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Interaction of cannabidiol with other antiseizure medications: A narrative review

Open ArchivePublished:October 03, 2020DOI:https://doi.org/10.1016/j.seizure.2020.09.010

      Highlights

      • Pharmacokinetic and pharmacodynamic interactions occur with multiple ASMs.
      • Pharmacokinetic interactions are frequently attributed to CYP2C19 and CYP3A4.
      • Known interactions may not alter the ASM level outside the therapeutic range.
      • There is limited evidence currently for many ASMs.
      • There is limited evidence for the clinical relevance of many interactions.

      Abstract

      Objective

      Cannabidiol is efficacious as an adjunctive treatment in children with epilepsy associated with Dravet and Lennox-Gastaut syndromes. As its role is currently adjunctive, we reviewed the interactions of cannabidiol with other antiseizure medications (ASMs).

      Methods

      A search of Cochrane, Pubmed and Embase databases from January 2015 to April 2020 was performed. All original research papers discussing interactions between cannabidiol and ASMs were included. Bibliographies of review articles were searched to identify further papers. Adverse events and side effects were excluded.

      Results

      Cannabidiol interacts with ASMs through both pharmacokinetic and pharmacodynamic mechanisms. Thirty studies were identified (eighteen observational cohort studies, two randomised-control trials, three case reports/series, three animal studies, two briefing reports, an analysis of cohort data and a clinical trial simulation). There is potential for pharmacokinetic interactions between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam. An animal study identified that the brain concentration of ASMs may be altered while the serum concentration remains the same.

      Conclusion

      Pharmacokinetic and pharmacodynamic interactions exist between cannabidiol and ASMs. The cytochrome p450 system in particular has been implicated in pharmacokinetic interactions, although not exclusively. The existing literature is limited for some ASMs by studies having relatively small cohorts. As increasing numbers of patients use cannabidiol, specialists need to monitor closely for interactions clinically and with blood levels when required.

      Abbreviations:

      ASM (antiseizure medication), AUCtau (area under plasma concentration-time curve over dosing interval), CBD (cannabidiol), CLB (clobazam), Cmax (maximum plasma drug concentration), EMA (European Medicines Agency), FDA (Food and Drug Administration), GABA (γ-aminobutyric acid), LEV (levetiracetam), MDZ (midazolam), NICE (The National Institute for Health and Care Excellence), N-CLB (N-desmethylclobazam), OCS (observational cohort study), PD (pharmacodynamic), PK (pharmacokinetic), POCS (prospective observational cohort study), ROCS (retrospective observational cohort study), SRSE (super-refractory status epilepticus), STP (stiripentol), VPA (valproate)

      Keywords

      1. Introduction

      Cannabidiol (CBD), a non-psychoactive cannabinoid, is efficacious as an adjunctive treatment in children with epilepsy associated with Dravet (DS) and Lennox-Gastaut syndromes (LGS) [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ,
      • Devinsky O.
      • et al.
      Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome.
      ,
      • Devinsky O.
      • et al.
      Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome.
      ,
      • Thiele E.A.
      • et al.
      Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.
      ,
      • Rosenberg E.C.
      • Patra P.H.
      • Whalley B.J.
      Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.
      ,
      • Chen K.-A.
      • et al.
      Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.
      ]. Thus, the FDA [
      Drug approval package: epidiolex (Cannabidiol).
      ], EMA [
      Epidyolex.
      ] and NICE [

      ‘Overview | Cannabidiol with clobazam for treating seizures associated with Lennox–Gastaut syndrome | Guidance | NICE’. https://www.nice.org.uk/guidance/ta615 (Accessed 07 January 2020).

      ,

      ‘Overview | Cannabidiol with clobazam for treating seizures associated with Dravet syndrome | Guidance | NICE’. https://www.nice.org.uk/guidance/ta614 (Accessed 07 January 2020).

      ] have licensed highly purified CBD (Epidyolex® or Epidiolex®), with the EMA and NICE specifying this as an option for adjuvant therapy with clobazam in the treatment of DS/LGS. Interactions may influence the efficacy or concentration of medications at their sites of action as well as contribute to side effects and adverse events. With the role of CBD primarily adjuvant, it is important to determine interactions with other antiseizure medications (ASMs).
      Interactions may be either pharmacokinetic or pharmacodynamic in nature. Pharmacokinetics describes how the concentration of the drug changes with time, which may be influenced through effects on drug absorption, distribution, metabolism (e.g. through the cytochrome P450 system) or excretion [
      • Rang H.P.
      • Ritter J.M.
      • Flower R.J.
      • Henderson G.
      Rang & Dale’s pharmacology.
      ]. Pharmacodynamics describes the effects of the drug after binding to its receptor, so may describe interactions at the receptor level, via the signalling pathway, or on the effect of the drug [
      • Rang H.P.
      • Ritter J.M.
      • Flower R.J.
      • Henderson G.
      Rang & Dale’s pharmacology.
      ]. Pharmacodynamics is therefore a more subjective term: two drugs acting in entirely different pathways yet sharing an outcome may be termed ‘pharmacodynamic’, for example non-steroidal anti-inflammatories and corticosteroids in reducing inflammation.
      This literature review is the first to investigate the pharmacokinetic and pharmacodynamic interactions of cannabidiol with other ASMs. We aim to inform clinicians and identify areas where further research is required. We report key findings for some specific ASMs and highlight shortfalls in the literature at present.

