Category Archives: Epilepsy

Coadministered cannabidiol and clobazam: Preclinical evidence for both pharmacodynamic and pharmacokinetic interactions.

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Epilepsia banner“Cannabidiol (CBD) has been approved by the US Food and Drug Administration (FDA) to treat intractable childhood epilepsies, such as Dravet syndrome and Lennox-Gastaut syndrome. However, the intrinsic anticonvulsant activity of CBD has been questioned due to a pharmacokinetic interaction between CBD and a first-line medication, clobazam. This recognized interaction has led to speculation that the anticonvulsant efficacy of CBD may simply reflect CBD augmenting clobazam exposure. The present study aimed to address the nature of the interaction between CBD and clobazam.

RESULTS:

CBD potently inhibited CYP3A4 mediated metabolism of clobazam and CYP2C19 mediated metabolism of N-CLB. Combination CBD-clobazam treatment resulted in greater anticonvulsant efficacy in Scn1a+/- mice, but only when an anticonvulsant dose of CBD was used. It is important to note that a sub-anticonvulsant dose of CBD did not promote greater anticonvulsant effects despite increasing plasma clobazam concentrations. In addition, we delineated a novel pharmacodynamic mechanism where CBD and clobazam together enhanced inhibitory GABAA receptor activation.

SIGNIFICANCE:

Our study highlights the involvement of both pharmacodynamic and pharmacokinetic interactions between CBD and clobazam that may contribute to its efficacy in Dravet syndrome.”

https://www.ncbi.nlm.nih.gov/pubmed/31625159

“Our results here suggest a novel benefit of CBD and clobazam combination therapy on premature death, a devastating aspect of the Dravet syndrome phenotype.”

https://onlinelibrary.wiley.com/doi/full/10.1111/epi.16355

Effects of cannabidiol (CBD) in neuropsychiatric disorders: A review of pre-clinical and clinical findings.

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Progress in Molecular Biology and Translational Science“Cannabis sativa (cannabis) is one of the oldest plants cultivated by men. Cannabidiol (CBD) is the major non-psychomimetic compound derived from cannabis. It has been proposed to have a therapeutic potential over a wide range of neuropsychiatric disorders.

In this narrative review, we have summarized a selected number of pre-clinical and clinical studies, examining the effects of CBD in neuropsychiatric disorders. In some pre-clinical studies, CBD was demonstrated to potentially exhibit anti-epileptic, anti-oxidant, anti-inflammatory anti-psychotic, anxiolytic and anti-depressant properties. Moreover, CBD was shown to reduce addictive effects of some drugs of abuse.

In clinical studies, CBD was shown to be safe, well-tolerated and efficacious in mitigating the symptoms associated with several types of seizure disorders and childhood epilepsies.

Given that treatment with CBD alone was insufficient at managing choreic movements in patients with Huntington’s disease, other cannabis-derived treatments are currently being investigated. Patients with Parkinson’s disease (PD) have reported improvements in sleep and better quality of life with CBD; however, to fully elucidate the therapeutic potential of CBD on the symptoms of PD-associated movement disorders, larger scale, randomized, placebo-controlled studies still need to be conducted in the future.

Currently, there are no human studies that investigated the effects of CBD in either Alzheimer’s disease or unipolar depression, warranting further investigation in this area, considering that CBD was shown to have effects in pre-clinical studies.

Although, anxiolytic properties of CBD were reported in the Social Anxiety Disorder, antipsychotic effects in schizophrenia and anti-addictive qualities in alcohol and drug addictions, here too, larger, randomized, placebo-controlled trials are needed to evaluate the therapeutic potential of CBD.”

https://www.ncbi.nlm.nih.gov/pubmed/31601406

https://www.sciencedirect.com/science/article/pii/S187711731930095X?via%3Dihub

European drug agency approves cannabis-based medicine for severe forms of epilepsy

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“The European Medicines Agency (EMA) has approved the first cannabis based medicine to treat two rare and severe forms of childhood onset epilepsy, although hurdles remain before the drug becomes available on the NHS.”

https://www.bmj.com/content/366/bmj.l5708.full

Cannabis-based treatments as an alternative remedy for epilepsy

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Integrative Medicine Research“Much of the initial reports for cannabis use in seizure control centered on the compound 9-Δ-tetrahydrocannabinol (THC). However, due to the psychoactive properties of THC potential utility was somewhat limited and recent research has focused on non-psychoactive compounds such as cannabidiol (CBD).

