Category Archives: Epilepsy

CBD and the 5-HT1A receptor: A medicinal and pharmacological review

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“Cannabidiol (CBD), a phytocannabinoid, has emerged as a promising candidate for addressing a wide array of symptoms.

It has the ability to bind multiple proteins and receptors, including 5-HT1AR, transient receptor potential vanilloid 1 (TRPV1), and cannabinoid receptors. However, CBD’s pharmacodynamic interaction with 5-HT1AR and its medicinal outcomes are still debated.

This review explores recent literature to elucidate these questions, highlighting the neurotherapeutic outcomes of this pharmacodynamic interaction and proposing a signaling pathway underlying the mechanism by which CBD desensitizes 5-HT1AR signaling.

A comprehensive survey of the literature underscores CBD’s multifaceted neurotherapeutic effects, encompassing antidepressant, anxiolytic, neuroprotective, antipsychotic, antiemetic, anti-allodynic, anti-epileptic, anti-degenerative, and addiction-treating properties, attributable in part to its interactions with 5-HT1AR.

Furthermore, evidence suggests that the pharmacodynamic interaction between CBD and 5-HT1AR is contingent upon dosage. Moreover, we propose that CBD can induce desensitization of 5-HT1AR via both homologous and heterologous mechanisms. Homologous desensitization involves the recruitment of G protein-coupled receptor kinase 2 (GRK2) and β-arrestin, leading to receptor endocytosis. In contrast, heterologous desensitization is mediated by an elevated intracellular calcium level or activation of protein kinases, such as c-Jun N-terminal kinase (JNK), through the activity of other receptors.”

https://pubmed.ncbi.nlm.nih.gov/39778776/

“Cannabis was one of the first inhaled drugs utilized by humans, with evidence of use for gout, rheumatism, and malaria dating to 2737 BCE”

“The concurrent literature revealed that CBD produces several therapeutic effects through its complex pharmacodynamic interactions with 5-HT1AR. Therapeutic applications of CBD, including its anxiolytic, antidepressant, antipsychotic, anti-degenerative, neuroprotective, anti-epileptic, and anti-addictive properties were mediated, at least in part, by its binding to 5-HT1AR.”

https://www.sciencedirect.com/science/article/abs/pii/S0006295225000048?via%3Dihub

Cannabichromene from full-spectrum hemp extract exerts acute anti-seizure effects through allosteric activation of GABAA receptors

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“The approval of Epidiolex, an anti-epileptic drug containing cannabidiol (CBD) as its active component, has brought hope to patients with refractory epilepsy. However, the anti-seizure effect of full-spectrum hemp extract (HE), a CBD-enriched hemp oil, remains unclear.

In this study, we investigated the anti-seizure effect of HE using drug-induced seizure models.

Our findings revealed that HE significantly reduced seizure susceptibility comparable to CBD at the same doses. Moreover, we explored the pharmacokinetic properties of CBD in HE and observed improved characteristics such as faster oral absorption, enhanced brain distribution, and slower elimination.

We further assessed the anti-seizure effects of the other five main non-addictive components in HE.

Among these components, cannabichromene (CBC) and cannabinol (CBN) showed significant anti-seizure effects. To gain insights into the mechanisms of CBC and CBN, we investigated their allosteric modulation on the GABAA receptor.

Our results revealed that CBC enhanced GABA-induced currents in both Xenopus laevis oocytes and mouse primary cortical neurons. Additionally, we identified V436 in the β2 subunit of the GABAA receptor as a critical binding site for CBC.

These findings provide compelling evidence for the anti-seizure activities of HE and shed light on its underlying mechanisms.

Our study provides insights into the broader therapeutic potential of hemp extracts and suggests their possible development as anti-seizure treatments.”

https://pubmed.ncbi.nlm.nih.gov/39734535/

https://www.sciencedirect.com/science/article/pii/S2667325824001572?via%3Dihub

Medical cannabis for severe treatment resistant epilepsy in children: a case-series of 10 patients

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“Objectives To report the findings of a case-series of 10 children suffering with intractable epilepsies in the UK to determine the feasibility for using whole-plant cannabis medicines to treat seizures in children.

Setting This study was conducted retrospectively through collecting clinical data from caretakers and clinicians on study outcome variables. Participants were recruited through the MedCann Support and End our Pain charity groups which are patient representative groups that support children who are using medical cannabis to treat their epilepsies. Medicines were prescribed to patients by clinicians in both National Health Service and private medical practices. Follow-up calls were conducted throughout the period January 2021 to May 2021 to keep data recorded up to date.

