Serotonergic drugs.

Discussion in 'Pharmacology' started by Paracelsus, Mar 30, 2007.

  1. Paracelsus

    Paracelsus Platinum Member & Advisor

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    Certain combinations of serotoninergic drugs (substances which raise serotonin in one way or another) can result in serotonin syndrome/serotonin toxicity (ST) when combined with each other or with MAO inhibitors (non-selective MAOIs or selective MAO-A inhibitors).

    Some combinations are more hazardous than others. For example, serotonin reuptake inhibitor + MAOI (both in therapeutic doses) can cause severe and potentially fatal ST. The only other combination that can result in fatal ST is serotonin releaser + MAOI (e.g. MDMA + moclobemide). Other combinations produce mild or moderate toxicity, or none at all.

    Please add information (accompanied with references) to the thread (particularly info for the red sections). Please keep this list to drugs that either have been implicated in ST or have high enough serotonergic potency that it is safe to assume that they can precipitate ST when combined with the wrong drugs.

    Note that this list is under construction and will be included in a Wiki article I am writing. Pardon the bold text in parentheses (they are temporary references so I don't lose track of my sources).

    Serotonin reuptake inhibitors (SRIs)

    Selective serotonin reuptake inhibitor antidepressants, SSRIs (paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram, etc.): Often implicated in ST. Overdoses of SSRIs alone can cause mild to moderate ST (not fatal) (ST.doc).

    Serotonin-norepinephrine reuptake inhibitor antidepressants, SNRIs (venlafaxine, duloxetine, milnacipran): Often implicated in serotonin toxicity (similar to SSRIs) (ST.doc).

    Tricyclic antidepressants, TCAs: Only clomipramine and, to a lesser extent, imipramine have been implicated in ST. Other TCAs (e.g. amitriptyline) have not been implicated in ST, as they do not have significant serotonergic potency (ST.doc).

    Saint John's Wort (Hypericum perforatum): Herbal antidepressant. Indirectly inhibits reuptake of monoamine neurotransmitters. Occasionally implicated in ST (Herb-Drug.pdf).

    Tramadol: Opioid analgesic and serotonin-norepinephrine reuptake inhibitor. Often implicated in ST when combined with SRIs and MAOIs (possible fatalities with MAOIs) (MOI-OA-ST). One case report suggests that tramadol by itself can cause ST in overdose (find PDF).

    Dextromethorphan: Antitussive and dissociative anaesthetic. Therapeutic doses (up to 30 mg every 6 hours) are unlikely to cause ST but should be avoided if MAOIs are used. One reported fatality involved approximately 60 mL cough syrup containing dextromethorphan (likely 60-180 mg dextromethorphan) and phenelzine (Rivers & Horner). High-dose dextromethorphan (recreational use) has been implicated in ST when combined with SRIs (chlorpheniramine, fluoxetine, paroxetine) (Ganetsky et al, Navarro et al, Skop et al) and MDMA (Ecstasy).

    First-generation antihistamines: chlorpheniramine is a relatively potent SRI (Hellbom) and has been implicated in ST when used intravenously (ST.doc). A reported case of ST involved a combination of 64 mg chlorpheniramine and 480 mg dextromethorphan (both 16 times the therapeutic dose) (Ganetsky et al). Diphenhydramine has a lower serotonergic potency than chlorpheniramine (Hellbom) and has not been implicated in ST. Chlorpheniramine analogs (brompheniramine, dexchlorpheniramine) should be regarded as similar to chlorpheniramine regarding the possibility of ST.

    Sibutramine

    5HT releasers

    Amphetamine-type stimulants (incl. methylphenidate, phentermine, fenfluramine, etc.)