      2. Methods

      A search of Cochrane, Pubmed and Embase was performed for dates of publication from 1st January 2015 to 30th April 2020. The search term combined “cannab*” with “epil*” or “seiz*” alongside the terms “absorption”, “distribution”, "protein binding", "tissue binding", “metabolism”, “excretion” and “interaction*”. All search results were reviewed. For inclusion in this review, search results were required to directly discuss interactions between cannabidiol and other antiseizure medications. This included pharmaceutical / pharmacokinetic interactions, absorption, distribution (protein binding, tissue binding), metabolism (hepatic, nonhepatic), excretion (renal, nonrenal) or pharmacodynamic interactions (direct, indirect). Only original research papers in the English language were selected, including studies involving humans (adult and paediatric populations), animals or laboratory studies. Review bibliographies were searched to identify any further papers. Other cannabinoids under development, not currently of therapeutic use in epilepsy, were not classed as ASM. An adverse event or side effect was not classed as an interaction in this search, as these are not necessarily pharmacokinetic or pharmacodynamic in nature. This search disclosed 354 results on Embase, 312 results on Pubmed and 30 trials in total on Cochrane; 30 of these met selection criteria for this study. Selected results were analysed, with key results and commentary recorded in Table 2 in the Supplementary material. This was re-tabulated for interactions with each ASM in turn in Table 1.
      Table 1Antiseizure medication interactions with cannabidiol.
      Antiseizure medicationHighest evidence (nature of interaction)Effect of CBD on ASM pharmacokineticsEffect of ASM on CBD pharmacokineticsPharmacodynamic interactionTherapeutic effect of interactionMechanism
      ASMs with either unanimous or conflicting evidence for interaction
      BrivaracetamPOCS (PK)↑ [brivacetam] with CBD (POCS with 4 pts, CBD ≤ 20 mg/kg/d [
      • Klotz K.A.
      • Grob D.
      • Hirsch M.
      • Metternich B.
      • Schulze-Bonhage A.
      • Jacobs J.
      Efficacy and tolerance of synthetic cannabidiol for treatment of drug resistant epilepsy.
      ]; case series of 5 pts [
      • Klotz K.A.
      • Hirsch M.
      • Heers M.
      • Schulze-Bonhage A.
      • Jacobs J.
      Effects of cannabidiol on brivaracetam plasma levels.
      ]).
      No studies investigating [CBD] with brivaracetam.N/AChange in [brivacetam] may be outside therapeutic range [
      • Klotz K.A.
      • Grob D.
      • Hirsch M.
      • Metternich B.
      • Schulze-Bonhage A.
      • Jacobs J.
      Efficacy and tolerance of synthetic cannabidiol for treatment of drug resistant epilepsy.
      ,
      • Klotz K.A.
      • Hirsch M.
      • Heers M.
      • Schulze-Bonhage A.
      • Jacobs J.
      Effects of cannabidiol on brivaracetam plasma levels.
      ].
      Partly through CBD inhibiting CYP2C19 which metabolises brivaracetam [
      • Klotz K.A.
      • Hirsch M.
      • Heers M.
      • Schulze-Bonhage A.
      • Jacobs J.
      Effects of cannabidiol on brivaracetam plasma levels.
      ].
      Clobazam (CLB)RCT (PK)

      Preclinical (PD)
      ↑ [N-CLB] with CBD in OCSs [
      • Geffrey A.L.
      • Pollack S.F.
      • Bruno P.L.
      • Thiele E.A.
      Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.
      ,
      • Gaston T.
      • Bebin E.
      • Szaflarski J.
      Importance of monitoring clobazam and N-desmethylclobazam levels in treatment with cannabidiol (CBD) for epilepsy.
      ,
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ,
      • Sommerville K.
      • Crockett J.
      • Blakey G.
      • Morrison G.
      Bidirectional drug-drug interaction with coadministration of cannabidiol and clobazam in a phase 1 healthy volunteer trial.
      ,
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ,
      • Wheless J.W.
      • et al.
      Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy.
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ,
      • Savage T.E.
      • et al.
      Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.
      ,
      • Klotz K.A.
      • Grob D.
      • Hirsch M.
      • Metternich B.
      • Schulze-Bonhage A.
      • Jacobs J.
      Efficacy and tolerance of synthetic cannabidiol for treatment of drug resistant epilepsy.
      ] and a RCT [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ,
      • Patel A.
      • et al.
      A dose ranging safety and pharmacokinetic study of cannabidol (CBD) in children with Dravet syndrome (GWPCARE1) (P4.108).
      ,
      • Wright S.
      • et al.
      Cannabidiol (CBD) in Dravet syndrome: a randomised, dose-ranging pharmacokinetics and safety trial (GWPCARE1).
      ]. This rise was variable and most commonly significant.

      [CLB] may ↓ [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ], not be affected in a statistically significant manner [
      • Geffrey A.L.
      • Pollack S.F.
      • Bruno P.L.
      • Thiele E.A.
      Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.
      ,
      • Gaston T.
      • Bebin E.
      • Szaflarski J.
      Importance of monitoring clobazam and N-desmethylclobazam levels in treatment with cannabidiol (CBD) for epilepsy.
      ,
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ,
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ], or ↑ [
      • Sands T.T.
      • Rahdari S.
      • Oldham M.S.
      • Caminha Nunes E.
      • Tilton N.
      • Cilio M.R.
      Long-term safety, tolerability, and efficacy of cannabidiol in children with refractory epilepsy: results from an expanded access program in the US.
      ,
      • Wheless J.W.
      • et al.
      Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy.
      ].

      The SEs of somnolence, sedation and lethargy observed when CLB and CBD are co-prescribed [
      Drug approval package: epidiolex (Cannabidiol).
      ] have been associated with ↑ mean [N-CLB] [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]. This was only significant in the adult arm of this study [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ].
      ↑ [7-OH-CBD] (active metabolite) with CLB [
      • Sommerville K.
      • Crockett J.
      • Blakey G.
      • Morrison G.
      Bidirectional drug-drug interaction with coadministration of cannabidiol and clobazam in a phase 1 healthy volunteer trial.
      ,
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ,
      • Wheless J.W.
      • et al.
      Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy.
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ].

      ↑ [CBD] with CLB reported [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ,
      • Wheless J.W.
      • et al.
      Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy.
      ], yet disputed [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ].
      PD interaction via GABAA receptors in preclinical study [
      • Anderson L.L.
      • et al.
      Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.
      ].
      Disputed if CLB contributes to efficacy of CBD: recent studies argue CBD efficacy independent of CLB [
      • Gaston T.E.
      • et al.
      Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.
      ,
      • Savage T.E.
      • et al.
      Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.
      ] (see main text).

      Potentially more pts with worsening of seizures on CBD alone than CBD + CLB [
      Drug approval package: epidiolex (Cannabidiol).
      ,
      • Rogawski M.A.
      Reduced efficacy and risk of seizure aggravation when cannabidiol is used without clobazam.
      ].
      PK: CBD inhibiting CYP2C19, which in turn metabolises N-CLB to inactive metabolites [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]. Mechanism for rise in 7-OH-CBD not determined, yet may result from CLB inhibition of UGTs or CYP enzymes [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ].