Participants Ten children, 18 years old or under, with intractable epilepsies were recruited from two charities. There were no limitations on diagnosis, sex or ethnic origin.

Interventions Participants were treated with a range of whole-plant medical cannabis oils. Individual dosing regimens were determined by clinicians.

Primary outcome measure The primary outcome measure was seizure frequency.

Results Seizure frequency across all 10 participants reduced by 86% with no significant adverse events. Participants reduced use of antiepileptic drugs from an average of seven to one following treatment with medical cannabis. We also noted significant financial costs of £874 per month to obtain these medicines through private prescriptions.

Conclusions This study establishes the feasibility of whole-plant medical cannabis as an effective and well-tolerated medicine for reducing seizure frequency in children suffering with intractable epilepsies. These findings justify the potential value of further research into the reported therapeutic benefit of whole-plant medicinal cannabis products.”

https://bmjpaedsopen.bmj.com/content/5/1/e001234

“Epileptic seizure frequency fell by 86% in kids treated with whole plant medicinal cannabis”

https://medicalxpress-com.cdn.ampproject.org/c/s/medicalxpress.com/news/2021-12-epileptic-seizure-frequency-fell-kids.amp

Current and Potential Use of Biologically Active Compounds Derived from Cannabis sativa L. in the Treatment of Selected Diseases

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“Cannabis sativa L. contains numerous compounds with antioxidant and anti-inflammatory properties, including the flavonoids and the cannabinoids, particularly Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD).

Cannabinoids have an effect on the endocannabinoid system (ECS), a cellular communication network, and are, hence, widely studied for medical applications.

Epidiolex®, a 99% pure oral CBD extract, has been approved by the FDA for the treatment of epilepsy. Nabiximols (Sativex) is an oromucosal spray containing equal volume of THC and CBD, and it is commonly used as an add-on treatment for unresponsive spasticity in multiple sclerosis (MS) patients.

Several in vitro and in vivo studies have also shown that cannabinoids can be used to treat various types of cancer, such as melanoma and brain glioblastoma; the first positive clinical trials on the anticancer effect of a THC:CBD blend with temozolomide (TMZ) in the treatment of highly invasive brain cancer are very promising.

The cannabinoids exert their anticancer properties in in vitro investigations by the induction of cell death, mainly by apoptosis and cytotoxic autophagy, and the inhibition of cell proliferation. In several studies, cannabinoids have been found to induce tumor regression and inhibit angiogenic mechanisms in vitro and in vivo, as well as in two low-numbered epidemiological studies.

They also exhibit antiviral effects by inhibiting ACE2 transcription, blocking viral replication and fusion, and acting as anti-inflammatory agents; indeed, prior CBD consumption (a study of 93,565 persons in Chicago) has also been associated with a much lower incidence of SARS-CoV-2 infections.

It is postulated that cannabis extracts can be used in the treatment of many other diseases such as systemic lupus erythematosus, type 1 diabetes, or various types of neurological disorders, e.g., Alzheimer’s disease.

The aim of this review is to outline the current state of knowledge regarding currently used medicinal preparations derived from C. sativa L. in the treatment of selected cancer and viral diseases, and to present the latest research on the potential applications of its secondary metabolites.”

https://pubmed.ncbi.nlm.nih.gov/39684447/

“C. sativa L. is an extraordinary plant that provides a valuable raw material for medical applications. Its secondary metabolites, cannabinoids, have attracted growing interest in the fight against illness, mainly due to their effect on CB1 and CB2 cannabinoid receptors.”

https://www.mdpi.com/1422-0067/25/23/12738

Successful management of refractory epilepsy in creatine transporter deficiency with cannabidiol and clobazam: A case report

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“Creatine transporter deficiency (CRTR-D) is a rare X-linked inherited disease belonging to the group of cerebral creatine deficiency disorders. Major clinical features include developmental delay and epilepsy. To date, fewer than 200 individuals with CRTR-D have been reported. As a result, there is little evidence for effective treatment. Available therapies are creatine precursors, with a mild effect on disease progression. Concerning epilepsy, standard management is recommended and no specific anti-seizure medication (ASM) has been shown to be effective in refractory cases.

We report the case of a 28-year-old male patient with CRTR-D and childhood-onset refractory epilepsy. He had an average of 10-20 focal motor seizures with impaired consciousness per month. He had tried several ASMs without significant improvement.

