Final analysis of potential drug–drug interactions between highly purified cannabidiol and anti‐seizure medications in an open‐label expanded access program

Abstract

Objective

The aim of this study was to assess potential drug–drug interactions between highly purified cannabidiol (CBD) and anti‐seizure medications (ASMs).

Methods

Our group previously reported that in a sample of adults and children receiving CBD in an open‐label expanded access program, there were several ASMs noted to increase in serum levels with increasing doses of CBD. We analyzed if an increased number of observations over time resulted in changes in potential interactions and if potential interactions were associated with time since enrollment, demographics, or the overall rating of adverse effects.

Results

In 169 participants (80 adults), with increasing weight‐based CBD dose, there were associated increases in serum levels of clobazam and N‐desmethylclobazam, free valproate, felbamate, and topiramate in the adult and pediatric arms combined, levetiracetam in the pediatric arm only, and permapanel in the adult arm only. There were no associations noted in these level changes with time since enrollment, biological sex, and adverse events profile scores.

Significance

This study confirms some previously identified interactions with CBD and identifies other potential pharmacokinetic interactions; however, the clinical significance of these observations is likely minor, and there is no effect of time on these findings.

Key Points.

• In an open‐label study of cannabidiol (CBD) for refractory epilepsy, we investigated changes in serum anti‐seizure medication (ASM) levels with increasing CBD dose in 169 participants.

• Increases in levels of clobazam, N‐desmethylclobazam, free valproate, felbamate, topiramate, perampanel, and levetiracetam with increasing CBD dose.

• Aside from clobazam and N‐desmethylclobazam, level increases on average in other ASMs were within accepted normal therapeutic ranges.

• The changes in serum level had no association with time since enrollment, biological sex, and adverse events.

1. INTRODUCTION

There is ample quality evidence for the use of highly purified plant‐derived cannabidiol (CBD; Epidiolex®, Jazz Pharmaceuticals) in the treatment of seizures in Lennox‐Gastaut Syndrome, ¹ , ² Dravet Syndrome, ³ and tuberous sclerosis complex. ⁴ Open‐label studies have shown similar efficacy in treatment‐resistant epilepsy (TRE). ⁵ , ⁶ Given this product is plant‐based from Cannabis Sativa, there is often the incorrect assumption from the public that there are no safety concerns or drug–drug interactions with this medication. While highly purified CBD has been found to be mostly safe, there are known adverse events and safety considerations that require lab monitoring in the first 6 months of initiating treatment and drug–drug interactions that are largely due to CBD's hepatic metabolism and effect on numerous cytochrome P450 enzymes. ⁷

Many studies have documented a clear interaction between CBD and clobazam, with levels of clobazam's active metabolite N‐desmethylclobazam increasing with increasing CBD dose and resulting in increased sedation. ⁸ We previously published data on a sample of 81 adults and children enrolled in a large open‐label expanded access program investigating the use of highly purified CBD for the treatment of TRE. ⁹ We found that serum levels of rufinamide, topiramate, N‐desmethyclobazam increased with increasing CBD dose in adults and children, and levels of zonisamide and eslicarbazepine increased similarly but in adults only. However, beyond the clobazam interaction, the clinical significance of our findings was uncertain. Further, an additional analysis did not reveal any difference in seizure frequency and severity in participants who were or were not receiving anti‐seizure medications (ASMs) noted to have an interaction with CBD. ¹⁰ The aim of the present study is to determine if any of the potential interactions between CBD and ASMs noted in our original analysis are still present upon study completion and a longer period of CBD treatment, and if so, whether any of these interactions appear to have clinical relevance in regards to adverse effects.

