Clinical implications of trials investigating drug-drug interactions between cannabidiol and enzyme inducers or inhibitors or common antiseizure drugs

“Highly purified cannabidiol (CBD) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut syndrome or Dravet syndrome in randomized, double-blind, add-on, controlled phase 3 trials.

It is important to consider the possibility of drug-drug interactions (DDIs). Here, we review six trials of CBD (Epidiolex/Epidyolex; 100 mg/mL oral solution) in healthy volunteers or patients with epilepsy, which investigated potential interactions between CBD and enzymes involved in drug metabolism of common antiseizure drugs (ASDs).

CBD did not affect CYP3A4 activity. Induction of CYP3A4 and CYP2C19 led to small reductions in exposure to CBD and its major metabolites. Inhibition of CYP3A4 activity did not affect CBD exposure and caused small increases in exposure to CBD metabolites. Inhibition of CYP2C19 activity led to a small increase in exposure to CBD and small decreases in exposure to CBD metabolites.

One potentially clinically important DDI was identified: combination of CBD and clobazam (CLB) did not affect CBD or CLB exposure, but increased exposure to major metabolites of both compounds. Reduction of CLB dose may be considered if adverse reactions known to occur with CLB are experienced when it is coadministered with CBD.

There was a small increase of exposure to stiripentol (STP) when coadministered with CBD. STP had no effect on CBD exposure but led to minor decreases in exposure to CBD metabolites. Combination of CBD and valproate (VPA) did not cause clinically important changes in the pharmacokinetics of either drug, or 2-propyl-4-pentenoic acid. Concomitant VPA caused small increases in exposure to CBD metabolites. Dose adjustments are not likely to be necessary when CBD is combined with STP or VPA.

The safety results from these trials were consistent with the known safety profile of CBD. These trials indicate an overall low potential for DDIs between CBD and other ASDs, except for CLB.”

https://pubmed.ncbi.nlm.nih.gov/32918835/

https://onlinelibrary.wiley.com/doi/full/10.1111/epi.16674

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Add-on cannabidiol significantly decreases seizures in 3 patients with SYNGAP1 developmental and epileptic encephalopathy

“Mutations in SYNGAP1 are associated with developmental delay, epilepsy, and autism spectrum disorder (ASD). Epilepsy is often drug-resistant in this syndrome with frequent drop attacks.

In a prospective study of add-on cannabidiol (CBD), we identified three patients with SYNGAP1 mutations: two boys and one girl. Seizure onset was at 3.5, 8, and 18 months (M), respectively, with numerous atypical absences per day associated with eyelid myoclonia (2/3 patients), upper limb myoclonic jerks (2/3 patients), and drop attacks (all patients). Seizures were resistant to at least 5 antiepileptic drugs (AEDs).

After CBD introduction, two patients were responders since M2 and achieve a seizure reduction of 90% and 80%, respectively, at M9 with disappearance of drop attacks. EEGs showed an improvement regarding background activity and interictal anomalies. The last patient showed a late response at M7 of treatment with an 80% decrease in seizure frequency. Caregiver in all three evaluated as much improved the status of their children. Treatment was well-tolerated in all, and no major adverse events (AEs) were reported.

CBD showed efficacy in patients with drug-resistant epilepsy due to SYNGAP1 mutations. Other patients with rare genetic developmental and epileptic encephalopathies with drug-resistant epilepsies might benefit from CBD.”

https://pubmed.ncbi.nlm.nih.gov/32913957/

“CBD add‐on therapy in patients with SYNGAP1 encephalopathy showed a good response in three patients with a good safety profile and a late response in one patient. This therapy should be included in the treatment algorithm of patients with SYNGAP1 mutations presenting drug resistance epilepsy and might be expanded to other rare genetic epilepsies that might not be included in formal trials.”

https://onlinelibrary.wiley.com/doi/full/10.1002/epi4.12411

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Effectiveness of Cannabidiol in a Prospective Cohort of Children With Drug-Resistant Epileptic Encephalopathy in Argentina

“We report our preliminary findings regarding effectiveness, safety, and tolerability of cannabidiol (CBD) added to antiepileptic therapy in a cohort of children with drug-resistant epileptic encephalopathies (EEs) with a mean follow-up of 8.5 months (range, 3-12 months).

