CBD and benzodiazepines: the clobazam trial and what it means for Xanax and Klonopin
Bottom line. Benzodiazepines are primarily CYP3A4-metabolized. CBD inhibits CYP3A4. The most direct clinical evidence comes from Geffrey 2015, which found that adding CBD to clobazam (Onfi) in pediatric Dravet syndrome patients raised clobazam plasma levels 60% and the active metabolite norclobazam by 500%. Alprazolam (Xanax) and clonazepam (Klonopin) use the same CYP3A4 pathway. Talk to your prescriber before combining.
Key takeaways
- Most benzodiazepines are CYP3A4-metabolized; CBD inhibits CYP3A4.
- Geffrey 2015 documented a 60% rise in clobazam and 500% rise in its active metabolite when CBD was added.
- The interaction means benzodiazepines clear more slowly, raising plasma levels and intensifying sedative effects.
- Clobazam also uses CYP2C19, which CBD inhibits — making this a dual-pathway interaction.
- Do not adjust benzo doses independently. If combining, tell your prescriber and watch for increased sedation.
What the science says
The Geffrey 2015 finding
Geffrey 2015 studied children with Dravet syndrome taking Epidiolex (pharmaceutical-grade CBD) alongside their existing antiepileptic regimen, which included clobazam. After CBD was added:
- Clobazam plasma levels rose by approximately 60%
- Norclobazam (the active metabolite of clobazam) rose by approximately 500%
- Several patients required clobazam dose reductions due to side effects
This is the most directly documented CBD-benzodiazepine interaction in the clinical literature. It was observed at pharmaceutical CBD doses (often 10–25mg/kg/day in pediatric epilepsy — much higher than typical wellness dosing), but the CYP mechanism applies at all doses; the magnitude is dose-dependent.
The broader CYP evidence
Bansal 2023 (n=18 RCT, healthy adults) confirmed that CBD raises CYP3A substrate plasma exposure 56–207% at research-equivalent doses. The same mechanism applies to alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), and lorazepam (Ativan) — all are CYP3A4-dependent.
The dual-pathway complication for clobazam
Clobazam is metabolized by both CYP3A4 (parent drug) and CYP2C19 (norclobazam conversion). CBD inhibits both enzymes. This is why the norclobazam rise (500%) was so pronounced — it accumulated because both its formation and clearance pathways were affected. Other benzodiazepines don't have this specific dual issue, but their CYP3A4 dependence is still the primary concern.
What this means for you
- Tell your prescriber. Whether your benzo is for anxiety, sleep, or muscle spasm, your prescriber needs to know you're considering CBD. The conversation should include which benzo, at what dose, and how frequently you use it.
- Watch for increased sedation. The main clinical sign of elevated benzo plasma levels is more sedation than usual. If you feel unusually drowsy after adding CBD, that's a signal to discuss with your prescriber — not to independently reduce your benzo dose.
- As-needed vs daily benzos differ in risk profile. Daily benzo use with daily CBD creates continuous CYP3A4 inhibition. As-needed (PRN) benzo use means the interaction is episodic — still real, but more manageable.
- Format matters for exposure. Oral CBD produces the highest CYP3A4 inhibition due to first-pass metabolism. Topical CBD (roll-on) has minimal systemic absorption and the lowest interaction risk. Discuss format with your prescriber.
- Don't stop benzos abruptly. Benzodiazepine withdrawal can be dangerous. If you're concerned about the interaction, the answer is a prescriber conversation — not stopping your medication.
Common benzodiazepines and their CYP pathways
| Drug | Brand | Primary CYP | CBD interaction |
|---|---|---|---|
| Alprazolam | Xanax | CYP3A4 | Plausible — same pathway as clobazam parent drug |
| Clonazepam | Klonopin | CYP3A4 | Plausible — same pathway |
| Clobazam | Onfi | CYP3A4 + CYP2C19 | Documented (Geffrey 2015) |
| Diazepam | Valium | CYP2C19 + CYP3A4 | Plausible — dual pathway overlap |
| Lorazepam | Ativan | Glucuronidation (UGT) | Lower CYP risk; CBD inhibits UGT — residual concern |
Lorazepam is glucuronidated rather than CYP-metabolized, making it the benzo with the lowest CBD-interaction risk from a CYP perspective. CBD does inhibit UGT enzymes, so the concern isn't zero, but it's substantially lower than for CYP3A4-dependent benzos.
Frequently asked questions
Can I take CBD if I'm on Xanax or Klonopin?
Talk to your prescriber first. Benzodiazepines are CYP3A4-metabolized, and CBD inhibits CYP3A4. The best clinical evidence (Geffrey 2015) showed CBD raised clobazam levels 60% and active metabolite 500% in epilepsy patients. Alprazolam and clonazepam use similar pathways. Do not adjust your benzo dose without prescriber guidance.
Does CBD have the same sedative effect as benzodiazepines?
No — CBD does not work on GABA-A receptors the way benzodiazepines do. But additive sedation is a real concern: CBD may cause drowsiness at higher doses, and if CBD raises benzo plasma levels, the sedative effect intensifies. The concern is pharmacokinetic (higher benzo blood levels) not a direct receptor synergy.
I only use my benzo occasionally. Is the risk lower?
Somewhat. If you take CBD daily and use a benzo occasionally, the benzo is cleared more slowly than your baseline whenever you take it. The as-needed interaction is more manageable than a daily benzo interaction, but your prescriber should still know.
References
- Geffrey AL et al. (2015). Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. PMID 26296473
- Bansal S et al. (2023). Cannabidiol effects on the pharmacokinetics of substrates of cytochrome P450 enzymes. PMID 37313955
- Nachnani R et al. (2024). Cannabidiol-prescription drug interactions: a systematic review. PMID 38868665