The anti-seizure effects of CBD may come from mechanisms such as functional agonism or antagonism at several 7-transmembrane receptors, ion channels, and neurotransmitter transporters.

Recently, another compound that also is without psychoactive effects known as CBDV has also shown anti-seizure properties both in vivo and in vitro.

Many reports exist on illicit cannabis use through the smoking of marijuana by patients as a self-treatment.

Cannabis and cannabis-based treatments offer promising alternatives to traditional antiepileptic drugs (AEDs).

Due to the unfortunate fact that many patients suffer from Drug-resistant epilepsy (DRE), cannabis-based treatments have great value.

Cannabis-based treatments offer some patients with DRE a great remedy for their condition with limited side effects.

This option may prevent some patients with DRE from needing to consider more invasive options such as surgical interventions. In case studies, open label studies, and RCTs, one can see drastic improvements in the frequency of seizures in patients with certain forms of epilepsy.

It is imperative to continue research into cannabis as a potential primary treatment for epilepsy, particularly those with DRE, to help improve quality of life for millions of people suffering from epilepsy.”

https://www.ncbi.nlm.nih.gov/pubmed/31463193

https://www.sciencedirect.com/science/article/pii/S221342201930157X?via%3Dihub

Clinicians’ Guide to Cannabidiol and Hemp Oils.

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Mayo Clinic“Cannabidiol (CBD) oils are low tetrahydrocannabinol products derived from Cannabis sativa that have become very popular over the past few years. Patients report relief for a variety of conditions, particularly pain, without the intoxicating adverse effects of medical marijuana.

In June 2018, the first CBD-based drug, Epidiolex, was approved by the US Food and Drug Administration for treatment of rare, severe epilepsy, further putting the spotlight on CBD and hemp oils.

There is a growing body of preclinical and clinical evidence to support use of CBD oils for many conditions, suggesting its potential role as another option for treating challenging chronic pain or opioid addiction.

Care must be taken when directing patients toward CBD products because there is little regulation, and studies have found inaccurate labeling of CBD and tetrahydrocannabinol quantities.

This article provides an overview of the scientific work on cannabinoids, CBD, and hemp oil and the distinction between marijuana, hemp, and the different components of CBD and hemp oil products.

We summarize the current legal status of CBD and hemp oils in the United States and provide a guide to identifying higher-quality products so that clinicians can advise their patients on the safest and most evidence-based formulations.

This review is based on a PubMed search using the terms CBD, cannabidiol, hemp oil, and medical marijuana. Articles were screened for relevance, and those with the most up-to-date information were selected for inclusion.”

https://www.ncbi.nlm.nih.gov/pubmed/31447137

https://www.mayoclinicproceedings.org/article/S0025-6196(19)30007-2/fulltext

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

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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

The safety, tolerability, and effectiveness of PTL-101, an oral cannabidiol formulation, in pediatric intractable epilepsy: A phase II, open-label, single-center study.

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“Several works have reported on the antiepileptic impact of cannabis-based preparations in patients with treatment-resistant epilepsy (TRE). However, current formulations suffer from low bioavailability and side effects. PTL-101, an oral formulation containing highly purified cannabidiol (CBD) embedded in seamless gelatin matrix beadlets was designed to enhance bioavailability and maintain a constant gastrointestinal transit time.