2. METHODS

The University of Alabama at Birmingham CBD program was a large, open‐label, expanded access program that investigated the use of highly purified CBD for TRE and spanned over 4 years. The study was IRB approved, and FDA and DEA approvals were also obtained (clinicaltrials.gov NCT02695537 and NCT02700412). There were separate study clinics for adult and pediatric age groups, and all participants or their caregivers signed informed consent prior to initiating study procedures. Consented participants were started on CBD at 5 mg/kg/day divided into twice daily dosing, and the dose was titrated every 2 weeks to a maximum of 50 mg/kg/day depending on response and/or tolerability. Other ASM doses were stable for 1 month prior to enrollment but could be adjusted at the discretion of the study clinicians (usually clobazam due to sedation with increasing CBD dose, but valproate dose was also adjusted when elevated transaminases were identified). Labs were obtained at most study visits (including prior to CBD initiation), which included serum levels of other ASMs taken by a particular participant. Participants remained in the study unless they withdrew due to lack of efficacy or side effects or until study completion, when the product was FDA approved and available for prescription. Detailed recruitment information, inclusion/exclusion criteria, and study visit schedules have been previously published. ¹¹

Given the naturalistic study design and numerous variables, in order to assess the clinical significance of any potential interactions, the adverse events profile (AEP) was used. The AEP is a 19‐item questionnaire that queries for adverse effects of ASMs; higher scores indicate increased severity of adverse effects. ¹² The AEP was completed prior to starting CBD treatment and at every study visit.

The effect of CBD on serum levels of other ASMs taken by study participants was investigated using a linear mixed models analysis that included five independent predictors: CBD dose, medication dose under evaluation, age, sex, and the interactions between the two drug doses, as well as a random intercept and repeated measures within participant. Further analyses were performed to determine if any ASM levels that increased with increasing CBD dose were dependent on the calendar time enrolled in the study, sex, or pediatric versus adult arm. Finally, if an ASM serum level was found to change significantly with increasing CBD dose, an analysis was performed to determine if these changes were associated with the AEP score.

3. RESULTS

There were a total of 169 participants with data available for analysis: 80 adults and 89 children. The demographics of participants are presented in Table 1. There were a total of 23 ASMs that had serum level to analyze for potential interactions. Each data point consisted of the ASM level, the ASM dose, and the CBD dose. In both adult and pediatric study arms combined, with increasing CBD dose, there were significant increases in levels of clobazam (P < 0.0001), N‐desmethylclobazam (P < 0.0001), free valproate level (P = 0.0036), felbamate (P = 0.0013), levetiracetam (P = 0.0207), and topiramate (P = 0.0003). No adjustments were made for multiple comparisons in order to have a low threshold to identify any potential interactions or safety concerns, but we do not expect 6 of 23 (or excluding clobazam and N‐desmethylcobazam as expected, 4 of 21) by chance, that is, Type I errors. In adults only, there were increases in levels of peramapanel (P < 0.0001). Further, the increases in levetiracetam level seen in the combined arms analysis were only seen in the pediatric arm (P = 0.0250) when analyzed separately. Data from the analysis of all ASMs is presented in Table 2. None of the identified potential interactions were found to be dependent on time since study enrollment nor biological sex (all ps >0.05).

TABLE 1.

Study demographics.

Study arm	N Obs	Variable	Freq.	Mean	SD	Min	Max
Adult	80	Age (years)		32.86	13.56	19.0	74.0
		Sex	36 M 44 F
		Race	American‐Indian/Alaska Native: 1 Black/African American: 6 White: 73
		Number of ASMs on enrollment		3.10	0.89	1.0	5.0
		Number of ASMs tried		9.46	3.90	1.0	20.0
		Age of epilepsy onset (yrs)		9.12	11.68	0	62.0
Peds	89	Age (years)		9.89	4.88	1.0	19.0
		Sex	43 M 46 F
		Race	Asian: 3 Black/African American: 16 Native Hawaiian/Pacific Islander: 1 White: 69
		Number of ASMs on enrollment		2.88	1.03	1.0	5.0
		Number of ASMs tried		7.73	2.77	2.0	15.0
		Age of epilepsy onset (yrs)		2.09	2.72	0	13.0

Abbreviations: ASM, anti‐seizure medication; F, female; M, male.

TABLE 2.

Anti‐seizure medication (ASM) level changes with increasing cannabidiol (CBD) dose via mixed models analysis.

