Category Archives: Epilepsy

Cannabis-Based Phytocannabinoids: Overview, Mechanism of Action, Therapeutic Application, Production, and Affecting Environmental Factors

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“This review provides an overview of cannabis-based phytocannabinoids, focusing on their mechanisms of action, therapeutic applications, and production processes, along with the environmental factors that affect their quality and efficacy.

Phytocannabinoids such as THC (∆9-tetrahydrocannabinol), CBD (cannabidiol), CBG (cannabigerol), CBN (cannabinol), and CBC (cannabichromene) exhibit significant therapeutic potential in treating various physical and mental health conditions, including chronic pain, epilepsy, neurodegenerative diseases, skin disorders, and anxiety.

The cultivation of cannabis plays a crucial role in determining cannabinoid profiles, with indoor cultivation offering more control and consistency than outdoor methods. Environmental factors such as light, water, temperature, humidity, nutrient management, CO2, and the drying method used are key to optimizing cannabinoid content in inflorescences.

This review outlines the need for broader data transfer between the health industry and technological production, especially in terms of what concentration and cannabinoid ratios are effective in treatment. Such data transfer would provide cultivators with information on what environmental parameters should be manipulated to obtain the required final product.”

https://pubmed.ncbi.nlm.nih.gov/39457041/

“Phytocannabinoids, including THC, CBD, CBG, CBN, and CBC, present broad therapeutic potential in a wide range of physical and mental conditions. They have shown efficacy in treating chronic pain, reducing seizure activity, slowing neurodegenerative processes, psoriasis, acne, loss of appetite, sleep disorders, and psychosis. Dose dependence was notable in most cases, and thus, this requires careful management.”

https://www.mdpi.com/1422-0067/25/20/11258

Phytocannabinoids restore seizure-induced alterations in emotional behaviour in male rats

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“Epilepsy often presents with severe emotional comorbidities including anxiety and abnormal fear responses which impose a significant burden on, and reduce, quality of life in people living with the disease. Our lab has recently shown that kindled seizures lead to changes in emotional processing resulting from the downregulation of anandamide signalling within the amygdala.

Phytocannabinoids derived from the Cannabis sativa plant have attracted a lot of interest as a new class of drugs with potential anticonvulsant effects.

Among the wide number of compounds occurring in Cannabis sativa, Δ9- tetrahydrocannabinol (THC), the one responsible for its main psychoactive effects, and the nonpsychoactive cannabidiol (CBD) have been extensively examined under pre-clinical and clinical contexts to control seizures, however, neither have been assessed in the context of the management of emotional comorbidities associated with seizure activity.

We used two behavioural procedures to assess anxiety- and fear-like responding in adult male Long-Evans rats: elevated plus maze and auditory fear conditioning.

In agreement with previous reports, we found seizure-induced increases in anxiety- and fear-like responding. These effects were reversed by either CBD (vaporized) or THC (oral). We also found that antagonism of serotonin 1 A receptors prior to CBD exposure prevented its protective effects.

Phytocannabinoids offer a novel and reliable opportunity to treat seizure induced comorbid emotional alterations.”

https://pubmed.ncbi.nlm.nih.gov/39433952/

https://www.nature.com/articles/s41386-024-02005-y

Psychiatric comorbidities before and after cannabidiol treatment in adult patients with drug resistant focal epilepsy

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“Cannabidiol oil (CBD) has been approved as an antiseizure medication for the treatment of drug -resistant epilepsy in pediatric patients in 2018 for some special types of epilepsy.

Since this time its use was extended to other forms of epilepsy. However, to date, there are few publications on the use of CBD in adult patients with drug-resistant focal epilepsy and psychiatric comorbidities. We conducted a prospective, observational, open cohort study, with a before-after design, in adult patients, we assessed the effectiveness, dosage, and tolerance of adjunctive CBD treatment.

Our study concluded that CBD was effective and safe.

Our study in line with others examining CBD use in adult patients with drug-resistant epilepsy, omits consideration of psychiatric aspects. The aim of this study was to evaluate, in the same patient population that was part of a previous observational study, depression, quality of life, anxious symptoms and daytime sleepiness before and after CBD treatment.

RESULTS: Forty-four patients were enrolled in the study. Prior to CBD treatment, 50 % of participants exhibited symptoms of depression. Following CBD treatment, 95.4 % of these individuals demonstrated a marked improvement (p = 0.001). Among this cohort, 71.5 % of patients reported minimal or no depressive symptoms post-treatment. Moreover, 68 % of patients experienced an enhancement in their overall quality of life. Comparative analysis of BDI-II and QOLIE-10 scores before and after CBD treatment revealed a statistically significant positive correlation (p < 0.036 and < 0.001, respectively). Improvements in depressive symptoms were found to correspond with enhancements in quality of life. In terms of anxiety symptoms, 54.5 % of patients exhibited such symptoms prior to CBD treatment, with 71 % showing improvement post-treatment.