      PD: GABAA
      EslicarbazepinePOCS (PK)↑ [eslicarbazepine] with CBD [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ] (4 pts, p = 0.04, CBD dose ≤50 mg/kg/d, mean change within therapeutic range [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]; 1 pt, MCT-oil-based solution CBD [
      • Klotz K.A.
      • Grob D.
      • Hirsch M.
      • Metternich B.
      • Schulze-Bonhage A.
      • Jacobs J.
      Efficacy and tolerance of synthetic cannabidiol for treatment of drug resistant epilepsy.
      ])
      No studies investigating [CBD] with eslicarbazepine.N/AMean ↑ [eslicarbazepine] within therapeutic range [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ].

      PK interaction may not have therapeutic effect - no difference between pts on any of rufinamide, eslicarbazepine, zonisamide or topiramate (+ CBD) with pts receiving none [
      • Gaston T.E.
      • et al.
      Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.
      ].
      Uncertain – may involve excipient sesamin [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ], yet this questioned by similar result when different formulation used [
      • Klotz K.A.
      • Grob D.
      • Hirsch M.
      • Metternich B.
      • Schulze-Bonhage A.
      • Jacobs J.
      Efficacy and tolerance of synthetic cannabidiol for treatment of drug resistant epilepsy.
      ].
      GabapentinPreclinical (PK)Mouse study: ↑ [gabapentin]serum & brain with CBD.Mouse study: ↔ [gabapentin] with CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: CBD ↑ activity of gabapentin (may however be at least in part a result of PK interactions) [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: CBD ↑ activity of gabapentin [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Uncertain- may be attributed to brain penetration or kidney elimination (gabapentin not bound by plasma proteins or metabolised by CYPs, & is excreted as unchanged drug) [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ]
      LacosamideConflicting POCS with preclinical (PK for CBD on lacosamide).

      Preclinical (PK for lacosamide on CBD).
      POCS: ↔[lacosamide] with CBD (20pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).

      Mouse study: ↑[lacosamide]brain with CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: ↑ [CBD]brain with lacosamide [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: no effect of CBD on lacosamide activity.Mouse study: no effect of CBD on lacosamide activity.May be ↑ penetration of blood brain barrier by CBD & lacosamide [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ]. Lacosamide inhibits CYP2C19, CYP3A4 & CYP2C9 [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      LevetiracetamPreclinical (PD)

      RCT (no PK)
      ↔ [LEV] with CBD (POCS 20 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]; RCT CBD ≤ 20 mg/kg/d [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ]).
      Mouse study: ↔ [CBD] with LEV [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: ↓ activity of LEV with CBD (PD) – concerning [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      UnknownPD: uncertain [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      OxcarbazepineConflicting POCS with RCT (PK for CBD on oxcarbazepine).

      Preclinical (PK for CBD on oxcarbazepine)
      POCS: ↔ [oxcarbazepine] with CBD (12pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ])

      Mouse study: ↑ [oxcarbazepine]serum with CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: ↑ [CBD]brain with oxcarbazepine [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ]
      Mouse study: CBD ↑ activity of oxcarbazepine (may however be at least in part a result of PK interactions) [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: CBD ↑ activity of oxcarbazepine [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      CBD inhibits UDP-glucuronyl transferase which conjugate active metabolite of oxcarbazepine. Oxcarbazepine may ↑ brain uptake of CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ]
      PhenobarbitalConflicting POCS (PK for CBD on phenobarbital)POCS: ↔ [phenobarbital] with CBD (5pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).

      POCS: ↑ [phenobarbital] with CBD (↑[phenobarbital] from 43 to 55 mg/L in 1 pt, CBD ≤25 mg/kg/d [
      • Sands T.T.
      • Rahdari S.
      • Oldham M.S.
      • Caminha Nunes E.
      • Tilton N.
      • Cilio M.R.
      Long-term safety, tolerability, and efficacy of cannabidiol in children with refractory epilepsy: results from an expanded access program in the US.
      ])
      No studies investigating [CBD] with phenobarbital.Mouse study: anticonvulsant effect of CBD not affected by phenobarbital [
      • Jones N.
      • Hill T.
      • Scott C.
      • Stephens G.
      • Williams C.
      • Whalley B.
      Assessment of the anti-convulsant effects of cannabidiol when co-administered with anti-epileptic drugs in acute models of seizure and their individual tolerability profiles.
      ].
      Mouse study: anticonvulsant effect of CBD not affected by phenobarbital [
      • Jones N.
      • Hill T.
      • Scott C.
      • Stephens G.
      • Williams C.
      • Whalley B.
      Assessment of the anti-convulsant effects of cannabidiol when co-administered with anti-epileptic drugs in acute models of seizure and their individual tolerability profiles.
      ].
      Phenobarbital is a CYP2C8/9 substrate which CBD inhibits [
      • Brown J.D.
      • Winterstein A.G.
      Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use.
      ]. Phenobarbital induces both CYP3A4 & CYP2C19 & so theoretically may ↓[CBD] [
      • Brown J.D.
      • Winterstein A.G.
      Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use.
      ]
      Potassium bromidePOCS (PK)↑ [KBr] with CBD (1 pt, CBD ≤25 mg/kg/d [
      • Sands T.T.
      • Rahdari S.
      • Oldham M.S.
      • Caminha Nunes E.
      • Tilton N.
      • Cilio M.R.
      Long-term safety, tolerability, and efficacy of cannabidiol in children with refractory epilepsy: results from an expanded access program in the US.
      ]).
      No studies investigating [CBD] with potassium bromide.N/AIn 1 pt recorded, rise in [KBr] was 21 %.Uncertain [
      • Sands T.T.
      • Rahdari S.
      • Oldham M.S.
      • Caminha Nunes E.
      • Tilton N.
      • Cilio M.R.
      Long-term safety, tolerability, and efficacy of cannabidiol in children with refractory epilepsy: results from an expanded access program in the US.
      ].
      PregabalinPreclinical (PK)↔ [pregabalin] with CBD (2pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).

      Mouse study: ↔ [pregabalin] with CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: ↑ [CBD]brain with pregabalin [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: CBD ↑ activity of pregabalin (may however be at least in part a result of PK interactions) [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: CBD ↑ activity of pregabalin [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Uncertain – pregabalin may ↑ brain uptake of CBD similar to oxcarbazepine [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      RufinamidePOCS (PK)↑ [rufinamide] with CBD (14 pts, p < 0.01, CBD ≤ 50 mg/kg/d, mean change within therapeutic range [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).
      No studies investigating [CBD] with rufinamide.N/AMean ↑ [rufinamide] within therapeutic range [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ].