    MDMA (Ecstasy): Empathogen, serotonin releaser. Causes ST by itself in overdose. Can cause serious and potentially fatal ST when combined with MAOIs. SSRIs were found to block the serotonin release and subjective effects of MDMA, and cases of ST following MDMA with SSRIs are not known (Silins' Qualitative Review). ST may be a consequence of combining dextromethorphan with MDMA (the former is sometimes present in pills sold as the latter) (citation needed). A case of ST involving MDMA followed by 200-250 mg l-tryptophan, "'several' St. John's Wort tablets," and an unknown over-the-counter cold medication (Bryant & Kolodchak).

    MDMA analogs (incl. PMA)

    AMT, AET: 5HT releasers, MAOIs

    5HT agonists

    Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, zolmitriptan): Anti-migraine drugs. A 2007 analysis of 29 reports of supposed ST from concomitant use of triptans and SSRIs or SNRIs revealed that none fulfilled modern criteria for diagnosis of ST, although hundreds of thousands of Americans were exposed to this combination during the period of the reporting of these cases (Evans, FDA Alert). This suggests that there is virtually no risk of ST from combining triptans and SRIs. Risks of combining triptans with serotonin releasers or MAOIs are unknown.

    Psychedelics (5HT2A agonists)

    Dihydroergotamine: Anti-migraine drug.

    Buspirone: Anxiolytic.

    Miscellaneous, unclassified

    Opioid analgesics: Some opioids (other than tramadol) have rarely been implicated in interactions with other serotonergic drugs, particularly MAOIs, some of these interactions having been identified as ST. Fentanyl has been involved in several interactions with MAOIs (one possible death) and venlafaxine (MOI-OA-ST WS). Two cases of ST involving oxycodone and SSRIs have been reported (Karunatilake, Rosebraugh). Pethidine (meperidine), a weak SRI, has been implicated in ST when combined with MAOIs, and some fatalities are known. Two cases of a "potentiation" of propoxyphene by phenelzine (a MAOI) have been reported. These "weak serotonergic opioids . . . are capable of precipitating serotonin toxicity, but this is only likely with susceptible individuals, or with particularly large doses" (MOI-OA-ST WS).

    S-adenosylmethionine, SAMe: Coenzyme supplement sometimes used as an antidepressant. Increases serotonin biosynthesis in rat brain (Otero-Losada & Rubio). A case of ST caused by 100 mg SAMe (daily by intramuscular injection) and 75 mg clomipramine. ST developed after daily clomipramine dosage was increased from 25 to 75 mg daily (Iruela et al). This suggests that SAMe has a low potential to cause ST.

    Metoclopramide: Antiemetic. Three cases have been reported in the literature, in one of which the drug precipitating ST was probably misidentified. They involved metoclopramide in combination with sertraline, venlafaxine, and tramadol, respectively (Fisher & Davis, Kung & Ng).

    Serotonin precursors: L-tryptophan and 5-hydroxytryptophan (5-HTP) are amino acids that are converted to serotonin in the body. L-tryptophan may cause mild ST symptoms in combination with SRIs or MAOIs (ST.doc). In a small-scale human trial, daily doses of 2 grams l-tryptophan, in combination with fluoxetine, did not cause ST (Levitan et al). 5-hydroxytryptophan (5-HTP) increases serotonin levels to a greater extent than l-tryptophan (ST.doc). No ST was noted in several human trials of 5-HTP in combination with clomipramine (a SRI) and MAOIs (Turner et al). These data suggest that l-tryptophan and 5-HTP do not have the potential to cause ST when taken as supplements, in normal dosage.

    Co-amoxiclav, Augmentin: One case of possible ST caused by administration of co-amoxiclav to a patient on venlafaxine has been reported (Connor 2003). Possibly not ST, or very rare.

    Ginseng (Panax ginseng)

    DA agonists: bromocriptine, cabergoline, levodopa, bupropion, amantadine (Mason et al 2000)

    Ondansetron, granisetron

    Ciclosporin (Wong et al 2002)

    Valproate

    Lithium: Mood stabilizer often used in conjunction with SSRIs in the treatment of bipolar disorder.

    Piperazine stimulants (BZP etc.)