Adjunctive CBD treatment in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated and associated with significant improvement in depressive symptoms, anxiety and quality of life.”

https://pubmed.ncbi.nlm.nih.gov/39433001/

https://www.epilepsybehavior.com/article/S1525-5050(24)00414-1/abstract

Decoding the Therapeutic Potential of Cannabis and Cannabinoids in Neurological Disorders

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“For millennia, Cannabis sativa has served diverse roles, from medicinal applications to recreational use. Despite its extensive historical use, only a fraction of its components have been explored until recent times.

The therapeutic potential of Cannabis and its constituents has garnered attention, with suggestions for treating various conditions such as Parkinson’s disease, epilepsy, Alzheimer’s disease, and other Neurological disorders.

Recent research, particularly on animal experimental models, has unveiled the neuroprotective properties of cannabis. This neuroprotective effect is orchestrated through numerous G protein-coupled receptors (GPCRs) and the two cannabinoid receptors, CB1 and CB2.

While the capacity of cannabinoids to safeguard neurons is evident, a significant challenge lies in determining the optimal cannabinoid receptor agonist and its application in clinical trials. The intricate interplay of cannabinoids with the endocannabinoid system, involving CB1 and CB2 receptors, underscores the need for precise understanding and targeted approaches. Unravelling the molecular intricacies of this interaction is vital to harness the therapeutic potential of cannabinoids effectively.

As the exploration of cannabis components accelerates, there is a growing awareness of the need for nuanced strategies in utilizing cannabinoid receptor agonists in clinical settings. The evolving landscape of cannabis research presents exciting possibilities for developing targeted interventions that capitalize on the neuroprotective benefits of cannabinoids while navigating the complexities of receptor specificity and clinical applicability.”

https://pubmed.ncbi.nlm.nih.gov/39410886/

https://www.eurekaselect.com/article/143747

Cannabinoids and Genetic Epilepsy Models: A Review with Focus on CDKL5 Deficiency Disorder

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“Pediatric genetic epilepsies, such as CDKL5 Deficiency Disorder (CDD), are severely debilitating, with early-onset seizures occurring more than ten times daily in extreme cases. Existing antiseizure drugs frequently prove ineffective, which significantly impacts child development and diminishes the quality of life for patients and caregivers.

The relaxation of cannabis legislation has increased research into potential therapeutic properties of phytocannabinoids such as cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC).

CBD’s antiseizure properties have shown promise, particularly in treating drug-resistant genetic epilepsies associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and Tuberous Sclerosis Complex (TSC). However, specific research on CDD remains limited. Much of the current evidence relies on anecdotal reports of artisanal products lacking accurate data on cannabinoid composition. Utilizing model systems like patient-derived iPSC neurons and brain organoids allows precise dosing and comprehensive exploration of cannabinoids’ pharmacodynamics.

This review explores the potential of CBD, THC, and other trace cannabinoids in treating CDD and focusing on clinical trials and preclinical models to elucidate the cannabinoid’s potential mechanisms of action in disrupted CDD pathways and strengthen the case for further research into their potential as anti-epileptic drugs for CDD. This review offers an updated perspective on cannabinoid’s therapeutic potential for CDD.”

https://pubmed.ncbi.nlm.nih.gov/39409097/

https://www.mdpi.com/1422-0067/25/19/10768

Nabiximols (NBX) suppresses tremor in a rat Harmaline model of essential tremor

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“Background: Essential tremor (ET) is one of the most prevalent movement disorders; despite this, there remains an unmet need for novel therapies. The treatment of rats with harmaline modulates the rhythmicity of inferior olivary neurons, resulting in generalized tremor with a frequency of 9-12 Hz in rats, comparable to that of human ET (4-12 Hz).

Purpose: Interestingly, cannabinoids reduce tremor, therefore we have assessed the cannabinoid nabiximols (NBX; marketed as Sativex) a complex botanical drug mixture, in the harmaline-rat model of ET.

Method: We tested the effects of acute (single dose) and subchronic (10 days) treatment of NBX (at 5.2, 10.4 and 20.8 mg kg-1 p.o.) administered prior to harmaline and acute NBX (20.8 mg kg-1) administered post-harmaline in male SD rats. Propranolol (20 mg kg-1 i.p.) was used as a positive control. Observed Scoring (OS) was carried out prior to placement in a tremor-monitoring apparatus for the calculation of Tremor Index (TI) and Motion Power Percentage (MPP).