ASM level analysis
ASM level	Adult	Peds	Total	P‐value
Carbamazepine	7	0	7	0.6576
Clobazam	19	40	59	<0.0001
N‐desmethylclobazam				<0.0001
Clonazepam	17	28	45	0.6367
Clorazepate	2	8	10	0.4423
Eslicarbazepine	10	2	12	0.7122
Ethosuximide	0	9	9	0.8956
Ezogabine	4	0	4	0.5677
Felbamate	5	2	7	0.0012
Gabapentin	5	2	7	0.8160
Lacosamide	25	20	45	0.4971
Lamotrigine	34	29	63	0.4587
Levetiracetam	26	25	51	0.0222
Lorazepam	6	2	8	0.2969
Oxcarbazepine	16	12	28	0.4701
Perampanel	4	13	17	<0.0001 (adults only)
Phenobarbital	5	4	9	0.8230
Phenytoin	7	4	11	0.6529
Pregabalin	3	0	3	0.2059
Rufinamide	12	16	28	0.9952
Topiramate	17	15	32	0.0003
Valproate	16	35	51	0.3386
Free valproate				0.0036
Vigabatrin	0	5	5	0.2137
Zonisamide	18	15	33	0.7598

Note: ASMs that had significant increases in serum level with increasing CBD dose are in bold.

To investigate the actual changes occurring in ASM levels with changes in CBD dose, we plotted CBD dose (mg/kg/day) versus ASM serum level at different dose ranges of ASM in the medications/levels we noted a potential interaction (clobazam/N‐desmethylclobazam, free valproate, felbamate, levetiracetam, topiramate, and perampanel in adults only). Trend lines were fitted for a particular dose range to observe if a particular change in serum level could be explained by the ASM daily dose. These data are presented in Figure 1. R‐values for the trend lines are presented in the Supplementary Table S1.

FIGURE 1.

Graphs of anti‐seizure medication (ASM) serum level (y‐axis) and cannabidiol dose (mg/kg/day, x‐axis) for dose ranges for particular ASMs (total mg/day). Normal reference ranges are in parentheses: A, clobazam (30–300 ng/mL), B, N‐desmethylclobazam (300–3000 ng/mL), C, perampanel (180–980 ng/mL), D, topiramate (4.5–20 ng/mL), E, felbamate (40–100 μg/mL), F, levetiracetam (10–40 μg/mL), G, free valproate (6–22 μg/mL).

Rises in clobazam and N‐desmethylclobazam levels with increasing CBD dose were fairly consistent across all dose ranges. However, with all of the other potential interactions, the trends were inconsistent. Some observations from these graphs include increases in felbamate levels, particularly in participants on higher doses of both CBD and felbamate, some differences in rises in levetiracetam levels with higher levetiracetam doses, and a negative slope to the trend lines with free valproate level, except at higher valproate doses.

Finally, when looking for trends in AEP scores in participants taking a potentially interacting ASM with CBD, AEP scores remained relatively stable, and the only statistically significant increase in AEP scores due to the interaction of CBD dose was with levetiracetam (P = 0.0053). However, for example, if a participant received a CBD dose of 10 mg/kg/day and a levetiracetam dose of 2000 mg/day, the interaction would account for less than a 1‐point increase on the AEP score.

4. DISCUSSION

The purpose of this analysis was to determine if previously identified potential pharmacokinetic interactions between CBD and ASMs continued to be present in an expanded sample or if new potential interactions appeared over the entire study period of an open‐label EAP of CBD for the treatment of refractory epilepsy. In our prior study, we found pharmacokinetic interactions between CBD and clobazam, rufinamide, topiramate, zonisamide (adults only), and eslicarbazepine (adults only). ⁹ In the present analysis, we noted significantly increasing levels of clobazam/N‐desmethylclobazam, free valproate, topiramate, felbamate, levetiracetam, and peramapanel (adults only). While the analysis revealed that CBD dose had an effect on the increasing levels, there was no effect of time or biological sex on the results.