      PK interaction may not have therapeutic effect - no difference between pts on any of rufinamide, eslicarbazepine, zonisamide or topiramate (+ CBD) with pts receiving none [
      • Gaston T.E.
      • et al.
      Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.
      ].
      Uncertain – may involve excipient sesamin [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ].
      Sirolimus/ everolimusROCS (PK)↑ [rapamycin inhibitors] with CBD (25 pts, p = 0.0003, CBD 5-20 mg/kg/d [
      • Ebrahimi-Fakhari D.
      • Agricola K.D.
      • Tudor C.
      • Krueger D.
      • Franz D.N.
      Cannabidiol elevates mechanistic target of rapamycin inhibitor levels in patients with tuberous sclerosis complex.
      ]; 1 pt CBD ≤ 20.4 g/kg/day [
      • Wiemer-Kruel A.
      • Stiller B.
      • Bast T.
      Cannabidiol interacts significantly with everolimus-report of a patient with tuberous sclerosis complex.
      ]).
      No studies investigating [CBD] with sirolimus/everolimus.N/AIncrease was statistically significant (p = 0.0003) & in some patients the trough level of mTOR inhibitor doubled or tripled with CBD [
      • Ebrahimi-Fakhari D.
      • Agricola K.D.
      • Tudor C.
      • Krueger D.
      • Franz D.N.
      Cannabidiol elevates mechanistic target of rapamycin inhibitor levels in patients with tuberous sclerosis complex.
      ]. Dramatic ↑[everolimus] in case report [
      • Wiemer-Kruel A.
      • Stiller B.
      • Bast T.
      Cannabidiol interacts significantly with everolimus-report of a patient with tuberous sclerosis complex.
      ].
      CBD may inhibit CYP3A4, which metabolises everolimus [
      • Ebrahimi-Fakhari D.
      • Agricola K.D.
      • Tudor C.
      • Krueger D.
      • Franz D.N.
      Cannabidiol elevates mechanistic target of rapamycin inhibitor levels in patients with tuberous sclerosis complex.
      ]
      Stiripentol (STP)RCT (PK)↑[STP] with CBD (unknown cohort, CBD ≈20 mg/kg/d [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ]; 12 pts, CBD ≤ 20 mg/kg/d [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ])

      or ↔ [STP] with CBD (unknown cohort, CBD ≤ 20 mg/kg/d [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ]) (RCT).

      STP blocked ↑[N-CLB] when CBD + CLB [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ].

      If CBD and clobazam have any synergistic activity, which is disputed, this interaction with STP may be of particular relevance.
      STP  may ↓ [7‐OH‐CBD] and ↓[7‐COOH‐CBD] (12 pts, CBD ≤ 20 mg/kg [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ]), although this is disputed (unknown cohort, CBD ≈20 mg/kg/d [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ]).
      N/AAuthors concluded direct interaction between STP & CBD unlikely to be clinically relevant [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ]. STP effect on [CBD] not powered for statistical significance [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ]. If CBD and CLB have therapeutic synergy, STP may theoretically influence this.
      ↑[STP] may result from CBD inhibition of CYP2C19 [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ]. STP is metabolised by CYP2C19. CYP3A4 & CYP1A2 and inhibits both CYP3A4 and 2C19 [

      ‘Stiripentol’. https://www.drugbank.ca/drugs/DB09118 (Accessed 16 July 2020).

      ]

      Prevention of ↑[N-CLB] may result from maximal inhibition of CYP2C19 by STP prior to CBD administration [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ].

      Mechanism for ↓[CBD metabolites] unknown [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ].
      TiagabinePreclinical (PK)Mouse study: ↑ [tiagabine]brain with CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: ↔ [CBD] with tiagabine [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: CBD ↑ activity of tiagabine (may however be at least in part a result of PK interactions) [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: CBD ↑ activity of tiagabine [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      CBD may inhibit CYP3A which metabolises tiagabine. Tiagabine is P-glycoprotein substrate which CBD inhibits [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ]
      TopiramateConflicting POCS with RCT (PK for CBD on topiramate).

      Preclinical (PK for topiramate on CBD)
      RCT: ↔ [topiramate] (unknown cohort, CBD ≤ 20 mg/kg/d [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ])

      POCS: ↑ [topiramate] with CBD (20pts, CBD ≤ 50 mg/kg/d, mean change within therapeutic range [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ])

      Mouse study: ↑ [topiramate]serum with CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].

      The higher pt cohort in POCS vs RCT (& so potentially greater power), or the higher CBD dose used may explain their discrepancy.
      Mouse study: ↑ [CBD]serum & brain with topiramate [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: CBD ↑ activity of topiramate (may however be at least in part a result of PK interactions) [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Human and mouse study conflict.

      Mouse study: CBD ↑ activity of topiramate [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].

      POCS: no difference between pts on any of rufinamide, eslicarbazepine, zonisamide or topiramate (+ CBD) with pts receiving none [
      • Gaston T.E.
      • et al.
      Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.
      ]
      Topiramate inhibits CYP2C19 [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ] yet induces CYP3A4 [
      • Brown J.D.
      • Winterstein A.G.
      Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use.
      ]. Topiramate is P-glycoprotein substrate, which CBD inhibits.
      ValproatePreclinical/ briefing (PD)

      RCT (no PK for CBD on [VPA])

      POCS (PK for VPA on [7-COOH-CBD])
      ↔ [VPA] with CBD (22 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]). Repeated by 2 RCTs [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ,
      • Ben-Menachem E.
      • et al.
      A phase 2 trial to explore the potential for a pharmacokinetic drug‐drug interaction with valproate when in combination with cannabidiol in adult epilepsy patients.
      ,
      • Tayo B.
      • et al.
      Exploration of the potential for plasma protein binding displacement and drug-drug interactions of valproate in combination with cannabidiol.
      ] and 2 POCSs [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ].

      Plasma Cmax & AUCtau of VPA & metabolite 2-propyl-4-pentenoic acid ↓ with CBD in one of these RCTs [
      • Ben-Menachem E.
      • et al.
      A phase 2 trial to explore the potential for a pharmacokinetic drug‐drug interaction with valproate when in combination with cannabidiol in adult epilepsy patients.
      ,
      • Tayo B.
      • et al.
      Exploration of the potential for plasma protein binding displacement and drug-drug interactions of valproate in combination with cannabidiol.
      ], yet ratio point estimates were similar to placebo.