Results: Acute and subchronic NBX significantly attenuated harmaline-induced tremor at 10.4 and 20.8 mg kg-1, respectively, for each parameter (OS, TI, and MPP) when administered pre-harmaline as did propranolol (20 mg kg-1). NBX did not attenuate harmaline-induced tremor when administered post-harmaline.

Conclusions: These data suggest efficacy of acute and subchronic NBX to reduce tremors, based on OS, TI and MPP readouts if administered prior to harmaline. These data are the first to indicate the preclinical effects of an oral botanical cannabinoid formulation, NBX, in an animal model of ET.”

https://pubmed.ncbi.nlm.nih.gov/39368533/

“Cannabinoids may represent potential therapies for essential tremor.”

https://www.sciencedirect.com/science/article/abs/pii/S0014488624003145?via%3Dihub

Successful use of cannabidiol in nonconvulsive status epilepticus in Angelman syndrome

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“Angelman syndrome (AS) is a rare neurogenetic disorder characterized by developmental delay, epileptic seizures, cognitive impairment, electroencephalographic epileptiform and slow interictal abnormalities, and motor dysfunction.1

In AS, nonconvulsive status epilepticus (NCSE) is frequent, is characterized by period of decreased responsiveness which may last hours to days, and it occur in about 20% of patients.2 Treatment of NCSE in AS is challenging and no specific drugs are approved with this purpose.

Epidyolex® is approved by EMA up to a dose of 20 mg/kg/d for individuals >2 years with Lennox–Gastaut Syndrome (LGS) or Dravet Syndrome (DS), and with a higher maximum dose of 25 mg/kg/d in those with tuberous sclerosis complex (TSC) (EMA).3

We recently treated an 8-year-old boy with AS expressing deletion of 15q11.2q13 (6.23 Mb). At the age of 2 years, he started to present with asynchronous bilateral upper limbs myoclonia. He was treated with clonazepam and ethosuximide with good effects, being almost seizure-free until the age of 5 years, when myoclonia associated with poor responsiveness reappeared consistently.

At the age of 8 years, he was receiving ethosuximide (20.5 mg/kg/d) and clonazepam (0.08 mg/kg/d), he presented with marked drowsiness and an increase of myoclonia (Figure 1A). He was admitted in our Department of Neurology (Bambino Gesù Children Hospital – Rome, Italy). Long-term EEG monitoring showed a NCSE pattern (Figure 1A,B), clinically characterized by a reduction in motor initiative and an increase in tremor. This pattern resolved only intermittently during intravenous Midazolam administration. Intravenous valproate (bolus at 30 mg/kg/d and then continuous infusion at 2 mg/kg/d) (Figure 1C) and levetiracetam (bolus at 60 mg/kg/d) (Figure 1D), were ineffective and therefore stopped.

We added Epidyolex® CBD, with a faster titration than usual, starting with 10 mg/kg/d up to 20 mg/kg/d in 8 days. After 1 week, he became more responsive (Figure 1E,F), and after 1 month, he was seizure-free, and the EEG was significantly improved (Figure 1G,H). Epidyolex® was added to ethosuximide and clobazam which were not effective alone. After 4 months of follow-up, no clinical-EEG modifications were observed. The patients did not present adverse events both in the acute phase of administration and during the follow-up.

This case has shown the potential benefits given by Epidyolex® CBD for the treatment of NCSE in a patient with AS. The faster titration was well tolerated.

Given the need for innovative treatments, especially for drug-resistant epilepsies, Epidyolex® CBD may be a promising anti-seizure medication and has been given “off label” to people with epilepsy syndromes outside LGS, DS, and TSC.4 Interestingly, acute CBD (100 mg/kg) treatment attenuated hyperthermia- and acoustically induced seizures in a mouse model of AS supporting the hypothesis that CBD may alleviate seizures and EEG abnormalities in AS, putting the basis for a rational development of CBD as treatment for epilepsy in AS.5 The use of CBD in refractory status epilepticus has been recently reviewed, and in 9 out of 11 treated patients the outcome was favorable.6

We believe this is the first report of the use of CBD in the acute treatment of NCSE in patients with AS. Although anecdotal, this observation ought to encourage further trials and confirmation from future studies.”

https://onlinelibrary.wiley.com/doi/10.1002/epi4.12948

Neuroprotective Efficacy and Complementary Treatment with Medicinal Herbs: A Comprehensive Review of Recent Therapeutic Approaches in Epilepsy Management

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“Central Nervous System (CNS) disorders affect millions of people worldwide, with a significant proportion experiencing drug-resistant forms where conventional medications fail to provide adequate seizure control. This abstract delves into recent advancements and innovative therapies aimed at addressing the complex challenge of CNS-related drug-resistant epilepsy (DRE) management. The idea of precision medicine has opened up new avenues for epilepsy treatment.