Treatment with cannabidiol (CBD) and clobazam (CLB) in combination was added. The patient became seizure-free from the first week, and up to 1 year of follow-up. Behavioral improvement was also noted by his caregivers. No adverse effects were reported. Very few cases of CRTR-D with refractory epilepsy have been reported.

This calls for more extensive research and suggests a possible role for CBD in cerebral creatine metabolism and transport and valuable option for future studies.

PLAIN LANGUAGE SUMMARY: Creatine transporter deficiency (CRTR-D) is a rare genetic disorder causing mental, behavioral, and movement problems. More than half of patients also have seizures, but because there are fewer than 200 known cases, it is difficult to know the best treatment options. We present a 28-year-old man with CRTR-D who had severe developmental delays and frequent seizures since childhood, despite trying many medications. After starting cannabidiol and clobazam, he has been seizure-free for a year. Sharing this success might help other people with CRTR-D benefit from similar treatments.”

https://pubmed.ncbi.nlm.nih.gov/39679854/

https://onlinelibrary.wiley.com/doi/10.1002/epi4.13116

The role of the endocannabinoid system in the pathogenesis and treatment of epilepsy

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“Epilepsy is a group of chronic neurological brain disorders characterized by recurrent spontaneous unprovoked seizures, which are accompanied by significant neurobiological, cognitive, and psychosocial impairments. With a global prevalence of approximately 0.5-1 % of the population, epilepsy remains a serious public health concern.

Despite the development and widespread use of over 20 anticonvulsant drugs, around 30 % of patients continue to experience drug-resistant seizures, leading to a substantial reduction in quality of life and increased mortality risk. Given the limited efficacy of current treatments, exploring new therapeutic approaches is critically important.

In recent years, Gi-protein-coupled receptors, particularly cannabinoid receptors CB1 and CB2, have garnered increasing attention as promising targets for the treatment seizures and prevention of epilepsy.

Emerging evidence suggests a significant role of the cannabinoid system in modulating neuronal activity and protecting against hyperexcitability, underscoring the importance of further research in this area.

This review provides up-to-date insights into the pathogenesis and treatment of epilepsy, with a special focus on the role of the cannabinoid system, highlighting the need for continued investigation to develop more effective therapeutic strategies.”

https://pubmed.ncbi.nlm.nih.gov/39660979/

https://www.degruyter.com/document/doi/10.1515/revneuro-2024-0114/html

“Anticonvulsant nature of marihuana smoking”

https://pubmed.ncbi.nlm.nih.gov/808653/

Use of Cannabis-Based Medical Products for Pediatric Health Conditions: A Systematic Review of the Recent Literature

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“Introduction: Cannabis policy is rapidly changing in the USA and across the globe, with 24 states legalizing cannabis for adult use and 38 states making medical cannabis available for those with qualified conditions. Building on prior evidence, we reviewed the recently published literature (from the past 5 years) focused on the treatment effects of naturally derived medical cannabis products within the pediatric population.

Methods: We conducted a systematic literature review of three electronic databases using MeSH terms and free-text. A study was eligible for inclusion if it investigated the efficacy of medical cannabis for any condition, it was published in 2019 or later, and the mean age of participants was under 21. We excluded studies that tested the effect of pharmaceutical cannabis-derived drug products.

Results: We identified a total of 10 studies that met our inclusion/exclusion criteria. Of the 10, 2 utilized a double-arm randomized control trial (RCT) design, 3 used a single-arm trial design, and the remaining were observational studies, a case series, or a qualitative design. Aside from autism spectrum disorder (ASD) (n = 4), studies focused on cancer, treatment-resistant epilepsy, and Sturge-Weber syndrome (SWS). Four of the five single- or double-arm trials used a CBD:THC compound in a specific ratio as treatment. Both RCTs found significant improvement in ASD-related validated measures. Other studies found general improvements in validated measures of efficacy for SWS and epilepsy. Minimal adverse events were reported.

Conclusion: In the pediatric population, emerging evidence, combined with existing literature, suggests medical cannabis may be beneficial for quality-of-life symptoms related to specific conditions, like cancer, ASD, treatment-resistant epilepsy, and SWS. More clinical trial data are necessary to establish medical cannabis as an addition to established medical guidelines.”

https://pubmed.ncbi.nlm.nih.gov/39659365/

“While more research is necessary, this review, together with other reviews of the literature , suggests that medical cannabis is potentially a viable treatment option alongside established medical treatment guidelines. This is especially true for pediatric ASD.”

https://karger.com/mca/article/7/1/257/917351/Use-of-Cannabis-Based-Medical-Products-for

Rapid seizure resolution with cannabidiol in medically refractory epilepsy with myoclonic-atonic seizures

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“Epilepsy with myoclonic-atonic seizures (EMAS) is an early childhood epilepsy syndrome with an explosive onset of multiple seizure types in a previously healthy child. EMAS often evolves to a drug-resistant epileptic encephalopathy before a variable degree of remission around 3 years from onset.