Methods: A prospective cohort study was designed with the aim of assessing the effectiveness, safety, and tolerability of the addition of CBD to standard antiseizure medications (ASMs) in children with drug-resistant EE enrolled at a single center (Neurology Department, Hospital de Pediatría “Juan P. Garrahan”, Buenos Aires, Argentina).

Results: Fifty patients were enrolled between October 2018 and October 2019, 49 of whom had a follow-up of at least 3 months at the time this interim analysis was performed. Mean age at enrollment was 10.5 years (range 2-16). Median age at first seizure was 7 months. Up to the last visit of each patient (follow-up 3-12 months) 39/49 children (80 %) had responded to treatment with a decrease in seizure frequency. Overall, 77.6 % of the patients had a seizure reduction of at least 25 %, 73.5 % had a ≥ 50 % reduction, and 49 % had a ≥ 75 % reduction. Mean monthly seizure frequency was reduced from 959 to 381 (median decrease from 299 to 102, range, 38-1900; median decrease 66 %, p < 0.001). All adverse effects were mild or moderate. The most common adverse effect was drowsiness (in 32 %), usually reversed by adjusting clobazam dose (in 12 children).

Conclusion: In children with drug-resistant EEs, CBD oil as an adjuvant therapy to antiepileptic therapy seems safe, well tolerated, and effective.”

https://pubmed.ncbi.nlm.nih.gov/32544657/

“Cannibidiol showed good effectiveness, with a ≥ 50 % reduction in seizure frequency in 73.5 % of the patients. Good results were obtained in patients with Lennox-Gastaut and Dravet syndromes. In epileptic encephalopathies other than Lennox-Gastaut results were also good. Cannabidiol showed good safety and tolerability as all adverse effects were mild or moderate.”

https://www.seizure-journal.com/article/S1059-1311(20)30167-9/pdf

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Does Cannabidiol Have Antiseizure Activity Independent of Its Interactions With Clobazam? An Appraisal of the Evidence From Randomized Controlled Trials

 Epilepsia“Four pivotal randomized placebo-controlled trials have demonstrated that adjunctive therapy with cannabidiol (CBD) improves seizure control in patients with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

Between 47% and 68% of patients allocated to CBD treatment in these trials were receiving clobazam (CLB), which shows complex interactions with CBD resulting, in particular, in a 3.4- to 5-fold increase in plasma concentration of the active metabolite norclobazam. This raises concern as to the role played by these interactions in determining the reduction in seizure frequency in CBD-treated patients, and the question of whether CBD per se has clinically evident antiseizure effects.

We appraised available evidence on the clinical consequences of the CBD-CLB interaction, focusing on subgroup analyses of seizure outcomes in patients on and off CLB comedication in the pivotal CBD trials, as provided by the European Medicines Agency Public Assessment Report.

Evaluation of the results of individual trials clearly showed that improvement in seizure control over placebo was greater when CBD was added on to CLB than when it was added on to other medications. However, seizure control was also improved in patients off CLB, and despite the small sample size the difference vs placebo was statistically significant for the 10 mg/kg/d dose in one of the two LGS trials.

Stronger evidence for an antiseizure effect of CBD independent of an interaction with CLB emerges from meta-analyses of seizure outcomes in the pooled population of LGS and DS patients not receiving CLB comedication.

Although these results need to be interpreted taking into account methodological limitations, they provide the best clinical evidence to date that CBD exerts therapeutic effects in patients with epilepsy that are independent of its interaction with CLB. Greater antiseizure effects, and a greater burden of adverse effects, are observed when CBD is combined with CLB.”

https://pubmed.ncbi.nlm.nih.gov/32452568/

https://onlinelibrary.wiley.com/doi/abs/10.1111/epi.16542

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Is cannabidiol a drug acting on unconventional targets to control drug-resistant epilepsy?

Publication cover image“Cannabis has been considered as a therapeutic strategy to control intractable epilepsy.

Several cannabis components, especially cannabidiol (CBD), induce antiseizure effects. However, additional information is necessary to identify the types of epilepsies that can be controlled by these components and the mechanisms involved in these effects.