      Neither CBD or 7-COOH-CBD affected plasma protein binding (PPB) of VPA [
      • Ben-Menachem E.
      • et al.
      A phase 2 trial to explore the potential for a pharmacokinetic drug‐drug interaction with valproate when in combination with cannabidiol in adult epilepsy patients.
      ,
      • Tayo B.
      • et al.
      Exploration of the potential for plasma protein binding displacement and drug-drug interactions of valproate in combination with cannabidiol.
      ].
      ↔ [CBD] with VPA (unknown cohort, CBD ≈20 mg/kg/d [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ]; 12 pts, CBD ≤ 20 mg/kg/d [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ]).

      Slight ↑ [7-COOH-CBD] with VPA reported [
      • Cross J.H.
      • Cock H.
      A perspective on cannabinoids for treating epilepsy: do they really change the landscape?.
      ] yet disputed [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ].

      VPA did not affect PPB of CBD or 7-COOH-CBD [
      • Ben-Menachem E.
      • et al.
      A phase 2 trial to explore the potential for a pharmacokinetic drug‐drug interaction with valproate when in combination with cannabidiol in adult epilepsy patients.
      ,
      • Tayo B.
      • et al.
      Exploration of the potential for plasma protein binding displacement and drug-drug interactions of valproate in combination with cannabidiol.
      ].
      ↑ serum transaminases may result from PD interaction at mitochondria [
      FDA briefing document. Peripheral and central nervous system drugs.
      ].

      Rat study noted ↑efficacy when CBD + valproate co-prescribed [
      • Jones N.
      • Hill T.
      • Scott C.
      • Stephens G.
      • Williams C.
      • Whalley B.
      Assessment of the anti-convulsant effects of cannabidiol when co-administered with anti-epileptic drugs in acute models of seizure and their individual tolerability profiles.
      ]. Serum drug conc.s not recorded & published as abstract - cannot determine if represents a therapeutic PD interaction.
      Where identified, authors still believed rise in ↑ [7-COOH-CBD] unlikely to be clinically relevant [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ].

      ↑ serum transaminases must be monitored.
      PD: Unclear – may involve interaction at mitochondria [
      FDA briefing document. Peripheral and central nervous system drugs.
      ].

      PK: valproate is a UGT1A9/2B7 substrate, which CBD inhibits [
      • Brown J.D.
      • Winterstein A.G.
      Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use.
      ].
      ZonisamidePOCS (PK)↑ [zonisamide] with CBD (14 pts, p = 0.02, CBD ≤ 50 mg/kg/d, mean change within therapeutic range [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]). Only in adult arm of study; [zonisamide] positively correlates with age [
      • Miura H.
      Zonisamide monotherapy with once-daily dosing in children with cryptogenic localization-related epilepsies: clinical effects and pharmacokinetic studies.
      ,
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]
      No studies investigating [CBD] with zonisamide.N/AMean ↑ [zonisamide] within therapeutic range [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ].

      PK interaction may not have therapeutic effect - no difference between pts on any of rufinamide, eslicarbazepine, zonisamide or topiramate (+ CBD) with pts receiving none [
      • Gaston T.E.
      • et al.
      Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.
      ].
      CBD may inhibit CYP3A4, which metabolises zonisamide [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ].
      ASMs with no evidence currently for interaction
      CarbamazepinePOCS (no PK)↔ [carbamazepine] with CBD (4 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).
      No studies investigating [CBD] with carbamazepine.N/AN/ATheoretically, as carbamazepine induces both CYP3A4 and CYP2C19, it may  ↓[CBD] [
      • Brown J.D.
      • Winterstein A.G.
      Potential adverse drug events and drug–drug interactions with medical and consumer cannabidiol (CBD) use.
      ]
      ClonazepamPOCS (no PK)↔ [clonazepam] with CBD (25 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).
      No studies investigating [CBD] with clonazepam.N/AN/AClonazepam is structurally different to clobazam (1,4‐benzodiazepine vs 1,5‐benzodiazepine) which may account for differences [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]. Clonazepam metabolites are inactive regardless of any change [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ].
      EthosuximidePOCS (no PK)↔ [ethosuximide] with CBD (5 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).
      No studies investigating [CBD] with ethosuximide.N/AN/AN/A
      EzogabinePOCS (no PK)↔ [ezogabine] with CBD (5 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).
      No studies investigating [CBD] with ezogabine.N/AN/AN/A
      FenfluraminePOCS (no PK)↔ [fenfluramine] with CBD (14 recreational drug users, CBD ≤400 mg BID [CanniMed Oil 20 CBD:1 THC] [
      • Boyd B.
      • Smith S.
      • Farfel G.
      • Morrison G.
      A phase 1, single‐dose, open‐label pharmacokinetic study to investigate the drug‐drug interaction potential of ZX008 (fenfluramine HCL oral solution) and cannabidiol.
      ]), although PKs of fenfluramine affected in a non-statistically significant manner [
      • Boyd B.
      • Smith S.
      • Farfel G.
      • Morrison G.
      A phase 1, single‐dose, open‐label pharmacokinetic study to investigate the drug‐drug interaction potential of ZX008 (fenfluramine HCL oral solution) and cannabidiol.
      ].
      No studies investigating [CBD] with fenfluramine.N/AN/AN/A
      LamotriginePOCS (no PK)↔ [lamotrigine] with CBD (30 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ])

      Mouse study: ↔ [lamotrigine] with CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: ↔ [CBD] with lamotrigine [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      Mouse study: ↔ activity of lamotrigine with CBD.N/AN/A
      MidazolamPOCS (no PK)↔ [midazolam] with CBD (unknown participants, CBD 750 mg B.I.D [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ]).
      No studies investigating [CBD] with midazolam.N/AN/AThe absence of an observed effect by CBD on midazolam has been used to argue that CBD has limited clinical effect on CYP3A4 [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ].
      PerampanelPOCS (no PK)↔ [perampanel] with CBD (8 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).
      No studies investigating [CBD] with perampanel.N/AN/AN/A
      PhenytoinPOCS (no PK)↔ [phenytoin] with CBD (3 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]).
      No studies investigating [CBD] with phenytoin.N/AN/AN/A
      VigabatrinPOCS (no PK)↔ [vigabatrin] with CBD (3 pts, CBD ≤ 50 mg/kg/d [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ])
      No studies investigating [CBD] with vigabatrin.N/AN/AN/A
      [ASM] = concentration of ASM; OCS = observational cohort study; PD = pharmacodynamic; PK = pharmacokinetic; POCS = prospective observational cohort study; Pt = patient; RCT = randomised controlled trial; ROCS = retrospective observational cohort study; SE = side effect; ↔ = no significant change; ↑ = increase; ↓ = decrease.