The results of the current analysis provide additional evidence for an already fairly well understood interaction between CBD and clobazam, which is thought to be in large part due to CBD's inhibition of CYP2C19, which metabolizes clobazam's active metabolite N‐desmethylclobazam. ¹³ This interaction may be the reason for the increased reports of sedation, per our previous analysis. Compared to our previous analysis with fewer participants and data points over a shorter duration, we noted increasing levels of clobazam with this analysis and not with the prior. This is likely due to rapid clobazam dose reduction early in our study, with clobazam doses stabilizing over a longer duration of time. Topiramate levels were again noted to increase with increasing CBD dose in our expanded study sample. This finding has not been seen in the randomized controlled trials, ¹⁴ but a mouse model has also suggested a potential pharmacokinetic interaction between CBD and topiramate, ¹⁵ with a proposed mechanism of CBD inhibiting p‐glycoprotein, which in turn could decrease renal and bile excretion of topiramate.

With this larger analysis, we saw overall increases in felbamate, free valproate, levetiracetam (driven by the pediatric arm as this was not seen in the analysis of the adult arm only), and perampanel (adults only) levels with increasing CBD dose, which were not seen in the earlier analysis. However, as demonstrated in Figure 1, these changes were inconsistent and likely do not represent clinically significant PK interactions. Further, aside from clobazam, most data points are within the accepted therapeutic range for the respective ASMs. Felbamate is largely excreted unmetabolized in the urine, but about 50% is hepatically metabolized by enzymes including CYP2C9 and CYP3A4 ¹⁶ ; CBD's known inhibitory action on many CYP enzymes could explain why these levels were increased. Interestingly, in this analysis, it appears that these changes are only noted at higher doses of felbamate and CBD.

A pharmacodynamic interaction between valproate and CBD has been previously established, with treatment with both of these medications increasing the likelihood of a reversible elevation in liver function tests. ¹³ However, in this analysis, we noted significant increases in free valproate concentrations with increasing CBD dose at high valproate doses only. A small amount (12%) of free valproate concentration variability has been accounted for by factors such as free fatty acids which compete for valproate binding sites, which could potentially explain a transient effect if CBD (compounded in sesame oil) and valproate were taken together. ¹⁷ Further, free valproate concentrations are found to increase quadratically at total valproate concentrations >60 μg/mL ¹⁷ ; therefore, our finding of increasing free valproate levels with increasing CBD dose could be suggestive of a subtle pharmacokinetic interaction between CBD and valproate seen only with higher doses of valproate. While there has been a pharmacodynamic interaction between levetiracetam and CBD noted in an animal model (decreased levetiracetam activity in the presence of CBD) ¹⁵ and a pharmacokinetic interaction with a similar medication brivaracetam, ¹⁸ to date, there is no data on a potential pharmacokinetic interaction between CBD and levetiracetam. Levetiracetam is largely excreted unchanged, but its main metabolic pathway is via hydrolysis by β‐esterases. ¹⁹ There are data to suggest that CBD can inhibit one of the β‐esterases, carboxylesterase, which could explain our findings. ²⁰ Perampanel is largely hepatically metabolized by CYP3A4 and 3A5, followed by glucoronidation. ²¹

Our results differ somewhat from the prior analysis, which is likely due, at least in part, to the increased number of observations in the current analysis. However, there is also likely a large contribution from our naturalistic study design, multiple variables, and overall “noise” in the data, for which reason our results should be interpreted with caution. Further, the AEP analysis revealing no significant change to scores with any of the potential interactions suggests that overall there is likely only minor clinical significance to the noted changes. However, our results highlight the importance of ASM level monitoring in selected instances and provide further evidence toward potential pharmacokinetic interactions between CBD and certain ASMs (though the clinical significance of these potential interactions is in general likely minimal).

Certainly, there are limitations to open‐label observational studies, which are well recognized. The use of unadjusted P‐values must also be taken into account given the multiple testing. However, when looking for safety concerns, it is important to err on the side of caution. We also note that even though repeated observations on these 169 participants generated 4360 individual observations (not all with dosage samples), the power to detect interactions is still somewhat limited. Thus, while these observations are notable, other studies need to replicate our findings before specific cautions can be warranted.

