The short answer
Repeated St. John’s wort use can lower midazolam exposure, especially after oral dosing. The effect varies by preparation and duration, and separating the doses by a few hours is not a reliable solution.
What this answer covers
Hypericum perforatum products; hyperforin content and repeated versus short-term use matter.
- Supplement or preparation
- Hypericum perforatum
- Medication ingredient
- midazolam
Repeated use changed oral and injected exposure differently
One human study found a larger reduction in oral than intravenous midazolam exposure after repeated St. John’s wort. Short-term use in the same study had no measured enzyme effect.
Low-hyperforin products had a smaller effect
A separate trial found only a small exposure change with one low-hyperforin product, judged not clinically relevant by its authors. An unknown product should not be assumed equivalent.
Stopping does not reverse induction immediately
One study found progressive recovery over days after the herb was stopped. This explains why a same-day gap is inadequate, but the observed recovery time is not a universal washout instruction.
Plan changes with the treating team
Tell the procedural or prescribing team before starting or stopping the herb. The interaction concerns metabolism and exposure, not proven reduced intestinal uptake. Follow the exact midazolam product and rescue instructions rather than changing doses yourself.
Evidence and practical considerations
Absorption & effectiveness
Direct human repeated-use evidence supports reduced exposure and conditional loss of effect; short-term/low-hyperforin signals and route differences retained. No universal interval or proof of reduced intestinal uptake.
- Exact scope
- Hypericum perforatum products; hyperforin content and repeated versus short-term use matter. with Midazolam6960 IN; oral hydrochloride syrup, IV/IM hydrochloride and intranasal midazolam distinguished.
- Medication form and route
- oral medication; intravenous medication; intramuscular medication; intranasal medication; oral supplement
What remains uncertain
- No unmeasured pair incidence, blanket class transfer or arbitrary spacing interval.
Factors that may matter: Preparation; Dose; Other medicines; Organ function.
Read the supporting source summaries
Source 1: current product label
dailymed.nlm.nih.gov · Source check Sep 10, 2026
Population: People prescribed midazolam
CYP3A metabolism, CNS-depressant and respiratory risks; not intended for chronic home sedation.
How this applies: Exact midazolam RxCUI 6960 IN, with stated salt/formulation/route bridge.
Adult oral probe trials not automatic pediatric dosing or nasal/injection interaction magnitude.
Source 2: current product label
dailymed.nlm.nih.gov · Source check Sep 10, 2026
Population: People prescribed midazolam
Sedation/respiratory and CYP3A interaction precautions.
How this applies: Exact midazolam RxCUI 6960 IN, with stated salt/formulation/route bridge.
Bypasses intestinal absorption; oral exposure findings cannot be assigned unchanged.
Source 3: current product label
dailymed.nlm.nih.gov · Source check Sep 10, 2026
Population: People prescribed midazolam
CNS-depressant and CYP3A interaction precautions; formulation-specific rescue instructions.
How this applies: Exact midazolam RxCUI 6960 IN, with stated salt/formulation/route bridge.
Not oral procedural dosing; do not delay prescribed seizure rescue to implement an invented herbal gap.
Source 4: original human study
pubmed.ncbi.nlm.nih.gov · Source check Sep 10, 2026
Population: 12 healthy adults.
Short-term dosing had no measured CYP effect; repeated use reduced oral midazolam AUC more than IV AUC.
How this applies: Specific regimen in healthy adults; no single effect size for all products or routes.
Specific regimen in healthy adults; no single effect size for all products or routes.
Source 5: original human study
pubmed.ncbi.nlm.nih.gov · Source check Sep 10, 2026
Population: 20 healthy men.
Small AUC decrease considered not clinically relevant by authors; no significant Cmax or half-life change.
How this applies: One low-hyperforin preparation does not guarantee safety of unknown products.
One low-hyperforin preparation does not guarantee safety of unknown products.
Source 6: original human study
pubmed.ncbi.nlm.nih.gov · Source check Sep 10, 2026
Population: 12 healthy men.