Herbs such as curcumin, ginkgo biloba, panax ginseng, bacopa monnieri, ashwagandha, and rhodiola rosea influence the BDNF pathway through various mechanisms. These include the activation of CREB, inhibition of NF-κB, modulation of neurotransmitters, reduction of oxidative stress, and anti- inflammatory effects. By promoting BDNF expression and activity, these herbs support neuroplasticity, cognitive function, and overall neuronal health. Novel antiepileptic drugs (AEDs) with distinct mechanisms of action demonstrate efficacy in refractory cases where traditional medications falter. Additionally, repurposing existing drugs for antiepileptic purposes presents a cost-effective strategy to broaden therapeutic choices.

Cannabidiol (CBD), derived from cannabis herbs, has garnered attention for its anticonvulsant properties, offering a potential adjunctive therapy for refractory seizures.

In conclusion, recent advances and innovative therapies represent a multifaceted approach to managing drug-resistant epilepsy. Leveraging precision medicine, neurostimulation technologies, novel pharmaceuticals, and complementary therapies, clinicians can optimize treatment outcomes and improve the life expectancy of patients living with refractory seizures. Genetic testing and biomarker identification now allow for personalized therapeutic approaches tailored to individual patient profiles. Utilizing next-generation sequencing techniques, researchers have elucidated genetic mutations.”

https://pubmed.ncbi.nlm.nih.gov/39069797/

https://www.eurekaselect.com/article/141950

In the weeds: A comprehensive review of cannabis; its chemical complexity, biosynthesis, and healing abilities

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“For millennia, various cultures have utilized cannabis for food, textile fiber, ethno-medicines, and pharmacotherapy, owing to its medicinal potential and psychotropic effects. An in-depth exploration of its historical, chemical, and therapeutic dimensions provides context for its contemporary understanding. The criminalization of cannabis in many countries was influenced by the presence of psychoactive cannabinoids; however, scientific advances and growing public awareness have renewed interest in cannabis-related products, especially for medical use.

Described as a ‘treasure trove,’ cannabis produces a diverse array of cannabinoids and non-cannabinoid compounds. Recent research focuses on cannabinoids for treating conditions such as anxiety, depression, chronic pain, Alzheimer’s, Parkinson’s, and epilepsy. Additionally, secondary metabolites like phenolic compounds, terpenes, and terpenoids are increasingly recognized for their therapeutic effects and their synergistic role with cannabinoids. These compounds show potential in treating neuro and non-neuro disorders, and studies suggest their promise as antitumoral agents. This comprehensive review integrates historical, chemical, and therapeutic perspectives on cannabis, highlighting contemporary research and its vast potential in medicine.”

https://pubmed.ncbi.nlm.nih.gov/39056093/

https://www.sciencedirect.com/science/article/pii/S2214750024000684?via%3Dihub

Multifaceted targets of cannabidiol in epilepsy: Modulating glutamate signaling and beyond

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“Cannabidiol has been reported to interact with broad-spectrum biological targets with pleiotropic pharmacology including epilepsy although a cohesive mechanism is yet to be determined. Even though some studies propose that cannabidiol may manipulate glutamatergic signals, there is insufficient evidence to support cannabidiol direct effect on glutamate signaling, which is important in intervening epilepsy. Therefore, the present study aimed to analyze the epilepsy-related targets for cannabidiol, assess the differentially expressed genes with its treatment, and identify the possible glutamatergic signaling target.

In this study, the epileptic protein targets of cannabidiol were identified using the Tanimoto coefficient and similarity index-based targets fishing which were later overlapped with the altered expression, epileptic biomarkers, and genetically altered proteins in epilepsy. The common proteins were then screened for possible glutamatergic signaling targets with differentially expressed genes. Later, molecular docking and simulation were performed using AutoDock Vina and GROMACS to evaluate binding affinity, ligand-protein stability, hydrophilic interaction, protein compactness, etc. Cannabidiol identified 30 different epilepsy-related targets of multiple protein classes including G-protein coupled receptors, enzymes, ion channels, etc. Glutamate receptor 2 was identified to be genetically varied in epilepsy which was targeted by cannabidiol and its expression was increased with its treatment. More importantly, cannabidiol showed a direct binding affinity with Glutamate receptor 2 forming a stable hydrophilic interaction and comparatively lower root mean squared deviation and residual fluctuations, increasing protein compactness with broad conformational changes.

Based on the cheminformatic target fishing, evaluation of differentially expressed genes, molecular docking, and simulations, it can be hypothesized that cannabidiol may possess glutamate receptor 2-mediated anti-epileptic activities.”

https://pubmed.ncbi.nlm.nih.gov/39047503/

https://www.sciencedirect.com/science/article/abs/pii/S0010482524009831?via%3Dihub