong on something or if you've explicit knowledge to the contrary of anything I've said on my talk pageRotogenRay (talk) 05:05, 12 August 2014 (UTC)

Completely wrong, certainly not. However, the confusion is sometimes due to correct but limited -- perhaps more accurately, focused -- consideration. I believe you may fall prey to that just as the article does, by considering only "drug interactions". In my experience, of the 3% or so who've taken SSRIs alone and had problematic side effects were simply called "allergic", but were for the most part showing early symptoms of serotonin syndrome (agitation and confusion). One situation I've studied for some time involves the hypopigmentation condition known as vitiligo. In this condition, the precursor tyrosine is blocked from becoming melanin, and instead ends up as noradrenaline and adrenaline. A chronic overload of these results in increased MAO-A production to keep them in check. The increased MAO-A also catalyzes serotonin, which does not share the increased production. In order to maintain roughly normal serotoninergic activity, there is receptor upregulation. With reuptake blocked, increased synaptic serotonin in a field of receptors of a much larger number than usual produces a massive increase activiation. Yes, there are other substances involved, but all are endogenous, thus this is not a drug interaction.

A minor point in Signs and Symptoms: headache is a referred pain, a matter of nociception, and thus is somatic, not cognitive. Drmcclainphd (talk) 13:25, 28 November 2015 (UTC)

Moved

There "Agonists and metabolic affect

Singular use of LSD or other 5-HT agonists is unlikely to cause serotonin syndrome in lieu of other metabotropic properties which affect the serotonin system. However, agonists at 5-HT would increase the severity of certain symptoms associated with serotonin syndrome, depending on the 5-HT subtypes for which the agonist is selective. The effect of agonists do not explicitly qualify as a syndrome of serotonin (the ligand) but may be considered a syndrome which affects the serotonin system, i.e. 5-HT receptor syndrome. Agonists cause sensitization to the presence of the ligand or directly stimulate receptors, hence the temperature increase is produced by increased physical activity. In the classical case of serotonin accumulation syndrome, temperature increase is mediated by enzymatic activity of MAO-A. The nature of serotonin syndrome may be understood in general terms of affect on serotonin metabolism, e.g. to catabolic or anabolic. SSRIs and releasing agents bias the serotonin system towards catabolism by blocking reuptake, while monoamine oxidase inhibitors inhibit catabolism of serotonin (shifting to anabolic). The acute combinatory danger of any substance which acts as a catabolic shunt with monoamine oxidase inhibitors is not their obvious potential for causing dangerous serotonin accumulation. In many cases a number of different enzymes are inhibited or acted upon which interfere with the metabolism of the combination of drugs taken and prolong serotonergic effects. This extended enzyme interference describes deaths attributable to the combination of MDMA and moclobemide"

Moved as poorly referenced Doc James (talk · contribs · email) 07:30, 23 March 2016 (UTC)

Dosage

This article gives no indication at all of how much medication causes this. Should one call an ambulance immediately if one has taken one standard dose of SSRI/SNRI/MAOI/TCA/tramadol on the same day that one has taken another SSRI/SNRI/MAOI/TCA/tramadol? Correctrix (talk) 09:03, 10 February 2018 (UTC)

References

LSD

Lots of ref support https://www.mayoclinic.org/diseases-conditions/serotonin-syndrome/symptoms-causes/syc-20354758

Doc James (talk · contribs · email) 14:07, 19 November 2019 (UTC)

Including http://www.njmonline.nl/getpdf.php?id=245 Doc James (talk · contribs · email) 19:37, 12 December 2019 (UTC)

Hi, I removed this part because your paper, The Serotonin Syndrome, doesn't explicitly state LSD as being implicated in Serotonin Syndrome. The chart referenced in the paper is regarding mechanisms implicated in SS (incl. Serotonin stimulation), and it mentions LSD as an example of a drug that stimulates 5HT receptors. It's fallacious to say that LSD causes Serotonin Syndrome because it's a 5HT-receptor stimulant, especially considering LSD has a biased agonism that favours the Beta-arrestin pathway over G-protein activation. — Preceding unsigned comment added by 27.32.180.153 (talk) 23:59, 10 May 2020 (UTC)

Doc James, if you're going to include that additional citation for LSD, could you please consider revising the other source, [18]? It's not suggesting LSD causes Serotonin Syndrome, it's only suggesting that LSD stimulates the Serotonin receptors. I'm unfamiliar with Wikipedia editing so I'm not going to try edit it again, but the source doesn't suggest LSD causes SS.