Induction progressively resolved; oral clearance returned to baseline by7days in this study.
How this applies: Abstract only after fullXML404; not a universally validated washout schedule or dose instruction.
Abstract only after fullXML404; not a universally validated washout schedule or dose instruction.
Research assessment: · Open full citations ↗
Timing & monitoring
Direct human repeated-use evidence supports reduced exposure and conditional loss of effect; short-term/low-hyperforin signals and route differences retained. No universal interval or proof of reduced intestinal uptake.
- Exact scope
- Hypericum perforatum products; hyperforin content and repeated versus short-term use matter. with Midazolam6960 IN; oral hydrochloride syrup, IV/IM hydrochloride and intranasal midazolam distinguished.
- Medication form and route
- oral medication; intravenous medication; intramuscular medication; intranasal medication; oral supplement
What remains uncertain
- No unmeasured pair incidence, blanket class transfer or arbitrary spacing interval.
Factors that may matter: Preparation; Dose; Other medicines; Organ function.
Read the supporting source summaries
Source 1: current product label
dailymed.nlm.nih.gov · Source check Sep 10, 2026
Population: People prescribed midazolam
CYP3A metabolism, CNS-depressant and respiratory risks; not intended for chronic home sedation.
How this applies: Exact midazolam RxCUI 6960 IN, with stated salt/formulation/route bridge.
Adult oral probe trials not automatic pediatric dosing or nasal/injection interaction magnitude.
Source 2: current product label
dailymed.nlm.nih.gov · Source check Sep 10, 2026
Population: People prescribed midazolam
Sedation/respiratory and CYP3A interaction precautions.
How this applies: Exact midazolam RxCUI 6960 IN, with stated salt/formulation/route bridge.
Bypasses intestinal absorption; oral exposure findings cannot be assigned unchanged.
Source 3: current product label
dailymed.nlm.nih.gov · Source check Sep 10, 2026
Population: People prescribed midazolam
CNS-depressant and CYP3A interaction precautions; formulation-specific rescue instructions.
How this applies: Exact midazolam RxCUI 6960 IN, with stated salt/formulation/route bridge.
Not oral procedural dosing; do not delay prescribed seizure rescue to implement an invented herbal gap.
Source 4: original human study
pubmed.ncbi.nlm.nih.gov · Source check Sep 10, 2026
Population: 12 healthy adults.
Short-term dosing had no measured CYP effect; repeated use reduced oral midazolam AUC more than IV AUC.
How this applies: Specific regimen in healthy adults; no single effect size for all products or routes.
Specific regimen in healthy adults; no single effect size for all products or routes.
Source 5: original human study
pubmed.ncbi.nlm.nih.gov · Source check Sep 10, 2026
Population: 20 healthy men.
Small AUC decrease considered not clinically relevant by authors; no significant Cmax or half-life change.
How this applies: One low-hyperforin preparation does not guarantee safety of unknown products.
One low-hyperforin preparation does not guarantee safety of unknown products.
Source 6: original human study
pubmed.ncbi.nlm.nih.gov · Source check Sep 10, 2026
Population: 12 healthy men.
Induction progressively resolved; oral clearance returned to baseline by7days in this study.
How this applies: Abstract only after fullXML404; not a universally validated washout schedule or dose instruction.
Abstract only after fullXML404; not a universally validated washout schedule or dose instruction.
Research assessment: · Open full citations ↗
Review and change history
- Publication status
- Published research summary
- Clinical review
- Not yet recorded
| Date | Update |
|---|---|
| Research summary published | |
| Article prepared | |
| Prepared exact midazolam article with formulation-specific evidence and uncertainty. |
Article revision: 7a4d1668f4c6241f
This guide brings together the evidence records used by our interaction checker. Each finding retains its own preparation limits, research date, and source summaries.
Full citations require verification. Reading this answer and the source summaries does not.
Taking other supplements or medications?
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Open the interaction checkerInformation, not medical advice. Do not change prescribed treatment based on this guide.