    Cocaine (Silins' Qualitative Review)

    Kanna (Sceletium tortuosum), Rhodiola rosea: POTENCY? (no reported incidents)

    Reserpine
     
    Last edited by a moderator: Sep 10, 2017
  2. Paracelsus

    Paracelsus Platinum Member & Advisor

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    Re: Serotoninergic drugs.

    Rewritten and bumped (old).
     
  3. kareena

    kareena Newbie

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    Interesting to see mirtazapine listed under 'other possible serotonergics' as it's classed as a 'noradrenic and specific serotonergic antidepressant'.

    Some of the serotonergic actions are widely disputed as studies have shown serotonin syndrome is unlikely when combined with other serotonergic drugs:

    ABSTRACT
    A systematic review of the serotonergic effects of mirtazapine in humans: implications for its dual action status.
    Gillman PK
    A systematic review of published work concerning mirtazapine was undertaken to assess possible evidence of serotonergic effects or serotonin toxicity (ST) in humans, because drug toxicity and interaction data from human over-doses is an useful source of information about the nature and potency of drug effects. There is a paucity of evidence for mirtazapine having effects on any indicator of serotonin elevation, which leads to an emphasis on ST as an important line of evidence. Mirtazapine is compared with its analogue mianserin, and other serotonergic drugs. Although mirtazapine is referred to as a dual-action 'noradrenergic and specific serotonergic drug' (NaSSA) little evidence to support that idea exists, except from initial microdialysis studies in animals showing small effects; those have not subsequently been replicated or substantiated by independent researchers. Also, new data indicate its affinity for Alpha 2 adrenoceptors is not different to mianserin. It appears to exhibit no serotonergic symptoms or toxicity in over-dose by itself, nor is there evidence that it precipitates ST in combination with monoamine oxidase inhibitors, as would be expected if it raises intra-synaptic serotonin levels. Mirtazapine has no demonstrable serotonergic effects in humans and there is insufficient evidence to designate it as a dual-action drug.
    http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16342227


    Probably not best to play around with mirtazapine and other serotonergic drugs but the fact that this study shows no level of toxicity when it's combined with MAOIs, notorious for causing toxicity when combined with serotogenic drugs, does suggest mirtazapine's level of serotonergic activity as indicated by the makers is questionable (activating on the 5HT-1 receptor, not on the 5HT-2 and 5HT-3).
     
    Last edited: Jul 31, 2007
  4. Pino

    Pino Gold Member

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    The main active alkaloid in kanna is mesembrine, which is a potent SSRI, so it is better not combined with other serotonergic drugs.
     
  5. tayo

    tayo Silver Member

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  6. Paracelsus

    Paracelsus Platinum Member & Advisor

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    kareena: Check out www.psychotropical.com . The guy seems to be very knowledged about serotonin syndrome (since that is his field of study). And he doesn't think that mirtazapine contributes to serotonin syndrome. That's why it's in 'possible serotoninergics'.

    Pino: Thanks, I added the info to the original post.

    tayo: Do you have any sources about methcathinone (since it is a quite poorly researched substance)? Dextroamphetamine is included in amphetamine (which is the racemic mixture - 50% levo and 50% dextro).
     
  7. Pino

    Pino Gold Member

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  8. Lehendakari

    Lehendakari Gold Member

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    I've never been able to find a study that supports that claim.

    Recent research suggest that mesembrine is an inhibitor of PDE4 similar to rolipram.
     