Here is a paper that affirms my concern about suggesting LSD can cause SS: https://headachejournal.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1526-4610.2009.01575.x — Preceding unsigned comment added by 124.170.15.81 (talk) 01:25, 12 May 2020 (UTC)

I have had difficulties tracking the source to the claim that LSD can cause serotonin syndrome, whether by itself or with other compounds. Absence of evidence is not evidence of absence, but some published material indirectly suggests it does not cause it (like the one by the IP that posted above me). I have some objections with the sources:

1. The citation [18] (Bijl D (October 2004). "The serotonin syndrome". Neth J Med. 62 (9): 309–13) has a single reference to LSD. There is a table titled "Mechanisms of serotonergic drugs involved in serotonin syndrome", it has a category "[s]timulation of serotonin receptors" and LSD is an entry there. There are two relevant citations: one is to a Dutch pharmacology textbook or reference book titled Farmacotherapeutisch Kompas 2003, and in the 2009 edition (couldn't find 2003) there is a table almost exactly as the one in the paper. In turn, this chapter, which is about depression, cites a dozen sources of which only one seems relevant to me (all the other are directly related to depression and its treatment only): "Boyer EW, Shannon M. The serotonin syndrome. N Engl J Med. 2005 Mar 17;352(11):1112-20. doi: 10.1056/NEJMra041867", which includes a reference to "drugs of abuse" being "associated with the syndrome", but the references it cites don't mention this anywhere I could find.
2. The second citation, [19] for Rosen's Emergency Medicine - Concepts and Clinical Practice simply cites the Bijl article, and it's therefore redundant, so I will remove it.

Unless we can find a source that actually has evidence of LSD causing serotonin syndrome, I think it should be removed from the article. Or perhaps take it out from the table of drugs that "can cause" the syndrome and state that "LSD has been associated with serotonin syndrome" somewhere in the section, and cite something like the Boyer and Shannon paper, where that claim is made. Paper wobbling sound (talk) — Preceding undated comment added 07:58, 14 February 2021 (UTC)

Table of causes: is the "other" section too long?

Currently these are the drugs listed as "other" in the table of causes: Tryptophan,[4] L-Dopa,[22] valproate,[4] buspirone,[4] lithium,[4] linezolid,[4][23] dextromethorphan,[4] 5-hydroxytryptophan,[9] chlorpheniramine,[10] risperidone,[24] olanzapine,[25] ondansetron,[4] granisetron,[4] metoclopramide,[4] ritonavir,[4] metaxalone[4]

I am not sufficiently informed to decide how they should be grouped, but I can see some small groups in there without even recognising half of the drugs: tryptophan and 5-hydroxytryptophan are serotonin precursors (which would very logically cause serotonin syndrome if improperly administered) and L-DOPA as a dopamine precursor could then possibly be grouped with them as neurotransmitter precursors. Risperidone and olanzapine are both antipsychotics. Of the others I don't see large groups as I only recognise valproate, lithium, and ritonavir, but I would not be surprised if there are further appropriate groups, especially if we take into consideration that currently the "5-HT1 agonists" class consists only of "triptans" (although I do realise that that is a class of drugs, not a single one)

I personally think that the "other" section should really be for drugs that are not related to any of the others, and I imagine that to the layperson the way it is currently set out implies that this long list of drugs are all unrelated despite that not being the case.

Further input would be much appreciated.

Anditres (talk) 22:39, 28 December 2020 (UTC)