Serotonergic drugs.

[Paracelsus]

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

Reputation Comments on this post:

excellent.