This review presents a summary of the discussion carried out during the 2nd Latin American Workshop on Neurobiology of Epilepsy entitled “Cannabinoid and epilepsy: myths and realities.” This event was carried out during the 10th Latin American Epilepsy Congress in San José de Costa Rica (September 28, 2018).

The review focuses to discuss the use of CBD as a new therapeutic strategy to control drug-resistant epilepsy. It also indicates the necessity to consider the evaluation of unconventional targets such as P-glycoprotein, to explain the effects of CBD in drug-resistant epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/32140642

“Cannabidiol is a multitarget drug that represents a new hope to control drug‐resistant epilepsy.”

https://onlinelibrary.wiley.com/doi/full/10.1002/epi4.12376

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Cannabidiol attenuates seizures and EEG abnormalities in Angelman syndrome model mice.

 Image result for J Clin Invest.“Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, lack of speech, ataxia, EEG abnormalities, and epilepsy. Seizures in AS individuals are common, debilitating, and often drug-resistant. Therefore, there is an unmet need for better treatment options.

Cannabidiol (CBD), a major phytocannabinoid constituent of cannabis, has antiseizure activity and behavioral benefits in preclinical and clinical studies for some disorders associated with epilepsy, suggesting that the same could be true for AS.

Here we show that acute CBD (100 mg/kg) attenuated hyperthermia- and acoustically-induced seizures in a mouse model of AS. However, neither acute CBD nor a two-weeklong course of CBD administered immediately after a kindling protocol could halt the pro-epileptogenic plasticity observed in AS model mice.

CBD had a dose-dependent sedative effect, but did not have an impact on motor performance. CBD abrogated the enhanced intracortical local field potential power, including delta and theta rhythms observed in AS model mice, indicating that CBD administration could also help normalize the EEG deficits observed in individuals with AS.

Our results provide critical preclinical evidence supporting CBD treatment of seizures and alleviation of EEG abnormalities in AS, and will thus help guide the rational development of CBD as an AS treatment.”

https://www.ncbi.nlm.nih.gov/pubmed/31503547

https://www.jci.org/articles/view/130419

“CBD Could Help Treat Angelman Syndrome, Says Study”   https://www.analyticalcannabis.com/articles/cbd-could-help-treat-angelman-syndrome-says-study-311798

“Medical marijuana saved the life of 8 year old boy with Angelman Syndrome”   http://www.chicagonow.com/soapbox-momma/2016/05/medical-marijuana-saved-the-life-of-8-year-old-boy-with-angelman-syndrome/

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Cannabidiol reduces seizures following CNS infection with Theiler’s murine encephalomyelitis virus.

Publication cover image“C57BL/6J mice infected with Theiler’s murine encephalomyelitis virus (TMEV) develop acute behavioral seizures in the first week of infection and later develop chronic epilepsy. The TMEV model provides a useful platform to test novel antiseizure therapeutics.

The present study was designed to test the efficacy of cannabidiol (CBD) in reducing acute seizures induced by viral infection.

RESULTS:

Cannabidiol (180 mg/kg; 360 mg/kg/day) decreased both the frequency and severity of acute behavioral seizures following TMEV infection, but 150 mg/kg of CBD did not improve overall seizure outcome. The time to peak effect (TPE) of CBD in the 6 Hz 32 mA psychomotor seizure test using C57BL/6J mice was observed at 2 hours post-CBD treatment. Interestingly, CBD (150 mg/kg) significantly reduced frequency and severity of TMEV-induced acute seizures at 2 hours post-CBD treatment. These results suggest that CBD could be effective in decreasing TMEV-induced acute seizures when the seizure test is conducted at the TPE of CBD.

SIGNIFICANCE:

Cannabinoids are increasingly studied for their potential antiseizure effects. Several preclinical and clinical studies provide evidence that CBD could be an effective therapy for intractable epilepsies. The present study corroborates those previous findings and provides an opportunity to investigate pharmacokinetics, pharmacodynamics, and mechanism(s) of antiseizure effects of CBD in the TMEV model, which may help to design future clinical studies more effectively.”

https://www.ncbi.nlm.nih.gov/pubmed/31440724

https://onlinelibrary.wiley.com/doi/full/10.1002/epi4.12351

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Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy.

 “Cannabidiol (CBD) is a major active component of the Cannabis plant, which, unlike tetrahydrocannabinol (THC), is devoid of euphoria-inducing properties.

