serotonin syndrome
23 interactions related to serotonin syndrome
adderall + st. john's wort
Adderall (amphetamine/dextroamphetamine) raises synaptic norepinephrine, dopamine, and serotonin. St. John's Wort inhibits serotonin, dopamine, and norepinephrine reuptake. Combined, the serotonergic load can produce serotonin syndrome and a hypertensive response, while St. John's Wort's CYP3A4 induction may also alter amphetamine metabolism.
methylphenidate + st. john's wort
Methylphenidate inhibits dopamine and norepinephrine reuptake and modestly affects serotonin signaling. St. John's Wort adds reuptake inhibition of serotonin, dopamine, and norepinephrine, plus weak MAO inhibition. Combination risks serotonin syndrome and a published case series suggests reduced methylphenidate efficacy for ADHD.
sertraline + st. john's wort
Sertraline is an SSRI that blocks serotonin reuptake, and St. John's wort independently inhibits serotonin reuptake and contains constituents (hyperforin, hypericin) that elevate central serotonin. Combining them can trigger serotonin syndrome, a potentially life-threatening syndrome of altered mental status, autonomic instability, and neuromuscular hyperactivity. St. John's wort also induces CYP3A4 and CYP2C19, which can lower sertraline plasma levels and undermine treatment.
fluoxetine + sam-e
SAM-e has independent antidepressant and serotonergic activity, and combining it with fluoxetine can additively raise serotonergic tone, increasing the risk of serotonin syndrome and hypomania. Fluoxetine's long half-life means this risk persists for weeks after the last dose.
duloxetine + st. john's wort
Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI), and St. John's wort independently raises central serotonin through reuptake inhibition. Combined use can precipitate serotonin syndrome, and St. John's wort induction of CYP3A4 and P-glycoprotein may also alter duloxetine exposure.
fluoxetine + tryptophan
Fluoxetine blocks serotonin reuptake while tryptophan supplies raw material for serotonin synthesis, and the combination can produce serotonin syndrome. Fluoxetine's very long half-life (active metabolite norfluoxetine persists for weeks) extends the window of risk well beyond the last dose.
tramadol + st. john's wort
Tramadol inhibits serotonin and norepinephrine reuptake, and St. John's Wort increases central serotonergic activity, so combining them raises the risk of serotonin syndrome. St. John's Wort also induces CYP3A4 and CYP2B6, which can reduce tramadol's active M1 metabolite and weaken analgesia.
maoi + st. john's wort
St. John's Wort inhibits serotonin, dopamine, and norepinephrine reuptake and has weak MAOI activity in vitro. Combined with a prescription MAOI, monoamine clearance is blocked at multiple levels, producing serotonin syndrome and/or hypertensive crisis.
maoi + 5-htp
5-HTP is the direct precursor to serotonin and bypasses the rate-limiting step of serotonin synthesis. Combined with an MAOI, which blocks serotonin breakdown, intracellular and synaptic serotonin can rise to toxic levels, producing serotonin syndrome.
sertraline + 5-htp
Sertraline blocks serotonin reuptake and 5-HTP (5-hydroxytryptophan) is the immediate biochemical precursor of serotonin, so it directly increases serotonin synthesis. Combining the two stacks production and reuptake blockade, which can precipitate serotonin syndrome.
paroxetine + st. john's wort
Paroxetine is an SSRI with potent serotonin reuptake inhibition; St. John's wort independently inhibits serotonin reuptake and induces CYP3A4 and P-glycoprotein. The combination can precipitate serotonin syndrome and is among the most frequently reported SSRI plus St. John's wort interactions in published case series.
amitriptyline + st. john's wort
St. John's wort induces CYP3A4 and CYP2D6 enzymes that metabolize amitriptyline, reducing its plasma concentrations by up to 22%, while simultaneously adding serotonergic activity that can trigger serotonin syndrome. The combined result is paradoxical: less antidepressant effect plus higher risk of a potentially fatal serotonin reaction.
venlafaxine + st. john's wort
Venlafaxine is a serotonin-norepinephrine reuptake inhibitor (SNRI). St. John's wort independently inhibits serotonin (and to a lesser extent norepinephrine and dopamine) reuptake. Combining them can drive a sharp rise in synaptic serotonin and trigger serotonin syndrome, and St. John's wort can also alter venlafaxine pharmacokinetics through CYP3A4 induction.
fluoxetine + st. john's wort
Fluoxetine is an SSRI with a very long half-life (its active metabolite norfluoxetine persists for weeks), and St. John's wort independently raises serotonin via reuptake inhibition. Combined use can precipitate serotonin syndrome and, because of fluoxetine's slow elimination, the risk window extends well beyond the day of last dose.
trazodone + 5-htp
Both trazodone and 5-HTP increase central serotonin activity. Trazodone blocks the serotonin transporter and acts on 5-HT2 receptors, while 5-HTP is a direct precursor to serotonin and bypasses the normal regulation of tryptophan availability. Combining them can produce additive serotonergic effects and risk of serotonin syndrome.
alcohol + tramadol
Tramadol combined with alcohol produces additive CNS and respiratory depression, and the combination significantly lowers the seizure threshold, increasing the risk of convulsions, serotonin syndrome, and overdose death. Tramadol has unique serotonergic and noradrenergic activity that compounds alcohol's effects beyond what occurs with pure opioids.
sertraline + sam-e
SAM-e (S-adenosyl-L-methionine) has its own antidepressant and serotonergic effects, and combining it with the SSRI sertraline can additively raise serotonergic activity and increase the risk of serotonin syndrome. Case reports describe mania and serotonin-toxicity-like presentations in patients combining SAM-e with SSRIs.
cannabis + ssris
Cannabis cannabinoids inhibit CYP2C19, CYP2C9, and CYP3A4, raising plasma levels of SSRIs such as sertraline, citalopram, and escitalopram. Cannabinoids also modulate serotonin signaling, and case reports describe serotonin syndrome precipitated by high-potency cannabis in patients on SSRIs.
fluoxetine + 5-htp
Fluoxetine is an SSRI that blocks serotonin reuptake, and 5-HTP is the direct precursor that the body converts into serotonin. Combining them can raise synaptic serotonin to levels associated with serotonin syndrome, and fluoxetine's long-lived active metabolite norfluoxetine extends this risk for weeks after the last dose.
tramadol + 5-htp
Tramadol inhibits serotonin reuptake, and 5-HTP is a direct precursor to serotonin that increases central serotonin synthesis. Combining them can cause serotonin syndrome, a potentially life-threatening reaction.
escitalopram + st. john's wort
Escitalopram is a highly selective SSRI metabolized largely by CYP2C19 and CYP3A4. St. John's wort independently inhibits serotonin reuptake and strongly induces these same enzymes plus P-glycoprotein. Combined use risks serotonin syndrome and can also lower escitalopram plasma levels, blunting its antidepressant effect.
sertraline + tryptophan
Sertraline is a selective serotonin reuptake inhibitor (SSRI) that increases synaptic serotonin, and L-tryptophan is the dietary precursor to serotonin. Combining them can excessively elevate serotonergic activity, raising the risk of serotonin syndrome (agitation, tremor, hyperthermia, autonomic instability).
cacao + maois
Raw, unroasted cacao (often sold as ceremonial cacao or raw cacao paste) contains higher levels of tyramine, tryptamine, and phenylethylamine than processed chocolate. With irreversible MAOIs in the system, these vasoactive amines can drive a hypertensive reaction and, theoretically, contribute to serotonin syndrome.