AUTHOR CONTRIBUTIONS

Tyler Gaston: Writing‐original draft preparation, writing—review and editing, data curation, investigation. E. Martina Bebin: writing—review and editing, conceptualization, funding acquisition, methodology, data curation, study supervision. Gary Cutter: writing‐review and editing, formal analysis. Leslie Grayson: writing‐review and editing, data curation, investigation. Jerzy Szaflarski: writing—review and editing, conceptualization, funding acquisition, methodology, data curation, study supervision.

FUNDING INFORMATION

Funding for this study was provided by the State of Alabama through “Carly's Law” and an in‐kind donation of Epidiolex from GW Biosciences, Ltd.

CONFLICT OF INTEREST STATEMENT

Tyler Gaston: Consulting fee/Advisory Board: Jazz Pharmaceuticals/Neurelis, funding from Department of Defense, honorarium from American Academy of Neurology. E. Martina Bebin: consultant for Jazz Pharmaceuticals. Gary Cutter: Data and Safety Monitoring Boards: Applied Therapeutics, AI therapeutics, AMO Pharma, Astra‐Zeneca, Avexis Pharmaceuticals, Biolinerx, Brainstorm Cell Therapeutics, Bristol Meyers Squibb/Celgene, CSL Behring, Galmed Pharmaceuticals, Green Valley Pharma, Horizon Pharmaceuticals, Immunic, Karuna Therapeutics, Kezar Life Sciences, Mapi Pharmaceuticals LTD, Merck, Mitsubishi Tanabe Pharma Holdings, Opko Biologics, Prothena Biosciences, Novartis, Regeneron, Sanofi‐Aventis, Reata Pharmaceuticals, Teva Pharmaceuticals, NHLBI (Protocol Review Committee), University of Texas Southwestern, University of Pennsylvania, Visioneering Technologies, Inc. Consulting or Advisory Boards: Alexion, Antisense Therapeutics, Avotres, Biogen, Clinical Trial Solutions LLC, Entelexo Biotherapeutics, Inc., Genzyme, Genentech, GW Pharmaceuticals, Hoya Corporation, Immunic, Immunosis Pty Ltd, Klein‐Buendel Incorporated, Linical, Merck/Serono, Novartis, Perception Neurosciences, Protalix Biotherapeutics, Regeneron, Roche, SAB Biotherapeutics. Cutter is employed by the University of Alabama at Birmingham and President of Pythagoras, Inc. a private consulting company located in Birmingham AL. Leslie Grayson: speaker board for Jazz Pharmaceuticals. Jerzy Szaflarski: Funding: NIH, NSF, DoD, State of Alabama, Shor Foundation for Epilepsy Research, UCB Pharma Inc., NeuroPace Inc., Greenwich Biosciences Inc., Biogen Inc., Xenon Pharmaceuticals, Serina Therapeutics Inc., and Eisai, Inc. Consulting/Advisory Boards: Greenwich Biosciences Inc., NeuroPace, Inc., Serina Therapeutics Inc., AdCel Biopharma Inc, iFovea Inc, LivaNova Inc., UCB Pharma Inc., SK Lifesciences Inc., and medico‐legal services. Paid Editorial Work: Editor‐in‐Chief—Epilepsy & Behavior Reports. Dr. Szaflarski has served as a member on the Alabama State Medical Cannabis Study Commission. Dr. Szaflarski serves on the Alabama Medical Cannabis Commission (2021–2025).

ETHICAL PUBLICATION STATEMENT

We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

INFORMED CONSENT STATEMENT

Informed consent was obtained by all subjects or their caregivers in the study.

Supporting information

Supplementary Table S1.

Gaston TE, Bebin EM, Cutter GR, Grayson L, Szaflarski JP. Final analysis of potential drug–drug interactions between highly purified cannabidiol and anti‐seizure medications in an open‐label expanded access program. Epilepsia Open. 2023;8:1405–1412. 10.1002/epi4.12815

DATA AVAILABILITY STATEMENT

The deidentified data from this analysis may be shared after obtaining a data sharing agreement and approval from appropriate authorities for 3 years from the date of acceptance of the manuscript.