      3. Results

      Our search revealed thirty studies meeting inclusion criteria. The interactions identified for each antiseizure medication are summarised in Table 1, with critical appraisal of each selected search result included in Table 2 in the Supplementary material. Reports of pharmacokinetic interactions were identified between CBD and brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide (Table 1). Of these pharmacokinetic interactions, clobazam, its active metabolite (N-desmethylclobazam, N-CLB), brivaracetam and sirolimus/everolimus have been found to have their serum concentrations altered beyond the therapeutic range [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ,
      • Klotz K.A.
      • Grob D.
      • Hirsch M.
      • Metternich B.
      • Schulze-Bonhage A.
      • Jacobs J.
      Efficacy and tolerance of synthetic cannabidiol for treatment of drug resistant epilepsy.
      ,
      • Ebrahimi-Fakhari D.
      • Agricola K.D.
      • Tudor C.
      • Krueger D.
      • Franz D.N.
      Cannabidiol elevates mechanistic target of rapamycin inhibitor levels in patients with tuberous sclerosis complex.
      ,
      • Klotz K.A.
      • Hirsch M.
      • Heers M.
      • Schulze-Bonhage A.
      • Jacobs J.
      Effects of cannabidiol on brivaracetam plasma levels.
      ,
      • Wiemer-Kruel A.
      • Stiller B.
      • Bast T.
      Cannabidiol interacts significantly with everolimus-report of a patient with tuberous sclerosis complex.
      ]. Furthermore, Gaston et al., 2019 questioned whether any interactions with rufinamide, eslicarbazepine, zonisamide or topiramate affect treatment response [
      • Gaston T.E.
      • et al.
      Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.
      ]. Pharmacodynamic interactions were identified for clobazam, valproate and levetiracetam.
      There is currently no evidence for interactions between CBD and carbamazepine, clonazepam, ethosuximide, ezogabine, fenfluramine, lamotrigine, midazolam, perampanel, phenytoin or vigabatrin. However, this may be a result of firstly small patient cohorts and secondly a lack of investigation: for all apart from lamotrigine, there are no studies investigating how the concentration of CBD or its metabolites may alter with concomitant ASM.