Highly purified cannabidiol (CBD, available in United States as Epidiolex®) has demonstrated efficacy and tolerability as an adjunct in medically refractory EMAS. We present two cases of medically refractory EMAS achieving rapid seizure freedom (7-30 days) with CBD, illustrating CBD as a potential effective monotherapy in EMAS.”

https://pubmed.ncbi.nlm.nih.gov/39641913/

https://onlinelibrary.wiley.com/doi/10.1002/epd2.20321

Update on Cannabidiol in Drug-Resistant Epilepsy

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“Cannabidiol (CBD) has arisen as a promising therapeutic option for children with drug-resistant epilepsy (DRE). CBD has received regulatory nod from different regulatory authorities in the United States, Europe, and India for children with DRE particularly, Dravet syndrome (DS), Lennox Gastaut syndrome (LGS), and Tuberous sclerosis complex (TSC).

Recent clinical trials and observational studies highlight the potential of CBD to lower seizure frequency and provide better quality of life in children affected by these disorders.

The safety profile is generally favorable with minor common adverse events such as somnolence, diarrhea, and gastrointestinal issues. Furthermore, the expense associated with CBD remains a notable concern, especially in low- and middle-income countries such as India, where access to this promising treatment may be constrained. This draws attention to the cost-effective perspective of CBD.

This review aims to explore the pharmacological properties of CBD, its mechanisms of action, and the clinical evidence supporting its use in various pediatric epilepsies, including LGS, DS, and TSC. Additionally, this review sheds light on the current regulatory landscape in India where CBD use is still in its nascent stages, and discusses the challenges and opportunities for integrating CBD into clinical practice.”

https://pubmed.ncbi.nlm.nih.gov/39585547/

https://link.springer.com/article/10.1007/s12098-024-05337-1

Cannabis use, sleep and mood disturbances among persons with epilepsy – A clinical and polysomnography study from a Canadian tertiary care epilepsy center

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“Objective: Interest in anti-seizure properties of cannabinoids is increasing, with the rise in prevalence of recreational and medical cannabis use, especially across Canada. In a recent study on people with epilepsy (PWE), cannabis use showed a strong association with poor psychosocial health. Sleep and mood comorbidities are highly prevalent in epilepsy, and are common motivations for cannabis use. The primary objective of this study was to assess demographic, subjective and objectively assessed sleep quality and mood related differences among PWE who regularly use cannabis compared to those who do not.

Methods: Consecutive consenting patients with a confirmed epilepsy diagnosis, admitted to our Epilepsy Monitoring Unit, over a 3-year period (2019-2022) were enrolled. Detailed epilepsy-related data and self-reported sleep [Pittsburgh Sleep quality index (PSQI)], Epworth Sleepiness Scale (ESS)], mood [(Beck’s Depression Inventory (BDI) and Beck’s Anxiety inventory (BAI)] and cannabis use related data were collected. Overnight polysomnography (PSG) was conducted on the first night of admission, with simultaneous 18-channel video-EEG. Sleep (PSG) scoring followed American Academy of Sleep Medicine guidelines by a scorer blinded to clinical details.

Results: Among 51 patients with similar seizure control, 25 (13 F) reported cannabis use (mean age 36.3+14.8 years) and were significantly younger than 26 (18 F) non-users (mean age 48.3+15 years). Cannabis users had significantly better subjective sleep quality (mean PSQI scores 7.2+2.9 vs 10.2+5.2 respectively). Most patients endorsed sleepiness (Cannabis users with ESS scores greater than 10; 91.3 %, 77.3 % in non-users) and moderate to extreme depression (BDI) scores. No significant differences were observed in objective sleep parameters. BDI score significantly predicted PSQI and ESS scores on multiple logistic regression analysis.

Significance: Despite a significant age difference, self-reported sleep quality is better among PWE who report regular cannabis use compared to non-users. However, there is no significant difference in objective sleep quantity and quality from PSG between the two groups. Additionally, severity of depressive symptoms is a significant predictor of sleep quality and of excessive daytime sleepiness among PWE.”

https://pubmed.ncbi.nlm.nih.gov/39586190/

https://www.sciencedirect.com/science/article/pii/S0920121124001943?via%3Dihub