What happens when you take nortriptyline with st. john's wort?
Nortriptyline is a secondary-amine tricyclic antidepressant used for depression, neuropathic pain, and migraine prevention. It is the active metabolite of amitriptyline and is cleared by the liver, mainly through the enzymes CYP2D6 and CYP3A4. St. John's wort is a herbal extract from Hypericum perforatum whose main active compound, hyperforin, switches on the body's drug-clearing machinery. When the two are combined, here is what unfolds:
- St. John's wort revs up drug-clearing enzymes. Hyperforin activates the pregnane X receptor, which upregulates CYP3A4 and the P-glycoprotein transporter. This effect builds up over roughly one to two weeks of regular dosing rather than appearing immediately.
- Nortriptyline is broken down faster. Because nortriptyline relies on these same enzyme pathways, the induced enzymes clear it more quickly and its blood level tends to fall.
- The antidepressant effect can weaken. As levels drift down, depression or neuropathic pain symptoms can return, and patients often do not connect the change to the supplement.
- Serotonergic activity stacks up. St. John's wort adds its own serotonergic tone on top of nortriptyline's serotonin-reuptake blockade. This gives an additive, theoretical increase in the risk of serotonin syndrome.
- Stopping the herb can swing levels the other way. If St. John's wort is stopped, the enzyme induction takes a week or two to fade. During that window nortriptyline levels can climb back up or overshoot.
Why is this important?
Nortriptyline has one of the better-defined therapeutic windows in the tricyclic class, so anything that shifts its blood level in either direction matters clinically. A controlled human study found that St. John's wort meaningfully lowered the blood levels of amitriptyline and its active metabolite nortriptyline, confirming the direction of this interaction is real and not just theoretical.
The bigger picture is that this interaction can fail in both directions. While the herb is on board, too little drug may reach the bloodstream and the antidepressant or pain-relieving effect can fade. If the herb is then stopped without a plan, the enzymes return to normal over the following one to two weeks and drug levels can rise again. Tricyclic antidepressants at high concentrations can affect heart rhythm and the nervous system, so an uncontrolled rise is the part of this interaction that deserves the most caution.
The serotonergic effect is a third consideration. Symptoms of serotonin syndrome include tremor, sweating, agitation, fever, overactive reflexes, and confusion. Reported cases with St. John's wort plus tricyclics are far less common than with SSRIs, so this part of the interaction is best described as additive and theoretical rather than a frequent event. Even so, drug-safety databases consistently flag the overall combination as a major interaction.
What should you do?
If you take nortriptyline, the simplest and safest step is to not start St. John's wort, and to choose a different mood-support strategy with your provider instead. If you are already taking both, the change should be planned with your prescriber rather than made on your own.
- Before any change: Tell your prescriber and pharmacist about every supplement and herbal product you take, including "mood," "calm," "stress," and "PMS" blends that may hide St. John's wort. Do not start St. John's wort if you are prescribed nortriptyline.
- Every day, while both are in use: Watch for two opposite patterns. Returning depression or pain can signal that levels have fallen too low; new confusion, agitation, palpitations, or worsening dry mouth can signal that levels are climbing too high. Report either pattern to your prescriber.
- After a change: If you and your prescriber decide to stop St. John's wort, do not stop it cold turkey on your own. Because the enzyme induction reverses over a week or two, your prescriber may want to monitor you, and possibly recheck a nortriptyline blood level, during that period.
Also avoid pairing nortriptyline with other serotonergic medicines such as SSRIs, SNRIs, tramadol, triptans, or MAOIs unless your prescriber specifically directs it.
Which specific products are affected?
This warning applies to all nortriptyline products, including generic nortriptyline hydrochloride capsules and brand-name versions such as Pamelor and Aventyl. Because the mechanism applies to the whole tricyclic class, related drugs including amitriptyline, imipramine, desipramine, clomipramine, doxepin, and trimipramine are affected in a similar way.
St. John's wort is sold as standalone capsules, tinctures, teas, and as an ingredient in many combination supplements marketed for mood, calm, stress, or PMS. Common branded products include Kira, Perika, and Movana, alongside many drugstore generics. Always read the full ingredient list of any herbal supplement before adding it to a medication regimen, since St. John's wort is often blended into multi-ingredient products.
The science behind it
The strongest direct evidence comes from a small human pharmacokinetic study. Johne and colleagues gave St. John's wort alongside amitriptyline (which is converted in the body to nortriptyline) and measured a clear drop in the blood levels of both amitriptyline and its nortriptyline metabolite, consistent with enzyme induction by the herb. A later review by Nicolussi and colleagues re-examined the clinical relevance of St. John's wort drug interactions and confirms that hyperforin-driven induction of CYP3A4 and P-glycoprotein is the well-established mechanism behind reduced levels of many co-administered drugs.
- Johne A, et al. Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's wort. J Clin Psychopharmacol. 2002;22(1):46-54. PMID 11799342. (Human controlled pharmacokinetic study, 12 subjects.)
- Nicolussi S, et al. Clinical relevance of St. John's wort drug interactions revisited. Br J Pharmacol. 2020;177(6):1212-1226. PMC7056460. (Review.)
Frequently Asked Questions
Does St. John's wort make nortriptyline stop working?
It can reduce how well it works. By speeding up the enzymes that clear nortriptyline, the herb tends to lower its blood level, which can let depression or pain symptoms return. If your medication suddenly feels less effective and you have started a supplement, mention it to your prescriber.
Is the risk of serotonin syndrome high with this combination?
The added serotonin effect is real in principle, but reported cases with St. John's wort plus tricyclics are uncommon and much rarer than with SSRIs. Treat it as an additive, theoretical risk worth knowing about rather than a frequent event, and watch for symptoms like tremor, agitation, sweating, or confusion.
Can I just stop the St. John's wort myself?
It is safer not to. The enzyme induction reverses over a week or two after you stop, and during that window nortriptyline levels can rise. Plan any change with your prescriber so you can be monitored as your levels readjust.
How long until the interaction appears or fades?
The effect builds up over roughly one to two weeks of regular St. John's wort use, and it takes a similar one to two weeks to fade after stopping. This is why both starting and stopping the herb deserve a plan rather than an abrupt change.
Does this apply to other antidepressants too?
The enzyme-induction mechanism applies across the tricyclic class, so amitriptyline, imipramine, desipramine, clomipramine, doxepin, and trimipramine can be affected similarly. St. John's wort also interacts with many other drug classes, so it is worth reviewing all your medications with a pharmacist.
What can I use instead for mood support?
Talk with your provider about options that do not interact with nortriptyline, such as therapy, exercise, light therapy, or a medication your provider recommends and can monitor.
Key takeaways
- St. John's wort can lower nortriptyline blood levels and weaken its effect by speeding up the enzymes that clear it.
- The herb adds serotonergic activity, an additive and largely theoretical increase in serotonin-syndrome risk.
- Do not start St. John's wort if you take nortriptyline; tell your prescriber and pharmacist about every supplement.
- Do not stop the herb abruptly on your own, because levels can rebound as the enzyme induction fades over one to two weeks.
- Review any change with your doctor or pharmacist.