      4. Discussion

      The complex pharmacology and pharmacokinetics of cannabidiol lends to the possibility of drug interactions. CBD acts through several multifaceted pathways to reduce neuronal excitability. Proposed mechanisms include antagonization at GPR55 receptors, desensitising TRPV1 channels and inhibiting ENT1 adenosine reuptake pumps [
      • Cross J.H.
      • Cock H.
      A perspective on cannabinoids for treating epilepsy: do they really change the landscape?.
      ]. The action of CBD potentially extends to further targets, including the 5-HT1A receptor, other TRP channels and even diverse voltage-dependent sodium and potassium channels [
      • Billakota S.
      • Devinsky O.
      • Marsh E.
      Cannabinoid therapy in epilepsy.
      ]. The pharmacokinetics of CBD are similarly promiscuous. CBD is metabolised by the cytochrome P450 system, specifically by CYP2C19 to its active metabolite 7-hydroxy-cannabidiol (7-OH-CBD) and then by CYP3A4 to its inactive metabolite 7-carboxy-cannabidiol [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ,
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ,
      • Jiang R.
      • Yamaori S.
      • Takeda S.
      • Yamamoto I.
      • Watanabe K.
      Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes.
      ,
      • Zendulka O.
      • Dovrtělová G.
      • Nosková K.
      • Turjap M.
      • Šulcová A.
      • Hanuš L.
      • Juřica J.
      Cannabinoids and cytochrome P450 interactions.
      ]. Other hepatic cytochromes are also capable of metabolising CBD including CYP1A1, CYP1A2, CYP2C9, CYP2D6 and CYP3A5 [
      • Jiang R.
      • Yamaori S.
      • Takeda S.
      • Yamamoto I.
      • Watanabe K.
      Identification of cytochrome P450 enzymes responsible for metabolism of cannabidiol by human liver microsomes.
      ]. Furthermore, CBD inhibits CYP2C19 and CYP3A4 [
      • Billakota S.
      • Devinsky O.
      • Marsh E.
      Cannabinoid therapy in epilepsy.
      ]; these interactions are thought to be important contributors to the pharmacokinetic interactions of CBD [
      • Anderson L.L.
      • et al.
      Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.
      ,
      • Billakota S.
      • Devinsky O.
      • Marsh E.
      Cannabinoid therapy in epilepsy.
      ]. However, the relevance of CYP3A4 interactions clinically has been disputed [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ,
      • Morrison G.
      • Taylor L.
      • Crockett J.
      • Critchley D.
      • Tayo B.
      A phase 1 investigation into the potential effects of cannabidiol on CYP3A4-mediated drug-drug interactions in healthy volunteers meeting abstracts: view.
      ]. Cytochrome P450 enzymes are not the exclusive route for pharmacokinetic interactions with CBD: CBD has also been shown to inhibit drug transport via P-glycoprotein (P-gp) [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ,
      • Zhu H.-J.
      • et al.
      Characterization of P-glycoprotein inhibition by major cannabinoids from Marijuana.
      ], an ATP-dependent efflux transporter expressed at the intestinal epithelium, hepatocytes, placenta, renal tubular cells, and blood-brain barrier [
      • Zhu H.-J.
      • et al.
      Characterization of P-glycoprotein inhibition by major cannabinoids from Marijuana.
      ].
      The strongest evidence basis for an interaction with CBD exists for clobazam (CLB). When the two ASMs are administered in combination, a rise in concentration of the active metabolite of clobazam, N-desmethylclobazam (N-CLB), results [
      • Geffrey A.L.
      • Pollack S.F.
      • Bruno P.L.
      • Thiele E.A.
      Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.
      ,
      • Gaston T.
      • Bebin E.
      • Szaflarski J.
      Importance of monitoring clobazam and N-desmethylclobazam levels in treatment with cannabidiol (CBD) for epilepsy.
      ,
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ,
      • Sommerville K.
      • Crockett J.
      • Blakey G.
      • Morrison G.
      Bidirectional drug-drug interaction with coadministration of cannabidiol and clobazam in a phase 1 healthy volunteer trial.
      ,
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ,
      • Patel A.
      • et al.
      A dose ranging safety and pharmacokinetic study of cannabidol (CBD) in children with Dravet syndrome (GWPCARE1) (P4.108).
      ,
      • Wright S.
      • et al.
      Cannabidiol (CBD) in Dravet syndrome: a randomised, dose-ranging pharmacokinetics and safety trial (GWPCARE1).
      ,
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ,
      • Wheless J.W.
      • et al.
      Pharmacokinetics and tolerability of multiple doses of pharmaceutical-grade synthetic cannabidiol in pediatric patients with treatment-resistant epilepsy.
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ,
      • Savage T.E.
      • et al.
      Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.
      ,
      • Klotz K.A.
      • Grob D.
      • Hirsch M.
      • Metternich B.
      • Schulze-Bonhage A.
      • Jacobs J.
      Efficacy and tolerance of synthetic cannabidiol for treatment of drug resistant epilepsy.
      ]. This is thought to result from a pharmacokinetic interaction through the cytochrome P450 system: CYP3A4 metabolises CLB to N-CLB which in turn is metabolised to inactive metabolites by CYP2C19 [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ,
      • Giraud C.
      • Tran A.
      • Rey E.
      • Vincent J.
      • Tréluyer J.-M.
      • Pons G.
      In vitro characterization of clobazam metabolism by recombinant cytochrome P450 enzymes: importance of CYP2C19.
      ], and CBD inhibits CYP2C19 [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ,
      • Anderson L.L.
      • et al.
      Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.
      ]. The inhibition of CYP2C19 by CBD is regarded as the basis of the rise in N-CLB concentration [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]. Co-prescription of CLB and CBD has been shown to increase the frequency of side effects experienced by patients, specifically somnolence, sedation and lethargy [
      Drug approval package: epidiolex (Cannabidiol).
      ]; the adult arm of Gaston et al., 2017 found an association between the mean level of N-CLB and total frequency of sedation [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]. However this association was not significant in the paediatric cohort, nor across the overall study population [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ], limiting interpretation of the relevance of this pharmacokinetic interaction to drug side effects.
      The role of the increased concentration of N-CLB in the efficacy of CBD has been much debated. Early prospective observational cohort studies identified a higher treatment response to CBD in patients receiving clobazam [
      • Devinsky O.
      • et al.
      Efficacy and safety of Epidiolex (cannabidiol) in children and young adults with treatment-resistant epilepsy: update from the expanded access program.
      ,
      • Devinsky O.
      • et al.
      Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.
      ,
      • Hess E.J.
      • et al.
      Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.
      ], and a recent clinical trial simulation concluded that the reduction of median drop seizure frequency observed in the CBD trial GWPCARE3 may be explained by a rise in N-CLB concentration [
      • Bergmann K.R.
      • Broekhuizen K.
      • Groeneveld G.J.
      Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop-seizure frequency.
      ]. However, there is significant evidence to the contrary. An abstract pooling data from the GWPCARE3 and 4 trials by Thiele et al., 2017 noted responses to CBD were independent of whether patients were co-prescribed clobazam [
      • Thiele E.A.
      • Devinsky O.
      • Checketts D.
      • Knappertz V.
      Cannabidiol (CBD) treatment resporders analysis in patients with Lennox-Gastaut syndrome (LGS) on and off clobazam (CLB).
      ]. Two recent studies by Savage et al., 2019 and Gaston et al., 2019 have further investigated this question [
      • Gaston T.E.
      • et al.
      Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.
      ,
      • Savage T.E.
      • et al.
      Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.
      ]. Savage et al., 2019 retrospectively analysed data from 47 patients, and found that after two months of treatment, at the best point of seizure control, there was no significant difference in the mean reduction in weekly seizure frequencies between patients receiving clobazam and those not [
      • Savage T.E.
      • et al.
      Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.
      ]. They only identified a weak, non-significant correlation between N-CLB concentration and reduction in weekly seizure frequency [
      • Savage T.E.
      • et al.
      Efficacy of cannabidiol in subjects with refractory epilepsy relative to concomitant use of clobazam.
      ]. Gaston et al., 2019 conducted a larger prospective study of 132 participants, and even using a maximum dose of 50 mg/kg/day CBD, there was no significant difference in seizure frequency or severity reduction between those receiving clobazam and those not after 12 weeks [
      • Gaston T.E.
      • et al.
      Drug–drug interactions with cannabidiol (CBD) appear to have no effect on treatment response in an open-label Expanded Access Program.
      ].
      A pharmacodynamic interaction between CBD and clobazam has also been recently proposed to occur through the GABAA receptor, with this demonstrated in a mouse model to enhance efficacy [
      • Anderson L.L.
      • et al.
      Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.
      ]. Interestingly, this study showed that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations; however N-CLB concentrations were not recorded in this particular experiment [
      • Anderson L.L.
      • et al.
      Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.
      ]. The authors conclude that although there may be synergistic action through GABAA, the enhanced anticonvulsant effect of CBD and CLB in combination is likely multimodal, involving distinct mechanisms of action such as CBD acting at GPR55 [
      • Anderson L.L.
      • et al.
      Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.
      ]. What is not often considered is whether clobazam increasing the concentration of 7-OH-CBD may also contribute to efficacy [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ]. It should be noted that there have been concerns raised regarding the safety of CBD administration without concomitant CLB [
      • Rogawski M.A.
      Reduced efficacy and risk of seizure aggravation when cannabidiol is used without clobazam.
      ]: clinical trials have demonstrated a greater proportion of patients experience a worsening of seizure frequency when prescribed CBD without CLB [
      Drug approval package: epidiolex (Cannabidiol).
      ,
      • Rogawski M.A.
      Reduced efficacy and risk of seizure aggravation when cannabidiol is used without clobazam.
      ]. An analysis on the safety of CBD is beyond the scope of this review, however further research into this would be prudent.
      Co-prescription of CBD with valproate is well-known to produce a rise in transaminases [

      ‘Epidiolex (cannabidiol) oral solution: prescribing information’, [Online]. Available: https://www.epidiolex.com/sites/default/files/pdfs/EPIDIOLEX_Full_Prescribing_Information_04_16_2020.pdf.