  9. Pino

    Pino Gold Member

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    I couldn't find support for it either, except in some shady patent. I also found in pubmed an article stating it is a serotonin re-uptake inhibitor:

     
  10. tayo

    tayo Silver Member

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    Last edited: Jul 8, 2007
  11. kareena

    kareena Newbie

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    cool site SWiPara, I understand why mirtazapine is classified as 'possible', never seemed to have noticeable serotogenic affect on SWIM or my friends (obviously only when prescribed; of course ADs have no recreational value)
     
    Last edited: Jul 15, 2007
  12. tayo

    tayo Silver Member

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    Oh also, I believe that Rhodiola Rosea acts as one,

    http://www.herbalgram.org/new-chapter/herbalgram/articleview.asp?a=2333
    "
    Overall, in small and medium doses, R. rosea stimulated norepinephrine (NE), dopamine (DA), serotonin (5-HT), and nicotinic cholinergic effects in the central nervous system (CNS). It also enhanced the effects of these neurotransmitters on the brain by increasing the permeability of the blood brain barrier to precursors of DA and 5-HT.
    "

    and for Methcathinone...

    www.neurophys.wisc.edu/~cozzi/Methcathinone%20is%20a%20SERT%20substrate.pdf
     
  13. kareena

    kareena Newbie

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    Not sure if your question marks after substances meant you were unsure but on a few of them:


    Trazodone is a serotonin reuptake inhibitor and is also a 5-HT2 receptorantagonist.
    http://en.wikipedia.org/wiki/Trazodone


    Nefazodone is closely related to trazodone (trade name Desyrel). Nefazodone is not considered to be an SSRI, MAOI or tricyclicantidepressant. It is not chemically related to either bupropion/amfebutamone or venlafaxine.

    It operates by blocking post-synaptic serotonintype-2Areceptors and, to a lesser extent, by inhibiting pre-synaptic serotonin and norepinephrine (noradrenaline) reuptake. Nefazodone is also a relatively potent alpha-1 adrenoceptorantagonist. [So, it has some serotonergic effects].
    http://en.wikipedia.org/wiki/Nefazodone


    With regard to ginseng:
    "Daily administration of ginseng extract also lowers serotonin level in the cerebral cortex and brainstem, which can influence mood, appetite, sexual function, gastrointestinal function, blood pressure, and sleep(Zhao et al. 1998)."
    http://sulcus.berkeley.edu/mcb/165_001/papers/manuscripts/_221.html
     
    Last edited: Jul 31, 2007
  14. kareena

    kareena Newbie

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    Paracelsus, I created this thread in another sub-forum on psychiatric drugs and later realised it could be helpful for clarifying serotonergic properties in this thread here.

    I couldn't see any information on metoclopramide or chlorpheniramine (two of the three you've still got question marks about) but it says lithium is a 5-HT autoreceptor antagonist.

    There are probably a load of psych drugs in that list from the first link in the thread I made that you might find have serotonergic actions but I doubt you'd want to go through them- there's a lot!

    Not sure how reliable the source is but it looks pretty decent (until you go to the homepage- Bruce Springsteen anyone? :eek:) but I doubt the author of the homepage compiled the what-looks-to-be a very well thought out and comprehensive list of psychiatric drugs and their mechanisms.

    http://sl.schofield3.home.att.net/medicine/psychiatric_drugs_chart.html
     
  15. Paracelsus

    Paracelsus Platinum Member & Advisor

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    Forgot to update the original post in here. Metoclopramide is a 5HT agonist (some cases of SS when used in patients on sertraline and venlafaxine). Chlorpheniramine is a 5hT reuptake inhibitor. I didn't add anything about Lithium (most sources say that it causes a nonspecific increase in serotonin activity).
     
  16. tayo

    tayo Silver Member

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    I insist Rhodiola Rosea is added as well. It certainly has incredible mood lifting capabilities.
     
  17. Paracelsus

    Paracelsus Platinum Member & Advisor

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    Bump (updated). Next update will differentiate between theoretically serotonergic drugs and drugs which have been reported to cause SS (and are therefore the more potent ones).
     
  18. JTC3889

    JTC3889 Silver Member

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    what about sam-e?
     
  19. Paracelsus

    Paracelsus Platinum Member & Advisor

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    There is only one documented case report of serotonin syndrome involving SAMe (that involved injecting it), which means that serotonin syndrome from this is extremely unlikely (especially considering its widespread use). I'll add it, though.
     
  20. JTC3889

    JTC3889 Silver Member

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    k thanks