During the last 10 years, there has been increasing interest in the use of CBD-enriched products for the treatment of epilepsy.

In 2018, an oil-based highly purified liquid formulation of CBD (Epidiolex) derived from Cannabis sativa was approved by the US Food and Drug Administration for the treatment of seizures associated with Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

The mechanisms underlying the antiseizure effects of CBD are unclear but may involve, among others, antagonism of G protein-coupled receptor 55 (GPR55), desensitization of transient receptor potential of vanilloid type 1 (TRPV1) channels, and inhibition of adenosine reuptake. CBD has complex and variable pharmacokinetics, with a prominent first-pass effect and a low oral bioavailability that increases fourfold when CBD is taken with a high-fat/high-calorie meal.

In four randomized, double-blind, parallel-group, adjunctive-therapy trials, CBD given at doses of 10 and 20 mg/kg/day administered in two divided administrations was found to be superior to placebo in reducing the frequency of drop seizures in patients with LGS and convulsive seizures in patients with DS.

Preliminary results from a recently completed controlled trial indicate that efficacy also extends to the treatment of seizures associated with the tuberous sclerosis complex.

The most common adverse events that differentiated CBD from placebo in controlled trials included somnolence/sedation, decreased appetite, increases in transaminases, and diarrhea, behavioral changes, skin rashes, fatigue, and sleep disturbances.

About one-half of the patients included in the DS and LGS trials were receiving concomitant therapy with clobazam, and in these patients a CBD-induced increase in serum levels of the active metabolite norclobazam may have contributed to improved seizure outcomes and to precipitation of some adverse effects, particularly somnolence.”

https://www.ncbi.nlm.nih.gov/pubmed/31372958

https://link.springer.com/article/10.1007%2Fs40265-019-01171-4

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From Cannabinoids and Neurosteroids to Statins and the Ketogenic Diet: New Therapeutic Avenues in Rett Syndrome?

Image result for frontiers in neuroscience “Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused mainly by mutations in the MECP2 gene, being one of the leading causes of mental disability in females.

Epilepsy is one of the most common symptoms in RTT, occurring in 60 to 80% of RTT cases, being associated with worsening of other symptoms. At this point, no cure for RTT is available and there is a pressing need for the discovery of new drug candidates to treat its severe symptoms.

New and exciting evidence has been gathered and the etiopathogenesis of this complex, severe and untreatable disease is slowly being unfolded. Advances in gene editing techniques have prompted cure-oriented research in RTT. Nonetheless, at this point, finding a cure is a distant reality, highlighting the importance of further investigating the basic pathological mechanisms of this disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31333401

“Very recently, a new study using CBDV has confirmed the potential of this particular phytocannabinoid in RTT.  The promising antiseizure effects of CBD, even in cases of refractory-epilepsy, observed in both clinical trials with humans and in laboratory animals, the effects of combinations of CBD and Δ9-THC in controlling muscle spasticity and motor symptoms, and the positive results of CBDV administration in two different mouse models of RTT, place cannabinoids as a viable therapeutic strategy in RTT. Moreover, CBD positively modifies impairments in motor, cognitive and social processes in animal models, further highlighting the potential of cannabinoid molecules to tackle RTT-symptomology.”

https://www.frontiersin.org/articles/10.3389/fnins.2019.00680/full

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Cannabidiol as adjunctive treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome.

“Epilepsy is one of the most common chronic disorders of the brain affecting around 70 million people worldwide. Treatment is mainly symptomatic, and most patients achieve long-term seizure control. Up to one-third of the affected subjects, however, are resistant to anticonvulsant therapy.

Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) are severe, refractory epilepsy syndromes with onset in early childhood. Currently available interventions fail to control seizures in most cases, and there remains the need to identify new treatments.

Cannabidiol (CBD) is the first in a new class of antiepileptic drugs. It is a major chemical of the cannabis plant, which has antiseizure properties in absence of psychoactive effects.

This article provides a critical review of the pharmacology of CBD and the most recent clinical studies that evaluated its efficacy and safety as adjunctive treatment of seizures associated with LGS and DS.”

https://www.ncbi.nlm.nih.gov/pubmed/30938373

https://journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summary_pr?p_JournalId=4&p_RefId=2909248&p_IsPs=N

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