St. John’s Wort and SSRIs: The Hidden Danger of Serotonin Syndrome

People take St. John’s Wort because they want something natural. It’s sold next to vitamins in drugstores, labeled as a dietary supplement, and marketed as a gentle fix for low mood. But here’s the truth: combining it with common antidepressants like sertraline or escitalopram can push your body into a dangerous, sometimes deadly, state called serotonin syndrome.

What Is Serotonin Syndrome?

Serotonin syndrome isn’t just a side effect. It’s a medical emergency. Your brain needs serotonin to regulate mood, sleep, and muscle control. But when too much builds up-fast-it overloads your nervous system. Symptoms start mild: sweating, shivering, restlessness, nausea. Then they can spiral: high fever over 106°F, muscle rigidity, seizures, irregular heartbeat, kidney failure. In severe cases, it kills.

This isn’t theoretical. Between 2018 and 2023, the FDA issued 12 safety alerts about St. John’s Wort causing serotonin syndrome. In 2025, a European review documented 17 confirmed cases where people mixed this herb with SSRIs. Ten of those cases involved sertraline or paroxetine. One patient died.

Why St. John’s Wort and SSRIs Don’t Mix

SSRIs-like fluoxetine, sertraline, escitalopram, and paroxetine-work by blocking serotonin reuptake. That means more serotonin stays active in your brain. St. John’s Wort does the same thing. It’s not just a placebo. Studies show it inhibits serotonin reuptake and weakly blocks monoamine oxidase, another enzyme that breaks down serotonin. So you’re doubling down on serotonin buildup.

But that’s only half the problem. St. John’s Wort also contains hyperforin, a compound that turns on your liver’s drug-processing system. It forces your body to break down SSRIs faster-except not evenly. Some SSRIs, like sertraline and escitalopram, are broken down by enzymes (CYP2C19) that St. John’s Wort strongly activates. That means your body might clear the SSRI too quickly at first, making you feel like it’s not working. Then, if you keep taking both, serotonin levels spike unpredictably.

Worse, people don’t realize they’re mixing them. A 2021 study in JAMA Internal Medicine found only 33% of people taking herbal supplements told their doctor. Many assume “natural” means “safe.” It doesn’t. St. John’s Wort is a potent biochemical agent. It’s not tea.

Who’s at Risk?

Anyone taking an SSRI and thinking about trying St. John’s Wort is at risk. But some face higher danger:

• People on sertraline or escitalopram-these are metabolized by CYP2C19, which St. John’s Wort strongly induces.
• Those taking higher doses of either substance-900 mg/day of St. John’s Wort plus 100 mg/day of sertraline is a known recipe for trouble.
• Older adults or those with liver issues-their bodies process drugs slower, making buildup more likely.
• People who stop one and start the other without a washout period-stopping St. John’s Wort doesn’t immediately reverse its effects. The enzyme induction lasts days.

Even if you’ve taken St. John’s Wort alone for months without issues, adding an SSRI can trigger serotonin syndrome within 24 hours-or up to two weeks later. There’s no safe window.

What the Experts Say

The American Psychiatric Association’s 2022 guidelines call combining St. John’s Wort with SSRIs “contraindicated.” That’s medical speak for “don’t do it.” The European Medicines Agency bans it outright. The Mayo Clinic, Cleveland Clinic, and FDA all warn against it in plain language: “might raise the risk of a buildup of high serotonin levels,” “can lead to a life-threatening increase in serotonin,” “don’t use.”

Dr. B. Peterson’s 2023 review in StatPearls, a trusted clinical reference, states plainly: “One of the primary adverse effects is the risk of a life-threatening increase in serotonin.”

And yet, sales in the U.S. topped $156 million in 2022. It’s the third most popular herbal supplement for mental health. People are using it-and they’re not telling their doctors.

Other Dangerous Interactions

St. John’s Wort doesn’t just clash with SSRIs. It messes with a long list of medications:

• Birth control pills: It cuts hormone levels by 30-50%. There are documented cases of unplanned pregnancies in women taking both.
• Warfarin: It reduces INR by 25-35%, raising the risk of blood clots.
• Cyclosporine and tacrolimus: Used after transplants. St. John’s Wort can drop blood levels by 60%, leading to organ rejection.
• Seizure meds like phenytoin and carbamazepine: It lowers their levels by 20-40%, increasing seizure risk.
• HIV drugs like indinavir: A 57% drop in effectiveness has been measured.

Why? Hyperforin. It activates the pregnane X receptor (PXR), which turns on liver enzymes that flush out drugs. This isn’t a minor interaction. It’s a system-wide reset of how your body handles medicine.

What Should You Do?

If you’re on an SSRI and thinking of trying St. John’s Wort: don’t. Period.

If you’re already taking both and feel off-sweating more than usual, anxious, shaky, nauseous, or running a low-grade fever-seek help immediately. Tell your doctor you’re taking St. John’s Wort. Don’t wait. Don’t assume it’s “just stress.”

If you want to stop St. John’s Wort and start an SSRI, or vice versa, you need a washout period. Experts recommend at least two weeks between stopping one and starting the other. But even that’s not foolproof. The enzyme effects linger.

There’s no safe dose combination. No “low dose” version that’s okay. The risk isn’t proportional-it’s binary. Either you’re taking both, or you’re not. If you are, you’re playing Russian roulette with your nervous system.

Is There a Safe Alternative?

Yes. If you’re struggling with mild depression and want to avoid pharmaceuticals, talk to your doctor about evidence-backed options:

• Exercise: 30 minutes of brisk walking five times a week has comparable results to SSRIs in some studies.
• Cognitive behavioral therapy (CBT): Proven effective, no side effects, no interactions.
• Light therapy: Especially helpful for seasonal depression.
• Prescription alternatives: If you need medication, your doctor can adjust your SSRI or try something like bupropion, which has lower serotonin activity.

St. John’s Wort isn’t the only natural option-and it’s the most dangerous one. The idea that “natural equals safe” is a myth that costs lives.

Regulation Isn’t Keeping Up

In the U.S., St. John’s Wort is sold as a supplement, not a drug. That means the FDA doesn’t test it for safety or efficacy before it hits shelves. Manufacturers don’t have to prove it works. They don’t have to warn you about interactions. Labels say “for mood support”-not “may cause fatal serotonin overload.”

Canada banned over-the-counter sales in 2023 after 17 serotonin syndrome cases. The FDA is now proposing new labeling rules requiring clear interaction warnings. But until then, the burden is on you.

If you’re buying it, read the label. Look for “Hypericum perforatum.” Know the dose. And if you’re on any medication-especially antidepressants, birth control, or blood thinners-ask your pharmacist before taking it. Don’t rely on the store clerk. They’re not trained for this.