      ]. This however does not occur through a pharmacokinetic alteration in valproate or CBD concentrations [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ,
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ,
      • Patel A.
      • et al.
      A dose ranging safety and pharmacokinetic study of cannabidol (CBD) in children with Dravet syndrome (GWPCARE1) (P4.108).
      ,
      • Ben-Menachem E.
      • et al.
      A phase 2 trial to explore the potential for a pharmacokinetic drug‐drug interaction with valproate when in combination with cannabidiol in adult epilepsy patients.
      ,
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ]. The FDA proposed that this may result from a pharmacodynamic interaction in mitochondria [
      FDA briefing document. Peripheral and central nervous system drugs.
      ]. A slight increase in concentration of a metabolite of CBD (7-COOH-CBD) has been observed with valproate administration [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ], yet has been disputed [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ]. This is not thought to be of clinical relevance [
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ].
      There is debate as to whether a pharmacokinetic interaction exists between CBD and topiramate. No alterations in serum concentration of topiramate were found in a randomised controlled trial [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ], while they were identified in an open-label trial [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]. A mouse study supports evidence for an interaction [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ] and discussed plausible underlying mechanisms, e.g. through CBD inhibiting P-glycoprotein and so reducing renal or bile excretion of topiramate. Topiramate was in turn shown to elevate serum and brain concentrations of CBD in this study, potentially through inhibition of CYP2C19 [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ].
      The pharmacokinetics of stiripentol may be affected by CBD [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ], although this is disputed [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ]. Whether stiripentol alters the concentration of CBD is similarly debated [
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Critchley D.
      • Morrison G.
      Drug-drug Interaction (DDI) Studies with Coadministration of Cannabidiol (CBD) and Clobazam (CLB), Valproate (VPA), Stiripentol (STP) or Midazolam (MDZ) in Healthy Volunteers (HVTs) and Adults with Epilepsy (S3.003).
      ,
      • Critchley D.
      • Szaflarski J.
      • Patsalos P.
      • Gidal B.
      • VanLandingham K.
      • Morrison G.
      Drug-drug interaction studies with coadministration of cannabidiol (CBD) and clobazam, valproate, stiripentol or midazolam in healthy volunteers and adults with epilepsy.
      ,
      • Morrison G.
      • Crockett J.
      • Blakey G.
      • Sommerville K.
      A phase 1, open-label, pharmacokinetic trial to investigate possible drug-drug interactions between clobazam, stiripentol, or valproate and cannabidiol in healthy subjects.
      ], although this would be likely not be of clinical relevance. A randomised controlled trial demonstrated that stiripentol blocks a rise in N-desmethylclobazam caused by CBD with clobazam [
      • Devinsky O.
      • et al.
      Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.
      ], which may result from stiripentol being both metabolised by and inhibiting CYP2C19 and CYP3A4, the same enzymes CBD interacts with. If, although disputed, the rise in concentration of N-desmethylclobazam contribute to the efficacy of CBD [
      • Bergmann K.R.
      • Broekhuizen K.
      • Groeneveld G.J.
      Clinical trial simulations of the interaction between cannabidiol and clobazam and effect on drop-seizure frequency.
      ,
      • Anderson L.L.
      • et al.
      Coadministered cannabidiol and clobazam: preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.
      ], it may be extrapolated that stiripentol may affect this. Further investigations are required to inform clinical practice.
      Although no pharmacokinetic interactions have been identified with levetiracetam, a mouse study identified that CBD at a dose of 100 mg/kg decreased the antiseizure activity of levetiracetam against 6 Hz-induced psychomotor seizure [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ]. Neither levetiracetam nor CBD were reduced in serum concentration when co-administered, suggesting this to be pharmacodynamic in nature [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ]. Although this interaction is concerning, it must be noted that this dose was significantly higher than what is clinically prescribed at present. This pharmacodynamic interaction has not been investigated in human studies either. This same mouse study identified increases in the activity of multiple ASMs (topiramate, oxcarbazepine, pregabalin, tiagabine, and gabapentin) upon the addition of CBD [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ], however none of these could be classified as purely pharmacodynamic interactions, as pharmacokinetic alterations were simultaneously detected. Regardless, this is an example of the term pharmacodynamic indicating a therapeutic benefit of two medications used in combination, and so may not in fact indicate interactions at either receptors or signalling pathways.
      Analysis of the literature revealed a paucity of studies investigating the effect of ASMs on the pharmacokinetics of CBD. Furthermore, the evidence base for some ASM interactions was remarkably small, e.g. for eslicarbazepine the total patient cohort was only five [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]. Comparison between studies is complicated by varied trial durations: a time delay may be required for interactions based on altered enzyme expression to occur. There appears no consensus on how long patients ought to be investigated for all interactions to manifest.
      A further difficulty for investigating interactions is that an excipient in the formulation of Epidyolex® may interact with ASMs, with Gaston et al., 2017 reporting that sesamin may influence interactions for rufinamide [
      • Gaston T.E.
      • Bebin E.M.
      • Cutter G.R.
      • Liu Y.
      • Szaflarski J.P.
      • UAB CBD Program
      Interactions between cannabidiol and commonly used antiepileptic drugs.
      ]. Additionally, human trials may be unable to detect all pharmacokinetic interactions; an animal study demonstrated elevations in the brain concentration of tiagabine while its serum concentrations remained unaltered [
      • Socała K.
      • Wyska E.
      • Szafarz M.
      • Nieoczym D.
      • Wlaź P.
      Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies.
      ]. There may therefore be pharmacokinetic interactions altering brain ASM concentrations in patients, which cannot be readily detected. Although animal studies provide the opportunity to detect such interactions, there is difficulty in comparing mouse and human studies directly due to differences in the cytochrome P450 systems. Our analysis also revealed multiple conflicts of interest in this field, although the extent of this varied. This is partly expected for studies discussing a drug under development, yet must be kept in consideration when analysing the literature.

      5. Conclusions

      Cannabidiol (CBD) interacts both pharmacokinetically and pharmacodynamically with multiple antiseizure medications, most notably with clobazam. Pharmacodynamic interactions have been detected between CBD and clobazam, valproate and levetiracetam, and there are reports of pharmacokinetic interactions for brivaracetam, clobazam, eslicarbazepine, lacosamide, gabapentin, oxcarbazepine, phenobarbital, potassium bromide, pregabalin, rufinamide, sirolimus/everolimus, stiripentol, tiagabine, topiramate and zonisamide. These interactions do not all affect therapeutic action. For many of these ASMs further larger studies are required to determine how these interactions influence clinical practice. Additional interactions may be present with other ASMs where the current evidence base for no interaction is small; this is particularly the case regarding whether ASMs affect the pharmacokinetics of CBD. As the evidence is currently limited for a number of ASMs, clinicians should carefully monitor both clinical and laboratory parameters when introducing or changing CBD dosage, whichever ASM the patient is receiving.

      Declaration of Competing Interest

      The authors report no declarations of interest.

      Appendix A. Supplementary data

      The following is Supplementary data to this article:

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