RESULTS:

Sixteen patients (age: 9.1±3.4) enrolled in the study; 11 completed the full treatment program. The average maintenance dose was 13.6±4.2mg/kg. Patient adherence to treatment regimens was 96.3±9.9%. By the end of the treatment period, 81.9% and 73.4±24.6% (p<0.05) reductions from baseline median seizure count and monthly seizure frequency, respectively, were recorded. Responders’ rate was 56%; two patients became fully seizure-free. By study end, 8 (73%) caregivers reported an improved/very much improved condition, and 9 (82%) reported reduced/very much reduced seizure severity. Most commonly reported treatment-related adverse effects were sleep disturbance/insomnia, (4 (25.0%) patients), followed by somnolence, increased seizure frequency, and restlessness (3 patients each (18.8%)). None were serious or severe, and all resolved.

CONCLUSIONS:

PTL-101 was safe and tolerable for use and demonstrated a potent seizure-reducing effect among pediatric patients with TRE.”

https://www.ncbi.nlm.nih.gov/pubmed/31394352

https://www.epilepsybehavior.com/article/S1525-5050(19)30305-1/fulltext

Cannabis and Epilepsy.

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 Publication Cover“In recent years, the use of cannabidiol in the treatment of refractory epilepsy has been increasingly investigated and has been gaining public support as a novel way to treat these disorders.

Marijuana has been used for medical purposes for thousands of years, and a lot of research has been conducted over the last several decades into the chemistry and pharmacology of marijuana and its many compounds, including cannabidiol.

There are historical and recent scientific developments that support the use of cannabidiol in rare severe epilepsy syndromes.”

https://www.ncbi.nlm.nih.gov/pubmed/31385740

https://www.tandfonline.com/doi/abs/10.1080/15504263.2019.1645372?journalCode=wjdd20

Pharmacological and Therapeutic Properties of Cannabidiol for Epilepsy.

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 “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

Dosage Related Efficacy and Tolerability of Cannabidiol in Children With Treatment-Resistant Epileptic Encephalopathy: Preliminary Results of the CARE-E Study.

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 Image result for frontiers in neurology“There is uncertainty regarding the appropriate dose of Cannabidiol (CBD) for childhood epilepsy.

We present the preliminary data of seven participants from the Cannabidiol in Children with Refractory Epileptic Encephalopathy (CARE-E) study.

Methods: The study is an open-label, prospective, dose-escalation trial. Participants received escalating doses of a Cannabis Herbal Extract (CHE) preparation of 1:20 Δ9-tetrahydrocannabinol (THC): CBD up to 10-12 mg CBD/kg/day. Seizure frequency was monitored in daily logs, participants underwent regular electroencephalograms, and parents filled out modified Quality of Life in Childhood Epilepsy (QOLCE) and Side Effect rating scale questionnaires. Steady-state trough levels (Css, Min) of selected cannabinoids were quantified.

Results: All seven participants tolerated the CHE up to 10-12 mg CBD/kg/day and had improvements in seizure frequency and QOLCE scores. CSS, Min plasma levels for CBD, THC, and cannabichromene (CBC) showed dose-independent pharmacokinetics in all but one participant. CSS, Min CBD levels associated with a >50% reduction in seizures and seizure freedom were lower than those reported previously with purified CBD. In most patients, CSS, Min levels of THC remained lower than what would be expected to cause intoxication.

Conclusion: The preliminary data suggest an initial CBD target dose of 5-6 mg/kg/day when a 1:20 THC:CBD CHE is used. Possible non-linear pharmacokinetics of CBD and CBC needs investigation. The reduction in seizure frequency seen suggests improved seizure control when a whole plant CHE is used. Plasma THC levels suggest a low risk of THC intoxication when a 1:20 THC:CBD CHE is used in doses up to 12 mg/kg CBD/kg/day.”

https://www.ncbi.nlm.nih.gov/pubmed/31333569

https://www.frontiersin.org/articles/10.3389/fneur.2019.00716/full